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Lorillard

3-Phenyl-5-Methyl-1,2,4-Oxadiazole (Pmo)

Date: May 1973
Length: 1325 pages
80402001-80403325
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snapshot_lor 80402001-80403325

Fields

Type
SCRT, SCIENTIFIC REPORT
BIBL, BIBLIOGRAPHY
CHAR, CHART/GRAPH/MAPS
DRAW, DRAWING
FOOT, FOOTNOTE
OUTL, OUTLINE
Area
SPEARS/OFFICE
Alias
80402001/80403325
Site
G65
Request
R1-004
R1-041
R1-045
R1-046
R1-048
R1-061
R1-068
R1-125
R1-132
R3-003
Named Organization
Chem Revs
Ciba Geigy
Crl, Charles River Breeding Lab
FDA, Food and Drug Administration
Fdrl, Food & Drugs Research Labs
Fortschr Chem Forsch
Gardner Graham
Hazleton, Hazleton Labs
Jt Baker Chemical
J Lab Clin Med
Karolinska Inst
NCI, Natl Cancer Inst
New England Nuclear
Swedish Medical Board
Univ of Wi
Borr, Borriston Labs
Named Person
Angelini
Barron
Beilstein
Bevegird
Bolduc
Brinkman
Burkhalter, A.
Catanese
Cochran
Dahlgren, S.E.
Dalhamn, T.
Ellman, G.L.
Eloy, F.
Flataker
Francesco, A.
Freund
Gaffney
Gardner
Griffith
Jones
K, D.
Ladou, J.
Lenaers, R.
Lewis, C.I.
Lipschitz
Litchfield
Marmor, R.
Micheal
Minnemeyer, H.J.
Quick
Raud
Reid
Reid, J.R.
Rylander, R.
Schickedantz, P.
Seeman
Sen
Silvestrini
Snedecor
Stolfo, J.
Tong, H.S.
Wasserman
Weinstein
Wiesburger
Wilcoxon
Winter
Wolf
Date Loaded
27 Feb 1998
Master ID
80402001/3325

Related Documents:
Litigation
Stmn/Produced
Stmn/Selected
Author (Organization)
Lor, Lorillard
Characteristic
CONF, CONFIDENTIAL
MARG, MARGINALIA
PARE, PARENT
UCSF Legacy ID
gdr91e00

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Page 1: gdr91e00
APPENDIX 6 CON'T PLATELET ADHESIVENESS AND_ AGGREGATION CODE 11 EXPOSURE TI1iE 1400 DAYS ADP 2XI0 11 COLLAGEN 0.26 Mr,/11L ANIMAL >ADNESIVENESS Y.ADNESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXI'QSU:iE NUMBER PRE EXPOSURE POST EXPOSURE ('/. AGGREGATION) ('/. AGGREGATION) (X AGGREGATION) (:: AGG.'.EGATI011) 5052 59 43 48 51 48 63 5 129 56 47 54 45 65 62 5148 71 70 12 28 20 26 5153 67 65 59 49 59 56 5165 69 67 48 44 60 52 5233 84 82 62 50 50 52 5237 61 60 52 44 42 38 MEAN 66.7 62.0 47.9 44.4 49. 1 49.9 SD 9.4 13.5 16.7 7.8 15.1 13.4 N 7 7 7 7 7 7 voIEotioe
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rt^a 5 APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 32 EXPOSURE TIME 200 DAYS .aM i^1 aY i AM ADP 2Xt0 M COLLAGEN 0.26 MG!ML ANIMAL )GADHESIVENESS XADHESIVENESS PRE EXPOSURE - POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE t% AGGREGATION) (/ AGGREGATION) ('l. AGGREGATION) (: AGGREGATION) 5299 78 68 52 58 35 N.R. 5342 59 63 88 60 78 25 5344 68 65 74 68 84 78 5360 52 52 52 86 85 86 MEAN 64.3 62.0 66.5 68.0 70.5 63.0 SD 11.3 7.0 17.7 12.8 23.9 33.2 N 4 4 4 4 4 3 g01COVOR
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APPENDIX 6 CON!T PLATELET ADLIESIVENESS AND AGGREGATION CODE It EXPOSURE TIME 1500 DAYS ADP 2X10 M COLLAGEN 0.26 MG!tt;. ANIMAL XADHESIVENESS %ADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EX1'OSURE NUMBER PRE EXPOSURE POST EXPOSURE ('/. AGGREGATION) (% AGGREGATION) (% AGGREGATIOM) (% AfGP,EGAfIOtI) 5052 61 58 48 38 40 44 5129 66 66 44 23 42 34 5148 45 55 20 19 36 36 5153 46 55 38 29 52 3C 5233 54 52 20 36 60 50 5237 64 47 24 28 54 If 6 MEAN 56.0 55.5 32.3 29.7 47.5 41.0 SD 9.1 6.3 12.5 6.8 9.4 6.5 N 6 6 6 6 6 6 soyeovos
Page 4: gdr91e00
ADP 2X/0 M COLLAGEN 0.26 MG<ML XADHESIVENESS 'PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXP-OSURE POST"EXP05URE (: AGGREGATION) (: AGGREGATION) ('/. AGGREGATION) (X AGGRrGATION) 5042 75 76 70 62 55 44 5053 74 82 67 74 54 26 5085 77 77 74• 78 74 74 5119 87 88 68 68 38 38 5151 88 89 70 84 42 26 5228 86 91 N.R. N.R. N.R. N.R. 5299 69 78 76 64 N.R. N.R. 5342 69 83 68 80 72 80 5354 59 72 74 78 60 46 5360 53 77 72 76 72 66 MEAN 73.7 81.3 71.0 73.8 58.4 50.0 SD 11.7 6.4 3.2 7.5 13.8 21.0 N 10 10 9 9 8 8 1 y PLATELET ADHESIVENESS AND AGGREGATION CODE 32 EXPOSURE TIME 600 DAYS Vlll[.l/VOt3
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APPENDIX 6 CUN'T PLATELET ADHESIVENESS AND AGGREGATION CODE 32 EXPOSURE TIME 400 DAYS ADP 2Xt0 M COLLAGEN Q.26.MG/ML ANIMAL XADHESIVENESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXP05URE NUMBER PRE EXPOSURE POST-EXPO§URE E7. AGGREGATION) (Y. AGGREGATION) E%C AGGREGATION) (2 AGGREGATION) 5042 74 79 78 75 70 70 5053 69 80 62 62 20 22 5085 77 71 65 80 80 72 5119 77 80 84 74 76 85 5151 79 86 34 30 20 78 5I75 67 70 80 82 74 75 5206 70 67 99 99 74 74 5228 79 69 58 76 56 82. 5299 87 86 68 68 92 86 5342 84 85 68 ' 74 75 76 5344 80 82 78 78 N.R. N.R. 5360 81 83 80 8U 76 80 MEAN 77.0 78.2 71.2 73.2 64.8 72.7 SO 6.1 7.0 16.2 16.2 23.7 17.6 H 12 12 12 12 11 11 'aJi€:0v08
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APPENDIX 6 CON"T PLATELET ADHESIVENESS AND AGGREGATION CODE 32 EXPOSURE TIfIE 1000 DAYS AUP- 22f 10 t1 COLLAGE7 0.26 6 t:Gi11L ' A11ItIAL 'f.ADHESIVENESS Y,ADIIESIVEHESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POSI EXFOSL'"E f NUt1DER PRE EXPOSURE POST EXPOSURE ('!. AGGREGATION) (Z AGCREGATION) (': AGGREGATIUI.1) (Z 1Gt,LLGAT1U11 I ) 5042 73 74 68 72 74 74 I 5053 68 70 64 68 70 72 5119 70 70 70 74 64 66 5151 80 82 36 26 80 S0 5228 63 69 74 76 72 72 5299 29 36 26 26 40 3 5342 37 40 30 16 44 IO 5344 33 35 25 25 38 27 C1EAN 56.6 59.5 49.1 47.9 60.3 50.5 5D 20.2 19,1 21:7 26.6 16.9 31.7 N 8 8 8 8 8 8 7 L aLTEOfirQR
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APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 32 EXPOSURE TIME 800 DAYS ADP 2XI0 M COLLAGEN 0.26'MG/ML ANIMAL %ADHESIVENESS Y.ADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMOER PRE EXP05URE POST EXPOSURE f%: AGGREGATION) E% AGGREGATION) - ('/. AGGREGATTON) (% AGGREGATION) 5042 69 78 80 52 H.R. N.R. 5053 77 _ 71 62 . 72' N.R. N.R. 5119 74 81 74 74 68 66 5151 74 76 28 26 H.R. N.R. 5228 47 53 82 72 N.R. N.R. 5299 61 61 68 67 N.R. N.R. 5342 62 53 69 70 60 52 5344 52 59 72 76 28 38 MEAN 64.5 66.5 66.9 63.6 52.0 52.0 51) 10.9 11.4 1 7.0 16.9 21.2 14.0 N 8 8 _ 8 . 8 3 3 Gil lcD IroCJ
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APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 32 EXPOSURE TIHE 1400 DAYS ADP 2X10 II COLLAGEN 0.26 MGtrIL ANIMAL X_ADNESIVENESS 2ADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EY.POSU"E P_oSf [xPO,Ur.E NUMOER PRE EXPOSURE POST EXPOSURE (i AGGREGATION) (: AGGREGATION) (: AGGF.EGATID11) (i AGGREGAiI0;1) 5042 76 69 45 38 62 52 5053 72 72 54 42 68 56 5i19 65 66 60 50 60 51 5151 68 66 16 NR 46 3:[ 5228 57 38 41 43 44 30 5299 58 52 50 45 54 47 5342 56 47 41 40 42 43 5344 52 44 31 24 47 39 MEAN 63.0 56.8 42.3 40.3 52.9 45.1 5D 8.5 13.0 13.8 8.1 9.6 9.6 N 8 8 8 7 8 Is I zil!T ll Yl/p
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"".NO mmmm .11im m mmmm m m m Jd i i APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 68 EXPOSURE TIME 100 DAYS ADP 2Xt0 M COLLAGEN 0.26 MG/ML ANIMAL XADHESIVENESS XADHESIVENESS _ PRE EXPOSURE PDST EXPOSURE PRE EXPOSURE f'DST EXPOSURE __ _ _ NUMBER PRE EXPOSURE POST EXPOSURE ('. AGGREGATION) ('. AGGREGATION) (7 AGGREGATION) (% AGGREGATION) 5039 84 80 84 84 56 68 5046 80 80 80 72 73 75 6014 81 83 68 68 N.R. 43 MEAN 81.7 81.0 77.3 74.7 64.5 62.0 SD 2.1 1.7 8.3 8.3 12.0 16.8 N 3 3 3 3 2 3 qyIc0v08
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AAA -® A A AA A AI---A---~ ~ m--w7K-u APPENDIX 6 CON'T PLATELET ADIIESIVEa1EsS AND AGGREGATION CODE 32 EXPOSURE TIt1E_1500 DAYS ADP 2X10 M COLLAGEII 0.26 i1G/ML ANIMAL XADNESIVENESS 7ADNESIVENESS PRE EXPOSURE PDST EXPOSURE PRE EXPOSi1RE P05T [;fRSURE IIUIIDER PRE EXPOSURE POST EXPOSURE (X AGGREGAfION) (i AGGREGATION) (i AGGItEGATION) (2 AGGREG,1TI010 5042 48 56 34 20 50 40 5053" 46 52 22 20 35 3? 5119 61 73 38 46 50 65 5151 66 71 YO 22 32 42 5228 42 55 33 38 52 64 5299 56 56 37 42 50 52 53ti2 49 48 30 30 44 4 2 5344 50 48 28 33 35 40 MEAN 52.3 57.4 29.0 31.4 43.5 !i7.3 SD 8.1 9.6 9.2 10.2 8.2 11.2 N 8 8 8 8 a a ~~yr.ovoq
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APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 68 EXPOSURE TIME 200 DAYS ADP 2X10 C COLLAGEN 0.26 MG/ML ANIMAL XADHESIVENESS XADHESIVENESS PRE EXPOSURE P-OST EXPOSURE PRE EXPOSURE POST EXPOSURE HUMBER PRE EXPOSURE POST EXPOSURE ('f. AGGREGATION) ('._AGGREGATION) (X AGGREGATION) ('/. AGGREGATION) 5039 67 65 80 78 N.R. N.R. 5046 56 58 80 76 76 72 5106 55 53 58 82 66 62 5109 56 55 44 60 20 N.R. 6014 78 67 72 76 64 70 6018 30 47 80 78 64 H.R. 6038 51 55 72 74 N.R. N:R: 6039 75 55 74 78 N.R. N.R. MEAN 58.5 56.9 70.0 75.3 58.0 68.0 SD 15.2 6.5 12.8 6.6 21.8 5.3 N 8 8 8 8 5 3 9LiE0V0R
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Jr J~ JI~ 51^~I J~ in AI .in in is in PLATELET ADNESIVENESS AND AGGREGATION CODE 60 EXPOSURE TIME 0 DAYS ADP 2X10 M COLLAGEN 0.26 MG/ML ANIMAL XADNESIVENESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXP05URE P05T_EXPOSURE ('/. AGGREGATION) (Z AGGREGATION) ('/. AGGREGATIOH) (Z AGGREGATION) 5039 91 xax 52 xxx 78 xxii 5046 92 axx 90 xxx 78 ax;t 5106 96 xxx 90 Kkx 86 aaa 6014 91 xxx 66 xxx 70 Ri~r 6038 82 xxx 30 xxx xxx aaa 6039 90 xxw 48 xxx xxx MEAN 90.3 xx xy 62.7 xxxx 78.0 aKKx 5D 4.6 xxxx 24.1 Kxxx 6.5 xxxx H 6 -1 6 -1 4 -1 i
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APPENDIX 6 CON'T PLATELET ADNESIVENESS AND AGG'EGATION CODE 32 EXPOSURE TIME 1200 DAYS ADP 2X10 M COLLAGEN 0.26 F1G[11L ANIMAL iADNESIVENESS XADIIESIVENEGS PRE EXPOSURE I'OST EXPOSURE PRE EXPO:iUE;E POST EXI'CSU2E NUt1DER PRE EXPOSURE POST EXPOSURE (Y. AGGREGATION) (: AGGP,EGATION) ('/. AGSP,E6,1T1011) (;: AGC.f'EGrITION) 5042 30 24 50 61 68 66 5053 27 26 50 32 70 63 5119 63 67 72 56 73 ',6 5151 52 48 20 HR 50 60 5228 48 50 55 62 56 63 5299 51 57 58 48 55 5 0 5342 49 48 58 62 58 62 5344 61 58 24 40 60 49 MEAN 47.6 47.3 48.4 51.6 61.3 59.3 SD 13.0 15.1 17.7 11.9 8.2 8.0 Il 8 8 8 7 8 8 i LIif;OVOR
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APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 68 EXPOSURE TIME 600 DAYS ADP 2X10 M COLLAGEN 0.26 MG/ML ANIMAL XADHESIVENESS X_ADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE _POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE (X AGGREGATION) (X AGGREGATION) ('/. AGGREGATION) E'!. AGGREGATION) 5039 43 41 44 31 62 49 5046 40 38 42 50 64 55 6014 31 38 64 40 68 50 6039 47 35 34 I1 64 34 5106 26 20 58 38 64 36 5109 36 32 65. 72 75 70 6018 34 24 62 58 64 64 6038 40 43 66 65 78 72 MEAN 37.1 33.9 54.4 45.6 67.4 53.8 SD 6.8 -8.1 12.5 19.8 5.9 14.4 N 8 8 8 8 8 8 4 RUMOg
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APPENDIX 6 CON'T. PLATELET ADHESIVENESS. AND AGGREGATION CODE 68-EXPOSURE TIME 800 DAYS ADP 2_X10 M COLLAGEN 0.26 MG/ML ANIMAL 3:ADNESIVENESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE (% AGGREGATION) (% AGGREGATION) (X AGGREGATION) (% AGGREGATION) 5039 41 38 34 55 58 53 5046 44 44 60 62 60 64 6014 38 41 50 56 56 50 6039 44 42 63 48 63 62 5106 56 54 60 68 66 65 5109 62 67 60 56 67 62 60t8 52 54 63 68 65 56 6038 65 67 60 65 59 70 MEAN 50.3 50.9 56.3 59.8 61.8 60.3 SU 10.0 11.5 9.9 7.1 4.1 6.7 N 8 8 8 8 8 8 6IL(.OYQt3
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A A A A A AA AMA A A A Aml/ MR a APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 68 EXPOSURE TIME 400 DAYS f ADP 2X10 M COLLAGEN 0.26 MGlML ANIMAL XADHESIVENESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXI'OSURE NUMBER PRE EXPOSURE POST EXPOSURE (: AGGREGATION) (Z AGGREGATION) (X AGGREGATION) (X AGGREGATION) 5039 71 51 80 98 38 14 5046 65 66 82 80 16 22 6014 64 62 84 ~ 82 11 40 6039 62 62 77 _ 88 N.R. H.R. 5106 46 53 68 68 76 H.R. 5109 52 52 70 76 64 72 6018 49 53 68 68 70 68 6038 50 55 66 68 66 66 MEAN 57.4 56.8 74.4 78.5 48.7 47.0 SD 9.2 5:7 7.2 10.8 26.9 25.3 N 8 8 8 8 7 6 I-11c0 vOR
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APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 68 EXPDSURE TIME 1100 DAYS ANIMAL %ADHESIVENESS YADHESIVENESS ADP 2X10 M PRE EXPOSURE POST EXPDSURE COLLAGEN 0.26 MG/ML PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE (i AGGREGATION) (: AGGREGATION) (% AGGREGATION) (r AGGREGAiIUN) 5039 50 53 16 14 40 38 5046 75 74 26 22 48 40 5106 34 50 40 45 46 54 5109 57 59 40 34 48 46 6014 65 67 18 18 41 44 6018 44 47 28 38 40 44 6038 58 61 30 30 34 38 6039 55 52 22 10 42 39 MEAN 54.8 57.9 27.5 26.4 42.4 42.9 SD 12.5 9.2 9.1 12.3 4.8 5.4 N 8 8 8 8 8 8 F iseicV KOR
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APPENDIX 6 CON'T PLATELET ADNESIVENESS AND AGGREGATION CODE 68 EXPOSURE TIME 1000 DAYS ADP 2X10 M COLLAGEN 0.26 MG<ML ANIMAL 7._ADHESIVENESS X ADNESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER _ PRE EXPOSURE POST EXPOSURE ('/, AGGREGATION) (% AGGREGATION) ('/, AGGREGATION) ('/. AGGREGATION) 5039 51 46 26 40 40 4 8 5046 40 11 34 13 40 16 5106 48 44 26 24 52 48 5109 64 54 40 38 46 50 6014 52 48 28 34 34 50 6018 55 54 50 50 55 55 6038 62 54 23 22 36 43 6039 48 35 16 10 48 24 MEAN 52.5 43.3 30.4 28.9 43.9 41.8 SD 7.8 14.6 10.7 13.9 7.6 14.0 N 8 8 8 8 8 8
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AM M M aa am AMA Wan a a S APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 67 EXPOSURE TIME 100 DAYS ADP 2X10 M COLLAGEN 0.26 MG<ML ANIMAL yADHESIVENESS XADIIESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXP05URE POST EXPOSURE (% AGGREGATION) (X A GGREGATION) (: AGGREGATION) (Z AGGREGATION) 5054 74 88 38 32 72 78 5124 89 88 100 92 100 65 5155 84 88 50 42 82 N._R. 5157 77 79 96 100 92 92 5171 80 87 58 80 H.R. N.R: 5178 72 83 86 78 N:R. H.R. 5185 88 87 34. 30 76 48 5278 87 87 86 90 58 80 6009 75 83 78 82 N.R. 58 6010 82 88 72 72 76 58 6011 90 86 78 80 N.R. N.R. 6012 81 83 82 84 N.R. N.R. 6020 75 72 82 86 78 74 6021 70 69 54 58 80 N.R. 6030 86 79 74 62 N.R. H.R. 6031 78 77 62 64 N.R. N.R. 6035 85 91 86 88 N.R. N.R. i r MEAN 80.8 83.2 71.5 71.8 79.3 69.0 W 3D 6.3 _ 6.1 19.2 20.9 11.9 14.5 11 17 17 17 17 9 8 C-pl # =3 -a4i 4 t<~:: 1 ~ ~ ~ czyeotto&
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,,. m m m m m m m m m m m 0 m m m m a a APPENDIX 6 CON'T PLATELET ADNESIVENESS AND AGGREGATION CODE 67 EXPOSURE TIME 400 DAYS ADP _2XI0 M COLLAGEN 0.26 MG/ML ANIMAL XADHESIVENESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER P-RE EXPOSURE POST EXPOSURE (% AGGREGATION) (`/. AGGREGATION) (2 AGGREGATION) ('/. AGGREGATION) 5054 53 65 70 72 66 62 5124 r 73 74 71. . 71 75 68 5158 N.R. N.R. 68 68 69 68 5157 41 55 68 80 N.R. N.R. 5171 68 80 N.R. N.R. N.R. H.R. 5185 79 60 65 64 54 32 6009 5/ 59 80 72 70 48 6010 54 57 70 72 50 _ N.R. 6011 47 58 56 8 20 16 6012 69 69 68 72 60 24 6020 65 75 70 75 N.R. N.R. 6021 51 56 72 78 64 76 6030 81 8f 76 78 N.R. N.R. 6031 60 44 60 67 N.R. 11.R. 6035 69 71 73 73 N.R. N.R. i MEAN 61.5 64.6 68.4 67.9 58.7 49.3 .~ 5D 12.3 10.8 8.0 . 17.8 16.5 22.8 ~ 0 N 14 14 14 14 9 8 1 F~"1 ~ r
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.X.,ar jm ir in at ar ,r sir m m M m a M J!! ~~ APPENDIX 6 60N1T , PLATELET ADHESIVENESS AND AGGREGATION CODE 67 EXPOSURE TIME 1100 DAYS ADP 2X10 M COLLAGEN 0.26 MGiML ANIMAL 7.ADHESIVENESS $ADHE5IVENESS PRE EXPOSURE YOST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE (% AGGREGATION) (Y. AGGREGATION) (: AGGREGATION) (2 AGGREGATION) 5028 55 60 42 36 64 52 5054 58 62 42 34 49 43 5124 68 59 40 46 58 60 5145 69 61 34 40 60 57 5171 52 59 52 40 60 50 6009 51 54 50 46 62 50 6010 46 49 62 45 64 46 6011 46 49 18 24 50 32 6020 67 77 38 38 50 53 6030 58 59 25 22 57 46 6031 57 61 34 26 58 67 6035 60 67 22 28 53 50 MEAN 57.3 59.8 38.3 35.3 57.1 50.5~ Sil 7.9 7.5 12.8 8.5 5.4 8.8 N 12 12 12 12 12 12 11r szleovob~
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~.. ~.. .,.. A. V- A M M M R APPENDIX 6 CON'T PLATELET ADHESIVENESS AND CODE 67 EXPOSURE TIME AGGREGATION 0 DAYS ADP 2X10 M COLLAGEN 0.26 MGEML ANIMAL Y,ADH€3IVENESS 1:'ADHESIVEHESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE HUMBER 5054 PRE EXPOSURE 90 POST EXPOSURE xxk (: AGGREGATION) 88 (G AGGREGATION) xxx (y AGGREGATION) (: AGGREGATION) 84 xiix 5121 44 NHx 70 xxx xxK xkx 5124 86 xxx 86 xxx 70 xxx 5145 80 xxx 90 xxx 88 xxx 5157 75 xxx 78 xxW 78 xaN 5171 68 Mxw 88 mmx xxw x~x 5178 40 xxx 70 xxx wKr xRx 5 185 8 t 8uK 64 ~ ifKtf 70 xxli 5278 86 xxx 86 xxx 92 xax 6009 69 8K>' 20 NMat x>:x xx K 6010 71 xxx 68 xxx 68 xx.lt 6011 71 KxX 55 SatB xxa iixH 6012 90 xxx 90 xxx 80 xxx 6020 86 xxx g4 xxx 80 X x x 6021 83 xxit 76 xxx 65 xh x 6030 84 xxx 82 xxx 78 xxx 6031 82 KMM 76 nrx 70 xx3f 6035 83 xxx 80 xxx 80 xxx MEA11 76.1 xxxx 75. 1 xxxx 77.2 xxxx L] 9D 14.2 xx~K 16.9 xxxk •. 8.1 x~~x v N 18 -1 i8 -I 13 5 Zr.IeQtrof3
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A A A M M M iM = aM at sM M m m aa a, APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 67 EXPOSURE TIME 600 DAYS ADP 2X10 M COLLAGEN 0.26 MG/ML ANIMAL XADHESIVENESS YADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE (/ AGGREGATION) (% AGGREGATION) (Z AGGREGATION) ('/. AGGREGATION) 5054 71 66 82 70 80 78 5154 60 59 65 62 72 68 6031 48 53 82 76 79 79 6030 63 56 66 72 74 70 5171 51 47 72 • 60 64 72 6009 46 49 80 72 66 64 6010 47 46 68 70 64 68 6011 46 48 58 46 66 74 5124 57 52 66 63 74 68 5157 44 41 45 68 48 62 6012 47 44 66 68 68 72 6020 49 45 68 60 72 72 6035 56 55 50 40 78 70 MEAN 52.7 50.8 66.8 63.6 69.6 70.5 5b 8.1 6.9 11.2 10.5 8.5 4.8 N 13 , 13 13 13 13 13 C.75 ~ 4 t^'7 ~ ~ 9zleovos
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.. ,*006, PLATELET ADHESIVENESS AND AGGREGATION CODE 67 EXPOSURE TIME 800 DAYS ADP 2X10 M COLLAGEN 0.26 MG/ML ANIMAL Y.ADHESIVENESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMOER PRE EXPOSURE POST EXPOSURE (Y AGGREGATION) (7. AGGREGATION) (X AGGREGATION) (% AGGREGATION) 5028 60 5054 62 5124 54 5145 61 5157 45 5171 33 6009 44 6010 54 6011 39 6012 5!i 6020 58 6030 51 6031 54 6035 53 MEAN 51.6 SD 8.5 N 14 45 50 30 61 20 10 59 50 56 51 29 30 45 32 58 59 62 76 54 33 30 48 63 72 45 17 10 52 39 42 56 65 56 50 20 18 53 26 22 55 29 60 T""IIUOVoR
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~ ~.~ ..~ ._... ~. .....~ - ~ ~ APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 67 EXPOSURE TIME 1000 DAYS ANIMAL %ADHESIVENESS XADHESIVENESS ADP 2X10 M PRE EXPOSURE POST EXPOSURE COLLAGEN 0.26 MG/ML PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE (: AGGREGATION) (i AGGREGATION) (X AGGREGATION) (r AGGREGATION) 5028 71 61 46 50 62 60 5054 59 58 52 49 52 48 5145 56 60 48 54 50 40 5171 70 56 40 43 55 54 6009 58 40 48 30 64 52 6010 73 71 64 48 66 50 6011 62 73 23 13 20 10 6012 82 74 33 45 46 50 6020 63 50 63 57 55 48 6030 51 50 38 52 34 26 6031 57 54 44 54 44 44 6035 80 74 46 40 66 58 MEAN 65.2 60.1 45.4 44.6 51.2 45.0 SD 9.9 11:0 11.5 12.4 13.8 14.2 I N 12 12 12 12 12 12 w r RZA I coVoR
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A -MAMA A A AMA A M1X ARM R OR APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 67 EXPOSURE TIME 200 DAYS ADP 2X10 M COLLAGEN 0.26 MGlML ANIMAL XADHESIVENESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST-EXPOSURE NUMBER PRE EXP05URE POST EXPOSURE AGGREGATIONJ (y AGGREGATION) (Y. AGGREGATION) ('/• AGGREGATION) 5124 71 72 82 84 62 64 5145 83 86 72 80 48 50 5157 62 69 72 . 70 68 66 5171 69 83 72 75 42 28 5178 75 64 80 100 N.R. N.R. 5185 68 78 80 82 50 24 6009 82 82 90 88 14 25 6010 80 82 72 •_ 85 45 40 6011 75 80 H.R. N.R. N.R. N.R. 6012 57 60 28 32 80 78 6020 71 71 76 82 52 N.R. 6021 74 77 94 92 60 30 6030 79 78 96 90 80 74 6031 77 84 90 86 68 20 6035 82 83 26 24 N.R. N.R. 5178 78 N.R. 82 N.R. H.R. N.R. 5278 81 N.R. N.R. N.R. H.R. N.R. MEAN 74.9 76.6 74.1 76.4 55.8 45.4 W S0 8.3 7.8 20.8 21.8 18.3 21.8 17 15 1§ 14 12 1T DUCOVaR
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J.r Ar aIr im .im in ,r" a n ~ APPENDIX 7 CON'T SERUM PROTEIN ELECTROPNORESIS CODE 68 EXPOSURE TIME 100 DAYS DOG ALBUMIN ALPHA I ALPHA 2 BETA GAMMA TOTAL GLOBULIN A:G RATIO (10. (G!DL) • (G/DL) (GiDL) (G/DL) (G/DL) (G/DL) 5039 3.90 0.21 1.06 1.29 0.51 3.08 1.27 5046 3.60 0.23 0.99 1:62 0.65 3.48 1.03 5143 3.40 0.17 0.95 1.70 0.56 3.38 1.01 6014 4.00 0.17 0.89 1.27 0.37 2.70 1.48 6016 3.90 xxxx xxxx xxxx xKKx xxxK x_xxwm 6039 3.80 0.16 1,11 1.72 0.68 3.67 1.04 MEAN 3.77 0.19 1.00 1.52 0.55 3.26 1.16 SD 0.23 0.03 0.09 0.22 0.12 0.38 0.21 N 6 5 5 5 5 5 5 I Z3ICUV\IR
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APPENDIX 7 CON'T SERUM PROTEIN ELECTROPHORESIS CODE 68 EXPOSURE TIME 200 DAYS DOG ALBUMIN .ALPHA 1 ALPHA 2 BETA GAMMA TOTAL GLOBULIN A~G RATIO f10. (G/DL) (G/DL) (GtDL) (G/DL) (G/DL) (G/DL) 5039 4.00 0.19 1.15 1.19 0.42 2.95 1.36 5046 3.40 0.22 1.18 1.61 0.61 3.62 0.94 5143 3.00 0.25 1.25 2.04 0.68 4.21 0.71 6014 4.10 0.29 1.04 1.18 0.41 2.93 1.40 6016 3.10 0.23 1.41 1.77 0.49 3.89 0.80 6038 3.43 0.11 0.78 . 1.49 0.50 2.87 1.20 6039 3.70 0.18 1.16 1.48 0.47 3.28 1.13 MEAH 3.53 0.21 1.14 1.54 0.51 3.39 1.08 §D 0.42 0;06 0.19 0.31 0.10 0.53 0.27 11 7 7 7 7 7 7 7 c9lE0v(l~3
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r.n. wra a" im Am AM AM w APPENDIX 7 CON'T I ~ rn SERUM PROTEIH ELECTROPHORESIS CODE 68 EXPDSURE TIME 0 DAYS TOTAL A~G DOG ALBUMIN AIPHA I ALPHA 2 BETA GAMMA GLOBULIH RATIO NO, 5039 (G/DL) 3.75 (GtDL_) 0.26 (GsDI) 1.37 (G1DL) 1.33 (G/DL) 0.49 (G<DL) 3.45 1.09 5046 2.97 0.22 1.01 2.03 076 4.03 0.74 5106 3.02 0.17 1.03 1.31 0.57 3.08 0.98 5109 3.07 0.24 1.09 1.10 0.57 3.03 1.01 5143 3.19 0.31 1.07 1.66 0.57 3.61 0.88 6014 3.12 0:18 1.06 1.24 0.51 2.88 1,08 6038 3.59 0.13 0.92 1.25 0.42 2.71 1.32 6039 2.83 0.30 1,14 1.49 0.45 3.37 0.84 MEAN 3.t9 0.23 1.09 1.43 0.53 3.27 0.99 50 0.32 0.06 0.13 0.30 0.11 0.53 0.18 N 8 8 8 8 8 8 8 r9LEOVoR
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..~> ^-o.F!.a:i'+w ,,•o,;,.r18!M. ..-,,A•1';~, APPENDIX,7' CON'T', SERUM PROTEIN ELECTROPNORESIS CODE 68 EXPOSURE TIME 600 DAYS DOG H0. ALBUMIN (G/DL) ALPHA I (GiDL) ALPHA 2 (G/DL) BETA (G/DL) GAMMA (GtDL) TOTAL GLOBULIN (GtDL) A:G RATIO 6014 3.16 0.27 0.60 1.48_ 0.66 3.01 1.05 5039 3.48 0.39 0.71 1:56 ` 0.43 3.09 1.13 5046 3.49 0.38 0.60 1.70 0.71 3.39 1.03 5143 3.39 0.25 0.66 1.66 1.12 3.69 0.92 6016 2.89 0.25 0.42_ 1.71 1.00 3.38 0.86 6039 3. 11 0.48 0.61 1.70 0.68 3.47 0.90 5106 3.23 0.21 1.22 1.38 0.63 3.44 0.94 5109 3.56 0.10 1.04 1.43 0.85 3.42 1.04 6018 3.53 0.10 0.98 1.45 0.92 3.45 1.02 6038 3.41 0:16 1.04 1.59 0.77 3.56 0.96 MEAN 3.32 0.26 0.79 1.57 0.78 3.39 0.98 SD 0.22 0.13 0.26 0.12 0.20 0.20 0.08 H 10 10 10 10 10 10 10 N Q r "`r{ lr~
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,0 m in im in in m m m m m w m w m m m n n APPENDIX 7 CON'T SERUM PROTEIN ELECTROPHORESIS CODE 68 EXPOSURE TIME 800 DAYS DOG N0. ALBUMIN (GIDL) ALPHA I (G/DL) ALP-HA 2 (G/DL) BETA (G/DL) GAMMA (G/DL) TOTAL GLOBULIN (GiDL) A:G RATIO 5039 3.38 0.24 1.44 1.30 0.62 3.60 0.94 5046 3.00 0.21 1.05 1.29 0.73 3.28 0.91 5106 4.62 0.28 1.61 1.65 0.72 4.26 1.08 5109 3.81 0.25 1:35 1.68 0.98 4.26 0.89 5143 3.28 0.19 1.38 1.62 0.79 3.98 0.82 6014 3.39 0.17 1.13 1.24 0.45 2.99 1.13 6016 3.36 0.53 0.95 1:31 0.54 3.33 1.01 6018 3.68 0.28 1.45 1.94 1.13 4.80 0.77 6038 3.02 0.26 1.31 1.75 0.84 4.16 0.73 6039 3.06 0.68 0.87 1.65 0.82 4.02 0.76 MEAN 3.46 0.31 1.25 1.54 0.76 3.87 0.91 SD 0.49 0.16 0.24 0.24 0.20 0.56 0.14 N 10 10 10 10 10 10 10 ' •' !'.liV vL/N
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,WaA,.. ir. m.. ar mr im am ARis a~ ~ m"m mm i K APPENDIX 7 CON'T SERUM PROTEIN ELECTROPHORESIS CODE 68 EXPOSURE TIME 400 DAYS DOG NO. ALBUMIN (GtDL) ALPNA 1 (G/DL) ALPHA 2 (G/DL) BETA (G/DL) GAMMA (G/QL) TOTAL GLOBULIN (GtDL) A:G RATIO 5106 3.28 0.14 1.27 1.36 0.52 3.29 1.00 5109 3.11 0.19 1.18 1.71 0.78 3.86 0.81 6018 3.34 0.16 0.90 1.52 0.76 3.34 1.00 6038 3.21 0.19 0.97 1.71 0.58 3.45 0.93 MEAN 3.23 0.17 1.08 1.57 0.66 3.48 0.93 SD 0.10 0.02 0.17 0.17 0.13 0.26 0.09 N 4 4 4 9 4 4 4 ro w . 9t COllOR
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At" Am JOL APPENDIX 7 CON'T SERUM PROTEIN ELECTROPHORESIS CODE 67 EXPOSURE-TIME 100 DAYS TOTAL A:G DOG ALBUMIN A_LPNA I ALPHA 2 BETA GAMMA GLOBULIN RATIO N0. (GtUL) (G/DL) (G/DL) (G/DL) (G/DL) (GiDL) 6031 3.70 0.23 0.88 .1.37 0.54 3.02 1.23 6032 4.00 0.16 1.03 1.25 0.57 3.01 1.33 6034 3.90 0.18 1.00 1.30 0.48 2.97 1.31 6035 4.50 0.23 1.14 1.35 0.44 3.15 1.43 6037 3.60 0,18 0.94 1.30 0.51 2.93 1.23 6040 3.80 0.14 0.93 ,1,28 0.46 2.80 1.36 MEAN 3.71 0.20 1.02 1.38 0.51 3.12 1.21 SO 0.33 0.05 0.15 0.19 0.12 0.33 0.20 _ N 54 54 54 54 54 54 54 2,':,Tcovw3
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7-$ mmmmm Amm MAMMA MR U-S APPENDIX 7 CON'T SERUM PROTEIN ELECTROPHORESIS CODE 68 EXPOSURE TIME 1100 DAYS TOTAL A:G DOG ALBUMIN ALPHA I ALPHA 2 BETA GAMMA GLOBULIN_ RATIO N0. (G%DL) (G/DL) (G/DL) (G_/DL) (G/DL) (GiDL) 5039 3.65 0.37 1.29 1.17 0.79 3.62 1 .01 5046 3.83 0.19 0.98 1.46 0.71 3.34 1.15 5106 2.77 0.60 1.03 1.60 0:77 4.00 0.69 5109 2.97 0.58 0.84 1.47 0.91 3.80 0.78 5143 3.42 0.19 1.22 2.10 0.84 4.35 0.79 6014 4,39 0.25 1.06 1.41 0.47 3.19 1.38 6016 3.44 0.28 1:28 2.01 0.87 4.44 0.77 6018 3.20 0.38 0.91 1.64 0.95 3.88 0.82 6038 3.21 0.43 0.91 1.39 0.64 3.37 0.95 6039 3.38 0.32 1.09 1.23 0.85 3.49 0.97 MEAN 3.43 0.36 1.06 1.55 0.78 3.75 0.93 SD 0.46 0.15 0.16 0.30 0.14 0.43 0.21 N 10 10 10 10 10 10 10 ; R=91COtiOe
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AM Arr AN JW i APPENDIX 7 CON'T SERUM PROTEIN ELECTROPHORESIS CODE 67 EXPOSURE TIME 200 DAYS DOG N0. ALBUMIN (G/DL) ALPNA I (G/DL) ALPNA 2 (G/DL) ' BETA (G/DL) GAMMA (G/DL) TOTAL GLOBULIN (G/DL) A:G RATIO 6028 3.10 0.23 1.12 1.23 0.40 2.97 1.04 6030 4.00 0.17 1.03 1.17 0.47 2.84 1.41 6031 3.30 0.24 0.88 1.46 0.57 3.15 1.05 6032 3.50 0.10 0.79 1.19 0.67 2.75 1.27 6034 3.20 0.17 1.06 1.25 0.53 3.01 1.06 6035 2.70 0.10 0.76 1.22 0.29 2.37 1.14 6037 2.80 0.17 0.91 1.59 0.74 3.41 0.82 6040 3.10 0.17 0.99 1.40 0.65 3.22 0.96 MEAN 3.35 0.19 1.02 1.36 0.55 3.17 1.08 SD 0.32 0.05 0.16 0.18 0.14 0.55 0.18 N 56 56 56 56 56 56 56 1 4 - MIi.QYOC7
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APPENDIX 8 CON'T CLINICAL CHEMISTRY - CODE 68 EXPOSURE TIME 0 DAYS DOG BUN GLUCOSE CREATININE CHOLESTEROL CALCIUM PHOSPHORUS SGOT SGPT TOTAL PROTEIN NO. (MGiDL) (MG/DL) (MG/DL)- (MGiDL) (MG/DL) (MGiDL) (MUiML) (h1U/ML) (G/DL) 5039 11.6 t15.0 0.8 141.5 11.1 4.1 18.6 21.0 7.20 5046 15.5 116.0 0.8 NNNNN 9.5 3.5 20.4 27.0 7.00 5106 12.3 95.0 0.8 212.0 11.2 3.6 13.5 22.0 6.10 5109 20.5 97.5 1.1 183.0 10.5 4.2 21.0 83.0 6.10 5143 15.0 113.5 0.9 222.0 10.1 3.8 15.4 27.0 6.80 6014 13.5 115.0 0.6 145.0 10.8 4.3 27.0 15.0 6.00 6038 13.0 110.0 1.0 153.0 11.1 5.1 22.5 31.5 6.30 6039 13.4 105.0 0.9 182.0 11.6 3.6 22.5 36.0 6.20 MEAN 14.35 108.38 0.86 176.93 10.74 4.02 20.11 32.81 6.46 30 2.80 8.31 0.15 32.07 0.68 0.53 4.27 21.29 0.47 N 8 8 8 7 8 8 8 8 8 TTLCOYlJC3
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~ in-F-ici JK JW JO AM M M APPENDIX 8 CON'T CLINICAL CHEMISTRY CODE 68 EXPOSURE TIME 100 DAYS DOG NO. BUN (MG/DL) GLUCOSE (MG/DL) CREATININE (MG/DL) CHOLESTEROL (MG/DL) CALCIUM (MGEDL) PHOSPHORUS (MGIDL) SGOT (MUiML) SOPT (MUtML) TOTAL PROTEIN (GiDL) 5039 22.0 103.0 0.7 170.0 10.7 4.2 15.0 41.0 6.70 5046 33.0 98.0 0,5 202.5 10.4 5.2 21.0 57.0 6.80 5143 26.0 95.0 0.6 225.0 10.0 5.5 21.0 47.0 6.80 6014 21.0 118.0 0.6 465.0 10.1 3.3 26.0 40.0 6.60 6016 25.0 111.0 NwMr 190.0 10.2 4.6 15.0 63.0 N9 MkN 6039 21.0 113.0 0.6 182.6 10:4 5.0 17.0 42.0 7.10 MEAN 24.67 106.33 0.60 189.18 10.20 4.63 19.17 48.33 6.80 50 4.59 9.07 0.07 22.17 0.17 0.80 4.31 9.54 0.19 N 6 6 5 6 6 6 6 6 5 ZrVcv`OV
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APPENDIX 8 CON'T CLINICAL CHEMISTRY CODE 68 EXPOSURE TIME 200 DAYS DOG N0. BUN (MG/UL) GLUCOSE (MG/DL) CREATININE (MG%DL) CHOLESTEROL (MG/DL) CALCIUM (MG/DL) PHOSPHORUS (MGlUL) SGOT (MU/ML) SGPT (MUlML) TOTAL PROTEIN (G/UL) 5039 15.0 110.0 1.5 155.0 9.6 3.7 21.0 45.0 6.60 5046 15.0 117.0 1.5 160.0 9.3 3.2 30.0 33.0 6.95 5143 19.0 100.0 1.4 200.0 10.2 4.1 27.0 55.5 8.20 6014 13.0 124.0 1.4 150.0 9.8 3.0 41.0 43.0 7.00 6016 23.0 85.0 1.5 162.5 9.9 4.3 24.0 63.0 7.90 6038 18.0 i14.0 1.0 130.0 10.0 3.3 24.0 33.0 6.30 6039 13.0 125.0 0.4 165.0 9.6 3.7 18.0 48.0 7.10 MEAN 16.57 109.29 1.24 160.36 9.77 3.61 26.43 45.79 7.15 3U 3.64 14.30 0.41 21.04 0.30 0.48 7.50 11:04 0.68 N 7 7 7 7 7 7 7 7 7 C-D ~ ca,! 4 C= ~ ~ zr- CLZCOVOS
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~ JK m m m m m APPENDIX 8 CON'T CLINICAL CNEMISTRY CODE 68 EXPOSURE TIME 400 DAYS DOG NO. BUN (MG/DL) GLUCOSE (MGfDL) CR_EATININE (t7G<DL) CHOLESTEROL (MG/DL) . CALCIUM (MG<DL) PHO§P-IIORUS (MG/DL) SGOT (MU/ML) SGPT (MU/ML) TOTAL PROTEIN (G/DL) 5106 9.0 96.0 0.8 205.0 8.7 3.0 20.0 36.0 6.60 5109 13.0 96.0 0.9 (70.0 8.4 3.3 34.0 51.0 7.00 6018 15.0 100.0 0.8 161.0 8.9 4.0 22.0 60.0 6.70 6038 13.0 112.0 0.9 155.0 9.0 3.2 48.0 66.0 6.70 MEAN 12.50 101.00 . 0.85 174.25 8.75 3.38 31.00 53.25 6.75 5D 2.52 7.57 0.06 21.50 0.26 0.43 12.91 13.05 0.17 N 4 4 4 4 4 4 4 4 4 • TUQYOC3
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APPENDIX 8 CON'T CLINICAL CHEMISTRY CODE 68 EXPOSURE TIME 1000 DAYS DOG NO. BUN (MG/DL) GLUCOSE (MG%DL) CREATININE (MGiDL) CHOLESTEROL (MG/DL) CALCIUM (MG/DL) PHOSPHORUS (MG/DL) SGOT (MUlML) SGPT (MUiML) TOTAL PROTETt+ (GiDL) 5039 20.0 115.0 0.7 160.0 11.4 6.6 40.0 50.0 6.90 5046 28.0 115.0 0.7 170.0 10.8 5.9 48.0 48.0 7.50 5106 14.0 110.0 1.0 170.0 9.6 3.6 210 39.0 6.60 5109 23.0 105.0 1.0 160.0 9.4 4.5 40.0 330.0 7.10 5143 20.0 120.0 0.8 220.0 11.0 5.7 28.0 46.0 7.80 6014 15.0 135.0 0.8 185.0 10.6 5.2 36.0 52.0 7.00 6016 26.0 110.0 0.9 205.0 11.4 5.2 78.0 73.0 7.40 6018 22.0 120.0 1.0 170.0 9.6 4.2 25.0 50.0 7.60 6038 24.0 130.0 1.0 145.0 9.0 4.4 25.0 40.0 6.80 6039 18.0 130.0 0.7 165.0 11.2 5.3 26.0 54 .0 7.00 MEAN 21.00 119.00 0.86 175.00 10.40 5.06 36.70 78.20 7.16 SD 4.52 9.94 0.13 22.48 0.91 0.89 16.89 88.97 0.38 N 10 10 10 10 10 10 10 10 10 p /1-MOVOR
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APPENDIX 8 CON'T CLINICAL CHEMISTRY CODE 68 EXPOSURE TIME 600 DAYS DOG H0. BUN (MG/DL) GLUCOSE (MG/DL) CREATININE (MG/DL) CHOLESTEROL (MG/DL) CALCIUM (MG/DL) PIIQSP_HORUS (MG/DL) SGOT (MU/ML) SGPT (MUiML) TOTAL PROIEIN (G/OL) 6014 15.0 Y16.0 0.8 150.0 8.8 3.3 28.0 36.0 6.20 5039 15.0 132.0 0.7 165.0 9.2 3.1 18.0 45.0 6.60 5046 12.0 100.0 0.7 175.0 9.4 3.9 26.0 48.0 6.90 5143 18.0 116.0 1.0 225.0 9.1 3.6 26.0 66.0 7.10 6016 15.0 112.0 1.0 180.0 9.2 4.0 18.0 57.0 6.30 6039 14.0 112.0 0.7 160.0 9.6 4.3 18.0 60.0 6.60 5106 15.0 96.0 0.8 215.0 8.7 3.0 18.0 36.0 6.70 5109 t 5.0 112.0 0.9 185.0 8.4 3.3 26.0 72.0 7.00 6018 _ 9.0 124.0 0.8 220.0 8.9 4.0 16.0 135.0 7.00 6038 18.0 128.0 1.0 170.0 9.0 3.2 26.0 63.0 7.00 M€AN 14.60 114.80 0.84 184.50 9.03 3.57 22.00 61.80 6.74 50 2.63 11:32 0.13 26.50 0.35 0.45 4:71 28.50 0.31 N 10 10 10 10 10 t0 10 10 10 L ~;IzeoVoe
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K It K K ~ K K K - -- , APPENDIX 8 CON'T CLINICAL CHEMISTRY CODE 68 EXPOSURE TIME 1100 DAYS DOG BUN GLUCOSE CREATININE CHOLESTEROL CALCIUM PHOSPHORUS SGOT SGPT TOTAL PROTEIN NO. (MG/DL) (MG/DL) (MG/DL) (MG/DL) (MG%DL) (MG/DL) (MU/ML) (MUi1lL) (G/DL) 5039 28.0 120.0 1.3 200.0 12.2 5.1 31.0 50.0 7.30 5046 16.0 115.0 1.0 150.0 11.8 5.2 43.0 45.0 7.20 5106 14.0 105.0 0.9 170.0 9.4 3.6 20.0 42.0 6.80 5109 19.0 120.0 1.0 130.0 9.0 3.9 35.0 48.0 6.80 5143 25.0 145.0 1.0 220.0 9.6 4.8 27.0 53.0 7.80 6014 26.0 130.0 1.0 170.0 11.2 5.0 47.0 54.0 7.60 6016 20.0 120.0 1.1 175.0 8.8 3.5 29.0 64.0 7.90 6010 22.0 130.0 1.0 150.0 9.0 3.1 22.0 52.0 7.10 6038 26.0 110.0 0.9 100.0 9.6 4.1 33.0 46.0 6.60 6039 24.0 120.0 1.0 140.0 8.8 4.1 23.0 50.0 6.90 MEAN 22.00 121.50 1.02 160.50 9.94 4.24 31.00 50.40 7.20 5D 4.64 11.32 0.11 34.52 1.29 0.74 8.86 6.08 0.45 N 10 10 10 10 10 10 10 10 10 4 IzEoVOR
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(COHTINUEO) APPENDIX 8 CON'T CLINICAL CHEMISTRY I CODE 67 EXPOSURE TIME 100 DAYS DOG NO. BUN (MG/DL) GLUCOSE , (MG/DL) CREATININE (MG/DL) CHOLESTEROL (MGiDL) CALCIUM (MG/DL) PHOSPHORUS (MG/DL) SGOT (MUiML) SGPT (MUtML) TOTAL P-ROtEIN (GiDL) 6023 32.0 90.0 0.8 175.0 9.8 3.9 31.8 42.0 6.60 6024 28.0 90.0 0.8 182.5 10.5 5.1 30.3 47.0 6.75 6026 18.0 93.0 0.7 140.0 10.4 3.9 34.5 33.0 6.45 6027 21.0 93.0 0.7 135.0 10.1 5.1 35.1 48.0 6.40 6028 21.0 1Q0.0 0.6 185.0 10.5 50 . 27.0 50.0 6.43 6030 1 8:0 97.0 0.7 147.5 9.6 4 .0 32.1 20.0 5.70 6031 19.0 98.0 0.7 145.0 10.2 3.6 37.5 30.0 6.38 6032 8:0 103.0 0.6 190.0 9.9 3.4 34.5 24.0 6.00 6034 10.0 120.0 0.5 155.0 10.1 4.8 33.0 74.0 6. 16 6035 19.0 105.0 0.7 180.0 10.4 4.3 33.0 51.0 6.80 6037 17.0 103.0 0.6 178.0 10.1 5.5 34.5 50.0 6.25 6040 13.0 135.0 0.7 152.5 10.1 3.0 38.1 39.0 6.25 MEAN 16.90E- 100.19 0.66 165.108- 10.01 4.16 32.30s+ 45.77 6.43 SD 6.44 13.95 0.09 27.65 0.32 0.67 6.08 19.02 0.29 N 54 54 54 54 54 54 54 54 54
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APPENDIX 9 CON'T PULMONARY NEASUREMENT FOR TFIE CODE 68 GROUP AT 0 DAYS EXPOSURE 112 IJASIIOUT DOG -------------ARTERIAL BLOOD GASES-------------- 02HB 118 COIIB PH PC02 P02 VOL. TO 2'/. 112 CLOSING ----VOLUME---- VITAL CAPACITY PHASE III SLOPE MINUTE VOLUME H0. (!) (G</00 ML) (%) (MM NG) (MIi /1G) (ML) (ML) (/) ((IL/KG) (% H2iL) (MIJ MINtKG) 5039 94.8 15.5 0.8 7.45 29.6 116.4 5930.0 280.0 2/•0 95.2 7.0 193.0 5046 95:4 14.6 0.7 7.46 23:6 105.3 4450.0 190.0 18.0 84.8 7.0 240.0 5106 95.4 18.0 1~KM~ 7.36 26.6 97.2 4850,0 140.0 13.0 96.5 9;5 208.7 5109 96.4 15.3 w~kN 7.42 25.9 93.4 6910.0 200.0 2_3.0 97.8 9.0 195,6 5143 94.8 16.3 0.8 7.45 21.1 115.4 6320.0 180.0 16.0 91.2 9,5 184.0 6014 93.6 14.2 0.6 7.46 27:7 94.3 4920.0 150.0 17•0 72.8 7.5 160.0 6016 94.8 15.5 0.5 7.45 22.8 112.6 4880:0 150.0 14.0 85.6 7.0 152.0 6018 96.2 14.6 KKMN 7.40 23.8 93.9 6280.0 120.0 14.0 69.2 8.5 304.6 6038 94.2 16.3 MMNIf 7.40 25.4 86.4 7210•0 2_80.0 26.0 /10.0 7.5 187.0 6039 94.0 15.6 0.8 7.44 28.5 108.0 6120,0 150.0 16:0 81.7 9.0 226.0 MEAH 94.96 15.59 0.70 7.43 25.50 102.29 5787.00 184.00 17.8 88.48 8.15 205.09 SD 0.92 1•10 0.13 0.03 2.69 10 _60 953.6) 56.02 4.3 1 2.26 1:06 44.0) H _ 10 10 6 10 10 10 10 10 10 _ 10 t0 10 T9ZEOtrOt~
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~ W W Y N M H~:\~Nn~Op~n~~PO.PT~O~nPP~hil~lM~CdM~^N.tfii•GPP~.paO o0:~L1u1~ 2J..PU1o~.ut0'.P~p~V1Md'o:O.a:^N.uleO:noN<O.Tn~tO~.O~ ~.•-•-OfQ:N.NJNIU~~MP~O~v.P~pjO:P/~~~ ~>'\~N:N~NiMN!~1NMMN~.t~MM.~T..M.M'M~M'v1,~M~T.T~T^M Mi E r. v .. W ~ d\.~ O.UI O:IfI O If7 i0 IIY Ifl' G~O lt1 ~O~ lLt 611 L^I ~O. o.u1111 O tf1'O ul . I 11 11 W I 4 il -Y. I I I q ~ ~T N' ~Il } H ~. •Ji••~(:J:_pU1_'O_'~41'h0^~.S~P~fiTN^~TNY10N1l1~~f00~T~ n~^111 < U Y: . . . . . . . . . . . . . . . . .. . . . . .~. . P~T N~ 1+•Q\n~..TMOpOpl1'1~OnCp:TH'NP~P~IfiN.1•.~TPO~P.S.OM~O~. Fw~1.'.J~OOO~n.00~W0,-T~t[1CO:hC7:00:T~C0~OQn~l~~~0.^OO~Ca,.O:P~~ •pldY'. 1 p~oo~oo'o~o:poOOO~oo~x~.o~.oO:o.zxxox:o I EQO.p~n.11~1~PN9~O~Mh?~~epiX~T~U1x: x~X^ x'~'1 f,71 (rp^_~-NI~'~^^MiN~^N~Nx.NN~N, x.N ZW .. f O .~ J O o n o N N t,.>.>~~ p:OpCp:oo~oGpoCO.OZ:po~~p'o:.x:x~~x:oz.o p.tp~. 1 i. . . . . . . . . . . . . . . x : . .. . ~ . x x x . x: 1 JO:OO.OO~OO:OO.OOOOOZ~00:CO~x X x:O.xO N • • 1 ~.^'nP~_^nO:~11~(1MP-^iltznM~n~Txxz:~[lzN~ ~~ I NN.NNNNN, NP N H G1~~M. 00000~.00:00:00~00:0.0:0000:00~000'O. .pO~IdY'. W cz 1.ff'.• JOiN~.T~N~N111.0:~11O~..D.O~n~..}tAO~eq:M_N(1!^.fPMin. M W Yn <'J\~~Mi.p~O~-~.~'^T~.ON~GWI~N,P~P~T~Il1POIn~M^~OMNIOQ~. ~ O:N Iv.Op IN~^ P~P Iq .G iP~M:P ~ N, _'oJ. P~V1 O.P ap:^ ^ n n.p ~O YfS:•p .p ~P 2 O H (L )Q 0, W ~j~ T e0~1lY b T.O ~dl 00 ~T ~D .G:1[1 •0:4f1 N Gp..0:.0 ICI'n h~T •G:~(~1 Ml~ M M~ ~ W N: f O } 1 ~, ~"~ H<:. I 0~~1<1 •O:M~ Op ~.CQ .T P K1't1~1'^ O P~ O:O .t z.p O• M.O:d N Iq'. O: 1fl Mf ~.t~ Z LO: W 1 N Z~ . . . . . . ... . . .... .~. .,.z . .,. . . . . . I 0 OMN~NO~tHV1~~(1N.O/.~-Cp~OP~z~O~001P~TO~L'I~T~00~. O N N • C ~ dr Ofp:OQ:TO.00qnOQPPOp~PCp.PCQxP~P~hO~,h~P~P~P~ i .. tp0. 2 < t~ ' ~ lul d G ¢ '. C O N~C, 1:O~.p:N~^'h~00.OP~.pN.ti00:Op:P~hO~X~M~'YI O~N,.Tl[10'~ p.M MM:r7Mwl.T~MM:NI~ MM~- NK1M.x~M1:M~ n7MMMM1i ~ .T.P~~T. M N1 < 1: Z CD O ~NI J M ~ A CGC7Nif1^I"~.n~xo :OO>710c 0'J' N C ~ . ~ . x. . ~COI.t .' d W ' G G7 C7 O'tLT~.-.Y'10'^~•p.P~POJ~D00~~.4[1~MU0~TVI~CT~P~M'..OEO:O:N.tN•O' COMif! J O O~\~ m'C U v M L/1 t[1'~T M1 tfi N, N u1 ,P9 w- J a ., m CC'W=~if1Yl.T~TnOP~MM:.ONNP^NO^^OhtMN,~d1:N HLU••+^'^^^`^'0--- -- -p-^'NNfVNNNNINNiM OC'. fr 0• ^ N LO P~.O M:Yf 0~_ •O.O:O ~.Op: P'N~ O~P Cp OJ v~ ^ OJ .O f10 2 O:.T V1~ •C ~u1~ ~!y ~~t tfY'.•O. i(1 u11~ n .O .T '.O .T M .T .T .t'~(t .1 ~.T~ .t .ttt '. Nou'1 T .G N ^ N 0 0 ~ i 1 m PNI:~ NCVO:M-N"'adM~NNebeOIn~.NIOP~u~NUIN rnN.T I S•~• ~ - • x: oQ, eR N Qv~PPPOJ:P~O~:PPP~P~P~PPP~PP~X~P~PP~P~PP~PP~ ~T~M~ P Q~Q:OG~~00'.O^'~- ^'N~NN~NN.N.N~MMMNY~M~M1~Me+1~. 0~ 2 uti v'i u1 in ~ul ~a1 u1 ul ~a1 ~n ~'1 ~r1 ~u1 ul ~u1 ul ~~11 ~n~~[l in~itl iu1~~(1 i~l ~a'~ ~ 2 G W C ~ cn:Z -322-
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I e \ I I I' i ~ 1 1' I Expired nitrogen concentration was measurediusing a Hewlett Packard Model 47302 A f'ast response nitrogen' anallyzer, and the expiired gds volume was collected in a 1'3.5 liter water seal spirometer (Warren E. Colllins, Braintree, Massachusetts). Volume to' 2% nigrogen, tidal volurne, respiratory rate, andim'rnute vol'ume were determilned from the spiromet'er tracingl. A9'1 volumes were corrected fdr body temperature pressure sat'urated (BTPS). • M'inute Vol'ume, Tidal Vollume and Respilratory Rate - Miinute volume„ ti'dal volume, and respiratory rate were determined from the spirographic tracing obtainedifrom the N2 washout t'est. A111 volumes were correctedd to BTPS (body temperature, ambient barometric pressure, 38°C, saturated wiith water vapor):. . - ` • Sing7e Breath N2 Test (Vital Capacity,, Alveolar Plateau„ and Cllosiing Volluime) - After the N2 washout test, each dog was allowed a' minimum of 20 minutes to eGuilibrate to room air. The tracheostomy tube, with cuff deflated, remained'in place during this ti'me. Each dog, after receiving Acepromazine© approximateiy, one hour before, was then anesthetized with sodiium pentobarbitall (26'.4 mg/kg)'. The anesthetic was slowTy administered ilntravenously until the d'esired level of anesthesia was attained. The dog was then placedlin a supine position at an angle of 30° with the head at the highest leveT. A'n esophageaT ball'oon was iinserted into the esophagus and pTaced approximatelly iin the middle third port'ion to determine pleurall pressure. The balloon, containing T.O' cc of air,, was connected via 60 cm of PE-240 tubing to a dhfferential' pressure transducer. Pressure cal'ibrations were performed using a water rmanometer. Transpulmonary pressure (Ptp) was recorded as t'he difference between the esophageal balloon pressure and the pressure at the opening of the tracheostomy tube. Volume was derived from the eTectronic integration of the fl'ow signad obtained from a Fleish No. 11 pneumotacho- graph, and percent N2 was measured with a rapiid response N2 anaTyzer. Nitrogen concentration versus volume was disp7ayed on an X-Y plotter. Tihe:maneuNer was performed by twi'ce inflating the dog's lungs with breathing quaTiity air to +30cm HZ0 transpulmonary pressure (Ptp) to: -11-
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i,n -r,, 'I f:I hi L and chartered on a' standard' Levx-Jennings chart. The Platelet Calibrator was assayed by the l'aboratory upon receipt and verified every three montlis thereafter until the lot expired. The assay, was performed by counting blaod specimens on' the phase mrcroscope, caTi'brating the Autocounter to the counted va]ues and then processing,numerous randomly selected samples of'the ca7ibrator material through the Autocounter. The average of the cal'ibrator results was used as the assay value during subsequent runs. CliniicaJl chemistry tests on the Technicon A'utoanalyzer I'I were monitored through the use ofi SMA Reference Serum 2'as a standard and Monitrol I and II as control'. TFie standard and blank were run at the beginning of the day and aften every'20 samplles_ The control's were run at the beg,inning of the day and after interruptions in the testing process. Serum electrophoresis was moniltored'before and after every six samples using the Dade electrophoresis controT ('Dade Division, American Hospitall Supply Corporation, Miami, Florida). The percent of total integrations for each protein fraction as well as totall integrations were recordbd on Levy-Jennings charts. TERMPNAL STUDIES SCHEDULED SACRIFICES Initially, schedulied sacrifices were performed on dogs fhom' each of Codes 11, 13, 32, and 33 at 200 day intervalis. Scheduled satrifices on all codes were suspended'as of September„ 197& due to high mortality i!n some groups. NECROPSY Dogs scheduled for sacrifice were euthanized with an intravenous injection of T-61'(National Laborat'ories Corporation, Subsidiary of American Hoechst Corporation, Somerville, New Jersey) and exsanguinated. A complete necropsy was performed on each animal at the ti'me of sacrifiice or death by a modified Rokitansky technique. SpeciaT care was given to organs of the respiratory and cardiovascuTar systems. T!he larnyx. trachea, and llungs were removed ern cZoc and examined visuallly and by palpatiorr. The trachea was separated just distal to the tracheostomy stoma, and the proximal portion opened longitudina'lly, and inspected'for gross lesions. The cranial section of trathea was tFien fixed in 10% neutrall buflfered formalin so7ution. -1'5-
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~~~ C ~, .~~,.~~,~~ ~~ a~~.T s~~ The distal trachea and lungs were fiked by intratracheal, perfusion of 101" neutral buffered formalin at approximately 25 cmiof water pressure while suspended in formalin solution overnight. Following fixation, total lung volume was determiined by volume displacement. Following separation from the lungs, the heart was examined for gross lesions and the coronary arteries were removed and fiixed in 10% neutral buffered formalin. The following organs and tissues were removed from each dogi„ examined, and fixed in 1'0% neutral buffered formal'in:: skin sample spleen eyes l i'ver salivary glands gallbladder sternal bone marrow, kidneys rib:junction adrenals " ` peribronchial lymph nodes urinary bladder esophagus prostate thyroidl testes stomach femoral vein duodenum braini jejunum spinal cord'' ileum pituitary cecum aorta large,intestilne diaphragm pancreas At the time of necropsy any gross pathological alterations were recorded. PATHOLOGY, AND MORPHOMETRY Alll tissues saved at necropsy were fiorwarded t'o~Dr. Auerbacn, V.A'. Hospital, East Orange,N.a'. Dr. Auerbach was responsiblle for blocking!the lungs, preparing staimed sections of'the tissues, and examining the tissues for detailed gross and mncroscopi'c pathology. The following procedures were to be followed by Dr. Auerbach's group in the histopathological evalluation: Trachea~- T!he tracheobronchiall tree is examined for changes in the epithelliurm bronchial walls, andlmucus g,lands. Twolcross-secticns per tracheal ring of 5 microns each are dehydrated in a graded series of allcohol, clearedlin xylene,, embedded in Paraplastc ", sectioned, and st'ained with hematoxylin andleosiln (HF;E) and Periodic-AcidlSchiiff (PA'S). The H8E stained sectiions are examined for evidence of epithellial hyperplasiai, metaplasia, and neop7asia. The PAS-stained sections are examined for evidence of increased mucus secretion. -16-
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C 01-~~~otul T1:i1' 4 01 I I I I I I I I subgroup V3, and! Code 32 subgroup W3 at 200 days, Codes lil „ 13, and 32 at 400 days and Code 67 and PMO sham cont,rol' baseline studies were performed at Borriston. Blood profiles were also determined on all Code 117,13, and 32 and sham control animals following 600, 800,1000,,12001, 1400, and 1500 days of exposure, and the Code 67 and PMO sham conta'rol animals following 400, 600,,800, 1000,, and' 11'00idays of'exposure. Dogs schedulled for sacrifice at these intervals were sampled prior to euthanasia. References for clinical laboratory procedures are presented iniAppendi'x 10. HEMATOLOGY Blood for hemat'ology studies was colllected fromithe jugular veini into 5 ml evacuated tubes containing tripotassium EDTAas the anticoagulant. Hematology parameters evaluatedwere erythrocyte count, total and differentiad! 1'eukocyte counts, platelet count, hemog1obin level,,hematocrit, mean corpuscular volume (MCV), meani corpuscular hemoglobin (MCH), and meani corpuscular hemoglobin con- centration (MCHC). Erythrocyte and leukocyt'e counts, hematocrit, MCV, as well as hemoglobin concentrations were det'erminedlusing a Coulter Counter Model ZF-5 (Coulter Electronics, Inc., Hialeah„ Florida),. Platelet counts were performed oni a Technicon Autocounter module of a Techniconi Autoanalyzer I'I ('Technicon Instruments Corporation„ Tarrytown, N.Y.). The erythrocyte indices (MCH and MCHC) were calculated. For differential leukocyte counts, 100 leukocytes stained with Wright-Giesmaistain were classified. HEMOSTASIS The criterion for evaluating hemastasis was platelet adhesiveness. Bllood samples were coillectediprior to, smoking and fifteen minutes after smoking the first cigarette ofthe day. Blood for platelet adhesiveness testing was collected from the jugular vein into a plastic syringe using a 19 gauge butterfly infusilon set and then forced to flow thraugh a glass beadldeviice at a constant rate of 3.5 ml/minute. The first 2 mi of blood was discarded and the third and fourth ml were each colllected into a tube containing tripotassium EaTA. Platelet counts were performed on each of these samples and compared to the counts obtlained on native whole bloodlt'oideterniine the percent of platelet adhesiveness. Platellet aggregation studies were performed by the method described by Born usiingia platelet aggregometer. The change in light transmittance following the -113,
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i ~i~~ l:~r^rI~ilDe~ ~~ay ~ltla, .1' . -1 I ! I If addition of exogenous triggering~agent's (adenosine diphosphate (ADP) and collagen) was measured. Blood was collected from the jugular vein into a syringe containing sodium citrate as the anticoagul!ant. PTatleJet-rich plasma (PRP) was obtained by centrifuging the blood at 500g for ten minutes at 23°C. The PRP'was recentrifuged at 1800 x g for 30 minutes to obtain platelet-poor plasma (PPP')I. The samples were transferred with pllastic~pipets to plastic tubes, covered, allowed to stand for one hour at room temperat~ure and then analyzed. The ADP and collagen were prepared according,to the manufac- turer's specifications (Bio/Data Corporation,Horsham, PennsyTvania) in order to obtain concentrations in the test system of 2 x 10-5M and 0.26'mg/ml, respectively. CLINICAL CHEMISTRI' ~ Blood flor clinical chemistry determinations was collected from the jugular vein prior to the animall smokimg the first cigarette of' the day. Ten milliliter serumiseparation tubes without anticoagulant were usedifor blood collection to assure fibrin-free serum samples. The blood was allowed to clot for thiirtyy minutes and centrifuged at 1800 x g for li2'minutes. Aliquots of the serum were quick-frozen at -40°C for subsequent clinical' chemistry testingi. Serum protein elsctrophoresiis was performed by the zip-zone cellulose acetate method on fresh serum samples within 24 hours of collection. The folllowi'nglclinical chemistry parameters were determiined on thawed serum sanpfiess using the Technicon Autoanalyzer II;, albumin, bloodi urea nitrogen, cholesterol',. calcium, creatinine, glucose, glutamic oxaloacetic transaminase, glutamic pyruvic t,ransaminase, inorganic phosphorus,,and total proteini. QUALITY CONTROL The accuracy of clinical laboratory values was assured by the routine calibration of'instruments using commercial standards. Normal andlabnormal levelis of the Coulter 4C Cell Controll were documented daily on the Coulter Counter Model ZF-5. The Coullter Hemoglobinometer was calibrated monthly usingithe hemo- globin standard Hb10 and Hb20. The TechnicaT Autocounter platelet analyzer was standardized prior to each use using the Technical Normal Calibrator. The sensitivity reading from the Autocounter was taken at the beginning of each run -14'- ~.-___
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RESULTS J~~ 'J~ IW; I HEMATOLOGY' Individual hematology data are presented in Appendix 5 and mean values are presented' in Tablle l'. Mean values marked with S+ or S- are statiistically significantly higher (S+) or llower (S-)' than the respective control value as measured by Students t-test at P<0.09. I ~ Hematology data on Codes 13, 11, 32, and 33'at Days 0 and 100 andlon Code 33'at Day 200 were not coll'ected at:Barriston, and are therefore not included in thils report. All testing not performed at this laboratory was conducted at BNWiprior to transfer of the dogs to Borristan. RBC, Hematocrit; and EemogZobtin - Statistically signiifi¢ant decreases in RBC count's, hematocriits, and hemog,lobin values were noted in Codes 1'3 (low)i„ 11 (mid),, and 32 (hiigh) as compared ta' Code 33 at the 600„ 800, 1000, 1200, 1400, and 1500 day intervaTs (except for Code 11 hematocrit at 1000 days),. These findings are considered to be related to chronic smoke exposure. Iin addition, statistically significant lower hemoglobin val!ues and RBC counts in these three codes at 400 days suggest an early response to the smoking regimen. RBC, hematocrilt, and hemogllobiin values for Code 67 (PM0) were g,enerallly lower than Code 68 (PT40 control) values from Day 0 through 600 days of exposure. The statistical significance of these l'awer values was sporadic and is not considered treatment related through 1000 days. These erythracyte parameters were statistically significantly lower than Code 68 contrals after 1I00 days of exposure. These fimdings: were similar to the other smokingi groups and suggests that the smoke effect for Code 67 dogs may have been delayed because of the RMO' in these cilgarettes. l,,BC - White bllood cell caunts for Codes 13, 111, and 32' at the 400, 600, 800 1000, 1200, 14'00 and 1500 day intervals and Code 67 at the 100, 200, 400, 600', 1000. and11,100 day intervalis were statistically significantly higher than those of the respective control groups_ The magnitude of'the elevated WBC counts were simil'ar for Codes 13, Tll, and 32', while increases in WBC's for Code 67 were not as large as those far the other three codes. Statisticall evaluation ofi the WBC differential data showedlna treatnent-related changes. Sporadic dfifferences fnom controT were noted. -19-
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CGINFULji ~11lA 1 11, 11 14 4 4 I I if I I The external diameter of at least five c,ircuiar arteries in each section, expressed as the mean of two measurements taken at right angles to each other, of the distance between diametrically opposedipoints in the external el'astiic l'amina is made. The medial thickness is estimated from the mean,of four measure- ments taken at approximately equally spaced points around the vessel wall. The thickness of the media is expressed as alpercent'age of the external diameter.Systematiic Vasculature - Hematoxyllin and eosin and Verhoff-Van Gileson stained secti'ons of the small arteries and arterioles in the gastrointesti'nal tract, pancreas, and adrenals are prepared. Two sections from each adrenal are pre- pared. The thickness of the arterial and arteriole walls is estimated similarly to the method described above for the pulmonary arteries and arterioles. Aorta - The formalin-fixedlthoraciic and!abdominal aorta are grossl~ stained and evaluated using the methodlof Holman, McGiill, at aZ. This method employes Sudan IV which st'ains the fatty streaks andideTineates any fibrous plaques. The severity of these two gross lesions is scored andithe stained'aorta is stored in plastic bags. Remaining Organs - Because of the uncertainty of the clinicall siigns and the results of the cliinical and physiological measurements, the remaining,organs flixedlat necropsy are held for possible hilstologicall eval'uati'on,. Sections are preparediand microscopic evaluations are made of the remaininglorgan systems as indicated!by the results of the various observatiions during the course of the study. -18-
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nirp establish a constant volume history, followed by a passive exhadlation!. This maneuver also rendered the dog apneic. The lungs were deflated to -10 cm HZp Ptp (residual volum:e) followed'by an infl'ation with 100% 02 to +30cm: H20 Ptp (tot,al lung capacity). The lung was again deflated to residuall volume while recording N2 concentration versus volume on the X-Y plotter. A final~ inflation of the l!ungs to near total lung capacity were performed in order to prevent possible respi'ratory effects which could result from the deflation to residual volume. Inflation and deflation rates were 76,m1/sec. Vital capacity, alveolar plateau (slope of Phase IUI), and clo5ing,volume (Phase IV) were l i at d f thi l l t ero s 4 I I I I -1 9 cacu m po. Mi Arterial Blood Gases - Immediiately fdlllowing,administration ofsodhum pentobarbital for the single breath N2 test, arteriall blood was colTec,ted anaerobically from the femoral artery using a heparinized glass syringe. Blood was analyzed immediately iniorder to minrimrize any changes in the blood gases whiich occur when the bllood stands at room temperature. An Instrumentation Laboratory Blood Gas AnaTyzer (Model 213)iat 38°C was used to determine the pH and partiali pressures of oxygen (Pa02) and carbon dioxide (PaC02)1. The blood gas analiyzer was calibrated twice dailly. Oxyhemoglobin saturation(Hbo2) was determined from the arterial blood sample with an Instrumentation Laboratory Model 182 Qo-Oximeter. Hemoglobin content was measured with a Coulter Hemoglobinometer and the Model 182 Co-Oximeter which had been calibrated wilthinormal dog blood. CLIiNICAL LABORATORY STUQIES Blood samples for hematology', hemostasis, andiclinical chemistry profiles were colliected from all animals at scheduled intervals. Baseline and 100 day exposure values on the sham controlis and all Code 11, 13,,and 32 animals, and 200 day exposure values on all sham controls,Code 11 subgroups X1 and X2, Code 13 subgroups V1 and'V, 2, and Code 32subgroups l•ll and WZ were determinedl at BNW. Clinicali laboratory studies of Code 11 sudaroup X3, Code 13 -12-
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4ONfIBENTlAL 11 It 4 4 4 I I I 1 I I PLATELETS The f'ollowing statistical'.ly significant changes in platelet count weree observed: r Higher than control for Codes 13, lll, and 32 at 600 and T000 days. M Higher than control for Codes l'1 and 13 at 400'days. I Higher than control for Code 11 at 800 days. t Lower than control for Code 32 at 1200 days. . Lower than control for Code 11 at 1400 days., • Higher than control for Codes 13 and 32 at 1500 days. No treatment-rellated pattern can be ascertained. Platelet counts for Code 67 (1PMO) were statistical'lIy signifilcantlly eTevatedl on Day 400 and statistical'ly significantly lower than control at Day 1000 but were similar toicontrol levels at the other intervals. Platellet results from all treatment groups in this study are within the normall range for beaglle dogs. HEMOSTASI,S Individual hemostasis data are presented in.Appendix 6 and mean values are presented in Table 2'. Coagulation data on Codes 13, 11, 32, and 33 at Days 0 and'1'00 and an Code 33' at Day 200 were not collected at Borriston, andiare therefore not iincludad in this report. All testing not performed at this llaboratory was conducted at BNW prior to transfer of the dogs to Borriston. PZateZet Adhesiveness - No difference in the pre- and post-smoking results were noted between Codes 11 (low), 111 (mid), 32'('high)i, and 33 (controll) at any of the clinical intervals. Additiionalily, no dilfferences were noted between pre- and post-smoking levells for Codes 6'7'(PMO) or 68 (PMO control) and no evidence of a treatment-related finding was notedl. It should be noted that the platelet adhesiveness test is a qualitative platelet function study and'that wide fluctuations in the normal range have been noted by many laboratories performing this test. These fluctuations can be noted in this deta when comparing intervaT to:interval. -20-
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I I I . I t I I l, li I 'I L The degree of'atyprism is recorded for bronchii and trachea:. Important changes in degree of basal cell hyperplasia and squamous metaplasia are recorded. The number of goblet cells per nuclei is determined fromleach of upper, midportion, and lower trachea,,and each.lobar bronchus. The proportion of mucous glands in the tracheal' and bronchilal' walls„ and the relative size, are estimated by a point oounting method and~determination of' the Reid I'ndex, respectively. Lun - The fixedlvolume of lung is determined by water immersion. Each lobe of the lunglis cut into 1 cm slices. Three sections (lx2 cm) are taken from the apical, vasal, and midportion each of one lateral slice, one medial sl'ice„ andl one mediastinal slice. Each section is dehydrated in a graded'series,of alcohol', cleared in-xylene, embedded in ParapTast~', sectioned atl 5 microns, and stained with hematoxylin and eosin (H&E), PAS„ and Verhoff-Van Gieson stain for elasticc fibers and colilagen. Observations are made for fibrotic changes in the walls of alveolar septa as we1i1 as rupture and tearing of'the alveolar septa,. Bronchial Epithelium - Epithelial hyperplasia in the bronchial mucosa is quantitated by recording the number of rows of' basal cells and degree of atypism in 1'0 widely separated cross-sections from three different bronchi in each of two lobes.. Twenty longitudinal sections of terminali and'respiratory bronchioles are examined for epithelial hyperplasia, metapdasia,neop1asia,,and size of mucous glands. The parenChymalof'the lungiare examined:for enlarged alveoli andlother evidence of'emphysema. PulMonary Vascu]ature - The pulmonary arterioles and arteries are examined using the Verhof'f-Van Gieson stained sections. Changes in hyaTiine thickening of arterioles and intimal thickening of arteries are noted with the degree of atypism. Ten measurements of inedial, thickness of the transverse sections of the pulmonary trunk and aorta are made with a calibrated eye piece.. The meam medial thickness of'the pullmonary trunk (PT) iis expressed as a ratio of the meani medial thickness of't'he aorta (A)' -(PT/F ratio). -1 7-
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cc~~FrDEc+ailAi PULMONARY FUNCTION Individual pullmonary function data are presented in Appendix 9 and mean values are presented in T!abl'e 5. Graphic representatiion of PaOZ and PaCOZ is presented in Figure 1, N2 washout to 2% in Figure 2, closing volume in Figure 3', vital capacity in Figure 4. and Phase I'II slope iin Figure 5. Mean values marked with an S+ or S- are statistically significantly higher (S+) or llower (S-) thanithe respective control value as measured by Student's t'-test' at' P< 0. 05. Pulmonary data on Codes 13, „ T1, 32, and 33 at Days 0 and 100 and on Cod'e 33' at Day 200 were not co1Tected at Borrigton, and are therefore not incTuded in thiis report. A11i testing not performed at this laboratory was conducted at BNW prior to transfer of the dogs to Borriston. PTase IIr SZore - The Phase III slope for Codes 13, 11, and 32 were stlatistiicallyy significantly higher than control valves on Days 400, 800, and'1000 and for Code ll only at'i400 and T500idays exposure (mo siignnficance was noted at 1200 days, although Code ll was 15% higher than the control group vaI ue )'. Phase LII sTope was also statisticallly significantly hi!gher than controli f'or Code 67'at 100„ 200, 400, 600, T000, and 1100 days exposure (no significance was noted at 800 daysc P= 0.06). Based on the above, treatment-relat'ed dnfferences were apparent in the ventilation distribution between smoking and non-smoking groups. However„ no apparent difference in the Phase III slope was noted between smoking groups with differing levels of nicotine or PM0 present. CZaszng uoZur,e - Closing vol'ume for Codes 13, 11, and 32'did notl differ signrificantly from control values at any testing interval (400 days through 1500 days). Code 67 didinot differ significantly from control values at any measurement time except Day 200 ('stat'istically, siignificantlly llower than contro1). Nz w, s:out - Codes 13, 111 , 32', and 67 showed larger N2 washout vollumes than thertr respective control groups at all exposure ti'mes except for Code 13 at -23-
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i TABLE 1 SUMMARY OF HEMATOLOGY DATA AT 0 DAYS EXPOSURE WDC RBC IIGB HCT MCV MCH SEG. BAND MCHC NEUTRO NEUTRO LYMPH -- - ATY. LYMPH ~ MONO EOS BASO NRBC PLATELETS GROUP (X10lMM)(X10/MM) (G/DL) (%) (U) (UUG) (%) (G/DL) (%) (%) (%) (%) (%) (%) (%) (X10/MM) CODE 33 DATA NOT COLLECTED AT BORRISTON .. .a ea ea .. .. (COIITROL) CODE 13 +. .: " DATA NOT COLLECTED AT BORRISTON (LOU) COUE 11 aa aa aa a• DATA NOT COLLECTED AT BORRISTON .+ (i11U) CODE 32 a+ aa +a ee re " DATA NOT COLLECTED AT BORRISTON .. (H1GII) CODE 68 MEAN 11.89 7.13 16.89 50.36 69.6 23.87 33.81 58.7 0.2 32.3 0.0 7.2 1.8 0.0 0.0 256.7 (PHU CONTRUL) SU 2.74 0.32 0.73 2.69 2.0 0.66 0.79 6.9 0.4 7.2 0.0 1.2 1.6 0.0 0.0 14.6 N 7 7 7 7 7 7 7 6 6 6 6 6 6 6 6 ~ 6 CODE 67 MEAN 10.02 6.65°- 15.520- 46.38°-69.0 23.33 33.45 62.2 0.1 28.9 0.0 6.9 2.0 0.0 0.0 281.8" -(PF10) SD - 2.13 0.50 1.24 3.42 _2:5 -0:99 1.00 10.1 0.2 9.2 0.0 2.8 2.0 0.0 0.0 81.4 N 59 59 59 59 59 59 59 54 - 54 54 54 54 54 - 54 54 59 s• statistically significantly higher (e+) or lower (a-) than control value as measured by a student's t-test at ps0.05 4
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U ~~FID4.NITyl PZatelet Aacrecctuon - Results from Codes 13, ill, 32, and 33 at 200, 400, 600, 800, 1000, 1200, 140&, and 1500 days and'from Codes 67 and 68 at 100, 200, 400, 600, 800, 1000,. and 1100 days showed no differences between pre- and post- smoking vallues in either ADP or collagen data. Platelet aggregation is a qualitative platelet function study and, therefore, wide variations in the results have been noted. Platelets are extremely sensitive to experimental conditions which contributes to the lack,of standardization and reproduciibility of this test. Due to differences between the reaction mechanisms of adenosine diphosphate (ADP) andlcodllagen, the non-surface dependent ADP reaction would be expected to be more reproducible. This is observable in the data by the i'ncreased incidences of negative responses to the collagen stimul'i. - Collagen is a surface-dependent reaction. In orderv for a surface- dependent reaction to take place, certain criteria must be met. The first criterion is a change in shape of the platelets which occurs when an aggregating stimulus is introduced into the platelet suspension. Fol'liowiing the shape change, an adhesion reaction must take place with pllate1ets adhering to foreign surfaces such as collagen fibers. Once adhesion is initiated, platelet aggregation begins. Aggregation is the property of pTatelets adhering;to each other. During aggregatiioni, platellets release sub- stances such as ADP into the surrounding medrium producing the second phase of aggregation;. the total effect being cumulative. The release ofADP causes a secondary wave of aggregation which, in turn, causes further ADP'release. In some cases,,the secondary wave of aggregation is not discernible, with the aggregation response appearing as a continuous reaction from introduction of ai stimul'us to total aggregation. In vztro, using dbg pl'atelets, the colllagen concentration must be sufficiently high to provide the required surface area to which the platelets may adhere. The data through 1000'days exposure for Codes 13, 11, 32and the control group indicate that an increased concentration of colllagen is required to decrease the incidence of negative responses. -21-
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CuQFolz;ITlA1 W I . I I 1i I I Due to extraneous variables such as stress-induced plasma catechoTamines and finee fatty acids on aggregatilon, an increased concentration of collagen may not decrease the number of negative responses. SERUM PROTEIN ELECTROPHORESIS Individual electrophoretic data are presented'in Appendix 7 and mean values are presented in Table 3. Mean values marked with an S+ or S- are statistically significantly higher (S+) or lower (S-) than the respective control valiue as measvred'by St'udent's t-test at P< 0,05.. Electrophoretic data on Codes 13, 11, 32, and 33 at Days 0 and 100 and on Code 33'at Day 200 were.not collected at Borriston, and are therefore not i'n- clluded in this report. All t'esting, not performed at this laboratory was conducted at BNW prior to transfer of't'he dogs ta~Borriston. Several statistical'ly significant differences iin various electrophoretlic values were noted between smoking groups andicontroll groups; however, these findings are considered sporadic ininature and not considered to be treatment- related. CLINICAL CHEMISTRY Individual clinical chemistry data are presentedlin Appendiix 8 and mean values are presented in Table 4'. Mean vallues marked with an S+ or S- are statistically si'gnificantly higher (S+) or lower (S-) tlhan the respective controllvalue as measuredlby Student's t-test at P'<0.05. Clinical chemistry data on Codes 13, 111,32, and 33 at Day 0 and 100, andlon Code 33 at Day 200 were not collected at' Borriston, and are therefore not imcluded in this report. All testing not performed at this laboratory was conducted at BNWiprior to transfer of the dogs to Bbrriston.. Sporadic incidences of statistically significant differences between smoking groups and controls were noted iin the eval!uation of the clinical, chemistry data. However, no evidence of a treatmerit-relatedieffect is apparent. -22- JI
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t -- ~....t .~: s -:. ~ ~ TABLE 1 CON'T SUMMARY OF HEMATOLOGY DATA AT 400 OAYS EXPOSURE SEG. BAND ATY. WBC RBC HGB HCT MCY MCI1 MCHC NEUTRO NEUTRO LYMPH LYMPM MONO E0S BA50 NRBC PLATELETS GRuUP (XIOI(1M)(X10/MM) (G/DL) (X) (P) (uuG) (OlDL) (x) (z) (x) (z) (8) (z) (x) (x) (Xlo/r+al) CODE 33 MEA_N ]0.16 6.86 16.65 47.46 68.6 24.29 3_5.23 61.8 0.2 30.8 0.0 4.4 2.8 0.0 0.0 261 4 (CON]ROL) ----- 50 2.76 0.59 1.28 4.52 - 4.9 0.93 2.60 12.0 0.4 11.1 0.0 1 8 2.2 0 0 0.0 . 98 1 N 27 27 27 27 27 21 27 26 26 26 26 . 26 26 . 26 26 . 27 CODE 13 MEAN 17 05g+ 6 548- 16 OOe- 46 49 69 7 24 46 34 51 + " (LOU) - SD . . 3.15 0.51 . . -1.25 4.12 . 3.9 . 0.70 . 2_.37 66.7 7.8 0.1 0.3 27.0 7.6 0.0 0.0 4.0 2.0 2.2 2.0 0.0 0.0 0.0 0 2 342.8 81.3 N 44 44 44 44 44 44 44 44 44 44 44 44 44 44 . 44 44 COUE I1 MEAN 18.19H+ 6.56° 15.68a 46.09 69.4 23.92 34.21 68.8a+ 0 3 25 3e 0 0 4 0 1 7H 0 0 0 0 s+ (MIU) SU 4.55 0.48 _ 1.04 4.40 3.8 0.96 2:74 8.5 . 0:8 . 7.3 . 0.0 . 2.2 . 1.5 . 0:0 . 0 0 336.O 89 0 N 46 46 46 46 46 46 46 46 46 46 46 46 46 46 . 46 . 46 C_OUE 3Z MEAN 16.08g{ 6.458 1_5.638- 45.40 70.0 - 24.25 34.52 69.08+ 0.1 24.68- 0.0 4.3 2.0 0 0 0 0 294 4 (HIGII) SD_ 4.42 0_.46 1.23 3.72 4.4 0.84 2.68 10.2 0.3 9.2 0.0 2.4 1.9 . 0.0 . 0 0 . 70.9 N 44 44 44 44 44 44 44 44 44 44 44 44 44 44 . 44 44 CODE 68 MEAN 10.55 7.04 16.67 46.25 65.5 23.66 36.04 67.7 1.7 28.4 0.2 1.2 0.8 0 0 0 0 342 5 (PIi0C011T80_L_) 50 1.89 0.32 0_.61 1.96 1.5 0.73 0.96 8.3 1.2 8.8 0.4 1.5 0.9 . 0 0 . 0.0 . 42 7 N 10 10 10 10 10 10 10 10 10 10 ]0 10 10 _. 10 10 . ]0 COOE 67 - MEAN 12.90"' 6.70e- 15.93a- 45.00 67.2"+ 24.43 35.44 69.3 3.2"t 23.6 0 1 2 0 78+ 1 0 1 0 28° 6"* 406 (PM0) SU 2.51 0.60 1.42 3.14 4.1 3.78 1.28 6.6 2:8 6.6 . 0.4 . 1.7 . 1.8 . 0.5 . 0 5 . 8 5 8 M 47 47 47 47 47 47 47 47 47 47 47 47 47 47 . 47 _ . 47 a= statistically signiflsantly hlgher (a+) ar lower (a-) than control value as measured by e student's t-test at ps0.05 - - - C96(OYOB
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TABLE I CON'T ".i SIRTMRY OFHEMATOLOGY DATA AT 600 DAYSEXPOSURE GROUP CODE 33 MEAN (CONTROL) N0 . CODE 13 MEAN (LOW) SD N CODE I1_ MEAN (MID) SU N CODE 68 MEAN (PVIO CONTROL) SDN CODE 67 MEAN (PM0) SO N IIBC RBC HG SEG. BAND ATY B (X10f1fi1)(z1o/FPI) (GfuL) HCT (%) MCV (U) MCH (UUG) MCHC (G/DL) NEUTRO (X) NEUTRO LYMPH (%) _(S . LYMPH ONO OS ASO RBC PLATELETS ) (%) (X) (Z) (%) (X) -Cx 10/MM). 10.30 6.99 2 07 0 56 16.64 48.02 68.4 23.81 34.85 61 9 3 2 2 . . 27 27 1.38 5.81 6.3 0.81 2.37 . 7.7 . 3 8 8.6 8 0.4 3.2 2.7 0.0 0.1 316 8 27 27 27 27 27 27 . .1 0.9 2.2 2.4 0 0 0 3 . 116 5 27 27 27 27 27 . 27 . . 27 27 15.13" 6.39 - 15.41a 44.44e- 69 5 24 13 3 't 3.67 0.44 - 1.09 2.88 . --3 2 . 0 84 4.67 0 99 64.2 5.3 26.2 0.3 2.4 1 6e 0 ek 37 37 37 37 . 37 . 37 . 37 9.2 37 3.2 8.8 0.8 2.6 . 1.5 .0 0.0 0.3 0 7 392.2 82 2 37 37 37 37 37 37 . 37 . 37 16.14ft+ 6.52°- 15.658- 44.32a- 67.9 24 00 35 32 8t 4.09 0.45 1.14 2.89 2 3 . 1 03 . 1 14 65.2 5.4 23.18- 0.8 3.6 1.8 0 0 0 4 a° 41 41 41 41 . 41 . 41 . 41 7.9 41 4.8 9.2 1.1 2.2 1.6 . 0.2 . 0 8 434.0 104 41 41 41 41 41 41 . 41 .8 41 ]4.29a+ 6.41- 4 50 0.48 15 600- °- 44.168- 68.9 24.22 35.31 63.3 1" 7 24 5 8- . 1.31 3.29 2.5 1 08 0 85 . . 0.6 3.1 1.4 0 0 0 4 4 "+ 35 35 35 35 35 . 35 . 35 8.6 35 5.4 8.3 1.0 2.4 1.6 . 0 0 . 0 7 02.1 132 9 35 35 35 35 35 . 35 . 35 . 35 8.85 6.81 1 75 0 32 16.75 50.85 14.1 24.56 32.91 61.2 1 4 29 6 . . 10 10 0.72 2.79 2.9 0.57 0.92 5.8 . 2 0 . 5 0.0 4.4 3.2 0.2 0.2 417 0 10 10 10 10 10 . .7 0.0 1.8 1.1 0.4 0 4 . 7 10 10 10 10 10 10 10 . 10 3.5 10 15.54" 6.74 5 84 0 63 16.41 44.07®- 65.1e- 24.35 31.22" 69.18+ 1 4 2 4s- e" - . . 37 37 1.49 3.77 3.8 1.49 1.91 7 8 . 2.5 4. 7 9 0.2 2.4 2.3e 0.0 0.4 461.0 37 37 37 37 37 . 36 . 0.6 1.6 1.5 0.0 0 7 111.0 36 36 36 ' 36 36 36 . 36 37 s• s[atist3cally siynlflcantly higher (®r) or lower (a-) than control value as measured by a student's t-test at p<0.05 t I- V3G40V0R
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C 0 :;1 F1~~E eI T~~~ M 11 tj 60&days (control larger thaniCode 13 group) andiCode 67 at 1001days (control i'arger than Code 67 group). The above larger or increased NZwashoutl volumes were,statistically significant at the folilowing exposure times: • Code 13 (1ow): Days 400, 300, 1000'„ 1200', 1400 •i Code 11 (mid): Days 400, 800,,10001, 1200, 1400 • Code 32 (high): Days 400,800, 1200, 1400 • Code 67 (PM0): Days 400, 600, 1000 As seen with the Phase III slope results, treatment-related differences were apparent in the ventilationidistribution between smoking and non-smoking groups; no difference was noted among srmokiing,groups. uita? C=aLi*tu - Vital capacities remainediessentiaTl'y unchangedian all codes for all exposure intervaTs„ and no significant differences between codes were noted. Since vital capacity generally does not change markedly until a more chronic smoking,condition is obtainedi, one would not expect to see a significant difference at the tested exposure times. PaO~ nd fc^CZ - Codes 32and 11 showed statistically signifiicantly lower Pa02 at 1400 andil500 days exposure. A' significant increase in PaDZ was seen at 1000 and 110&days exposure for Codes 32 and 67, respectively. As can be, seen in the graphs of Pa02for all' smoldiing groups, the plotted values were generalTy consistent with those of the non-smoking groups. Stati'sticaTTy significantly higher PaC02 levels were observed for Codes 13, 11, and32 at Day 400 compared to Code 33, and a significantly Tower PaCOZ level for Code 11 (mid) was observed on 600 and 1500 days and Code 67 at 800 days exposure. The very high Pa02,leveTs and low PaCO 2 levels for Codes 67 and 68 on Day 0 are considered to be a result of hyperventilation during blood sampl'ing. The arteriiaT blood sampling procedure was changedlafter Day 0 testing,, and the values returneditoinormal in subsequent tests. RAW DATAAND FI'NAL REPCRT STORAGE All raw data and the final report will be housed indefiniitely in the archives of 8brriston Laboratories, Inc. 5050 Beech Place, Temple Hillis, Marylland 200311.. -24-
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- - ""."'[^.., 7r} .. rMF , l .::.r u u u L--i Lr+r TABLE 1 CON'T _5U_M1AR_Y OF kIEMATOLOGY DATA AT -200DAYS EXPOSURE GRuUP WBC RBC (%]0/IM1)(%10/MM) HGB (G/OL) HCT (X) MCV (ll) SEG. BAND MCH MCHC NEUTRO NEUTRO LYMPH (000) (G/DL) (%)(X) (X) ATY. LYMRH (X) MONO (X) EOS (X) BASO (x) NRBC PLATELETS (Y)(XIO/MM) COGE 33 .. a+ .• DATA NOT COLLECTED AT BORRISTON (C011TROL) CUDE 13 MEAN 16.75 6.41 14.99 44.38 68.8 23.37 33.76 67.2 0.0 25.3 0.0 5.4 1.9 0.0 0.1 375.6 (LQII) So 3.09 0.41 1:07 2.84 1.3 0.52 0.84 -7.I 0.0 7.6 0.0 2.4 1.3 0.0 0.3 73.7 N 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 COUE 11 MEAN 18.23 6.49 15.36 45.43 69.4 23.66 33.82 68.5 0.1 23 7 0.0 5 7 0 2 0 0 0 0 387 5 (ialu) So 3.47 0.48 1.25 3.41 1.8 0.88 1.03 6.2 0.3 . 6.2 0.0 . 2.2 . 1.6 . 0.0 . 0.0 . 70.4 N 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 COOL 3e MEAN 15.30 6.50 15.01 45.61 69.6 23.11 32.97 67.5 0.1 24.3 0.0 6.2 2.1 0.0 0.0 324.1 (H1011) So 2.85 0.35 0.91 3.05 3.2 0.69 1.04 7.4 0.3 7.3 0.0 3.1 1.4 0.0 0.0 79.4 N 17 17 17 17 17 17 17 12 12 12 12 12 12 12 12 17 N V COOL Lcf MEAN 10.21 6.93 17.33 47.60 68.6 25.01 36.46 61.6 5.9 26.9 0.3 4.0 1.5 0.0 0.4 438.0 (Pllu CuliTltut ) -- SI) 1.71 0.46 1.34 3.24 2.2 0.80 0.97 8.5 5.3 10.1 0.9 3 4 3 1 0 0 0.5 56 5 N 10 10 10 10 10 10 10 10 10 10 10 . 10 . 10 . 10 10 . 10 COOE 67 MEAN 12.91" 6.79 16.06"- 45.79 67.5 23.66®- 35.070- 67.6 3.2 23.2 0.3 3.8 1.8 0.0 0.1 2 76.4H- (1'NU) SD 2.72 0.55 1.40 3.62 -- 2.2 0.82 0.75 7.5 4.9 7.5 0.7 2.1 1.7 0.3 0.4 _ 84.5 N 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 o = statistically significantl higher (si) or lower (a-) than control value as measured by a student's t-test at p<0.05 6 =7= z9szOV()R
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M A M r.w~ r,.1 ~ .• ) ~ - -~ ~ ~ ~~l R A A A A TABLE 1 CON'T SUI91ARY OF HEMATOLOGY DATA AT 100 DAYS EXPOSURE SEG. BAND ATY. WBC RBC HGB HCT MCV MLH MCIIC NEUTRO NEUTRO LYMPH LYMPH MONO EOS BASO NRBC PLATELETS GROUP (X1Q/MM)(%10/MM) (G/DL) (X) (U) (UUG) (G/DL) (X) (%) (X) (X)(X) (X) (x) (1) (X1U/MM) CODE 33 (GOpTROL) CODE 13 (Lou) COUE 11 (MID) COOL 3[ , (iif6ii) ** ** ** ** DATA NOT COLLECTED AT BORRISTON !! DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON ** N - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - CODE 66 MEAN 9.50 7.05 16.85 47.58 66.2 23.92 35.40 67.2 0.0 27.3 0.0 3.3 2.2 0.0 0.0 360.0 (P1-10 COqTRUL) SO 1.26 0.34 0.79 1.46 4.1 0.71 1.02 11.3 0.0 9.3 0.0 2.0 2.5 0.0 0.0 97.9 N 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 CODE 67 MEAN 12.91g+ 6.91 16.41 45.808 66.4 23.53 35.80 67.9 0.1 25.0 0.0 4.8 2.4 0.0 0.0 358.3 (0140) Sq 2.18 0.64 1.51 4.01 2.5 0.78 1.08 9.5 0.3 8.6 0.0 3.1 2.1 0.0 0.0 60.4 N 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 s= statistically significantly higher (st) or lower (a-) than control value as measured by a student's t-test at p0.0S ** ** ** ** ** ** ** ** +.* 1'~GZAnVU9
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TABLE I CON'T _S_U_M_M_RY OF HEMATOLOGY DATA AT 1200 DAYS E3(P05URE SEG. BAND ATY. NBC ROC IIGB NCT MCY MCII MCMC NEUTRO NEUTRO LYMPN LYMPH MONO E0S 10550 NRBC PLATFLETS GROUP (X10/Mt4)(X10/MM) (G(DL) (X) (U) (UUG) (G/DL) (X) (X) (8) (X) (%) (%) (%) (%) (X107MM) CODE 33 MEAN 9.43 6.73 16.30 48.28 71.3 2_4.21 33.72 64.6 0.5 21.1 0.0 4.7 3.2 0.0 0.1 397.6 (CONIROL) SD 2.25 0.47 0.94 2.75 2.6 0.85 0.73 9.2 1.0 9.2 0.0 2.7 2.1 0.0 0.3 68.2 -- -~ N 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 MEAN 12.92 r 5.88 = 14.84 43.52'- 73.5°~ 25.22''~ 34.12 65.3 0.7 25.3 0.45+ 5.5 2.9 0.0 0.5' ~ 433.4 51) 3.12 0.54 1.29 4.52 2.8 1.02 1 .40 8 .3 1 .5 8 .3 0 .8 3 .0 2.3 0.0 0.7 76.6 N 28 28 28 20 28 20 __ 28 _ 28 _ 28 _ 28 _ 28 _ 28 _ 28 28 28 23 COOE I1 ME{IN 13.13'Sk 5.88` 14.64'S- 43.285- 72.9 24.815* 33.87 69.0 0.9 23.8 0.5'+ 3.2 2.6 0.0 0.5'+ 452.0 (MIU) SO_ 2.48 0.44 1.31 4.63 4.3 1.04 1.65 7.0 1.0 6.9 1.0 2_.7 2_.2 0.0 0.7 117.2 N 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 CODL 32 MEAN 11.405` 5.915- 14.175- 42.485- 71.3 23.92 33.35 67.5 0.9 23.2'+ 0.8 5.0 2.5 0.0 0.4 35L Z' ~ (111611) SD 1.88 0.49 1.40 4.06 2.8 0.97 1.46 4.8 1.1 5.2 1.6 2.8 2.0 0.0 0.8 79.5 t,.) N - 24 24 24 24 24 -24 24 24 24 24 24 -24 24 24 24 24 N I 1100 DAYS EXPOSURE COOL (8 MEAN_ - 8.78 6.78 16.61 49.25 72.1 24.46 33.68 71.4 0.4 22.5 0.1 2.9 2.7 0.0 0.1 373.6 (P1 •)OCONTIfUL) Sli 1.35 0.26 0.62 1.74 1.2 0.39 0.33 7.8 0.7 8.4 0.3 1.4 2.2 0.0 0.3 117.7 N ]0 10 10 10 10 ]0 10 10 10 10 10 30 10 ]0 10 10 COOE 67 MEAN 12.84'} 6.08'S 14.20'- 42.45° 69.3'- 23.30'- 33.40'- 72.6 0.2 22.0 0.0 2.6 2.6 0.0 0.4 290.5 (1410) SD 3.09 0.43 1.11 2.93 2.3 1.10 1.04 6.9 0.5 7.9 0.0 1.8 1.8 0.0 0.6 83.8 N 30 30 30 30 30 30 30 30 30 30 30 30 30 30 JO 30 -- - s= statist~al9y 31g-5i#71can-t-Ty-fifgher--5• or lower (s-) then control valun as measured by a student's t-test at p43.05 C: y J 4 . f'='1 :;i:- .._•1 r"~ A96z0t,0~
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11.J u ~..1 wj TABLE I CON'T SUM4ARY OF HEMATOLOGY DATA AT 1000 DAYS EXPOSURE WI1C RDC IIGB HCT MCV MCH MCHC SEG. NEUTRO BAND NFUTRO LYMPH ATY. LYMPH MONO EOS BASO NRBC PLATELETS GRUUP (XIO/r4M)(X10/MM) (G/DL) (X) (U) (UUG) (G/DL) (X) M (S) (S) (X) (%) (X) (X) (X10(t1T4) CODE 33 MEAN 11.17 6.74 16.25 44.23 65.3 24.08 36.67 68.1 0.9 25.5 0.2 3.7 1.7 0.0 0.5 342.7 (CONTROL) SU 3.89 0.59 1.56 3.51 2.5 0.93 1.33 6.7 1.1 7.3 0.5 1.9 2.0 0.0 0.8 55.8 N 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 CODE 13 MEAN 15.79°+ 6.17° 15.138- 42.418- 68.5a+ 24.50 35.69"- 70.8 2.00' 22.6 0.1 2.68- 2.0 0.0 0.5 404.38* (LOU) SO 3.93 0.41 0.95 2.87 3.6 0.79 2:07 7.0 1.5 6.4 0.3 1.6 1.4 0.0 1.0 71.9 N- -28 28 28 28 -28 28 28 28 28 28 28 28 28 28 28 28 COOE 11 MEAN 15.05" 6.07- 15.058- 42.45 69.5" 24.75"+ 35.47H 67.9 3.1"+ 24.0 0.4 2.9 1.6 0.0 0.9 466.2" (1410) SU 2.61 0 .49 1.29 3.82 3.7 0.71 1.87 8.5 2.5 -8:5 1.1 1.6 1.6 0.0 1.4 73.2 - - N- _ 32 32 32 - 32 32 32 32 32 32 32 32 32 32 32 32 32 ~ CODE 32 MEAN 14.34" 6.118- 15.078- 41.76e- 68.08" 24.65a+ 36.06 66.1 1.3 25.2 1.2" 3.2 3.08' 0.0 0.6 385.69± (Ilfcif) SD 3.18 0.53 1.18 2.86 3.8 0.65 1.97 6.8 2.2 6.8 1.9 1.8 2.5 0.2 1.0 8 3 .8 i N 25 25 25 25 25 25 25 25 25 25 _25 _25 25 25 25 _ _ 25 CODE 68 MEAN 9.55 6.61 15.84 47.05 70.9 23.92 33.60 63.3 0.0 28.9 0.0 4.1 3.7 0.0 0.3 284.0 (Po•10 CONTNOL) SD 1.41 0.44 1.02 2.55 1.9 0.70 0.56 8.4 0.0 8.6 0.0 2.3 2.8 0.0 0.7 29.7 N 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 CODE 67 MEAN 13,20" 6.22''- 14.89 43.715- 69.9 23.92 34.00 73.45* 0.7Sb 19.8'S- 0.45*' 3.8 1.9 0.0 0.5 225.6 (PMO) SO 2.57 0.53 1.34 3.56 2.2 1.18 1.07 6.6 1.1 6.6 0.7 2.2 1.6 0.0 0.7 58.8 N 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 e= statistically significantly higher (ae) or lower (a-) than control value as measured by a student's t-test at p<0.05 4 y9G,ZOtiUW
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.."r ra dM AM AM J" WA ,r" +r.or r..ri ma M A TABLE I COq'T SLO#IARY OF HEMATOLOGY DATA AT 800DAYSEXhOSURE NBC RBC HGB HCT MCV MCH SEO. BAND ATY. uNuuP (X1o[144)(X10/MN) (6(DL) (x) (U) (UUG) MCHC (6dDE) NEUTRO (z) NEUTRO LYMPH LYMPH MONO EOS BASO NRBC PLATELETS (x) (x) (z) (r) (x) (x) M (x1D/MM) CODE 33 (CONTROL) MEAN SD 10.35 7.12 2.01 0 68 16.71 46.81 1 35 65.6 23.47 ' 35.70 61.5 3.6 31.1 0.0 0 8 3 0 0 N . 36 36 . 3.70 36 36 2.1 0.84 0.69 10.3 2.6 10.9 0.2 . 1.3 . 2 5 .0 0 0 0.2 0 370.4 36 36 36 36 36 36 36 36 . 36 . 36 .5 36 68.5 36 CODE 13 (LOH) MEAN SD 16.938F 6.508- 4 28 0 69 15.32Q- 42.868- 1 79 66.0 23.56 35.75 69.4g~ 5.3 21.58- 0.38- 1 2 1 8 N . . 33 33 . 4.82 33 33 2.5 1.07 0._99 9.2 5.0 9.1 0.6 . 1.1 . 4 2 0.0 0.0 0.7 389.5 33 33 33 33 33 33 33 33 . 33 33 2.1 33 81.6 33 CODE 11 (MI0) MEAN SO 15.59"+ 6.178- 3 49 0 54 14.718- 41.31e- 66.88* 23.81 - 35.39 71.4" 4.6 20 3"- 0 1 2 8* a- N . . 35 35 1.33 3.66 35 35 2.4 0.69 3 0.98 9.3 4.4 . 6.0 . 0.2 .3 1.8 1.3 1 7 0.0 0 0 0.5 0 428.784 5 35 35 35 35 35 35 35 . 35 . 35 .8 35 71.1 35 CODE 32 (0I011) MEAN SD 14.50a' 6.14"- -2.69 0.58 14.328' 41.138- 1.30 3 51 67.O0t 23.33 2 6 0 87 34.79a- 0.7 69.68+ 3.8 23.98- 0.0 1.3 1.5"- 0.0 0 1 395 6 .o N 26 26 . 26 26 . . 0 8.8 4.2 9.8 0.0 1.5 2.2 0 0 . 0 . 26 26 26 25 25 25 25 25 25 . 25 .3 25 73.1 26 CODE 68 (P6IU CONTROL) MEAN SD 10.97 6.39 2.44 0 50 15.50 45.40 1 16 70.5 24.23 34.14 65.8 1.2 25.2 0.2 4 9 2 7 0 0 N . 10 10 . 3.86 10 1 1.3 0.41 0.69 10.3 1.9 8.2 0.4 . 4 1 . 2 6 . 0 0 0.1 . 384.0 0 10 10 10 10 10 10 10 . 10 . 10 . 10 0 3 10 141.5 (0 CODE 67 (51)0) MEAN SO N 11.83 6.35 2.20 0.52 34 34 15.40 45.41 1.28 3.50 34 34 71.1 24.20 2.8 0.81 33.82 1.12 68.6 8.8 1.6 1.7 22.8 8.7 0.0 0.2 4.9 2.6 2.1 2 2 0.0 0 0 0.4 351.9 34 34 34 34 34 34 34 34 . 34 . 34 0.9 34 63.5 34 a= statlstically s officantly higher (at) or lower (a-) than control value as measured by a student's t-test at p<0.05 S3EZOVOR
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SEG. BAND ATY. N8C ROC IIGB IICT MCV MCII MCNC MEUTRO NEIIIRO LYMPII LYMP11 MONO E0S BASO NRBC PLATFLETS GROUP (x10/IM/)(R10(MN) (G/OL) (z) (U) (uuG) (G/DL) (x) (s) (x) M Ix) (x) (z) (x) (x1olMM) CODE 33 MEAN 10.00 6.53 15.80 46.24 70.2 24.13 34.15 64.2 0.1 24.2 0.0 5.0 6.4 0.0 0.4 330.9 (Cng niOL) So 1:92 0.77 1.85 5.63 2.4 0.71 0.68 8.8 0.5 8.5 0.2 3.3 3.2 0.0 0.7 43.8 N 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 CODE 13 MEAN 15.00'+ 6.02'S- 14.385- 42.855- 70.6 23.86 33.54s- 71.7 s+ 0.5 s+ 19.BS- 0.5S+ 4.6 2.7 0.0 0.2 354.2 (LQW) SD 3.93 0.52 1.19 3.65 2.1 0.92 0.80 6.5 0.9 6.4 0.9 2.7 2.2 0.0 0.5 69.6 N 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 COOL 1I 1fEAN 14.B5'S+ 6.07S- 14.42s- 43.07 117 70.5 2 3.695- 33.42'S- 72.45+ 0.5S+ 20.0 0.55+ 3.4S- 3.25- 0.0 0.4 3i4.5'S- ..(MIU) SD 2.80 0.44 1.11 3.23 1.6 _ 0.66 0.42 7.1 0.7 6.5 1.0 1.5 2.2 0.0 0.8 117.9 N 28 28 28 28 28 28 28 28 28 28 28 28 28 28 29 28 CUDL 32 MEAN 13.085l~ 5.88s- 14.045 41.485- 70.1 23.83 33.81 71.45+ 0.3 22.7 0.1 2.3s- 3.1s- 0.0 0.3 314.0 ~ s~ (IIIGII) SD 3.31 0.52 1.20 3.60 1.8 0.75 0.85 5.9 0.8 6.0 0.3 1.5 2.8 0.0 0.6 89.9 w 11 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 CODL 68 (/1,li)-i:DNTIiOL) CODE 67 MEAN S0N MEAN ..(1'140) SO N s=-sl.atTs..ct~1-aTTy Tnificantly higher (s+) or lower (s-) than control value as measured by a student'i t-test at P~0.05 TABLE 1 CON"T SURfIARY OF HEMATOLOGY DATA AT 1400 DAYS EXPOSURE &7U[~.OYOR
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.:. ..j t.,_.J ._.1 +<. _1 .: .:J TABLE 2 SUMMARY OF PLATELET ADHESIVENESS AND AGGREGATION AT 0 DAYS EXPOSURE ADP 2X10 M COLLAGEN 0.26 MGfML GROUP % ADIIESIVENESS PRE EXI'OSURE % ADHESIVENESS POST EXPOSURE PRE EXPOSURE POST EXPOSURE (% AGGREGATION) (% AGGREGATION) PRE EXPOSURE (% AGGREGATION) POST EXPOSURE (% AGGREGATION) ~ ~ i CODE 33 (CONTROL) CODE 13 ..(LOW).. CODE 11 (MID) ODE 32 (111GH) MEAN SD N MEAN SD... N MEAN SO N MEAN SO N a DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON ATA NOT COLLECTED AT BORRISTON e CODE 68 MEAN 90.3 - 62.7 78.0 (PMO C T OL) SO 4.6 - 24.1 6.5 ON R N 6 0 6 4 0 CODE 67 MEAN 76.1 ' 75.1 - 77.2 (PM0) SO 14.2 - 16.9 - 8.1 N 18 -I 18 -1 13 -1 C-3 r" 1 EJ Y~
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WBC RBC 11GB IICT GROUP (x10/MF1)(x10/MM) (G/DL) (x) 16.17 48.20 0.97 3.11 23 23 14.385-43.045- 1.12 3.38 26 26 14.055-4130S- 1.27 3.81 27 27 14.005-41.805- 1.45 4.44 23 23 TABLE 1 CON'T SUPYIARY OF IIEINTOLUGY DATA AT 1500 DAYS EXPOSURE SEG. BAND ATY. MCV MCII MCIIC NEUTRO NEUTRO .. LYMPH LYMPH MONO E05 BASO NRRC PLATEIETS (U) (uuG) (G/0L) (x) (x) (z) (x) (X) (%) M (%) (R(0/MM) 71.2 24.00 33.51 68.8 0.1 24.4 0.0 2.3 4.4 0.0 0.4 359.6 2.4 0.79 0.44 6.2 0.3 4.6 0.2 1.7 3.4 0.0 0.7 17.4 23 23 23 23 23 23 23 23 23 23 23 23 71.4 24.00 33.37 69.3 0.3 24.8 0.1 2.8 2.55- 0.0 0.2 393.3s+ 2.5 0.76 0.47 8.2 0.7 6.4 0.4 2.2 2.3 0.0 0.4 40.9 26 26 26 26 26 26 26 26 26 26 26 26 70.7 23.90 33.59 72.9$+ 0.65+ 20.55- 0.1 3.1 2.9 0.0 0.1 358.5 2.0 0.75 0.39 6.9 0.7 6.8 0.3 2.1 2.3 0.0 0.5 112.3 27 27 27 27 27 27 27 27 27 27 27 27 70.3 23.68 33.47 69.8 0.3 23.0 0.0 3.4 3.4 0.0 0.2 412.8's+ 1.5 0.59 0.41 8.6 0.6 9.8 0.2 2.4 2.8 0.0 0.4 112.7 23 23 23 23 23 23 23 23 23 23 23 23 ~-s aT;flcally significantly higher (s+) or lower (s-) than control value as nteasured by a student's t-test at p<0.05 ~'~E„Z0~OR
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TABLE 2 CON'T SUMMARV 0F PLATELET ADNESIVENESS AND AGGREGATION AT - 200 DAYS EXPOSURE X ADIIESIVENESS % ADIIESIVENESS ADP 2810 M PRE EXPOSURE PO ST EXPOSURE COLLAGEN 0.26 MG(ML PRE EXP(1SURE POS1 EXPOSURE GRUUI' PRE EXPOSIIRE POST EXPOSURE _ (% AGGREGATION) (X AGGREGl1T10N) (% AGGREGATION) (% AGGREGAIION) CODE 33 (CONIROL) MEAN SO N a. DATA NOT COLLECTED AT BORRISTON ae CODE 13 MEAN 68.5 70.5 8 0.5 80.0 75.0 72.8 (LOU) SD 16.7 19.6 _ 6.8 8.0 0 1.6 N 4 4 4 4 1 4 CODE 11 MEAN 51.5 55.5 88.0 85.0 59.0 03.0 (MID) SD 19.1 7.8 2.8 4.2 26.9 4.2 N 2 2 2 2 2 2 ~ CODE 32 MEAN 64.3 62.0 66.5 68.0 10.5 63.0 ~ (IIICdI) SU 11.3 7.0 17.7 12.8 23.9 33.2 ~ N 4 4 4 4 4 3 COIIE 68 MEAN 58.5 56.9 70.0 75.3 58.0 68.0 (PMU CIINTROL) SD 15.2 6.5 12:8 6.6 2 1.8 5.3 8 8 8 8 _ 8 3 CODE 67 MEAN 74.9 76.6 74.1 76.4 55.8 45.4 ( PM(1) SD 8.3 7.8 20.8 21.8 18.3 21.8 N 17 15 15 14 12 I1 i t"r
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TABLE 2 CON'T SUMMARY OF PLATELET ADNESIVENESS AND AGGREGATION AT 100 DAYS EXPOSURE w rn CODE 13 MEAN (LOU) SD N CODF 11 MEAN (MID) SI) N CODE 32 MEAN (1I1G11) SD N ADP 2X10 M COLLAGEN 0.26 MG/ML x ADIIESIVENESS Z ADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE PDS1 EXPOSURE PRE EXPOSURE POST EXPOSURE (X AGGREGATION) (X AGGREGATION) (Z AGGREGATION) (X ACGRFGATION) CODE 68 (PMO CONIROL) COOE 67 MEAN SD N MEAN 0.8 (f'MU) SD 6.3 N 17 DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT 80RRISTON DATA NOT COLLECTED AT BORRISTON T-fIV( QYOR
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TABLE 2 CON'T SULHARY OF PLATELET ADIIESIVENESS AND AGGREGATIUN AT -- -- 800-DAYS EXPOSURE-- --- ADR 2Ri0_ M COLLAGEN 0,26 MG7ML X ADNESIVENESS - f ADIIESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE GRi,UP PRE EXPOSURE POST EXPOSURE (% AGGREGATION) (X AGGREGATION) (Y. AGGREGATION) (XAGGREGATION) CODE 33 MEAN 66.7 69.2 72.0 68.7 35.2 22.0 (C_OUFROL) SU 11.1 13.5 3.6 8.3 22.9 16.2 N 6 6 6 6 5 4 CODE 13 MEAN 62.7 66.7 62.6 67.7 59.3 53.0 (LOU) SO 11.7 14.1 6.4 8.2 8.1 12.5 N 7 7 7 7 6 6 COOL Il MEAN 48.1 48.8 69.0 69.4 59.8 57.0 (141U) SU 15.3 18.5 5.1 5.7 6.3 13.1 N 9 9 9 9 6 7 CODE 32 MEAN 64.5 66.5 66.9 63.6 52.0 52.0 a 0 (111G11) SD d 10.9 8 11.4 8 17.0 8 16.9 8 21.2 3 14.0 3 COOE 68 MEA N 53.1 54.1 57.8 61.3 62.6 61.3 (P1'10 CONTHOL) _ _ SI1 9.5 11.1 8.2 6.8 3.9 6.3 N 12 12 12 12 12 12 COOL 67 MEAN 51.6 52.4 38.2 40.7 44.1 56.6 (PIdU) SU 8.5 5.4 .8 16 22.3 20.5 14.1 N 14 14 _ 14 14 9 8 / I- -V- 3LV[.OKVR
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TABLE 2 CON'T SUMMARY OF PLATELET ADIIESIVENESS AND AGGREGAT1pN AT 1400 DAYS EXPOSURE AUP 2X10 M COLLAGEN 0.26 MGlML - GIIUUP X ADIIESIVENESS PRE EXPOSURE % ADIIESIVENESS POST EI(PqSURE PRE EXPOSIIRE (% AGGREGATION) POST EXPOSURE (X AGGREGATION) P_RE EXPOSl1RE (X AGGREGATION) POST EXPOSURE (X AGGIIEGATI(IN) CODE 33 MEAN 53.9 54.5 57.5 59.6 62.8 63.8 8 5 (CONTROL) 51) 10.6 • 10.4 4.5 10.8 7.4 . N 10 10 10 ]0 10 10 CODE 13 MEAN 46.4 54.7 59.0 57.9 69.6 67.8 4 (LOII) 58 12.5 12.3 18.0 23.3 14.0 1 .7 9 I N 9 9 9 9 9 CODE 11 MEAN 66.7 62.0 47.9 44.4 49.1 49.9 (MID) 50 9.4 13.5 16.7 7.8 15.1 13.4 N 7 7 7 7 7 7 CODE 32 MEAN 63.0 56.8 42.3 40.3 52.9 45.1 ~ . (HIGII) SO 8.5 13.0 13.8 8:1 9.6 9.6 W N II 8 8 7 8 8 CODE 68 MEAN (PMO CONTR01_) SD . ... ..__ __. N C_ODE 67 MEAN (I'Ml)) SO N '"~V(~O Yl/.~
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TAOLE 2 CON'T SUMMARY OF PL_ATELET ADHESIVENESS AND AGGREGATION AT 400 DAYS EXPOSURE ADP 2X10 M COLLAGEN 0.26 MG/ML % ADHESIVENESS x AOIIESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE GROUP PRE EXPOSURE POST EXPOSURE (X AGGREGATION) (X AGGREGATION) (S AGGREGAII(1N) (% AGGRCGATION) CODE 33 MEAN 78.4 80.6 72.8 68.6 75.8 72.3 (CONTROL) 50 8.0 8.6• 9.8 18.6 5.9 13.9 N 8 8 8 8 8 8 CODE 13 MEAN 79.3 77.6 70.0 66.3 72.2 74.0 (LOW) SD 9.5 7.8 13.6 22.2 20.5 8.7 N 10 10 10 10 9 9 CODE 11 MEAN 75.7 75.1 68.4 72.4 74.1 74.2 (M10) SO 7.8 6.1 17.1 15.0 6.7 5.7 N 10 10 10 10 9 10 CODE 32 ' MEAN 77.0 78.2 71.2 73.2 64.8 72.7 (IIlfN) SO 6.1 7.0 16.2 16.2 23.7 17.6 ~ w _ N 12 12 12 12 11 11 ~ CODE 68 MEAN 57.4 56.8 74.4 78.5 46.7 47.0 (PMO CONTROL) SD 9.2 5.7 7.2 10.8 26.9 25.3 N 8 8 g 8. 7 8 CODE 67 MEAN 61.5 64.6 68.4 67.9 58.7 49.3 (pM0) S() 12.3 10.8 8.0 17.8 16.5 22.8 N 14 14 14 14 9 8 ~~UZADYUR
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TABLE 2 C0N'T SUlfMRY OF PLATELET ADIIESIVENESS AND AGGREGATION AT 600 DAYS EXPOSURE ADP 2X10 M COLLAGEN 0.26 MG(ML % ADHESIVENESS % ADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE GRGUP PRE EXPOSURE POST EXPOSURE (% AGGREGATION) (X AGGREGATION) (% AGGREGATION) (X AGGREGATION) CODE 33 MEAN 76.2 79.4 77.0 77.5 68 3 63 7 (coin goL) w 9.4 9.7 11.3 12.9 . 21.8 . 24.5 R 10 8 10 8 10 6 CODE 13 MEAN 81.8 82.4 54.7 51.7 46.9 43.2 (LUI!) SD 6.9 7.8 14.4 15.0 15.1 20.0 N 9 7 9 7 7 5 CODE 11 MEAN 73.7 73.2 72.4 73.2 64.0 65.0 (IiIU) SO 9.1 10.6 12.0 11.6 20.2 17.9 N 10 9 11 10 9 8 COUE 3C MEAN 73.7 81.3 71.0 73.8 58.4 50.0 ~ (UIGB) SIl 11.7 6.4 3.2 7.5 13.8 21.0 N 10 10 9 9 8 8 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - CODE 68 MEAN 37.1 33.9 54.4 45.6 67.4 53.8 (1110 COWROL) SU 6.8 8.1 12.5 19.8 5.9 14.4 N 8 8 8 8 8 8 COUE 67 MEAN 52.7 50.8 66.8 63.6 69.6 70.5 (PHO) SD 8.1 6.9 11.2 10.5 8.5 4.8 N 13 13 13 13 13 13 i VLszoVOR
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TABLE 2 CON'T SLMMRY OE PLATELET ADHESIVENESS AND AGGREGATION AT 1000 DAYS EXPOSURE ADP 2X10 d COLLAGEN 0.26 MG{ML GRUUP % ADHESIVENESS PRE EXPOSURE % ADHESIVENESS POST EXPOSURE PRE EXPOSURE (% AGGREGATION) POST EXPOSURE (% AGGREGATION) PRE EXPOSURE (X AGGREGATION) POST EXPOSURE (X AGGREGATION) COUE 33 MEAN 58.7 64.7 72.7 70.3 76.3 75.3 (CUIITROL) SD 11.3 8.1 11.1 15.8 3.9 10.3 N 6 6 6 6 6 6 CUDE 13 MEAN 42.5 44.7 56.5 60.2 56.3 66.0 (LOU) Sf) 19.7 22.6 24.6 28.7 26.8 8.0 N 6 6 6 6 6 6 COUE 11 MEAN 59.0 57.3 69.0 71.8 71.1 72.3 (wIU) SU 10 .7 12:3 4:3 4.2 2.2 5.3 N _ 8 8 8 8 8 8 CUUL 31 MEAN 56.6 59.5 49.1 47.9 60.3 50.5 (III6U) SO 20.2 19.1 21.7 26.6 16.9 31.7 ~ ----- N-- 8 8 8 8 8 8 t? COUE 68 MEAN 52.5 43.3 30.4 28.9 43.9 41.8 (PI-10 COHINOL) SD 7.8 14.6 10.7 13.9 7.6 14.0 N 8 8 8 e n 8 COUE 67 MEAN 65.2 60.1 45.4 44.6 51.2 45.0 -(P11U)- SD 9.9 11.0 11.5 12.4 13.8 14.2 N 12 12 12 12 12 12 yf4E>v~~~~
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TABLE 3 SUMVIRY OF SERUM PROTEIN ELECTROPf10R_ESIS AT 0 DAYS EXPOSURE GROUP CODE 33 ALBUMIN (G/DL) R*_ ALPHA 1 (G/DL) ff ALPIIA 2 BETA (GfDL) (G(DL) DATA NOT COLLECTED AT BORRISTON GAMMA (G/DL) ** TOTAL GLOBULIN (G(OL) ** A:G RATIO ** (COIITROL) CODE 13 DATA NOT COLLECTED AT BORRISTON ** ** *e (LOW) CODE 11 DATA NOT COLLECTED AT BORRISTON *" ** ** (M1U) •CODE 32 *_* ±e DATA NOT COLLECTED AT BORRISTON ** *i ee (IIIGII) ~ CODE 68 MEAN 3.19 0.23 1.09 1.43 0.53 3.27 0.99 (Ph10 CONTHOL) . . SD 0.32 .. 0.06 0.13 .... 0.30 0.11 0.43 0.18 N 8 8 8 8 8 8 8 CODE 67 MEAN 3.25 0.29" 1.01 1.49 0.60 3.44 0.96 SI) 0.30 0.13 0.21 0.32 0.14 0.41 0.17 N 59 59 59 59 59 59 59 e- statistically significantly higher (a±) or lower (a-) than control value as measured by a student's t-test at ps0.05 C-m.11) EM =2 ORG(.O YO(3
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TABLE 3 CON'T SUMMARY OF SERUM PROTEIN ELECTBOPIIOR_ESIS AT ]00 DAYS EXPOSURE GROUP ALBUMIN (G(DL) ALPNA 1 (G/DL) ALPNA 2 BETA -(G/OL) (6(DL) GAMMA (G/OL) TOTAL G_LOBULiN (GEOL) A:G RAT10 CODE 33 .• ee DATA NOT COLLECTED AT BORRISTON .. .* .. (CORTROL) COOE 13 s. .. DATA NOT COLLECTED AT BORRISTON a .. .* (LOW) COIIE 11 (IqIU) I CODE 32 * DATA NOT COLLECTED AT BORRISTON ~ (111GH) DATA NOT COLLECTED AT BORRISTON CODE 6B MEAN 3.77 0.19 1.00 1.52 0.55 3.26 1.16 (PI•10 COUTHOL) 50 0_._23 - 0.03 0.09 0.22 - 0 .12 0.30 21 0 . N 6 5 5 5 _ 5 5 _ _ 5 CODE 67 ' MEAN 3.71 0.20 1.02 1.38 0.51 3.12 1.21 (f 110) SD . 0.33 0.05 0.15 0.19 • 0.12 0.33 0.20 N 54 54 54 54 54 54 54 e• staTls-t c l]yYTgntflcantly hlgher (e+) or lower (e-) than tontrol value as measured hy a student's t-test at p<0.05 C, TR6~nt,0~?
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„sn TABLE 2 C0N'T SUl141RT OF PLATELET ADIIESIVENESS AND AGGREGATION AT 1200 DAYS EXPOSURE ADP 2X10 M COLLAGEN 0.26 MG111L GRUUP X ADHESIVENESS PRE EXPOSURE % ADIIESIVENESS PRE EXPOSURE POST EXPOSURE (X AGGREGAiION) POST EXPOSURE (S AGGREGATION) PRE EXPOSURE (X AGGREGATION) POST E7lPDSURE (% AGGRTGA110N) CODE 33 MEAN 51.2 49.2 50.2 47.2 60.2 62.3 (CONTROL) so 13.4 11.6 12.5 12.6 12.4 3.7 N 6 6 6 6 6 6 CODE 13 MEAN 54.7 56.1 57.0 59.6 71.3 69.0 (LON) SD 15.5 16.6 11.6 12.9 3.9 6.5 N 7 7 6 5 4 4 CODE 11 MEAN 51.0 48.5 25.8 31.6 46.5 48.0 (MID) so 12.4 10.2 15.2 12.8 1.9 5.0 N 8 8 8 8 4 3 CODE 32 MEAN 47.6 47.3 48.4 51.6 61.3 59.3 (IIIGII) SD 13.0 15•1 17.7 11.9 8.2 8.0 v N 8 , 8 8 7 8 8 CODE 68 MEAN 54.8 57.9 1100 DAYS EXPUSU~ 27.5 26.4 42.4 42.9 ( PMt) COylR01 ) SI) 12.5 9.2 9.1 12.3 4.8 5.4 N 8 8 8 8 8 Il CODE 67 MEAN 57.3 59.8 38.3 35.3 57.1 50.55' (PMO) SD 7,9 7.5 12.8 8.5 5,4 8.8 N 12 12 12 12 12 12 s=stat{s[~ca-signlficantly higher (s+) or lower (s-) than control value as measured by a student's t-test at p<0.05 ls G6ZAnVUR
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TABLE 3 CON'T SUMMARY OF SERUM PROTEIN ELECTROPNORESIS AT 200 DAYS EXPOSURE GROUP ALBUMIN (G/DL) ALPIIA I (G/DL) ALPIW 2 BETA (G/DL) (G/DL) GAMM (G/DL) TOTAL GLOBULIN (G/DL) A:G RATIO CODE 33 .. DATA NOT COLLECTED AT BORRISTON es (CONIROL) CODE 13 MEAN 2.94 0.23 1.14 1.43 0.58 3.39 0.88 (LOW) SO 0.32 0.04 0.20 0.20 0.13 0.37 0.16 N i8 18 18 18 18 18 18 ! ~ CODE 11 MEAN 2.97 0.24 1.20 1.38 0.58 3.41 0.88 i (19I0) SD 0.26 0.04 0.16 0.16 0.15 0.33 . 0.13 1 N 17 17 17 17 17 17 17 I ~ CODE 3e MEAN 3.11 0.23 1.16 1.33 0.62 3.36 0.93 J (FIGII) 50 0.37 0.03 0.13 0.16 0.24 0.30 0.15 ~ N 17 17 17 17 17 17 17 CODE 66 MEAN 3.53 0.21 1.14 1.54 0.51 3.39 1.08 (PM0 CONTROL) SO 0.42 0.06 0.19 0.31 0.10 0.53 0.27 N 7 7 7 7 7 7 7 •CODE 67 MEAN 3.35 0.19 1.02 1.36 0.55 3.17 1.08 (f'I10) SD 0.32 0.05 0.16 0.18 ~ 0.14 0.55 0.18 N 56 56 56 - 56 - 56 56 56 e- statistically significantly higher (e+) or lower (a-) than control value as measured by a student's t-test at p<0.05 6 j ZlV(.eOVVC3
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TABLE 3 CON'T SIJp#1ARY OF SERIR9PROTEIN ELECTROPNORESIS AT _ ____ .. . .. . 1000 DAYS EJ(ROSURE GROUP ALBOMIN (GlDL) ALPNA 1_ (G/oL) . ALPIIA 2 (G/OL) BETA (G/DL) GAFi4A (G/OL) TOTAL GLOBULIN (G/DL) A:G RAT10 - CODE 33 MEAN 3.24 0.18 0.99 1.67 0.61 3.45 0 97 (LONTROL) 5D_ 0.22 0_._09 - 0.21 0.37 0.12 0.52 . 0.19 N 24 24 24 24 24 24 24 CODE 13 MEAN 3.079 0.308k 0.99 1.79 0.79H+ 878i 3 0 81"- (LOw) - sU 0_.25 0.16 0_.21 - 0.38 0.27 . 0.63 . 0.15 N 28 28 28 28 20 28 2II CODE 11_ M10 MEAN 3.30 0.25e+ 0.93 1.78 0.858+ 3,81®f 0,89 ( ) SD 0.42 0__.14 0.27 0.32 - 0.28 0.56 0.20 N 32 32 32 32 32 32 32 ~ COQE 3E MEAN 3.21 0.21 0.94 1.56 0.10 41 3 0 99 a n (NIGO) SD 0.24 0.07 0.16 0 36 0.28 . 61 0 . 20 ~-~ N 25 25 25 . 25 25 . 25 0. 25 CO DE 68 MEAN 3.67 0.23 1.15 1.34 0.75 3.47 1.07 _ (P110 CONTNOL) 5D 0.36 0.17 0,13 0.27 0.23 0,34 0.19 - _ N 10 -10 10 10 -10 ]0 10 CODE 67 MEAN 3.43 0.43' 1.09 1.5157 0.85 3.94'+ 0.88'- (RMO) SD 0.25 0.21 0.26 0.19 0.16 0.33 0.10 N 31 31 31 31 31 31 31 s• sr.atlstically signtficantly htgher (®+) or lower (s-) than '.ontrol value as measured by a student's t-test at ps0.05 t. 9~Gzot,o~
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i Al in A A .n .7 ZI .M z A A A__A_ R x TABLE 3 CON'T SUMMARY OF SERUM PROTEIN ELECTROPHORESIS AT 800 DAYS EXPOSURE GROUP ALBUMIN (G/DL) ALPHA I (G/DL) ALPIIA 2 (G[DL)_ BETA (G(UL) GAMMA (G/DL) TOTAL GLOBULIN (GfDL) A:G RATIO CODE 33 MEAN 3.17 0.16 1.08 1.71 0.54 3.54 0.92 (CONiROL) SD 0.26 0.02 0.18 0.32 0.14 0.51 0.18 N 36 36 36 36 36 36 36 CODE 13 MEAN 2.868 0.20et 1.12 1.67 0.75°} 74 3 0 784- (LON) SD 0.36 0.04 0.23 0.30 0.26 . 0.50 . 0.16 N 33 33 33 33 33 33 33 CODE 11 MEAN 2 90"- 8, °+ (MID) SO . 0.28 0.18 0.03 1.18 0.17 1.66 0.25 0.73 0.20 3.76 0.44 0.78"- 0 13 N 25 25 25 25 25 25 . 25 ~ CODE 32 MEAN 2 95- 19H* 8- . 0. 1.03 1.51 0.65 3.39 0.88 o (H1G11) SU 0.28 0.03 0.13 0.25 0.23 0.48 0.14 i N 27 27 27 27 27 27 27 CODE 68 MEAH 3.46 0.31 1.25 1.54 0.76 3 87 0 91 (PH0 CONTROL) S_0 0.49 0.16 0.24 0.24 0.20 . 0.56 . 0.14 N 10 10 10 10 10 10 10 CODE 67 MEAN 3.12 0.28 1.020- 1.44 0.76 3.50 0 90 (FMO) SD_ 0.27 0.12 0.16 0.22 0.15 0.32 . 0.12 N 34 34 34 34 34 34 34 e- stattsttcally significantly higher (e+) or lower (a-) than control value as measured by a student's t-test at p<0.05 53; VRfiZQV()q
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I TABLE 2 CON'T SUMIARY OF PLATELET ADIIESIVENESS AND AGGREGATION AT 1500 DAYS EXPOSURE ADP 23(10 M COLLAGEN 0.26 MGIML GRUUP i ADIIESIVENESS PRE EXPOSURE % ADIIESIVENESS POST EXPOSURE PRE EXPOSURE (S AGGREGATION) POST EXPOSURE (X AGGREGATION) PRE EXPOSURE (X AGGREGATION) POST EXPOSURE (% AGGREGAIION) CODE 33 MEAN 56.7 59.3 46.7 42.8 49.2 42.5 (CONTROL) SD 11.3 • 10.7 19.0 16.0 3.3 10.2 N 6 6 6 6 6 6 CODE 13 MEAN 56.3 51.2 30.2 33.3 43.5 46.3 (LON) SD 7.6 9.9 10.1 12.4 6.4 8.6 N 6 6 ~ 6 6 6 6 CODE 1I MEAN 56.0 55.5 32.3 29.7 47.3 41.0 (MID) SD 9.1 6.3 12.5 6.8 9.4 6.5 N 6 6 6 6 6 6 CODE 32 MEAN 52.3 57.4 29.0 31.4 43.5 47.8 (IIIC41) SD 8.1 9.6 9.2 10.2 8.2 11.2 N 8 8 8 8 8 8 CODE 69 MEAN (PMO CONTROL) SD . . ...... . . N CODE 67 MEAN (PMO) SD N i G I ,p4f;ZnVUf3
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I ._.~ .-J=MMAAJ!~ AAR TABLE 3 CON'T SUMMARY OF SERUM PROTEIN ELECTROPIfORE515 AT 400 DAYS EXPOSIIRE --- --- ' GROUP CODE 33 EAN ALOUMIN (G/DL) 3.51 ALPIIA 1 (G/DL) 0.19 ALPHA 2 (G/DL) 1.00 BETA (G/DL) 1.47 (G/DL) 0.57 TOTAL GLOBULIN (G/DL) 3.25 A:G RATIO 1.13 (COIITROL) SD 0.33 0.05 0.15 0.36 0:17 0.59 0.29 N 26 26 26 26 26 26 26 CODE 13 MEAN 3.22°- 0.21 1.04 1.47 0.688" 3 39 0 981- (LQy) sll 0.32 0.09 0.17 0:28 0.21 . 0.47 . 0:22 N 45 45 45 45 45 45 45 CODE 11 MEAN 3.11"- 0.18 1.04 1.42 0 59 23 3 0 988- (I11D) SD 0.24 0.06 0.14 0.23 . 0.18 . 0.41 . 0.17 N 46 46 46 46 46 46 46 CODE 31 MEAN 3.330= 0.19 1.06 1.34 0.54 3.13 . 1.08 (111611) SU 0.28 0.09 0.17 0.18 0 16 0 38 0 19 c:o N 44 44 44 44 . 44 . 44 . 44 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - CODE 68 MEAN 3.23 0.17 1.08 1.57 0.66 3.48 0.93 (P1 10 CONTRDL) 50 0.10 0.02 0.17 0.17 0.13 0.26 0.09 N 4 4 4 4 4 4 4 CODE 67 P MEAN 3.028- 0.23g} 1.24 1.73 0.64 3.81 0.80 ( 40) 50 0.40 0.13 0.16 0.32 0.20 0.50 0.11 N 29 29 29 29 29 29 29 a- staTTstlcally significantly higher (ar) or lower (.-) than control value as measured by a student's t-test at p<0.05 I qszoVOR
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ENS rn APR .~ mmmmm AM,MM TABLE 3 CON'T SU6TOIRY OF SERUM PROTEIN ELECTR_0_PNORESIS AT 600 DAYS EXPOSURE GROUP ALBUMIN (G/DL) ALPHA I (G/DL) ALPIIA 2 (G/DL) BETA (GIUL) GAbTUI (G(DL) TOTAL GLOBULIN (GfDL) A:G RATIO CODE 33 MEAN 3.29 0.22 1.04 1.67 0.64 3.58 0 94 (CONTROL) s0 0.25 0.05 0.20 0.36 0.11 0.58 . 0 16 N 25 25 25 25 25 25 . 25 CODE 13 MEAN 3.60e# 0.188 1.04 1.58 0.69 3.47 1.06 t (LOW) SU 0.40 0.04 0.22 0.35 0.19 0.61 0.22 N 37 37 37 37 37 37 37 COOE 11 MEAN 3.35 0.22 1.210" 1.73 0.74" 3.91" 0.87 (1•11D) SD 0.34 0.05 0.10 0.27 0.19 0.46 0.13 N 41 41 41 41 41 41 41 CODE 32 MEAN 606' 3 ® e- g " 1. (H1G_N) SD . 0.49 0.10 0.06 1.02 0.14 1.40 0.23 0.63 0.22 3.24 0.44 1.13 + 0.22 u7 N 33 33 33 33 33 33 33 CODE 68 MEAN 3.32 0.26 0.79 1.57 0.78 3.39 0 98 (%90CONIROL_) SD 0.22 0.13 0.26 0.12 0.20 0.20 . 0 08 N 10 10 10 10 10 10 . 10 CODE 67 MEAN 3.36 0.20 1.088± 1.52 0.58e- 3.39 1 02 (ri~o) sD 0.40 0.11 0.21 0.27 0.18 0.47 . 0.25 N 37 37 37 37 37 37 37 s- statistically sig-nTfTc-antly higher (.+) or lower (e-) than control value as measured by a studeat's t-test at p<0.05 i V17GZA1/ V0C3
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TABLE 3 CON'T SUMIARY OF 3ERI1t1 PR0iE1N ELECTROPIIORE315 AT 1500 DAYS EXPDSURE GRUUP ALBl1MIN (G/DL) ALPIUI 1 (G/DL) ALPIUt 2 (G/DL) BETA (0/DL) GAM1A (G/DL) TOTAL G_L080LIN (G/UL) A:G RATIO COOE 33 NEAN 3.43 0.37 , 0.95 1.46 0.71 3.49 1.01 (LUU1kUL) SD 0.31 0.16 0.14 0.33 0.20 0:51 0:22 N 23 23 23 23 23 23 23 CUUf L3 MEAN 3.24 0.265- 1.08St 1,68 0.88s+ 3.90St O.B7S- (LOU) S0 0.39 0.10 0.19 0.46 0.27 0.77 0.25 N 26 26 26 26 26 26 26 COUE I1 MEAN 3.11~ 0.29 1.06 1.49 0.90~f 3.75 0.865- (i+10) 50 0.39 0.14 0.20 0.19 0.25 0.42 0.18 N 21 27 27 -27 --27 27 27 i CODL 3'[ MEAN 3.Ois- 0.43 1.05 1.59 0.935+ 3.99S+ 0.185 01 (111GI1) SU 0.32 0.23 0.16 0.31 0.36 0.69 0.18 1 N 23 23 23 23 23 23 23 LOI1E 68 MEAN (PI•I(1C011INOL) SD- N COOL 67 MEAN _(ih41)) SD N a~ statlstlcally slgnlflcantly htgher (et) or lower (a-) than control value as aea;ured by a student's t-tezt at P<0.05 . . . .. .. .. _._.. ... . _ . . .. , .. . .. ... _ 4.?.=9 G~L~~ YU~
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TABLE 4 SLRWIRY 0E_ CLINICAL CHEMISTRY DATA AT 0 DAYS EXPOSURE .~.. .r.... .1=.. ... GROUP BUN (MG/DL) GLUCOSE (MG/DL) CREATININE (F1G/UL) CHOLESTEROL CALCIUM (MG(DL) (MG/DL) PHOSPHORUS (MGfDL) SGOT (MU/ML) SGPT (ML1lML) TOTAL PROTEIN (G/DL) CODE 33 DATA I10T COLLECTED AT BORRISTON (CONIROL ) CODE 13 !+ ** ** DATA NOT COLLECTED AT BORRISTON ~r ** ** (LDw) COOE 11 .. DATA NOT COLLECTED AT BORRISTON r. *. *. (MID) CODE 32 ** .. .* DATA NOT COLLECTED AT BORRISTON ** a .. (111GI1) rn CODE 68 MEAN 14.35 108.38 0.86 176.93 10.74 4.02 20. 11 32.81 6.46 (P6.10 COIITROL) ~ - --....... SU 2.80 8.31 0.15 32.07 0.68 0.53 . 4.27 21.29 0.47 N 8 8 8 B 8 8 8 8 8 CODE 67 MEAN 15.79 108.48 0.75 159.99 10.47 3.75 27.07 38.73 6.70 (('110) SD 4.35 11.52 0.10 24.89 0.57 0.54 8.19 19.77 0.44 N 58 52 58 59 56 55 55 50 59 e- statistically sfgnlflsantly higher (at) or lower (s-) than control value as measured by e student's t-test at p<0.05 ossZoVoR
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A= ax rJL k:.1 L-i, r.._..k 23C=Z='r - ~!!N TABLE 3 CON'T SU?MRY OF SERUM PROTEIN ELECTROPIN)RESIS AT 1200 DAYS EXPOSURE _ - ALDUMiN ALPN1 1 ALPIIA 2 BETA GAlf9A TOTAL GLOOIILIN A:G RA110 I;RUUf' (G/DL) (G/DL) (GlDL)_ (G/DL) (G/DL) (GfUL) COQE 33 MEAN 3.13 0.26 t 1.05 1.56 0.82 3.68 0 86 (CONIROL) SD 0.31 0.09 0.16 0.31 0.17 0.46 . 0 15 N 23 23 23 23 23 23 . 23 CODE 13 MEAN 3.11 0.26 1.11 1.64 0.86 3.86 84 0 (LOw) s0 0.31 0.12 0.23 0.36 0.26 0.67 . 20 0 N 28 28 28 28 28 28 . 28 COOE 11 MEAN 03 3 21S- 0 (111U) SDN . 0.26 . 0.04 1.10 0.16 1.57 0.18 0.82 0.16 3.69 0.34 0.83 0.12 32 32 32 32 32 32 32 CODE 32 MEAN 23 3 S+ 0 3 cn N (n1cn) Su N . 0.27 24 . 8 0.21 24 0.98 0.18 24 1.43 0.37 24 0.76 0.27 24 3.55 0.57 24 0.93 0.16 24 1100 DAYS EXPOSURE CODE 68 MEAN 3.43 0.36 1.06 1.55 0.78 3.75 93 0 (PMO CONINOL) SD 0.46 0.15 0.16 0.30 0.14 0.43 . 0.21 N 10 10 10 10 10 10 10 CUUL 67 MEAN 3.10 0.30 0.96 1.54 77 0 3 57 88 0 (1110) SON 0.22 0.13 0.19 0.26 . 0.13 . 0.32 . 0.13 29 29 29 29 29 29 29 - statistically significantly higher (a+) or lower (s-) than control value as neasured by a student+s t-test at p<0.05 I r,RGzQVoR
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TABLE 3 CON'T SUMMRY OF SERUM PROTEIN ELECINOPI(OR_ESIS AT 1400 DAYS E%POSORE -- LI2UUp CODE 33 EAN ALBUMIN (cfoL) 3.26 ALPIIA 1 (G/DL) 0.38 ~ ALPIIA 2 (c/oL) 1.02 BETA (GlDL) 1.54 GAMMA (c/oi) 0.72 TOTAL GLOOIILIN (G7DL) 3.67 A:G RATIO 0.91 (CUNIRUL) 50 0.25 0.18 0.28 0.25 0.16 0.54 0.15 N 23 23 23 23 23 23 23 CUIIE. 13 MEAN 3.28 0.39 1.14 1.785f 0.91Sr 4.225+ 80'- 0 (U Ou) --~--- SD 0.42 0.23 0.19 0.51 0.25 0 78 . 0 19 N 26 26 26 26 26 _._ 26 . 26 CDUE 11 MEAN 3.41 0.285- 1.215{ 1.62 0.85so. 3.955+ 0.87 (MIU) SD 0.51 0.13 0.19 0.22 0.19 0.44 0.15 N 28 28 28 28 28 28 28 CODE 32 I MEAN - 3.475+ 0.36 1.19st 1.67 0.86S+ 4.085+ 87 0 in (II C,II) SO 0.23 0.16 0 27 0.28 0 23 0.59 . 0 16 w I N 23 23 . 23 23 . 23 23 . 23 CODE 68 MEAN (PMO-CURINIIL) SD_ N CUDE ti7 MEAN (Im11)S(fN 7 .= sFatlstlcally ;Ignlflcantly higher (e±) or lower (a-) than control value as measured by a student's t-test at p<0.05 4 RRGzoVoR
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r~.J . ~.....! w..-.1 _ TA8LE.4 CON'T S_UiRAARY OF CLINICAL CHEMISTRY DATA AT 600 DAYS EXPOSURE GROUP BUN (MGlDL) GLUCOSE (MG/DL) CREATINIME (MO(DL) CHOLESTEROL (MG/DL) CALCIUM (MG/DL) PHOSPHORUS (MG/DL) SGOT (MUfML) SGPT (MU/ML) TOTAL PROTEIN (G/DL) CODE 33 MEAN 20.10 96.24 1.17 146.30 10.24 3.86 33.20 59.52 7.06 (CONiROL) 50 8.06 13.02 0.31 29.54 0.41 0.94 8.80 18.11 0.66 N 25 25 25 25 25 25 25 25 25 CODE 13 MEI1N 18.76 94.19 0.92®' 159.44 ]0.00®- 4.36®~ 33.78 45.35®- 6.91 (LON) SD 4.30 15.76 0,27 28.17 0.41 0.70 12,93 19.43 0.73 N 37 37 37 36 37 37 37 37 37 COQE 11 MEAN 18.20 96.98 1.06 157.12 9.998 4.24 30.35 47.438 7.22 (1110) 51) 5.19 14.50 0.33 34.27 0.42 0.72 13.17 12.13 0.54 N 40 41 41 39 41 41 40 41 41 CODE 3Y MEAN 17.52 97.06 0.87s' 163.71g+ 10.06 4.27 33.24 44.52"' 6.56H' ,,., (HIGH) SU 4.76 16:85 0:33 2_7:64 0_;34 0:67 13.40 12:80 0:45 n N 33 33 33 33 32 32 33 33 33 CODE 68 MEAN 14.60 114.80 0.84 1 84.50 9.03 3.57 22.00 61.80 6.74 (Pb10 CONTROL_) S6 2.63 11.32 0.13 _ 2_6.50 0.35 0.45 4.71 2_8.50 0.31 N 10 10 10 ]0 10 10 10 10 l0 CODE 67_ MEAN 15.92 108_86 0.75 172.43 8.90 3.96 41.22Br 59.19 6.78 (Ph10) 50 6.34 17.08 0.34 28.10 0.48 1.27 39.47 13.54 0.42 N 37 37 37 37 37 37 37 37 37 s~ stattst1fally significantly M gher (a+) ar lower (e ) than control value as moa;ured by a student'a t-test at p<0.05 ) :~J a~.Ta ~- l16~\/ Y'l/ ~)
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i MM MM M M J" M - W-4 , - p"" TABLE 4 CON'T SUMMARY OF CLINICAL CIIEMISTRY DATA AT 800 DAYS EXPOSURE GROUP BUN (MG/DL) GLUCOSE (MG/DL) CREATININE (MG(DL) CHOLESTEROL (MG/DL) CALCIUM (MG/OL) PHOSPHORUS (MG/Dl.)- SGOT (MUfML) SGPT (MU/ML) TOTAL PROTEIN (G(DL) CODE 33 MEAN 17.88 89.08 0.97 151.92 10.25 4.00 26.33 45.13 6.72 (CDtITROL) SD 4.00 12.99 0.15 29.37 0.69 0.68 6.84 21.75 0.49 N 24 24 24 24 24 24 24 24 24 CODE 13 MEAN 16.79 85.30 0.94 157.88 10.32 4.13 36.308' 48.45 6.61 (LOW) Sb 5.13 10.96 0.13 28.01 0.49 0.75 15.50 19.87 0.47 N 33 33 33 33 32 33 33 33 33 CODE 11 MEAN 17.40 94.32 0.94 162.72 10.24 4.07 33.360' 55.92 6.67 (MID) SD 3_.79 9.41 0.13 47.90 0.64 0.63 14.49 64.10 0.50 N 25 25 25 25 24 25 25 25 25 orn 0 CODE 32 (HIGH) MEAN SD 17.63 5.55 96.528* 12.39 --- 0.91 0.15 -- 145.85 33.62 10.06 0.40 3.82 0.56 37.52g± 20.43 45.19 19.90 6.34" 0.55 N 27 27 27 27 26 27 27 27 27 CODE 68 (PbIO COH11tU ) MEAN 15.60 122.00 0.87 168.00 10.60 4.75 72.00 57.60 7.35 L SD 3.72 7.89 0.12 31.38 0.59 0.54 47.79 11.31 0. 88 N 10 10 10 10 10 10 10 10 _ 10 CODE 67 MEA14 16.71 104.97 0.86 162.94 9.465- 4.49 39.35 46.715- 6.645- (1T'10) - SD 4.37 14.01 0.10 36.99 0.66 0.53 8.95 16.50 0.41 N 34 34 34 34 34 34 34 34 34 a- statlstically stgnTflcantly higher (ar) or lower (s-) than control value as measured by 4 student's t-test at p<0.05 C 3 t. J rI SfiFic"".0 VUg
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6. TABLE 4 CON'T SUlTNRY OF CLINICAL CNEMISTRY DATA AT 100 DAYS EXPOSURE GROUP BUN (MG/DL) GLUCOSE (MG/DL) CREATININE (MG/DL) CHOLESTEROL CALCIUM PHOSPHORUS (MG/DL) (MG/DL) (MG/DL) _ SGOT (MU/ML) SGPT (MU/ML) TOTAL PROTEIN (G/DL) CODE 33 (CONTROL) CODE 13 (LDU)- CDDE 11 (MID) ~ CODE 32 cn (HIGH) rn i .. •r .+ • .. ~ DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON •4 R ~3 , +* ~• e ~ • CODE 63 (P910 CONTROL) MEAN SIl 24.67 106.33 0.60 189.18 10.20 4.63 19.17 48.33 6 80 N 4.59 6 9.07 0.07 22.17 0.17 0.80 4.31 9.54 . 0.19 6 5 6 6 6 6 6 5 CODE 67 (PMO) MEAN 16.900- 100.19 0.66 165.10e- 10.01g- 4.16 32.308' 45 71 6 438- SD N 6.44 54 13.95 0.09 27.65 0.32 0.67 -6.08 . 19.02 . 0.29 54 54 54 54 54 54 54 54 ®- statistically significantly higher (e+) or lower (a-) than control value as measured by a student's t-test at p<0.05 tF,GZ0V08
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sir AN r 4M TABLE 4 CON=T SUMMARY OF CLINICAL_ CHEMISTRY DATA AT 400 DAYS EXPOSURE GROUP BUN (MG D GLUCOSE CREATININE CHOLESTEROL CALCIUM TOTAL / L) (MG/DL) - (MG/DL) - (MG/DL) (MG/DL) PNOSPNORU_S (MG/Dl) SCOT (MUIML) SGPT (MU/ML) PROTEIN (G DL CODE 33 (CONTROL) MEAN SD 19.71 5 82 105.73 0.75 157.29 10 64 / ) N . 26 10.64 0.12 28.11 . 0 35 3.34 32.04 53.21 6.72 26 25 26 . 12 0.69 12 8.72 2 21.71 0.41 4 26 26 CODE 13 MEAN 23.58"+ 94.00 0 71 (LON) SD 8 84 3 . 159.14 10.218- 28e+ 4 N . 45 1 .32 45 0.10 23.34 0.38 . 0 67 32.35 25.90"- 6.60 45 45 44 . 45 31.17 45 13.51 44 0.42 45 CODE 11 (14 MEAN 18.46 104.09 0 1D) SD 5.93 .72 160.25 10 39 er 4 N 46 9.95 46 0.07 46 26.05 46 . 0.53 .53 0.87 37.38 23.67 34.16® 26.08 6.39H- 0.35 46 46 ~ cn CODE 32 I/IGN ( ) MEAN SD 19.00 5 28 102.59 0.608- 157.92 10 43 e+ ~ r N . 44 13.65 44 0.09 32.65 -- . 0.53 4.19 0 87 36.32 38.§58= 6.53 44 44 44 . 23.08 16.23 0 44 - - - - - - - 44 44 44 . 44 - - - - - - - - - - - - - - - - COOE 68 (H4U CONT80L) MEAN SD 12.50 2 52 101.00 0.85 174.25 8•75 3 38 N . 4 7.57 0.06 21.50 - 0 2 . 0 43 31.00 53.25 6.75 4 4 4 . ~ . 12.9~ 13.05 0.17 4 4 CODE 67 MEAN 17.21"+ 94 76 e+ (fYdO) SO 3.83 . 12 41 0.97- 150.59 10.22"+ 54 3 9 N 29 . 9 0.16 22.44 -0.70 . 0 61 2 .72 41.03 6.84 2 29 29 29 . 5.62 ]0.72 0.77 29 29 ® e stattsticrtly slgnlflcantly higher (e+) or lower (a-) than control value as measured by a student's t-test at p<0.05 4 t CL)G"V MOi7
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Y .~1 .m ~i in is 1'~ ~ :~ ,~ a~ ~ ~ .~ TABLE 4 CON'T SII!T_1ARY OF CLINICAL CIIEMISTRY DATA AT 200 DAYS EXPOSURE GROUP BUN (MG/DL) GLUCOSE (MG/DL) CREATININE (MG/DL) CHOLESTEROL CALCIUM PHOSPHORUS (MG/DL) (MG[DL) (MG/DL) SGOT (MU/ML) SGPT (MU/ML) TOTAL PROTEIN (G/DL) CODE 33 (COIIIROL) es rr •r DATA NOT COLLECTED AT BORRISTON ±r rr CODE 13 MEAN 17.22 95.19 0.75 179.44 10.11 4.03 26.81 39.20 6.33 (LOW) SO 4.31 16.80 0.15 31.00 0.69 0.52 8.57 18.15 0.37 N 18 10 18 18 17 18 16 18 18 CODE 11 MEAN 16.37 99.61 0.82 179.76 10.42 4.03 42.02 39.42 40 6 (111D) SD 3.92 9.71 0.11 33.46 0.61 0.53 28.79 18.09 . 0.40 N 18 18 15 17 17 17 17 18 18 CODE 32 MEAN 14.94 108.03 0.78 181.50 10.08 3.66 31.12 33.56 6.41 ~ (IfIGH) SD 3.46 10.45 0.10 24.83 0.41 0.65 7.30 7.12 0.33 N 17 17 17 17 17 17 17 17 17 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - CODE 68 MEAN 16.57 109.29 1.24 160.36 9.77 3.61 26.43 45.79 7.15 (PFIO CON11tOL) SD 3.64 14.30 0.41 21.04 0.30 0.48 7.50 11.04 0.68 N 7 7 7 7 7 7 7 7 7 CODE 67 MEAN 17 44 10 96 848' 0 148 06 9 86 4 30af 8- (P110) 50 . 4.43 . 11.83 . 0.29 . 23.25 . 0.54 . 0.80 28.31 10.63 55.97 15.82 6.44 0.50 N 52 53 56 53 53 53 52 53 56 e- statistically significantly higher (e+) or lower (e-) than control value as measured by a student's t-test at p<0.05 "-`f;C;[' l / voC7
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TADLE 4 C_ON'T 5_1_R_tM_ RY OF CLINICAL CIIENISTRY OATA AT - - 1400 DAYS EAPOSURE GNUI/I' BUN (MG/Ol) GLUCOSE (MG/Dl) C_REATININ_E (-MG/DL) CIIOLESTEROL (MO/UL) CALCIUM (MG/DL) PIIOSPIIORUS (MG/DL) SGOT (MU/ML) SGPT (MU/ML) lOIAL PR01[IN (/:{Ill ) C001 33 MEAN 16.52 104.57 0.97 158.48 ]0.08 4.27 45.65 63.52 6.97 (CUliluOL) Sli 3.68 15.14 0.15 31.20 0.80 0:48 8.13 17.83 0.52 N 23 23 23 23 23 23 23 23 23 EUOL 13 MEAN 15.69 1 14.815} 0.95 163.46 ]0.31 4.53 40.12 52.355- 7.52Sr (lln+) 50 3.51 _ 14.80 0.10 25.25 0.87 0.50 8.98 15.39 0.82 N 26 26 26 - 26 26 26 26 26 26 CIIOI II NEAN 18.68 117.865+ 0.865- 173.75 10.10 . 4.52 46.86 57.32 7.39Sr (Idl(l) SU 7.40 12.13 0.14 60.09 0 . 55 0.99 14.84 13.71 0 .70 N 28 28 28 28 _ _ 28 28 28 28 _ 28 GUU1 72 MEAN 18.43 116.525~ 1.05 168.26 10 14 4.45 47.39 57.74 7 58'* (Illl.l1) 38.. 6.54 ]0.38 0.20 84.26 . 0.74 0.87 11.06 12.71 . 0.55 N 23 23 23 23 23 23 23 23 23 CUIII 6d (R(IU CQI111111L) MEAN 50 60111 67 N 11E05 (IY10)- SDa a-- statlstlcally slgnltlcantlY hl9her (a+) or lower (a-) then cantro) value as eeasurea oY a students t-test at p<0.05 4.
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.a~ .rd Awr Aoa a~ MM Am ,:~' ) I tJ ALL M M M TABLE 4 CON'T SURMWRY OF CLINICAL CHEMISTRY DATA AT 1000 DAYS EXPOSURE GROUP BUN (MG/DL) GLUCOSE (MGJOLj CREATININE (MG/DL) CHOLESTEROL_ (MG/DL) CALCIUM PHOSPHORUS (MG/DL) (MG/DL) SGOT (MU/ML) SGPT (MU/ML) TOTAL PROTEIN (G/DL) CODE 33 MEAN 15.96 112.17 0.78 160.21 8.88 3.82 39.25 59.50 6.72 (CONTROL) 50 4.11 10.38 0.17 19.94 0.43 0.79 22.86 13.98 0.43 N 24 24 24 24 24 24 24 24 24 CODE 13 MEAN 16.93 107.14 0.75 164.54 8.86 3.79 33.21 63.32 6.96 (LOW) SD 5.22 18.29 0.14 26.09 0.46 0.80 11.11 32.82 0.57 N 28 28 28 28 28 28 28 28 28 COOE 11 MEAN 17.28 104.008 0.78 171.87 8.77 3.91 81 34 55 13 13~t 7 _ (MID) SD 5.29 13.59 0.11 36.82 0.31 0.67 . 15.15 . 16.41 . 0.45 N 32 32 32 32 32 32 32 32 32 CODE 32 ~ MEAN 14.00 96.48e 0.79 163.00 8.72 3.64 32.56 54.24 6.71 (DIGII) 51) 3.43 13.58 0.12 49.33 0.33 0.57 8.38 14.82 0.52 N 25 25 25 25 25 25 25 25 25 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - CODE 68 MEAN 21.00 119.00 0.06 175.00 10.40 5.06 36.70 78.20 7.16 (P110 CONTkOL) SD 4.52 9.94 0.13 22.48 0.91 0.89 16.89 88.97 0.38 N 10 10 10 10 10 _ _10 10 10 10 CODE 67 MEAN 18.58 110.32 0.91 170.48 10.45 4.84 46.81 68.39 7.39 (FMO) SD 4.15 18.21 0.09 54.15 0.56 0.75 10.10 18.93 0.46 N 31 31 31 31 31 31 31 31 31 a- statistically slgntficantly higher (s+) jr lower (a-) than control value as measured by a student's t-test at p<0.05 ==i ~,z 9ClG(iOVQR
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TA_BLE 4 C_ON'T SUMMARY OF CLINICAL CIIEMISTRY DATA AT 1500DAYS EXPOSURE GNllU1' BUN (H(-,711L) GLUCOSE (MG7DL) CREATININE CIpLESTEROL (MGlOL)-(MGfDI)- CALCIUN (MG7DL) PHOSPHORUS (MO7DL) SGOT (MUlML) SGPT (MU7N1.) IUTA1. PIt01LIN (f/UI) CoDE 33 MEAN 19.91 102.17 0.89 157.61 10.43 4.78 40.61 65.00 6.95 (CiD11tOl) SD 4.90 14.37 0.16 25.40 0.82 0.59 13.11 14.91 0.38 N 23 23 23 23 23 23 23 23 23 CUUL 13 MEAN 21.00 113.27sf 0.92 160.96 9.96s- 4.70 32.50'S- 49.125- 7.17 _ (i0u) SD 4.72 12.57 0.16 25.30 0.68 0.51 9.24 17.48 0.57 N 26 26 26 26 26 26 26 26 26 COOL 11 MEAN 20.11 106.85 1.10S+ 167.59 9.83S- 4.60 40.59 53.07s- 6.94 (rflU) SD 4.95 14.02 0.19 65.15 0.68 0.97 15.21 12.32 0.42 N 27 27 27 27 27 27 27 27 27 cOUL 3[ HEAN 18 78 57st 114 0 83 161 52 9 82S- 4.335- 73.96 49.55"- 7.03 i rn A i (iilril) SD N . 4.80 23 . 9.28 23 . 0.12 23 . 63.18 23 . 0.68 23 0:55 23 -_ 23 11.81 22 0.53 23 CODE 6d MEAN (It1U (0111N0L) SD N CUUE 67 MEAN (1710) $D N a- statistically significantly higher (a+) or lower (a-) than control value as measured oy a student's t-tesc at pe0.05 I Gf6Z0V0R
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TABLE 4 CON'T Sl_MNRY OF CLINICAL CIIEMIST_R_Y DATA AT 1200DAYS EXPOSIIRE - GIitAIP @UN (MG/DL) GLUCOSE (MG/nL) CREATININE --(MGlDL) CIqLESTEROL (M9/OL) - CALCIUM (MG/OL) P_I_10SPIIURUS (MG/Dt) SGOT (MU/ML1 SGPT (MU/ML) TOTAL PR0ILIN (/:/bl) CUOE 3.1 MEAN 14.00 112.96 0.91 156.30 9.24 3.90 35.35 63.04 6.83 (Ciil~]N01) SD" 3.71 22.91 .09 0 2_7.93 0.97 0.48 10.55 23.38 0.38 N 23 23 _ 23 23 23 23 23 23 23 COUE 13 MEAN 15.39 97.685- 0.845- 190.54 9.27 4.415< 35.57 56.25 7.00 (tbu) SD 4_.82 17.72 0.10 8fi.25 0. 90 0.72 15.08 28.50 0.58 N 28 28 28 28 _ 28 28 28 28 28 COpI 11 MEAN 15.16 112.62 0.855 160.31 9.48 4.23 39.97 46.665- 6.75 (wIU) SD 3.02 10.93 0.09 42.54 0.78 0.75 16.35 12.52 0.32 N 32 32 32 32 32 32 32 32 32 t C00L 32 MEAN 14.33 107.29 0.87 159.58 9.32 4.29St 38.17 48.045 6.80 ~ N (il(w0) so 4.33 11.52 0.20 52.56 0.62 0.49 8.69 12.15 0.60 N 24 24 24 24 24 24 24 24 24 - ---------------------------------------------------------------------------------------------------- ----------------------------- 1100 DAYS EXPOSURE Cool 6d MEAN 22.00 121.50 1.02 160.50 9.94 4.24 31.00 50.40 7.20 (Iaiu EuUIItuL) SO 4.64 11.32 0. 11 34.52 1.29 0.74 8.86 6.08 0.45 N 10 10 _ 10 10 10 10 10 10 10 COUE 67 MEAN 17.285 103.45~ 0.94 163.45 9.66 4.00 36.59 52.28 6.695- (rrwu) SD 3.53 12.96 0.13 36.53 0.54 0.60 6.52 18.79 0.26 N 29 29 29 29 29 29 29 29 29 .- statlstlcally significantly higher (.r) or lower (a-) than control value as Aeasureo oy a student's t-tesc at p<0.05 C /"sszoVOR
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TABLE 5 CON'T SUMIARY OF pULMONARY MEASUREMENTS AT 400 DAYS EXPOSURE ARTERIAL BLOOD GASES N2 MAS/IOUT VOL. TO CLOSING VITAL PHASE III MINUTE 0211B 118 C011B P PCO2 P02 2% N2 Vq~LUME CAPACITY SLOPE VOLUME GROUP (X) (61100 ML) (X) (MM 116) (hTl HG) (ML) (ML)- (X) (MLlKG) (% N2fL)(MLIMINfKG) CODE 33 MEAN 93.30 16.77 0.15 .7.43 27.54 89.41 5653.87 177.08 17.9 84.06 10.31 261.12 (CONTROL) SD 1.60 1.26 0.34 0.03 4.12 13.06 675.21 53.77 4.6 14.86 1.68 --- 101.75 N 25 25 20 25 25 25 24 24 24 24 24 24 E.ODE 13 MEAN 93.18 14.55a 1.11°r. 7.388- 32.898+ 96.35 6679.488+ 216,07er 21.8®; 84.79 13.82e+ 277.17 Lou) 50 1.41 2.07 0.54 0.04 4.59 15:09 929.82 65.20 6.1 16.26 5.05 79.12 N 42 42 42 42 42 42 42 42 42 42 42 42 CODE 11 MEAN 92.54 15.68a 1.10e+ 7.398- 30.75°r 90.20 7080.978{ 189.25 18.2 87.07 15.82®+ 304.78 (MI D ) SD 2.26 1.05 0.52 0.05 4.28 14.58 1309.39 70.91 6.0 15.84 7.-47 112.61 _ _ N 42 42 38 42 42 42 42 40 40 42 42 42 COOE 32 MEAN 92.34 15.64Q 1.188+ 7.408- 33.54e+ 92.63 7059.768t 195.90 19.3 84.69 14.38$+ 247.45 (111GFi) SD 3.41 1.27 1.07 0.04 5.14 16.21 1832.41 59.01 5.2 15.80 5.44 81.60 N 40 41 38 40 40 41 41 39 39 41 41 41 Orn 0, CODE 68 MEAN 94.86 16.67 1.61 7.41 31.10 80.08 6390.80 254.00 23.6 84.75 8.05 286.64 (PMO CONIROL) SD 2.68 0:61 0.16 0.03 1.70 13.94 1584:71 82.09 6.5 7.96 1.80 92.61 N 10 10 10 ]0 10 10 10 10 10 10 10 10 CODE 67 MEAN 92.06 15.97H 2.07 ~ 1.41 30.79 77.17 6949.09 283.49 26.9 88.58 12.008' 372.708* (PM0) SO 4.14 1.42 1.06 0.05 3:b9 12.63 1205.51 98.49 7.3 12.38 4.20 112.73 N 46 46 44 46 46 46 46 43 43 46 46 46 1 - - s~ statlsttcally stgntftcantly hlgher (..) or loyer (a-) than control Value as lnessured by rt student's t-test at p< .05 r'1 C :'l t~ 1 EnU~O~~b?
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I in M M M a,~ rf _J ~_1 ~~ .~~ TABLE 5 CON'T SUMMARY OF PULMONARY MEASUREMENTS AT 100 DAYS EXPOSURE .1m im +m ARTERIAL BLOOD GASES N2 WASHOUT VOL. TO CLOSING VITAL PHASE 111 MINUTE 02HB HB COIIB PI1 -M2 P02 2% N2 V L M CAPACITY SLOPE VOLUME GROUP (S) (G/100 ML) (X) (MM HG) (MM HG) (ML) M X (ML/EG) (X N21L)(ML/MIN/KG) ~ ~ CODE 33 (CONIROL) CODE 13 (LOW) CODE 11 (MID) COUE 32 (HIGH) .r .. . .. •r . .. . DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON DATA NOT COLLECTED AT BORRISTON •r f-f •• •. *R ee rr f! e+ .. rf --_- CODE 68 MEAN 91.23 11.00 1.22 7.42 32.63 81.15 7521.28 213.33 20.7 79.57 7.83 245.07 (PM0 CONTROL) SO 3.01 0.33 0.58 0.02 2.45 14.32 1810.82 79.41 7.5 9.70 1.17 94.48 N 6 4 6 6 6 6 6 6 6 6 6 6 CODE 67 MEAN 91.48 16.311" 1.23 7.40 31.23 83.82 6677.28 229.80 22.8 89.06 13.138+ 309.29 (PH0) SO 2.49 1.54 0.77 0.03 3.71 8.75 1094.96 95.88 7.1 17.18 --- 6.47 120.85 N_ 50 50 49 50 50 50 49 50 50 50 50 50 p- statlstlcally slqnlflcantly higher (a+) or lower (a-) than control value as measured by a student's t-test at p<0.05 R to0eoVoe
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in im " m m =,~-3 l ---~ :J = m m M M A M M TABLE 5 CON'T SUTtARY OF PULMONARY MEASUREMENTS AT 200 DAYSEXPOSURE~~~~~~ N2 WASHOUT ARTEjjAL BL00D GASES VOL. TO CLOSING VITAL PHASE III MITIUTE 02HB IIB COIIB PH PCO2 -PO2 2% N2 V0 UM CAPACITY SLOPE VOll1ME GROUP (x) (G/100 ML) (Y) (MM HG) (MM NG) (ML) ML n% (ML/kG) (X N2/L) (ML/MIII/KG) CODE 33 (CONTROL) r* r• rr •r rr u DATA NOT COLLECTED AT 80RRISTON •• •• CODE 13 MEAN 91.66 15.12 2.03 7.43 26.19 96.64 6744.12 125.83 12.8 87.27 19.83 254.42 (LOW) SU 3.30 1.03 0.30 0.04 4.75 13.12 1419.70 50.54 4.8 10.99 10.59 88.55 N 18 18 18 18 18 18 17 12 12 18 18 18 CODE 11 MEAN 93.11 15.36 1.89 7.44 27.86 95.66 7343.89 142.73 12.9 95.28 19.84 290.19 (M1D) SU -- 1.18 1.25 0.31 0.05 3.22 7.94 1980.66 46.50 3.6 • 18.44 7.42 99.59 11 17 18 18 17 17 17 18 11 li 18 18 18 CODE 32 MEAN 93.31 15.01 1.79 7.47 26.49 87.91 7713.53 186.43 16.7 100.29 11.56 243.82 (HI68) SU 1.53 91 0 0.48 0.06 4.66 10.31 2422.06 87.32 6.4 15 38 4 53 101 41 rn N 17 . 17 17 17 17 17 17 14 14 . 17 . 17 . 17 CODE 68 MEAN 91.50 17.10 1.06 7.41 30.61 72.76 5455.41 303.33 27.2 89.92 8.39 296.42 (P140 CONIROL) SD 3.85 1.37 0.45 0.03 3.49 13.47 889.09 58.74 4.7 12.83 2.33 122.51 N 9 8 9 9 9 9 9 9 9 9 9 9 CODE 67 MEAN 92.35 16.12 1.18 7.40 32.16 81.95 6305.18gt 246.04023.6 89.68 12.948r 304.20 (M10) §D 2.62 1.39 0.57 0.04 3.56 11.80 1075.60 92.29 7.1 15.07 6.04 83.96 N 53 51 50 53 53 53 51 53 53 53 53 53 a- statlst1ca11y significantly higher (a+) or lower (a-) than control value as neasured by a student's t-test at P<0.05 aOCoVoR
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I r°r 01" ~ i.a a-- . ~ __J -d rL-4 .ls" _iw .111111111111 .IM im Am a TABLE 5 CON'T SUMMARY OE PULMONARY MEASUREMENTS AT 600 DAYS EXPOSURE ARTERIAL BLOOD GASES N WASINNIT - VUL. T0 OSING CL VITAL PIIASE III MINUTE 0211B IID PRE POST PCO POg 2% N; _ CAPACITY SLOPE VOLUME GROUP (E) (G/100 ML) C0110 (i) C0118 (X) p'1 (MN I~G) ~ (MN 116) (MLI TML % (ML/KG) (X N,/L) (ML/MIN/KG) COUE 33 MEAN 92.07 16.65 1.04 - 7.40 32.74 81.52 5988.89 222.69 22.9 83.45 10.29 260.08 (CONTRO[) SD 2.69 1.40 0.61 - 0.02 2.31 11.05 1210.74 77.54 5.3 16.16 3.39 95.77 N 26 26 25 - 26 26 26 26 26 26 26 26 26 COUE 13 MEAN 92.81 15.42S- 1.56s+ - 7.41 32.33 84.81 6011.41 220.56 22.3 85.64 13.68Sf 265.34 (LOII) SD 1.99 1.10 0.49 - 0.03 3.00 11.47 1006.10 80.96 7.1 15.40 5.48 71.52 N 36 36 36 - 36 36 36 36 36 36 36 36 36 CODE 11 MEAN 92.28 15.63S- 1.62S+ - 7.41 30.475- 78.67 6510.32 218.25 21.9 85.06 15.31St 269.40 (MIU) SO 2.38 1.09 0.69 - 0.03 2.65 8.91 -- 1115.45 84.39 6.7 16.40 6.62 75.15 N 40 40 26 - 40 40 40 40 40 40 40 40 40 I CODE 32 NEAN 92.32 15.705- 1.47$; - 7.41 33.01 80.58 6505.51 206.36 19.85- 83.21 13.87st 301.47 m (il1GII) SD 2.19 1.25 0.59 - 0.03 3.03 10.01 1433.56 84.10 6.1 14.72 5.26 108.23 ~ N 33 32 19 - 33 33 33 33 33 33 33 33 33 CODE 68 MEAN 97.27 16.75 2.17 1.77 7.34 37.73 86.63 5745.80 214.44 19.3 88.28 8.90 301.65 (PH0 SU 1.98 0.72 0.49 0.17 0.10 3.29 12.89 831.73 94.88 9.0 17.61 2.72 74.92 CDNTROL) N 10 10 10 10 10 10 10 10 9 9 10 10 10 CODE 67 MEAN 92.89'S- 16.41 1.485~- 3.455k 7.39 35.55 79.43 6957.97'S+ 267.58 25.0 89.77 14.085} 314.60 (PI•q) S0 5.79 1.49 0.55 1.40 0.07 3.17 13.69 1126.29 82.24 6.4 16.53 7.55 95.74 N 37 37 37 37 37 37 37 37 33 33 36 37 37 ---- S- statistically signlficantly higher (5*) or lower (S-) than control value as measured by student's t-test at p<0.05 . r lJV COVQ9 4 0
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ar.u rU fl^0 - - SUt~MAR - - TABLE 5 Y OF PULMONARY MEASUREMENTS AT - -- 0 DAYS EXPOSURE ~..,1 ,Z N2 WASIIOUT I• -.~ ARTERIAL BLOOD GASES VOL. TO CLOSING VITAL PHASE III MINUTE - 02110 COIIB I'N PC02 P02- 2% N2 VOLUM CAPACITY SLOPE VOIUt•1E GROUP (4) (G1100 ML) (x) (MM IIG) (MM IIG) (ML)(ML) X (ML/KG) (% N2(L) (I1L/MIM(Y.G) (.... 1 CODE 33 (CONTROL) AM DATA NOT COLLECTED AT BORRISTON f• CODE 13 (LOW) •+ •~ •A •• DATA NOT COLLECTED AT BORRISTON •• •• •• ff CODE 1I •• ~4 •• •• DATA NOT COLLECTED AT BORRISTON •* •t •r (1110) CODE 32 ~ (HIGH) •+ te •• ~r DATA NOT COLLECTED AT BORRISTON ~s (31 Ln CODE 68 MEAN 94.96 15.59 0.70 7.43 25.50 102.29 5787.00 184.00 17.8 88.48 8.15 205.09 (P1d0 CUNiROI.) SD 0.92 1.10 0.13 0.03 2.69 10.60 953.61 56.02 4.3 12.26 1.06 44.01 N 10 10 6 10 10 10 10 10 10 10 10 10 CODE 67 MEAN 92.87° 15.41 1.690+ 7.396- 24.28 102.90 6227.62 190.00 18.1 92.99 8.61 228.16 (I740) SD 3.24 1.23 0.56 0.04 3.66 8.98 1719.64 81.56 6.3 16.20 2:58 99.61 N 61 61 58 61 61 61 61 55 55 61 61 61 a- statlsttt411y slgntftcantly higher (s+) or lower (a-) than control value as measured by a student's t-test at p<0.05 000COVUR
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TABLE 6 GROSS NECROPSY FINDINGS CODE -33_ 11 - 13 _ 32 _ _. 68_ 61 EYE Papilloma on lower lid 1 Ovoid focus on cornea 1 Corneal opacity 1 1 White raised area on cornea 1 SALIVARY GLAND Congested 2 Left, shrunken 1 Firm 1 Enlarged i THYROID Clear cys_t 3 ~ Enlarged 2 3 1 .P Small 1 Round borders 1 White pinpoint foci 1 3 3 1 1 Firm 1 Raised white area 1 White discoloration 1 HEART Enlarged 3 2 Coronary arteries accentuated or distended 2 3 1 Bicuspid value thickened Walls thickened 2 2 3 1 2 Dark red areas I Pale yellow areas or discoloration 2 Yellow streaks on wall I Discoloration of the muscle of the wall 1 4 White areas 1 Pinpoint hemorrhagic foci _ I Distended and irregular in shape 1 S0JepvpB
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_ - - . -- - ,._. i ..,J -J „_;~ .t...~ .C_ .~ .- .~ _ ~ - TABLE 5 CON'T . SUMMARY 0F PUL1pHARY MEA3UREMENTS AT 1200 DAYS EXPOSURE ARTERIAL 6(,000 GASE& N NASIIOUT - - - - VOL TO CLOSING VITAL PHASE 11I MINUTE 02118 IIR PRE POST PCO2 POg . _ 2% N; CAPAC/TY SLOPE VOLl1ME GROUP (%) (G/100 NL) COIID (X) C0110 (%) pH (MM IiG) (MM 116) (BL+ ML -(% (ML/KG) (f NZ/L) (MLfMIN/KG) COOE 33 MEAN 95.72 16.30 2.08 1.95 7.41 36.35 82.24 5386.66 161.81 18.4 79.57 12.50 2_97.07 (CUNTROL) SD 3.43 0.94 0.31 0.24 0.07 5_.41 13.22 1013.74 87.65 10.2 22.42 3.82 56.10 N 24 23 23 23 24 24 24 24 16 16 24 24 24 CODE 13 MEAN 96.38 14.865 1.695 4.685+ 7.41 37.72 87.73 6199.335' 176.67 16.4 85.25 13.12 89.39 2 (LOII) SD 2.44 1.31 0.42 1.34 0.04 3.87 11.98 1069.56 8 3:63 7.5 ]fi.91 5.64 _ 75.17 N 26 21 27 27 26 26 26 27 __ 21 21 26 26 27 CODE 11 MEAN 95.29 14.705 1.075 5.095~ 7.39 38.67 83.45 6721.485* 221.18 19.1 86.67 14.77 343.415* (M10_) SD 4.48 1.28 0.47 3.00 0.07 4.49 12.61 1 39 5.20 113.79 8.3 19.17 5.88 89.99 N 31 31 31 31 31 31 31 _ _ 31 17 17 31 31 )1 i CODE 32 MEAN 93.02 14.175- 1.755 3.645+ 7.40 3 8.17 77.51 6328.00~~ 203.57 17.0 90.27 13.06 337.46 N (IIIGN) Sp 6.02 1.40 0.72 1.47 0.05 _ 4.14 14.79 1523.64 ]05.36 8.3 18.40 5.44 111.34 ~ N - 24 24 24 24 20 23 23 - 24 14 14 23 24 24 1100 DAYS EXP05URE CODE 68 (PNO MEAN 70.63 16.77 2.25 2.20 7.45 33.12 56.56 6426.70 206.67 19.2 82.53 7.43 288.37 0061801) SD 15.86 0.44 0.45 0.33 0.08 3.73 8.50 1445.13 03.22 7.0 15.83 1.66 60.99 N 9 6 10 10 9 10 10 10 9 9 10 10 10 COIIE 67 MEAN 82.71 14.20~ 2.14 4.635~ 7.40 32.35 66.845~ 6632.07 210.00 19.3 89.30 10.855~ 2E4.18 (P1K1) SO 14:28 1.11 0.58 1.01 0.15 4.25 9.35 1327:06 56.17 4_.1 20.23 5.11 85.12 H 30 30 30 30 30 29 29 30 • 23 23 30 30 30 -- --- - 5 e statlsticaily significantly higher (S}) or /oper (S-) than contcol value aS measured hy atudent's t-test at p<0.05. f^ i [:`~ rkr ~ ~ r- .4OJCOt'Q~
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d.r om TABLE 5 CONIT SUMMARY OF PULMONARY MEASUREMENTS AT 1000 DAYS EXPOSURE ARTERIAL BL00D GASES N NASIN)UT 02110 1i8 PRE POST PCO P0 ~ VOL. T0 2% N CLOSING ~f~LI1ME VITAL CAPACITY PHASE III SLOPE MINUTE YOLIIME crsoUP (%) (G/100 ML) COIIB (~) COIIB (f) pH (1Nf h1G) (!M 1 16) ; (MLI ,_, ____ (ML)-- - -(3) (MI/K6) (T N2/L) (ML/r41_N/KG) CODE 33 MEAN 93.11 16.25 1.59 1.76 7.37 33.62 79.40 5782.16 211.11 20.2 86.27 10.47 314.57 (CDNTROL) SD 4.19 1.56 0.49 0.88 0.09 4.47 17.30 963.78 86.56 6.3 17.99 3.41 105.07 N 24 24 24 24 24 24 24 24 18 18 24 24 24 CODE 13 r4EAN 94.18 15.135- 1.86 5.905+ 7.32 34.68 82.66 6558.595" 201.40 19.6 83.93 15.BOS+ 291.70 (LDII) SD 3.15 0.95 0.52 1.96 0.19 3.06 10.25 1040.86 62.31 5.2 17.10 7.05 90.84 N 28 28 20 28 28 28 28 29 25 25 28 28 29 C_ODE 11 _ MEAN - 93.17 15.055- 1.62 4.57S11 7.35 35.21 83.56 6741.56Sf 185.93 17.2 87.85 15.23S* 330.94 (M1I7) SIY 6.03 1.29 0.60 1.59 0.07 3.56 14.52 1273.49 56.72 4.6 17.94 7.88 110.10 N - 32 32 32 32 32 32 32 - 32 27 27 32 32 32 ~ CDDF 32 MEAN 94.83 15.07'S- 1.72 4.O8S+ 7.39 34.94 88.0554 6365.36 221.50 20.0 86.97 14.645+ 344.82 ~ (III(II) SD 3.32 1.18 0.60 1.13 0.08 3.39 10.23 1396.20 91.44 6.3 15.71 6.65 92.63 ~ N 24 25 25 25 24 24 24 25 20 20 25 25 25 CODE 68 MEAN 78.05 15.84 1.97 2.11 7.41 35.85 72.16 6118.10 261.25 22.0 93.35 7.75 249.69 (PMII SD 16.77 1.02 0.46 0.39 0.11 4.15 15.57 1183.56 80.97 6.3 16.31 1.93 124.06 CONTROL) N 10 10 10 10 10 10 10 10 8 8 10 10 10 CODE 67 MEAN 95.OOS` 14.895 2.09 4.435+ 7.41 37.20 88.49`{ 7339.625+ 247.20 22.4 89.01 13.975+ 322.39 (PPq) SD 3.72 1.34 0.76 0.69 0.06 5.17 17.47 1695.71 80.70 5.7 18.63 5.51 86.52 N 32 31 31 31 31 32 32 32 25 25 32 32 32 S= statistically si9nificantly higper (S*) or lower (S-) than control value as measured by gtudent'3 t-test at p<0.05. f = 900COVOR
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M M M :®1 M M M TABLE 5 CON'T SUMMARY OF PULMONARY MEASUREMENTS AT 800 DAYS EXPOSURE ARTERiAL BL000 GASES N wASNOUT 0211B IIB PRE POST PCO POz VOL. TO 2t N CLOSING VITAL CAPACITY PHASE 11I SLOPE MINUTE VOLl1ME GROUP (X) (0!100 ML) C0118 (Z) COIID (t) DIl (MM AG) (MM116) (MLI ML X. (MLfNG) (X N11L)(ML(111N/kG) CODE 33 MEAN 94.35 16.75 0.83 0.95 7.41 32.26 79.26 5296.55 - 204.09 20.8 81.37 10.18 275.72 (CONLROI) SD 3.27 1.34 0.80 0.89 0.04 4.64 10.71 968.36 77.81 6.7 14.07 2.50 113.89 N 24 24 23 22 24 24 24 24 22 22 24 . 24 24 COOE 13 MEAN 93.57 15.32'S- 1.50'5+ 5.47s+ 7.41 31.70 74.85 7100.585+ 185.19 18.2 83.25 13.115* 332.52 (LOU) SD 3.69 1.77 0.95 2.28 0.03 4.08 9.99 1952.75 77.73 6.1 15.54 5.49 121.10 N 33 33 28 32 33 33 33 33 27 27 33 33 33 CODE 11 MEAN 92.01S- 14.78'S- 1.50s; 4.345+ 7.41 31.17 74.42 7020.505+ 204.85 19.7 84.73 14.965* 331.75 (MID) 50 5.20 1.29 1.30 2.11 0.04 3.34 15.52 1446.61 72.07 -4:9 13.98 5.34 130.29 N 34 34 32 33 34 34 34 34 33 33 34 34 34 CODE 32 MEAN 92.92 14.46$- 1.53 5.565} 7.42 30.99 75.84 6959.528t 225.00 20.6 85.65 14.585r 343.46 (111G11) SO 4.37 1.25 0.89 1.93 0.04 4.49 13.24 1616.14 63.00 4.5 14.76 7.01 134.91 0 N 24 25 24 25 25 25 25 25 22 22 25 25 25 CODC 68 MEAN 95.60 15.50 1.60 1.28 7.40 40.82 85.91 5568.00 244.00 22.2 84.86 9.40 293.75 (Prio 50 2.33 1.16 0.29 0.44 0.03 5.44 7.78 859.48 86.49 8.7 12.80 3.78 90.15 CONTROL) N 10 10 10 10 10 10 10 10 10 10 10 10 10 CODE 67 MEAN 95.14 15.40 1.83 4.6957 7.40 36.21S- 81.18 6248.91 244.21 22.0 89.17 12.31 319.61 . (I'pp) SD 4.32 1.28 0.67 3.36 0.04 4.03 14.45 1189.52 87.58 7.0 18.76 5.48 110.87 N 36 - --34 ----- 34 34 36 36 36 36 19 19 35 35 36 S= statlstically s19nTficantly higher (S*) or lotrer (5-) than control value as measured by student's t-test at p<0.05. a'OOCOVUR
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i1 TABLE 6 CON'T GROSS NECROPSY FINDINGS HEART - CON'T Left A.V valve thickened at luminal surface Large masses in ventricles Pericardium hemorrhagic foci Possible parasite on outside surface LUNGS Soft white streaks Small lobe(s) Atelecsis Dark red or dark red foci All lobes dark green Enlarged Right apical and/or left cardiac lobes white purulent covering Bright red spotting Grey firm raised area Red discoloration White lobes or white area(s)/foci (areas) Consolidation Small pinpoint cyst or nodules Firm granular area, some raised Black foci Firm or rough granular white or grey area Firm lobes Firm nodule or nodule(s), some raised Adhesions Scar-like area with firm consistency Pinpoint dark red foci Greyish-white (areas) Cyst-like areas Reddened or blue areas or foci Congested Firm areas, some clear NoJule(s) Greenish-or greyish-brown discoloration CODE _3_ .11_ 13 12 68 1 1 1 1 3 8 F 2 1 2 1 2 1 3 1 4 1 2 1 2 2 3 4 3 1 1 1 3 2 2 5 1 2 1 1 3 1 3 3 5 1 1 2 1 1 C-3 1 7 Cn 1 1 ~y 1 1 r°"'"~ 3 1 1 2 2 3 3 1 1 1 1 r 5 2 2 orocovQ'
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,+.r ~ arm arr a. TABLE 6 CON'T GROSS NECROPSY FINDINGS CODE _33_. 68 63 SPLEEN-CON'T ~ Round brown nodule(s) 1 i Raised crust-like areas or lesions 1 2 3 Firm round and raised or white and/or granular nodules 3 1 Greyish-white nodules-lobulated 1 _ Swollen 1 2 Foci 1 Grey raised areas 1 Firm consistency (thickened) i 1 1 White scar (firm) 1 1 Dark red areas on borders 1 White focus on parietal surface 1 Tan coloration 1 2 Dark blue-black 1 Yellow focus 2 Fibrosed i White congested areas 2 ADRENFlLS Cortex accentuated 1 Medulla accentuated 1 Enlarged 2 2 Raised white foci 1 1 1 2 Clear raised cyst(s) 1 White raised nodule-like areas 1 1 Pinpoint brown or red foci 1 1 Raised nodule-like areas 1 1 -- - Clear area(s) 1 Pinpoint nodules 1 1 1 Transparent raised foci White area(s) 1 Round foci ~ 1 Cyst-like lesion 2 Dark red focus 1 4UCpVOR
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TABLE 6 CON'T GROSS NECROPSY FINDINGS CODE 11_ L 68 - 67 KIDNEYS Distinct division between cortex and medulla 1 White coloration 1 1 Dark red focus 1 1 Dark brown streak between cortex and medul la 2 _ _ Yellow and/or brown discoloration Pale i 1 3 Rough area on surface 1 Cyst i Dark red raised foci 1 Left, slightly enlarged 1 Flottled 1 Congested 1 v Fibrous ' one 1 m _ Masses 1 Rough surface 1 Shrunken 1 PANCREAS White foci 1 LYMPII NODES Tracheal Enlarged and dark green or black 8 Enlarged and dark red 1 €nlarged 1 1 2 Dark grey 1 Greenish-grey 1 ~ Bronchial Dark red with white foci 1 Enlarged 1 4 2 1 3 Dark red ~ 3 ~ Dark grey 1 1 Greenish-grey 3 1 1 t- Dark blue-black 1 1 Dark brown 1 CtOCOt,O ~
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.a.r am a AN TABLE 5 C0N'T SUMMARY OF PULMONARY MEASUREMENTS AT - 1400 DAYS EXPOSURE ARTERIAL BLOOD GASES N NASN OUT - - - _ VOL. TO OSING CL VITAL PHASE III MINUTE 02118 IIO PRE POST PCO~ Po 21 N _ CAPACITY SLOPE VOLUME GROUP (I) (G(100 ML) CONB (X) CONl1 (X) pN (MN IIG) 66 (MM ) (MLj ML (X (MI/KG) (f N2/L) (ML/MINlKG) CODE 33 MEAN 92.59 15.89 1.04 1.64 7.37 40.83 87.55 5734.11 217.22 20.5 E4.55 11.54 262.93 (C0N1R0L) S0 5.94 1.10 0.60 0.59 0.06 4.14 16.09 1013.30 89.89 7.8 20.65 3.70 88.56 N 26 26 26 26 25 26 26 26 18 10 26 26 26 CODE 13 MEAN - 95.325* 14.38;- 1.88 5.135+ 7.39 38.83 91.86 6299.54Sf 212.86 18.3 92.38 13.89 277.42 (LIIW) SD 2.89 1.19 0.38 1.52 0.05 4.58 15.30 981.21 81.31 5.2 26.81 8.60 71.69 N 26 26 26 26 26 26 26 26 21 21 26 26 26 CODE 11 MEAN 94 78 43s- 14 38St 2 155+ 5 r'+ 5+ Ss . . . . 7.30 40.23 81.46 6759.07 193.64 17.0 86.32 13.97 313.39 (VI1D) SU 4.28 1.11 0_.51 1.49 0.13 20.50 19.14 1672.03 104.45 8.3 16.41 4.09 90.06 N 26 26 26 26 28 28 26 20 22 22 27 28 28 CODE 32 11EAN 93.08 14.045- 2.15 5.O0St 7.38 38.59 75.67;- 6619.765+ 234.76 19.6 94.03 13.20 303.82 (IIIGII) SD 7.79 1.20 0.75 1.08 0.04 5.50 15.13 1359.65 86.81 5.6 18.76 6.67 64.93 fl 23 23 23 23 23 23 23 23 21 21 23 23 23 - - - - - - - - - - - - - - - + - - - - - - - - - ' 1500 DAYS EXPOSURE CODE 33 14EAN 78.00 16.17 2.10 1.66 7.39 35.80 33.40 5648.95 203.12 18.0 86.93 9.93 273.51 (60ilIROL) SI) 18.74 0.97 0.37 0.44 0.06 4.59 29.08 1222.22 98.77 8.0 23.31 3.66 74.01 N 22 23 23 23 22 22 22 22 16 16 22 22 22 CODE 13 MEAN 87.53 14.38' 1.92 4.08'* 7.40 34.75 70.90 6003.27 179.41 15.2 88.01 11.86 242.37 (LOU) - SU 13.45 1.12 0.59 1.33 0.06 3.47 15.95 1455.91 85.11 4.8 23.16 4.93 70.09 N 25 26 26 26 25 26 26 26 17 17 26 26 26 CODE 11 MEAN 83.49 14.055 2.905' 5.145* 7.44 32.635 60.22S6655.22 197.60 18.9 85.39 3.145+ 1 294.41 (IIID) SO 15.02 1.27 1.05 1.37 0.11 4.56 14.08 1495.61 102.36 8.1 14.47 _ 6.14 71.91 N 27 27 27 27 27 27 27 27 25 25 26 27 27 COUE 32 MEAN 90.965+ 14.005 2.29 4.965r 7.40 34.73 63.145 6282.96 186.45 22.6 93.70 10.90 322.61 (111611) SD 6.42 1.45 0.70 1.63 0.04 5.60 16.42 1439.74 00.09 23.9 23.34 4.61 119.31 N 21 23 23 23 22 23 22 23 23 23 23 23 23 S= statistically signiflcantly hi9her (5+) or lower (S-) than control values as measured by,student's t-test at ps0.05. 8nllC0VObZ
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TABLE 6 CON'T GROSS NECROPSY FINDINGS CODE ~~ 1L_ _11 ~L 68 -67 PARATNYROIDS Enlarged 2 f;aised dark focus 1 OTHER Inquinal region contained a subcutaneous hematoma 1 Abdominal region contained a subcutaneous hematoma i Skin of animal appeared jaundice 1 Skin of animal appeared to indicate dehydration 1 Thoracic cavity filled with fl uid 2 Several adhesions between pericardium and lungs 1 ~toeotoe
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~W jo Am in M 4_~ C__~ .1--i ~ X-3 a is A A Ji1 A M M TABLE 6 CON'T GROSS NECROPSY FINDINGS CODE -32 6il- 67 PROSTATE Enlarged 6 4 1 1 1 2 Raised brown irregular areas 1 Dark red areas_ 1 Hemorrhagic 1 Bluish color 1 Right, cystic 1 Small 1 URINARY BLADDER Thickened walls or mucosa 1 2 2 1 7 Filled with white calculi 1 Slightly congested 1 Bluish red near neck of serosal s_ur€ace 1 _ Ulcerated areas on mucosa 1 Mucosa red 1 1 Raised firm red focus 1 LIVER White streaking on ventral lobe of left laterial lobe I Enlarged 1 1 Lobe(s) thickened 1 2 Raised white areas or white areas (foci) 2 1 White scar or scar-like areas 2 White pinuoint spots (or foci) 1 1 2 White firm discolored areas 1 1 Raised brown focus 1 Yellowish-brown 1 C-3 Accentuated lobulation 1 White capsular thickening (areas) 1 ~--i Siderotic nodules 1 Notched lobe borders 4 1 ~ Pale granular appearance 1 --i Capsular thickening 1 r~--s-- Pale yellow 1 Mottled 1 White consolidated areas 1 9TOCQVOR
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~ ~.~..~ r-.~ .~.~ ~.,... ~._.- W:.1 4.4 Aza " M M M M M TABLE 6 CON'T GROSS NECROPSY FINDINGS CODE .-U_ 11_ 13 _ 32 68 b7 LYMPH NODES-CON'T Mesenteric Dark red 1 2 Red 1 Enlarged 1 1 2 1 MEDIASTINAL Dark red 1 Slightly enlarged 1 MANDIBULAR Slightly enlarged 1 1 Dark (red) PANCREATIC Enlarged 1 i 1 Dark red 1 ~ STOMACfI Distended with gas Blood vessel prominant_ i 1 Yellow mucoidfluid 1 Bile 1 White area on pyloris GASTROINTESTINAL TRACT Raised area on duodenal surface I 1 Ileum congested i 1 1 Dark grey streaking of colon 1 2 i Duodenal white raised area Jejunum congested 1 3 2. 1 C-75 Small intestine, mucosa congested and red 1 1 1 c'7 Jejunum and/or ileuni red 1 3 1 1 3 ;- Spherical nodule on jejunum 1 y Duodenal nodule(s) 2~ 2 Jejunum, raised areas 1 ~ Ileum or jejunum appeared hemorrhagic or bright red 3 1 2 4 1 Duodenum, bright red 2 1 lllcerated-like areas on ileum 1 Duodenum and ileinn slightly thickened 1 f"rJeQVO&
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I Ana m,~M ILI" TABLE 6 CON'T GROSS NECROPSY FINDINGS CODE _33 _ 1L 68 _ 13 JZ 67 _ - GASTROINTESTINAL TRACT-CON'T Colon/rectum mucosa slightly folded 2 Black foci on cecum - 1 Appeared small, filled with gas 1 Jejunum, reddened areas on mucosa 1 1 Colon, white nodules on mucosa 1 Rectum, white nodules on mucosa 1 Cecum, enlarged 1 1 Peyer's patches prominent 1 Red with petechial foci 1 Colitis 1 Hemorrhagic 1 Circumscribed area 1 Reddish-blue discoloration White frothy material 1 Ulcer between stomach and duodenum 1 Cecwm/colon, dark red streaks on mucosa 1 TESTES Small 3 1 3 Enlarged 1 Congested Red- Bluish raised foci I I 1 Areas of firm consistency 1 Surrounded by brownish-yellow fat 1 Epididyinis enlarged Epididymis thickened Thi k d 1 C-3 ene c Left, found in abdominal cavity I - --- - ~ =:z
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ii .m .= am an t,...j A M A A M TABLE 6 CON'T GROSS NECROPSY FINDINGS CODE -3_ 1L__ 13 32 6E1 67 LUNG-CON'T Thickening of visceral pleura I Brown . i i Hemorrhagic 1 3 Edematous 1 1 Diffuse red areas Anthacosis i 1 Mottled 1 ESOPHAGUS Brittle 1 TRACHEA Foam present 1 Red frothy material 1 2 i Mucosa thickened 1 Rough surface near stoma 1 Frothy mucosa 1 Blood with foam 1 Mucus with blood 2 2 Lesions on lumina 1 Congested 1 Mottled 1 Ilemorrhagi c 1 SPLEEN Mass on border or surface 2 Raised dark and/or red nodule(s) or area 4 1 Siaaa l l White pinpoint material or foci 1 2 2 r.-°a Pink or white streaking 1 1 Consolidated area(s) Enlarged 2 2 3 Raised (white) areas or foci 3 2 4 1 5 - i Round nodule(s) on surface 1 6 6 4 2 6 In- White nodules or nodule(s) 12 7 3 2 White pinpoint (Raised foci or white areas) 2 5 1 2 3 R- II0f;QVUe
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TABLE 6 CON'T GROSS NECROPSY FINDINGS CODE _a3_ 11 13 32 68 - 67 GALLBLADDER Mucosal wall thickened _ 2 1 Contents bright red 1 Grainy 2 Distended with purulent material on mucosal wall 2 Small pinpoint cyst 1 Pinpoint (white) foci on mucosa 2 Nodule with thick contents 1 Raised pinpoint black or grey foci 2 1 Raised areas Round and creamy white Nodule(s) 1 1 2 Mass on mucosa greenish yellow 1 Greyish foci (some raised) 1 ~ Pinlioirit yellowish white foci 1 1 Black or grey nodules or foci 3 Pinpoint dark red areas or foci 2 Distended 1 Contained semi-coagulated material Thick bile I 1 Black bile Bile duct occluded 1 6RAIN Cerebrum congested 1 Blood vessels dilated 1 /lccuirwlation of cerebral spinal fluid i V-5 PITUITARY E";> ~.~ Pinpoint cysts, small cyst(s), or clear cyst 3 4 2 ldhite foci Congested Reddish color 1 ~ Transparent cyst-like mass 1 1 Raised area or focus 1 Enlarged and cystic 1 Translucent area I I I-10COVOR
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UN{i MENTIAL I I • APPENDIX 4 CIGA'RETTE AND SMOKE ANALYSIS Resi'stance to Draw • Tray Sample Cigarette Weight • TPM of Tray Samples I I • TPM of Exposure Room Samples • Nicotene Content of Tray Samples 1 • Nicotene Content of Exposure Room Samples 1 r Water Content of Tray Samples • Water Content of Exposure Room Samples I • • PMO Content of Exposure Room Samples Machine Caiibration an IRI Cigarette I. I I I f I -87-
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APPENDIX 1 S_MO_KE EXPOSURE SGIEDULE SI/AN CONiNOLS G80UP (00E 33 COOE 13 COOE 11 COOE 32 CODE 6T _COOE 68 SE1 Ut Ui Vt 42 V3 Xt Jcy X3 YI II2 Y3 1 2 3 5halu ** 110. 0005 PEN SIIJ 12 16 12 17 18 12 18 18 12 Il U 20 20 20 10 STANIEO SM(1KE 12-15 12-24 12-15 12-24 12-20 12-15 12-24 '12-20 12-IS 12-24 12-20 3-04 4_-08 4-18 9-09 11tA1N18G 16 76 76 76 76 76 76 , 76 76 76 76 7T 77 71 77 AEEAINED FUEL 12-29_ 1-01 12-29 1-07 1-03_ 12-29 1-07 1-03 12-29_ 1-07 1-03 4-02 5-06 5-15 9-09 EXPOSURE 76 77 76 71 71 76 77 71 76 17 11 11 11 77 11 (12 (1G.lpAY) -- I/l0 OAY FiihOSURE • " 10-08 11-11 11-20 12-17 71 77 77 7) 200 DAY • • • 3-06 ! • 3-13 • ! 3-20 I-16 2-19 2_-28 2-19 ExPOSUeE 77 77 77 18 18 78 78 400 OAY 6-04 8-23 6-18 7-26 9-22 7-02 8-09 9-29 6-25 8_-02 10-06 8-04 9-07 9-16 10-12 EXPOSukE 11 71 77 71 T1 77 77 11 77 17 77 18 78 78 78 6(10 PAY 12-21 3_-11 12-27 2-04 4-08 1-09 2-25 4-18 1-16 2_-11 4-11 2-20 3-26 4_-04_ 4-30 EuPOSUNE 77 78 11 18 78 78 19 78 78 18 78 79 79 79 19 000 OAY 7-09 9-27 7-IS 8__-23 10-25 Z 28 9-13_ 11-04 8-04 8-30 10-28 9-09 10-12_ 10-21 11-16 I%I'OSUNE 78 78 18 78 78 78 78 78 18 78 78 79 79 79 79 I(I(10 IiAY 1-25 4-15 1-31 3-11 5-13 2_-13 4-01 5-23 2-30 3-18 5-16 3-27 4-29_ 5_-O8 6-04 EYPOSi1GE 19 19 79 19 79 19 79 79 79 79 79 80 80 80 80 1/(xl nAY €MP0$(1RE 1_0_-21 4-29 9-12_ 10-IB 80• 80 80 80- 1200 OAY 8-13 11-1 8-19 9_-28 11-30 9-01 10,18 12-09 8-1,4 10-05 12_-03 €tPOSIINE 79 79 79 79-- 7979- 19 79 79 79 79I41u1 DAY 4_lll 5-20_ 1-28 4-16 6=i1 4-19_ 5-05 6-20 3-26_ 4-22 6-19 FtF!OSI(NE 80 -00 0080 8() 80 80 80 80 8(1 80 1400 094 6_-00_ 9_-OB 5-04 8-04 9-24 10-24 8-I8 11-01 1-07 7-30 ~ 10-12 EAF03(1R€ 80 80 80 8080 80 80 808080 80 • 0rcu_rred at Oattelle Nnrtbwest lahnr-atorles. •• Sham EMpnzed dpgs wrre rsot connected-to machlnes wtth clgarettes. v L1J~O~lI/(3
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I I I 4 3 I j ! 1 . I I APPENDIX 3 SMOKE DELIVERY SYSTEM C.,~ !~.TraT~. t 4! I~~:~:y l~ Systemit'o deliver smoke to tracheostomized dog. (Smoke fol'lows the trail of the arrows. 1. Tracheostoma Z. Cuff'ed' Cannula 3, Inflatable Cuff 4. Trachea 5. T-Tube,Adazter 6'.One-YJay Va l ve 7:Sinoke Wolding/DeTi'very Tube 8. Cigarette -86-
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AIM A :® is A A APPEFIDIX 4 CON'T MACHINE CALIBRATION ON IRI CIGARETTE DATE MEAN TPM (MG) SD N NICOTINE (MG/CIG.) MEAN SD N 9%78 47.7 4.67 30 3.4 0.29 30 10/78 45.5 34.36 60 3.3 0.27 61 11/78 44.8 4.02 50 3.4 0.23 49 12/78 42.2 4.14 18 3.2 0.22 18 1/79 41.3 2.87 26 3.6 0.34 26 2/79 43.2 2.94 19 3.9 0.53 19 3/79 41.5 1.94 18 3_5 0.40 18 4/79 40.4 2.30 35 3.2 0.25 35 5/79 40.2 2.89 11 2.8 0.29 11 6/79 38.3 4.37 5 3.1 0.41 5 7/79 38.3 5.06 10 2.9 0.38 10 ~ ~ MACHINE CALIBRATION ON IRI CIGARETTE TPM (MG) NICOTINE (MGtCIG.) DATE MEAN SD N MEAN SD N 8/79 xxxxx xxxxx 0 yyxxx xxxxx 0 9/79 BKBrm xx)(mK 0 xxxxx xxxxx 0 10H9 38.9 6.91 23 3.1 0.42 30 11/79 )(Xxxx xxxxx 0 xxxxx xrrxx 0 12/79 34.7 3.66 39 2.9 0.45 39 1/80 38.1 4.36 101 3.2 0.35 100 2/80 40.6 3.83 95 3.4 0.28 95 3/80 42.4 4.28 82 3.6 0.41 82 4i80 42.4 4.96 81 3.4 0.44 _ 81 5/80 43.0 4.45 50 3.5 0.50 50 6/80 40.1 2.69 12 3.5 0.53 12 7i80 47.1 6.98 35 3.5 0.33 35 8/80 xHxxx xxxxx 0 xxNi4x 1xxxx 0 9/80 45.1 20.94 165 3.3 0.26 165 10f80 xxxxx xxxxx 0 xxairr xxx><x 0
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.. w,...?,, APPENDIX 5 CON'T HEMATOLOGY DATA CODE 68 EXPOSURE TIME 100 DAYS DOG WBC RBC H¢B HCT MCV MCH MCHC SEG. BAND NEUTRO NEUTRO LYMPH ATY. LYMPH MONO E05 BASO HRBC PLATELET'. N0. (X10/MM) (3X10iMM) (G/DL) (Y,) (U) (UUG) (G/DL) ( :)--- --('/.) ('/,) (4) ('/.) ('/.) (7.) (X) (X(0%MF1) 5039 8.5 7.06 17.3 48.5 60. 24.5 _ 35.7 53 0 38 0 2 7 0 0 290 5046 9.5 6.67 16.4 47:0 70. 24.6 34.9 60 0 33 0. 6 1 0 0 370 5143 9.3 7.63 18.1 49.5 65. 23.7 36.6 66 0 29 0 4 1 0 0 395 6014 11.7 7.23 16.8 46.0 64. • 23.2 36.5 78 0• 18 0 2 2 0 0 350 6016 9.9 6.87 15.8 46.0 67. 23.0 34.3 63 0 32 0 5 0 0 0 330 6039 8.1 6.83 16.7 48.5 71. 24.5 34:4 • 83 0 14 0 1 2 0 0 425 MEAN 9.50 7.05 16.85 47.58 66.2 23.92 35.40 67.2 0.0 27.3 0.0 3.3 2.2 0.0 0.0 360.0 SD 1.26 0.34 0.79 1.46 4.1 0.71 1.02 11.3 0.0 9._3 0.0 2.0 2.5 0.0 0.0 47.9 H 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 w ~~(jIV. nVUR
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APPE!!DIX 6 PLATELET AD_IIESIVENESS AND AGGREGATION CODE 33 EXPOSURE TIME 400 DAYS ADP 2_X10 M COLLAGEN 0.26 MG/ML ANIMAL XADHESIVENESS 1(ADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXP05URE NUMBER PRE EXPOSURE POST EXPOSURE ('!. AGGREGATION) (Z AGGREGATION) (Y, AGGREGATION) (i AGGREGATION) 5031 83 83 84 82 82 80 5239 67 69 78 70 72 58 5074 92 89 54 34 76 50 5080 82 89 65 82 70 60 5082 73 68 75 45 70 80 5/70 83 87 68 80 78 80 5186 75 76 78 76 72 86 5217 72 84 80 80 86 84 MEAN 78.4 80.6 72.8 68.6 75.8 72.3 SD 8.0 8.6 9.8 18.6 5.9 13.9 N 8 8 8 8 8 8 a w 1
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li .1/-.>i A Ji A A A m m A in A B S APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 33 EXPOSURE TIME 800 DAYS ADP 2X10 M COLLAGEN 0.26 MG/ML ANIMAL XADHESIVENESS tiADHESIVENESS _ PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE (Z AGGREGATION) (i AGGREGATION) (: AGGREGATTGN) (% AGGREGATION) 5031 71 83 74 70 36 12 5074 84 85 72 72 14 N.R. 5080 72 72 74 72 N.R. N.R. 5082 56 63 76 74 36 12 5217 62 62 70 52 72 46 5239 55 50 66 72 18 18 i MEAN 66.7 69.2 72.0 68.7 35.2 22.0 SD (l.' 13.5 3.6 8.3 22.9 16.2 N 6 6 6 6 5 4 0 qRJEOvUf3
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,,o.r .rrri ~r1 ~ ~ APPENDIX 6 CON'T PLATELET ADIIESIVENESS AHD AGGREGATION CODE 33 EXPUSURE TINE 1000 DAYS ADP 2X10 M COLLAGEN 0.26 (iG[tiL ANIPIAL 'f.ADHESIVENESS GADHESIVEHESS PRE EXPOSURE POST EXPOSURE P_RE EXPOSUftE POST EXPUSII^E N(JCIHER PRE EXPOSURE POST EXPDSURE (X AGGREGATION) (i AGGREGATIDN) (i AGGREGATT011) (: AG ';L ATION) 5031 55 55 12 80 76 22 5074 72 70 90 80 80 78 5080 41 70 74 84 78 E3 5022 54 55 76 76 80 $0 5217 69 74 56 44 70 FS 5239 61 64 68 58 74 70 P1EAN_ 58.7 64.7 72.7 70.3 76.3 75.3 SD 11:3 8.1 11.1 15.8 3 .9 10.3 N 6 6 6 6 _ 6 G 4 s~oeoVo~
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APPENDIX 6 GON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 33 EXPOSURE TIME 600 DAYS ANIMAL XADNESIVENESS XADIIESIVENESS ADP 2X10 M PRE EXPOSURE P-OST EXPOSURE COLLAGEN 0.26 MG/ML PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE (X AGGREGATION) (`/_AGGREGATION) (X AGGREGATION) (X AGGREGATION) 5031 80 83 74 82 87 N.R. 5074 89 87 84 77 74 78 5080 76 84 82 89 80 78 5082 71 81 100 98 88 88 5170 85 85 70 68 70 54 5186 75 75 78 78 66 64 5217 79 83 72 56 58 N.R. 5239 59 57 74 72 12 20 5170 84 N.R. 56 . N.R. 70 N.R. 5186 64 N.R. 80 N.R. 78 N.R. MEAN 76.2 79.4 77.0 77.5 68.3 63.7 SD 9.4 9.7 11.3 12.9 21:8 24.5 11 10 8 10 8 10 6 VROCO i OV
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A M M M - -- -- - ~ - APPENDIX 6 CON'T PLATELET AD_NESIVENESS AND AGGREGATION CODE 33 EXPOSURE TIME 1200 DAYS ADP 2 X10 M COLLAGEN 0.26 MG/11L ANIMAL YADNESIVENESS %ADIIESIVENESS _ PRE EXPOSURE POST EXPOSURE PRE EXP-OSURE POST EXI'OsURE NUMBER PRE EXPOSURE POST Eaf'OSURE (% AGGREGATION) (% AGGREGATION) (': AGGREGATION) (% AGGRCGA(IQII) 5031 47 43 66 60 72 64 -5074 66 56 40 33 64 68 5080 35 51 41 42 55 60 5032 43 32 38 32 40 • Su 5217 69 66 64 47 73 60 5239 47 47 52 64 57 64 tfEAN 51.2 49.2 50.2 47.2 60.2 62.3 _ SD 13.4 11.6 12.5 12.6 12.4 3.7 N 6 6 6 6 6 6 i i.,.l)Oc\/YVN
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,t i i - - i - - i i - ~ - - - - - - - -- APPEND(X 6 CON`t / PLATELET AD_IIESIVENES5 AND AGGREGATION CODE 33 EXPOSURE TIME 1400 DAYS AFIIMAL '/.ADHESIVEHESS XADHESIVEt1ES5 ADP 2X10 M PRE EXPOSURE POST EXPOSU COLLAGEN 0.26 MG/:IL RE PRE EXPOSURE POST EXI'U U E NU(IBER PRE EXPOSURE POST EXPOSURE (X AGGREGATION) (% AGGREGAT ION) (Z AGGREGATION) (G AGGF(cG9Ii0/1) 5031 52 59 54 70 62 70 5031 52 59 54 70 62 70 5074 67 69 62 46 72 64 5074 67 69 62 46 72 64 5080 58 46 62 73 66 70 5080 58 46 62 73 66 70 5082 54 56 58 55 62 66 5082 54 56 58 55 62 66 5217 47 49 50 55 46 54 5239 30 36 53 53 53 44 P1EAN 53.9 54.5 7.5 5 59.6 62.8 63.8 SD 10.6 10.4 _ 4.5 10.8 7.4 8.5 N 10 ]0 10 10 to 10 Ui w "7UcO VQ[~
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APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 13 EXPOSURE TIME 600 DAYS m m ADP 2X'IA M GACEoGEK A.14 Rr.RTC __ _ ANIMAL '.ADHESIVENESS XADNESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE ' NUMBER PRE EXP_D5URE POST EXPOSURE AGGREGATION) ('/. AGGREGATION) (y AGGREGATION) l. AGGREGATION) ( 5041 80 80 38 40 32 34 5125 93 93 38 40 32 34 5135 91 89 54 44 42 N.R. 5169 76 82 80 80 36 20 5204 76 N.R. 62 H.R. 54 N.R. 5212 76 75 42 50 68 68 5235 88 87 70 64 64 60 5352 79 71 56 44 H.R. N.R. 5352 77 N.R. 52 H.R. N.R. N.R. MEAN 81.8 82.4 54.7 51.7 46.9 43.2 56 6.9 7.8 14.4 15.0 15.1 20.0 H 9 7 9 7 7 5 2 t; oEp {,ObZ
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B -- _ ~ - ------+.~.. APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 33 EXPOSURE TIME 1500 DAYS ADP 2 X10 11 COLLAGEN 0.26 MGitIL ANILIAL %ADIIESIVENESS 'GADUESIVENESS PRE EXPOSURE POST EXPOSURE PRE E::POiURE POST EXIf15UEE NUIIDER PRE EXPOSURE POST EXPOSURE (Z AGGREGATION) (Z AGGREGATION) (2: AGGREGATION) (R Ac;GRf;;ATION) 5031 55 60 50 48 46 22 5074 70 75 62 61 47 48 5080 45 56 62 40 46 411 5032 42 48 60 58 50 47 5217 64 68 20 20 53 4ri 5239 64 49 26 30 53 46 P1EAN 56.7 59.3 46.7 42.8 49.2 42.5 SD 11.3 10.7 19.0 16.0 3.3 10.2 N 6 6 6 6 6 6 t G.`"~ocn vQR
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APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 13 EXPOSURE TIh1E 800 DAYS ADP 2Xt0 M COLLAGEN 0.26 MGiMI ANIMAL XADHESIVENESS Y.ADHESIVENESS PRE EXPOSURE POST EXPGSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE ('/. AGGREGATION) (% AGGREGATION) (Y, AGGREGATION) (X AGGREGATION) 5041 71 69 52 60 54 54 5125 72 74 72 78 . 70 60 5135 38 38 60 54 64 50 5169 65 65 68 74 N.R. N.R. 5204 68 84 62 70 64 58 5212 66 68 64 68 48 30 5235 59 69 60 70 56 66 MEAN 62.7 66.7 62.6 67.7 59.3 53.0 _ SD 11.7 14.1 6.4 8.2 8.1 12_.5 H 7 7 7 7 6 6 i 6 `~()il4 U KOC7
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/lPPENDIX 6 CON'T PLATELET ADHESIVENESS AND_ AGGREGATION CODE 17 EXPOSURE TIME 400 DAYS ADP 2X10 M COLLAGEN 0.26 MG(ML ANIMAL XADHESIVENESS Y,ADHESIVENESS PRE EXPOSURE P05T EXPOSURE PRE EXPOSURE POST EXf'OSURE NUMBER PRE EXPOSURE POST EXPOSURE (% AGGREGATION) (: AGGREGATION) (Y. AGGREGATION) (% AGGREGATION) 5041 65 70 82 84 82 72 5050 62 62 48 42 20 N.R. 5125 89 80 90 85 80 82 5135 84 75 74 84 92 74 5169 82 78 56 . 74 N.R. 78 5204 72 73 70 48 78 78 5212 83 82 80 , 80 72 84 5235 84 82 54 78 72 72 5306 88 87 68 20 76 72 5352 84 87 78 68 78 54 MEAN 79.3 77.6 70.0 66.3 72.2 74.0 SD 9.5 7.8 13.6 22.2 20.5 8.7 N 10 10 10 10 9 9 b Tf,UcDvDg
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aO-A ./ ./ A A AM M A A.® .® A AMA AS APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 13 EXPOSURE TIME 200 DAYS ADP 2 .';1,1 M COLLAGEN 0.26 MGtML ANIMAL kADHESIVENESS XADHESIVEHESS _ PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER _ PRE EXPOSURE POST EXPOSURE (X AGGREGATION) (% AGGREGATION) ('!. AGGREGATION) (X AGGkEGATION) 5212 76 85 86 84 75 83 5306 81 84 72 68 N.R. 68 5352 73 70 78 84 N.R. 66 5369 44 43 86 84 N.R. 74 MEAN 68.5 70.5 80.5 80.0 75.0 72.8 S0 16.7 19.6 6.8 8.0 xKyw 7.6 N 4 4 4 4 1 4 f1rU£ovo&
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APPENDIX 6 CON'T PLATELET ADNESIVENESS AHD AGGREGATION CODE 13 EXPOSUP.E TIME 1200 DAYS- ADP 2_X10 M COLLRCEN 0.26 FIG:ML ANIMAL Y.ADHESIVENESS XADIIESIVEFIESS PRE EXPOSURE POST EXPOSURE PRE EXPOGURE POST E'(JSIIRE NUMBER PRE EXPOSURE POST EXPOSURE (% AGGREGATIOM) (% AGGREGATION) (X AGGRCGAIIOH) (7. AGGft[GhTION) 5041 43 42 64 72 63 69 5125 52 60 55 60 73 7S 5735 41 42 60 HR 76 72 5169 43 45 39 38 IIR L'R 5204 78 85 HR HR HR HR 5212 47 48 68 62 65 60 5235 74 7? 60 66 HR HR MEAN 54.7 56.1 57.0 9.6 5 71.3 69.0 SU 15.5 16.6 11.6 _ 12.9 3.9 6.5 H 7 7 6 5 4 4 v r, f~# ~ ~ '-~i)JE!)KOt3
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.+.er A.r .ar JW i J= M JW M JK M APPENDJX 6 CON'T PLATELET ADNESIVENESS At{D AGGREGATION CODE 13 EXPOSURE TIME 1000 DAYS ADP 2_X10 M COLLAGEN 0.26 t1G•'t L AIIIMAL 7._ADNESIVENESS XADNESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSU;:E POST EltI'b511tzE NUMBER PRE EXPOSURE POST EXPOSURE (i AGGREGATIDN) (% AGGREGATION) (X AGGREGATION) (i AGGKEGl:1TON) 5041 55 53 76 68 76 68 5125 66 63 72 78 72 70 5135 4i 47 76 80 80 75 5169 51 66 51 76 50 60 5204 10 5 52 54 52 56 5212 32 34 12 5 8 tlf' MEAN 42.5 44.7 56.5 60.2 56.3 66.0 _ SD 19.7 22.6 24.6 28.7 26.8 8.0 N 6 6 6 6 6 5 Vf QCQVOg
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Jm J= is JoNd Jr r,a..r jwr aw ,rr i.r APPENDIX 6 CON'T PLATELET ADNESIVENESS AIID AGGREGATION CODE 13 EXPOSURE TIME 1500 DAYS ADP 2X10 M COLLAGEII 0.26 I'.L ANIMAL 'GADIIESIVENESS Y,ADNESIVEIIESS PRE EXPOSURE POST EXPOSURE PP.E EXPOSURE POST E-4I'OSU!?E NUMBER PRE EXPOSURE POST EY.POSURE ('/. AGGREGATION) ('/, AGGREGATI011) (: AGGREGATION) (I., AG;Cf:GATJOlI) 5041 58 39 40 46 40 66 5125 59 52 45 50 40 45 5135 43 42 23 34 34 46 5169 60 57 20 28 50 48 5212 53 51 29 20 43 33 5235 65 66 24 22 49 60 MEAN 56.3 51.2 30.2 33.3 43.5 46.3 SD 7.6 9.9 10.1 12.4 6.4 8.6 N 6 6 6 6 6 6 rn N "&cV(.ovQ&
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A,H AN JI. .® in A A A A A Jr A AMR An APPENDIX 6 CON'-T- P_L_ATELET ADHESIVENESS AND AGGREGATION CODE 11 EXPOSURE TIME 200 DAYS ADP 2X10 M COLLAGEN 0.26 MGtML ANIMAL XADNESIVENESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE P05T EXPOSURE ('>. AGGREGATION) (L AGGREGATION) (X AGGREGATION) (X AGGREGATION) 5337 65 61 90 82 78 86 5345 38 50 86 88 40 80 MEAN 51.5 55.5 88.0 85.0 59.0 83.0 3D 19.1 7.8 2.8 4.2 26.9 4.2 N 2 2 2 2 2 2 4 R[)V i.oYOs
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APPENDIX 6 CON'T PLATELET ADNESIVENESS AND AGGREGATION CODE 11 EXPOSURE TIME 800 DAYS ADP 2X10 M ANIMAL XADNESIVEHESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXPOSURE (% AGGREGATIDN) (7 AGGREGATION) 5052 67 5129 53 5148 72 5153 52 5165 34 5233 46 5233 35 5267 49 5337 25 MEAN 48.1 SD 15.3 N 9 COLLAGEN 0.26 MGlML PRE EXPOSURE -P05T-EXP05URE ' (Y. AGGREGATION) (% AGGREGATION) 69 74 60 N.R. N.R. 59 72 64 60 60 55 58 74 N.R. H.R. 56 66 72 54 58 44 74 10 N.R. 30 52 71 6$ 69 53 23 72 69 64 65 62 66 68 60 64 14 68 80 52 70 48.8 69.0 69.4 59.8 57.0 18.5 - 5:I 5.7 6.3 13.1 9 9 9 6 7 t
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.aari .~d .~BI im xim im AK ju APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 13 EXPOSURE TIME 1400 DAYS ADP 2X10 Pl COLLAGEN 0.26 A11111AL XADIIESIVEIIESS ZADHESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSOfRF PUsT E'LPOSL'RE NUIlBER PRE EXPOSURE POST EXPOSURE ('/. AGGREGATION) (X AGGREGATION) (X AGGREGAHON) ( ; AGCCE60I011) 5041 31 36 82 74 82 74 5041 31 36 82 74 32 71, 5125 48 60 62 76 77 79 5125 48 60 62 76 77 79 5135 39 51 64 61* 77 73 5135 39 51 64 64 77 73 5169 65 68 36 24 50 40 52 12 56 61 4 9 55 56 58 5235 61 69 30 14 ~, 8 k 0 61EAN 46.4 54.7 59.0 57.9 69.6 67.8 SD 12.5 12.3 18.0 23:3 14.0 14.7 N 9 9 9 9 9 9 rn 990COV0R
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AN " " li " " JM AM " " M ~1 An m = m Am AN im APPENDIX 6 CON'T , PLATELET ADIIESIVENESS AND AGGPEGATION CODE 11 EXPOSURE TIt1E 1000 DAYS ADP 2X10 M COLLAGEN 0.26 tiG[ML ANIMAL 'I.ADNESIVENESS %ADNESIVEIIESS PRE EXPOSURE POST EXPOSURE PPE EXPOSIIPE PUST E~I'(t;iU.^.E tIUMDER _ PRE EXPOSURE POST EXPOSURE ('. AGGREGATION) (:_AGGREGATION) (: AGGREGAfION) (7. AGGP,FGA(IOII) 5052 56 48 74 74 69 66 5129 56 56 68 68 70 72 5148 49 45 62 68 72 6!t 5153 41 40 64 68 70 78 5165 66 65 74 70 72 76 5233 72 72 70 72 70 7A 5237 61 59 70 80 70 7?i 5267 71 73 70 74 76 70 t1EAN 59.0 57.3 69.0 71.8 71.1 72.3 8D 10.7 12.3 4.3 4.2 2.2 5.3 N 8 8 8 8 8 8 1 4 zlll>i.QYVC3
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A.. Ao i..r ,r® irel ,e.N AN ~ APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 11 EXPOSURE TIME 600 DAYS X10 M ADP 2 COLLAGEN 0.26 MGfML ANIMAL Y.ADHESIVENESS X_ADNESIVENESS _ PRE EXPOSURE POST EXPOSURE PRE EXPOSORE --POST EXPOSURE NUh1BER PRE EXPOSURE POST EXPOSURE (Y. AGGREGATION) (Z AGGREGATION) (X AGGREGATION) ('/. AGGREGATION) 5052 86 87 74 76 N.R. 74 5Y29 85 86 74 74 74 70 5148 80 76 52 48 N.R. N.R. 5143 N.R. H. R. 76 62 26 N.R. 5165 66 _ 67 82 84 34 24 5233 76 77 78 82 64 64 5237 70 65 74 64 70 62 5261 68 74 82 82 78 80 5267 79 74 78 80 68 66 5337 57 53 80 80 80 80 526 1 70 N.R. 46 N.R. 82 N.R. MEAN 73.7 73.2 72.4 '73.2 64.0 65.0 5 D 9.1 10.6 12.0 11.6 20_2 17.9 _ N 10 9 11 10 9 8 I v0 ir(eO VQC3
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APPENDIX 6 CON'T PLATELET ADHESIVENESS AND AGGREGATION CODE 11 EXP05URE_TIME 400 DAYS ADP 2X10 ,~M COLLAGEN 0.26 MG/ML ANIMAL XADHESIVENESS XADNESIVENESS PRE EXPOSURE POST EXPOSURE PRE EXPOSURE POST EXPOSURE NUMBER PRE EXPOSURE POST EXP-OSURE (7. AGGREGATION) AGGREGATION) (X AGGREGATION) (: AGGREGATION) 5052 72 75 70 78 H.R. 68 5129 81 81 74 82 82 70 5148 79 79 30 34 70 78 5153 63 63 86 ~ 84 80 76 5165 77 74 62 80 70 80 5233 80 80 74 76 66 66 5237 81 78 84 84 77 82 5261 63 66 68 68 68 68 5267 87 80 52 64 70 76 5337 74 75 84 74 84 78 MEAN 75.7 75.1 68.4 72.4 74.1 74.2 5D 7.8 6.1 17.1 15.0 6.7 5.7 N 10 10 10 10 9 10 ~~ V~ o I O V
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APPENDIJf 9 CON'T PULMONARY MEASU_RE_MENT FOR THE CODE 68 GROUP AT YOO DAYS EXPOSURE N2 WASHOUT DOG -------------ARTERIAL 9LOOD G_ASES-------------- 02118 HB COtIB PH PC02 P02 VOL. TO 2: 112 CLOSING ----VOLUME---- VITAL CAPACITY PHASE III SLOL'E MINUTE VUI.UFiE Ho. 5039 (:) (GL100 ML) (7.) (M_M HG) (MM HG) 92.2 11.0 1.5 7.41 30.7 79.1 (ML) 9763.0 (ML) 200.0 (f) 15.0 (ML/KG) 85.8 (( N2iL) 7.5 (ML(lIINlK_G_) 224.3 5046 89.5 >E+~~>4 1.3 7.41 32.5 75.2 8834.0 160.0 16.0 70.3 7.5 377.7 5143 94.8 *K 0.2 7.44 30.3 105.9 6545.0 370.0 35.0 84.8 9.0 145.2 6014 40.5 11.0 0.9 7.43 33.6 74.0 7920.5 160.0 17.0 ' 72.8 7.0 196.2 6016 93.8 11.4 1.6 7.40 31.7 88.1 7464.8 210.0 19.0 93.3 6.5 318.3 6039 86.6 10.6 1;8 7.43 37.0 64.6 4600.4 180.0 22.2 70.4 9.5 ISd.7 MEAH 91.23 11.00 1.22 7.42 32.63 81.15 7521.28 213.33 20.7 79.57 7.83 245.07 SD 3.01 0.33 0.58 0.02 2.45 14.32 1810.82 79.4Y 7.5 9.70 1.17 94.48 N 6 4 6 6 6 6 6 6 6 6 6 6 ` z9zf:oto~3
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APPENDIX 9 CON'T PULMONARY MEASUREMENT FOR TIIE CODE 68 GROUP AT 400 DAYS EXPOSURE DOG ------ 02HB N0. (i) 5039 97.3 5046 96.3 5106 92.4 5109 96.3 5153 97.0 6014 89.8 6016 97.9 6018 93.4 6038 95.8 6039 92.4 h N2_ WASHOUT ------- ARTERIAL BLOOD G_ASES-------------- HB COIIB PH PC02 P02 (G_/I00 ML) (7.) (MM HG) (MM HG) 17.1 1.6 7.44 27.7 91.4 17. 1 1.4 7.37 31.2 73.6 17.3 1.6 7.45 29.1 88.2 16.1 1.6 7.42 29.8 81.3 17.0 1.9 7.42 32.7 93.4 16.3 1.6 7.39 32.9 59.5 16.2 1.4 7.44 3i.9 101.1 17.3 1.8 7.44 32.1 68.2 15.5 1.7 7.37 32.2 82.0 16.8 1.5 7.41 31.4 62.1 VOL. T0 CLOSING VITAL PHASE III HEFIIITE -2: N2 ----VOLUME=--- CAPACITY SLOPE VOLQtlE (ML) (ML) ('l.) (19L[KG) (: H2/L) (ML1191NiKG) 6934.0 400.0 27.6 87.9 4.0 39L.7 6063.0 220.0 20.2 80.7 8.5 320.1 5547.0 220.0 18.0 94.6 9.0 175.9 9653.0 240.0 26.7 90.9 6.5 213.9 6329.0 270.0 26.0 81.3 11.0 219.4 4343.0 150.0 16.0 75.2 7.5 185.8 6847.0 130.0 12.5 85.3 8 .5 368.3 7862.0 330.0 32.0 73.1 7.5 .i09.3 4368.0 330.0 30.6 97.3 8.5 247.9 5962.0 250.0 26.5 81.2 9.5 437.5 6390.80 254.00 23.6 84.75 8.05 286,64 1584.71 82.89 6.5 7.96 1.18 92 .61 10 10 10 10 10 10 ~ MEAN 94.86 16.67 1.61 7.41 31,10 80.08 51) 2.68 0.61 0.16 0.03 1.70 13.94 j 11 to to to 10 to 10 C-3 cm ~ -rtI ~ ~ -~ ~ v97EOv08
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ANIMAL r Ajll MM_w APPENDIX 6 CON'T PLATELET ADHESIVEfIESS AND AGGREGATION CODE I1 EXPOSURE TIME 1200 DAYS ADP 2X10 M iADHESIVENESS XADHESIVENESS PRE EXPOSURE POST EXPOSURE HUf10ER PRE EXPOSURE POST EXPOSURE (% AGGREGATION) (: AGGREGATION) 5052 42 5129 53 5148 39 5153 31 5165 67 5233 60 5237 55 5267 61 MEAN 51.0 SD 12.4 N 8 COLLAGEN 0.26 CIC/ML PRE EY,P05U[?E COST FXI'USURE (y• AGG(tEGATION) ( : AG;I;EGATIOH) 45 49 53 HR NP. 49 44 43 HR IIP. 46 20 21 I;R IIR 3Ii 37 42 NR IIs' 37 12 18 44 NP. 63 12 30 48 58 54 14 22 48 113 60 18 2 1-1 46 53 48.5 25.8 31.6 44.5 43.0 10.2 15.2 12.8 1.9 5.0 8 8 8 4 3 t!ol[•UYQC3
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~~~~~~ n A"---j on m m I A m a a 2_m_A APPENDIX 9 CON'T PULMONARY MEASUREMENT FOR THE CODE 68 GROUP AT 200 DAYS EXPOSURE -------------ARTERIAL BLOOD GASES-------------- DOG 0211B NB COHB PH PC02 P02 110. (:) (G<100 ML) (~) (MM HG) (MM HC) 5039 92.8 17.8 0.6 7.39 31.1 79.5 5046 95.6 13.9 0.9 7.45 30.0' 96.4 5i06 87.8 18.1 1:4 7.36 33.3 60.1 5109 83.4 18.0 1.4 7.39 37.5 53.9 5143 94.6 17.6 0.7 7.44 29.7 85.4 6016 93.7 17.2 1.4 7.39 25.6 79.2 6018 92.4 NNK)( 1,2 7:41 31.5 69.3 6038 93.2 17.5 0.3 7.44 26.7 62.9 6039 90.0 16.7 1.6 7.41 30.1 68.1 MEAN 91.50 17.10 1.06 7.51 30.61 72.76 51) 3.85 1.37 0.45 0.03 3.49 13.47 N 9 8 9 9 9 9 S N2 WASHOUT VOL. TO CLOSING VITAL PHASE III MI11U1E 27. N2 ----VOLUME---- CAPACITY SLOPE VOLUMF (ML) (ML) ( :) (MLiKG) (% N2 iC) (11LiMIi;/KG) 6933.6 400.0 28.0 84.1 5.0 2~i9.0 5190.5 250:0 22.9 75.2 7.5 181.2 4944.9 250.0 23.5 84.1 10.5 213.5 6465.7 280.0 30.4 97.8 8.0 578.0 5929.4 290.0 27.6 80.8 8.0 196.3 5336.3 240.0 19.7 101.7 6.0 340.2 5623.2 370.0 30.8 74.4 7.5 357.7 4441.6 290.0 26.8 102.8 12.0 306.3 4233.6 360.0 35.0,. 108.4 11.0 245.6 5455.41 303.33 27.2 89.92 8.39 296.42 889.09 58.74 4.7 12.83 2.33 122.51 9 9 9 9 9 I 9 r-- cgzcovoe
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APPENDIX 9 CON'T PULMONARY MEASUREMENf FOR THE CODE 68 GROUP AT 1100 DAYS EXPOSURE ----------------ARTERIA__L PRE BLOOD POST GASES------------------ N_2 WASHOUT OL TO CLOSING VIT PLi SE III MINUT DOG 02HB HB COHB COIIB PH PC02 P0 2 V . 27. 112 ----VOLUME---- AL CAPACITY A SLOPE - VOLIIN N0. (i) (G<100 ML) ('/.) (%) (MM IIG) _ (MM NG) (ML) (ML) (%) (ML(KG) (Y. F12/L) (MLiMIH< 5039 53.0 17.4 2.4 2.1 7.52 33.0 _ 47.8 7855.0 240.0 16.3 87.0 5.5 282.5 5046 58.0 16.4 2.0 2.0 7.49 36.8 54.9 7899.0 150.0 20.3 'i8.0 5.5 2_43.8 5106 90.4 2.9 2.8 7.33 31.8 62.5 4221.0 200.0 16.4 92.4 7.5 184.9 5109 90.4 ~>F?1) 2.7 2.6 7.39 30.6 58.4 5382.0 180.0 18.9 97.9 8.3 335.6 5143 66.5 16.6 1,7 1.9 7.42 37.7 72.4 6564.0 400.0 35.4 81,9 8.5 206.0 6014 60.4 17.2 2.0 2.2 7.46 30.9 50.9 7313.0 xitxltl~ )*xxat 68.7 7.0 334.6 6016 63.2 16.3 1.9 T;7 7.54 27.9 50.9 8510.0 100.0 8.8 87.0 8.0 324.8 6018 92.8 KK*K 2.8 2.4 7.34 35.8 67.8 6304.0 200.0 18.5 75.5 6.0 276.9 6038 uxxx xt~xx 2_.4 2.2 i4xxN 38.0 48.4 5078.0 220.0 19.8 103.7 7.0 332.6 6039 61.0 16.7 1.7 2.1 7.52 28.7 51.6 5141.0 170.0 18.1 83.2 11.0 367.0 I MEAN 70.63 16.77 2.25 2.20 7.45 33.12 56.56 6426.70 206.67 19.2 82.53 7.43 288.8 SD 15.86 0.44 0.45 0.33 0._08 3.73 8.50 1 445.13 83.2_2 7.0 15.83 1.66 60,9 N 9 6 10 10 9 10 10 _ 10 9 9 10 10 f0 w w L e9reotut
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. . APPENDIX 9 CON'T I PULMONARY MEASUREMENT FOR THE CODE-68 GROUP AT 800 DAYS EXPOSURE ----------------ARTERIAL PRE DL00 POST D GASES--.-----------.----- H2 WASHOUT VOL T S DOG 02NB_ NB COHB COHB PH PCO2 P02 . O 2% N2 CLO ING ----VOLUME---- VITAL CAPACITY PHASE III SLOPE MINUTE VOLUME Fio. (i) (GEt00 ML) (s:) (:) (MM HG) (MM HG) (ML) (ML) (X) (biL/KG) (Z N2/L) (ML /MINtK 5039 96.4 14.9 1.6 0.6 7.43 31.6 82.2 6880.0 300.0 20.1 88.7 6.0 _ 277.7 5046 96.7 13.2 1.3 0.4 7.41 39.9 88.3 6271.0 360.0 37:1 67.8 4.5 247.3 5106 96.2 16.1 1.7 1.4 7.37 46.2 93.2 4861,0 140.0 14,7 73.6 11.0 218.7 5109 89.6 16.0 1.4 1.6 7.39 41.8 76.5 5045.0 H*xb11 1Q0.0 8.5 478.0 5143 96.7 15.1 2.0 1.5 7.44 40,9 83.9 6181.0 xxwxx txx~ 't7.9 15.0 197.6 6014 95.8 15.6 1.7 1.3 7.37 45.3 78.6 4731.0 200.0 21.0 79.2 7.5 252,1 6016 98.5 16.4 1.9 1.8 7.41 33.7 100.1 5569.0 220.0 17.9 94.6 8.0 327.6 6018 95.4 17.2 1:7 1.5 7.39 46.3 94.0 6662.0 xxttxx axXA 85.6 6.0 293:5 6038 94.7 14.1 1.0 1.2 7.37 46.2 83.8 4828.0 xtixKx ttxxx 107.5 12.5 206.9 6039 96.0 15.8 1,7 1.5 7.38 36.3 78.5 4652.0 xxxxx xgxx 73.7 15.0 408.1 E1EAN 95.60 15 .50 1.60 1.28 7.40 40.82 85.91 5568.00 244.00 22.2 84.86 9.40 293.75 51) _ 2.33 1.16 0.29 0.44 0.03 5.44 7.78 859.48 86.49 8.7 12.80 3.78 90.15 N 10 10 10 10 10 10 10 10 5 5 t0 10 10 ~ !"P9 ~ ~"J .~ _.., ~ ...~ .~, , 99ZCOV0R
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` APPENDIX 9 CON'T P-ULMONARY MEASUREMENT FOR TIIE CODE 67 GROUP AT IOO DAYS EXPOSURE w V -------------ARTERIAL BLOOD GASES-rrr--r------- DOG 02118 HB COHB PH PC02 P02 N0. (:) (G<100 ML) (i) (MM HG) (MM HG) 6028 91.3 18.6 1.8 7.40 34,7 83.4 6030 93:2 16.3 0.1 7.42 28.2 90.5 6031 88.0 17.0 2.0 7.38 32.2 81.9 6032 94.3 17.3 7:6 7.39 31.3 87.3 6034 91.4 18.9 1.0 7.35 28.8 92.3 6035 93.0 17.4 1.3 7.45 27:5 87:5 6037 92:9 16:2 0.6 7.37 31.7 89.3 6040 92.2 16.8 2.0 7.42 29.1 86.6 MEAN 91.48 16.383 1.23 7.40 31.23 83.82 56 2.49 1.54 0.77 0.03 3.71 8.75 N 50 50 49 50 50 50 N2 WASHOUT VOL: TO CLOSING VITAL PHASE III MIIIUTE 2% 112 ----VULUME---- CAPACITY SLOPE 40LUME (ML) (ML) (Y) (MLiKG) (k N2tL) (t7llMIlitKG) 5616.0 300.0 33.0 75.9 17.5 277.2 6041.5 220.0 23.0 75.2 10.0 /80.6 6307.2 130.0 16.0 66.7 32.0 151.2 6458.4 210.0 24.0 80.9 10.0 141.4 6264.0 170.0 15.0 89.3 1_2.5 257:6 6436.8 200.0 22.0 72.8 9.5 i72.8 7000.0 120.0 13.0 93.7 15.5 404.2 7063.2 120.0 14.0 61:5 10.0 288.0 6677.28 2_29.80 2_2.8 89.06 13.13fi± 309.29 1094.96 95.88 7.1 17.18 6.47 I20._85 49 50 50 50 50 50 7 ~
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m ."~ u u M M AL M m m m APPENDIX 9 CON'T PULMONARY MEASUREMENT FOR THE CODE 68 GROUP AT 1000 DAYS EXPOSURE ---------------- ARTERIAL PRE DOG 02HB HB COHB NO. (%) (Gt100 ML) (:) 5039 91.6 16.8 2.1 5046 87.2 16.5 2,4 5106 58.3 13.8 1.4 5109 51.2 14.7 1.7 5143 96.6 16.9 2.0 6014 93.8 16.0 2.7 6016 91,1 16.6 2.5 6018 62.0 16.0 1.9 6038 67.1 15.0 1.4 6039 81.6 16.1 1.6 MEAN 78.05 15.84 1,97 SD 16.77 1.02 0.46 N 10 10 10 BLOOD GASES------------------ N2 WASHOUT POST VOL. TO CLOSING VITAL PHASE III MINUTI COIIB PH PC02 P02 2% N2 ----VOLUME---- CAPACITY SLOPE VOLUMI (%) (MM RG) (MM lIG) (ML) (ML) (Y.) (ML/KG) f_X N2/L) (ML/11INi1 2.4 7.37 39.4 85.5 6564.0 370.0 24.3 87.4 5.5 150.9 2.1 7.29 41.2 74.1 7286.0 190.0 17.3 71.0 8.5 208.9 1,8 7.52 34.5 66.9 4708.0 350.0 28.4 98.4 7,5 158.4 1.7 7.58 29.4 45.1 5698.0 210.0 21.6 98.0 7.0 575.5 2.6 7.30 39.6 95.8 7177.0 280.0 23.7 86.1 12.0 194.8 2.6 7.31 37.2 86.7 7494.0 290.0 28.4 80.3 7.0 172.3 2.4 7.31 33.1 73.3 5162.0 130.0 9.1 109.2 8.0 295.7 1.8 7.56 29.8 56.7 7414.0 )s)()(x>t xxxa 75.4 8.5 223.3 1.5 7.45 39.0 78.9 4840.0 K!1KxK iFli+()( 123.2 8.5 240.8 2.2 7.38 35.3 58.6 4838.0 270.0 23.3 104.5 5.0 276.3 2.11 7.41 35.85 72.16 6118.10 0.39 0.11 4.15 15.57 1183.56 10 10 10. 10 10 261.25 22.0 93.35 7.75 249,6! 80.97 6.3 16.31 1; 93' 124.0( 8 b L9zzw E0V0R
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a A A A iff ,.r~ JIYI ~ ~L J"W'~ iur ~..~~- r + J ~ APPENDIX 9 GON`T.. PULMONARY MEASUREMENT FOR THE CODE 67 GROUP AT 200 DAYS EXPOSURE N2 WASHOUT DOG ------------- ARTERIAL BLOOD GASES-------------- VOL. TO 02HB HB - COHB PH PC02 P02 2'/. N2 CLOSING ----VOLUME---- VITAL CAPACITY PHASE III SLOPE MINUTE VOLUI9c N0. ('/.) (G/100 ML) (X) (MM HG) (MM HG) (ML) (ML) (Y,) (ML/KG) (X 142tL) (MIiI91Nii;G) 6024 94.8 7.42 30.0 94.3 4880.0 490.0 37.0 117.3 7.0 215.0 6026 93.0 18.6 1.9 7.35 37.3 79.7 8467.0 330.0 25.4 100.0 5.5 2i5.8 6027 93.0 19.8 2.2 7.40 42.6 77.9 5642.0 270.0 28.4 86.4 12.0 327.9 6028 93.4 *xxx x*Ha 7.38 33.9 81.7 5983.2 130.0 14.8 80.0 14.0 392.7 6030 91.4 17.5 1.2 7.40 31, 1 74.5 7236.0 200.0 21.3 78.3 15.0 216.0 6031 93.8 16.0 1.4 7.41 33.4 90.4 5616.0 160.0 20.5 74.3 30.5 181.0 6032 92.3 16.1 1.6 7.40 33.4 76 .7 6307.0 280.0 31.8 83.8 10.5 306.5 6034 92.8 16.0 1.0 7.40 27.3 76.2 x>Exasitx1 450.0 34.6 113.1 8.0 229.1 6035 91.8 15.9 1.7 7.43 29.7 73.2 t4xxkxx1 360.0 3.6 90:9 9.5 219.9 6037 94.4 16.4 1.0 7.45 27.1 77.7 6977.0 290.0 32.2 87.4 10.0 337.7 6040 88.6 17.4 1.4 7.41 33.3 61:7 6336.0 200.0 22.5 68.5 14.5 372.2 MEAN 92.35 16.12 1.18 7.40 32.16 81.95 6305.188+ 246.048 23.6 89.68 12.940+ 304.20 SD 2.62 1.39 0.57 0.04 3.56 11.80 1075.60 92:29 7.1 15.07 6.04 83.96 N 53 51 50 53 53 53 51 53 53 53 53 53 R v=0VUR
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APPENDIX 9 CON'T PULMONARY MEASUREMENT FOR THE CODE 67 GROUP AT 400 DAYS EXPOSURE -------------ARTERIAL BL00D GASES-------------- DOG 0211B HB COHB PH P-C02 P02 NO. ('/.) (Gl100 ML) (`/.) (MM HG) (MM HG) 6034 93.3 18.2 1.7 7.42 28.7 86.7 6035 95.4 16.1 2.6 7.46 30.4 92.7 6037 89.7 17.0 1.9 7.52 30.4 65.0 6040 95.6 17.6 1.7 7.62 25.0 94.9 MEAN 92.068 15.97s 2.073+ 7.41 30.79 77.17 SD 4.14 1.42 1.06 0.05 3.69 12.63 H 46 46 44 46 46 46 N2 WASHOUT VOL. TO CLOSING 2% H2 ----VOLUME---- (ML) (ML) (R) 7238.0 370.0 25.6 '8074.0 200.0 21.7' 6468.0 280.0 28.5 6776.0 250.0 25.2 VITAL PHASE III MINUTE CAPACITY SLOPE VGL1119E (ML/RG) (% N2/0 (ML/MIN/KG) 111.6 6.0 293.3 70.7 14.5 275.8 94.2 13.5 357.5 73.3 11.0 462.8 6949.09 283.49 26.9 88.58 1205.51 98.49 7.3 12.38 46 43 43 46 s+ s+ 12.00 372.70 4.20 112.73 46 46 9fAzcOvOR
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11 CE1a~r1011ri'1AL APPENDIX 10 REFERENCES HEMATOLOGY AND HEMOSTASIS Ez^y,thr.ec~ te Count, Leu'eocyte Count and gemegZo: i~n - Coulter Electronics, Inc., Hrf'aleah, Flordia if &ematocrit - Mialle, John B. 1972. L'aborator Medncine;. Hematology„ 4th ed. p. 1!205. If f PZateZet adr.esiveness - Salzman,, E.W'. 1963. Measurements ments of'platelet adhesiveness: a sample in vitro tech- nique demonst'rating, an abnormality in Von WiTliebrand''s disease. J. Lao. CZin. Nred. 62':724-735. ~ PZateZet Aggregation __ Born, G/V.R. 1962. Aggregation of blood platelets by adenosine diphosphate and its rever- sadl. Nature. '194:, 927-9291. I I ' I I 4 I PZateZet Cozozt - Technicon Instruments Corporation; Tarrytown, N.Y. PZateZet Rererence N Assay - Wiintrobe, M.M. 1967. ClinicaT Hematology, 6thied. Lea andiFebiger, Philladelphia, Pa. p. 303. CLINICAL CHEMISTRY AZbtanin - Doumas, B.T., D.D. Ulmer, and H.GI Bigg$. 1971. Standards and the measurement of serum albumin with bromcresoT green. CZ'in. Chim. Acta. 3'1:87-96. BZood Ure Ni tragen - Ma rsh „ W. H., B'. Fi nge rh ut and H. Mi l l er. 1965. J., CZin. Cherr.., 11 (6). CaZciur7i-- Kessler, G., andl M. Wolfman. 1964. An auto- mated procedure for the determination of caillci'um and phos- phorous. CZin. C74er.r. 10:,586-703. CFiaZesteroZ - Levine, J., S. Morgenstern, and 0. Vllastel'ica. 1968. A direct Li'ebe mnan - Burchard method'for serum choles- terofi. Automation in anal'yticall chemistry. Technicon Sym* posial„ 1967, White Plains, N.Y., Med::ad :nc., pp 25-28.. I -34C-
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I I I I ~ 11 I J CURTIDfNrIAL APPENDIX 1'0 CON'T REFERENCES Cre4tun.e Pnosphakzr.cse _ RosaTki, S.B. 1967. A'ni improved proced'ure for serum creatine phosphokinase determination. J. Lab. CZi:rs. Med. 691:5961. Creatinine - Chasson, A., H.T. Grady andMlA'. Stanley. 1961 Akn. J. CZ'in. Path. 35:83. GZucose - Bittner, D.L., and J. Manning. 1967. Automated neocuprovine glucose method: critical factors andlnormal values. Automation in analy,tical chemistry. Technicon ' Symposia,1966, Uoll. 1, Whit'e Plains,,N.Y. Mediad Inc. pp 33-36. GZutom•t;c Qx:Zacetie Trmesarrnase and GZuta^;t:cPyruvate '^rar:s=.in:se kessler„ G~ „ R. Rush, L. Leon, A. Delea, and R. Gupiol'a. 1971. -Automated 340 nm measurement of SGOT,SGP'f and LDH. Advances in autamaGed analysis. Technicon International Congress, 1970, VoT 11,, Miami, Florida. Thurman Associates. pp67-74. Inor^anic Phospnorus - Hurst, R. 1964. The determination of nucleotide phosphorus with stannous chloride hydrazi'ne suTphate reagent. Can. J. Biochem. 42:287-292. L.atic De'r.ydrogenase - Wacker, N., D.D. Ulmer„ and B.L. Va1Te_ 1956. Metalleonzymes and Myocardial Infarction. New Bnolan4' J. Med: 255:449. Serwn Protein ELectroahoresis - Zip-Zone cellluTose acetatemethod',. Helena Laboratories, Beumont, Texas. TotaZ P'rotein. - Skeggs, L.T. J?-., and1H. Houchstrasser. 1964. CEin. Chem. 10:918. PULMONARY PHYSIOLOGY Nitrogen Washout , Luft, V.C., E.H. RoorbacFi,, and R.E. MecQuigg. 1955. Pulmonary nitrogen cl-arance as a criterion of ventilatory efficiency. Am, Rev. Tuoerc. 72:465-478'. Singue Breath Nitroaen - Mead, J.W. andlJ.L. Wittenberger. 1953. Physical properties of humamlungs measured duringispontaneous respirat,ion. J. Apai. Physiol. 5:779-796.
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UNThENTlAd APPENDIX 10 COPdT'D REFERENCES E Comroe, J.H., andlW'.S. Fowler, 1'9511. Detection of uneven alveollar ventilation during a single breath of oxygen. American J. of ^4ed: Apr. 4 :408-47 3'. Lenahan, J. and Smith, K. (T976)'. "Hemostasiis Seminar," 111th Edhtion, pg. 50; General Diagnostics Division of Warner- Lambert Co., Morris PTains, N.J. 07950. Levine, P.H. (1973). "AniAcute Effect of Cigarette Smoking on P1'etelet Function."' Circu?auzon 48!:619. Mead, J., and C.R. Colliier. Relation to volume hi'story of lungs to respiratory mechanics in anesthetized dogs. J. AppZ. Phy~ioi. 1'4:.669-678', 1'959. Meadl„ J. and E. A. Gaensler, Esophageal and pleural pressures in man upright and supine. T.ApgZ'. Physioi. 114':81-83, 11959. Millic-Emiili„ Ji., J. M'ead, and J.M. Turner. Improved technique for est'imatingipleurall pressure from esophageaT balloons. J. AppZ. FhysioZ. 19:207-211, 1'964., Swatman, L.E. "Shouldi You Do Qualitative Screens?" Med~c Z Labs:pg. 27. 0 1K I -3410-
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CGNTi]DEMTIAL 9 9 11 I It I I g mi cl I c I cli 9 LL tm 4 8 r p o ppp ~^ op p p p ~ O~ C ~~~. O O~ C O O~ O~. ~. O. Gi. CO', I\,. ts ~ u"i~ z7` f.1~ (lj~ ,-y~ (W h(1'1mA -35G O
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71 I f D I I ~ Ka S i O M, p. 111, 0.,. '~ I O V' 1' j 8 (A') v) AlI7Hdv3 lVl;A/"10n SPIVSDID -3~~- i
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, w W 100 200 F1W. 2 CODE 13 N2 WASHOUT TO 2% 1100 609 DAYS OF DQ 05URE = = m m m m m m " X-X fADE 13 (LOw) 0-0 CO(E 33 (CQNTROL) 1401) 15M RNUOVUR
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AROPERTY OF LOt1LL:RD-TRADE SECRETS AND CG"1FIDENTIl9L- SUBMITTEDTO CI3l.GEIGY PURSUWNT TO NON-DISCLOSURE A~e su~ tsT -3- CLL '~ F( ~'EUflAi A top flavor containing sclareolide was developed which masked' the Pf30 flavor. Twenty-two thousand PMO ciga- rettes were preparedifrom Max tobacco sprayed with the maskiing,flavor and PMO. Ren:t 85 filters were attached'd to these cigarettes. The cigarettes were foundlto contain 1.29% PMO on the tobacco portion and delivered 1.1 ng PMO to the mainstream smoke. Biologiicail Experiments Date of Experiments: 1977 to 1978 Where Reported: "'Protective Action of PMO Against Cigarette Smoke Induced Inhibition of Mincociliary Particl!e Transport in the Chicken Trachea",, J. S. Heck and H,. S. Tongi„ Lori'llard Report No. 1'04!4, Aug. 18', 1977. "Mucociliary Particle Transport in the Isol!ated Chicken Trachea: Effects of 20 ml Puffs of Cigarette Smoke:,, P340 vapor, and Smoke of 2% PMO Treated!Cigarettes"„ J., D. Heck, and H. S'. Tbng, Lorillard Report No. 123'2, Aug. 9, 1978. Admi'nistration:r PtiO vapor or tobacco smoke containing PMO was passed over excised chicken trachea in a speciall chamber which permitted continuous observation of changes in rates of mucociliary particle transport. Purpose: To see whether the ilsolatedichicken trachea couTdlbe used to detectr anti-ciliostatic activity. Resul!ts:, Statistical,analysis of,the data collected shows no significant difference between the ciliostatic activi- ties of cigarette smoke„ P230 vapor,,or, the smoke of 2% PMO cigarettes., Date of Experiment:, 1977' Where Reported: "Analgesic Activity of PMO: in the MOuse" , Hi. S'. Tbng, Lorillard Report Na. 1060, Oct. 4,, 1977. Adminiistration:, Several groups of six Swiss-Webster male mice were administeredlvarioue amounts of PMO or phenylbutazone orally. The animals were then made to writhe by an i.p. iinjiection of 3% ' acetic acid.
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PROPERTY OF LORILLARD'TRADE -4- rcCRETS AND CONFIDENTI'AL-~ SU9MiTTED TO CIHA GEIGY PURSUAf:T T0, NQN, D15CLOSURE AGREEMENT. C(.l!:'f luB.',1 1'AIIL, Purpose: To compare the analgesic action of'PMO with phenyl- butazone,by counting the number of'writhes in a 2-0 minute periodl. Results: PMO has 0'.75 the analgesic activity as phenyl!butzone on, aiweight basis. PMO Analogs Synthesized at LRC' Date of Experiment:: 1975. Where Reported: "PMO and Drugs Used in Lung Therapy. A Computer-AssistedlStudy of'Molecular Similari- tiies"„ R. S. Marmor memo to H. J. Mi~nnemeyer,. Feb. 18, 1975. - Purpose: To use an in-house computer programito compare the molecular volume and electron density of PMO with that of 3'0:other drugs used in lung therapy. Results: Cluster plots of the computer data indicate a close relationship of PMO to those of' the benadryl and, epinephrine type of drugs., ---------------------------------------------------------------- Date of Experiment: October 1975 to March 1976. Where Reported: "Synthesis of'PMO Derivatives",, R. S. Marmor memo to ff. J., Minnemeyer, Apr. 13',, 1976. Purpose:: Tb prepare PMO analogs to be tested for physiological activity and compared to PMO. Results: Twenty-one compounds were synthesized for:testing. ---------------------------------------------------------------- Date of Experiment:: 1977. Where Reported: "Mutagenicity Assay of PMO Analogs", J., D. Heck and H. S. Tong, Lorililard, Report IVo.973', Mar. 14!,, 11977. Purpose:! To determine the mutagenicity of':2-0 PMO analogs usingi the Ames Salmonella,/Mammalian Microsome Mutagenicity test. Results: None of the PMO analogs submittedlby Dr. Marmor were mutagenic under the conditions of'the test. Further- more,, there was no indication,of tox,ici~ty at the high dose level.
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PROPERTIY'OF LORILLARD-TRADE SECRfiT!SI AND CONFIDENTIAL•. SUBMITTED TO CIBA~GEIGY PURSUANT TO NONI-DISCLOSURE AGRfEMENT,. -5- PMO Material Balance on Ciigarettes Date of Experiment: Before 1975. ~L,~EFI&E ~~iil Where Reported: "Material Balance Studies on Cigarettes Contain- ing 3-Pheny-5-methyl-1,2„4-oxadiazole"„ R. S., Marmor,. H. Ji. Minnemeyer,, Beitr. Tabakforsch. 1975,, 8('4) , 199-203., - Purpose:! To determine the distribution of PP:•10 in mainstream, and sidestream,smoke and on the butts, filters and ashes of PM0'impregnated' ciigarettes.. Results: Using 14C rad'iiolabeTed PMO, 96% ' of' the radiolabel' was accounted for upon analysiis of the smoking,products_ A L J
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PROPERTY OF LORILLARD•TRADE SECRETS A'ND: COFJFIDENTIIA'L- SUBNIITTED TO C]EA,GEiGY' PURSUANT TO tVON•DISCLOSURE AGREEMENT., Resultsr -8, Tobacco smoke produced inflammatory changes in the respiratory tract and increased the amount,of certain proteins inithe mucus. PMO in the smoke did not increase inflammation but did not seem to prevent it.. On the other hand, PMO was associated'withifurther increase of protein:in the mucus. It was uncertaini whether this arose from mucosal irritationior implied only stimulationiof a-antiitrypsiniproduction for protective purpases., Date of Experiment: Falll 1980 - Summer 198'1. Where Reportedl: Part-tiime Results from on-going Pilot, Study of Clinical Effects of PMO", G. Hillerdal, Progress Report Feb. 28',, 19811„ Pldininistrati~oni: Fifteen human volunteers who are smokers and have chronic bronchitis are to receive 125 mg PMO x 4 orally for four weeks. Purpose: To investigate the effects of PMO on lung function off subTectivel!y healthy smokers.. Results: Only ten patients have been started on PMO and an, analysis of the data has not been made yet.
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" m m m m = = "- a 10,000 9,000 8.000 7,000- 6,000 5,003- Y,VW 3,000 2,000 11000 100 200 FIGUf,E 2 (EaNrirniEn) COCE 32 N2 WASHOUT TO 2% X-X CQDE 32 (HIGH) 0-0 CODE 33 (CONTROL) 40Q 600 1400 1`M DAYS OF D'OSU(E QGZCQVUR
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PROPERTY'OF LORILLFlRD-TRADE SECRETS AND CONFIDENTIAL. -9~ SUBMITTED TO CIBA,GEIGY i PURSUANT T0 NON•D18CLOSURE AGREEN1fNT. RAT PMO SM'OKIiNG EXPERIMENTS - BROMPTON HCISPITAL Date of Experiment: 1971 'a. Where Reported: "Protection:of Rat Bronchial Epithelium Against Tobacco:Smoke", R., Jone:s„ P. BoldUc artd L. Reid,. Brit. M'ed., J'. 1972, 2', 142-144. Admini'stration:, Fifteen Sprague-Dawley rats were exposed to cigarette smoke, 15 more were exposed to the smoke from 28 PMO cigarettes and 11 were con- trols. The first twa groups were exposed to the smoke of 25 ci'garettes each day four days a weekk forsiix week:s:.. Purpose: To test the effect of BMO in cigarette smoke on the increase in goblet cells andion the nature of the distribution of acid glycoprotein they contain, on the ceTls in mitosis, and on the epithelial thickness. Resu:lts: The animal!s receiving PMO:smoke showed less immediate distress after exposure, a smaller tracheal' goblet ce11 count, less thickening of the trachea,l epithelium and less ceTls in mitosis than those exposed to ordinary tobacco smoke_ Date of Experimentc, 1971 b,. Where Reported: "Goblet Cell Glycoprotein and Tracheal G1'and Hypertrophy im Rat Airways. Effect of Tobacco Smoke wiith or Without the Antiinflammatory Agent Phenylmethylioxadiazole", R. Jones, P'. Bolduc,, L. Reid, Brit. J. Exp. Pathol 1973',, 54,(2), 229-39. A'dministratiion: Nine rats exposed to tobacco smoke, nine rats exposed!to smoke from 2% PMO:cigarettes and siixx controls were taken from the 19711 a' experiment. Purpose: To study the effect of tobacco smoke alone and smoke from 2% PMO cigarettes in regard to the size of the secretory mass iir the goblet cells„ the type of glyco- protein present and with the hypertrophy of'the tracheal, g,l a nd ., Resul'ts: The goblet cells in the animals receiving tobacco smoke and tobacco smoke pl'us PMO secretedlgreater amounts of g,lycoprotein thar, the control animals. Those receiving PMO have more ceTTs in both' the ax:iali and lateral pathways of the lung which secrete acid glycoprotein than in,the contro:l animals or in the aniimals receiving tobacco smoke alione. It appears that addition of PM0
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PROPERTY OF LORILLARD~TRADE SECRETS AND CONFIDENTIAL• -6- SUB4!ITITED TO CIBA~GEfGY LVi~fIi'~ PURSUANT TO NDN-DISCLOSURE AGREEMENT. STUDIES PERFORIv1ED AT UPPSALA UNIVERSITY Imhalation ofPM&V'aporby Healthy Subjects IDate:, January 1976. Administration: PMO vapor (0.42 mgLinin. ) was inhaled, periodically (l hr./day, 5 days/wk.) over a span of three weeks by aipanel of eigiht (3F, 5M). It is estimatedthat a total of 378 mg of PMO was: inhaled by each subject over this 15 hr. period. A control group of four (2M, 2F) inhaled menthol on the same regimen. Purpose: Tb obtain physiological data comparing inhalation of PMO with inhal'ation of menthol. Results:: Subjects were,given a clinical' examination, urinary analysis, blood multi-test analysis includling,acid-base balance and blood!gases in arterial!ized and capillary blioodl, and lung function measurements before and after PtSO inhalation., All subjects had normal spirometric values before and after the inhalation period. PMO caused no signiificant changes in vital capacity, expiratory andiinspiratory flow rate or maxim,al volun- tary ventilation. Menthol caused a slight decrease in expiratory flow rate measured as FEV 1 0. Both PMO and menthol caused a significant decrease in Po2,in arte- rialized capillary blood. This:is not considered serious and probably results from the use of the face masks themselves. ---------------------------------------------------------------- PI40 Cigarettes Date: M'arch, 1977. Adhinistration: An experimentall group of ten (6M, 4F) smoked PI•10 cigarettes containing 11.291% PI40 over a period of six weeks. A control group,of ten (3M, 7F) smoke a similar cigarette, but without PNO, over the same period. It is estimated that the PMO smokers inhaled from 0.5 to 1.5 g of PtIO via the 70~-201 cigarettes per week smoked., Purpose: To make clinical and lung function observations of healthy smokers before and after inhaling PMO1from cigarettes:. Results: There were no significant differences in subjective symptoms or spironetric values before and after the six weeks smoking period for the PMO smokers. In the:
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PROPERTY OF LORILLARD,TRADE SECRETS AND! CONFIDENTIAL• -10- SUBM9TT'ED TO CIBA•GEIGY PURSUANT TO' NON• DISCLOSURE AGREEMENT. C'G(~tf huENIIlIA~L to the tobacco:causes an increase in the size of the secretory mass of acid glycoprotein within the cell. PMO does not prevent any change in~the nature of the glycoprotein synthesized by the gpblet:cells but prevents or partially suppresses the discharge of the secretory granules. Date of Experiment:! 1977 or before. Where Reported:: Regulation of the Secretory Cycles of Mucous and Serous Cells in the Human Bronch,ial Gland", S. T. Coles, AdV. Exp. Med. Biol. 1977, 89, 1i55-1168'. - Administration: Exposedirats for six weeks toltobacco smoke,_ tobacco smoke plus PMO and PMO alone. Purpose: Examine the effect of the above exposures on the size and' the mucous secretory rate of tracheal and laryngeal gland's of'rats iniordor to elucidate mechanisms leading to chronic bronchi~tis~inhumans. Results: Ekposure to tobacco smoke causes hypertrophy of mucous tubulles and in the secretory rate of mucous cells. Administration of PMO1along with tobacco smoke, partiall~y prevents the increase in gland size and completely abolishes the tobacco smoke-induced increase in the secretory rate of mucous cells. The effect of PMfJ:onian,imals receiving tobacco smoke appears to occur at the,level'. of discharge and/or glycoprotein synthesis since bothithe secretory index mucous values and precursor incorporation are lower in animals~recei'ving only PMO., Date of Experiment: 1978 or before. Where Reportedl: "Secretory Cell Hyperplasia andlModification of Intracellul'ar Glycoprotein iin Rat Airways Induced by Short Periods of Exposure to Tobacco Smoke,, and the Effect of the Antiinflarunatory Agent Phenylmethyloxadiazole", R. Jones,. L. Reiid, Lab., Invest. 11978, 39(11), '41-9. Administration: Forty male rats were exposed to either tobacco smoke or PMO containing smoke for 11,2 and 3 days or for 1 and12 weeks for 6 days a week.
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PROPERTY OF LO;aILL'ARD -TRADE SECRETS AND CONFIDENTIAL- SUBMITTED TO C1BA7GEIGY PURSUANT TO hION-DISCLOSURE AGREEMENT. CCf''FIi;ENT 1Q control group the vital capaci'ty, FEV , and MW40 were slightly higher at the end of tha-$eriod., ---------------------------------------------------------------- Date of Experiment: 1980 or before. Where Reported: "Effect on the Protein,Pattern in Respiratory - Tract mucus and on Repiratory Mucosa of SO with and without 3-Phenyl-5-methyl-1,2,4-oxadia3ole (PMO)'", S. Dahlgren and T. Dalhamn, Manuscript in a lletter from T. Dalhamn to A. Wi. Spears May 30, 1980'. Adminiistration:, Three groups of ten Spragiue-Dawley rats were comparedl. One group was exposed to:15 ppm SO2 for three hrs./day five days per week for six weeks., Another group was administered PMO (20 mg/kg) before and after each SO exposure. The third group served a&the contrL., Purpose: To eluci'date the influence of PMO in connection with SO exposure by studying changes in hiistology or protein patte=in the mucus,secretions. Results:: The histological analysis along with other observations: !, showedino damage to the mucosa causedlby this low level ofSO administration. SO iincreased'the % protein in the mucus, particularly at2pH 41.7-4.9. An even higher amount of protein was found in this regionin animalls receiving PMO along with the SO2. Date of Experiment: 119801or before. Where Reportede, "Isoelectric Analysis:of Respiratory Mucus and Histolcogic Findings in Respiratory Mucosa from Normal Rats and Rats Exposed to tobacco Smoke with and without Added 3-Phenyl-5-methyl-1,2,4-oxadiazole (PMO)", S. Dahlgren and T. Dalhamn, Manuscri~pt in alletter from T. Dalhamn to A. W. Spears,, May 30, 11980. Admiinistratiion:! The experiment was divided into three groups having ten rats each. One group received!tobacco smoke onfive days a week for six weeks. Another group received the smoke from tobacco containing 1.84% PMO. A third group served as:the control. Purpose: Tolobserve the effect of tobacco smoke with and without added,PMO on the composition of protein in respiratory tract mucus from rats.
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pROPERTY, OF L10RICLARD•TRADE S_CF ETS AND CONRIDENTIAL- SU?Mf!~TED TO CIBA-GEIGY PW°5UF'~NT TO NON•DISCLOSURE AGREEt41ENT, Purpose: -14- CD fRFII~iNTi'Al To quantify the number of ciiliated and non-ciliated cells in the upper third of the trachea. Results: The cil'iated cel'1 count increased for animals receiving tobacco smoke alone,but not for those receiving PMO smoke. Little or no q,ualilative differences were observed in animals receiving the two types of smoke. Date of Experiment: 19@'2 or before_ Where Reported:, "The Effect of PM0 on Tobacco Smoke-Ind'uced ProstagLandlin Production in Rat Trachea: 3 t4bnth, Report", Ds, F. Rogers and P. K. Jeffery, a report iincluded'in a letter from P. K:. Jeffery to T'. Dalhamn Feb. 16, 1982'_ Pldininistratiion:, Rat trachea is grown in vitro in such a fash:ion that tobacco smoke with' or without PItO can be passed intermittantlly into the tracheal lumen and colllecti!on of effluent made at regular intervalls., Purpose: To determiine whether the antiflammatory mechanism of PMO activi'ty iis similar to ind'omethacin or aspiriin which inhibit prostaglandin rellease. Results: Prostaglandins af'the E series in the effTuent increas- ed' in response to tobacco smoke. The work with Pt<i0 had not commenced yet.
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PROPERTY OF LORILLARD-TRADE SECRETS AND CONFIDENTIAL• SU9!AI,TTEDT0CIBA-GEIGY PURSUANT TONON-DISCLOSURE AGREEMENT. Resuits -16- C [*, IF, sF l~-',`N, 'TI A I After 1100 (PMO)' - 1500 (Control) Days Exposure: The data on respiratory functions indicate that PMO does not have a pulmonary effect. The hematology uallues indicate PMO,has aiprotective effect in that it apparently delays the onset of potential' pathological changes in the blood resulting from smoking exposure., ----------------------------------------------------------------
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PROPERTY' OF LOKILLARD-TiRADE, SECRETS' AND CONFIDENTIAL- SUBMITTED TO CIPA GEIGY PURSUANT TO NONI•DISCLOSURE A'GREENIENT., Purpose:, C 011'FID E 11TIAI To analyze the early response of the airway surface epithelium to tobacco smoke with regard to cell number and'intracelllular glycoproteins; and also to examinet the,effect of PMO add'ed'to the tobacco., Results:, The present study confirms the earlier findings that. PMO:"protects"'against increase in secretory celll number in extrapulmonary airways but not,in ilntrapul- monary ones. It does not prevent an increase in mitotic activity or cell'. concentration but it does prevent the start up of glycoproteins synthesis in nonsecretory cells. In actively synthesizing cellls iinn seems that PMO does not prevent the shifts in enzyme activity that produce either the acid or neutral forms of,glycoproteins. Date of Experiment: 1I979 or before. Where Reported: "Hypersecretion of Mucous Glycoproteins in Rat Airways Induced by Tbbacco Smoke", S. J. Coles, L. R. Levine, L. Reid, Am. J. Path. 1979,, 94(3), 4 9'9'-72 . - Administration: Rats were exposed for 6 weeks to tobacco smoke with and without adtninistration~of PMO. Purpose:: To study chronic bronchitis by simulation in an,animal model. Results: The laryngeal and tracheal,glands were studied in vitro by organ culture to analyze gilycoprotein precursorr incorporatiion and glycoprotein incorporation by ind!ivid- ual cells. The in vivo administrationiof PMO blocked the cellular rate of gl!ycopratein secretion produced by tobacco smoke exposure. The in vitro work showed that PMO modified cell function directly by reducing the rates both of glycoprotein discharge and of precursor incorporation into intracellular gllycoprotein:s. Date of Experiment: 19'80 or before. Where Reportedl: "Long, Term Effect of Tobacco Smoke with,Pf•:O onn the Onset and Development of Bronchitis a:ndl Emph-ysema", T. Betts, Quarterly Report„ April 11,, 1980.
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PRO!'ERTY'OF LORILLARD•TRADE SECRET'S AND CONFIDENTI'AL- _ , ~,, ~' SUS~r1ITTED TO, CIBA-GEIGY -12 ~,~~1tf I~,(~11I1A'l PURSUANT TO NONrDISCLOSURE AGREEtv1ENT., Administration: Nine strains of'rats were exposed'to the smoke from fermented, unfErmented and flue curedl tobaccos for 101days.. Purpose: To evaluate the suitability of the strain of rats.and, other changes in the smoke exposure system before startiingi a 3 month study with and without PMO addod to the tobacco.. Results: The smoking apparatus was deemed satisfactory andia colony of Germ Free Liverpool rats was started for thee long;term experiment. ------------------------------------------------------------=--- Date of Experiment: 1980 or before., Where Reportedr "The Effect of Tobacco Smoke with or wiithouti Phenylmethyloxadiazole (PIw10) on Rat Bronchial Epitheliumr, A Light and'E'lectron Microscopic Study",, P. K. Jeffery, L. M. Reid,, J. Pathol. 1981, 133 (,4)',, 3I41i-3'59. Administration: Sprague-Dawley rats were exposed to tobacco: smoke or smoke from cigarettes containiing 2% PMO0 for 4 hours a day over aiperiod of 6' weeks. Purpose:: Using rats~as a model for human chronic bronchi'tis:the "bronchitic" effects of tobacco smoke and'theiir modifi- cation by PMO were stud'i~ed. Results: Addition of 2% PMO to tobacco diminished the increase in,bronchial epitheliail th:ickness,, cell size, mucous cell number and percentage of dividing cells seen after tobacco smoke alone. The shift in the proportion of various cell types was similar except that the increase in ciliated celll number was muchigreater than the increase with tobacco smoke alone., Date oflExperimentr 1981 or before. Where Reported: "Mitotic Activity of Airway Epithelium After Short Exposure to Tobacco Smoke and the Effect of the Anti-Inflammatory Agent:Phenylmethylox- adiazole", P. Bolduc,, R. Jones and L, Reid, Br.. J. Exp., Pathol. 1981, 62, 4'6'1-7. Administration: Twenty two Sprague Dawley rats were exposed either to tobacco,smoke or smoke from tobacco containing 2% PMO for 4 hours a day up to 2' weeks..
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PROPERTY OF LORILLARD-TRA'DE' SECRETS AND CONFIDENTIAL- ' ' -15- ~ SU ;MdT .E~D TO CIflA,GEIGY 7' ~j'~~i ~I1glE~~i'I' All RURSiJ,4NT TO NON-DISCLOSURE' AGREEtaEN T: NCI STUDY'BY ENVIRO CONTROL (BORRISTION,LAB6) USIiNG DOGS Date of Experii ment 4 Nov. 197'6 - Oct. 19M Where Reported : 1) H. J. Minnemeyer memo to File, Nov. 7',, 1977 2), Progress Reports No. 16-18', A. G. M'anu:s, Mar.-Aug. 1978 3)' Progress Reports, No. 25-28, V., PiccirilLo, Feb.-June 1!97'9 4)i "Inhaliation Bioassay of Cigarette Smoke in Dogsr, Nicotine and PMO Effects" Borriston Laboratories,, 3rd Annuall Report Nov. 19'78-Oct.: 1979, ~ 5) H., J. Minnemeyer memo to A. W. Spears, Oct. 1'979 6) H. J. Minnemeyer memo to A. W. Spears,, Sept. 12',, 1980 7) H. J. Miinnemeyer memo to:A. W. Spears, Nov. 5,, 1'98'0 Administration: Two hundred forty male beagle dogil each exposed to the smoke of 12 cigarettes daily via a tracheal cannula.The cigarettes were made fromlSEB'. IV tobacco and contaiined1varying amounts of nicotine and PMO. Purpose: To determine the effects of chronic smoke exposure by' studying pulmonary physiology,, hematology, hemostasis, clinical chemistries, gross and microscopic pathology and' morphometry. Results After 800 (PMO) - 1000 (Control) Days Exposure: Pulmonary Physiology. - Continued exposure to smoke from all llevelis of nicotine and PMO:content cigarettes showed a decline of pulmonary function compared to the control animals., Hematology. - RBC', hematocrit, and hemoglobin levels were generally lower in the smoking groups than inithe controls. White blood cell counts were elevated in the smoking groups. Results After 850 (iPMO) and 1200 (Control)' Days Exposure:: BiocYiemi!cal tests reveal essentially no differences between,PM,O dogs and controls-just some subtle changes in the clinical pathology.,
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P1'O^ ^'TY OF'LOi'ILLARD•TIRhDQ', S CRETSI A'ND' COidFiDENT1AL• S'JBir"ITTED TO CI°A GEIGY PUFSUANT T0 NON•DISCL'OSURE AG~ NJ T,//~ . J MEIYIORAPVDUM CO fWIDICNTiAL Jantiary 18, 1984 TO: H. J. Minnemeyer FROM: P. D.,Schickedantz SUBJECT:, "'PM0 GYeen Book" - Update since 1982 A search of'the published literature from June 1982'to the ' present (L.R.C. Literature Search No. 512, January 12, 198!4)' turned up no new references relating to the tiial'ogical effects of PMO. However, a paper by Reid and Jones was found' which had been, overlooked in previous searches. (See attached bibliograph;.). Although' no reports have been issued from our own 1'aboratories in' this period„ two manuscripts were received from Dr. Dalhamn which summarize many of hils previous reports. Since chemical papers were nct included'in the 1982'upd'ate, ten papers are listed which were not cited iin the original "Green Book," the 1976 ,revision, or the 1982'update. P. ID. Sctiickedbntz ~ , /tb:2' Xca R., S. Marmor Attachment
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,PUBLICATION'S AND PATENTS ON Pt;4O - DALHAIeSN„ RYLANDER,, REID, SCHICKEDANTZ & MARMOR'
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_. ~.U ~ir.:~..~ SR~,~E~S~ O~DLCOfvrlD-tdTII~L- ~ „~ ~~ ('?, FI!~ff'NT~~i~~l S~}g;:"~IT?~D TO CI~,, GFIGY PL'~"5'J~"7T~ Tq N~O;~~~D{S~L05UF2E~ AG!~DE«fhJT. 7. "Formation and Thermal Transformations of Extended Dipolar Imidoylazimines", J. J.~ Barr and R. C., Storr,, J. Chem~. Soc.,. Perkin Trams. 1, ('1),, 185-91 (,1979); C.A. 91:7456'7r. 8'~. "Polarographic Redhction of Methyl- and Phenyloxadiazoles in. Anhydrous IDimethylformamide"', I. GI. Markova,, M. K. Polievktov and S. D. Sokolov Khim~. Geteroski. Soedin.,, (;1), 38-40 (1979);~ C'.A.~ 90:1151193z (1979). 9. "1,,3-D:ipolar Cycloadditions. 68. Additi~ons of Nitrile Oxi~d'es to CN-multiplie Bonds", K. Bast, M:., Christl, R'.. Hui~~.sg,en and W. Mack, Chem. Ber. 105(9),, 282'5-40 (1972) C'.A. 77~:,152-067'e (Q972). 10. "Silver Carbonatie.Oxidations., X'SI. Nitrogen Functional. Gronps"„ M. Fetizon,, M. Golfiier, R. t!li~lcent and L. Papadakis, Tetrahedron„ 311(2), 1165-70 (1975); C.A. 82:155613u (;1975~.
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77 PROPERTY OF LORlLLARD~TRADE SECRETS AND CONFIDENTIAL- SUBMITTED TO CIBA-GEIGY PURSUANT TO NON•DISCLOSURE %REE FN EN~T. rpose: -13- CGcsF l~ENTiIAL To examine the mitotic activity of rat airway epithe- lium,, from the larynx to lung periphery, after short exposures to tobacco smoke of 1,2,3',7 or 14 days, with and without the addition of PMO. Resultsa A single exposure to tobacco smoke alone or tobacco smoke plus PMO~causes an increase in mitotic activity in extra- and i'ntrapulmonary airway epithelium. Subsequent exposures to smoke showed a variance in the timing of the mitotic response depending =the pre- sence or absence of PMO. PMO did not change the locatiionofthe mitoses which,in extrapulmonaryairways occur in the basal region, whereas in the intrapul- monary airways they are located mainly at the mid and superficial level. ---------------------------------------------------------------- Date of Experiment: 1982 Where Reported': "Report on the Exposure of Ratsto Stnoke of Tobacco and Tobacco Plus PMO", T. E. Betts, a report included inia letter fromiP., K. Jeffery to T. Dalhamn Feb. 16, 1982. Administration: Liiverpool Hooded rats were exposed for three months to the smoke of Virgi'nia tobacco withior without 2% PMO. The trachea and lungs were then removed for histological examination., Purpose: To determine whether there is a sex difference. Resultsz The epithelial height for the mid!trachea increased in both males and females on exposure to either type of smoke. However the height increase was greater for males than for females., ---------------------------------------------------------------- Date of Ekperiment: 1982or before. Where Reported: "Effect of T. S. or T. S. + PMOlon:Surface Ciliation - Tracheas", P. K. Jeffery and T. Betts, a report included in a letter from, P. K. Jeffery to T. Dalhamn Feb. 16, 1982.Administration: Nine animals were exposedf'or six months either to tobacco smoke alone or smoke from tobacco containing 2% PMO. Four animals were usedias controls.
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~j I PROPERTY OF LORILLARD-TRADE [{;~ `;I~ I~I[(sl'I SECRETS AND CONFIDENTIA'L• ~ SUS11,~11TTED TO CIBA-GEIGY PURSUA'NTT0 N(JN-D~SCLOSUREPublishe~GPOFSiological Literature 1!. "Mucous Membrane of Respiratory Epithelium'",, L. M. Reidiand, R. Jones Environ, Health,Perspect. 35, 113-1!9 (1980):; C.A. 93:1162020d (19:80). Summaries of PMO Studies at University of Uppsala 1. "Studies on the Effect of Phenyl-methyl-oxadizaole (PMO) on Healthy Subjects. Clinical, Biochemical and Cardiiopulmonary Effects of Inhalation and Oral Administration", S. Bevegiard and T. Dalhamn, undated., 2. "Anti-Irritrant Effects of 3^-Phenyi-5-methyl-1,2„4-oxadizaole (PMO)., Animal and Human Experiments with Special Reference to the Respiratory Tract", S. Bevegard an&T'. Dalhamn, ~ undated. Additions to PMO Chemical Literature 1976-1983 1. "Reaioselectial Synthesis of l,2',,4-Triazole and 1,2,4'-oxadi- azole Derivatives", M. A. Pe:rez, C. A. Dorado, and, J. L. Soto, Synthesis (6), 4'83-6 (1983); C'.A.99r,158329t (1983). 2. "Amidrazonn. 8. Synthesis of 1,2,,4!-Oxadiazoles by. Therm- olysis of N -Acylamidrazone yli~desi', R'. F.Smith,,K. J. Coffman, and S!. M.Geer, J. Heterocvcl. Chem.2-0(1), 69-71 (11983)~; C.A. 98:198117h (1983)1. 3. "Two Novel Syntheses of Substi:tuted 1,2,4-Oxadiazoles form Am2doximes", W. Steglich andl T. Van Ree, Syr.th. Cbmmun. 12(6)~, 457-61 (1982);, C-A. 97:92213a (1962). 4. "Reactivity of 3-Aryll-d2 -1,2,41-oxadiazolin-5-ones and Their N-Methyl Derivatives Towards GrignardReagents", F. M. A. Abdel-Megeid, M.A. Salama, F. Mi. Maliti and N. M. Yousif, Egypt. J. Chem. 22(1), 53-7 (1979) ; C.A. 96:~162608p (1982). 5. "Formationiand Thermal Reaction of 0-(N-acetyl-benzimidoyl)- benzamiidoxime: Comparison with the Formation of 3,5-Disub- stiltuted 1,2,4'-Oxadiazoles from O-Acetylarylamiidoximes and O-Aroylaoetamildoxiimes", N. S. Ooi, D. A. Wilson, J.Chem. Sbc., Perkin Trans. 2, (12), 17'92-9 (1980); C.A. 9.4:10235bc (1981) . 6. "Reaction ofBenzonitrile Oxide with 2-Iso~~_azolines",, Ji., P. Gibert, R. Jacquier, and P. Clement Bull. Sbc. Chim. Fr., (5-6, Pt. 2)1,, 281-8 (1979),; C.A. 92:110927'q.
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OXOLAMIVE AN©. RESPIRATORYINFLA1t.M1fATIOV2$7 ' and the, Instiiutee of: F9'ygi;ene, -cden. erimentalh•, P'roduced ry~ Orm'an9' h;tmn ti'e commonestcauses of ~a?es, in air pollution cancrencc; compared xk itfi the a. emph}sema; etc. These lales• but in recent sears ercountniesr particularly nd allied,conditions have"•er. thetnt'en5lhcattonafl t ciearette smoking have , months or more of'each 'tedl British definition of)6-1) has defined chronic "y excessive mucus sccre- -'hronic or recurrent'pro- ts should be present on the }ear' and for not less ,x be rcmc cd• chronic Iltiom Nb addquate; drug(r neNt' druc is shoNt nito ial usefulness in chronic icn a promi~im_ field for ne (3-pltcml-';(3-diethyla- .Inim;tl, experiments by . ~tLVESTRrvt & POZZATTI (1961). The antitussive action of oxolamine;was ,hawnito be predominantly peripheral, with a relatii.•ely small effect on .he cough centre. DALHAstv(U955):hasIlkewise; observed an antitussive ::ction of axolamine citrate in animal experiments. An anti-inflammatory, action of oxolaminecitratewasalso described oySttiVBSTrtuNt &PozzA~rrt(;196'1). Theytest'ed the ability of'oxolamine.o diminish aedema produced ih the rat foot by the method of RAti'DAtL, _ ~t3LtTTO& VALDES (11957)I, Clinical observations on the antitussive andi anti-inflammatorv action t8'oxalhmine citrate werie published by CORBLLLA (1960), Di1DUS(1960). .tePACt (1960)andITROPtA ('1967),, Trials on, human subjects, howner; present, many pitfalls as tests of' '.lie efficacy of drugs in chronic respiratory tract intlammatiiin. We have •lierefore tested the anti-inflammatory action of'o.rolamine cito-.ate on the espinatoryorgans of guinea pigs. Bronot it was the oxol'umine citrate preparation used. Parallel tests .cere run N~ith a substance of known anta-inflammataryprbpa:rties- ohenx lbutazone: Mpthods Twoseriesofo guineaa pigsweres used, each contu:ning]0; animals. Eachi serias •xas. su.bd-des into 4.groupsof5' guinea.pies (A6 B, C'a.nd D):, Theanimu:lsin group A receised noo pharmacoldeical substances;, but inn all otF.cr re->pects. ~.ere trea:tedlinaHe same, wayasthe experimental groups. In groups B, C and.D non,dacterialiin0ammation,of therespi~rato:ry;tractwas produced byinhalation of'.acrolc~in aerosol (\~tnTeR &Fr,aTAKrR 195'4i, The strength.o.f the acrolein solution.ttas.0.0J5~°;,, andd the erposurewas made for 100 miirutess in a plexigLass cylind.er me,asuring;a.bout200g z 1?0.mm and.h'tted with a Pari nebuhzer(tig; I). Fig..I. A PSri nebuAizer fitted,to.a plc.:iclLsseylinder usedlfbr, ezposure, too ucrolcin. i 9 I 11 t. ! !
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Acta phar»racol. et toxicol. 1966, 24; 2E6-296. Fromthe. Ihstitute of Pathology, Karolinska Sjukhuset a.nd the Institute-e of Hygiene, Karolinsk'',a Institutel, Stockholm, Sweden: The Effectl of Oyolamine Citrate on Experimentally Prodhced Ihflammation ini the'R!espiratory Organs gy Sven Dahigren and Tore Dalhamn (ROceiive~d Felirua.ry. 10; 1966) Cigarette smoke and airpollut'oon are amone the commonestcausesoft disorders of therespiratory tract. Sudden increases in air pollution eanprodtlee acute sumptoms: but this is a rare occurrence compared with the chronic,formsof'bronchitisand bronchiallasthma, emphysema, etc. These diseases arenat'oriouslypteealent in the B'ritish'Isles: but in; recent }•earstheyha~eatt'racted increasineattention in other countries, particularlyin the U.S.A. Im Sweden, chronic bronchitis and allied conditions ha~e hitherto been regarded as relatively rare. H)owever: theintensiticationi of air pollution in our, cities and the increase in cigarette smokine, hatie focused attention on these problems here too: Chronic productise cough most days for three months or more of each of' two successice years is a commonly accepted British definition of chronic bronchitis, In theU.S.:'1, Het>tsN (196-1)', hasdehned chronic bronchitis as "aclinicul disordorichnracterized by excessnemucus secre- tion in the bronchial tree. ft,is manifested by, ehronio or recurrent pro- ductihe cough. Arbitrarily, these manifcstations should be present' on most dnysfor a minimum of three montlisin, the year and for not' less thanitw4 s'uccessi%e_\eara'. If' thesourceof' respiratory irritation cannot beremt,%edL chronic bronchitistend, tohea highltirefructory'condition, No ;tdcyuntedrue treatment isa%ailahle as Net. Therefore, Mien a newdruei, shoevn't:) posse,santi-inliammatory properties. its potcntial usefulnesti' in chronic inflammatory diseases of the respiratorytr:tet cffcrs a promisiiig ficld f..r imestieadcn.. T'he pharmacoloii,~al properties of o.eolamineli3.pliany!-~(3-dieth}la- mincetliy l4,?,,.1-osudiaTole)werestudledi inanimal experiments b}' i
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788 S. DA:HLGR'£Iwp;N®.T: DAHLA:61N Ihnmed.iatety.a:fterthe,acrotein iahala:tion, intraperitoneal injections:were given; they were Group C; oxolaminecitrade; 80omg;kg,6odyweight; _ - Group D;,phenylbutazone, 300 mglke bodyweight; GioupA, sodium ehloride, IiSmllkg body, weight. , The: injectlons.weres repeated in all three groupss ufter 7., 6, 91,2A„28, 32., 48, 52;.5:5; 722 and. 76hours. The-tcpeat doseswere:5.J.3s mg;kg,osotamine citr te; '_O.mg;kg phcnylhutaeonee andl0t mI;t00: sodiumic:htoridi j .. ... g: were: thenidissected.free: and weighed. The: thoracie: organasserefised in 10"o formalin. Ma:teriat.fqe.mi¢roscopyl wasda:ken from the.truehea and:.fromthe, bronchi of bothlungs. Tfssue,fromu111ung.lobes:wasembeddcd.in paraPtin„sectlonediund:stufned'.wi'th van i7iosun and haemataxyliir-eo=in:, - The:intlammatory,ehanges sceniat-mieroscopy,- ocdemu., granutbcytee inlatration a.nd hypersemia.- were:gRadcd according to.thefoltowingscale: 0. =no:inflammatorychanges. O.S'=mild inftammaxion1.0 = fairtysecereinflammatian 2:0: = aevcre intlammation:. The t}iara.cii: organs' were remotied en: blhe nnd c.caminedd meroscopic;aily. Tldc lungs response:tuthis substxnce: The ezperimentswerestopped after SO.hours. 71his time was chosen aftecpilhr.cxqeri- ments.had~shownthut the:iritlammatory-changes weree then maxi.mallt . derelopcd.. Thirtec.n oftfic.gulnea.-pies diedd beforethe, 80-hour limit:. The:y! were.examincd.tmmcCmtely, atler, death: the unimalss that'sunivedlal the:end of:the.eYpenments:were.killed byblt`ed.ing.and immed.latelyy autopsied: wis:hedd to check the:quelityof the experimenta.llyprodu.ced inllh.mmation byobservingits beca.useof iiss know-n anti-inflammatoryeffeet.(so', REcnr_tiucrsc1964), 416rcose:r; wec The.sizese of the doscsadminlgtereS were basedd onthen recommendistionss for thcrapeutic: dosage: Phenylbu.tazane:(3;5 dioxy1,2•dlphenvl-4-n-buty)-pyruzo11a3ine;.Burazolldinj wasn used The macroscopie and microscapicassessmcnlsweremndb.byac patttolocist srho hadd noo prior knowledgc of the:grou.ps from whicnrthae indlsidua:l guinca~pigs hud!becn taken. nearly al(of thcse:animalk. Scsme of them also shosccd modl2rtuel}' setiere highlv raseui:trizc~d infiltrutii~n of dncumonic appcaraneewereseen in ehangcsin the nulmonaryparcncll~ma. Vnrving d'ecrrees ofdense; fairly inhal.uion ofacrz lcin {groups (3it and [3,) had macroscoleicintlitmmatt3ry Most of'tho guinca pies iiljecttid inttapcritoncallv swthV:tCI alicr epitltelium (11e: 3j. other 7-guinc:l pigs the sCructure and air ctnntc,nt oCthc fung,svero:normal (fig. ?) : The hrkmchii and the trachea sccrc lincd oidinormaleilfjtcd andA,), 3shoscedl mild inllammation ofthe pulhlonany tissue:, ln thc- OP the 10 guinca }yigsthat recoised no aerosol inhalhtion (Grioufps A1 Iland:?. The results for thevarioua eroupsaresummariced intctbla-3'. The maeroscopic and microscopiaohservations are repor:ted'in tnhles Results
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OXOLA~\tLN~~E'A'ND~~R~ESPIR'ATORY I'ti~FLA~~S1Sib1TION ions~sere.givcn; thev. were eight; zht: ehti '3;,3:?..48. 52, 56, 72 ~a;nd 4~~. '" h e;, (jutaeoln!ln) «'as~. used ~'c~196I6. "Ibreoser, ue mmation by ~obserctng Its ohosen.after pilotctperii riallydcccloptdi.Thirteen. ,.rr.nned . immediately af ter .:re, killcd by blxdine and -roswpicall;'. Thc.lungsc.ficed in 10"„ furmalln. bronchi of bothlungs. J 'stuined s4itN ean Gieson -i.nu;oe.vtie intiltrationiandd a patholopist.whohad no~pies had been taken. ire reported in~tables narized in tabie3'. ihalation (C-roups i'a tonary tissue. In thehe lune-s were normal ~~itfi normal ciliated :Ih N~ith \`aCI after ,sctepic inllammatory_rees of' de:nse, f'airl'y, ,arance NNt:re seen in. .d moderately severe I
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Acroelin acrusol-I- phcnylbulazpnc........ = no inFlammetary changes 36 37 38 39 40 295 280 290 270 260 iao 2nx 4.1~~ , I.JI 4.5) >.0u 535 2.15 3.50 5.94 4.lSi 0.5 0.5 0.5 = mild inflammation 1.0 -= fairly scycrc inllammation 2.0 m ss:vert inflamm 7 [+(1/e 3. A1cans of obscrnationti in lublcs I and 2 c;ronp Trc:ilmcnt W:ul gr.iiling of inllammalion i. rssrlss I(table I) S,risa Il (tuhle 2) lungs I bronchi I lreihra lotal lungs bronchil Irachca I total Ai i Aq None (Control )....... .... ~~ 0.1 u ~~ li~ r li7 AcrNei i acro 0I 4 soilir, l_0 Cr } C; Accrhu llcuinnlcucro.iol I o<ol~mint... cilralc ...................... 0.2 I)i + D:~ Acrplcin4crqspl I , ph~nylbutass,nc .............. 0.6 Ze74ZOYOV Mean relative 0.87 1 1.5N
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S. DA'HLGRF]'.r6.4uD T. DkLH 1'S1CV Fig:?~. Txormal.lu.ng(Animal.ti~o.3): ~ Fig...3~. Normal tranhca. (Animal Vo:.»~). Fig. 3:, Markcd inflarnmatorychan,cs.of'.tHe.lunu ~~ ithiempli% ~cmutous bleh, and destrvetion of hronehial epi[heLum (A,nimn.l No. 10). pulmonary emphysema. No other ;tbnormaliiics, wcremacroscotpicall} visible in the thoracic ors'ans or elseitiharc. Microscopy showed ihthe guinca piesofthe f3groups thutthe pul- monary parench}mal chanecsconsis4edl of agslomcrnionsrnfintiamma- torycells; which were often extensiceand contaiined mainl' v neuta•opilif granul'ocy,tes (fig. 4). Small areasofhicedinL and oedema were found in themostse,cercly atPcctod lunus.Themacro5copicalltilobsertied emphyscma was microscopica9ly, confirmed (fie. 5):, Ihbot1t wide andlfine bronchi there%cere car\ineamountsnf'er:mulh-cytes: The bronchial epitheliunr was partlk shed in the animal,with the mostses'ereehanees„ Sections from thetrachea sliowed essontialll' the same pic ltea.ily il abundanc When . ized in ti'-. hronchi:: the tr Fic.7. Tt., hypcrae.mi.-
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Table 2. Observations on guinea pigs afier inhalation of acrolcin and intraperitoneal injection of NaCI, oxolamine citrate or phenylhutazone Group Treatmcnt Guincu pig Body N'16I1t I no. (S) i Nonc(controbl . ....................... -?Z 390 27 360 28 4Al) 29 350 30 3111 D, .4crolcfn acrosol { sodium chloride ....... 31 300 32 320 33 300 34 290 35 290 Acroclin aerosol ~ oxolnmine citrntc ...... 41 300 42 300 43 44 2F+0 90 45 2 225 1), Aeroclm aerosol + phcnylhutnconc........ 36 295 37 '_N0 38 290 39 270 260 0 = no rnFlimmatory changcs 0.3 = mild intlammation 0 1 ~ _... . __. . . V.'ciEht Rcltivc i oflungs lung (g) - wetght ~ (B/IOllg) 2.15 0.5i 1.90 0.53 2.15 0.47 1.7(1 0.49 1.85 0.€~0 4.95 1 .65 2.55 0.80 7.70 2.57 2 05 0.71 2.03 11.71 2.10 0.70 2.55 0.1i5 5.40 '_OH 4.111 1.41 4.50 2.00 5.15 1.82 ?5 0Li0 1 s0 1.21 5.s)5 2.?1 4 85 1.1i7 hlicroscopy Infiammatory changes in lungslhronchi I trachea 0.5 0 -0 0 0 0 0.5 0 0 0 0 0 0 0 0.5 0 0 0.5 0.5 0 0.5 0.5 0.5 0.5 0.5 0 0.3 0.5 0.5 Total grading of in0umma- tion 0.5 0 0.5 0 0 3 3 4 2.5 2 1 1.5 3 1.5 1.5 2.5 2 3 3 3 - fnirly sc,'crc mllamnwtion 2.0 ~ scvcrc inflammation . _ ._ .. ...... r. .. . I+'4ZOVL/V
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29ti1 S'. DAHC6REN~A'ND~T..D.ALHIA'.'vfN~ Fig:, 3. Hvperaemia~onthe.lunge fram an animal.treatzd uithiaxolaminecitrate. NoiirdammatoryoFangesare. . noted_ (.A~nimal 1Vo;.18). Of the 10euinea' pigs injected s4ith ozoldmine citrate (groups.Cl and. C_):8lshosvcd inflammationof the respiratorytriact. Thiswas of essentially the same tspe as in,the NaCl-treated croups, butasa,rulewasconsidcrablyId~ss:secere. ;`1G patholoeical changes were discernible in 2 animals: Se.enal ofthe guinea pi g; showed varving decrees of h}peraemia in the tracheal wall'and in,the lungs. The t'racheal epi'thcliumin these animals wasnatlier thin• and the cilia were partially destro}edl The number of e'oblen cells seemed to tbe reduced (hgs. 7 and S). When phem,'Ibutazone wasinjected after exposure of thegminea pigs toacrolcini(grioups Di and D2), they showed intlammatorytchangessimilar to,,but milderthan thoseofthe NhCl-treated groups. fn'onlyI ofthel0f phen)Ibutazone-treatedl gpinea' pigs,, however; couldthe pathologieall chaneesin therespii'atoryorgansbeclassifi©d as mild. Einphysema of vary,ing secerity w'aspresentbesides inflammatory reactfons. The relatise weichts of the lungs.are shown in tahles I and 2' In all but oneof the acrolein-exposedd animal's therelatihelbng weiehtwashigher than in the controls, In the fl~st series (table I) the various sub« groups elearly dilfered inrelativc lung vti'ei¢hts. Thehiafiest mean value was' found in: the ld[tCl-injecte~d guinea pigs. Tlhemean relatis.; luntdweight in the oxol?7mine eiirate group (C1) w'as sienificantly lltwer than thaUin the NaCl group (analysis ofcariance) (E31). Therelative lun,weights of the acrolhiii-treated guinea' pigsin thesecond series (table?), wereoftenconsiderahly hi>`han tfian~ thos in the fint serics. 71hemecrosaf tlievaluesin tahle_' appeared to becreater'in the oxolaminecitrate jC~2)mnd phenclbutazone (D2) groupsttian in the hrdCligroup: (B2). Tliediflerencns were, liossercri, not statistic,allisignif- icant (anallysisaf v~ariance). Ih lioth series:, oceolaminecitrate sh<nved a distinct anti-inllammatora action: Asjudged fromthe microscopic,alll,r .Isrzssed derrreeof intlamma-tionplustherelatis'eweiiahtofthelunRs; this affeict' washiehl~•significant (analysisofvariance,:P' . O.OD1). (]labloIIT). The anl of~ phen\I The en' how ever, fairlv extu oxolaminr Inflamr guinea pi esperimci strcngert in obtttir. Within e;: B} inie andi phen bacterial ;. in this sm superior t .An anl stratedl Tinthebn> unti-infl;utliesis of ueolhrnin: Erorn t the anti-ii sen ed in ' sonte reld•One re (Jf tDxUlan llrotected Our ee; and crpe: citratc. l'' narticul:•,may be ~ vou~'h": - pain, thc adt; d au
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~uu~lLLF~~~~ INHIBITION OF THE CILIOSTATIC EFFECT OF CIGARETTE S3I'OKE' BY O'!FOLA:4IIINE CITRATE TORE DAS.9Allti Repci~ntedlfrom~.ka~ewic.a~Re- or SLeerrneTO~.nr Oter...ei. Vol. 9i:.\'o..5, ::ovemWee 1968 PrirWed'in~.U:S.A..
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OXOLA~M1IIN~E.AND,R~ES~PIR'~ATORY ICv`FLAS111.\TION'~ 293 ame picture as in the larger bronchii The trachealiwall, too• was fairly teavily infiltrate&w~ith 2nanulbcytes„ and! . inplaeesthelumen contained .bundhnr leucocytes (fig. b), When inflhmmatory changes were present, they were a,, ai rule general- zed in the respiratory t'ract;, involving:pulmonary,, parenchymttiaswellas,ronchi and!tracheal Fig.: $:. Emphvsama.in lheunimulllraa.ttJl-th sodiunu c.hl6ridc. (Animal Ao2 n)1. . eneph,cmatous bleb andl nimalV'o,. leli ies wwre macroscopically e, B eroups that the pul- omcratiana of inflamma- taincd mainlS• neutrophil~ Id oedcma werefound,inl alls obser\ed ompltysema. .ing amounts of granulo- I itn the anilnals \sitlt the a sho%ccd essentiallvthe Fig. 6. Inflammatory granuEocvtes arc.notcd wlihin tNetrachea.l mueosa andd trachcal lumen. The.cpithc'ium is d.estroycd.and.h'as loaserici.l1 from its,yasc h\nimjll No.. 77, Fig. 7, Truchcufronr thce animaf trcaacdd ttiilh uto.lemrree citrat' . .\otc, th, . sub^.i;hcllal hypcracmou. The.epithcium- thinner thaninormai und thb cilia hu- partk.disnppei.rod. No.g(unuloc,yticirniltralion ie.nuated IAnimullS"o. 19.1.
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~; Q~~;'; plf R . ,, c- 72) . GUTMENMI \! TIOI'-\TIIOGLNFTIC, CLf\IC:\L :\ND'TIiFR:\PFUTIC PROI3LE\iS PRC)C:F.©f)INGS nFANINTEKN.CTIOV1t SYVIPOSIUM RCILOGNA4 .N01F~IfiFR 7' A, 1957 . F_rlilnnc[l. Sii crsTrzlsl. Rnme, S. TuR,~, Bhlbuna Cn,c^<li rar 1b'. G. S'riolrq<. L-ndnn C I9 CI.ti~ FXCrRPT,aMI_niCA F-OI,vDATiON .
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SummarryTheeffeetlofoxolamine citrate on experimentally produced re.spiratcnrytract inflammation is reported. The inflammatory reactions were pro- duced by exposing the experimental animals to aniacrolcin aerosol. The studies were performed on two idcntieal series of rnenty animals. It, has been demonstrate& in this experiment t'hati oxoiaminecitrate has.a statisticallasienificant anti,inflhmmatorvefTect. CorbellL. E. G.: Esper3enzecfiniche prell-nurgcon qxolyminaatratqnu.owNec(nicodi siiutc- llilr. Wed- 1960; 51.4077-1030. DeiJUa. C.: Espericnzcetinishe sull Rcredron, un antit-e-entinriinimarariodi sinlev. ,Lfio-. ltleeL 1950! 51..40-9-1063. Heiman, H.: Airp,ollutionand resqiratorp di-se_ UhitedStutesGi»trnment~Printine officc, Washineton. D-C., 1963i, Randall, L.,,SelitW, J. QAaldes, 1.: Anti-inllammutory,efrcctsalsylopropyminc: Arelr. /nr: Phnrnrran.dtn,19.i7; 1113. _"•3-249. c, Rechenherg,H. IQ:: 6utuzolidiniPhrnylhuturon:G. THiemc. ~'crlau. Siuneart19fi1. Rtrpael, M.: Lirtlpreeo dell'orolaminacitmto nellaterapiu dcJlebronohrn senui. 1/irr. L/ed.19G0;5t, 3072_4077: Silceslrimi, B. &Phzeutti, C.: Phnrmucoloeioal proq¢rticso(E.-pherr~l-5'.dicthylammocth}i- 1,2;4-oxsd.iuzolc: Brlr,J. PIra,n~racr.l- 1961, 16.509-2_17. Tlropia, G.: Sullimpreeo dellbsolumioa citratonelld rccidi.e bronehitich<. llrm l(ed. 1961152,3750-3752. Ve'intor„ Ch. A. &Flltal.er, L.: Antitussi- compoundss: Icstinpmothod, and rewlts- JiPlrarnra.caF: Exper. Tfrer. 1954, tlZ, 99-10R.
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~ T.4IILI: 2 Trutst:rnEtcCr;ss.druoO e.u Ila:cuVe.tur oer'Ctct.rev Arrtvrrn' W+rtt eso wrrnnrrAosrnx't,.n;e-rnus oe UxoraOc[SF: Crn-tuae Cessauon ° I Rer~ >cep~! i O.st. - I e Ph ~ 4 O la~~m~rc~. '~ . PA ~ ?__ Car \ure+ber . Citrnre I Cax \umbcr S'o,tl m Chllnr~sie~. Cat~\'urmtrcr~ Crra.re~. i Cae \ mLcr~~Sm,hum ('hl,nrli~le. 11 J Irrrre.,.sed~~ Lfi I, llr trachrtr' 11 ~.120 inriiiut ~_ ~~16 Ar, r.~ v.•rr- 1@I Incrt r5eti 17 F IDrt trrcHea'~ ~ 12I I I351niinitro ~, 17~ ~ Sn r. vr-rc 13 ~ Iirrre,smd ~ 18. ! IDn ttrrheu 1/3~ 1>O~.nuiirntrs " 18 \u~ r crin. ld~ F Incroased " 19~. Ihr~re:r_e~edi ! ]N ~.A''i, reicrrverc. 19. 1129 n'riuntr~.r 15 II LrcretSCdl 20 . Uhy.trne.6ex , la ~~ IliUhnirutee ~ , ?p. iAu'~rrrncrrra. '~Trui~ralbecretiun;stt}ret'iu~r.uf'~r:ilru}~,rec~over~ nrnfterldOrrinutes~ t' li~rr..rrr•trurnl FIreda-itVr statusiirrirnedi.irtelv ~. after~eFigr+retttr sEuukiug - t~Tinrc hetxeerr admicistrntiou~nfloorrlanmiirm~ orrph}:siiilugic srrdlinu r6luridn ;trrd rr-';tbrutir~u~tu ar- tivlth- ofF h:Jflnf thle ciliuutadd surtarr. cat.s tG;rtt tiarre prrrtnr~dlratnd witir rso6arninr., lotnerrr. I, riorlsof srnokine: wr~rrn-rtuiirLd tn duenrtlr >t;,=istN:m in tho'~~Kioeuvnliiun r~Llu- ride a. prr-ma~rlirFlrioni. OYoItnion ,u1r ir i-;rrrrf afr.er=ratokin'_ h;r'~.i proriia~s ii rlYu:na-i<.FilIl,«•;rrr-.I tb'acerV rt ,rreeav rn ofLriir,lr, u~ticiip~., ThaF . ub>crvaunn' ronrr•rn,ng t i.7run>r of'trnrhrL.il 'x^cretinn to u.eolnnxinr• upl{1 ~..,n,rl too rns i ,,Ir«.rr,rl intr~rmr .LscorntL:urr~d Withrf --r.rtr~ nf'.rf rrrrr6 ~al mue'o's. irmm1diurr•l(• e[tr~r secukrue: :rll of'. the~ 5'5 eats'trr~trtrd w~ith utoldr;ninw~ >iroa-r, l di>tlrr+~tlv, ier- crcased sr~errrtion~ rri rnnr~rc•; u-6rrrrurhr, rctrlu:r. remsrins~d "iirn'' in 4 oT thn9 ~r,nUVll,eciF n:ris..Tiii= diffr~n-nrr- ma;. Lndp tbelurifr' thrr mL ~edr.uridm ui ciliasU.siU. Itt isnot imtlcoM1~:d,l,tlrur ther torc chusm of rNnupc' in ~ili,u'5 "Hr tt frr~u.iir511 ~i? arlher- ution at tdn~ trar!' ul.srrnrrtinn (:nunim[ 554 . r~is- cn-itn-).anrl tllnt Ihrr;uts;,l :ryrr7rt=, thrim lnrr,.;rrc, nat 7rrii,crril, ~ riliotosic. Con-rip,irntV}-..t1rrnnsullkcf ttlomtoriwrnta It ~ i,.frrr:~trrr}~r ar_•us'~-r tL,rt: . tir'id ~na. ~iear,trr =¢tokr' ivnLir. u-:rr .rlnr,tir,n or:rl', 015, . cr>_. coritt~rrr Iruth. oaul:rroinr,orrr.rtr~ -tirnrJ.dr~_ tl,' . prndnr'i,nio6trtus~r]..7~I1i,Lyt r il r- u,n.'l,r~.rii te•.rr~ri tlarrm.rulo!,l ,,ll,-. iinrvr,rrt it.i> noc~ : tr.rdiari-,IIHv tlr:eor . IFO.ni,rlle rr n, ul'.ne,l' u im~ d hari{, ~,,rrni :rn,l I s'.rn,' ~ rgm . ~t rrrn- tr:rr 'tirlu ~rnliumL-rll r,vl-II,I „:ruril,-i~rnriuv. /n.~ r„uAarpr, t)5' Lctn,u". r iir r'rr~, ndh u .'yi t ryuurll--. I 1^~;rO '.r ir lr.r.,tl:'' r-rlil,'t: uf tl,i,:n r n -r.ruh'r- Tinrr: I).ttnrurc lir:vGi[ rh-, u//IVpt~-nebirrr, 1 <=ka'.Ire~IL„tr.t; .rud 1).,>nr,r l „!' ~'. r.r..=,( ll~r,/i~ .ti'i,tl-,v,l'Irt:dit,it, lf',ibii,lL~attir. .YLl,rl,Jrr,lur,.<'rrr~itn. J!rnmrrn. 33, 17liri.
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V, ithoxolamine.citram:. No. INI. itrati;:(gnoups Ci and. This was ofessentiallurule was consi ierablc : in " animals, Several aemia in the tracheal se animals,was rather umber of goblet cells :oftheguineapiesto atorv, chances similar is. In only I ot:the 10 uldi the pathological mild. Emphy sema of . eactions. tables 1'' and 2. In i all'. Live lung weight' was ie I) the various: sub- e hiehcst mean value .: mean relatice lung ,nificantlv lower than d gruinea, piLsin theher than those in the ,.ired to be 2reater in ,) groups than in the ot'st'atisticall'y sienif- et anti-intlummatory dieree,of indamma-%as hi hly! significant xolamine citrate were almost free from emphysema. 'zirly' extensive emphysema, whereas the guinea pigs that had received , The emphysematous changes were difficult to classify. On the, whole, i phenylbutazone. OXOIJA~StIN~E~.eAND~~R~E~SPIRATORY~IN'~F1LA.~SfiN1:>,'TID?! The anti-inflammatory action of oxolamine citrate was superior to thatt owever~ the guinea pips injected with NaCI or phenylbutazone showed l Discussion Inflammatery cltan ges cere produced imthe respiratory organs of these. _uinca pigs by exposure toacrolein aerosol. Im, the second of the two ,~:poriimentui series, the inflammatorvreaetion seemedgenerallk to he triongerthafl in the flrst. probablv because of thedifficulty experienced nobtaininuthe same concentration ofacroleinaerosoll in the both. ;b:ithin each series, howecer: the strength of the aerosol was thesame. B}'injectimy the acrolein-exposed euineapigswith o.roljmine citrate .mdl plten} Ibutazone, the action of these substanceswar tested on non- '7acterial inflnmmationaf the respiratorv organs! Ox~olllmine oitrate .%as!n thisssay 'found to be a potenn anti-iitflammatcritia~uent. Its ethoct \cas,uperiori to that' of phcnclbutuzone: An antitussi%eactioniofoxolamine citrate lias,presiouslybeendemon-strvated. Thisimfpliesacme impairment of'thenaturai arcretor~mechani,m in the brionchi, Tliatoxolumine necrtl clesbpro~edto beamorcpo%~~erful antti-iitf3ammatoryagent thanphen~IHutazonclandssuppora to theh~~po-thesis of StLVLSTRtM &Pt)zz>sTn (1961) that the antibussise effect of ozolamine isddpendent mainly on i'tslocal anti-inflammatorY properties. Eromourexperiinents it isnotl pcossibla;todddiicethomcchaniFmiof the anti-inflammatory.actionofotolamino citratc. The h}perumia oh- servedlin the o.Yolamine-injected Luinea piis,,ho%te%er: may he a Ilwtor of somerele%ance. Oni:resul't, cfltVie combined .mti+inflammatorcandl antitussine actions of'o,rolamm;eeitrateseems to be thatthc pulmonary parenoll%ma is priotcctedlto asicniiicant de,~zreefrom t}ieda%elhpmerrUofemphy~stlma. Our evpcrir•.:entstliusseem toconfirm ohtervationsfromicardicr c!litical and etiperiinental'studicson the anti-intlannnatc)ryactionttf'oxnl:unine citratc. The ccmhiitcd antitusri%c and anti-inll;tmmtitor~clfe,c't should h~ particularly u,elui in the import; nt proup of respirator~ ~ disorders thatmay, beclltssified ,ts chronicnon-bacterial brunchiiu,, e.u. "-smuker , couph". Since such intlammator:'irnitaNunifroituxntl}i, a,sociated aith pain, the mildl I0call analei'sic action of oaolamine citrrete ;lioul i be an aci~anL.me. added s
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S. k: l]\lil'.kf\ \\'I~j . 1I I1!1\'1\ A Chamber B Spray. C Manometer D Air pressure E Intet F Outlet t!i.i1rtK'll Hlixfetnr c}lindar lirled -!h aPdr~ nSheJvcru,.:J fbn Ihc.ucrabeln ciprnare. \., ~,. nlint.l. ss°eigliedd andl material for mici esa.mination Isass taken from thce trachcal.. ``blronohi anrl all Ilm1-1 Iah._,. .~ I ~ .~. .,...~ . Theanli-tussire.studiesklereLartSirmedron;rnothcrthirtv.efilea~~i~s.,Thww.unimuls a'ereespo,od. to.I`(:"„ amin„ni,l, a dru~.II ith rtta !cd t.outh-r,mdhcin-' elTecti for' 3 rninutes.hj.the sum rem"A tedlniyuk: . ~sin theanti-inll.lnlrn!ltM }.stu~;irs. Tlh.c.num- I i'..,'~!, barofcti>ughs.rluning Ihr zrpei,tu~~ P ~tniorl .I a, ccrtnttctl. Im!nerli~lIel} ,.Iter,lmmoni.r --- ---- espocurothctei4 snlution,.I% arc. injcei intr;, pcnito ncaIlc. ~Iihirt¢ min~!trti Lster,.thc -fh,: . mi.an gri guii7eu pir~slkere saai!t c.~ps,rrl tlranln'1r ni;t.;ur thrce mMutL'., wul thenumhrn ofl .,s„L!m!ner.ilrar o'ou_dx 1ccr' unnni_J. t- IHaI of' hljrn Thc te>t a,lulinn.uee(l1kacrc ,uclium chlnri<Ie, f,roiarninc cilr.dtC anul codK•.in phnI--t„hielll•, ph2tc. a riFv; I~ilh I<nl)nn unti+tc ,.iie l-hte dff;r. \IanI rnc, tc.t't s111L~.twn per ~~v„L~.!nnur ,~.ilr.!t kilugr.Inrh~IJti c~ci hL.ih~..;mpnl~b_, mlh Ih, vnlution,~trr -,n~1c>I ~hollcri antlllhc I~! Ih,. seqneneeofs.llutWo,u.cr.l in e,!cH :uriln.rl "u. !:Irnl,mik~J In ;1 m;ln~~ar unl.nuv~n[n ,~1!n~.a l7r_, ,Il- the cnueh aOu.nlcr.A coueh inei_x' ulunHF,.r nI r.1uuh1 ?tl rninutI- Jter inleI~lii?n I+fI)o test olutirm I(W.nunl-,;r ()f cr,u~h~ he,fnrclhr !ni:ctinnli•,~°.1, r.tlcul:~tetilfnr avchexpenirrontaorl filr c;lehi ~uinC;l ul,nrrrr RVSl'I IS, Auti-in/Iamwwnrn arzli,al Th;. meun r1lutlve lu.ne \Iui1ht, Ic Ifllk_ li/m" ' ~rci_~hl'i :nr ,IUnntniYeJ in T;!h4e I.,In the.lint ~aric.lllcmy;ui \ailciitith.,~+v1111!m!n..c!II'ICenuil, %1,!, vic!:!I'c.:!nik InI%or thurt Ih"t in ILe„rJium Ld!l-rirlu crnun. I~1 Ilw.,c-nJ ,4rii..thc.rc ~~,arunn..t.~uvnt-,allv sii flillL•rnnrc, in lun~~ ~.ili!I, haucc~'ntV!, _-Wnu' e-oll". -{ h ,..,-Lf`1-4,-.i'PF+~it:Y:)i 7~
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1'. t..11n1I1.0R1\'~\\6e~r. t>ALII.\l7ti'~ Ttt1LE III Te:srse>lutiixn Moanic:' agt::caumt:ntten injcci~nn nf teet solotiimn Sodiumchloridc. 117 Oso;.imina ci[rale. NO CoJvine phnschsae. 49. COA1\irNT6. Cm'Nfl;~EIT~j Our zxpcriments' seem to conflrlm earllierdinieal ohscrnatlons oCthe anli-infl:.rnm;t- t'orv and anti-tussivecliecnof osnl tmine ci'trate: The mcch;rniim hchiirnl thc,.e ac'toons. howe:s 'er', hasnot bccn clarified. FNc:perucmin n"us.ofCcn'ohserv:d in thu' Itmg paretr ch}^.maa and the.wullcaf thc.lruc.hca'.nndlbronchi nfthc oinl;lminc<trcatotl'.aninialel possilil}' u f: ctor of somc rclar,rnce ilr tdla anti-infl_imrnntrirsmcchani,m. In a sturl~d b3 Ditlhamn 119Gb), itvs'asshovsmlhat o:roluminc citratc r ay hefp tii clrtmtcruct thc cilioslaua ctTeet of cieurettc smlr4te. Thi;clleta m:r.nl'sohc of ilnp.lrl.ince Is'hcnstudv:ing the antl-intlamm;rlbrti mechanism o4 oorla.mineei'trutecsnl inll:rmmuli,rclesibnxin tNe rcapiratir' tlas'u The comHimcd anti-tuv;iveaad ,rnli-im(lhmmatnrvactinrts of exnlaminc citr,ltuseem to protectlthc pulmonarc.p;lren¢:h}m;rf Mm antnli }"ematnu.s.eh,m_e,1: Sunvnar.r Im esperimcnis onauine:ll pia, oxalamine citrato' vvas shne n to prn,c,tun :rnti- in8ammathra . ac[Ion on chcmie.allc imlrlccd infllrmina;ion inthe ro~pin.lon' I areano. Ozolitminc ci'tratc 1110 harl ;Iltit:itivlioallOsi.=nillcmt'.unti-tus.ive clkat.nn esprnirrenl.all}produeed cnuehin enincn pies. The:comHine:d . anti-inll,tmm nlmn} ;Inrl ,rnti-tuv,ise'e(hoc.l cnuhll perhapshepalrti- cu.larle us¢fu.l in tho'.tre,umcnt ol n~tn-haetariill ~hrnnics hrnnLhill.- 5+ .'.mirlJir''vcou^h's ft'~I.I~( Rt.At-I S Cbanlr.urv. E G. (d7fifJ1- I~ V re Ci.d~:o nrcli.tr l cna n ..n,n:. -Iruro. nrn . hcrhrcn . Ii sintecl. .tliira~~.rt i~rcd'. S7: anin Du.rnvrv. TT f'Imihfii'l li I i.r ,nL iheuncn . cl`Arl „6 mru 10,01 1 ~4c hI nv I nv. cnr.1[c A'nro,, Km~~. rr~rp . Ilr,- ~~5, - i ~ - Dimiuv'. CP..IIFiMUI,.ly,ar,..n,c~lin, vIrc'..v,IlPerohn~r-'.m :unlto-.r-.,nitnl.inrm;tl:,n::• di ,inievI ,tt7nn~ria.nmu '_SI:AOb~: ; 31a.\IC'rHl\/..IS. ,In~l I'll//\fII,.Cr. II`/r,l). I'h.inn' ,l,~mulur'ii.allh::nncfnlu', I,: 1-hll~nnl-'-m!i,.l`i`.I.Inlull::- cSh\I-I.?1-m-Itli:u r,l~,.l7~r1-1'/'I1,rri:i„ . r ..'ll', TRt~l•rs. C, . !I'>hlltitill I lli'\ i_.,.: lil'i~~i\+mIhm:~in .i~~.Lrn'.m, rlilli.n\cI, .i.;.hli.tl.llir_he : 11;~~~~„i 3701. N'i.rl'aai.Ch. A5 and. Lilv' i.cF.ii, .. II livs:l7- ~\'nutu,av.~c iry'imu.ni h'. rc.tnic nnulh.,l,.ai:.l r..ul,.: J. etrr~rrmrrr„r: C ,p - 1)1r0 . )) C. vv. J: (-~~Iti:11l1l. rcl, n.cI_, Ir_, 1 \9 ; ~. ei . I I)..i:.' ,. \:u•r. IJd.ur I I-P~-a/,,..Li .1.
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n n~w J a ' 47 5l 63'~ 87 97' t01 a.~ I I THE EFFECT~OF'O\C)i.AC91NIc CITIR:I~~TE O\ E~VPERMt:N~F.1~LI.l- PROi)LCED 1A~FLk\CVL'V'i141A'~ AMD~ (~UUGl1 )epartment'uf',PatholoLv: 14nralinakuSjp liuaetl:rnd Ih~titttt ol f;i~+~icnc, Ifart~lin,4.sInStitut'ct: StocGHniml,Sk,cileni fhe, anti-iitH.unmutarnand anti-tttstitie actii)n of'oxoluminc ciiYntc tNasdCtnointttucd ia animal expcrimcnts, hySihe.ttini untL PO-r~rtti t II)(11'.unJl cliniualltih)Cirvi)clLu I196Q1;[Jeid,la t79G0) and TrnPPS (J9H1). umong, oxhcs,. h;~`ie.tudled thcelTl,ct ofl oxoluminuciilateon inflhmm; tnry diBCt"csof the rr,pinatnro[ract and it-s.,tnti-tu-i,oe,ffcctl. Inll:tmrnatorrchungc,.wcrc pr..dlic.M h_;.cxpa)nure.t--, ~wrah'in aer0.c)liand cou.Lhim_ h) esftm.urc tn ;)mmnnia uerv)tiol: The anti-inflitmmatary studle:~cerc rcpeatedlon t~so scrietinf ti~cnt,.animalti cucli. Each~eni~r o,tcsubr(i'iJ-~J into tiiur ~~.rnuL,1,1 li,r.^_uii)ca Litu, IA. 81 G, and. 1)Il 7hc °rr",p -A;tnimak.ucrc\ uxedlaisa uhcCl.! nn IHc 1:unJitiun nl' Ihc cuin~~:u Li',I anJ. « e:.ike.t no [re.;umetit at all. Inititoothcr crr,up, nnrn-.h;irtcrial indama):Ui..,n uae prr~Jtioc~l in thore.~Pirat~)r~ Iraet hv iitH'Jatinl; tn1G'iincr and Flatal.'cr( l`)n31. THe, c\pnvur; "a,nt.r.loil'n IM) nnniu.;in u r.llndr.r flitcJ wth eiP.tri nohuIIicnl I'iu: I): ;il(cr fil'. A:rnl~in ci)ru,uru, iinr;ip,;rilnn~.tll injtctians>.,crc t;,ll"-::, SVF141 ERIK D;\HLGRE`.` anJITQRG D:\LH:\\11' 'L\TFR~IAL .i`~1)~~ \iFLTIID)I)S, Gr.,, ~.r Tz~.! -ho w~~n AA n,, lra.l'nxn~l -. C \i~l S'f~l t)~ ~h'C[_~Li,i~„_.. THednsesurehtr,:a ornth., r'c.r~~nune,lJ;1ti1~n,P~,] Iher.'n1ulic.dl),:-t_e.. Thcinircli-n,aerc.reHe;ttcJ in z~rnuL,R. ( anrl I) clt•.\ en.1 Jurin_t tllc Il)!Idr.k in_ 7hlt,mn6 llhce ref4eutcd dn.e, per Lii.'a(l.uu hal1i1 l1u_ht nuPhen)1hutan.ncancl I rms. v1lJium rhloriel- I ha~hci iment..acrr. ,tnLrr~d a~i~+~St). houri. Pflnt s9udF,, Had .hm~nith.n ai thi. timl: . inVl.lmmu±nrc elial:u.:, "rrc.,u.thar pc;tk Thirt2cn.nnimali, cl.icd 1luriilrlha1~\hLrim' 'nt anJ "rrcc'anlinerl alter.lonih. Lhenthlr;iniinaf„1t~rcl.!i!lal_md inlnr..1ii;iidk :tuti'l)"C1LThclunse'%rre 0 47 rmc.lt<n Lg hrJj~.~a~l~.U CQNfIDgn1'hu I 411 t' i1. 4 `a f ~ f ~' ~-~~ 19W
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- _~ -_- ,---- _ .a _... r C V4Y;a,' f^#n.~ 24 T.DACHA\I\'S.L. Ai11'D animal was submitted to t'hrce tests; one with each solution', An interial of a few days was allo cedl het'nceen the tests. Code-labelled ampoules were prepared befor'ehand. The sequence of' test solutions used in eachi atiinea pig, was randomized and the observer'. counting the coughs was not told «0hat the ampouleshad contained, because randomizing',samples does notrule out' the triansgartationof infbrmation to the obsercer: A "cough inder" was calculated for , each experiment and each guinea pig as follows: V~o, of'coughs~30'min~~after injection,of~test solution X~~ 100 No. of coughs before the injection. was 117. This was a slight increase over the mcan pre-injectionicount. After injection of osotamine citrate themeun cough count in the30 guinea pigs was30. This cas30 per cent li+ss than the mean pre-injection cotmt'! After codeine phosphateinpectionthe' mean cough counU in, the 30 ex- periment5 was 49. The' decrease frionu the' pre-injection count's was about 3W per cent.. Statistical analysis(,Tuble l)'showed the differences betweenthet'estl sub-stances to be strongly signifiannt (P <0.0011' * * ). Special analcses showed significantl differences be-t«•een the results of' tests with SaCI When NaCI was usedi as the test sofu- and with oxolamine cilrate and be- tion, the mean number of coughs ini t~ccen oxolumine citrate and codeine the 30 guinea pigs after the injection phosphate ( P' < 0.05'")'• RESIB.LTS~
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~ ~ ~ CRtE;'11,~L. -:---.--- a:\'TITCSS{PE' EFFF.CT OF~O\OI.A\1[ME~.CITR.lTE: 25 ~ TU13LE l. Resutts, of $tatisticn! .i'naf~taer. L16'riab'fe P Tlesl 5ubstance! 0.00111 T!est day no: significanee~~ Guinea~a plg~~. 0.001 -~0:01. ) C CO~]f ]I E'\~T. This sludy confirms eardier clinicaG obsersatlions: concerning the antitus- sice properties of oxolamine citrate: hs compared with oodeine phosphate; however, oxolamine citrate was slight- ly, less effective in the present esperi- ments,in guinea pigs. Reprints~ may~ be requeste!dd from:~. R.E.E'E:R~~Fl \ Q E S Corbella. E.: G. (:19160ry. F,Sperien.zercliniche pre-liminsry. oon osolaminacilrat6~ nuoso' bechicu.di s:intesi. lfinerua l7ed. 31, J07'7-a080. Dahtgren.): S.Dalhamni.T: (1900, T!heeffect ofocalamine citra3ee un e,[perime.ntally producedd inflammatiun.in lh'ee respiratory, arga.ns, dcta, pharm. t'rn :4. 285-296.. Dofhanren, Z. (1966, . Inhihitinn o{f the cilio- staticeffect of cigarettesmrtWee by onol-amine: eitrate: {ne er. Reu. rrs.p. Drs. 93, 7'99=800. Deidda; C. 01960) Esperienzee ciiniche sut. Perebron, unn antitosse-antiinfla.mmatnnio d:i siirtesi. llinerua.lfed: 31„3059-J064.. Silo-es:trini, R. ,f-. Poc_a:tti,.C., (1951). Pharma•collrgica.] prope!rticsof3-phcn.l5-dicthpLL aminnc,thyl-1.,2;A-oxadlmzole: lieiC L Phar- maol. 16. ?09-210: Ptufessor~T'ore. Dh~lh'amn INstitu.tee ufl Hvgicne, Ku~.rnlinska~ lnstilu.tet. Stackholrn~60! Swedh!n. (
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CCI~ t~.TLL1 FREDUCTIION OF CIGARETTE S141'OkE CILIOTOXICITY BIY CEfiiTAiPVITOBACCO ADDITIVES bY Tore Dalhamn~and RagnartRy,lander ReF7runted Frarn A'mercanI Revievr~of~Restf irn toryD~~seute~ Volumat'03 Nurnberr6. Jdinc 1971
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THE EFIFE,CT 0F'~.rJ\nL'>\tl\f r17kNrF'~. ir\` I\rLa%l%f Nnrri,i \1!) (ot(;n ~Ic;cn r~•I~.1[i~~~~~~.un~ ~~iiel~I~~ tt;~.10©. g~No~~~ s.nyhtl Nome.(cuniroG) 05'N 0i3 AcrtdBinaeroad sodiumrhlorido IJK I."_v Acrolcin uerucoJ -owlami-ciuum 0:78 I140 Acrn'cux::crotul phu»Ihutaznuir 0!87 1158 The aorolain-treamd ,lnimuls hati dIl7eronrdeceo of tr;lchcnhriznclliti,;tnd hmuuho- qmeumunin. The inllumm.uor}ch.mucnsoen in histolngitcll ~ection,,,ot (ra.chca. N1011- chiandILng f:ucnch'>.ma<rfauchaninlalscercLraA(I;ISIoIlosss;6 -nuinll;imnut'Iii,n: 0.5 =mild inllammutinn; 1.0 fairlv ~c~oroiittlummation:'_.0= scl.crc inllamma-tidn. M-n yrag ~.tiilr,yn-1ii&ni,,n Thesc, ani mal5 nu elTect: for 3 rliea, Thcnum- ::Itcr amm0111t1 nmcs latcr. the Ihz number of J cnd,2in phos- st ,olution pcrahcll d and the or unklno%,rta Or iitPCtlionof ulalrci for each I in T.rhli~ I. In nl~c.inth.lo~ccr I'-- 1t,1ti1tic.,lly Noncrcouirrdli Acrolcrn soaliumihion,le Acrchvn dcrnro4 oxo4~minc.iiruic~ Acrolein~acrovel phc.nOb,nan•ne L.ume: Hronchi iFa~~h¢a. Total LuW•nhmcm Inselica Ibtai (t!I 01 0~. 0~-1 02 0 0 0'. 10 0 111 1.0 ?;N II"_ 1.0 Q,'~ "). 01 _ 0_4 03 0:9 0:5 0-6~ Qh IJ 06 0_' 0.3 L6 0:9 1 0 0-8' _, The meaneradeti foithc sariirus>•'.rr,up,are sli-sn in Tahle III III hu>oh,crics: oxolamiirc ciiratr ,ho.sr•,d it rlktircl :u7urintL nrntiltnrn :rctiu^ ssltiuh uuasufcri1>r to that of plrerWhuti!znne. 1, iuJLcd (r01711 tHe dc^ruc .)tinllL,mm;ili.in aa,a-d mlcnotcnIpirall";lnd t~IC roL:ni' u1J"t nt`th"' luns, tirc:rntl-inCamo"ilinnacLirrn III os„Gtmice cit,ratc:inhic!ik .icnili-1111 t;u1.11-, I' (illfll i. Inlhi Lnouhs nt irirn-ilrIrr;ucJ oith .nrli,im Mrfhcnr.lbur[:vnnc.sr)me pnine^ Pic..h-ual fltiiVs ,LL,soru'fulm~,nn~ ~irfhc.~>niui_Tlh~^_rotrf+ ,I usrrl:rminc- treateJri^_s. h~,r~csir. xscrr I,-rc I?umcrnhli-em;uou, ~ha.nncs. Amr=rtn wr arvlmr The re,ull,o! tlle nhru-~;nionwcnncrnine Ihe. :rnui-tu111-a1lirrn of r~xnLrn~inc citratc arccvmm,uiictliinhahlcIll. I hcJotrc:nr fn,mth-otprti--inlOctin~i cnuslrutZ Unll ual ahoutl _'llin Ihc -nl,iminy .ilralcHoaI~J .mintul':uxl ahiwt 'lDnhcni cOalcinr• fh ,PiiIrtr n;i~uvIrl a,lc.t s+,luli,,n. An.ik-rrs.~hrrs~~d,th;u Iho anu-lu,sisc.pr0hcrticsLilraI~`.rcllaurlic.illn.i-i'mlir,iI)lII" 09>1.Cnmh,ircJ-,~1111 aoetcinerHusq.h:ur. ii ,scc,,:r. ns`l.iniina- iilrnlr ss,iSIr:,cllcrtisc astrcuuel -,u SaIIt.
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a=' Scand~. JL re:p~. Dis.. (19R8'Y.39„23-25 ~. V p 17.1 r,2 7~f'Fi~j''~ ;l~f~7~ 4aA~i~ /_d7airl~.~A I The Antitussive Effect oE' Ox~o1aicnine ~ Citrate a~nd' Codeine ~ F~liaspha~~te~ i'.n G'~u~in~eu P~~i~s~~ T. DALHAMN S: A. R.aco Ius.titute'.ofHi'.g:icne, karollnska~ Institutee and.theStatistical Institute of'.. Strid:holrn~ Cnivcrsity„S,cdcn 1 ~ ~ Th~e antitussive ef{ect~~of ozolaminee citrate, .aa~~.s.comparedlwith thaC o~.f~ca.deine inn guinea~ pigs~~. esposed to' a2.8~. per cent~ a~,erosol of~ ammonia, .. The numher of coughs.sva~sregis~.tered~iin tests~e-ithiandl,ithout su.ch premedicat§nni.Both sub- stances had a.clearlp, significant cough-surypree:ssant: ~ a~.clioni. Codeine~e was~ some- wha.t~mare effccth- -1han.ozo.lamine~citralc: Ozotamine eitriate M-phenyliS B diet-hyl'-amihoethy'I-1,,, 2, 4-oxadiazole) as an antfilussive has been elinicallc studied by,manywriit'ers~ ('Corhellh1960, Deidda 1960„etc.). Its pharma- cologic praperties.cere described by Silvestrini & Rozzatitil t1tJ61). Thatlox- olamine citrate may help to colmteractt theciliostlatioaction of'cigaretile smoke was indicated in stludios by Dalhamn (1966). As a continuation of these studies and of an ear'lierr iheestig:rtion ontheanti-inflhmmatory,actionofoxo- lamine' citrat'e in the' riespiratory pas- sages (Dahlgren & ' Dalhamn 1D66)', the antitussive properticsofthiss'ub-stance were observed in animal ex- periments. 3l'A,TE~.RII~.a~L. AND \CE~T.HOD.S The technique was essentfiallv~ as, dh- scribe,d' by,~ Dahldren & Dalhamn, (1966K Theg;uinea pig thus Wa5placed in a special chamher' (F~igure 1), andi exposedito,the cou.~h-pre,ducin,',ogcnt; in this case a?.8~ per' cent'. ntnmoniai aerosol, for 3 minulcs. The number of coughs during the exposure per'iodd was counted. In order to exclude er- tremes, of neaction, only, guinea pigs with cuugh frequencies in the r'nnge, 10' to 40 were includUd. Immediatelv after the aerosol exposurethete.st so- lutianwasintrapenit'onealh'injected. Thirty minuteslater'theguinea pig wasaoainlexposed tbammonia aeriosot far. 3 minutes and the coughs were count'ed. Three test salutions were use.d: (1J~ physiologic NaCl, (2) oxolamihe ci+trnte, and (3) codeinephosphate: The dose in all cnses'.casA mg 'perkg bodf•weight ( = 0.11 ml of; solution/100, g body Nceigrit). Thirty guinea pigs wer'e testedi• Cach The~.investigation.w•~as~sUpparted tiy a~~, grant from hB!.T:ika„Cmc$~., Sweden,.
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448 burt~~.rather combustion~products,.Atthe:high.pre~-~ In judging~the,.obser.•ed anticili.ostatic.etTect, inn railing~g tempera.tures, (SIX)' C), di'••.compositionl the~present,ecperimen2s, it should be kept,n~mindu could~d have~~e occurredlin~ssreral ways, but primarily~ that th:s effect~may, have involved cilhry~~) acticit}-,.% by liberation of the~~ citi-ate:and diethylamine~~e com- mueus~seeretion~,or both functions together. T:iat~~ pone~.nts~:from~the oxadiazole group (figure~: 1):.. an efte~ct, on secretivann is~s hlighly~ probable~e was \-0 CH;COOH % C' ~ I GH. ~1~ -CH,-CH.-S~ C1 ~ \ I\ C_Hi. I COOH: CH,C6OH C C The~question~of'wh~ich~oompo:und orcompound;i were biolb~gioallv~ active in~ the~e studied 1 pro¢ess~. cann bee answeredI only~ tiy~ further~ biologic~ testss with pure~.substances,ande b;•~cliemical analyses~:of the~ smoke. General toxicity~ testing iss also necessarp-;, espe(iully~ in vieww of~ the pubdished report2 of diethplamine~ be~ing~, a ursnary~ bladder~ irritant inn some~animal.~specirs,.Ine those~ incestiga.ti.ons~, how-~ ecer; the~d6ses~ of dieth±vlamine (G'om~a0.to~.9iD0~.mg perr kg~~ bodgy weieht)~) were~ much higher than.in the~ p,re,ent ercperi~ments: SiM_trmi" and his~s c~o~- workors found no~.diethsdamine in the urine~: of~.fi0. perons~ irho, hadd received o<olamine~ oitratee byy mouth. ' Barron; C.: Exp j _),Solee. Path., 1963' (Supple-men t 7 p_ 1) . '°Sili•.esr,rini. B., Catanese:, B., and. Corsi, GI: J1,PNarm. PHarmacol..196a;,13; 3S'. Pia: 1 pointed out in an earlier paper.'«-he,ther the ob- sercatlans an these.animal lexperiments: are relevant for hu.man, su.bjec.ts cannot as yetl be stated, alth'ougH.there.seems tobe.some.likelihood.th.at this.is theoasee lh.summuryt OObserl-atiansi have been made of ciliary actiiitgin r_ats exposed inaiito: to: smoke from~non:ilter c:garettes and to cigarettes proeidedd with an~aceaa.te cellulEr_ee hlteq botN.kinds witti~a.ndd without~ oxolamine cctrateas, . an addPttMe_ Thee anticiliastatie: effect't off the: filter wass highlyy sl¢- nihlant,_ and thee e3ect of thee additivewase signit3-cant. TORE D{L[r1MV TheIhstitu.te of,Higiene: harol inska.Ii;saio.rtet. 5dockholm.3weden. Septemberl8, 1'J67
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REDUCTION, OF CIGARETTE SWIO!KE C]LIOTOXICITY'BY CERTAINI TOB11CC0 ADDITINES It' has,been shown previouslp~, thatt a~considerablee rediiction in~- the:ciiiotozlcitv of~.cigarette smoke~ can be-ach'i.eved..in acutc in.urisa ~expe:riments'~.in~ animala iff oxolamine: citrate is~ adm~.inistered~d to~ the animal'- before: exposure~e to~cigarette smoke, or~if'it:ir~adddd to.thr.cigarette.tobacco:. Ih rthee first set of~ experimencs~}i t00~ mg of oxola- mine~ citrate perkg~of'bodv wenght'in a 5.per cent! aqucouss solution was~s gicen to~~ rats~ by! mou.th. Some! animals~were gicen the oxolanuinee cutrate defore exposure~ too tobaccn! smoke,., andl others~~rcecived it.a:f[er ezposure wheniciliostasis~~. had ocaured ihn the~ tmchca..W~hcn oxolam~,ine was~~gisens bnfore exposure; tHe~e numbcr of~.pulHs requ.iredto praluce~~.ci.liostasis~in the trachea.of~a thee test' znimal§ was~s twice that! for-contmll anii~ mals f3(0~- and 155~5 puffs, respeetivell~). W~henn oxoiamina citrate- was~giccns aftcr ciiiostasii had' o¢eurred;,recovcry of ciliarv~activityy occurredd in. 4 o.f ~5' catss compared'.with one of-3 in the eanaroll group. The:mucus ~secretion, in ~tbe~~e trachea: of the ~. anfmals~s treated with oxola,minee waa~~ jNdged to~o be~e normal or~iiucreased in.contrzst~to~the, abnorr mal dr}~Pt+cs- noned~~in th'e animals th'at were ex-~ posed to totlacco smoke only. In~ the second'd experiment;2- oxolamine~ citnte was~added~s to~.the~tobacco 55 per cent by, weigh't.. The ~miean number ~oE ~. pudfs~~s required~ to produce eiliostasis~ins the:tracheae was~.39~. forthe animals receicing: smoke Bam~ treatedd cigarettea, corn- pared w~ith :00 puffs- in animals~~.receiving~smoks fiom untrratedlcontrol ciga,rettes: The~following~ezperuments were~undertaken to- el'ucidate.furtherthe:anticiliostmtice~Heet o6- oxolamiire citra:te~e a~.nd some of~.f iis~ d2risatives: Tke strueture.of':theoxol4minee ciirate- . molecule is shown in figure I. In the initial experime~nt, the suhstancce wasdicidedr intoo thrce constitucncs according to the heavv, lines elrawnacroasthe molccular structurei in thee figure: Thesee sub- stances,~ which wern tested,.werecitrie aod,.di- ethyiaruinecitrace; and phcnylrinsloxadiatull (PVQ):. Thcywerey addcdd to thetobacco.of a! standard filterless agarettein amo+mts- propart-tional to- the5! per cent oxo4amne ciirate: con, centratiom tezte~d eardinr: Because PVO.proved to be unstable andlha.d a! strong, tendenrryto pohrrreruzc, a, dericative, phenqltneth.loxadiaaole: (PS10), w-as preparedl amd testedin the second phase of the ex.periment. The smoke- fiom trexteded and controllcigarettef HI qH H I I I HI-C-'C- C-H I I I a~ l a~ I q~ i gq qH qH N - 0 //\\ ,_ ~/ I CHz,-CH~ \._/ C\ ~C-,CHI_CH2~ ®N/ /- \ H N / • CH2,-CHt, Fig. I. 9lolecular structu.reofoxolamine citrate, the-subcompou.ndsof which are.ee.parated b'y, the -.blackbars.k tDaJhamn, T., hmer- Rev. Rcsp. Dis., 19156, 94~, 7'99: 99,417, 2:Dzlhamn;, T.,,Amer.. Rev., Resp. D~is., 1969, naERte:av tncvit_woF iaesetw.azoRY utsl:nsr-: voeu+tr_loa' lolt 855
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A'cra pharmacol: et tbxicod: 1972, 31, 193-202. From.the! Department.of'. Pathology, Karolinska Institutet, Stockholm;,and, th'e Department'of. Hyg;ene, Uppsala University, Uppsala, Swedeni The Anti-Infl'ammatary~Actioniof~Phenlyl-M~ethyl;~Oxadliazole~ (PN~Ii01)~: A'n~Pxperimental Study on the G~uinea~-Pig~,Traehea By SveniE Dahlg[en and Tore Dalhamn(ReceivedlOctober2'1', 1971; Accepted Decemher 14;,1477) Abstract:.The.anti-infl'ammatoryaction ofphenyl-methyl-oxadiazote, (PNtO),was studied in: guineapiss: Irrflammation of the respiratory, organs, was indu.ce~dd chemicallybyy acrolein aerosol. In repeated experimental series, twoo intnolviiug, irttra:peritoneal.andl one withioral administration oflthe.test solhti,ons; ttiee anti- inflammatory, action wass found to 6ee statisticallysigniflcanti. ISey-words;. Phenyl-mahyl-oxadiazole -anti: inflammatoryaction on guinea: pig trachea- in vivo. Phenyl-methyl-oxadiazole (PNIO) is structurally related to oxolamine (3'-phenyl,5-diethyl-aminoethyL-1,2,4oxadiazole): Oxolaminecitratbhas an anti-inflammatorv and an anti+tussive actibnasdemonstrated clinically byCOxnccth (1960)l, Du1rnD.a(1960)and TaortA(1964)among others, andl experimentally by Slr-vtsTwr+t & PozzA1-]li (1960), DMlt.ceEti& D;iuustv~ (1966) and DAcltAnmr & RAUD (1968). In a previous, studythe authonswereable to~ demonstrate an anti-tussive action ofP'11'O (IDatit_(;tafN1 & D1t-rl.avtN, unpublished results) In the present investigation the anti-in- flammtnory action of PSIO has been tested on experimenttrlly produced inflammation ini the respiratory organs of guinea pigs. 1L=lethods Iiufhrmmationwasproduced~ in the respiratory organsof guinea: pigs,llhr. animals were Ihsne.vpo.ed too a,crotein inan plexiglasss cydinderflttadr withaHeyer-Picca4o sprayIDkur(;wev &Dka-uAs+v 1968):, Previouss pilot studdess had shown that the! optimumeeposure time andd concentration afacrolein.were 5'minutesand 5~per cent resprrct ively: Tlie.anti-inflammatoryproperties.ofP%tO and phenyltlutazone.were studic.d. Pheruql- butazonee wasused in orde,r to, comparee the effi+ct of~ PM17Owiththe knaswm a.nti- 13 Atn ~Pn,rn,ocoG,gyca. votl 32, ~Izsa..7-4 .
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856 NOTES was generated'.. by smokling a 35ml, two-second puffonce evcrv~minute with the~aid oflasyringe. Various amounuof this~. smoke werethen im- mediatelv administered to the animal. Chemical analyseswere performedlon the smokeusing gas chromatographic methods described earlierCi In addiiion, theamount ofP\IOin the smokewas delermined. Fullgrown cats were anesthetizttl a~~.nd their traleheal cilia obsened~ tNraughi a tracheotomy. A microscope 1. ith an in'cidelu light was co, nected to the trachea by means af an air tighnrubbe~rcuffiTlhemotion oftheciliaav the bottom ofthc trachca causcdla Oickering, light reflex tha:twas ~easil4 ob'serve~d. :L' glass tube, mn- tinuouslv,healed to3i°C andlw"ith avo6ume equalltothaaofa cat's mouthi wascomlected to the~tracheajuscbelow',the~larcnxand to a respi- ratorn pumpsupplt~tnglnoustair. The sm kc Pe-ncrat ,tas dexerT-I arlicr, was injected mto,the artihcial,"'mouth" abthebagin- ning of an mspirutibn appraximatelh once ~~.everw min'ute.7'.t passaqeoftheputfofonlvslightlL dilutedIsmokecouldbc. seenin the miero,cope. The nurnbcr of puffi' rcqturcd to errurct all caliary acGritvinthe tractiealar-odrsen~ed was registered for cach~ aniin'al. Studies of: mcaverv~ time wcrc not medc: Asa control ofthecondltionsimposedbythe exposure apparatus, certain anienalk wc.re: on necaedto~the apparatus for fixuroc macre hours. l:hqhcsc animals, norm~.al eiliarnactivitcpersisted for nroretfianfour how: s, indicaedngthat theex+ posumcquipmentitscffdiil not influence ciliary ~ activitn Ih~thescmnxl phase of theexpcrimenrwh'cn only PSIOwas tested,spariallmeasureshad to~be taken tosort ouraniinalsiirfectedlwith, uppcr respiratorr diseascs. Before bcing uwd in an ex perimienri all animals were connrctrdl to the experimental apparatus for one bour befdrre ex; TABLE 11 ANALYSES OF CIGARETTES USED~ IN CILICSTATIC'.EXPOSURE EXPERIMENTS IN CATS tld'Irive Am unt by Tobacro Weiqht (i'1 an N~icotine~ TPM+ (mgJ Cdntrol Citric aaid - 1.25 339 32.9 2:16 2:00 Diethyla:minecitrate 3.12. 32.4 2.00 Phenylonyloxadiazole 2.0232.22:00 Phemylmethy:loxadla¢ole 0_5-10 31.6 1.9 •'TPM =total ,aartfa,latematter. CONEDfr. -13MAL posure: Only those judged tohawe. normal ciliary activity at that timewere included inth'e ex- peri men ts- Tfie chemical analyses of, the cigarettes'. useid and theamounlsof the variousa~dditives are pre- sented inrtable 1. Analvsisshowed that, approxiinately, 12 per centof the PSIOaddedtothetobacco wascar- ried from the cigarettein the aerosol phaseof the smoke, where it constitutcdlapproximately 8 per cenr of thetotall partleulatc matter. Results ofthe citiastaticdcterminatipnsofcigarcites:contaihing eaaious compounds'. arefound in table 2. Ofldre dLrisativesof oxolamine citmte tested, onl) PL'O and, P\IO showed an anticiliostatic effcct. From cigarettos trcatm with these twoconrpr>unais,~ Itz:Sanaf 138: puffs, respec[ively;, wcrerequired toproducc cillostacls c. nrpared with 52 to 66 puffkforv the smokefn.m cigarettestreated with other comp<>undsClie dlffefence between P\ ~Wor I':ALO and othar compoun'ds was signlficantl TABLE2 NUMBER,OFPUFFS REOUI RED TO PRODUCE CILIOSTASISIINCATS" Si9nlfiranca af Difference from No~. Controll Typeof Cigarette oiP~ffs (P) Cantrol 7334~ Cit-acidl 6624~ NSt Diethylarmine citrate 52-34 NS Phenylvinyloxadiazole 135~~.129 00011 Phemylrnerhylo.aciazole(Z il 138'.'49001 •r•rtean ±S9 fpr 1011 imal9ine.achg:roop, 1Notsigmificant.. TABLIE 3: NUDr1BEROF PUFF'S REQUIRED TO PRODUCE C1L105TIASIS IwICATS A'mo unt 91gn~1 io3 nce of~ af,PMO Diiffe.rence fro:mCo.ntrol (°Po'f~ Noiaf Pufis lPfI 0 66 0.5 67 NSt 2 112 < 0!001 5 BB NS 10 49 N$ aDalhatrm. T., a:nd RsLandrri R, Arner Rev: •Mean x~SDfor5an5male -augroap Resp. Di;-, 1U68. 9&, GB!u. tNn-g,fica'nt_
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.r TH'EaNTICILIO9T\TIC EFFECT OF CTGARE7?TES, TREATED WITH OTiO'L.,0In''E CITR:aTE" i The'e antithssi~~e~ and~ anti-in©Lmma'tory~ action' of' oxolamine: cittste', frequentlyy has's been demon- strated~d in' human2 and inianimal expecments'."' ~ Oxolamine~e oitrate~~e admiuisteredd orally~ seems~ to~ have a protecdbee effect againstl the ciliostatic action of'ciga'rette~f smoke.°,'Inx the'~e present ineesti-~ gation. axolamine~ cittate' was~ added to~o cigarettes's thaG were °Amaked" by~ laboratory anima:ls~~s until ciliostasis occurred. Comparisonsiwere then madi"e with control clgarett.es'. f '~ The~~e method~d of'eaposu.re to cigarette~e smoke~:wa.s~~ J~ the ~samee as that ~u3edd in several . previous's studies" Cats.inhaled amoke~e on'eY-ery~ third: inspirationl,and the cigarettes were smakedlto a~ butt.length oI'28 mm, corresponding' to'o eigntt or~ . nine'e puffs per, cigarette. The volume~e of each . ouff' was adjusted to a calculamd''~norm,is human smoking~ (35'5 ml)~, and was: L.ml per cat neight of ~.a'pproxim:ately~2 kg. \oo pause:was allowedlbetween ctga:rettes~smoked by.thle same~cat;':the~~.exsperime'nts~.were'.oonduetedl as "chain~ smoking." Five cats's were used for each, . cigaret[e type. The exposures', were~ runn in th~ree~e series. The same~tobacco'type was', used.throughout.. O:olamine~ citrate was~~s addedd to~ create~e aa con- centration' of ~ 5'5 per oent~t of ~. the cigarette'e weight. Thee tar~~conte'~nt.was~~ 2~_SL' mg:g per, cigare'te„and, the'e nicotine~~.contentwaa 1.a~mg:. The~: number of puQs preceding:ciGostasis was:registered. The~e results.are~surceyedlin `.able'.1. In se'.ries:1'., in~ wh''ich~ alll the~: test varianta3 were~ included, the e':ffect:of~ filters was'.si'gni5eant (P < 0001). Thisi effect ~~ had been 1 obrern~ed~ in, . many ~ earlier' experit~ ments. The' effect.of~.added oxalaminee citratee was also si~gnificant ~(0:0a ,>~ P. > 0A1~.)'. In serie~s~2~.and.3~onlj•~~nonfiller cig3rettes.were~ used. IhI series~ 2~ the~ mean number off puffs preoeding' ciliostasis w'as'. 23' in the ~ cigarette'e with- out'~ oxolamine~e citrate;, and'~ 47' in those', to which, the agent hadibeen added. An identical differenee (2,4' puffs)~ was foundl in.se~ries~3. Because' th'ese'e diffhrenoee'- n-ere: so~o pronounced; statistical calcu-~ IaLione. of significanoe~ were~e judged~d to tie: un-~ nece'S3a'R". For the three seriea colleetis•ely„ thee mean, numberr of pu.ffs~.preceding~~ ciliostasis's was 39'w'hen non5lter, oxolam.ine~.citrate cig3rettes~were~: smoked whereas's onl!r~ 200 putTss of the'e cigarettes: with'.out oxolamine'citrate were~requimdlto: produce ci~lio- stas]s. CP~early„iherefore;,the effect of addedd oxolamin'e citrate~ in the~ cigarettes~~ was, to~o counteract the action.of the~smokein ca:t:trach_a~. Several im-~ por'.ant points, how'ever; require~ clarifica:tion. TABLE 11 TYPE'.oF CIG.IRETT£a \\'n~.NC'1fR.ER aF', Pl'FFS REFnnE~.CII.tfJb?'.tcl3~ sknra oxola-, ~ C-iir-: Addcd Azetaa~ ~ Celluilosa ~, P•.iEs~be(ore F~Ittr~ i C.i~.iosrasie I t + 45 33 + 25 ls 2' t I li 47 23 3 + ad. - ,~ 1.+2~~.t 3. t 3tJ. 20 TAe:size of:the dose.isof'considerable importance: Inn dogs Iv:t}l: tranheobranchial in9ammation', de Gregnrid- "gave' peroral doaes of.l.to.3'.mg',osola- mine citrateper kgg of'bodyf weightt four Limes daily; this was.equicalentl to a, ma'xlmal.daily dose of034 g: in.a' human subject -igi,inc. 70 kg. In the'.presentexperimrnts, the connentiarion.of ox- ol9mine citratein the cigsretteswn_.i' per ccrnt. Because the approximate w, ^ight, . ofe'sch ciearette'e was I g; the'e do'seiu.an'asulmed.con_cmption of IS5 ci'garrttrs per da}. nauld he:0:79 g. Three milli-gra.m.,: per kg.of:hodyw'eiglrtfour times a daypre-sum.ablvis:appreciablybelowtheV msnimal thera•peutco dose.o.f bsaVamine citrate: In thesmakingesperimenls', however,, the in-h'aled.subs.tane'e was in all proHabilitynotox'ola-mine.citrateas.such, or; oxola'mineai!hate.afon'e, ~ ! ~ ~ "Dalhamn;. T., and. Rv.lander, R.: Arch. Gto'- 'de~Gregorio;,Sf.: \linen^a.S1ed-„1960..51'..10.48. larvn&~(Chicago)~., 1965, SI; 379. ' d.e:Gregono; 14~.: Panmiher.a~lf.edl, 1p62,' a~, 43. ' AMEMICAY'REvtEw.OY. RE9PIrilTonP'DtfiE:ASE; ..VOLtiM~E. 99, 101>9' 447 'This inves'tigationn was supported Fiythe. P. Lorillard Company~ .`ewY'ork,.S'ew York; andldy' AB Tika, Ctne3;,dweden. 'Pala'zzo,. G., an'd: Corsi, G,:'. A'rzne'imittel- for-cHung., 1962; try' 3-F5': 'Dalhamn, T., and Raudl A.: 8can'd. J: Rbsp. Di's..(submitted for publication). •DaLhamn, T.,, and. Dahlgrenl.S:: Acta Pharma-cio1.,,1966,-'/r, 286: 'Dalhamn, T.: Amer. Rev: Resp. Dis',,,1966, 9y„ 799~
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GC~~F!~E~~i'"'i Ptt':TRItiFLh~t[vfATORY~ ACT[OY~ OOF~PDfQ~~ 197 • ~: ~ b a F'g, 4: Inflnmm:utory, lesion gracle3. MarAedd inflammatory, eell reyction, and dcn,s quarnation~of the; epithelial eells: Vlagnifieation~approslmate.,lyi5C)0: Table 2. fhflammatory resction inthen tracheal~ tissuc. h'vmNerofguincapigs Series. Test IDegrec ofinfLamm;ition. Totid pradln, af'! no. solYttiun NhneSlight 1lodhrrate. S'ec ereinflamm.qiom (0) (19. (2). 13)~ fmr:in calucli P5u0 z a o a o:7 I Pl7enclhutuzorue Methnczl 1. 1 3. 3. 1 2' 1 0 ].J L?,. Sodliim chloride 0 2. 3' f 1.8' . P570 3 3. 0~. 0 0Q5 ~ Phcny,lhuvezone 0 3 3' 0~ 1.5 b9ethocell 0 4 2' q 1.3~ Sodlum chluri~de~. 0 3. 3~ q 1.4 P511,) Phcrrvlhutlxzorue 7. 4 4 9 0: 1 1 a Ob O:ri 3 h ] Sfeihoccll SoJlum chloriJe 1 0 6 4 1 41 4 4 . 2.3
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tl~~nr,nir,ur ~~t,~r:w,r,.~,~Poe,rr:n-o~,a~.- . owt•~.n~~s,.qc ~~"I 9i; sa SJ S,r~enlber lbsea~j Yn nlyd'i 5~..{. RXEN'F IAL IriHIBITIONOF THE CI'I:IOSTATICEFFECT OF CI6ARETTE SMOKE BY OtiOLAM'ISE CITR>1TE" Sili-triBti and Pozzatti nvl thephar- matrologre c Hcet~ of oxolstnitu,citratn (3-lo6en}-1- 5g-lintNrl:unirnrrrtHrd-1,?,J-o_~-:rliazulc) in 1061," Amom: the factare th=tr,d. wns tlur anti,pnvnudirv rhTrat of thcdrua. L;inK ¢alina,apieinrrainrand a trunhlal chtuin prcpurattion tLay+ nh,xrrrrrll lrt rnltrrnntlnn= rrrrrs inducrri rc-,tlt hohne rlildrride:. hls4nminc ohloridr.:mri otlmr .15~tuucr>,Th,v notrd. alho; thatoso6:unine litrnte and uxal:uniirc llvdroehio-ridonrrn upprusiutrh-a~ ;unt,ytonl-:dlv:Irtsvr=. aap:ymrorin,, Full-erownl livr,cnts of hoth =I,sos trllrl: anc=- thrti-I mull YSIne_ of il nu6:uillt:ll -ndiluu (SrulLl t rIT'-9 pn Gdlrsrwn of I.ndv, wri[.,Ilr. nnd oxtlamin t . :udrnlni. t r n I r r t l l I 1 t 1^,Itill .t(Ilr,s:,s- Ir ~ t 1,i-nto -ralu6r~ r~1~IV.rtie~ I Iuiurn ropparatt" that hn, Lr~rn n,,1 in d- III arrton'in- numH- of otl- -p,rl T:iw prinr~i{,Ic ofi thrmethuxd is, that r6runil:ud inh.ula~ :t. tneul:utrxi voliln. ~ of frr•.bhprodurr i.rnokc an,l. tLr-ritcr- inl II., rrithont-.runFfl,lurins.trcrr rr~I~ir,Nton~ r}~,•Id~<." Cill'}*actlvit" in till ta.rr -.lua is. ub.rrnrll mr:unrd,ib- viai a, tnucl:rntnmG~ und :un Ultrulrak ulirru.-eol...~-' Tllr. ..~m ~kmtr~~. ia r, pu;lti,d ururillrrrml,lu'l~ nrn -t of ,~ili:an'nwo~~mol It ,n „Inok~~lll frum ,:Irli~ riKy- T-rnI "pnff. all, rrmtte, thrrc. i=no p:uua. hlrt .t ~ierrrrttr~. .An nrdinarv Irrand of noulillllrr"I riksrr,rtl.~. Icrd Oxalanlinn, citratr (2 tnl. pr•rk¢. (100 me,. Il,~r kt7 it, a 5 pnr rrnt, a IR-nd -luttant)) rru. lluut- istrnd to 9lcars., 15 mimttr,l,nfocr rs n.-,:mto mi¢:crrtte s.nohr. _l sr-rawd arcllp ,4 e 1.It•. urrri Rsrvntrltl!minl:ll= m~-~I~rld tllrsawn ~ultluuloi I Idvsuolomr n7iu1^I Id>nd,-. ' 't ~,6~ nntil In a v tn 1 1upl r n r nt 10 r+iliun~ a tl it Icul "l_ Im 1 Icl.rlr~It ~ncard Hufirhl, ,«t, rclrrt.i'rnocul nlic,. ntul 5 rxtnrrol. :ulim:Js wlrr u~io.n >udiuill I~~hlurnl6. in thr -rnr, dn>:eet~I-rl> :e+intllrflr_t trst, a f t l r r c f i " ~ l n i h , ~ rtn ,ton~rili:lrc, urnttn~ rcn= nlrse•nrdfnr tlu~l:r I:uu¢ Al :u,r L, r~llon th- Ir„~~ILI~, f7,L~'t. oB Il.i. 1~1111n- ^,ntul Irr6nnrnm, n~ . ~h~~ntmnx^ rl- i,rri„rm,,,l Ilrx ' Thik incr,rtit!rll innrvu, aiJ-l Ilw ' a¢r.lnt from t611 I?: I:r,rrll:lyd I S- Ynrk. and AI3 'Silrr>rtinl. I3,- :In+ll'6zr.atfi, C:.: Iihit. J. PYI:v- nlarn4-. I901', Id: 207. 'Ib.-JllaunnlT:. rlln Ii-n.,E, Il:ylnmd,A..,arn1 TCvlanlh~r. Il.: InlJ..AIttiCatrr CJlha, 1063i 7, alll. 'ID:Illlsnm. T.: .1rt.. F?hv..iul. ",rand., 1960:. 13; 242. a diEl,rrnt r,yt';. Theaniiuals ncrnI~lacrd in this smokinkmnnhin,^but mr-rn not rzpo-l to riqa- rnttnsunokl-. T61~w didInot reccirc axularnino or sodlum rhloridr: R hrln osolantinen~as gi,.rnIrafore expnsvrr to ciulrrrrtr~ Sanoka (tah4r 1), thcnnll' af[xnffs rerrnirodl to produ- Ih _tasis ra=aPl,roz:ma`rlv trcier- It Kr t a, rrhlvt th, prrnal Ii ~:utl- ron,l,rnd ofordium,rlilAri~{ranic. The dlftrr,nar wa=:i[;_ niflr:rn? IP < 0.06) Thrrnspnritnlnt, in ItilliirL~oxnl~rmir.n ritratr icas Ric,nimuw.,livlck aftrr rliarn~ untic.ilvha:rl 6urn arrn.=:ld 1- Lig:err!tt- =mokran+ r-viswi_~dintable 2. 1"In~;inirnals inini:i,11t1o,illnrcrrr,-rn' ,as dlse,rrnilll~.rur-rr nh,rnrll iur th, ftlll thrroLuur=. .nn/rr•nn~r.n oflr~lli~rr.flmrrinnu.-fouudin4 of'. tllr-.rr,Ihatl dl nr.icl.l usol:inlirrr:,iicr>'nlokint:.Lut iniunh.unnof tlrr-« theC -~-cd ~udiwu rlildnidr, r6u=imhr:,ilne_t.fanoratl. ul'I~rt o(w~nl:unlnl i. In tllr~ rrts tlmr lvl~m n~~d .u lonn~ol :Iniu-uls; nt rhan¢,- itr rlli:,rn~ ~.I~irv ~.ce: I lunli rlitrr rhrr,. Laur. uf 1A'.-l In r„malcriul;l6,L n<nlrs.oi tLnn~ rim„nis; nun ulr.~l k~,rpin I.nml tl,.lr11Vr u,uuL.~r ,I eats In,rdl,, o:u.nllx a.-rir. ~tns. =nrnll.:ln.l rLat tLrrl• rcas .rri,l,intn roul I,~uv,"n.r~aliin~ irotl." u nlni, luoil I~ats. Fnrlh-r, t61~Ilnur.< rr~l-rjntr„i i^ tllr>rrond ,reir>.rrrr u r..nriv. lllro.rhn:lrr~,m.r e,noll:- -Inns:rrr~m.~r-rth, Ir" nrrnli~~ll Inlainlv L,~rnu,w•. rLo 111_,nn -Ll,tttrunrr:~dto In thrrats that ,~mirr.l omlmluinrnituatc ^nd itr Illlo~ t6ut rr- II unl t I-i,dl t lit,. 1o ¢r , t. Oc I : I : n l n u I t c v , , , r uuri t tl - :r.f: l ~ITI" r ,n rlli,rr .u4icin~ ,rhr~tIl, r it rca9 11 1n I;,L_ fnrr,-:Jl,r-.Irrttr->olok-, In tlm T:U51:1: I Nivnr:m.,,e Cloalsr.rrrll'Irr. I'Itnrr.nrnn G,v- YI.I]rY: C, 11Iti, Iri~l~\lllll -IA \\Illlr,lrl 0\1 11.\\111l: ( lil l f_1IY: ilidr.1l,1 I'IIAI NiT 7!P.1', ]umLrr .,I rdT~ I a.t ]amLon Numtur ,rh.:n 4lHl rt I.i7 at:i - 2il1 91~'I 12'1~ _an', i 1l I"_v~ ~~~_., l In Ill." Vnn.61U Vlo:~ul: la;
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C'Q NFOr NTIA!. , 196 SUENI E: DAHLGREN AND TiQRE DALHAb9'-y r ~. _s ~ '- = ~ ~ .~.'- .o « w -00 4ft Fig! ZLInfI'ammatory.lesions grade~I in traeheal e~.pitheliunu.Note~~. Ihxs~ of~.ciliu, iirtra-.~ epithelial'oetlema and loss~of'goblencells:.S9~agn~ifica',tian appro,matcly, .-'~5'00! 6~ P 44;~,~F .i "]~-r - - -- - Fig. :i. [nfllimnt::tory, Iesions.gradb2. Ko.oilia. Modl.ratcinfLrnn••ato.ry cell'infiltr.O iun. Magnification approximatedyX 500.
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CRIN,FTE"MAL 857 NOTES' Res.ultss from~ experimentss in which h varying~ eoneentra~.tions~s of PXIO~ were added to~.ciga:rettes are~rcported'in~tablh.3. A 22 per cent concent- tion~ of P?t00 produced.a.significantd d:ecrcase~:in~ the.oiliotoxic:effect~of~.the: smoke.: The number~~ of'f puffs~s required to proatuce~e ciliostasis~ was~ 112 Z com- pared with fi6lfot ~thee control eiga~.rettes:.The. oth~- er~ concentrations of PS1oO didd noct signihcantlyy alter the ciliotoxic properties~~.oflthe smoke com- pared w~ith the controll eigarettes: The exposuremethode used.to.esaduatcd the cilio- tozidty'of'cigarettes with variousadditises.hasbeen.used previoush, toaludi," the.importanceofe several exposure" paratneters;, suchi as time be~ tween smoke puffsand the inflhence ofpuff tul~.umcs~ on cfliotoxicity;3;+ "Diic influence: of .ary, ing: mmposition ofthe. smoke Ita.. alsa be:cn studied. 5ieTheexperimental method usedl iircorporatoss theadvantagcsofin:niero mc,thods;iand the ez posure.is easonablycomparablc.to.humansmokingconditions:.lt must be:pointed out, however,. tha'tt thee me~thodl insnlvcs onlvthe studvof a F fects aften acute expmsureslasting, a! fewhrours!. A9though the volumrof'the indiriduall puffl of smoke g,ivento theanimall is relatenid to the hu- manpuff b' v an appropriato red'urtion faetor;x' a fairtyy intense exposurewids one puff: eaory• minutefor.60 minito 100'min i, required bcfneee the.studied effcetisachieved. Theresultshereshow-that the anticiliostasice effecrearlicr.shown.to exist for oxolaminc citratc. wa's,excPu.sivelyrelateel to onlyonn of.du.sub- eompounds tested, namely; phctnlrincldfiamlc From a ehemical,pointof:view, phenvhne.thsldia- zale.was.found to:be more stuble,.a.nd t} e erpcriment shoued.that thisaltcratiim in the.molc+adc did not affcct.the:anticiliostatie:ptopcrtics.: Cbmparedl with the~ results. nboainedd wlicnoxo6amine.citratewasadded,tbttte cigurettes;.thc number o@f puPPfr requircd to. protlucc clrinetasisin thee prescnt.expeeitrurnt'.was greater for: batheontrol, and treated eigarcttcv This differ, na-un pulf'~ Icvel.isattrilnntablel to metlieidolCy;ic- dilti•r- encesr betwecneartier exp-mcnts aad theprea;ent:onc..7lhe:ratio~b',twe- cantruh and.tiua.tcd. +Dalhantni.T., and Rstandcr. Rl, Arch:.Olola'ry':ng; tC,'Incagu/..l Oli~, Sl; 3 i'J. +~DaIliamni C.,, and R~lsnder, R., Arch.. Et,iviron. Hcalth ((ihlcugo);.J766, L3,-I7. eD.tlhamn. T., and.Rslandcr, R., Acta Phar- macol. (Kobonhavn), 1967, ?S;.J69, "+Dalhamn. T.. and. R~Iandcr, R., Scand. J. Resp D., 190, 70; 273: t' Rnla dd:r; RNat. Canccr. Inst. Nfonogr., 1908;,7d, 221. cigarettes, however„was:apprn.ximately.the sa~me: Althoughithe, numarr of animelss in which thevariou.s, conccntraSionsof P\tO. weree tcsteds.^as smalll . thee resultsind'icatedl that the anticilio> static: efTectt wa.soptirnal betwcen 035 per centt and 5.per cent:of PNtO inthetobacco. The mode, o6a'ctian of P}fO inthen cigarette smoke was not investigated further:.. Becau.se PiAfOls trotmd to~the particulatc phaseaud: be- ea:usean alhnost comp,leteredention ofpa:rticulate matterin the lungg hasleeu shown to.hepresent'o during, human scnokingconditions;atheg effect't is prob'abl,r mcdiatc il viaa thce paiticulato pliasc cither through dircet eumtaot after imping,ement't off the particulate ntattcr on the m ua.on aaa absorption in the:bl6xod:sessols in tlie~dusceppartse of.the.lung. Altkough in thisexperPmcnt onlvthey cilio,statie effecrt wass stuctlcd, exparur ftum , erlir.r csp,erSmcnts wiih~ oxolaminc cit e rutcmdiasted that the anticiliostaticefleet coutld. Fie uchievedd through aneffbcrn on mucuss sccretioni Expori,mems are n p og esstoelh late. fthcr thcmcchanis. ors responvbl- for ttie, anticilioxtarie cf fecnuOPSI(D and to studvthc nlfercts of long terat ezpasure to low coneontrations:of;thesulistane: Inn sumrnmry- The anticiliostatic effect of.aduii- tion ofoxolatnine.citrateto eigarettetoflaecoshaa:n in earlier experirnentsw~asfurtlier cJuci- ditcd using deravatiocss of thee origina.l com- poundl Citric:aeid, d'iethylam.ine:citrale„pkenyl- vinylosadiazole. (P%'.O),, and pherrylmn,thsloxu- diazolG (111fOl.werc.addiel eoeigarctte tobaccw Tlheeiliostaticebfcet of thesmoke nscsevaluateds inn short term, exp.osure: experimentss incantn vivo- Thc a:nucilirntatie effocrt was detnunrtrated f6r P40and PSftD. F.zpcrimentss with sarsliigg com entrations of P\f00 indica.tcd.th.u:t a m:cnmal effccc svasproscnr ac. concuntratiorn,ofl approxt ma t,l y.2~ pca ccn n o€ tobacco we igh t. TONaD \t~nA~t,\'t~ R:4t.\{p~ R]L:\\nFR lh.ttitttresoJ 1/ig-ne t.'pp,edn cear-ity and An.~,l~~~tl:nr~,t,ttrte; artd I Dep'ar¢me:nt oJ't'nwronnnentul IJ•:gi,eneN'utternalJiatd:niteo/Pl~hLcE7echh~ 5'rockhulmi ~ueden. Or-tuber 5;,1970~. B~Dtnlliamtr, T., EJfors, Stl. C., and R1landcr, R':,,:1rch- Ensirotr. Ifealltii /(-Inwgpi, 196;8;,17., 716. to'The -nthesis~~l af~ ttre. crrm~l>nunuls, andl the manuEtctutinF~of thc.r retn~s s t e- Ircr~futn~~~d by~ thc Rrxarrh, Di ~.~nn,of~ tl el -ll.hrd. Uor- pumuon, (Lrecuwbuca i .A~w th Cerullna. i
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1g$ SV~EN~ E: DA}ILGREN~ AND~~TORE.DALHANtt+b Eig: 5. tiloder¢te inflammatarychangcis, In aa mediumsiiedm bronohue. llhe. R:mon is partlpy abliterwted bydesqeumated ep4thelial cells. Magnifieatiitn approsimutely: ,° ?(N); Ta6le 3! Ihfiammatoryrcac,tion in the branchi. NumHerr of guincs qigv Scries Test~~t Degree ofinflli,mm;utii:n Ti>t:,l p.raJ'ng of no:, seilution. None. (0). Slight. fl). hfoelcrute (21 Sererc (3) infL:nr.m;mcn fine;m ialhc.i PDYO~. 2~ 3 1 Q 0:8~ Pheny;lbutazone 1 2~ 2' 1 1 5 ' 1 Ffethncccll 1. ?~ 2' I 1S~ Sodiitm chloriJe-. p 1 41 1 2I0 PS1O 2 2 . 0: 11(Y PFtlen lhuta one q' 5' 11 0~. 112. z y z Mhm,:eel Sodium chlorid.c~. a' U~~ . a~ _ z 3' a~ 1. ns I~.8~ PN10' 6~. 4 2 0~ 0.7~ Phcnylhutazune~ 3'. ft. 1. 0 O~.B' 3 btcthoecd 3'. Z. 4~ 3 ' 1.6 Soalluwn~cHkoridle 0~. 2~. 5 5~ 2',.3'
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Cf~~~~~ ~~ENTIAL i AriTI-INFLAR161ATORY ACTION OFPJIO 145 Table 1'. Differences in body weight from the beginning of the', experiment to the time when the animals died orwere killed. Diffe.renees in body weight (mean values in gram) Treatment Seriesl Series 2 Series 3 PMO -6.3~ + 6:7, + 0:6 Phenylbutazane -26.7 -21.0 - 18: 'vfethoeet -2.8 -17:5 -10.51 Sodium chlUrid4e -18.3 - 410 -22.4 Results During the experiment most animals lost weight. Only, in the PtitO treated groupsof animals was there a tendency to maintain or evcn gain hodyweight(tab1e 1). When present; the inflammatoryreaction inthe trachea was of the acute desquamating type. With only slight inflammation, an infiltration ofgranulo- ~ .l. ..~`- =~ _ c~rs ~, ,•~: - :.., --~:.-~~c~ ^' ~ r. ```.!~~ ~•"l;J~~ ..~~.+ . ~i.,a,. ... -. •. ~...+. • -' ___ - - ~ ~--~ .~.- _ Fig. 1. Normall guiirea,pigtrnehea. The pseudostratified columnar cilioted e;piihcliumi is well preserved. 1Tagnification approximatcly ;;500. u•
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C9 NT MIENT lA l 200 S`r'EN~ E:. D:?.HLGRE:J~ AND TOR~E. DALHAMN~ Table S:. Degree~~.of atekectasis,. Number of . guirreaa pigs Seiries Test~ Degree ofateiectasis Total grmdingof no.. solution. pl4one. (0), Slight (1): leladerate. (2) Severe (3) artelectack (Eoean value) PM'O~. 5. 1. 0~ 0 0!2~ Pheny;lbutazone 3~ 3~ 0~. 0 0.5~ Methoeel. 3~ 2' 1 0 0:7. Sodium chloridde~~, ~~ 1. 4 1 0 1.0 PVlO~ 5' ll 0: 0~ 0:2 Phenydbutazone~~. 4'~ 2~ 0~. 0: 0.3~ 2 Methocel 2 4 0 0~~ 0.7 Sodium chloride~. 1'. 5~ 0 0~. 0~.R PNIO 7~ 5' 0 0~. 0.4 Phemrlhutaz;one 6~; 6 0 0~. 0.5~ Methocel 3'~ 7' 2~. 0~. 0.9~~ Siadiumichloride 2' 8 2~. 0. 1.0: Table 6. Mean relauvee lungg we:ight' in acrolein exposed animalsafteri treatment with dlfferent test-soliitions. Mean relative lhng, weightIg~10D.g hody -~hu Treatment. Series 1 Series 2 Scr:cs 3, P3fO~~ 1.23' 0~.9E3~ 0:95~. Phenylhu.tazanc~ 1.30. 0_9S 0:76 Mcthace;l 0.97~ 1.12 L12' Sodium chl6ride~ 1.23 0.9i3~ 0~.95 cylesand interepithelial oedema waw found in' the tracheal t~alL 11he, cilia were destroyed andl onlya few cellsshotw(d remnants of ciliartistruclure (figs:, 1 and 2). fni moderate to severe inflammation, ~arious dcerccs<ef cpitheliall chaogeswereo6served up to the cxlreme of total rfe5yuamati<tn (figs. 3andl4), The degrceof'inflammationofl thetrachca is listod' in table 2. Thc ;mti- inf~lammatoryaction ofl P%lO is statisticallysignificant (,Pt <0.t1'?. P, < tl.(12 and Ri <0:0t1'1). when administered either orallc or intraperitoneallN.. None of the other test solution sho>-t^ed any sienificant anti-inflamnwtory
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194 . SVEN E. DAHLGREN'AND TORE DACHA\iN inflammatoryy action af.this substance (voN~Recttel.~aenG 1961). Onee group ofani.malx wastrea.ted.with sodium chloride.ascontrol and another group with meihocelY', the: suspending mediumi for PN1O: Thestudiese were repeated: on threee series of guineaa pigs. Irtn thee firstt twoo seriess the animals were treated by intraperitoneal injeuionss whileinithe.thi[d.group,the tnst'.solutionsweae:administrated orally:. AgroupA of sixguineapigsserved as ai controll. Three of the animals were killedd for examinationimmedialel,vbefore ttYee beginning of.the e~xposure of.the.oth'er groups andd threee immediatelyafteny the e.xposureperiod$ for the . others... None,.of the control animals showed any'significant'lesionsin th'eirrespiiatoryr organs. In the first two.series, the.test solhtions: were.injecctedinlraperitoneallye immedi.atelir+ afle:r the, acroleinexposure: The initialdose!s.for PtiIOO and phenylbutazonee were. 30.mg pe~r kg body, weiigh'tlb:w.l:Thereafter. thee injectionss in all thefour groups weree repeated eleven.timesduring.the following.76 haurs(aften 3, 6', 9, 2~4, 28;,32,, 48, 52;, 56, 72, 766 hours):, Each, repeated dosee was. 20 mg perkgbody w'eighU. Thee experi-mentsweres concluded after 80hours~ In all animals thee initiallyinjeetedvolumesoftestsolutionsy we,re. 0.15 ml per 100g. b.w: andd in, the repeated injections 0.10 rnl per 100, g b.w. In the thiidi serie,: after thesame. type of acroleiom exposure, thevaaious test substanceswereadmi.nistrated orally, The initiall doseswere. NaCI andl mathocel 0.15 ml per L00g.b..w:, and phenylbutazone: and. P%1O~30mg.per0 k'g.6'~w„ . Thereafter thee solutions weree administrated ten times(afteri 3, 6, 9, 25: 28. 32:,38, 52, 56and 7'L hours)! The doses being then inn lhe, NaCI-groupand meihocedgroupl res.pectivcly0.1. ml per 100 g~, b:w. and 200 mg per kg, . b.w. in the two other groups. The.experimentse weres2opped after 76 hours. Animals dying d'urikg thecou.rse of the.experiments.we~re immediately autopsied. Thee arrumalss wtiichsurvivedh the. 80+hour or 76-houri limit weree thenkilled and _autopsied.. The lungs were examinedl macroscopically,, weighed and the. Ihngs and trachea fi.xe~dd in 10! per centt formalin. After fixation, material from thee trachea andleach.lung lobewas.takenfor his,tologlcal.examinationi Thetissu.e.was embedded in paraffin, sectioned'andIstainedd with van Gieson andd with haemaioxylin-eosin. The degreee of ateleclasiswasmain7y, estimated according too thee macroscopic findings while the.degree of'inflammation was graded exclusivelyonthe histulogical material. The, degrees oflesionsf seen at the macroscop,icc andl microse.opic. examination were gradedd according, too thee following:g scale: 0=nolesions; l-slight lesionbt '_- moderate lesions, and13'.=severe lesidsns.~ Thee different typesof; inflammatory'lesions in the trachea, hronchil and lhng parenchym are.sh:own in flgs,.11-5'. The~ examiner hadd no knowledge of the lype: of' th'erapy'given to.theinrJ.ividhal animals:. Tlhestatistical calculations wereperfornte~d tly, analysis of'varinnce. The effects of tteatmentt withi PNtO, phenylhutazane and methocel were comparcdd with those of the sodiumchloride lreatedd control aniirtals withini cac'hseries., Thedegreese ofstatistioal significance a.ree expressedd as P value.s. M1llaterial Theintraperitoneal studiess were: repented in two series of twenry•four guineap,igs each (series 1 andi'_). I.n each series the animals weree randomlly diviiled m.to four groups.of six. In the, orol.(series 3)iexsperiment weusedl48'guiuea,pigs divided intofoun fourgroutwelhe.
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~r:~1iAl 202SVEVE. DAHLGAENA2JD TOREDALHAMN'. a pronounced damage to the epithelium in the tiachea, and' the branchi, resulting in seeondary inflammatory lesions in the lung,parenchyma, some- times comtiined' with atelectasis or compensatory emphyse°ma. Our result9h demonsttate that PIV10 possess a statistically significant anti-infl'ammatory effect on this type of acute lesions. The effect of' PNIO seems to be similar tothat of phenylHutazone but thediffbneneeisnot statistically, signifieant ! From the results it: i's~ not possible to explainthe' mechanism underlyingthe anti-inflammatory action of P120: There is no pathological-anatomicall difference tietticeen the PMOctreated anima]s and' those giiien phenyl- tlutazorlc. We beliece PMO to have a locali protective effect on the epi- theJiirl' cells and their cilia. Penhaps the basic effect is on the mucus, l`e have observed that animals treated with:PMO have a more µatery mucus than the control animals. fn, rigo' studies have even shown that P's10 treated animals, can inh'ale tobaceosmoke: for amuch longur~ time than' the untreated animals until astate' of eillary stasis w~asreached (DALnxan'R, RnASDER1971): REFER'B?dCES Corbetlla, E. G.: Esperienze eliniche preliminarycon aYollnmina citru:to n'uovobechicodi sintesi.,Mirse.eaMed.1960; St, 4077--1O8i0. D.ah'Igren:, S'. E. &' T: Da~.lhamn: The effectofoxolh:minet ciirate oni experimentallyproduced inflammation in tNe respiratoryorgans, Ar7aplmrnta'cad: ev rasiwl. 1966, 2:5, 296-296: Dahigren,. S. E. & T. Dalhamn: Thee cffect of ozolaminec citrate on esperimentally prod.ueed inflammation.and eough'. E.carryta Mtvlica Interre. Congre'rs. Seriec 19'68i 16]; 40-50. Dalhamn, TL & A:RSud: Thee anti-tussiver effectt of osoli,mincn ciirate, and, codcine' . phosphatee in guinea pigs. Scand, J: Resp..Dir: 1968!.49. '_3-25, Dalhamn, T. & R. Rylender: Rhaluetion of oigarette'e smokee ciliotosieityby certa,in toba'ceo additive:.s. A'nr. Rev. Rerp: Dis: 19711 in press: Deidda, C:: Esperienze cliniche.sut: Perebron, un a.ntitosse-antiinflammatorio.di siirte'i. M'inie.rvaSlerL,1960; 5'.11 4059-408411 vonRechenberg;. H. K.:. Bntrecn(id'ut. Phen_c1-butacon. G. 7lhieme. Verlag; StWigarb 1961. Silvc',strini, B. & C. Pozzattii. Pharmaeailugical properties. of 3-pHenyl-5diethy9aminoi erthyl-L2;¢u.xadiazoic: Brit. l. Pr'arniaco1,.1961, 16. 209-2•17:. Tropia}.G.: Sull'impiego delloso4aminaa citrato nelle recidice broncehitiche: :1'firnr.ra' Med. 1961,.52I, 3790-3752.
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3'. 3i4LUt2/ 7 Compound:. Concentra.tion; percent 3-phert.l-5'-diethslaminomethyl-t1,2;4-oxadiazole: 8 3-phenyl+5-d,imeth}IaminoethyP.l,214-oaad:iazole__ 5 3 - phenyl -S~th}Imeth;laminneehyl.d,Y,4-osadi~ azclg, ----------------------------------- 55I claim: 11 A smokirtgtobacco product consisting.g essentiallyofy tbbaccoo andi aa pharmacolociicallyy acceptable: salt off an oxadiazole.of.the, formulalo ~ ti-C-R wherein X is a member of'th'ef group consisting of Nydrn- 15 gen, Halomen iand. lower alk}i i has ing , from lI to 4 carbon atoms;,and R isanamino.radi¢al of'~the formula. (CH;1_NR~,R.; whereian is.an.integeir from 0 to4land: Rr and R~ are 20 41 each selectedfrom thee qroupconsistingof: aJl.y11 and' a~lkyl¢I havina.ftom.one.tofaur carbon atoms, the,amounte o6saidloxaxiiazolef being; suldicient ta antaronizeat, least partially the.cil:asiatic effectofitobaecu.smoke. Z.: AA smo.kin_; tobacco product't according to claim 1I whereini the amount ofsaidf o.radinzode isbetween I.Soand I IU% by ue.i;ht of the tobacco. 3: AA smoking tobacco prod.uctt according too claim lI wherein . said oxodiaeolehasbeen incorporatedl intothe-o tobacco byso}vcni impregnation. 4: A..smokinc tobaccoo prad:cctt according too claim I wheretn sai&oxadiazole is3.-ph'eny1,5~-dicthylaminoethyl,I;2,4 oradiazale ciirate. References~.Citcd~. UNITED~ STATflS ~~ PATEtiTS~. 3~.,251,365 5Y1966 Keith~et.al-------- _ 131-10.9~~X n1cLYlIV U..Kt1IV, PrrmQry Ez4miner. .v
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Co !a; !K N'T AL ANlTItINFLA61'stA'TORYACTIOM1 OF PMO 2011 activity, when injected intraperitoneally: After orall adrrtinistration phenyl- butazone had a statistically significanti anti-inflammatory action. The in- flammatorv changes; ini thebronehi~ (fig. 5), were in principle of thesamee type as ini the trachea. The anti-inflammatory, action of'the test solutions is listed in table 3:, In the first series PMO hadl a statistically significant antisinflammatory action as compared with sodium chloride(PGd,02). Ir:osignificant effect on the degree of inflhmmation was demonstrated in, the second series. In the third series both P:OO and phctrvdbutt3r:one had a~ marked effect on the inflammation which was statistically significant as compared with sodium chlorii3e(P'< 0.0005). The inflammatory lesions in the lung parenchvmal appeared as, an acute bronchopneumonia, somet'imes' combined with compensatory emphysema(fig. 6); The results oftheantl-inflhmmatory test are shownin tabld: 4. In all the three seriesP1r1O appeared to possess an anti-inflammatory ac= tivit}~. This was„ however, statistically significant only in the second and third experimental series (P 2 < 0:03' and Pa < 0.000?): As judged from the total degreeofihflammation, in the tYachca., bronchi and Ihngparenchv,mac the anti-inflammatoryactiow ofl P1'10is significant in all the series. In animals with trachea-bronchitis the bronchi were sUmetimesoccluded byinflammatory exudht5. eausing~ peripheral atelectasis, Thudegrec of atelectasis in thediflerent groups is seen in table3. Ini the first two series the extent of atelectasis wassignificantly less in the P1'10-treated animals than inithe sodium chloride controls:. The mean relative lung, weights (gj]100 g, body weight), are listed in table 6. Ih the first: fwo series thePfi10'-2reated groups had the lowest relative lung, , weights. In the third series the phenylbutazoneanimalsIrad a somewhat smalleri lung w'eieht than the PtitO-treatedl aniinalk. No statistt icallcsienificant differenccs, however, could be demonstrated in these experoments:. During the experiments seventeen animulsdied; six in the NnCI-treated animals: seven in the methocel-trcatcd animals and two animals cuch iw the PSIO and phenylbutazone treated grouPs. Discussion Theincreasing, prohlem of chronic bronchitis mostly initiated hy air pollution and smoking have stimulated a, search for drugswhicli~ might cure or proteeta,ainst the dli;casc. We ha%~c built up a model s.stem fhrtesting the effects ofselected drugs cencxperimentallyproduced non- bacterial intlammationiittherespiratory tract. The metliod used produccs
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Mi ,. ]a 1 . 1 1!YI ;:3: LTnited States Patent [II', 3,s47,1133 j7'2J Imenlor ToreDaJha~mn.. (567 References C'ited~ N' Bromma, Stockhblm, Sweden 771 989 UNITED STATES P.3TEtiTS~. [271 o.. APPI: , . 3;2' 5~1 365 5/1966' ith K t l 13~ 1 9 ~ (22jFiled Ocr.30,1968 , , . e e ia ... .................. .1/ 0. X . [45.j', Patenled. Dec, 15; 1970 3;9'~10;277 11/196fi Daihamn._ .................... 131/17~ 11731 AssiRnees I.orilllard Corporation, New t"ork; NiY.: , arorporation of Delaware'. Primary Ezaminer-Sam~uel K'oreni Atsi.rtan/ Exaneiner-~G. 6Y. Yahwak~. Attornev-Brumbaugh~, Graves, Donohue &~Raymond. (54) TiDBALCO.HA, 'IVG ANbOXAD1AZOLEADDIT[S~E 7'Claimts~, No~. Drawings. 15211 '~US'. CI......._ ................................................ . 1:31 /1'J,. 13.1/140. [5'.11j Int. CL.._._ ................................................. A24ti 19104'. (5'01 Fiedd ofSearch..._ ......................................... 131/V 40BL. 140,140R„17 qz ~'1,9~ F 2 1 1 ABSTRACT: M1bvelltobaoco.produots~arediscl6sed, eharac- terized bytheadditio:n ofvariausox~addazolcs,to the tobacco. S;moke.from the treated tohaoco.hasbeen found.to.exhiUitasignificantly lower ciliastatic effect.
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r :,~~'- a~, ~a~I'~.~il:. ,,. ANTIHNFLAMb7AT©RYACTION OF PMO, 199 J!Si „ :4t; ,it. ...,, .~w ~...,.~; ~ Fig,6.;tloderateinflammatonylesionn in lhng parenchymaandsmall trronchi. Slight compensatotry'em.physemai Magnification approsimatelyX80; Tcrb'le 4. Inflammatonyreaction,inthelung parenchyma. Number of: guine~~.. Serics Test Degree afinflammation, Total graddncof no. solution None (0) Slight (1) blodhrate (2) Se<cre (19)1 in{lummotion (meanalue)i P'vl(J 2 2 2 0 1.0 Phenylbutazone 1 2 2 1 L5' Nt et hocel 1 2 3 0 13 Sodium chloride 01 4 1 1 1.5 Ph10 0, 6 0 0 1.0 PHenvlbutazone 1 3 2 0 1.2 2: Nlethncel 01 2 3 1 L8 3Odium chloriJc 0: 2, 1 0 1'~.7 1?610~ 31 7 2 0 0.9 Phe~nyldutazone~. 3! 4 5 0 1.2 3 Rtethoced 1 3 7, 1 1~7 9bdium, chloridh 0~. 2 9.. 1 1.9~
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3,547,1133 4 uhere,nXic .elCct^d fromthe eroup consfsline of h}droecn: 4. A smokine tobacco product accordunR..to: claimI whe rein ammo: ar.k!.Jammoa diaik}Ihnuno, aik}i..cxc!nalk}Il.alken}II saidoxadtatolris3-phenvd-5'-- 1~2,1.ovadrazolh:. andaSll.:ociin.~ei,dikwi.c:.%c:oalkylandsikamigrouechacing, a, AsmokingtoPaccoproductaccordingtaclaim I wherern I tqI'..cartivm toms: R.i<.: •iected.tremitneCrouqconnstrnel saidoxudrarole.isJ-nhznvJ-5-methcl-I,:„SLuxadiazele ofp,hemllelkslesc!Salk'vl,ardalken}!¢,roupsofIto.l2c(ar- 5: 6~Asmokmetobacca.praductaceordmgtuclliml,wNerembam amms, und R'~,s selected from the_erawp.cnmsisting,.a6 saidosadtazo!eis3-pheri -ethxlll._.1-usaaiazn!e pRcnvd. alksl: ndoa:ksi anG alkeinvl groupshanirtgI toI_ . 7 p. smoking tohacco proa:.uct accordi:ne, to cla.im, l, carbonatoms, angof wwh:ehn:apbesubstituted w.ith haloien. wherein R.is qhemi..R'ix selected (Fnm the f;rnupcnnsislmg, : A smoking toHacco.orocuci acoo.rd n¢ t rcl.aim t hercinn of pHena .dkyl and alkcnrl erouns hzsine tr m I to . I_',car',on. the.amoumt o(szta ox.adiazo ~~ ir.betw~een 0 c:perccnt arvdI1~ IU. percent b}.we,iehtotthcaobaceo. atoms, enJl X is, seleetedd fre m the: e« ,up uom}isting, n( 3. A smoking tohac.o.product according..tocluimt wherein hydtogen, H;ulogen, and louerulkxl prnupeha mN frnm.l to 1_', saidoxad,iazol0hlas.beeninc:orporatedhntothe~tobaccohysol-carbaznatoms:d ventlmpre£naumn. 15'. 20 25' 30 75. 40 45 50 55 60 65 10 75
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54 nt: C.. " BUNDESREPUBLIK DEUTSCHLANW DEU'IISCHES' eo w PATENTANiT &A T T /// . ® 17 Deutsche KI.: 79 c, 1' j;, °'; i rFl i ~ ~ ~~~~~~~1~~~„T Offenlegnngsschrift 1'_ g54 786 Aktenzeichen: P 19'54 786.5 Anmeldetag;, 3'0! Oktober 1969 Ofienlegungstag: 18. Juni 1970 Ausstel I ungsprioritat: Unionsprioritar Datumi Land: Aktenzeichen:: ~ 30. Oktober 19% V: Sti v, Amerika 771981 (8 . Bezeichnung: R'auchtabak mit Oxadiazolzusatr Zusatz zw, ~ Ausscheidung,aus: Anmeltleri `Loew's Theatres, Inc:N~New York, Ni Y. (V, St. A.) Vertreter: Wuesthoff, Dr.-Ing. P.; Pblk, Dipl.-Ing; G:; von Pechmann, Dr. E:; Behrens, Dr.-Ing. D ,~Patentanwiilte, 8~0tJ0A1'unchen. ~ Als Erfinder benannt: Dalhamn, Tore,, Brommat, Stockholm (Schweden) Benachrichtigung gemaf3 Art. 7 § 1 Abs. 2 Nr. 1 d1 Ges. v:4. 9. 19fi7,(BGBL I S.960): 0 6,7q~ 0099 _5'1:09~ S~.'0~
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DR~, IYG. F'. \C.III!STlf OFE' DII'L I~_C(:. G. FCLS~ DR FV ,PISCIiVY.\~\ DR: PPd~G. U: llLIl,R13Y'~S'. PATENTAY.t>'A[.TE~ 1954786 B NIc:S~C:IIE\~ f)O~. BCII~IVEIOER1TiR:159E.2'. ' rsr.crox zzoeal '1'. CLiC'.l:~11'.w'>L>f ~w I/ N Ce9 C 1 wuortcrrw'r~anr !l.Ux~.o.us.x . 1A-3R'106 B' e s c h r e i b~ u n•g, zu der Patentanmeldung LOEN''S THEATRES, INC. 200 East 42hd Street, New York, New'York 10017, U.S.A'.. betreffend Rauchtabak mit Oxadiazolzusatz L Die Erfindumg bezieht sich auf' verbesserte Tabakprodukt'e,,, ipzbesondere,Zigaretten,' Zigarren und Rauchtabake,mit ver- besserten physi'ologischen Eigenschaften und besonders gutem A~roma. Der Bronchial- und d~er Si'.nustrakt sind auagekleiidet mit'~ echle'i'migeniMembranen, die Uberzogen sindt mit'' w:inzigen haar- ahnlichen Glebi~ldlenl, die als Cilia,-od'er Flimmerepithel bekannt sind. Die Funktiorr dieser Fli.mmerhdrehen, die in einem gut koordiinierten Rhytmus schwingen, besteht darin, die Atem'we.7e' kontinuierlich zu reinigen, indlem si'e die in den Schlleim ge~ Chtillten Fremdstoffe in den Nliandlbereich befordern. - 2 - ©C9825/12'08'. i
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8-E I Ca IN! FIE E;aTLIA L 1'A-37 106 Es ist bekannt und diurch Tierversuche bewiesen, daQ'Tabak- raucY: ei'.ne hemmen3le oder unbeweglich machende Wirkung auf'die ';ilia ausUbt. Wenn di'e Aktivitat des Flimmerepithel's durch Ta- Lskrauch behindert wird, werden klei'ne Kdrpercheny w:ie T'abak- rauchteilchen, atmospharischer Staub usw., nicht mehr richtig entfernt und konnen sich in den Lungen,, in den Bronchen und anderen Teilen dles Atmungstraktes ansammeln. Zwischen den Perioden der Raucheinwirkung wird die nor- male Tatigkeilt der Flimmerha:rchen wieder aufgenommen,und ein Teil oder alle angesammelten Fremd'stof'fe,werdeniauf normuTe Weise aus dem A,tmungssystem entfernt. Wairen die Fllimmerharchen' wahrend d'es:Rauchens nicht lahmgelegt, so,wurdien die Sohlleim- haute des Atmungstraktes iiber eine kUrzere Zeitperiode eiinerr niedrigen Konzentration von Fremdstoffenlausgesetzt werden, und es wUrden sich,weniger Fremdstoffe dauerndi auf dem Fliimmer- epithel ablagerni. Uberraschenderweise• wurdie nun gefunden, da.3 gewisse che- mische V'erbiind'ungen als Zusatze zu Tabak bewirken, da3 der Rauch gegenUber der Aktivi'tat der Flimmerharchen,weniger lah- i.end wirkt~ undi gleichzeiti'g ein zartes und gefall~iges Aroma annimmt.Die erfindungsgemaB zuzusetzetlden,chemischen Verbin- dungen sind Glieder d'er als Oxadiazole bekannten Reihe und entsprechen der allgemeinen Strukturformel X - R - Cj C - R' \,Bj worin X' fUr Wasserstofr, eine Amilno-, N!onoaTkylamino- oder Dialkylamilnogruppe mit 1 - 12 C=A'tomen,, ftir eine Alkyl-,, Cyclo- '' 0098 25/ 12'09
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3,547,,133 11 2' TOBACCO HAS'YSG A'V OA:4DIAZOLEE.ADDITIVE co:was allowed tostando inapencontanersa:t ambient condllionsfar 23 NuurSs to.allowfor ezaporauan oflthe.e,thanol land. TBls:rrtsenttortrclatesvoimprotements:intribaccopodueta, eqwhtirationofthe,moaturecontent! .\onfiltarag',arettex.85'r t,t' endd in parttcular toagarettes: cacursand smoking tobaccoo mns . ini length and 25mm5 innreumfe.rence: werethen , productshav.ngenhancedflavorandphystolo¢dealprope,rties. 5prepared5 usmg regulari manufactunne machmery and. . _ The bron¢hial and':.simus:tracts,arehned wrth..mucousmem- menhod.s: AA simd'dr nonflter65mm. controll s.a.mplewas ~ branes.whuchiare.covered wuh mmute hairbke'e structuress prepred.usVngth'esame.tobacco.bl@ndbut w.ithout the.ox: known ascdia.. It is theIunctton ofthe aiha, which beat in.an adiaznlC.addilivc: well coordmatedd rhythmi to contununmslycleanser the Both~thc treated: sample and: th'e.controi w.ere:tested for breathing passacesHy,movingdb.reigm material trapped inthe 10 their efTect un the.ciliarv.activrtyof expenmental animaissby mucous to.themautharea the, method desenbrd by, DaFhamninapaper enutled!"AItisu:ellestab6ished.thattabaccosmokehas:aninhibitnrt.•orl hlelhodlforStudymg:theEffcct.ofGasesand[JustconCliary gdnhaled.Parti¢Ics:and. immobihzinggg efiect on these eiiia m:expcrrmental,ammals. Acu -Whentha.aclrvrty.o('thecdiahibitedbctabaccosmoke, litv'inLlivmgAmmnls''appearrn m particfes,suchastobacconarpartUCles,atmospherie:dust.ete, IS'~'aqour(Purgam<mPress,l961), r- alre not properly removed and I macy colle:cl in the, lungs. BnetTy su mman zcd , th mte st5 we reca:rr le d a wa by p erf6 m bronehialtrce.onotherparts:oflhe.respuratorptraetb tn&a.irocheotormyg on anestheuzeidcats. Aniaperture was. Bctueen perimds.of smeake.eapmsure, normal aetionof thepVaeed.in thetrachea and.eniclbscd bdtaphragm~bIn mea:ns. cilia:isresumed,.andlsnmeoralloPtHcaa:ru.mulated.foreignafwhichamicroseopelcniscouidbcmounte,dto.obs erne.thea tmaterral§t areremovede fiom the hreathin¢! . svslem inthen nor- -~0 c:iliarv, movement: w:ittnn , the trachca. The micros.cope wast tmallrnanner:.ltrsobviesusthat'.iftfiecdiacvere,not~inhibited adap.tedtaaake,mouonpicturesoftheolrtiactiwly: dunng:smokine;th'emembranesafthererpirutory!tra':cuvrauldl The oat was plaa:ed ina: respnraton therebp to! control b'eexpased to:lowercon¢entratiamso(fbreign materials:Rrr breathtoan even ra;e. and thei cat:wasthe,n er.poredto shortendurations nnd lessmatenal would he.deposited per-periodicinhalaoons ofeic2rette:smoke (onee inha atronin manentlv! . 25cven four breaths.l. T1he foreeonugte,st is dcser:hed.in~greaten Quite:surprisinglyithasbe,eniftrundlthlatcertainc.he,mieall d:etadmthe.above-menttonedpaperl compowndS..when added totob'aeco; cause.lhesmokei to be. By mea'ns of the fortegome:testi the nu.mber ofpu:ffsof less.irehtbioors tawardttieeiliarcd ac7nitv.a:nd.atthe:sameumey tobaccosmoke:whichwerenecessaryunt:lerhmstasis.occmred produce a.smake:of aa smoothiandh pVcasimeflavor. Thesewe.re measvredd us ng~the srmok . fram ac~rettes wh'ich hvd ehemicalcompsunds:arememhersoftheclatis.Anownas.ox- 30beentreated.with3.-phe,ncl-5 inyi-l,'_;»-ox.tdiazoleand.oom- adiazole:sundarecharaetenzedlbythestructure paredwithtHemsmberotpuffs.unttlcildastasis•xherempldt.y- ing:eisorene, smoke from.thz.untreatcd conlrol ag5reae<. AV`0 statisucal treatmcnt!oi theresultsdhusohtamodshowsthatith'ee x-R-C\ ~iJ-R'. 35 deereasc in ther cihasticeffaet of tabacco.caused by treaung}.t ' thctobac:c'o'withith'e oxadiazole com.pound is. hiu,hiysicnfi_ - cant uhoremi XX isWydto¢en, zmino, monoadkqiaminoor dial- The! friregrrine exp,cnnrcnu:was rrpcated, this.tume u.smekylaminm'havinigl t~' I2 carbomatoms,alkjLcncloak!lvtona:l- tobacaotreateda!nh'_petcent5'-meth}I-?iphenyloia'rvale:e ken}ihu:vimgItodZtarbonatomsonu.Raloccni,Risphcn}lor d0,,}.stansueailsngmli.ani~,reuuicuanincrii t -t : usfeu.ndl analkctoralk'en}derou.p.oflltolC'earbonatom's:andlR~ Itma.}be.espe.tedthatsimilarrresults uld.he.ohtaincd:byhkcvisc.isphenyioraltoa?'earha-siky!,cycJoalk;lora!kled treatine:to.na¢cossithfr~•rtt~lpercent:tos'.percunl.oth'eruz-nyd group, anc of'which mav besabstuutcd unthhaloeenh adiazolss wivhin thee scope ofl lhiss irtsentun lllustrutnt A'minoeroupa,ifpresent.mavbecoimbinedaspha.rmaceutr- m.eten:Jsrncludes cally innocuous,.lditian salu.: y S! . Apreferreid cl:Nes of compou.ndRzvhich are easiEey svnth'es- ited and w.hich' prosidathe! destred hiolnietcal ff tswith 3-ph[rnvd-netfi-l-l,'.4 ol:rdiurole®reatestecpnomy'artceompoundsoftheforegomgdescnption 3,7?_,ymikiu tdtdt~l-1.S,;osndolein wHich Risphen}°J, X ishydroeen, halogenoclowe.ralk'yI iiroLslht itton•ti-I h_I-14-os- and R'isloueralF:yloralkc.nvlonp'hcntiL 50 ndiazoir;. The, tobaceo is:treated by. app,hine:a'solu.tion,oflt'he, aa- 3?rtNx'1-5-rurthv:l-1S_:4-nx:udiszalc a'diamle.c'pmpound uu a swtahle, solucnt'.or as atrou•dewr alter 3dirnrrh}1-1-}diuzo6e tha:loba~ceo leafhasbeenproeessed and !nccdc m theu¢uai 3 nI scll n thcl-I }s.d r I_ m~anner:huthefore:itasconve.rtedlintothefnishledlsmukinNar- 3 -flm th1•Ip<otzl`-"r- thv11,~4 diaeolrtic,le:T'helrea.lcdtotiacco.ma'y.c':ontanfromahrutQa'pamcnt: 55 8 3 csclbux Im th~i d .i-nsat .Ic. - 3-~41mrsIHx1 1 n ths'I-111azu6tnd0!percen'tof'.theoxadiazolebvwri¢ht!Thepreferahie.levcl i. 4loirlorophrml: S_nr-th 1-t." i ti eliazui~' aBtreatmentis:usualloabout'.Ipe.rcenttoSpe.rc tbvueioht! . 2zbutentf--im!trrrlli"4-oc::dinzolr_•' a6thesuhctitutedloaadluzote:T~hesolsent'used'lorr eppllcauoni pLenvl-5.1 r-p},Ill,°} o.tdir:z+iliti mas~ be apol9r organVc soesent, sueh as 2n alcnh'ol, ether, ete.. :{-)1Mrnvl-3'-ibI..'_'.-1-nc-2di:a'zalc: a,mixtureofrwoormore,oftheebovenraniaqucoas:mixturc.hDSI-li n•:i-.i :lilorcr rpcli-1,-;,3 osi-tazull nfane.nfltbese:.Thesolventhosensoas.to.gnegoodsolw~;-Ilnrncl-f o el Isi l f.ts-a~1 Nilitq aftbe:ozadiazolk.and.stidl bc. ~ad~Vy..nlttiM1e:ure:uilyS) 1.1-.~ I h sr I 1 '1-oxnd.ar.olrt lrh~cI I i.~~:. ill~ remo dfmm thetohaccoatier[r tt nt rthi ut t rf+rrng; pl .. .1_,}. :pt ;•-Ith~nvl.-1,' 4 t.:zdl4r- wrth thcmeisture: halance of theli aI tr at¢7 tnhac oA(tcrthe s I ent has cvaporated and thle f Ilm i stu e au11 tmcnti. 6S dan ismadc the,tobac a seoen dd nttitsln IsaLtbleform isa cmuk ncarucle inrthe usual mannen Iejnma A tnpical ezamp!ee u.hieh mavy hu usedlfbr ill :trat se pur 1',. A.m<kmR'1 0 0i"t sve II_ cit t.bcna:ndl posesisasfol,ovvs•s fromUlllp•rcentt IUp°rccttHsucue'nt fsaia:toNzco.ufa: Afte:r di lrpical commercial A'me,rican hlend of cearette 7f)dens° errl oxa aznlB.ai th u gcneral lornI u:a toharoirs h.:dd hecnadluatsvdton the, propcrmnisturer contcnc;, eased..tl.4so:reu.and Icut- a sctlutan of 3-phr•ns I-S-crrsi-l „,4- '1-q otaJir.zolam 45pvrcent ethanc>1 wasappiic^d hv mennso(la -- spras in,rna:mour.t!su¢hthlatinc.ozad.iazol'rad.ded.amounted t-H--C~--tt• tuT.pc:rcentof'thevriemaltufiacco:w!rreht.Ttie.tre-ated.toh~ao- 75. \~'~=
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~C. if,:, F! 'E N IR L 1954786 P 19' 54! 786.5 1A-37 106 18'. Marz 1'970 3-Athyl-5-methyl-1„2,4-oxad!iazol 3',5-Dimethyl-1,2„4-oxadi'azol. 3-(n-Hexyl)-5'-methyl-1,,2,4-oxadiazol 3-(4-1'Iethylpentyl)-5:-methyl-1,2„4-oxadiazol 3-Cyclohexyl-5-methy1'-1, 2', 4-oxadiazol 3-(4-Methylphenyl)-5-methyl-1,2,4-oxadi'azol 3-(4^Chlorphenyl)-5-methyl-1„2',4-oxadiazol 3!-(Buten-2')-5-methyl-1,2,4!-oxadiazoI 3'-Phenyl-5-prapyl'-1,2',4-oxadiazol 3-Phenyl-5-(buten-2)-1,,2',4-oxad~iazol ' 3-Ph enyll-5-( 3'-chl o rpr opyl )-11, ,2 ,, 4-oxadlia z ol 3-Phenyl'-5-cyclohexyl'-1, 2', 4-oxadiazol 3'-Phenyl-5-cyclohexany:1-1,2,4-oxadiazol3,5!-DYphenyl-1,2„4-oxadiazol 3-Phenyl-5-(2-phenyldthenyl)-1„2,4-oxadiazol Die erfindungsgemafien Tabakwaren aind„ sewed~t sie nicht zur Lieferung auderha113 des Geltungsbereiches des Lebens- mittelg,esetzes bestimmt s!ind, aufgrund der V'erordnung iiber Tabak und Tabckerzeugnisse (Tabakverordnung) vom 19. Dez., 1959 (BGBI, l1r. 52 v:om 22. Dez. 1959, Seite 730, besonders Anlagen Ziff. 5) zur Zeit nicht zugelassen., Patentanaprid'che 8647' 003825/12O~8'
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4 - 1'A-3710&_ Daa folgende Be1spiel erl'autert die Erfindung naher., B'eisniel Nachdem eine typische handelsUbliche amerikanische Mischung von Zigarettentabaken auf den richtigen Feuchtigkeitsgehalt ge- bracht, im geschlossenen Raum mit Aroma versehen und geschnit- ten wordeniwar, wurde sie mit einer Losung von 3-Phenyl-5- vinyll-1'„2',4-oxadi'azol in 95 % Athanol in einer siolchen Menge bespriiht, daLi' das zugefiigte OxadiiazoI 2 % des ursprUnglichen Tabakgewichtes betrug. Der Tabak wurde 24 Stdi beii normalien Umgebungsbed'ingungen in offenen Behaltern stehengelasmen, so diaIdas Athanol verdiunsten konnte und sich ein,Gleichgewicht des Feuchtigkei'tsgehal'tes einstellte. Unter Verwendung dier ub- lichen Einrichtungen und!Methodien wurden aus dem Tabak Ziga- retten ohne Filter von 85 mm Lahge und 25 mm Umfang hergesteilit. Zu Verglefichszwecken wurden aus der glei'chen Tabakmischung, jedoch ohne Zusatz von Oxadiazol, Zigaretten von ebenf'alls~ 85 mm Lenge hergestellt. Beide Produkte wurden nun auf ihre W!irkung auf dile Cilia- aktiv:itat bei Versuchatieren erprobt, wobei die von Dalhamn in "A Method for Studying the Effect of Gases:andiDusts on Ciliary Activity in Living Animals", erschien in Inhal'ed Particles and Vapour (Pergamon Press:, 1961'),beschriebene Methode angewandt wurde.. Die Versuche wurdenidurchgefiihrt mit Hilfe einer Tracheo- tomie an anasthetisierten Ratzen. An der Luftrohre wurde eine Offnung angebracht, die mit einem Diaphragma derart verschlos- sen wurd'e, d'aB~ man eine Mikroskopli~nse so anordnen k.onnte, d'af3 sich die Ciliarbewegung innerhalb der Luft'rohre beobachten lief3. Das:Mikroskop war so eingerichtet, da©'man die Tatigkeitt der Filimmerharchen auf'einen Film aufnehmen konnte. 5 0 0 9 8 2 5 / 1 2 0 8
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~ .;.~T 'e , VJL:,:'d~.Iua Y 1i954786 - 5 - 1A-37 1106 Das Versuchstier wurde in einen Respirator eingebracht, wa seine Atmungstatigkeit auf eilne gleichmaBige Creschwi'ndig- keit eingestellt werd'en konnte, worauf.die Katze periodiischen: Inhalationen von Zigarettenrauch ausgesetzt wurde (eine Inha- lation bei j;e vier Atemziigen). In dler oben*erwdhnteniArbeitt ist d'ie Versuichsanordnung und die DurchfUhrung der Versuche'e ilm einzelnenibeschrieben. Mittels des obigen Testls wurde die Anzahl an1Zugen van ~ Tabakrauch bestimmt, die zu Ciliastasis fUhrten, wobei dler Rauch aus Zigaretten, dieren Talbak mit 3'-Phenyl-5-vinyl-1,,2 „41- oxadiazol behandelt worden war,, verglichen wurde milt dlem Rauchi aus Zigaretten,, die aus unbehande3'tem Tabak hergestellt worden waren. Die statistische Auswertung dler so erhaltenen Resultate zeigt, da3: die ciliastati'.sche Vri~rkung von Tabak nach seirner Behandlung mit einer erfindlungsgema6en Oxad3azollverbindung ganz wesentlich zuruekgeht. Gleiche Ergebnisse erh3lt man, wenn maniden Versuch mit Tabak durchfUhrt, der mit 2' % 5-1,;'ethyl-3-phenyi'-oxadi'azol be- handelt wurde. Auch in dllesem Fall ergab das Versuchsresultat einen deutlichen Ruck.gang,der ciliastatischen Wirkung. Bei der Behandlung von Tabak mit anderen erfindungsge- ma0en Oxadiazolen in Mengen von 1 bis 5 % eindl praktisch die gl'eicheniResultate zu erwarteni.. Ala Beispiele fur OxadliazoTe, die unter die E'rfindung fallen, seien foTg,ende Verbindungem genannt: 3-Phenyl-5-ut',hyl-1,,2',4-oxadiazol 3-('2-Aminoat''hyl )-5-methyl-1 , 2, 4'-oxad i!azol 3-(',2-Diathyllaminaathyl)-5-methyl--1,2„4!-oxadiazol •1 0,0,9825/ 11208
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~11 `~r'dI~y ~~ C ~^*1Y ~~~~~.~'~~ Sa~ I - 3 - 1A:-37 106 a1ky1.- oder Alenyigruppe mit 1 - 12'C-A,tomen oder ftir Halogen steht, R eine Phenyl- oder eilne Alkyl- odier Alkenylgruppe mit 1 - 12 C-Atomen vertritt und R" ebenfalls eine Phenyigruppe oder eine Alky1-, Cycloalkyl oder Alkenylgruppe mit 11 - 12 C-Atomen i'st„ van denen jed'e durch Halogen substituilert sein kann. Ami.nogruppen konnen, falls sie vorhanden sind, mit dem Rest der Verbindung als pharmazeutisch unschadliche Add:itions- salze verbunden sein., Aufgrund' ihirer lei~chten Zugangl!ichkeit und der besonders guten bi'ologischen Wirkungen.bei gro3ter Sparsamkeilt sind Ver- bindungen der obigen Formel, in dlenen R eine Phenylgruppey I e1n Wasserstoff-oder Halogenatom oder eine niedere Alkylgruppe und R' eine niedere A1kylgrupFe oder eine Alkenyl- oder Phenyl- gruppe vertreten, bevorzugt. Der Tabak wird so behandelt, daB man eine Ldsung der Oxa- diazotverbindumg,in einem geeilgneten Lbsungsmittel oder diese V~erbindung a1sPuTver aufbringt, nachdem das Tabakblatt auf Ub- liche Wei'se zubereitet und gealtert~wurde, jedoch bevor esizu dem ferti'gen Rauchmaterial verarbeitet wurde. Der behandlelte Tabak kann etwa Q,5 bis 110 Gew.-%l Oxadiazol enthalten, wabei ein Gehalt vonletwa 1 bi~s 5 Gew. % bevorzugt i'st. Das zum Auf- bringeniverwendete Lbsungsmittel kann ein pollares organisches Losungsmittel,, wie ein Alkoholl„ einiAther o.dgl., eiln Gemisch aus zwei oder mehr dieser Substanzen oder ein wa3riges Gemisch aus einer derseliben sein. Das Lbsungsmittel wird so gewahlt, daB dae Oxadliazoli gut darin losliah ist und da3 es soweit~ flUssig iist, daB es sich leicht nach,der Behandlung aus demi Tabak austreiben 1a2t, ohne das Fieuchtigkeitagleichgewicht des fertig behand'elten Tabaks zu st©reni. 2lachd'emidas Lbsungsmittel abgetrieben ist und ggf. der endgtiltige Feuchtigkelltsgehalt eingestelilit ist, wird der Tabak aufubliche Weise in diejenige Form gebracht, inider er vom Verbravicher verlangt wi~rd. - 41 - 0098.Si1;Q8
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United States Patent Office I 3,410:277~ TIORACCDRA'1'tNG 4N1)kADL1ZQLE~ADDIT95'E Torellalhamn. Stoekholdn, Swede~n. assignor toPl Loril• lard Company;New Nork„N.Y:, a corploration of New Jersev, lNo Drawinp: Filed Aug. 10, 1966, Ser: No, 5'71,419 4 Claims. (Cl. 131-1~7~ This invention is related to improveme:ntsintobacco products, and in particular itrc,lalesto novel smoking tobacco products, such as ciearettes; cigars; pipe tobacco and thelikle havingiinproved physiologi:cal propertias In the respimtoryscstem, the mucousmembr.aees,ofthe,tracheaand bronchea are covered with minute hairs known ascilia which rhythmically beat up,ardly away from thelunes. These ciliatrap inhaledi.forei:n partio'.esand by means of their motion raise them to the phtarynx. Itrhasbeen established thatitob'accosmohe inhibitsthe activity of the c'iliated, mueoos-seorctinaeputhellutm tissuesofl the respiratory troct of experimental aniinals. When the activityoftheciliai is inhibited by tobacco srcnohe, particles;sua:hastobaecotar parttcld•s, pas,bythe less aetive:or quiescent cilia andleollect and' accumulate inth'e9Ungs and others of the respiratoo•y tracti Durinenon-smokingperiodS the ori,inal aotivityofthe cilia is reepainedJ andl some, bun not necessarily all. of the foreign matter enterinv the respiratorytractisdis• lodpzd. Itfsapparenl th,u ifth'e ci'.ia couldirmain,uccze during smo:ine;asu'nstantially incremed proportion of the tobaecosmohe partic'.es would be ctiszharcedby. the cilia. The quantity of particla:s,remainin, in the resplra- toryxractwoulJi be~corrcsaoni reduced. In accotrdancewithtleprescnt in.ention it has been found that theadditionofieertainoxsdla7olecompot:nJs to thetobacao exertsan. amictl]nstoi'o action ~chich antaronizes the inhibiiin~ eTeatsof tobacco smo',c on the ciliary motilityinIhe respiratory tracti Osadiazaaies usefullin the present invemion hase theformula 3,41!q;277 Patented Nov.. 12, 1963 2 solulion, thesolventis evaporated and the treated leafis stored inorder toI equili'orale it~to the proper moi,ture content. It is thenpre?ared into ciearettesor other: tobacsoproductsinaccordance, with standardlpraaedt:res: By way of illustration a typical toHaccois prepared by, adding55"G by wcicNtof'.3-phe,mi}5 dlcth} laminocithy]- 1,2,4-oxaa:iazolecitrateto ac.ornmeresl blend of,ei~,areate tobaccoi 7:he materiall wasaddhd to the tobaeco asasaturatedl methanol solution. Aft:r evaporation of the methanol undkrambicnt conditions, the, tob:jccoi wasstored untill it waseqpilibrated to thepraper; moisture c'ontent. Thereafter cicarettes were pre,pared. witHi the usual manuftrcturinp machinery:Filter andlnomfi.ter 85 mm. sample cieareties were prepared. as aell ascontr,l ciearettesofsimilarconstruction fromlobacco to which noosadiazolhhadbe~eniaddkd. Tests were performed to measure the anficiliastatif effect of the oxadiaro!e whichhadl been added to the cig-arettes. Thcse tests. wereperformed as dcr•ri^eJ !n the paperby Dalhamn entitl@d "AMelhod forS;adying the Effect of' G.,tcs and Dusts on Ciliarv Acticiov in Living Animals," ap{:earineinInhalhd Partic cs and Vapour. PercamonPiens1961i Bricfiv summarised.thetests were carried outbv ^er- formirv? a trachcotomy on anaesthized ca^s: An aerture wasplaeed in thatracheaandenetosed'byaidiaphracm by means of tatYi_hamiero,copelens could benauntca toobservetheeiliar.movemcntwithin the trac7ca.The micr~s,cpe: wa's. uJapted totake nlotion picturesof the ci.iarvactiwv. Thecarcas,placed in a respuratortherebylocontrul breathin_rto ane%cn rate: andhhecat was then erpu-dltbperiudie: inhal.ainnsof ciearette mo4.o fione intlaCitinn,n e,ery fiiurhreathsl, The fore^ui^^_test isdcs.-,tibe:J in Freater detail!in the a~ose-mentwned rarer. By means of lh~forccoinetesC then°.iml•erof puffsofltoFaecosmoAewhich we eneces,a;}until :iliuua~isoc+ eurred w-ere measured uringthemo4.e ffomiRLcrtip oica-raftesin which thetabareo,had been tre:dedwiih 7-pr:en.,l! S-dietfi}•IamihoetHyd-l,?',a-ox~ lii'zak eitr te and c n,,arcd with .henumbcr if pufisuntill ciliatiisi, x henert doying ci_-arettesmote from ci^_areftesmade bvuntre:rteJ tir-bac.o. Theresults are set forth in the followingtable_ 5 In IS °_0 15 4(1 wherein X~~. is hydtopem a halospn or a lower~.alkryl h:ninp from one to four carbon atomts,andlR is an aminaradical 45 of theformulafCHti)hNRIR, whercin it is frann 0 to 4, and Rt and Ra are alk}l or alA;iol radicalshasins from 1:to 4' carbon atoms. The oxadiazoles of the present irnentieam are! used in the forms of their neutral addition sa ts with ph lrm.tcn logically innocuoue a tds Preferred tids are or `,ni compounds such a5cn i tcctie, tart rr-, cluconic etc. Olherpharmaceutical!y acceptable a.ids,whlch nt.t5 be used!ineludetho stronem.ineral acids suchias sulp:huric acid, hydrohloricac:id h drahromic a idand mth:me- sulphonic acid. Itwill he urd rscood of cour e th,it the forecorngphtirmaca:o alhaccept bleacads irc rep~ resentativeonly of tho e wFich can beused vithinithe scope ofthe present ins nuon 50 T.4'i3 LF. I tat,.~,. mnret~~t r . No. caiu.,-st,s- I mr~ ll,l_-.aPlit.r_.------- 3 lrvl 5 11 'I 315~~. 215:4 tinEre~t~d rt^3n,tte, e~dle~toso ~ ts it a 9 s ~l u na~. ts4,9~ 13: tts Trea: d -,arcttenafittor.. t fi' t a tn. = taa~ a 4 B 15~ ^4) Lntre ..9 rcts: noiatrr .- /. t , _ ai I J' ..i 55 Tobacco is treated in a ordan e with the preseatim GO vention by appiyinnr a solutlon of a salu ofone ofthe~ abote-dkscrtbed oxadia clcs to,thc tobacco I6f tfter it has been dried and co-rted from fresh g~.rc n I-f into smoking tobac~co; The treutcd tob..ccomay~contain,tromi aboutll5b'~. to about; IuCc byweichtof the oxaJinioSc. G,-, Pte.ferablj^. ctbout 3 o to 8c th'ereoP is~~. emploccJ. 'fhe~~. solution from; w-hich theosadiazole is applied nrav be either aqueous or or=anic Alcoholic so:uliuns, such as methanol.,ethnno4 orpropanol areparticularlyprclerred~ .. sincrthcee solvents are~.volAtilcandcan b'e readil~, rer 70 moved:nfter application of the oxadiazole: Following :traatment of the ~.tobacco withth'e: ozaJi.uoie A statistical treatmentofth'e Rvegoinedatashows that lhe.ducrca:s¢ in iheeili:,vtatic cffett of N,haccocauael txy treatine the Ihbaoco withtlie uxadi,tzule compound is. hielily sicniGcant! Rcsu:isannlu^ousto the fireciniinp may simiiarly, He obtainedlby treatih^_ tobaerowith each or the fu]ldaw.mg oxadi:,iolc compounds at the followmg,lL%cl.
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r Reprinred jrom ~.rh~e ~~BR trtsH MEDtenL. JoUxhAL, 15 ~~AprJl ~.1972, 2,' .142~-144' CC's~o Et~T1AL Protection of iR'at Bronchial Epithelliumi a'gainst Tobacco Smo&e' ROSEhLARY JONES, P. BOLDUC,, LYNNE REID BriruhMrdl~n]]murnc/,.1972,,2, 142-144 Summary Xddition to totiacco of pbenylfnethylhxadlazale', (PNfO) protects rats agalnsR' some of' the adversr efiects of'f exposure to . cigarette smoke. Two groupss of15 rats were exposed'to 255 ciqarettes a day for 24' days; the'group whosee cigarette: JhcludedPNiO: . showed: le:ssImmediate distresss afterr exposure, a smalllr tracheal', goblet't ceil eount;less. tliickening.of the ~tracheal epithellum,.and' less~s cellii6mitosiss than: thosee exposed ta :ordlnary. tabacco. Introduction Human epidemiological studies have showtt that tobaccoo s'moking, causes hypersecretion of muctrs which, is typieal of'f chronia; bronchitis and that it indhces bronchial cancer: The' fundamental structutal changes se:em to be hypertrophyy of the lironchial.submucosal mucousglands andian inerease in' the number-ofgoblet.cellsand their'extension~intoperiphe'ral small airways that are'normalljefree of them. Sucn changes ean be producedexperimentally in.animalsn by.tobacco.smoke', and other' irritants-.such assulphur: dioxide'(i,amb and Reid., 1968, .. 1969; Mawdesiey-Thomas, Healey, and Barry; 1971) and nitrous.oxide (Ficeman and.Ha'ydon, 1964):.The'similarity, tothemorphologiealchangesino mant providesasa'tisfactoryanimal model lfor thee study of chronic: bronchitis'. (Reid;,1970). Ih anintals:thr,mitotic rate also isincrea'.se'ddurinQ,exposure to:an~irritancThis', increase.may,,in patt,,reflect the repair.ofulcerative'dama'ge seen in the firsr'' weeks'.afterexposure to sulphur: dioxide'.('L.amb: and Reid, 1,958),, but cell division does not always seem proportional to such d9maga For example, in:one series':of'experiments, though two types of'tobaceo prodtrced a: siinilar' increase'e in, goblec'eells flue-cured toba:ceo produced' many moree mitoses . than air-curedd tobacco(Lamb andl Reid, 1969). In rarsrthese',changes have'.not.beenseen todevelop intobronchiato caneer,.but a': high~ mitoticc countt offers evidencee of disttubance of'cell.division' and presents.featuresofbronchiad damage additional tothe increasee ingoblet cells. Detailed mitoei¢: countss after exposure to tobaecoo smoke', (Lamb and Reid,.1959) were not'.given in.the.previous.report and so:are reportedhere:forthe~firsttime. Furthermore.the higher.mitoric countafter exposure: to flue-cured,or batn-cured tobacco ratherthan'to air-cured or Burley tobacco aecordswith thee higherprevalence of human bronchial cancer.afte:r exposure tothe' D'ep.rrmenr of Experlmevta!1 Pat[tolagy„Inntltute .f Dk.eancn orthe. Qhear,.Btnmpron Iid.pir.i, Loud:on9.W.3. ROSFMARY. JQNES; r.t.m.L.r., Tedmieim P.. BOLDtIC.n..D.,.Research FellowLY:dh7f] ;RE I D., M.D., r':R.c'.PATH., PrO.fef fOP. 143' farmer.type of'.tobacco (passey, Blackmore„ Warbrick<Smith, and Jones, 1,97,1): Beeause af: the', relevance tohumano disea:se'e ofthe' changes' produced.experimenta7lyd by, tobacco.smoke-increase in goblet cellsand cells in~ mitosis--each count offersa,suitabie'.test forr screettingtobacco sutlstitutes.oradtlitives:. Dalhamn (1966) and Dalhamn and Rylander (1971) havr shown: that phenylmethyloxadiazole'(PMO), a.substance firstt used as's anantitussive: agent„offers', protection' against'the'.cilio- static:e~ffect'.ofltobacco smoke. Attheir:suggestion:we undertookk theexperiments reported here to test:the:effea:of this additive on the.increase.in goblet.cellsand onrthenature'.ofthe distribu-tion ofi aeid glycoprotein theycontain, an.the cedls~ins mitosisy and on the epithelial thickness.. The',histochemical studyof the: intracellular'mueus isre:porteds separately (Jones,, Bolduc, and Reid, 1972):. 1M'aterial': and , Method's ~. The~ effect~ of'' two~o types' of~ cigarettee was' Invasugated_ Each was made~e with the same: tobaeco; but.to:the tobacco~ fov one type.2~°o: by weight of PMO: was~s added. In the~ experiments de'scribcd~d here~ 41 Spragua-Dawleyy rats: . (Carwordii Europe; CFY~ strain)') fram speafi¢', pathoga.en-fiee stock~~ were~ used. The', animads, weigNed about 150 ~~ g~ at the: . start of'f the ex'prrfinent,.Lungs~ from~ addltional animalrs of ~thce same batch were~e exarru.ned mi.croseopicallyy to ensure th'at lymphaacyaic infidtra~~tion~ was' minimal I'Reid, 1970). The.rats were'.divided into~three.groups-(1) tob:acco; 15'~animads~~' exposed to~cigaratte.wiihout' any~additive;.(2) tobaeco and PMOl. 15'' anirnals~exposed to~o cigarettes~to which the anti:inflammatarv agent PMO: had'd beern: addiedl and (3) control, (a). 6~ rats: given~ a~: "sham" cxpo.sure in that they spent time'e in an~ exposure~.chamber as~s groups~ II and 2': but~ were sukiiected i only to~o airflow~ and'd noc' to adaied tobacca smoke, and~i(b)~, 5~5 animals~kept' in cagesn Sinrs~ statia-~ tical analysis~s shawed th'at gzo.ups~. 3a~.and~ 3b~.were indistinguishable~ for a'ny~ of ~the features~~ studiedl here, in thiss paper~ the rrsults~s are~e presentedd with igroups~ 3a'.and 3b' added', as the'cnntrol g,roup:. Groups 1 andl.2'.wtreexposedlto~2~.5~.cigarettes a day. The:animals-'~ were placed in~ an aluminium: chamber andd th•' eiRaretresr werz' bumv in a~. WrigHrA'utosmoker (Wright,,1972): Thedeta~~ls of'ex-~ posure aree sintila'r to! those~e reported by~ Lamb~ and Reid (d969): The animals ~. we,re exoosed four ~ dav~s ~, a~ week', for ~ six wec'ks~.. Thee mean values' o0'humi.dity~ andl temperature'' for' . each~ chambar~used~ for' tobaceo exposure' wcre' simdir. The d'ff-rence. bctween the' cagcs ~~. used i for tobacco~o andd shaan e<povures. was greatest ~. wiih re - spcct to humid:itv; douhdess~due in~part~to~fncreased~.waterlossfrom~ the~aniitull~ ind.uced eieherr hy, the grcaterrise in~temperaaure oc by a~ nicoti2e'effect;.and~ pe~~rhaps' bmcause'' ofif the waterr vapour ini tha toha'cco~ smoke',, tz has been sho,wn that: neither extremer of~ te!mne'~.ra'ure'' nor humidity~ influencee the~e number of'f goble'.t cells (Jones Baetier~,.and Reidi~.1971). Durineo the~e four anal a~half~hourr~or so<of exoosure no animad rcce~.ived foad~d or water and the mntra4 animalss were remo:vcd from the rootn. Apart~ from this~ perimdd all animali~ spont their'rime in the samee type of caP,e, in the same~ room, and: with: as much~ food: and~~drink~d a'e~~.required. Each day thc chambers and'd the'. AutD» smok ° r. were' eleaned'. Thee two types oE ciRazerte.su~nolied to. us were identlfied~ hw a: code numtar whosm.key.w'ac notknownrto~.anv~one:ofus; it was~.noa's brok°n until in had~~ been decided wh~~ich ciptarette had most eRect on thc.amimals.: Thc animals~s on whomom the miroei'.c studies, were'e to be~ made wa:re left quiedy ~ in~ the ~. samee room' for. 18' hourss~s defor', they~ were I 3l9/72 aorrRtGHT ~i972. .v.,.x~ct,rsor>scr:.eu,.c,:vs or,,,,, xrI,x:'.,r ,,r .csea.ru ~5 ,it .o_s,a~r,, ~r r„e w„wno
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143, killed.l Iniection of colehicine(0I. mg/'100.gbodyweight), adwayss at'.the sametime'of.day, wasgivcn,four h'ours,before.the.animals wass killedl All animals were killedl byintraperitonealy injection of' 1~1,5 rnl of pentobarbicane sodium. Siic of the animals were used for electron microsmpucal studies, two fromea,ch,ofm groups 1I and 2 and oneftom eachofh groups. 3a and 36. THee results's of: thee studie.ss arem reported elsewhere. Thee trachea, main bronchi,, and, lungs's from all ttiee animalss were: removedd eni bloc'c afterr being inflatedd withfixative throughw tracheal injeetionunuil the pleura was's tense. The: lungss ffom thee animals used for goblet cell counts (ninee animals from eachexposure' group andd six . controls) were inflated! with formol saline, and those from~ the animalsinjected with~ colchicine. (fourr animals from eaeh exposuregroupe and three con- trols) foer mi.mtie counts were inflated with Heidenhain Susa's:s solution: Lung sections-ern'm cut to include the~e full length of the main intrapulmonary bronchus and several ofifs:side branches:. For gqblet.cell counts:sectionswere stained withalcianblueh att pL-I'.2~.6 and periodic-acid Schiffl. Goblett cellrs were countedd underoil'tmmers'ion (field size0-1$mm) at three:aiivray levels:(a)'.along' thee full length off the trachea, (b)', aJongthe~g mediall wall of the axial pathwav;..and.(c)4 in, 20'fie7ds'0 each of'.the secondlandlthird laterall airways. By, thealaian blue andl periodic-acidl Schiff tech- niquee goblet't cells maystain blue:: orredr orasr a mixture oEf thesee twoo colours. Sections's forr mitot ic counts weree staiiled I wi th . haematoxy9in , and'd eosin. Cells in'mitosis were: counted'alongd the same levels of the a'irwaya~s.fory goblet ceII1 studies, savethate the! traeheaa wass con- sidexed' at upper, middlee and lower levels. AA section oPf oesophagus a¢ the.mid:-tracheal level wass inc1uded'. Results During~,the.first'eigHnexposures it'.was clear.thar.as judged by, their general condition of exhaustion~one group of~animalsf was~ affected~ more than~ the~ other". Within a~~ few minutes ~of~ removal ftom~the cabinet the animals that we subsequentlj.•~designated group 2 recovered~ quickly and started cleaning',themselves~g and moving~.about;.the~group.l animals~took~~about'.a.quarter of an~ hour be,fore starting this:aaivity, This assessment was made in ignoranee.of the~type of tobacco~used,.and it e,merged.only.later~d that the lesss affected animalss were receiving~~ P~.V1O. After'~ furtherr exposures: the~ difference~e was~~s no~longer~apparent: The~. mil& conjunctivitis-:seen dilring~the.first days~of'expasure:to tobacco~o smoke: was ~ similar~~r in both groups ~. ~ ~ ~~~i f~:p~T r~ I,{, seen.between~these~and the control ammal~s':(PE~.0-001.); The e animals expose;d' to : tobacco smokee failed . too gain weight ~~ on . the ~. days~~s of exposure ; inn the days between they gained weight faster and, aa leastt in the: first couple of weeks, their~weig,ht~~vittually ~ re!gaine~~d: the'~e normal value. GOBLET CEIiL. COL'`T In the tracheai the' goblet cell count in the group of animals exposed to tobacco~alone~~o was~significantly'above thai found~ either.in'the group exposed~d to tobacco:and P:MO (P' <~ 0~001) or~~ in the eontrol:.animals~. (P ~<~ 0:~01.):(Tab1e:I',);. there'.was~~e no~ si¢ni- ficant d:ifference'~e between'the'.control animals and.thase~exposed'd to tobacco and'Pti4O;~.Iir~the~.axial and laterallpathways'in the~e anidnals~s exposed~ to~~ tobaccoo goblet cellss were increased, thee increasee being greater.centrally~than.distally, although there was s no~s~.ignifica:nt diffe~re,nce~between any~of~~the groups. reateI-Mean GablerCN'lQoum (S.E: of.Nean)p~er 6' mm: oF Aiemay Epirhet- in Aranuatr Erpored'mTobbeca Almne(Groupa) or' Tdb6cco. and P.NO(Gravp.2, ' Control Group Groap 1 '~ -Group ]', TFachca: Axiai pthway' 5949naa9h. .~ lOW B4!25:51) 156-70ia4,1&) 128 il /17:04, 52`92r860; 14833 (2491)' aohwayer'2nd.. ~®750!15.801' hteral 9277'!16941 88I-50r22,74)i p ~'3rd, .. I 5700.(d1:45/ 66'55(1407) 60':2'2(@~64) E!PITHELIAL' THICK:\'ESSAND. CELL NUMBER In the uppertrachea theepitheliallthicknesswas measured.with an eyepiece gratjoule, ass thee vertical distance between'the'.super- ficiale snrface' of: the' basemenrt membrane andd tlieepithe!ial surface. Tenmeasure~ments'n w•ere,madeover'the' plates of cartil-age'and..I0:between„and the mean f6r.each sitewas'anaJvze,d both.for each animalland.for each group. Thesee were'assessedseparateri, because.of an apparent increase betwe;en the.plates, tiut:no d:iffereneein.any group:wa'sfound between the',values: for t'he.twosites(Table, IlI);.. rwaL,e~u-Epirheleal.Ttirckneu (um).and'.Crll'.Numbb~m rhe~Uyper~Traehea~ (S.E. aJ ~SPe- d,rem.,n Pa,renrhesn), WEIGHT GAIN ~ L EpurhehalTh,4'nem I Ce1l:tivmbar~ The panem of weightgain for each animal group is illustratedd '' Ovc Berwecn'. Over B'crwcen , i thi i th Ch Th i ifi d ffe ca:nrrolglrou~p~.1¢rlnlro~66; w75'r1~64). .2:3a(0: Zr7o~ro'171 rencee n s respect n e. art:. ere was :no s gn cannt l Groop.l'~ 213 o.bT 211Tr0571r 3a7'~p 3'90~~o1U.41 between,the two:tobacco groups':but'a.significanrdifferencewas GrouP~.2~ ~ 15'68(0.90:1: I18~41(0."!9)4` 29~:!0~19:.: 113:~16'0 - Tbbmcco ----- Tbba.cco. c.FMO. ---°°-• $ham a.cmrrol • E6porura dor, 5.~ .. ~..~ ... 5... i 0 25. 10 20 30 Doysof erperlment dt•e' ah't . gain ~ relared ~ to ~ e:poeure ro ~. ei rher~ cobac.ca or totlacroo aod PM(l: 0-1 =~~ Meaervnermrnte.mad! o.ver caruldpr plJrer: Berween~ = Mea.rremenra. made. between carul.neeplate..: •'P~<.0~rVl a~rt rolr. '~'. P<~001 a.p .i p,roup~.ll. 1'P~< ql e i, ruh. S~P'<~.O05.pa,mi ¢roop~.l':. P~~<~O~.a2~:apao i~ rola~. • N.S: aaa. i gxu~P l. 4 N~.S: aqaorv.t con:voW~ Heidenfiain-Susa's's solution being.a better cytological'..fiirative thanformalln; the.measurementse of epithelial thicknessand,cells number.weremadeon material fixedwithtti.is'soluuen. Evidencee of an increase in, cell.number.contributing to:the'.inerease in~ thickness of the surfacee epithelium wassought' byy counting:the'g number.ofnuclei transected.by the vertical line-:along,which'thethickness measurement was made. In ea~.chtobacco,groupthere' was a highlysignificant' increa:se in thicknesss compared with ~the controls, and this was greutest rn group 1. The difference', between group:l. and group'2was also highly significant. The resultss from the animalss whoseiungshad been fixed.in.farma:lin were alwayss similar, although thee dcgree ofsigniticanoe was not ass high. The: number of',cells:wass also increased ingraups: I and 2 compare~d with.thccontrols, although onlyy the: countsotltained over, the: cartilage:plates achleved's~ignificancr.
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'///~~~1,•- ~ - ~1'r ^ s' q (:! I . ~Ji Ii :71GII141lPS'I'i l'I•:LI, IIIIY('.UI'lill'f.l•:I\ .\\1) 'I'It'1\'('lll:;\'I.,III..\V.I1: 11\'I'I{It`I'.ItOI'IIII'. '~tl (^lln~l.lnnnxnrrmi,•nl,+.(nIn''InluJir Ill .reliline Iliqln uliurl.. t',inr'un ny1•lii1~rr• I;n1 tiriiL•. in h .r,olilin ,•.rllnuu9l :1'.rln5ro.lni•Inu~nl..1cl'rr•i,rlri Ill Illr ~•arlI ull~iil,• 1iq;.ILl • in,l.+ilnnli •rn di:un„Irr. I1~•rqrr~liCulurtna'111• lulurn uf Ihn unrlinsl, tLr hinsrnJininr,osmllll',I.till,-orll hrlplll:u(' II wnll (:A.!.). I'l-nm, lho~m tlu-~urinnr Qinlnnlrr. (Fl1nl Lll+n-lur•nlIni.ulhrnm• In bu.e~iu~~nt mrilrhr1lr11•. 511114 eIllc•ulnlrrl~. It Pal' 1.1:S:' rnblrl' rrlLn ('Ml'nnmLrr.-1':x3,nan'o ta tobat•c•/rslullka't•nu,<I'.S;I. ..ignilli',)nt int•ro;lsc' iir l:hu tntna nulnl,cr of i;01lilrt tcll, iu r,lt lnu~lltell 1'Ililln'liwnI (t,uLnc(•r)ic/1nCrnln. P'.( 0•UI), vs'hilt' t/c Itdtiitinn Ilf P\IOIllsvcntn snrll inrrr'na" (dullnroa:-I- I'1LO/contrrllsl'; _A`.tit tuhanro ~ 1'\[1);tubuc•1'oL' C Ui(Illl ). Int1hr asiill unll lutcrul. )Intl)ti'+tv,a nrithcn slnokr fr(1lutl)l):u,l'o Itlllnc nur ti`nln tr(L;latl);- I'1LtY ollnhl~5 n siguilil'nntl iilrrc,).,ain tLt'numlLe'r afl gc)lllot ct'II,(.Iunl's nl'nl:,, Iai'')! Ilirfr,mlirnliraL nunl,l/Yix~-'1'itlNcI irhoviu thonuu)Lcr /mf tal-h uf tlll' 1 tt' lu'sufgolrlctlrcll, inist'ot'iiuns at;lincd,l)V :Al3!1':ASs"at IIFI :-G, I;'I'')I::1131':Ar ;It )1131'_'1; IUnlllA li/I'_Ati /lt 3/fi 1~I1, nt clt(•ll .Iirsvnc lcvel, tb1'ouolnuf tho'3orl)nps afluoinealx. T~,vnuh I.-Gnblal'('r!/.t%(i~ulua~Aii"Irrnal oflrr,Srlcrfii~~r fihriili~il~/: (!'riul/1'u! (f'), 1'i,Girrro .d/ane' (~T) rutrl' To6ncro }-~PJ/CJI (T ~ R.l,i'(J~): A iu'u'rry~ GFrnl.§_-I (fLra~cdlrvt 3: (Axirrl~) (1l(ll :3~(lynlcrnl)', G~~bLrt a•il,! Sanininu'. Auwmnll :Aii~n5ny' ~~1'11Spu.anc, A'IS'Iui.,l,r, tCcHuiqu, gr.nlp: lucol I.iou,'u•. h' In1rll I.:u~„ tiiu,rll 0 . 1 I-ki' afI.i,1il ".'-li,i ." -'-sI .i1~Ji' It~i'I :11-!! ' 7-n5 ' .i_ I~a I'.L.,iii :1!1-s1 :11N1':\y~ '1 . I .',-5'!~' 1/7.1,` ;II -l'~3 ..- aa pHl-'rtl 741 5.4.' 15,:1+ 49 I7 a .~- !6i 3:C~_uI!1~11 .;:1~07. T~.rt I'M0~. I ' 111177 ~U.l' '"I`7a GIi':id 45292111.111. ~ 72 ~IIV a-v.i ai~!IV. _I/Ii. .~7 ~1., C I I-Ifl ":1,Y7 1-:2- .10.~ I-a:l 31.117, 11,0 75 al a'. 0.'1:/ 3:I1 IIll . I~.:L _'a11y. li~~.lll? '1' I II- I!1 !IV57 1G'~_'1'- Ia.,~5%' Itll _~U J-!lu S-W3 u:l!.7a: ;rlnl: RI 11S . 1',ll,. 7~{p ud-UB 7•}..I'\Ifu Il~llll !1)S:I'. I-:1:1'. !::1-:tl.l a~:li, al ~:t.7 ,'ll ' .7:1 111.119 s r,l 'ux7'.Jw L'J-.S;I C 3~uu _7~-7:, '. 11.1,11 I. `l '1.'/:1 111 -i13' 11,1111 7 :,-iG KR--Il[ o'' III' 1~01 IN~_D 4u-.77 I-.;ri' lu 74 plt l~-u~ Ct~uel II1-1_ u'i11i 'l~1 Ill-li4 1:17,1µ. lrl',11 1-73 •L'-'-1')IU 11 -L.d:l Ill-du !.Ir113 .C'.ay' IuLl~fi2 ' n~n 117'7+ !i•Gs, 17-7(1 1_r!~a„ U-u~l _.Ila. 1~i'uln tlll•sc 15511115 tlio:folluvVin;1 courittsiun, Ina~tln~ 11rasi1: .Atr'ar-ll Iri(45:u's' lbrol) iu Lntli tllc toblll•co:gruut/',nlclnc ;uul tl)c'tllhucco Y\1t1 irrunj,, n
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-,"-_._ ~/r/ Rn. J. i'.rp. I'hllr: (1973) 54, °C'.D. GO0 'IiT.I:'I' C1C~LTS GL~Y~C'(7T°IR~OTI:'1V~~ :AN7)~~'1'.R'.UCIIh:.1L GL.1'V'I) II1'1?I;IR-~ Tla~~Op'ILY'~ IN ~ R~~:A'I' 0b' 'I'f)B.1'C'CO~ U.l'IOIcE, 11"i''1'Il Of', 11"Ifl'IIO'~C'I' TIII ~ A'\'TG~INFL.1'.l'iJCA'L'O~1tY~ AGI.N~7,' PIII~,A]'LJIIC~TI~I~ILOX:kDIA7.DLI~.~ 13-. JO\ISS, P. BOLDtiUnauL. RIMUDFvnttv fke.Drjtnt•fute,dnfli:cpnriutrtalnll'idlfn7ng~, CitrdiotLnrncicInsdl'Nrle;,Bi'otnpttota l(nspilnl; Grndu~t 8:1V.3 Xhveieod forpublieatiou,Duc-hnr 1il„191"- 9ummor}•.-X quantitative aualcsiehas been made of tracheal gland, siveandi of histochentical cllam,±es occunrinfg in f;ablet cells of'tlu respiratory epithe- liunr, in rats exposed either to tobacco smoke alone or to tobacco smoke 'Aith pltenl~ImcthNloXatliazolLI Exposure to tobacco smoke alone causes an increase in fiablNt celll number with a shift from the production of neutralito acid glycoprotein, mainly sialidase eesistatusin7'ontucinbut sonusialidase sensitive siulomucin~:md~sulpltomucin: Acid alycoprotein, and each of its t}pes;, appears first at' the cell apex. The addition of I'1lO too thre tobacco~ protects af;ainst't thee increcuee in l;pblett cell number but 1;i1-esnoprorcction against the shift from neutral to acid glyco- protein and,causes a larger secretory mass within the aoblht cell. In the tracheal gland, esposuretosmoke from either tobaeeo~ al'oneor tobacco vt•ith PN1O causes a~signiricant increase in cell sieeand acinar diameter and a lesser increase in, II diameter. There is also an, increase in the thickness, ofithe gland and its dl'pth: G.ach of these gland changes is more pronouneed in those animalb receiving PNlO Nvith the tobacco. 'I'u i: adntihi.tr:,tionof lillcip-lnintltyloxnrliitzollt(PSLt)) h,is reoeutl }'l3cenislio+vtr or, to l,rote.rtt,r.,in'tthe cilio,tatit elFee•tof tohaeco,.moGe (llalh.uuu.u,d'L'.clltn(1 i1)7I )anci ,,L,oa,nii,'t other lunritlamn~,c anttscd toflhc rnt~ bY tuburco stnnlic, alt'houn(tthedh•greoufln'c,tretion affurtted agninsteaoliof'tHorli:ut~~rsth,ttooctrirod~ n~ar,not, t'hesnine(Jouoa,,Ni,idueautdl]Lcitl„IY)7_), Tltentiditionofl'1I(V~tothetuLaccol,rc~~rnte any incrc.,seini~(:nblet cell nutnlSerand I,:ii'tl}, I,rrN-cnts inercnse in oUitlinllul thit•Icness'and cell nutnber aud theuumboro0collsiituti't~osi.,; Lutdocy not: aRFettltotlrt•re>t,e iittite auin,nUa xcei~'lttgaiir, a decrnttsc prolVtvednt Ivust ill l,urt Lv, nicotiiic(I:Ison aud 1';t-rv; I fiG3); In I hent,rnutl t-at, goblt't ueIlx„re inotrnunteroutiin tlirlanne air,wt, v.;nndi nlnir..o ill l,ct'il,}heral airn;tY.v (\IbC;trth.%• uud Rti•id„ l.5tl4). Glycol,notoin.;witihiw thc goblet crlls nutn- lic ucuU',tl ur acitlir, includim, ill tlirr4it nsin tnauaither siulic :u,id(:vn'itiec or, t.e,.vi..t:rnt to tfic.enzvinesiali(lusr) or..ullihato. Niitlid.i.erosi,+t.,nt "iitlumut•,iir tutd stil(,hontucin ,ure found morc.contutoiil~• ill cent'ralairo-ng-.vttn(1 siitlitLt.oseusitivohialon,ucin toward the Peril,hcry nndl K:eid. Iall4). 'I'hc l,ecscut'~t udit~.4 ~,rcconconnrtl wiiih t'he c'ticetou t!1t•rrtt~ t,ir,v~,n ,of c~l,a,.,urc tontuu3ae,ofeilllt'rtull,truoalottam•of tol,accowith 1'.1411, lwrtieuLu•lY ,N~it'h tllc
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_'.i-1 it.. .l(1\t~)ti. I'. lilllll)I't:.\\I1 t.. Itl•:It) Inr~_crinthe toluu,r(I ; I'\IOnnilu+ll IHnn incitlian tlu• tuLaro(I :Ilun(• or tllecl)ntl'inle llctirrcll isHivll tii('rai.no .innilir.ult(liffi•rcuro. lli..inct4c;l.w•irn nrr•,1 ilt~ tllr n)h;l(•,(:o -: I'3LO: rntlinl,cl nliOrt• botll otlllcr ~miln;rlsisllhihlv .,ignilll~:ult ill linlll axial au(l lalcr:ll hathvvnvs (tolielccnl I'J[(.);tuir~icco, tul,~(cco -- 1'1[O'/`l~(mtrul /' < tGO(ll) buk dbo5 nut arhict'c sinuifii•,rucc irt tllotrr(cl)c,(. I':i'i(lonll,\ '' 111r.n(ltlition otI'\[('J ttr ihc toli;u•co cvin.vrxttir iucrcasc iu tllnsircoftlle soerc•tor,t' mlir.Tofi aci(l g1vcollrotciir withiu tl1ocoll. T c~trJlcrd jIR nd 'Clic revult of'trachrtl ~litud tncltturcrn('nthof(nliln,lls fiKlnl oanh~ of tllc :3 broup.xiaaiv^enilt 'l'altla I1°. Cotnl)Irir.cl witlt t6c control aniiuals, tllcre i5a T.eiti.r: IV'.-T'emJreril (Jlanrl'Jlrosu wrweuLs air Cr l/rol; 'L'oGFrro A Vo(e rn+d 7'uborrca -(- PJLG) .,I S+ii(eals \trm.n+inimu•\ih.uniiunl•n\t,•,un c•1,tl Ci ~ntr~~t diir.ulrtnr I}(inh dinm,!.lor I(eu) aCt~a.', :S11uU (1t~."l4) 571 r I~,ni) _(7 (O~' ItlI),, ^ ~ 'Lo6acoa 1':.7p '.~~ ~ ~ (7~RIt)(1, 7:i) 1(S), (0: T66nPr.~ 41 ~(JG _!I> I t1' 7~ -i-7'S4U (1'(1;) (t,a7) (O,Ifi)i ( )...i.~~clhcmo~in .ilnilnt' increus(• inLtn('+nl,;t('illne dirlnlrtre in ;nliln:iI.. (iXllosotl (•itllrrto cnu,llcfruln -, t',(lLai~r(I alnnoorfi-onl, tolluoco -~- I'Mt)(tolr)rcofeonttolsL' < U;ua; tnLL;((c(i 1'11t~)ooutri(lls l"< (('U') nn(l a..im' ;ind: Ili_hlt'.si';nili(Irlnl incro;l.<• inecll <ie( (14it' 1L~rt11tuli:ncvo!controls uu1 tI1L+t(•co-t-1P.1'Ll)'aontrols, !'< u~nul)I 1~'liilc tllu•mi.al~u,( u in(l"rn5)• iit In(nll Iwnrln (li.unotior in llntll~ grou)I; of anilu, c.clloSF'(L.to tblr)c.lu sln(SIcr;,tlli.v iil(~r(•n5cisnllt yiqriilic(nt o-h(~n.cnll)luu~cii icil,ll t.li(• c~onl'n'ul gr'(nlll: I:cldl•nn(• ofiu(rc;u(• in~ccll ociiltll wa..<ourllt hyrc~n~Il,lri'n~' tl)c nunlll(~t' oflluclri invlh(Ic(1 lu~r lulit L•n;;tllOfltilhulo; llut tlu•n• i1:Ls nostatititirnV lili~cranle llctivecn tiu~i~nlun.<GSr cur h anilnal'grou)1 (nlc;ut~ nnml,I•r utl nurl(•i );rr unit II•ni,ttlrofl~lunli:(uulcol I-(i) :',tnllarou~+rlona Itoll;lroo~-:- 1'llO I ln tllcoxllo.~,al'nniln~d., the occr+lll ill(rc,(scili ntrult :(cin:ir(liun)ctt•r is (Inc to )tnincro:uc iirthc t'+Ilt^rofltllraizcoftho,u•ini„tlint i:; l[rini,_rce(tertle~nl'/ljnneliilln(tcr a)/)irur. Lt~t'Ilc anim:Il,vcXql()scr1 to~tolL:ircu:lllluruaini ul( tolitn rnitdiitlnct(•r ~I)1)qrnr ln(I iu t'ho:ccc))a~•cd to tol)))cco - 1'l1K)', u), to1:3ujnui;l'i}*. I Iqv)mrt'n'ollilroftllrgluoll 0~nr,;ll5on0(.u',scclbx' ('om)urrinO thr nlcan utnnLrr uf tullttb'sin It tracHcal sca•tinn nnd tllc ))ro))nrtinuof.cctilon, thut iu(In(L•(l cd.ll;ll. .llilnn' Inon' tulVnl(•.,nrfonnd ii (llv ;tuiinsl,cX))oaTd totolr)rco--P.11O th:nl iui 0ithnn tlin,)nilnnisos)5o:cd to to6,u roalbnc 00 tlircontrol aslilnrnd,(tu1,arcr,-.- I'11OYtt,lincco tlimcP; U'(!Li tb;icco -h P\IOPcilutruls1''C 0~fll). 1V'liilr t:L rro)rc moric tuhulc,s iu tllc tohacconloncgrout) tl!an intiiuooo:trol ;nlinla'I:. tlio inrrcn.(~ d't)n.v not.)clliinve siLmitiOalicc(I:'i'. °_)1 SilniLirlti•, it )cns iir t'llo ;lulilnu;v(~sfusncl) t'n toliareo= P3LO~thut most sectionvinuhl(lyd gl:)nd, aVtliou eh intilc anim;)lscxposcd t'o tobncco+llonc luorcscction.v iltcludbd RLludltlt:rn in t'Ln cont,ols(Ilnitl;oftY:)nlioali Icny!tlt contliiningg)iund: coutroi.„ 3C~u7; tobaccoalonc t)9'ui~: toLacco -u P3I(0'
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•~--,-~. ~ . a..~ .~. ~, Jilu a al t',;i'_' It. JllNHS, I. 1101:UCi7.1\I) r'.. lil?til) si_nidic;ntt s}1iftoccln'.:toccllxwcrci aviil nl}'copl'o1c•inWt.s~~ '1'lii.iu shift oc'otlr.. Nt~6olh"n nr not there ii+;ru iitcroa'oiil the ;)h:ulatk• iutntlior af gcrlilt•foclls. I1i.+lrn'tic•uLu'ly: thcsmnll 1':1'tihoxitiroccll.ytlnt clwngc to sIn,tll rkli posiiLtttl butHi ofl:1'li hoxitivoccll nrniilcrcusodcuttl Dutltl ta•{)a-.y of PAti lloviciva c<•11ldocrc;tscd (°I'itUlo II). T:tnur. IL.-Typt+s of Guldrt Cell at Th'rne _91irvr'ny, La't:rl.y. Arlilrrl Pahlr+.v- (i) Tb(iacco ,?lmtc ala l(ui) To6acco+ 1'.1TC1! L'xpcctr+l oaldace-Cw11rr14 Trnclwa hsiitl pntlurny Lnior,d Imtli-Y Acecinl ]:cprcted UidT. ~ctunllF.~~Iwxtcel.lllT.'YActunl. Yi~l{~•ctoJ Uif7: ( i )~ Toh~~~rro 1Conl r~ef.r . I.rvryo G~. 11 -& a7 47 -10 3:1' 47 -14~~. P.A ~ ~ Ilo+i t ivo &nnll, ' 37 IhG -141) 270 309 ~ -39 2R8i :I1: -^_4 Iinry;o 92 12 -{-80 AO GO }141 104 117 -13 XII'pu.utiiro Snnll 2I1 137, -i-74 241 207 4 :141 2:11 :39 . _: 1•zt a 1 0,01 01001 (ii) ~.PoL~.~n~a 1'a10;Cb>drod.i I.nry;n 18. 111 }7 31 47 -M 24 17, -27 I',15puMiti- Smnll 126 ]A6 -59 2 6 3 301.) -164 _l:i 112 -97 Lnr};o 6t1 1'_', }47 8G Gli ~201 1'w4 117 . A73 p-Itivo 8tniall 141 1J7 -k4 307 ^0 7 -}-I1 35a '_'alT -n114 1'y< 0001 0-001 0o4)II In thetollaeea ;u10110 !ranit;,tlnabsoltrtouumbcr of botlC li ofSlil)o:itiN~c ccll inihothtlir trnchcsanclasinllpaiHwan• is inca'cn,od, lint iit, tlio l;ttotal Iiathxa%~ onla- the am;tll .-1'li l,ositinrcrll =Ico%ccau iitcrcamo. In tilotttuckca, the ;th:olutc ntuuhcr of wtu++li Ip:1,1;Ilovit',iva acllsisrctl)tccdt+cttlicaxial ItnrU I;ctcrnl 4-vclsLuthl+trg'o+lncll,lu;tll P!1Npo.ili ccll., ranl,t'in tl)nsantc('I'altlitI). InAlit• tubarco-- 1!\U) gronltthc nUsolutc ntunberof Ltrge r`,'13ponitivrccll.i~ iir tGt,trxchc;l iainct'cuNCt1, tluttofsmallP:1%~1)ovitliva ccllsliciitn rrduccd. Iittltc axiud luttllwa~-, tlio;tbsolutcnti ofUotlt~ .urll :[liand lnrLc PAS ho..itikcccll.,i;; ~rcutlti incronsacl, n'hilaitl tHclntcrall luitltonninllrr of ,nlall ,\Itposit ivoccll.;is incron.vetl nuclstnalll P_11 hositive c°Il.,rcclueesl', (`11itDle I)', Atcaclt level <rfthc a'l tlurourc vnnintions in reshonsclictwccll nuintala,withiu the rrouh, l:itollnllitnnl whotit•s asi increttaoitu tltclroloetiou of.alipo:,itirc ca'll, at soluclovi'l ofltLcairnnn- Tyttr.r of rtrid qlryrnttrrdcin yrauur7rstlvt/tiu a,cilrplrcnll.-Front Ri.+trrcltcmic;tl~ lululy','ix of the int r;trolllcl;tr tyTcsof acitl rl~'aolprol the followingt?1)o..of'o]>Ict colfcnnl lio'id'cntitl'odl: tho;cconta'ining(i) siudidnsovcn•itivr vi;tliiuiuciinand, vnr (ii) Siudiclase rosist:)nt anlY; (iii)thosaoonilbotll ~inlici.csc scl:~itixclutd resitit:utt sinimnatcin, .md (iv) those contaiitingsinlicLtso rrsistnatt sialonulcin ;tncl :)tilt)lion)ncin. yull;homucin„ and sonu,tin)cesiulid.cac rcvist;)ntsialhn)ncin; +arcfoluld otil~rrct the apex oftltc cell, Lutthpy?m+ly'.como tofillltllc x'holc cell. 'hhiY,
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rtDlttfl•:T t'4tT,L crY.cttPRtYi .\\n 9•H?Ua115;ti .ln~rl•it:'t•taurlt~l`°-:Oa. : Trnrlio•n. i~ntl~~wnv ~ f.rvtr.rnl I,~kr1V~.n~~ Krnup VV'idih Iicµ;IVtAnvr. ACidih ]]ripht. :\rrn \41d11: ]Iright -Ar~-n Coutrol 3I 8 _1 ;,fi~1J~ G'~'il _ _ 3'6 _.II ,!1 ;r~F7 • lf (0/Riq (o 7r,) (6~, Afi)~ (O:~;P) ~. ' ~4N) (0 (4-27) (n ~f[I)I (0:ia). (i .;) 'Cqbuna. :, . ~ Yo lo „s 17'~U9 fJ ;tt G!.50~. Jd1 R^_ a,te, ;-n 30 r,a to ~n) (( ;3) (lC~9^_3 (U~~3tl), (o:~du)~, p ;v;) ((1-_:,)(u- t,o). (a. 2 2) To6neco R~7J 0 1~3:1~ Nro7' 7- So: 63 - - J I . 7 (1t u.pG ~l l }1!310 (0'47J. 0 ~9-6J (R, 4:Y)~ (o:._a)', (3~-) (0 - ,_w) (0:-33) :+ttr"rslst hnt nv1tvollilit•"insto secrctc a novv-t}'po of +vciii'' lYctilfrt'ttt•in, itd allpc;ti:Ylirst ;tt tlta cc1L+t1tox. Trlprs ofyolilrlrrll.v nouNti'nii+rl,wid plyr,>lrn/rira (,11111m.~if)'rn)~-Ih tlic U•;trlicaof tdtc controlnniinnlw tiItce fcw Itrgc:A16 Iw.itilrcccllk ;uru~i;tlid;t,w n sansii anrll t'csistuttt si;tlonrttcin: itt'tlioai ;rnd liatcrtl Iuttltoat}°stlht,Y nonttiirLotlt tltc .~on-sitiveandtheresi.t;utt fonn+, dctnottstr;rtcd Gv tt tiii;nific:uit', shift fronr Iltrrvo tosntatl :113I ha.itia•c ccVls ~ after the actioni of' sittlitla.~c (1',s C~ Ot)i„'1',ulilaI1). 'L'llcvmadl A1B ltositia-eccldlt armusu;tllt- ;iirlicln'crcsistaoit: thisgraup inc•Jndcas t'he snldtHomuciit~contaitliug c•cli that isorcahiimailY scen.In thc aniiuals exposed citlter toisutoke from toLeceoorfrotn tbbncco+ 1'\1O tnost lar~toA13dtositivccollscontniit 6ot1t li ofsihlotnuoiir (['v.sCi I, '11;t1ilrll) butsonic, partic•iila1r1}' iu thoi of'those exposed totnli;tcno;tlonc, may contnin ouly si;tli(lasr rrsii;t;utt sialonntcin. The sm;rll AItpotitiv-c coll (;ts, in thc contrK)l.,) coutn'inssialicd;tsc rrsistant sialoutucin and includostlingron)t,of oell..cont~ainingsnl)tNmnueiir, the fi•cqucncy oftho dattcr Lcingjncroasrd o+•crtiic cMoattroiv;thteonl}siu,thetrnehaaofthotbb;trcoa]mlcgrioul(,unclirrtlln'tii .utd axial pnthar.ey oftllctoliacca-{-PJIO nninl)tls. :irrn r f.+•rrrnlorq tuas.,•wilLiu .dRlro,eitirrarlls.-Ih ;ill';minutl.a: cxposcd' to ' tbT,ncco -I; P1It)~ tHoLrge AI$..t;rining, goblet cells ;tltpo;tred innrc di_:4ond:•d licr;nt,o oflun inorc;tst, intltr;tnvt ofgritnulcs, due tonn incrn;usc intheir gr;ntiilc mtnlh'•r ratlter tlt3n iw sizc. '1'his wa,~ r)uantiilntl hy mrnau'iii,tlx• Ili•i_lit: und veitlt4l ofthc ,vrct•ettnt•, v nt;un of:u•itl rl~': ultrot.•in~~cithin u, ct•II (J,tulgrtf ;ist,lie ;arru of,r;tnulcv .taining u-itld:A'B): :St'c;tcliIct+cllof lllrnirat-;n', mc+t~1:roiurnt.o wcru inntlrwhcn either thcHeiglttor u•idtliof tdic scc•retorv nla...,x-;t.,5nnitl.orninrc.ofthc rycpicce grnticuli,(;7 units-(i•3/ran)', 'f Itcproduct oPhcigllt autd width was n.nd ;tsan"iudcz " oft'Ite urca of tlicsecrotbrv- tus.<s. nnoaninr;il wahcii:,onnt rnnrlnn from o;telt ofltllrtMb;tt•conlt:ne antL control groups, untd 2 ;utiin;tl.'xfl'nintltntol:;tnrn -{- 1"tll )graiip. In .uniinnls ~cx)lavctl to toltacc•oalonc or totoUnroo-~- I'\1Mln,n;tllN';tha;nt l;irollsvouttiuii:n wlnrgc sarn•torv'ntnss-Ncrrt• (:rc'~t•iiCwitlliiiti t~4iclcn_(hofnir~carmr;:stn•t~dibutinlheoontn~tLiutint,tl~~onlv'::llottt7ct~llia. (~)f'lllt, 2 'nniinoti.vrxl:a7.cd t'io tolta:c.ao t P11O: rntrltad shown n nun'kcd nnd ot:u it 1.•>vrr shift to cells seeretin;,+,+tciilglYcopt'otein ltutllotluean-c ttihigit nrc;rindhx witlrlittlb~h dlffomncelictwrcn thrii at•K`avir.c: Tdtct'csult of mcasurcmcnt:sfor onrnninal fronrcnclt fironpi..girrn iirT;tLla IIL Atcncltlov-cl oflthn airway t~lto nrc;tlofli positive ccllsis sulistuntihlly 'Le'not: ISI.-1ff'irllli' nrtd, Ifr~iglrl~(ltva.) of,Scra-rlomy Jla." S'lait+irtp x•illr .4'r~, a~na~~lh'rir~ Pronl~iecl'~as~,rna Li;drs: of 9'rrn TLcec~.diirvt•ay Le:•ela, ivt Cbmh~ol, TbFlarco A~kriw and~~Toharcn~~-' ~P:1L0':lniinals~ t (, ).ei.o:,oC tlloma,in~
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a,aill d() Ir..tzn.nl :yluo pauutyuoo `fll".) 7a)rli)` oq'z JIt!q ltr.ya l7.row 'illl 'u p.t'n ~liruiitni )u.iluuu ,tqi ui .ao.ql Itrnpuo.nL a)Il lu lun:~l IIl'' lV, •unnpillula u) .)ottwrr)) ao .t.MajuA.r ~rnyi1ri.o1 iw0ur a~ll ~~1L !'P'o•i': unlar.t,as A . paO.tlr>;i luqp JI.M ~vu; tnrtl.t ')ra>t:.r.t.tni Jutn~t •l.rrpunn . IN.r qulrlo:' .>ixow oa.t1 I°"f.tur..tq uN1 Josurri;;a.l u! punu.l uoarl xrrl tnow.nlnA~ }tt.ro.)ouun)an)xxtil a11}01 1}ty`' Ivmirwy.rulay 1! a.)nlti ~kllao .%N,ru.{o Iti.triiilryo.w)r atll tuu.il al]n,t.iam 2r-Ui)>oui ut I- trltloo utnil)m ,Mur.tl.r luil/ , wY;: n*' ~'irl;l, ut~lu.tdlu~r:~~: ;o )iUl tl,r.i Ialrto`' ayT ~ut aJirl, v ~rl3i.u ipnlui.tosni~rnt .lar )rrlui.w,st: tpluq '.i.,rluniu Ilao 10)rlo' lit ,we.r.crtn rit! ui tn ~Il.a't 1opTn; tutl7rm ~In a.tnTlru •1Ill ni auwiilo urul .t.1y! l!a !11n.u.t .iaui untllnllnrlo .~u.n.tn! n> Ir.~lai~>Il.trtlkit~ ,tllnuiil' ir. !Pt.iaj j)tur ns.~~.mt~ 1ill,'I~I 'ssa .tit]ti) ]_1iy, r.ttoyl >'t nnilunMulrr,t .t•al.{t' Alua) qnr) a.tquintt )).t.i 7oFflo' .~st+o.i.rui ua jntturl u•r.nll snr{ ~~1r..t ql ,nnlLeu.tolii( .la .tuilcltu:ulovt,.txql[a'.Ir> Ilo!yrr.rlsiuirnjrv ,i4ll, '(li[I(TI fkSllil ,t.cul~ It)n1r lttnirl) a.xptunu'fpo aolqo~, (n o:u.i.unnntn rl)i.%l Auu p.ia.toi[.nl u.toij s.~; ~urtl.t ll.rns_Yl.nirr.~,~.rll :.roilwuu Il.t.t tqI)o:T ut asuos.)vt urnr )not ITi:».m.r0o ute.t ~'lloa Tol~lo` )trtrLrnn. T rrillli.t% ut.tlo.tafrt,>.~~: ~trt ~-.i:~uutl.~ )r.titu.trl.xt7 ~til ilunil•itllnl.i .w.t~.tnr l rr1 rao.ru11nlnl a.lir.urfzet;in.xullril aia.l} rrmutih•suil .e)nr,l, lti.rs;t.ul .tiljL i'll.'d , 111,11,19 SSJISRWAu ~ (w4m.;aluccp. 1cu.at+ 07T ~OOT bB .09 1 Ob .07 OI ()4C.I+o.3acqO,L I1uilttuo OZ 0f: T ~ Ut Si 7 OT JOE I!'S:i• '•tlld'r~l,l:ail•Llll (I'S\°ID 'Il':•IIIJW41,L U\1' \ilA,f•117I,I.ld,)'A?tt1 'I'lil.) :LS•I'171tr7 I fn !'~ ~
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. Uh~~'~`~ r' ~~t ~~1Z;T%L R: TONI~:S~, 1!1~I30LDUC S\~~D I.. I6F::1])~ s 1 Contro4 1)obacco Tob:wcorl'SI't> Ftc. .,.-ACrnn nunilicrnf'hibulve pcr trnchcal rin); in cantrub, labncicoaluno nud tuhu.ccu -I',ltU nnunut+. e ecll.contniniitg acid glt-cpllrotcin, .ialidasct'esist!;utti .iulotnuciu antl aulluhanntt in. tacrcdtrc.cutiu tGr ttaclmtt, audlbotlr;tswclL;tS si;tlid tlc scn:itivasialainucin iirtlic a5i:d +u)allatcrstt liathsvay'si utastsialidlt.,r SOnsitirosialotnocinltcing pnc5cnt iirtiioI;ilcrtl aiilv;ty's, (Jnlj nit ocwtvion;il ccll cotttnincd sull,hotn)tciit :tti uuyletx~l oft.hcLrioi~<•Itiiil trco:, :A sintilur lYtttcr)'taf di,tcilnttiatr of acid glycalproteina itax hrrondcsct7iUcd~ Ucy[c('.'n~~tllu and Itciti (191S-t)', but~ t'hc, ltrrltoncdcruluouof'ccllscout;tiitiitg ttctttrad qiucxtln•atoiir Itas not bccnreltortcd ltrtviott<1ys. AftercXjtootn~c t'o tobaccasmola•, citltcr tcitlL ar, tt~ititout tdtc ntdditittu of i".IIK)O tothctrtltaeco, tht rc tauh;t shiftto ccllslru)ducihg actd,g:vooltcotciit: tltc (Ifoth~il)u- tiouthrough tl)c llt oticliiai trcc of tt ltcs ofl;u td glvcolnrotcin retu;tiitcdtllc,.u)uaa tfiut fituncl iui cunttol auiniutlly, nlthoti,lititcrotwtauu inct•oaso in colla.ucrc•tiiiosulltltautuvin, lmrticul, rly iut6c tr;tcltca~, andfctr cellv,coutaincd..i;tlidaso.vcnsitivc siadonrttciir+tlanobnt tllixu'itsnott'ttsa;tllt•irt CainltinutioatOritlltllerosistant fitrnr. '['Li.cotuhiit.tzion of .iulatnncinSwithiir a ccll rcSultcdl iir tc, grtruter uumLcrof litrr~^ "' ecllw conhtiningnciil glycoproteiit in tlta esposcd th;ut iir tltoeontrole nniinul.. Prax•iouat•; hi tacltcnut tlly`u..c„edvltiftin acidolyooltratcin h+talicen rcportrd only for thc ccll patpul;ttinu; hcra:it 11;tvLcurthossihlctounulvsc tdtc cltnuoeu-itliiua:)inglc ccll; Oidy' cort;tin combiitatiornsofglycol>rot'cin +trcfouucd. 11'ltcu Itcutral glycopratcitr iv ibund tcith, ncid oly*oollrotcia, tllcacidl gly-coprot'rin i.v at thta cell apex; wllau eialidlus© wcnaitico nnd sialii3use rcsistantl furmsarotomcthcr:, e
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C'.~ i~~NTlAL CELLS IN MITOSIS The', number of cellk~s in mitosis for: the: three: groups: of animals is givenn in.Table III. At each~ of thee threee tracheal.levels~, in groups~~. I~ and 2~ the~ number~~r of cells ~. in mitosis: was~s found to ~be increased when~ comparedd withh than, of the controls, but the rtsire~. ut-af irarioCocm¢ per~~ 1,000 ,Cell s for rhe, T'hceeAnimaf GYoups ~, ' C .ntrol Givuv'. Growp J .. Gioup 2 T 1 tra.h 027t~ 2':943(P'<.005) 6650 (P < 00 Loper~~ d~ .. 0I~&341 ~ 7310+"P<a 3500.(P'< 0-02) \.,ddla rd .. 0`66F ~ 6250'P <.0F02?i 2930 Inirer,or ~mrd~ I.5'al ~ 6120;P<0:Oi5)~ 2 500 Aa,al Drnnchl,al path.vay~. 1-I66: I 0875 1 167' hsertal6oonichial ~ ~ pa,h..aY~ .. .. . I-900: 7~916~. ~ 1~625 ~~.11~000'~ 1 166'. 7 583 Onophag.us~~.~. .. ~~ 12-330: i ~32~~325~ 14 166. • Value of P'qi.ven onlv where. cowne in.ezposed lanimalswaa sigpuficanr-hencom-pared v:rtls' cort_l an,mals. increase.in~,group 1 wass higher than.that~in group:2~. At each level the~e mitotic'c count was~~.lower'in~ group 2 than.in~ group. 1, but art:no~ single level did.this'achieve significance: When all values were'.taken~~in.combination PMO:had caused a significantt reduction~ in~ celll division. In the alveolar, region group 2 was not different, from the control5' but the mitotic number'.in~groupar was~~.higher, although not' significantly~ so:. Thee oesophageal countt showed a~~ pro- gressivee increase~.from the~, controls~~.tos group. 2to'.group: J'„ butt these~ ditTerencrsl were also nott significant. I~rseems'~.thattobacco alone~led to:failure'to:gain weight:and to an.n increase in goblet cells, cells'~s in mitos:is;, and epitheiiall thickness. PMO gave~e completee protection~ againsn the increase~ in goblet cells, par[iallprotection.against.the increase'ine both, number of~cellk'f in.mitosis'n and epithelial thickness, and~had,no~~ effect on,the slower weight gain,, ,. Di's~cussiatu For'~ the~~e first time~e ann effective meanss of protection has~ been'n foundd against some~: of~ the changess produced in broatchiall e'~pithelium~by~tobacco smoke~. Inithis', the fitst.dhrtailedlquantifi- cation~of mitotic numbe:rs~in rat.lung after the application of~f tobacco smoke,, the~e increase~~e of cells~ im mitosis~~ wass found in.n largee airways-thee trachea~a and main bronchi-and nort in the~e intrapultnonary.ainvays'. In~the~~.alveolar.region there.wase no sig-~~ nificanr. d:ifference~e between any~of the~e groups~ investigated, al- though the animals~expased to tobacco~.a~~.lone'.showed some~e inerease~in'cells~inlmitosis. With light microscopy'inis'y possible~e to' identify dividing', epithelial cells~s inn the~ airways;, electronn microscopy~ is: necessary to identify ce11s~~ in the~e alveolar wall. Itv thee airwayss after'exposurer to~o sulphur dioxide iv has been. 144 mitotic c:ount' is'~not~necess'arilys raised. It.is't alsoo induced by~ thes parenteral administration of~ isopremaline~ and pilocarpine (iSturgCSs, 1970; Sturgessanl 1972)-that is;.experime,nt- ally induced by'irritation.or as~ a~a result ofl a~ pharmacological effect'. Histochemical analysi5'Jones~er~a1:,,1972)~.hasshown that' inn addition toi the~e increase in~ goblet cells~ tobacco~o produces~~s a change:in the distribution of~acidl glycoprotein throughoutthe goblet celll population. The failure' of~animals~~ exposedl to'~ tobaeco: smoke to~o gain weight' was~~ investigated' tiy~ Elson andi Passey' (1963). Theyy found a~ similar effeett from nicotine~ even, without tobacco smoke: L3art alll these changes~ resulting~~ ftomm the' effect' of tobacco smoke:were modified.by~PMO~~to the~sa~~.me.extent, confirming~~ thatt variaus~~ mechanismss are' concemed~ in~ their production, either singly, or in~ combination. W'hile PMD~O does~s not prevenrt the~metabolic:-mediated~ or nicotine.-mediated~d effe~ctin.completely, prevented an increase~in ~.gobleceells:. If there Is~ a.single~: cause'~e of ~ mitotic increase:it~ma~.ye be.modified by'PlvtO~.; if, ass seems~ likely, ar'.leas:t:two factors are operating;:one peculiar to rtobacco~smoke, thee other' non-specific, then itt may~ bee th3t~ onlyy one~e iss sus~-~ ceptible. In view~of~the~suppre:ssion'of goblet cell~increase itt may'be~that it' is~ the~e non-specific~ effect which is susceptible~. But until.the~effectof PIWtO~.on the epitHelial~response to other irritants~~s hass been foldowedd this~ is not certain. The preliminary~res:ults~of the histochemical.studies'l indicate: thattheeffect:of P.:FdO~.does not prevenradl effeeas~of~tobaccb smoke: on gobler, cells. For example, the: intracellular shift: in type: of acid glycoprotein occurs although gob!en cell'~~ increase~: is~suppressed:. This~is~.beinganalvsed.further, as is~the effect'of' PMO ~~ on~ the~e changes p.roduced I by~ tobacco ~smoke~. in, the'~e early, stage~of~exposure. In the'~e airways the: influence~ of P.'vtO ion ~. the'ciliostatic effect of:'tobaeco:s:moke has tieen~incestigated by~administering:P.ti4O mixed,with the:tobacco in~the:ciga:rerte~~.(Dalhamn and.Ryland:er, 1971.;~~and alsa,by'oral.administrauoni of oxolamine:citratey the~: parent compuund of PMO (Da:lhamnl 1966j. By~both routess a~a protective~~e effect'.was~~shown, suggesting: that.these~.compounds modifyy the tis'~sue not' the tobacco smoke. This substance justifies~~ fur2her st'udy~ as a'.possible additive~ to tobacco, bur whethei'orr norr it ultimately~ proves ~~.ofl va'lue. for ~ this~ purpose it~t ddaes permit a meare~: etioctiveanalysis~e of the~ damage done to~.airway epithelium,by.tobaceosmoke: W'e: aree g:ratefuil to, Professor Bernard Be,r)amn~ for advice wnhi the.s!atiitioallanal.vsi+, andlto~.ttie. Lorillard~Gamp'any> whoo pro,idedl thee ci4arette:s. Prefe»oc. T. Syminvton andd tne late~. ProfP.svar R:, Passey Fimalv~allowed'us.to~.use the~.smoF9mg m.achines in' Che,te',r~ Beauv R~,-:rch~ Inse~[ute.. This~ workk was supported by grants~~, from thC'~. Medical Research Council andd the~ Kamlmska Instiaute,. S'to,k hoim. shown (Lambb and Reidj. 19ti8) tharin the firsn twoo days epi- References thelial ulceration.was~much more severe than laten.and.that the'e associated.d healing le~d: to~ a great increase~ in cells~~s in division. Preliminary analysis~ of~ the number of'~ cells in mitosis~~s after short-terml e~~xposuree to tobacco: smoke has shownn a similar' e~ffeet~(Pi.Bolduc, unpublishedd obse~rvations:). Since~: healing:is~ usuallycomplete:w-ithin 14~~days~(iWilhelm, 1953)andah'e.oxperi- me'~nt described here:was~o£ stx~weeks' duration the tarlir+~acute~y d9mage is unlikely'to havebeen~ the c:ause'of~, thee increase:. In~n the large~r airways', during later weeks~~ of~f expasurce to sulphur dl'oxide the mitotic count w•as.some~what.raised, suggesting:s~omeg c'~ontinuing~damage. It:may~be'that~.such'aisituaoon occurs~~.a'lso~s after exposure to tobacco:smoke, but it~is likely that theree is;.inl addition, some:e4fect~on mitosis peculiar, to:tobaceo smoke;.This~ is: suggested by~the strtking:differenee in the number.of'~cells.in' mitosis arising~from exposure~, to.differenutyPes) of~tobaceo al- though goblet celll increasee was s'imilar (Lamb and Reid, 1965):~ A: vartety, of irrttantss have been shown~to.produce~n an'iitcrease in goblet~cells:~.This increase is~seen~in epithelium where~the~ Dzlh'-, T. (1111r. . A~.nenrUn Rrr,~.:r<~ ~nd'Rlrpnuemv'Ddua,e,, 9'i; ~:.R p. tt ~ th .I ~tcs~ofH ~ Dalh n,T.,a. diR'19 u1. R (1171 L,paala. Un vc'rs~tv. an.d Nuro6nska. I s :.a.ndi,he Dcparrr-,rnc~ Pf Fnsir„n~nr~~t:ditvq.ie~ne. ~'atwnalllo~tt teatPu.bhelle~alth,Sao~~kRoltln, S d.cu. Els L. A~,.a d t'assev,~Rl D: (19t,91:. A.uol tln,o~ lnrereunom~d;s Gdntra Cumc.unr~, 19, 7[5, ~ hreeman, G:,.an'J 1lavdom, G. R. (19ba'.. A*rh'rt- fh--nr,<oral~H.olch', Ntl"5 d,: d, L. (1971)- li:u„h' 7ournul' 4 Ir.Jwenal Jon . R Flaee , ier . .4 ~-, arud R9, SS1_k, in9. Jon R~- IY,I,1 1_ and R d U: l o'~, ' I p. C r n. Larno~.I).,~nJL.7- n,il, (torh.i,,, ... '13l<trnmlo4y.96, 97. La b U. rrd R d " f uh tP d / r,,s,rvaf I I 33 . ,S1awd sl~rv-T.......... ~ t., il I , 1'.., ~,nd L3 ~, t). I~I~ 7,. Ih 1~ -•',+W'r~ nJ'~n~l.~e nut~.ti..n~n~*,n.~n ,~n~lnh,nlyd 1 a.~rcle.; ed- W. li.: sCalEoni, I. I, ry,. ~ 1 d.an~, U ~ Flros-. a ~ R .~ (19T1l : Pa '; R.D., fi ~. k r; SY u.~~rhrr.k-Sm,th, D., nd Jones. 1D 6. SI. 1 1 1 19i ~ar.d . I 6 1~ Rc i 1..'(1970 . 1 h of t ~ Szu ges; J-/J"71he~.C....r,l ol IFe~nr.,nch,a~,l ~tu C:Inn.1s~1.nJ [heu s ~ i n. 1 5.1)~ t,,,d~ t St, I-oa~nJlk S I. 1 ; I cp ' tS'r~qnr; .Vt /lv . 5 hn,u, d t rr~~.o~~~ , om
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raimprt:; CO:BL15'0 C:f.L GI:C('<)I'ROTI;]S AND TIi'.YCIII•::1i, CL.Y\U, IR'PI:It'1'6(li'IIY. 239 -NtmTtuA. S[.. & . T.ratt.nNn; C.,P:,(1Qt{(i) 1Ci.ulinant'ngraphic: Comlutri5„n of'.t.ln•. U)Itnko of. GAhrl;iso-Ila ' uud ( Hto;,>c~ll~' in I lw Gull;i I,*i,gi,n of' V'itriuusCi•11..ticcrctinK, AI}'onpn,winsnr Afitreilto;l~.~~treluu'ido5. J. Cr}l'Binl!, 30, 137. 8fi,ctutr:SK, .1. (1!l;h)'I'hrC«mtrol aft'dte Itronchial Gliotd.I aud tJirir Socrotion. Pltil): L;on;lon Univer.ity. STtnti:~s,.1: & R'r:u1i L. (1973) Ilhpct~UrMthhY ofChlllo,t Ctsll_, and 4ulhnucrr~nl CLundw iitthc R~at'll;iahcnbronclii;til T'rce Causrd byINoPrrnalineorPilncarqiinc: Irtcludiity;Citmhnrison with Cltangew in~ tha Pancreas, Salivnry, Glandsanti, Ileart', lnPro[iaratii>n. \1'ticlt, R„ Hr:ttvcot-tcs, A. JILI , IaEInt.oNn, C.,P: (190;/)Rarli;)atrtographic Vi~unli~nt~ion of'' th;, ltteorpnraitiouofGitlltclox;-11I andl Jlunuosc+z11 lit,•ltat.~ ThYra,i;l iie t^ithu 12clatiinutn tlu'Stag*c,u of,'1'Jlyroi;loluilin NYndhc,is, J~ Ccdl. Riul., 43, 2,`{ll. \1•iumtm, ]t. .lf. (1;17t~,) 1\ Cigarottc Smokiug \litichine tbr: Anitnal P•.s)terimcnts. I iG, Pract., 21, u,41. u1Q :tY 7 inn -u 'ial iiilv ~1a1 i,ur
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8993 REG?r lTI0:1 OF'TPIE SECRE'1'ORY CYCLES OF :.NJC0DS A27D SERDuN Cs:LLS I IN~ '1"i3E~~ HUMA ~ ~ 3nC:IDHiAL. G~i 4i+Di Step}:en Coles Departaent of Experimental Pathclc~• Cardiatnoracic.Inst.i.tute„ Brompton Hosnital Fulhanm Road, Landbn„ SW3 6i:U.Y.. Thee mucincomponent of `iumai bronc.hi al secret.i~cns consists • of gly.coproteins of'h_gh.molecular •aeignt, syr.theai'.sed.and se.c.reted! bothh byy gpb:'iett eelic„ nrA enTi ini t!ie ai~rwoy epit:eliure,l and.mucous:and.s:e.rousd cells of.thef brcnciahal glands. t-lucus hy,persecretion i.n chronic bror.c_.itin isaFara:ctaricaed!byan inc,reaseinthe numberof goollet: celis and in *.:•:e si:.eand rate of'secretion of't'hebronchiali glanda (Reid„ li)j», SCurCassac9. Reid, 1972a)',. N.any~ techni.:iuess thst have. Ueen~ used~ to~ stu.l/~ t`le: controll of tironehial mucus aecretion havPe empioyede cae n..ati c:r ;.'~f a e.gr.~cr:t~ of the: trachea.a of anaesthet:ijsedd animals~~.. Ear 1y~ 'u=is of' this~c type ( Flor:ey~,. ett ad., 1952; .~Pe.rry~ an-1. Soy . 1911) •ls~i~.r.~g ..*cer cats~ or: r.abbi:ts, inv¢lved r~t asore.^ect of '.he vo:i~.:.-;e o~ob:on. Yia.l secretions or. '~respiratoryy tract.flui.d." n,rodocediin~r~e~sp.cnse~to~i nervouss or pharmacologi~caL st'imuli, °ecently~, a ~ n"or= acc_nrate rnethodd has~ b~een~n descrice-dd i.n.vhich~ tt.e ser:retion~ f~ '~1~50;, -labFl.ted~d tracheai' glycoprotein~s uas r:eacure~~;d in vi.vo~ in~ ac -- t:.eti.eed ca.t.s~ (Gallagl:e:r, et aZ'., 1J',5). Our orann studiesi.n t::_s: field h_s s beencot:c.~~rnod . wst:i gai~r.ing, ann undbrstar.di:ngg of taefa .;ors .._ trel_.i' g thesycthesi:s~ and secretion~ of' glyco:prctei.^.sbythemt:c~i .ec.rrrO nE,-. cells bOUhh in the: nornai ar.d di.seasedd auman r.e' pi.ra'.cr;/tr°.c:t. P.sih vivoe>.periments off the ty,pedbser'_be:i aoovearee not. ..o.ci:,l=in ma.^i, ve have dLvelored aa combined o:rCa..c cu_turea.,e oucrac'imC ^ ti.^ techni.quewhich h -:as alloved a.^.analy,sisto e . Tau- both ftn_secretoryeycles of'mucousand sencus.cellsc aerl.;;ome :c:f thee factors: controLli.ng: thee rats of'glyccprote. ,~___. _.,:, by these. ii ~!C~~_ ~~ ~~L~ , ® ® ® ©
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r,°~lac ~'.J~i~ai~iA~I i a3 " IL...I(t\Ev„1'. Itltt.l)C'c'SYl)JG. ItbllllD iittlr'el;uul',tlt'rrn~)tosinr to 1'311), '1'Ilun itieuultDsce ii)itll'tt in 14ta Iraollt.rntliu.liiintlus to "(iunl nuticit,cli4tintlic sitrGicc tnts 1rc'.at1let' in 11ic I'\[t)" Ilrotccth,il „aniin;il.., u~hioh soe•nix Ittv°ndoxirtl sinuc tltc off'i'ct' on satrGtcc c)iitltcliiuuof tlicUJ'1O tvu.to ItrG'vcnt ;in}`incrcasriu ~oltlct crllltnuttlicr, ;dtltoii;;h1in rcrt,tiirt\ (wwof gttltlrt ccll tltc rolhutc otlintr;trolInl;u ,ourt'tiontcaa inorC,ucrli .Sxinii,llt. cc)tLututiinr mieht llctltnt cli,tontlc'cl ecllY arc tHont;cl.'cw usourcca of aontittsrin); suintul,ttiuu. 'I'hc rrcent,dcmonstratiot of intru-cliitllcllnl uorn'c;t.wnsiulthc rttt cxtrat)totlhtomry ;tirrcavs, both scnsorl'+tttd motor; w:dcce titiy stit;;cstion ntm•cr.c;iuuunhlc (Jitffrc}';tutl 13oid, 1!)72j, 1Vuut'c tt'atlcfitl t'v 1[h'll: Rbtitv, Dejt,utiuicut of ltirtltll, y:+ics, Iitz;Glutc of (':utccr lZuscurait, Sttra'or, for ;tu;tl1'sisof ciq,nrttha; to A[isaG. LeLatllour for thc dittgri;uns;tnd toPhufessorl3. 13eujmttiitfor stati.~ticul uda-icc. 11'curu;tlsogr~atcfitl to I'rufe.soc 'I'. I9;lllimmm„ 1)cpurttnout of' Hygiatc, li}tlimla Uitivrraity,, ancl tlltc '. Rc.rtrtth l)ivi>,ioatof I.orillhrd,('htulton)- for the wttl)Plv 'of cigarcttc,. ']'Itistt~orla. wts sul>Iwrtctl liY tlto\leclirtl R'cse;trch ('buncil and thc A;rtiou,tl C'olti 13o;rd. I'.It. n'as sctltpo't'etl liy tfic lZ. Sattuucl \[hLatu~hlin~liotutrllttion, 'foronto: Ha'CFI.Rti\'CI';5' ~ lttuttc,.N. 11. & H. ti. (')SliI)AA"i'rt9irocctr )IcutL,runa' StuLili'i.;niim'L}'C<ontltamnd Ill. letrillvtt Iti•..e'vch Cont'r•r, C.yl:1. 1'. I:onillarilCo. lt;.,l.t..c'r,t\i~ It'. Alhw<-tm,ur.s:,D' (;I!)(Sd)pErN'thruo\'t'c 11ttnbrauv St+tl,idir.;niunu anil,l'Potein ltindinrol"orno :1nti-iutlnnintttt'nt;VDiiug.etnd of llcoxt'cholic:lcid, Binclrrrrr. /?Lnrarum., 1.& 171'ly, Dar.n.tMN. '1'. SRst.t~nFS¢, L. F2', (I!l, '1)LiSAnctiun of Cignre•tt'r Pinul4eCillothsicitv, Itv'Crrtnin'fitktacu :ldditikns. :1 m:Jlrr•. rri.'lt. l)la.,.103! 8:ra. l:r:aos. L.:A, A~ I. c'SwV. KI 1). j !1(i3).13iOclirmicn.l'.Efl-nct, of'fol"tcru.`inuolcr;tnd,-Nicutiitt+llnlutl.ttiatni, .-Irlnl'rt. iuL C'rrvrnr, 1B, 7,I:i. di;rrr:nt'. I'. A Raatt: I_ (;I!177{)~ Iutr,t-cpitlluHilll Scrvos in _l'orntnl Itat _luru~u)s-u (,}timttitatii.o. 1•:Ircnunmicro..k•r,liir. Stud1-. J'. aurn/..2. 11-1:. ,lb,m:s. It.. 13in.Urr, R. G Htuu, l.. (1972) Piutectlion of Itat l3runchiitllN;lutholiiun:1'i_:airi•t 'foliaac',r ~~ntulcc. lir rrrrd, . J., ii„14'?; Jomtis, R. &, ltiatu. L.,(1tl;3dr).'flicl'Cllrct. of ftlll on:l1cintt 13Vnc titainirtq,of 1':jtithrlinl ~ AoirL. (71Ycnltroriein.v 1. tiinluutuoinrrtud. Jullt6iunntoiny(,~iu~l~-. orr in. Sim('Ic Cumhinutioo). Il'.i.a~,Thrni.. J'.. 5, !1. JoNts. It. ,l I1'rau; L. (;I!IFCIr) Thc lsil-cct of O11 on <11eian I31iicStuining, uf, l:jlitholiui -:1ci(1 GIycolirirtciit~ 11. Flurnan ]ti-oncltiul S~ulrotuo,is:uU(:IanrL Llusln<'hrm. J., 3; 1!1. LAMnti 1)I, G ILvuu. L. (I116S) Jlitntic Rut'rw, Cnhlet~ Ccll lncrca"cana11 fiistue:homi"al Ci'han,r.:in AIliruw in Kat 13rnnrliiitllh:pithcaiuut7)hrin7, l:cllu.+ura to.:?ulpltur Uirraiilh:. .l. l'n!/r. Rrrr.l., 9Gi .97:, L.umo,, 11). A' Itrun. 1.. (1!)(;II) (I',Idm: Ccll li~rren.c in Rht Rinnrhinl l:j(idhrliu:n nftrr I:x(t~o.urr tir('i!inrtlc nnd Ci,_un'fulsrnro lniuko_ /ir'.: uscrl,.l., i', :f3'. i.,tM:, N.,,C,cun, IL. UTiutn.l'n:.aituun~t. L. It. ,CCountir.\':,(:. C. (1964) On tlic Sitc ufl Nlill':ttioo nf('olrniic CoWht .L. Crl1Jli,,t, 21. a:iU: 3fi'CAuTna. C. fi liSaoi I., (:!)I;O:loitl ]lair,t(tull~s.urhiuitlr in tlio Iti-,mahi;ti'fn•cin thc\luus,~nndll:;tt(tiiul~nnu~•.iii unrl.ti;rllihatoJ. (jrurra. J:,riryi. Sll. .l'lizt'.vttutt. l'_ C Nhx.vt. ti, ('1!II;S))Strrl,ilization of 1-:i(tttlloc.vtc .llian6ranr Lt-Son-..turoid. _Aotti-iutiuniiustnrn-I)rJ. Pbnr.rn. h'lrrrr.rnuc. 21, 3°_7. 11CZrnuntv L'., ti'iti.rn. S. C 1:cMA[tta. At. (197U)\Ibalnoflt;ihtli.tn~ :lctiOW of\on- stt tM irl :1uti titfLuum+tfiut'~- 1)i•u ooT 1?i'.~'tftrucy'tr;Jlc.tttlhotae. /tiuohew. L'Irrrrrrurc., 19 227.
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C C "A'az6~ r"~~'LA L ~ UQItI.I•:'.l' CI•:lil. (iLYlYlI'HOiI'EIVAND't"ItA(JIII{.1L GILVNU IIIVI'I:ICI'Itt)1'71Y 217 tht rnsi"t;tnt fJt'nt is ttl tItt t•c.lli;tltcx nntl ulicu ,i;tliida.<v rr.vis(nntl.tii,tloniuriu and ,ulld huutuvin nrotb6ctlicr, llicsttllllnnnuciit isut~ tllnccIl +ihe\. In rc~pir+ltur,)•, _uLlct ccll,tliouctctY)toof acid rlii-t•olu'otoin upJta;u -sliisU Itt; thccclllulm"s„tlirtt the ;ranulrv,incrca,c innuunbcr sotlutt ultiutulcllttlie cull ckiun};c.v ill tvllo:'Chcllrescnt5tudit•xthusu iitdicatctltat tllc+rddition of~acitl radiclc,to the n(? coprotcin t,tlccslilitcc intltc apic;tl rociou- Ii[osccVcr, the use ofautoiatliuorrtldiytnclclbctrontnitToIcolt~ stt,~~cststhutfartltcaoblctccllsitisintlioGolgialilutrutbta tlt;tttcrmiitad sugars,(\ctura and Lebloud, I966;11"1n111, Hct:vcovicsand!Lclifontl, 111G9)and'aullthntb ([.ancrtnl., 1964;Scutraand Lehlotld„ 11)G1;) are +tdtlt•.d. In, the airu;tn' goblbt'ccll it' is in tlto ;tltic+tl t•.cgiouAllat tlte,granulcybcroiue coutluon! (dclhh'c1'„1lorsonat contiuunic;ttion)I xndit mat- hethat tdlangcsbcfhre tliscGurgc are rusl)on•iblc for converting sialic acid to the cnzYntc rc,i,t:tnt furnt,uud licrhalp5i for ntodifving thcstillihutc, so thatlitisonlvnttile altcxt4lut, thcsetwobecotncsu.cchtiblc tostaiiline by the histoclictttical ticcltni~lucs~uso,tl hcro: Iir thc tutimalticclrosrd to tobacco - PJ'I(9„ sonttt r;oLlctccll.tiincludidl niora rivutulcs ofttcitlg(i-coltroteiu than iucit9tct' the control tutint;ilyorthc :tnituals c\llovctl totrtLacco nVonc. It secm,tlrtt P\I01 doe.y ttot Itrot-cnt unych:ntgc iyt the nnturcof`titcglYcoluxotoin synthesized byt11cgoLlct cell.v Lut, Itrcvcntv, or ltau•rtiallrsullin•t.,acsLtliedii>chttr"coftltcsoct•cton-1r,tantlC,. 'I'hisan~r~~~a.et~ltatl clt;tn ill the tt,-pe of~lYaoltrotrin ianotlt9tc rcsultofinotv:tsa=d secretion from the cell. '.I'lic rc,tnonfor tdtisI'\T()~cthcctixnot clcnr. Anumltct• of+tnti-inflitininalot•r +tgrntsItncc Uc.cnaiotnt toincro+t,c ninuil~r,iuout';tl,ilit v: C•htcuvsc, 16ist•,iani and l'iccinclli (19GJ) 1111 tl3lii.u.lliroa and N,i1:ai(~i19629); sttula'ing t,ho Itl!t, iun ntotnlLr.utcuf cr.\tltrooYtca, huveticniun, lratctd inarx•nav1 rc.,ixt:utcr to Ivltultmia ll;uiutolv..,i., and \[izu.,ltitnn, lailt+ti autl 1'.iuu:ntr:r (IIU77U) have tlintncidiu,tnti-inll~nutnuturttdrug.q,nrlr is indonictiiuriit rtoA llliruYIl)uluzuno hat•ctvaaUilir,inr,of}rct out cc•II mctcUr,tucluotcin,•. Broxn ind 'I'oti-,(ItJ71) Ituvcdentoustr,tted tltat Y1I0;tYhasiacontpottd, al,ocoufr,-sst.eLilig~ on tlincrvtiicotl"tontcntUrrtno:Ltin+t}•lic'uppo"cd that ii7ritation rt.usntnt•usdi.ch,rrgc frotu tJic cclli,nd~ tcitllinoruia,a•d titiiinulu:, iitrt'c•.uos.,t'nbhc.;i.s;u;d cdiscltnrosoth,tt c•t.ll turtwxcr is rttii:cd. Ifl:ut au't,ut were to protcctaruinst di.<charac Ity ,tahiliviu~f thcmcinLrunoofcit.ltcr the rt•Il ot•ittstr,uoilcs, a cclltnigllt maint.6111-\ -ntlu•siti, ot•.et•cniiucnoasuit„a lurgcr umoutit of.ccrn•tiou hu•iugretuinc•rl witihiirilict•cllj \1.hit6 NVouitl cX)il&in tJle incrcnsc iuitltc..ccrctot.vltrodhct fitttndttithiu tltec•clli, oftlioanint,tlArcceit•iug I1J'I40. It wou!li socnrthntitis only in tliu:113l,o.alii-cccllh,ttliu& tlti.voircur", tU,,tn is, ill tlto.c ccllk ~9-nt'dtrsizitt;; acid rlcc•oltrutcin. 'llliaad<ditinit of' 1'llO tcoitlll aoenw 14otlt~ tit prm-omt,t nun-sccrctbrt oell fi•oiW (1drecliq)iu~ intonsct•rct0r}' cc.lli +tnttG.wcenu'nge divclutrp;e from tlto,eccllsln•otlucin};oulYacidgIycoln'otcinl Icudingtwrctontii)itIII'tI1Pir 'ocrGtioll. Trnc/[rrrd sttb)mnroeml,y/awlsIt utavnot Lc.vr)n•i,iug, thatosno,urc to toLaccosmolcc ltrudtucslin l~crtruldn ofltltu ~ttLinuoo.:;t1 g)hntl., thr.ghuxl ~'olttnte liciittt iucrc,t~cd ,istcrll its tlti~ aca•rn~o diniuctrr of,toiiitt.;uul lltmcn itndlof the indii.•itluul coll. WIwt i.v.an-poi>iti_ i.,tltnt tilir +tddltiunuf1'1lO totliu tcolmct•o Irtl to: rwnirr im•r....... ill _Iautl .izcnltltoni;;h utinii.+, Itnnon +uul r'll tli;nn ct ,tya uwo ..iiniliu• tw tin-v ILuucl' +itlrr cxliu.;tu•otolulincco sntolcc+tlone, auoocstingtltitt cell tuuitilllicat.iuntt~it,"rrtttnr
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U!if I~~a1C~i ~/ ,L 158' COLES' ( S i RE . ^_ablee li•. Changesiln Di.^<ensionss and Grain~ Concent'rationof prr Mucous. Cel!1's Duringg. Stages i.n. Tt:eir Secretory Cyclle. di $e Grain level St.ge of Cell' Secretory cy^_ie heightt mass Gtaia densit, it ea (urm)('un2')' (~e/G) in Sr A Sy,nthesis 16.2 179 (0.4)~ (:3!.2)' OsG>6 (0.o04) B: Syntheois and 16.9 128' 0..12°, a A^_cu.aulation(:0..<) (',3,6) (O.C0f) pr r.e .. Pre-dicc',7r e 10.1 48' 0.171. p' (0.3) (,3.1) (0.003) y,rF D Di sc .arge 8.2 21 0.1'!+E CF (0.3) (1.6) (0.002). di E f Mueos cellsIab:elL.ed.with~ 33-threani.ne. Values are neans with S.c.t4. in pa_rentFiesis. t: icr a' T'r,ee r:.orpho'_b/ of the secretc_:•/ efe?:es~ af mu^¢us and. oero•.is~ ce11.s~ tY.us~ rpears to ~differ... Mtrcaus~,cell. _,_ tc alt' r_tely ~ accu• ulots ~. . 1 d._s,har; ~. se:: _tcr'y macrcrc 1... ules .rhi'~,D^. ._erous cealis have~e nc~o dist._~,ac:t~ priases cf ac^_ur..ula:.ion an3i cisc!;arC,=~. EF:'ECI oF °F°ACy'1'.A^_riD'•9II'.LC~ AGc_::o . Inne:rvatio^ of t`:e br ra'.`.i~al. glands'tiy~narasy ^~rat*;e"~~.i.c ,erves~ has.been i.dentifiea.by . li.ah~(El:t aa, 1963, ~. Spe...er an~' 19'64)I and.electrc~n .. ..copi^~stLd~.ies (~3t s.., et~a1'_., 1194 Meyric:t~ and. F2id~„ 19.',C).. ncrea:'ed dis:_i~.arge of ~:rcne::ia:'! cu^~.:c'~: after~r vagall ttr:~.:l._tio:~ or~~ a,.::.inist.rst_.^n of'i oar.a .~.. .'tl'•c ~.i':-.e:tic~. ager.ts Nas be•,n zoc•_. .n -x:ous sFecie; ;F,bn^y, et a1., 1931,~ Grillagr;er~„ et a.1~..,. 19'i'7~). Parasymrats.cmi,et_i^_ ngentsincrease tNei ser_r tor_ index (:5:.) af mucous an1d serumcelllc o.fthehur.carf brar c^ia< gla:::" •ahil'c atropinecause.se a.red:ction ia.secretory rate.(Stur,ess.and P.ei.d, 1972b) . T'he use od' .`.hee pullsc-c}:~oce sys:tem :;_.. _•^•able.dd us~ t.:~ ar.~a:ly~s:e mare~ preciisely tHe~ Ff.fec.t cf parasyat}:or~rnetic aPRnCs~~ onn secretcry,~ ratle andi precorccr~ incor o. ati~s:. onto glly.coproteia.~. Firam:' the r;esul t~~ pr .serntet ~ nl_r'_a 2It. _n' oe seen that ~ methaaholine c.aus:es~ an~ irnc a~e _., 5I mu.co ~.u ral•.:e~s cnl.y •,!ien ad~ded after t'ne puIlse~,..in1 ticg .ctlat.i'ts~ pr_nciFaD action~is: t.o 8- d' C. , ,4 M. P
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! !' o' !I9y f~ 'ti 111 i ?~ i. ~ ' ~JYk€~!I I~~ {, Y1 S.COLES REGULLYTIONOFTHE:SfCRETORYCYCLESOF'MUCUSIANDSEROUH.CELLS, 1'59 ;rcrnote discharge., Atropine aetagcniises the, eoethactroline-induel ie discharge stimulation but also causes a rediction in basal secretcr,', rate.when.add^.d.alone.inorgan culture, i.ndicating:that it cuay,antagonise.endngeaous:acetylchcli:nepresenty wi.thinthe explants. '"hiss is. F^cbablesi.^.ce the acetylotol.i'ne.s:teraseinhibitorphysostygn:i~ne c:ausesan incr=as.ebothin SI mucous and. - SI sercus values„ an effzct,antagenised by atropine. erves f, The methacholine-i'n3uced!increase in SI values does not _nroduce a correspon3ing increase in the incorporation of lab•'_led precursors i.nto.intracellular glycoproteins ~T'ablle. 2). Atropihe.,. however, re3uces.the incorporation of precursor;boa:^..in~the presence andd absence of n:ett:aenolin e.. I.tseemst rrcbaclee that, while an i~ncreasein thee rate.of'e dischargedbes:not cause:a change in t'iierateof glycanrcteinsynt.hesis, inhil, :it_`.an! cf'f disciiargee wit'h~ atrepi~nEe d_rv._.reas, . s,a::theticc rat rres:': ^,.ab.l;;{as aa fee3-bactresponse to lossof se^rato.ryy activity.The:organ cult'vretec`iniqa.ee hass ret yet enatled an analysis: too benade ¢f' the: effect.ofmet a_aiaiice.and at::.cpine.on thee secretory rate of gqbl=teells altoocg":.an incor..cration study has been carriedd out ('~alts az:d . i?.,i.l, :!76:)i., ..r_.,,:er :ir•,_g af^~ctsthc; incorporzt'ianicf' nrr. ...,:;rs int¢: g b.l._t. ee'~: glycopr .'cins. orhich pravi,°.hs:,. -_ -vt,, in•-0ir(--t: ev_.._ nc:_ t"na*t gobl!et ._~_ secret.i!orr r^sy.,,_Le uc3,:rp s.. -- e, -:eti^: con^.ra1 desr.it.e thee cresence ofmot~r nerves wi tz. the air:ra? ._...___..,.. 0Rhldi!n, 1')ho.;. JAffe.ry and .._ d, 1c,;3'). T'abl!e. 2.~_. F'ffectt of' Par3 cym_,:at. i~i~!c,.t!i.c Agents on SFcr_tory ~ I~.ndex (Z1) and Grain . Dens~::ty,~~ ofl"tucous~~. Cellls r.•.:.cousGrain. iecslyy (:g/G!) No .aro-~ir.e At,roniae No atropi :e Atr~)pi::e =us tic ~ Control 01.26 ' 0.13**' 0.'i21 0'.092**" (0 1.a3~)~ (o~.03 !) (!0~.a,i' ~) ~ (.0.002~), Methacholine 0.30 0.18* 0.129 0.7°~'**' (sI)~ +'~ P~ul~s~e~ (!a1.o2) ('~0~0a~) (!0~.a03)' (:0~.aG2~), ` Mlethacholir.e O.u3*"*' ' 0.33' 0.126 0.103** 'eid„ I post:-Pulse~: (o.a3!) (0.02) W i.v0l3): (0.0C3~)i e C P'nysostyQ::ine 0'.GG*** 0.32 '. nnst.-PP.1 s~~a, (If7i_(`?~I ('~,), _(1~~ ~~) Mean values are given '.n:tn S.1'.I:. ini par-th -sis, P values where signifieartly different fr:)m cor.trol (no atropine) * P'<, 01.05:;, *% P< C~.01;, r.r ?< OL'10]
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231), ItL.111V1^:.. P. IInI,IOLi1 .ANl) L. ItEa1) ~giryrt3T1~'~ +ivc rtft hr .rt+rt't oo't'Ina.v.,iltt lit, gnl>It•I 1•rlI.nnll tlttr tYl>euf gIY7•u)Irotciit 1)rc.wrnt., and tcitlt tlYr;h},(Il,rtrol7lLn' IttlIht• trarllcul "I:totd. .\tTI{Iti.tL A\ I) \I liTlfOl>5 Hl,lk varrroclp,.,,r1.S„ fi•nnraunt,fl:: typm-nf ri;;,trurtr. rnrli fro,nlin. thL»:•rn.l;t. nti~lurr nf ffunrurrrLund tuttin'nll v r,trrd Ir•,tfj6ut lu tG,r t"Lurrn, n('nur I.t~(1r• _',, L}' rr-ricl,t of R\I19 trn..nr4Lvl. :1nnlY+i++hancrrl littlly diff(•rv•n.- I,rtnr.•rnlhn.a vij,nrrlt-r•nnt:,ininc tnhnreo,tlnnr. rn• tolh,wcrv-_ 1'\IO: Vur rswnlt4r. furvi~,11,1I' n .K.,,nul:r•dlr„ In,ttl IrnCll, nl IIl u un,thrr,nrn.«aurv,nvllt+ for tnhnrnv ;tnQ. tuli:rrruI'.ll(1 i-l7r-rlivrlj' trr~rv pll nnJ l-.iR;,ti";,,tu;l:rtl°i .uf;aro,rntrnt. 0-77 ,nul'U~,v_IhufG•r.in~ il)-. Iailtutul IIi~FS,inrr.`i~iqnrrttr t,ternt,trnllund 1!Iti,uul' 1-94 n;}t/i•i);urrlt.• nir,dinr• r„r,ti.t. tt •1~1„•,tni,uullt-rrlrnrn x(,ooitlrlt,ttllo,gon.Grr..tnad: ((';u~rcurtli,lCur~,l(a~, b'I:V .Iruin): u,ul tcril±Lrrl u}lllrnxitn,tlrli'I.iU g,t6lllr ahtrt ufllhr u'prrr7uont. TLv}-ttr,r„vliciJrd int-4n,u,(rxInlr.mr„ ,tluu,r(p ntlN ,rs(t~txa~rl to tuhmrt•ottithnut nuw,rtlelitlitr). tnlw,rcn .~ I'11t1 (!N rute re(rn-~rltn Ir,6uoe•n tnollinltl"tll) had ILrrn ,udrlocI) . rr,ntTr,l.v(,i rnl~): 'I'In,,uti,,,:,L., ttv.n, um„ne't thnar GlrahirHtltr tutullgr,hlrl cr'll n,u„hon Ln+~lptrt~i,ma~' Lr,m mjlr,r1,~rl (.1„m•.w rl nl,. I117c11. In llmb (t,ytrr: di•,t,nil+,f if,., rs(ln-nr ,nul ti.vww• lm•Il:uvli„u ,urral..<, gis nn hrirllr. Ilu• nnintul.+terr'nrxl,vd tn'_'.i ri4)trrlti•v.md,t}-. 3dm'n nurolrliirli tcovk.i:,inuuLnni~ ^i;uu rnUii,et+tcith rt\Yrif;hb..\utt,nrnul:rn (\1•ri);Lt, 1:171). Cid,d;i. rrlln~. Nrrtinn.„ftll" Irnfl, Inug in tl,rmt'.. n siu~;ir'•. 1„L--tcrrrr„t tn inrlluL"tIL•f,ill n~i„ll (,nthr-v'an,l . ~r,otl „ft7uv I,ttrru,l l"ntLrcn-(li,utnb:mn,lI{rirl. I!hl.~): it, nll .rrlio,a+ n.rrl fnr rlu:r,,ritiralii~ot.Ilir ........ rl ,tnrll IhinlI-tnnl,~ . r.rr. iurliull•rl. GnLlrt rr.ll. torr~, c,,,niunrl. ,inrlnr iliuun„r.wn, alnu;;thr full Ir,,;;th ufl}hn",- :l trnn, rrlLinl, .vJt~,r~~l:,n,lhnrr,.nr„rnvnl (I,r.ttrr,~r, ;n,in,l lu,n III'I~I, tlin,n,~Jinl'.trnll „f'tN~•,t~{ul luut'l,tr,r~~. (l,,,tao,~,~n,6u,n,4 9u0 uC31) Itl'I' it ,,rll~,~f tlu,..ro,,nrl ,rn,llliinl tnu•nn „f lL„~,rtnrurna,nl+ bri„41n1[nnre~ tl,u~ ., Ltt;•r„I '~ llntht",' \t vwlu- Il+slr,rlr,~„rirul nnnly.vi.v,-AV'itl(iiu tllr Iznlllrt t•,d?, t6rl,rr.rnr•nulqt',n.,,ln-~ „fnr;Urnl ,u•i,l Lt', IHt• .Adciiu, LVi„•wrlln nvirl'.<;~hilll(oAI;; I'.-Ati},IOVLni,liu•: ~!r,it,ul~•.~,f,u~i,l cl~~or,lu„enin,,,rn.Alillla+ititr un,lith~,.r „f'ur;,lr„I ~lerr,llrntriu l'Ailn ..itii.~,•. TLr.\IR'I'.1'\irrhni,lur tln,.+,rlrn7ilion tJ,r l,ut nnttl,r• rrIllrJur•. In tl,i. nilh- a".,n:,ll " a•II i.. nn,.rno,Inini,r=,Knnu,Lw nutI",rl il.<,;Ir- un,l it •. InrR"' ro.ll ..,,,. lillriltrith ~runulr..ul,uv-rIIio I,•c.•1 .,fllinnuvlon.. L,nlr.iw~(x•.L,-,nl;i;l,nti- tinLl'~ trillrlLr rlnolnm.,nii.rn.ar,lto(.I,ffro..'. (rrc.,m,il r•nm,uuuii•ntiunl. Fin'r nl,r< nf t orld t,r. rrr~n~ni~i.nrl ln•rra LtrMnwi,f ,nroll I':ASItm.aiti- rrlllund ,tlagr ,rorl.,,mil AIB Ou~iticnrrlll 'fli7, I'.AN nrll onr;lnii,u•d unlN• „urt-N(m nt~~nutulr..l'n,ttrh,mar).td,r.11B pn.ilicrorll nt„\' llaor rrn,tainr,l nul~t.1'li:pnsilil~nR('nnt,l,r" a fi•tc 1':Yti lnrifiro u:,nc tcrm uflrn I,rc.r•nttrnc„nl th,, rrll b,rvt'. All w,i,ual><in Illi.:.+hu<lr vv„rnr-n,nirtarl tniJintifs tlu" tn,mlLOr nf ruLlrtlrnlk tr tiiuutLrr. urnlntf „.1 ,tci;i Rl,.N~r,qu-nlr•in:.drihilnrl lLi..t„a~lir,n,rtnl ,uwlt~sietv,,.+,vnrrirrI „ut un It nuiiunl+ fr,,t„i„ru~L7;nn,(,. • 9'Lwetrinu.«nriillr.:uiirlv+vvrrv idrnrifirrllFhY rrnnlv,vii,~.nne•ti,n, .atniu,vl'ncitl, .AIt; R:Avut Itll _~I{xilh a,ljurrr,l ,•rti,at+~.tr,vt7r.rl trillt tii„lirlu.+• Ir,•,,r.(,7r,r rL•ar,n'inccuz~~u,,: lillla ,J nwiim~l tv,itl; :1li'II'1AtS'nl 71lI':;i~,~r.~lnii,o-d t~itL aitfl':AS,tl Illll1j 'I'1n• In~r.,o-r,l'nnial~,nu,oin u,t.virlrnuili.rll I,pil+Glilurr tn it ritLor vcitd, :A13 nftrrrlnlLi.,• liVr•,ti, ,n(.ihl.i,ln.n•..,~n.i l ito.iitlhimnriutvith 113 ut II lii i'i,,li;l,tvv.<rn.itivnl i:lL,.~e• rr.i, tnt tl, ,uuri„ILV-.ni7L,rr „ffl,r.r• h•r•I,ni,luo.till,ho,u,u,in tv.;.a'IiI,iiv. T1L, ,1,•rlf Il,,, wl,uit,itI,~rliuirllu-~ ,tnrl ILrir,tl,lilicutiunSiir,luru.,tit,ttivrn4ualiu•+h,tt~.r Ilrrnrr•llnrrtoJ o.l.,mahon, nn71 Itiri7l, 111i:{nI TrruJ,rnd, qdauJ Tirllir nuth~,tn6r,t, ,wt Of Illm ~!Innd i..prr..rnf i n,navliulrlr.l l, v II„• I,u~t'u~nnrl lia~nenIll,~ ul,l„~r 3uuuu ,r~rlll„ 1uulc li~-(,ortn,1lLp~;,4't1r trnchr,ul Ni~nul. .11rv,v r , , , ; nr "Jll, l l , /dr t L . w t ~ I - c l l,n , r t rtuJ„in fi , n . , • n , H ., f ' , r t r a r • h •ul gluncl to. n+,,, I,,n,.vt,. uti,nrv „d11 nnth ick t r n 1, ,1 „ ul C. ,u rrnourtiuutltrrr;•+tninrdlly luo~,urtl;,~;v'liu un,llr ~,:nin ,wel frvnn tlir. r,lhorh~y:Adi;{'~1tint11112IG: r
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n C~~-1!Y~?r ' ~~~i ~l~i J!i ® cells (,Lamb and ??eid, 1!9E8'; Sturgess acid Reid, 1!972a &'o;, Reid, et a1., 1975)i. bti:TH©llS S: COLES~ Exnlants of bronehial^ucosa, obtained from fresh surgical re.s:ectionspec.imens, ared clllt.ured b}'a: m¢d.iifi.cationo.f'. Tr.owel1's. (1959) .technique. (Sburgeso ai;d Reid!, 1972a).. After a.shorta st.abi.lisaticnn pe.riodd inn org2n cult'uremediu.:.: (:TC'. 1,9,.. Wel!1!come Reage.ntsliirnited).,. thcexpls::ts ar.c: i.ncubated wi:th fresh r.:e.di',L-ni contai.ni.ng3i{-1'r_:oelled.g3.yeo_'rote.'n precursors, particularly, 3H-g1iucose.., 3n-tt:reo i,.~(10. uCi/ml!)or ''~--giuccsamine(25. hCi/m1)• psu,3llly, explaut.; are p,.lse-Litie-led witn, a~ preccrsorfor one hour and t'heecnased fara furtn^r threenours witii medium contair.:ng, no~ la6el.. Four h raurs, afterr acdition of ti:nee label, theea_cl!a.ntis: aree firi:zdd and ..:.toraaiogracz n prepared ofl't.'~:m sectionst,a .r-_i.r:th periodi.cc acid Schi~ff' (P.;S) .. Sturg-ss and Reid (197,23) 3escrib--dthe lecationofl'silver gr3inswith_n mucausand serois ce3ls, at 3ilf€erenr time .tiervaSs('.1-A. irours.)i a.ft.err adr7ltios of liab:e:lled'precursors. Withi--, mucous ceil:;. ,;raiin~ w,-',relocate,d initiallyat. the baseof. ...,.. cells then, at thc base of tnee cell and! extend.ing i.nto. '.he PAS-posi.ti.vee secreto'ry mass, t~hen att the, cell ap•xx an d' f..na11" at the cell apexand: on the, l.,mina'_ surface. ldit`:i.n sercus. .__._s . grains are located i:ni,t,ially thro,,g!:out: t'he.eytop_as^nand seeretoryy mas:s, ar.d then b.ec.c.me, elustere.dd att the cell an.cx.. ! © 156. It is passib~,/e~ to q;uant'i.fy~ thee rate at t whic h ~ E~1y^_crrotein~c. (~as~~autorad:iograpr.ic~.silv~r gra'ns) are se.c:reted ty~r.~e.au.: celis by~measnricg the percentag,~, oY'mucuus'cpllls~ discnarging g7;ycaproteins.(~.i..e. riavin;; grai~~.ns~ at,the~ce.l: apex.an.i: c:: t'he~ liLminall surface.)) at, aa suitablle~ ti:. -~(~asual'1•y. 1~ hours~~.), a.ft.e.r~ add'ition ef labeL St'urgess and tt ii (1).r2e) te.r i'this valce Se.cretorf~ Index~ (.Slid a.nd. foun °., in iuv:.an~ brc_ ebial glandc oP' normal size~„ thatt iit waso acpros~~ir:.at2ay~ Q~~.30 (i~.e: npro:• ~.a.te.'_y. 307~~ of'm~ucous~~ cellss weree dl:schargir.g~after~ ): '.:oarsj. ':!Ie~ ratec of~ secretion of sero~ . 2ells canibe~e silmi:lar».~ assessed alt:iou,;~::, since di.schac:ginb cel'.il.; are~ rarely~ seer (ithe: lum.,en of serc:., _2.._.. is~ invariiabiy~ sma11. or~ not viseble)i, the ..erc~nta,,e of serous~ ceils~wi~t:7 g.ains~at~*_he c:e:ll.aoex~~is u_-~.:ally~mF-a_:u.re.dy tl The exfc.G tr wrich 1!a ied precurr rs are i orco a* 9 into ntrac .luLe rl,,rccp ct n~ an be qi t_f : bsme u_ tLe dbns 'it/ rfsif i r g.rhi cvealyingg muo., s rr .,or ,,cb .'. cell 7n our l.ah r t-ry L,r1:r a rsa.~ ~ meas r_ by w;(. ref .c anc -ni-:ra ~.ory (R .. 10 1) ssi a ri s. 7+ May " Refle:ctanc Polari in , m: co~e R*'_e t nc- ^re urem nts (g) made overa_eaS cf c_il. cycpaasm (aprro> .",,;y. ,. 0721 are. , ®
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- "~,. rr y REGULATION ©F THE SECRETORYCYC.LES!OF M'UCUS AFfO:SEROUSCELLSI 161 E.__ '° OE CY^IOHEJIlt•1IDFi l'lU sAliltvLATO Cyclo},e:<imidn and sa1P:'c;;,late tlave b.e.N s.oun to ia?:itiit glycopretein synthesis in goblet,ceils o he^sma11' end large int vtir.ethroug;:_ffectsboth on po'.i,,'gepti:deand oli:p_asa era:ri'de. sid'e-c:nsina:-ser..bly(Al1en and.:Cent„ 1968; L.:Micand Farstr.er, 19'72')• _4 _W BatNcycl!ohe.xi:ce.de(10: M) andsal.ilcyl.ate(5x 10M6 reduce tneincarporatio::e af'.. 3E-threonine:,. 1H-gJ ucos„ ar.d. 3H-g,.::cosaainee i'nt.o ...oec':s ce1li.s (as well as.,er^-..5 an3 gpbSet.- r_:e.lis~.) andt::e ef°.Octt is mere mar'r.edd innorrialn than: ia hypertrop!iie:9 glsn ('z,'i„,irc L). Sin e tEa ra`'e oP diccnarGe of cells~ af hypertro ;i~,efl glands is greater than t.'hatt of'f glands of norc3l size„ it _:ikecly that thee latter effe,.t is.a.co-ee:qLenceof in..:r~•'ased! ~rr.it etic rate:. O..f r.,t.erest is ,,:r•e fi.ndino thA',, iS gobl.et cell::s ofexplac ts•.hich cc.n2'ain ~ hy,pertrophiedd c1.an3u, t}e e.ff?ctof cyclohexi.obdeand.salicyl-~te:on precurscrincor.coration~ iss lo'aer tha<:ingotlet c^_llsof e.:cpla.tss ccnt'ai.ningnorm3l' g~ands(Co1es and Rei?„ 13,76), indCeating tyat in^reased' syntheti~c ratee is: aa feat.ure ef al -m_c-.a:-secret.i.ng, cellss i'.r tnee bronchitic air.ray. F?igure2.. L.°fe.ct of !'.j:cl or.exini.I.(io M)an =~a:ieylat^ (5 x 10 M'> an the I'nccrncrat .• __ 'u~Pf;r,ncine„ 3H~s'ruccseani 3?i-' ~csanine int:o~Muccas. ^Nllo of Rcrms.l' and.Hyeertr~ahi:e: .Glands...
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.i'?pi....*tr!,9r, rnqI ~dTti7 9a:''.os~il'~iL z5' REGULATiIQW~OFTHESECRcTORY CYCLES'.OFMUCUS~AND :SERQUSCELLS~~ 157 eerrectedd fartlacl•t;.round andi cxuress, _-i as: a Pract.ion ,.f the reflectance oPf a~ light-fogg.-di autcradiic-rafh . (G):. Graia dersity isexpressed asthedi~me :_ar:les.. ._._ct _... g!'G: (Go13steinana Willia~ms, '-97I). In ourr studi•~s,., i~ron,.lii.all gla::d .,i_.ze . is ex~~r^cse.di asa. • gland/waliL ratio. (6WR)~ whi:ctr ist_s ratio ofglard t.ci.cfness to mueosaa thic_}:nea n.=:;ose: , f ec^e.i_c^ , nor.r,a1 glands aree us :allhY t,z'+,en~ as t:,ose .ni.thn a: WR :.eas than C'.30and tyF:ertt;mp:^ied g~;iis as: thcsew.irvh a..,W^n il:: er ..,...of 6,9U, S.:C 'tiii'C L . ~..., 'J`_ o. 3~ . ,_1= Tnee locat'_:cnn of silv,-r~ -:'.a... „~.r~i'.:~.~ ., ,cd .,.,ra~.s~ cells can,e oe~. rel :.I;d. to _c rr_t~ ry. ^vcl.__-r..r:_an v~itn t.".e_i "ocati.c.~, caer -.. ~r.n ~ :_ig':~ resa_utio n l_.t.cna. r,t,_1~~i„ pul::_-lab.~I ..._.^G~,.. ~ia_::6 ~~. s_ _..,-. i,, in t_. rot:g'nn ar,~. r..,, ••Alx:.,, r_._.. s. att ti~.e base~of td^ __s ';) ~a,..c . . ~r,.c~. . _ s .. _ci - ., ^ ---- c,~ o_n- as:a.. Lev~~l f;A i.r:. .. . o.. ~ c:e_1 .... ,. .. ~^c:; . 5:_ .._ _,,._.. ui tir the of ):.__, y. 3 i~s in se.raus _ells~ occar. . ujt_ou.t ti~.~ c . ,c.c-:7 ^eil.:., t.h~e laLl tnen mov•:.: to~ +:-~. a~.i gr,a^u1es~, are a.a _. .L_. -_ 3,, '.ar-=~ ._f synthesi7,: and _n.ra tellu: -_~ s_ . ,granullec .ther,~ move to: t:} C0!'_' anrx~ C, and ar:e. Siec:crrG:_dd int.., t.!Ie (L-~v~ Ib~,dis rge ~..:ge)~. (see T2ble~1). P r;;:i,iL)].y~, accu"tl_'at,i'an.af erains at.' p=z~ c.f sernus Com.~ ._--an of ,f . .d c...u-- i:ed and'. se:rcuss ee11;. . .r.in,;~, .ir .,,cr~%ta;,ry ~^1~s r~. . -r_s ._d d~".fere..n.ces. ln rr'_an d_. a°' norm. ..._... _I'1~s: wi't:h gnainss at Levels P:A or :, ar r~.oxtsately 1.7 :-m ia n~ anrl cantain~ a: 1:3r--^ int'~rx•,._.~.L. r. s a..s . of~ (Table 1) . Duri g,.,_ disc'r,a r~~~ sta:.. ,. the i.e::t s~ilz~ee oP~ t:a~. secr_t0.f, c.a... .._._~. a~. __ as ~ does t.-,_ o1l . t approxis2teiy,~ :, ,m).. 5 __cecm~ ._:ed~ !-,y~ ar~ incrca.~e~ _.n thee s~ize~~ of': t.^.e i~1=e:n. The iner^ase i:. the nne-il.j r rai 3 c:.er clcu_a «ll during. tae~ ..ta:~c ynti, ~,:~ i n that'~glyoprot_._ ,I~:aule, _r, at _ ^x~. prior~~ to~ arscLa.r.P^ _., 1rcr a.,•e .... ra::r .. .,._tJ.~ duri,ng~ dicchar~F~ -z : F~:rr~-m--bly . 3u, t:- -.; o`_r fn ~mi th,°~. ee111,. jy~ eo-;firast, t'r ncr _ . area. y_ ~ intracell•...la.r _.c1--s a___e.r ac_cr°ci,'bly d'uring~ the: stnc:rcory ~ eyr1,, cDran.: c- 11s..
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6iQllri P±]°^I . 5.~3:a'a~L'eg ~ I~A L 160, S. COLES The effect ofparasyr-patk:omim.etic agents ont?:e hypertropnied humanbronchial gland has been stuii-d (Sturg= .,andReid, 1972b). Parasymnathomimetic agents ircrease the SI of }.ypertr,)F:ied glandn to a greater degT2ethan normals while the irhibitorj ~ffect of at'roFi::eis 1essmartied. Physcstyg;ineincreases both Si mucous andSIsero;usvalues ofncrmal glnndsbutthe effeetisofgreaterv:agniaud'e in hypertrcptiied glands (Figure1). The nig`i basal secret'ory rate cf hypertrophied glands (Starg-ss ar:di Reid, 1972a) may thus be ac:.nsequeneeeitherofl'increased leve'_s of endogenous acetySciiclinu or enha:rc,2d receptor activit;/. The role of sym,pathetic nerves in bronehial mucus seere+.ion is not understood. Sturg-ss and Rei'd(1972Q) found no effect of a~ra.zge ofsympat};cmiinet:ic agentsonthe secretory rateo_` the human bronchialgland, alttcugh~6allag:er andico-wor:er.s (197,): havereported increa;ed secretisnof glycoproteins in thecar. traaheain responsetosfmpatheticnerve stia'iGation or 6-adrenergic compounds. By contrast, S'urgess and Reid (1973) have reported an increase in grblet cell m.:-mter and tracheal glan3 si..ze in rats administered hi~g: dosesrof isoore;alir.e. It is probablethat: thereisconsiderablespecies variaticni^ sympathetic efflectaStFough a vegetativeor possiblya direct effect ongland's and/or gob'_~,t ce'ils should not be Figure1. Bff'ect of Physoctygmine(C-1oCJCug/n1) on the Secretory RatejiMucous and Sercus CeIlsin Normal and Hy-pcrJro^i:_ed Glan3_;. J H EG gly int sid 197 re, 3H- c e: hyI ce no: of in thc ic- no: sy- b rc Fi~g
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. SI: muc:ocs~ Nor:.al tiynert:rcphie3 ;aT'IA!! 162' S. COLES Cyclohexinid•a reduces the inccrporation of different precursors into: mu.c:ous, serous: andd goblet ce'1s: by vary.i:ngg arso•.:nts... In P.igure 2, it.can he seentha:tn cycl.olexa^•ci,:e reduces 3h-t';reoaine ir;cc.rposatio^by n'j;' 3>;'-gluccse by 5?'„ whi:l'e: 3H-glucosar.i.c.eincorp.or.ati.on_... :eat:ced!byonly 1~5o inrm•,i.cc,isn c._llao:s no:rtzall glands. A aimilar pattern of effect aocurs in hynertrcphied glands, thcugh of'a,lover order of aasnitude. Since the princ:pal eff:ct of'cy,cliohexinide on gly,coprotein synthesis see^s to be at t',!:e ribcaotrual level.,, it is l..i.kelyth3t iitsdi.`f'eri~ng, effects, particularly between t.hreanine:a=_d glucosar.ine incurporation,, aredue.to the addition:o.f slucosanine to palyperti'de:sassembled. ~' beforetrea3da.tionof cyclonex.i:-.ide. Salicyl!ate, by contrast,, r-_dUees.the i,ncorp--rat.i:on.of 3H-tareonlr:e, 3H-gl,:cose and 3ii-giucosamii.ne 'aysiai:,'3ramour.tsI in mucous cells o:f ba th, nor^all andd hyrertr?phieai glands: (.Pi.F;ure2):. Triee difference in effe^t b:et:ae:e.z.cyclohexini.d's.and.sali.cylate seems to be that: the former inh°iaits only pclypepLi3e syntnesis while the latter interferes bot,h,wi:h rito3o^a1 po ype_t,i,de assecaly and oli~opsaco:":ari•.e side .-:adn synthesis. A si,milar findi:.g has beec made for g1yc~_ rc-ein s; E:tnesis in gob=.et cells of the small intest'i.ne. (L•alc~ie and. h!erstner:,. 197~)i. -4. Tab:lle. 3. Effect of ' Cy_ldr,exiMire (10M). andl Ealicylate(5 x. 10-~ M') Adde7 Befor°orA'ft.erFi'se-Lsbe:~li cnSI. Mucous Values cf !o^.cal anfl Hyp ..:_hie.d Glacds. Control 0.2) (0.02) 0.57 (,0.04) Cycllct,exicide Pbe-Pu1se0.uE*0.2°*(Ci.OL) (0.02) Past-_n;Llse 0.26 (C.dg) 0.,<0 (0.02) Control 0.26 0. 1'9' (0.a3) ('0.03) SaPicylate Pre-:i:lse O.Cj* 0.29~ (,0.0'2)' (0.02) PJst-P',ase 0.2a 0.45 . (01.03)' (0.on) Cells: were labelled wi-it 3'H-?hreocine. U.eac va=~ues areo given with S.c'.:'.. in parect.hesis:. *P<0.001 R
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REGULATIONOF THE SECRETORY CYCLESOF MUCUSAND SERqUS CELLS. 165'. Taale4. E`1feat of Oiartiiln (10: 1Wnen Adde3 Beflbreor A'iter Piilsn-;aoelli:.^, or, SSuccus ar.d. SI: Serous Values'.. SI mucoas SI serous Canorol 0.29 Oi.32 (0.03) (Oi.02)' Ouatiain Pre-Pulse 0..0?,* 0:•05*' ) Post-Put,e (~0.02) 0.25 ('0,.01 0.2? (~0.03) ('0'.01), CelJls weree labu]JL'e3 aiUh''H-t:;reonine.. give:n withS.1.I?. i.n. raren_hesis. ..ean va'i.__ a.r~e~. * g < 0.001 'iTabi~- ,. The: Ef'eat~ of Z co~ ,.. :.tit:h cr ~ .._.,,.,. Pi ~-nyl.. th;,'lo....i.ac.__ () l).)~. n.. ._._. S_z_ .:r.') cr^t^ry . Rot1e~ of~ E?at TI;-.:ich.~al acb . Lary~-,SesL Ola_.~_'s. 'fiihu=a~ o;eter S~I oucous~ .,..cin. (bce) aenu_ COntral 50'.1 0.=5 '7',tc:. (~ 1.5) (:0.03~) iaTa~, to a9 ~*s~ (~ 2~.2) Q.E4'*" (J.OeI) ('O:.C^?~)~ Tbbacac + P:1C 57. *~ 0.•i2~ 0~,1~', (~ i.9) (0.08) Pr40~ ~ 52.3' 0.21i~*~~ (~ z~.i ~1 (a.7E! (~,7~,095i. P values: *' _ ~ <~ 0:.0.`,. F - 0.01; xa*~. I < .,.^_i0i1. Cells. ...._.. 1aor,"_~_ . w~i''.'..:: ~ilte. . .. :c.e. :de- c .al::cs~ are given vi:t... 01.5 ...., in . _.eet:^.ec...is.,
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~J,:~112ENTIAL RE:GIULATI©NqFTHE~SECRETiQRYCYCLES~~.OFWIUCUS.AND~SEROUIS~.CELLS~~ 163 in discharge rate does nott cause aa conce::ita:,t i.ncreasr_-e in tr:ee rate of precurscr inccrpeeation isee ab~ve)i. consistent witrh the findingtha.t the r..ethac:.cl.`_ne-i ,_ced in^r.e:ase. Palade, 1971.)'.A si.^relar di .,o,i''nt.ion. int't oranc ia'l g3iand i.s diisc^argehas also been.dh=onstrated ini t3e: anc:reas(Jaraiesonandi same: rate~e as~ the controls. Diissoci.ation, of'f syntt:~•,sis~F from_. ,,~ of' cyclchexi^ride and saliaylate, wheniadded befdre the palise, is pres,mably due to a reduction in labelled glycc°rotein disc^ar5c whil.ee prefcrmed unlabelled gly,,cop,rotleins; are d.isc.carge.ad att t.hee by a redLeticn in the rate of glycnprotein.synt.hesis. Thee e.ffectt of'di.scharge of prefar:r.ed'g1y,.oprote3n,.molecuLes is uns:ffectedd neither cors..,a.ndd re:duces: SZ muco•sss values su.gge:stingthat t',he ratee valuesar:d the e:ff~ctis'.more marked.in norma:~ than i., hypertrophiedd gliands: (Tgble. 3). Wiieniad3ed pcs.t-:.uls:e,however, Wrieni'ncubatJedn wittlex,pl'ants beforee addit.i.on~ of thee puls.e„ both cyclohexinide andi salicyliate redlce SIi m,,;ccus~ (and SI sereus)i MUCOUSCELLS. -riedi ', oUAeIbNNO,- ~.,~.r. / ~,oe• om>~eo ~.ao l 2'Q:: 'M,Gic. 'H'-GIdd .e 3. Pli.g;ire3'• Effect', of ~unba~i:: (,i0 M ) or: 'he :;ecr ~t:.~ry E3t.ee a.d' Incorporat.on,f: 33-Threoriin^. jH-G:1uc^_sean,'.3H-Clur.oc:arair.ee i nt, . Muccus: Qellss ofl :Jormal and. Hy,p,rtrc;.phied Glands.
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P e* t q CI m 9 u: e v i1 I I E ~ll 1 - W- 168I S. COLES Galiag`.-,er, J.T., P:ent, P.',!'. , Pas:;atnre, At'. , Ptiippc, P'.J. and Ricna:rd5on,. P.S.. (1y75).- Proc:Foy.3oc.,. (:London B),.192, 49. Goldstein, D.J. aud Willia.~a~s, I::A. ('1971Y.J.,yicrnscopy, 94, 215.Ja3nieson, J.D. and Pallade, G.E. (1)7i1:). J.Ce1'1'Biol., 46, 503. 35. _ Jeffery, P.K. and Reid, L. (1973),. J.:;nat_, 114, Jones, R,, Bolduc, P. and i?eid, II. (i9?3). Brit.J.Exp.esthol., 54',, 229., Lamb, Di andi Reid,L'. (1968), 'i~n, Hyperse¢ret_cn 3ronc.hir,ue, pp.11-22. Colloqu,a Irterr.atianal de Pat:olagie ~ raciyce;, Lille. Lamb, D. and Reid, L. Brit.Med.J., 1',33. Lukile.,. B.L~, and. °orstr,nr,.G,G. (.1I?72). Biochin.Biophs,dcta.,. 273', 380 - 1Qeyriek, 9. and R^_d, i.. (197Di. J.AnaC., 2?1!. Meyrick, B. and Reid, L. (i1975)~• J.Ce11 Bio1., 67', ,. Pe~rmy, W'.F.and Boyd, 2.M., (.119L?).. J.1,harme.col:.Exp_Therap4, 73, 65.• Reid„ L. (1954,). Lancet, 1, 275.. Re:d, L. (19~G);. Thorax, 15, 11,32, Re,d~„ L. ,[feyri ck, n'. ard S. (13 i:5i- in Organ Cudtore in. Biomedical Research, :.e 47'~ »80 i'P3 ".,. °ai s a.^.d. M. a•.nickerda:~, .mar.ic~, Jniversit'yP1--ss,. london.. Rhodin, J. (1yG%~),. Aner.lteu.Respi.ra~tory, Dis~~_., 93~~, 1. Rbgers~,. A".;J. (~19F:I). Exp.CE-1.1.Rcs.,~ 24~,. 228~. Spencer, H. and' Loef, D~, .~ J'.IVrat., 98, 599. Sturges~s.,. J4, and Reid, L.. (1~:72a)~. Exp~ Mo1.ec Pat-hol'_.. 26, _°p2. Sturgess, J'. a:rd.Reid,.:.. (~19"-u). CIin.S~i~ ce,. 43, 533~. Sturg~ess, J~. tuid Rei'~.3,. h. Bni.G.J'.Exp.PaG'to1,.,~54',. 330'. Triouell, 0.A'. (,L959'). Exp.C~~~11 Res., 1'6'„ 1i"54 I P'MY'"
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I5r 1':iiJLJ~ijl~1 r1C1^_3-RiJ7/Th/9901-OIXi1150^_ 1%1/0 i 1db,tlce: Thls: naletial rnay, tle protne`Ca' + coaYli9h~' I~~~~(Titla .17 U.S: . Code) b9 y mi< i ]n+Fi-m_+C p,.ngha to 1928 b.e th l.luted Si ates~Ca~na,don Divisi.onof t5e.ln+.ernationa1 Acedemp of PsahoLogy' 8'494 N 1~39:,D1o~1 p.4d.15TL P~~t Secretory Cell Hyperplasia and I!/Iodification of' Intracellular Giycoprotein in Rat Airvlaays Induced by Short P'eriodls of Exposure to To'bacco Smoke, and the Effect, of the Antiinflarnmato'ry Agent P'henylmethyloxadia.zole RoSeMAlzY JoNFS, M. Px1L,,AND LYnNE R1:aU; M.D. Department ofExperimental' Pathoingy; Cardiothoracic Zn9tit'ute;,Bhompton FZospit'a1; I,ondon, Cnited'h'"ingrlam, Inhalation of'iiritants over seserallwceks,i>„ know-n to'causee secretoim'celllh.-perplasia iniairwav epitheliumand.to modifc intrac•.ellular gl..coprotein-tlhe airw'ay changes:characueristic oflhumanf chr:onic'hronchitis. In.the presentistndy secretarvy cellshave been examinurfUoth in.extrapulmunarcy and intrapulmo:narv,'airwati-ss:of ratsexposed for.betweenl.to 14 da.ys:toa.smoke.from uabacco; w-ith and w-fthout.the antiinflammat'ore.agentphenylmet'hyloxadiazole. The normal rat airw^apshow•s regional.variat6on in.Uoth secretor}•ce11 numberandglcroproteins. Inn theextrapulmonary airwa}!ss onl.;., thee first expo.uretoe tobacco smoke eauses a: falll inthen numher(s) of'secretory ce11s identifi'ed, since ocer..helmingdischargeof glycoprou•in reduces thcir apparent number. After 2 days ofexposure the amount of gl.coprotcin within cells is normal hut a discharge effect is seen again later when exposure follows a da3- of rest fi-om the irritont: the acquired tolerance to:theirritant:is.lost:.After3 days ofexpos:ure thenumberof secre.tory cells:in each extrapulmonary region and each intrapulmonarq rekrion ts significantti• incrc•nsed. Throughout the airw-ays thefiist exposure to smokemodlfies intracellular ylA,coproteiniin ccllk oft'he or~iginal popul©tion: when.they appearthe new cellsalread..have this modifihd pattern. [3oth the absolute numbenof secretory cells containing acid glccoprut'cin and their proporticm~ufthetotal secretory cell population increase. There isgroater uniformityof secretorycell t?pe thruughouitheairw-avsand both initially and Cinallc the mostcommon~uell is onecontL3 ininl;,bothacid and,neutral gl.•coprotein., A'ddition of phen.-Jmeth}•Jbxadiazo7e to.the'tobaccoo prev[•ntsincreases inthu'apparent secre,torv cell'number in~extrapulmonar?'y hut notlintrapulrnonarp.ainwa}'s. It does noLpresrnt.the diHcharge' effect normodifScation oflthef intruccllularr glvcuprotein. tldditional key wrord§:Irritation, Q~uantitation, A,cid andincutral {;/Ocoprotein. Increase in the numtier of secretorc cells of airwa} surface epithelium ischaracteristic ofhumanehronic Hronchitis 133, 38)-it affect_a. hoth larl;e and small ,+is- Wars andmavprecede funenionallchanee 1k°_L In hurnan adult trachea the mean seeretorvi cell densit} hlis heen estimated to be 6:600 per sq. mm.: in chrt,nic hronchitiss thisincreasesto 1(1.000per sq. mm. and secretory cellsare also numerous in the hrRinchiolitr rul,Tion uHere nor- r'allv thcv are ahsent (9, 350 ld'.pernlas~ia ofsecrcttory lls,ia accorrmuam.ed bvmodification of imracellular elc - I,rotein. The glc'coproteia, priociuced is not abnortnal hutthe degreeof'sulfation in cellsofthe airrnac surface is ihcrcased bothin, ohronic' bronchitis and in. cysticfibrcnsis ('?5+ 31)I and in the suh+nucoss l gl:md the prollor- tion~of cells svnthexizing the various t}pes of acld 6R co- lprotc-in incrc Iscs. I9~ °4, 391'. rIlhem auw ah'chrn e.ecanbeproducrdesperiilont:+llks lir l)i6i3, Reid ("3'I'first renorted the resultsofarncxper"' mental studv in which, in the a