Council for Tobacco Research
Advances in Modern Toxicology New Concepts in Safety Evaluation [St Syrian Hamsters Are A Valuable Option for Animal Experiments]
Abstract
MIS;ILL
Fields
- Master ID
- Ctrmn00041967-2810
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- Author
- Hemisphere Publishers
- Blumenthal, H., Fda
- Homburger, F., Bioresearch Inst
- Mehlman, M.A., Nih
- Shapiro, R.E., Natl Inst For Environmental Health
- Blumenthal, H., Fda
- Depository Date
- 08 Sep 1997
- Box
- 267
- Type
- SCIENTIFIC ARTICLE
- UCSF Legacy ID
- bot30a00
Document Images
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Advances in Modern Toxicology
, VOLUME 1, PART 1:
P,
NEW CONCEPTS
IN SAFETY EVALUATION
EDITED BY
MYR0NA. NfEHL%14`
\,kTIOI%AL 1NSTITL'TES OF HEALTH
RAYMOND E. SHAPIRO
M'1T1TE OF E%NIRO%,HE%TAL N.EALTH SCIENCES
HERBERT BLl,*\1E~THkL
F(DG:> >ND DR,G >D%!.\IiTRaT;O`
E
HEMISPHERE
PUBLISHING CORPORATION
W3shington London
'A HALSTED PRESS BOOK
JOHN WILEY & SONS
New York London Sydney
! )it
Torontu
EXHIBIT NO: L
N:T1 CE
This r, ='i''3f TaY :e
awt,^;eo OY Co;Yn~,t
(T~tl2 il u.5. COWt).
CTR NN 042627
I
t
CONTENTS
i
i
De1:i:tr,;n %
PP:' e r~,
L, . Frxcir-.Jn-.a Bp:e! B.gi~, :: vt
PART I INTER>CTIO\S I
CHAPTER ' Rnle of Interactn,n of Enwonment3l >gents in \1ud,f.tng
Their k3to!u_£i:3l a,tn!t% '.r.i ~, 3
T: \ 3
R: .rc^.:s ti
CHa?TER :
\tudcrn Cun;epts in Nutr:ttonzl Status and Fore:gn Compound
Tu.::,r.. TL* ..+ CJ-^,^tc!! I I
Fxe-¢:+ Co^.puunJ
\!e'~^,i ~^.i 1:
In%..;.:r.z Farr:,;, Cun-.counJ \te:113ousm IS
\t.. ~~. ^:\t..c. F.n,',,.n U%'ast k%~,nu S~ i,em I S
1t
Re;.,mmended Protu~uls iur S:uJ,cs ui Nwr,.ttun-Fore:¢n
C: rrround In!eru,uuns 21
Re:e:cnces :4
PART 11 CO%,CEPTI,'Al..1%D \tETHODOLOGICAL TOOLS 31
CHAPTER : Potential Contnbution of Inbred S%run H=sters to Future
Tu.rcolo¢v F llurDurger 35
35
S;e::,,: Chjra;ter,set,s ut H3msters 37
I :h :J L,nes .:I H,,rr.stvs 34
S;e.:ii l ses 2! Pe.,a,,r Inb:e : Hamster Susccpt;ti!tttes
S:!'e!. Tcst:re vi C eiret!c Smu:e 43
S.,.:~ n !hc Tj:t 45
u
43
Cf R MN 042622 8
/j
I
I
% ur
Stud:es on Su5:ut3neoUi SY.:I.^1 l.'. ....... .t i.. .. ~J1."i
o: S~rlla H3msters 46
SlJd:es on Indu;tion .f C.,,%... .. ~e L:... . 3..__.
Harnsters 46
St -iJies on the ii Re^~: :sins +n S. -.ar.
Hamsters 47
In,;rJcn:e of Spwntane,ius N,:o;:jsmsm S~::j:t Hlr.is;c:s 4'
App+it.auoit of the Abone Obier%3uuni w Sjiet~,
E%jlujtwns 49
Epilogue SI
Reicrcr.cts 51
1
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1
r
CHAPTER; Concepts in Health E%rluatiun uf Commer:tat and i:,du'tna!
Chemicals. B. P ti1c AJr>Jr1 61
(.,on¢Term %ersus Short-Term Tov:!t% Tests ol
Lepl Requirements for S3tet.
C`urii::als 61
Tini! RcquIred :u De ~r.,,.... \ ,.t ... ~ ...
Te;t .,;3i Inimmatta^ on t.a;tig-Te. -,ecs,;s S, :.
Ttitiaz ob
@3.i.:.~~nJ 66
sseil jnd !s!e n::j bb
Opinion from 0t,;c: b-
Elra S.cns jnJ T: s..: C
.. ~ _ .
Tcr:n \,Eiil;t 3-JI t.un._T:rn %..E.::;: 0 .:s "I
Repr~~ S5
S aes:ed
Tes:in¢ 96
Ger.e:al 96
C3r: ~;gen~:::} 10:
Rc~r~Ju::.~n l0:
Summary 103
References 104
appen3tx Data *r.,,, Snvc:Te:ni a-._ .. _Tr'^- :
Obt3rned fro:n %'3nous Ute:vutt S...:::: 1 to
References 136
.... .....
i
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,
wk
Conlenrt ix
CHAPTER 5 Assessment of the Value of Sy stemic Toaicitv Studies in
Experimental 4nimals. Tihvr &aa:s 141
Intr,)Ju:u,~n 141
Prospectrve S:udres
141
L:mitations 142
LD:O Drtermi.^..,:;ors 145
Tes:s 1-16
.,
R: . ,..;es 140
I
CHAPTER 5 Current Methodolop in Tento!oe% Rewarch
; . :: F V : : ,s . .: ! C .. :s
;!: ~^, ! ~5
n- :. ~es 15"
Er c.~:~.~::s ISS
100
F ., ... ('_.. . _ T.-. Ie3
F_. T:.. ,.. 164
N' .._ s It+tt
155
C`~ % PTER ' \on!erha! P3r3meters» Indices of Acute Toucrtv Inadequaev
of the >cute LD50 F,eJrr,cr
T: %; 1".
R;:erences 1Q9
P\RT III PH>RNACOKIN'ETICS A `EW TOOL 193
CNkPTER S Pharmaeokinetic Studies in Esaluation of the Toticological
and En.rronment3I Hatard of Chemicals.
P J GehnnS. P G. Isbran2be. jr;,; G E BlJu 195
b.tsic Cjn;eprs in Phv macoktnetres 196
Introdu;uwn 196
C)-.e C.:rnp.rtmert Open Mode! 198
TwJ-C_npJCtment k1u!u;omp3rtm.ett Open Model
S' S:tTS :05
Retvuted AJrrints:rvron or Repeated Et;esure :08
tanetics of Non,tnev or Svur,^!e Sss;er,s :11
C,%vent Bi.^.!:::e :j %1jcr,)rro!e;u!e) t Pr,i:e:n. DN A. and
RN al 215
/1
~ Tf~'. f 3 N 0422630
x C.- ,.^:t
E.3rr,pits oi Ph]rr..]cJK7neS1; Jr.Z i,!e:r C .,. _.._ .
HJr;r,1
_.=D:bromu:mtr:io~+r~~ptu^.~mtJt ~DB.\PAt. RJ,^:,:
E;trninatton 3nd Eaten~i.e Dee:a;.v.un ::0
=.4Dtnurcphtmol IUNP1. Lmtv
F..u;tdJu the Dti(erence in Sl+ectes S,is:ept:bwt. :: :`.:
CJuracto¢tn,c A;ttvrtv ::3
De;jbromudiphen.l Oude tUBDPOt:,+.J 0;:3t- ...
I tOBBPI Ltnar Phjrnu; Lsc_ S: .. ~
Curt;puund tor ReseJr;h 3nd Dc~ciuDT...' ::t
:.3'.3 Tetr~thl,~rndtheniu/+,au~tr, tTCDDt L.-.r_
Ph3rmJ6:oktnetra Used to Asetss Paten:.3; ror
lJtwn inJ ~\ssu.utcd T",.i. Itaiard
Pent3;hiorol+htnui IPCP1. Potenti:il k+. r I:;.
B>d. Bur,fen Js C3I;ulJted b%
C!u:j:tert/c PtiJrmJ;uktn.tics :3}
t:..: T
\, cimear P!:Jrnuc%'k:^.u;s J::Q S: ,:es'J ....-..es
_:3
~ `r.. Ch:oriJe tt C 1. \,1niir.m F: ..,;s. T:... . _ . _
St-jd. in¢ Phm ma;uktnttics .» I ^. :i 1
U:hcr Cft^i:;Ja. Ehde,,e wr ab
:46
- = Tetr3.hl,,rubirhe^,. S ..~c:.... s .:'. . C ..- .
~ s :n F.sh :4'
S :s:..j, ks:e::s :50
:50
[v^e~mcncJl Errors :53
Pjrj^e:er :53
P ..a:.. . Pa:3rneter Est,:^a::s .,5
.¢ \3nrneir :00
C .-,J~tr¢ Nv3-:erc:s
BjuJ;nc inJ '% :o.
E.;~trt^tcn!:: Dcvgn :65
R:icrencts :06
PART IV MET>BOLISH AND BIOCHEHICAL TO\ICITti :"1
CHAPTkK`+ R3droautoenphic Methods (or Phsrologtc Di%pu.rttur, Jcd
Tuvcolog. Studies.
h`bcrt H. Liss irrJ Chorles J Kirisler :' 3
Cp/ R 1 1l ! .r I' 26-23M.
a
Corrrnrt ti
Introdu.t:an ?'3
Me:hods :';
.ap;l;a:tz,r,s ="5
RJdio3utoe:].f:t; Sru~ies uf Drue
:'Y
N? ..c J.~n S:J~1,ri o t D.: U~Ir:C :j n :50
C::. .Jr R].':v]ut"trJ:fi~ :s
:
:S:
Dr.IT H]!~
ti :r. T:~S:.di =J1
E:c.. ur :91
E.~: .,. .. . l'. T ....t::es :93
~I Fe.. S:._ cs _a6
P r ..._ ~ : .
R:~. T .,
i D .. . . :00
~' ._.. ;01
R: . . ... 304
/I
CN aPTER ! 1 Siemfi;an,e of \tetabolrte\tedtatrd Tovcrties in the Safetv
E~]luJtaon uf Dru_ee and Chcmi;ih
r.,...c 30'
_.., n 30'
µltt.h F:re:.n C. mcow,Cs 4re
309
P]:hwa% s lea,!tne to Tovc \1etaNelites 309
4c:r.3uon Dr Epuvde FurmJ:wn 309
A,uvvton b~ OvJitwn vt a^ .: .s 315
A.tnnon b\, O:htr P]:hMJ.s 31,
A,ttvvwn tl the Gastru:rtc,c.r.3i TJ,t 31"
S,te of Tov::tv 31ti
\t.:Jbuitte Tovitty 319
DJse 3:0
P']sir.3 ]nJ Ttssue Cjn;entr3tions 3_1
Co~J:cnt Btnd:ne 322
\t ~. ..rs ut Due 326
Orhcr Drue InterJ.t1-1ti 3:g
Ut!:er FJ,tars T!:jt DJe
\1t:]h , ism 3.9
Is:-.ited Celis.
or S.:ten:, 331
(.r f R f f f"i 0`"f' .i'`.. 633 2
trr il#::ta::
T: , nc :hc SIeta ,:.:e )r 7.~v. ' 33=
Dri;1 Destcn 33_ -
:t i Tov,tt. ~`ter ~n U~cr..~e 3.i3
S::r:::r.u:y 334
ketere-t;:s 335
CHAPTER I I Intestin3l Drug Metabolism and the Broa%atlabt!ir% of [lrugs.
C. !. Pantuck. R. Aunt:mmn. aprJ A H. C.;nne, 34;
Introducuon 345
F:ie,t ui Crprette Scrowe »d Benioj,l; ~aae ,.. ..
l:,::stin:l Met3baltsrn of Phena;ettn 3;ti
E:;e;t of CharcoalBroiIcJ Beef on :he I;;:es:e-a: ut Phenaceun 354
'
Etr.;t of Rat Chow. Ve¢c:.b!es. and .:r. ~..~ 0:..
l.rdaIts on the Intestinal k1etaboitsm rr Dr is 3:5 ~
Efiect ui Drucs on the Intestini! s-
,rnJ Hcvrbirbual 3S'
C n,inswns 359
Rai:ren;es 364
CIiAPTER ;: Di,tnbutiun. Metaboltsm. and Pennatal Tou:u- of Pes:.;:Ces
..uh Rc(erence to Food Sa(et. E.a!wtjon 4 Re%teM of
Selected Literature. /1. S A'%:era 369
I:;I r-oJu;..:n 369
R.,c .i %1e:j^voc St~iC.a in Ta3' :c~... , ~. .. .. 3"0
0z.^".h;onne Insc;lI;rdts 3"i
DUT ird Re'.rteJ C.,:r.pour.ds 3';
a:-'-:n :r.'. D:e .'.rt" 3..
H;; :~...... ,tcJ lie^:a;',lor E~_.... ."
C!: If,~j.,,e 1~Q
L.!,.:jne 3S1
~t: .. ~\ % ;h:c: 3S:
C : :;r 353
T.~ ..~hen e 3S4
D!. .~:: i 3S4
ErE dosu 1 ~3 n 35S
Mtrex 3;6
F1i.:cnx,ed Bentc^ts 3145
Hc~7;h;orooe^tere 3SS
Ptn ~r.....r,%benttne 3s9
C.iroamites 391
C.rrb3r.-I 391
Doluo.vom.ttes 393
Tlrrrarr. 395
c~'R f fN 0",'~~ .~~'1
Con renrt ciii
Ferbam 396
Phenox%:ictd Herhtctdes 396
R::'eren;es 399
PART V TRA.NSPLACEVT.A:L TOXICITY 421
CHAPTER 3 Transplacental Toxicity of Diethyastilbestroa a Spectal
Problem in Safet~ E%aluatwn
J- h-. .a thL.urJn .P:,1 R h,-r L. D:x,:t 4:3
423
^ e:~.'st::~escro; l sate 4_4
Pti:r-ac.)JoT, ut Dtt:ti~t~;r.tiet'r:i 3.
R::at:C'i~1JD 1 )I' ...ft :J ~..:~:~ 3~
C i .In.1 %1e:ati"1 i:G
T. E ie;-s DES - H~r.:-s 4 3
T~._ ... f. ...+s Dt S a-.. _ s 435
-W I
R: . .:s 442
.4J
CTR ~~~~ 0426-o34
Chemieal CGrcinotenait in Srrtan Hamuers 147
C
EraomoTO et ol. (36J in randombred hamsters that had consumed about
300 ma of MC in their diet during a period of 10 months.
Age of the experimental animals at the time of carcinogen administra-
tion may also play a role, since ToTH (1ES) reported that higher numbers of
forestomach papillomas developed in animals given urethan at adulthood
than at birth. On the other hand, more intestinal tumors were found in those
hamsters under treatment as newborns.
In studies on anaer of the colon, the use of hamsters has also beee
minittul. WasaUttot=tt's rsview (194j only mentions that !,2-0imethylhydra-
sint auses colon tumors in hamsters as well as in rats and mice. To7tt (lf3j
reported that the incidence of these tumors was especially high in the txcura
(see'Liver'). Cyasin, according tn Htnot+^ et el. (7:J, pt;s;d fewtcr iniestitta)
(and rettal) tumors in hamsters thalt in rats (see 'Liver'). In our own MC
feeding studies, more than half of the male 15.16 and 17.20 BlO haauurs
had cancers of the large intestine, while all other strains tested wen relatively
resistant. So and WrNDttt (176J observed two invasive adenoarcinomas of
the colon in hamsters dying on the 2S7th day of an investigation employing
a.eL injections of 3,2'-dimethyl-4-aminobiphenyl (sa'Urinary Bladder').
Vitamin A palmitate prevented the induction of arcinotzta of the pmo-
intestinal tract by oral DMBA (19J (as well as uterine, cervical and tracht:o-
bronchial carcinogenesis), but So and WrxDttt (176J believe that this may
not be so for the lower intestinal traet.
We (Hoitovtteett et al., 801 failed to produce any gastrointestinal neo-
plasms by the feeding of 20% snuR in the diet, even though the aaimals of
the inbred hamster strain used wers susceptible to 6utrointestinal cancer
induction by MC pvaje.
CHU and Mwta.caw (1l): 71n oral ada+inistruioe of 7,l2dimetAylbeaamlvaeena
(DMCA) or t,auo(a)trm+K (l+10) to Syrias Itanstsn Induad dys6aatotic Itsioos and
earcinoma of the ronuon+adt arb srnaL intatina but only tM DM IIIA irdund drskaatotie
ttsions o/ the aoptu{ts Ysu+tinS tM o+ains aervia of SYrias trn+atets witti DM OA induoed
perinnl stia and.aSinal qreinwna in 100% of tNe a+aieub and eavid nreinoar iu 22%.
In animab similarly tntsted voith DMBA aP the addiuoo ot 0.!% vitamin A
polmiuu to the diet prevented tly denlopnatt of wn5noero ef t!K Sawoinaatiual tract;
adding the vitanun A polmitaM to the tlwd tsteJ for paintinj the oa.u Ore.eoel the
dOvtlopmtM o( qRiOolrle of Otqria and vapM tfM did not Inhibit ft deretopnent or
orcinan. of the tx++++nl stia The imptiession of the inlsit+itory a(i.a of vitamia A on
the induction ol apuamous oa(t oreirotn of t4. aweov nten+txsne i. tJ>r tsueatar i
eonsidersd. (Authorn' abutact.)
DruA 1Mr. (261: Administration by stoenaeA tube o( )6.30 dosa of 1 tTM of
20mrthylchotanthrene to S)rian poUen baeenten tardwd in tAe oavm,tes or.awmow
a!1 tumors of the foraiornxh, adenaareinanas of the unall and Lar=e inteiune, adeno- .
I
~`°~mR ~~~~ +~426~'~
E_1
Horrnacte
148
areinornas of the mammory glands. U+eeorws of the ervaries, and sebaaous wmorsa(
the skin and eer dutrt glands. Of these types of tumors. only a fetr spwmous cell pepil.
lomas of the foratomach were observed in control animeFe. Inflammatory ksions of the
intestine with hyp,erplastic and atypinl glands were a common WtdinS in both ewpcri
mental and control groups.
Durm.u and Surr;.. (33J: To a.Spr: . the lumn. of the hanWer efophagus, poly.
ethyk:ne cvffs wsrc surgically implante0 around the..opAeps juu above iu junetion with
the fortstomadt. This procedure resulted is atrophy of epirhdiuat at the level of the cuR
and pro.imal dilatation af the esophagus with hypertrophy eti muscle. lnuo(a)pyrene
(lfP/ in dimethsl sulfo>tidc (DMSO) eshlclewas instilled twia.eekly for 5 weeks in the
esophagus of hanwen w;th and without the constricting suRsft and eventually Rwpiaoma-
tnus lesions and stypias tkvcbped is the esophaius and pepiUomas in the lorcstonuch
of sonic ef the hamsurs that survived to ys orer 1 months. Though ksions developeJ
in the esophagus and foreston+xft in hamaers is both groups treated with DP, there wrre
differsnees in the typn of ksion. and in s+nirel tinta. ln the esophagus. a papillary tar
einoms. panillomatowm and an ares of alluqr etytw de.dopW in 3 of 1 hamsters with
constricted esophagus; a papillema and /i.e inuanees of cell atypia deveioped in 6 of
I t hamsters with nonconstricud esophaSus. The aSa of lunnten with ewphatcal laions
in the constricud group a.enpd 6.3 months kss than in the nonconstricted group. In the
forsstomack, thcr...n fe.er O.pillomu ar affected hamster in the constrined group.
even though thex hamuera.we 4 nsoetha taldec than thoosewitM qstrie pspllontae in ths
noncomtricted group. Cssrrie pepillotnef that h+d oroSrassd to eantinana stsre found
only in hamsters .+tlsout eonstrinioa of the aepAtSue.
Ewt*roro n d. (36J: The eemperstM tardnogenieitiat of 2aeetamidoAuorene. 3.
nr+ethykholanthrsrte, and 2aocumidoQuorane plue 3rnethylebolantNrene iri the hamstv
.+ere investipted. Unlike the eaaewith ran, eo iehlbieae of tumor Induction was observed
when 3~hykboianNreru was fed to hamsters sinr<dt;neoutlywith 2-ecsumidoAuorsrx.
Combined fecdinS or 2aeeuntidoAuorene and }or++dYykhoiarJthre>+e rasulted in adeno
orcinoma of the intrahepstie bile duev, penaatie aderoourinon+a. and mesentertal
sarcomas. while benipt cysudenoens of the intrshepstie bile ducts were the only tumors
observed in the hamsters fed 2,awumidaAuerene alone. AnaFyus for urinary meubolita
of 2.aceumidofluorene rewkal relati.e(y IutN elfa! of 3rnetAykl+olanthrene when fed
simultanoously with 2oeetamidoAuorarw. Likewiw, the continuous admtnistration of
smnhylt hobnthrsne in the diet sinwltaneously .me 3-ecsumidoAuortne aused no in
aease in the hepatic N-hydroeytatien at:tivity in .iiro aa compared to that of hamsters
fed only one of these compounds. One oossibk expt.rouon of the synergistic action of
the combined foedinS of Zaeaamidofluorens and 3methykhotantbrene in producing
tumors in auahepate tisirres is that d'+aary, 3nsthykholantltrats enAanoes the N-
hydroayladoe of 2sanaeudotluorene is thess tissuei
Hta%oLo (661: 23 rrq of Nh1U is 0.1 ml of nterwere given intravenously monibly
for 3-4 tt+oatM or I m{ NMU in 0.2 tal pnr..rs Siven inuat+eritoneally at weekly imer
.ek for 4-S months or tnuapsuitally, twiee a wark, for 4 months so groups or to Syrian
Aamsters of either sa. There wae 43 eonuols reooirinS no treatment. 'The sdenoeareno-
eus of the intestine isduwd in Syrian hamsun by N-mnhlINniuosourn (NMUI wcre
of two hiuolo{inl types, supe+flcial and intatinaL These types had distinctive characur
luits reprdinS pattsrn, q-toloSid fawres, secretioe of muao, aed trode of powth.
L..r ~f f`c. Hf''f S...l `W' 2C°'..It 3G
