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%s'ORASHOP: CARBON VONOSIDE s~D CVD 2 Is 0.5 FrG. 3. Ox)cen consumption and carbon monoxide emission in groups or Spracue-Das`ks mxle nts ordl(Tcrcm ages: rclalionship with body wcighls. monoxide b~their hemoclobins and plays a role in their possible resistance (or adaptation) to small concentrations of ambient carbon monoxide. CONCLUSION As was stated earlier, «e have studied the effect of acute doses of carbon monoxide and nitrogen h}posia on four types of .ertebrates: rats. mice. guinea pies. and quails. _ _ as a2 al C n Fi} 5 02 60v504PilaX IJ11/Ln 6a1 I r r r I r Y . 01 az _ as 10 Is 2,0 30 l0_ . Fle_ 4. Bi!ncanlhmic relationship beta-een carbon monoxidc cmission lordinalccl and ox.rcn con- sumplion fa ~-issas{. Measurements are made on one nonsmokieg man, groups or male raFbils, mIe nls, and male mice. 1 L -_ u ptV'd ISSaS

YIO_=" STCPFEL[raL- ralues (4, 15. 16). Some species hacc a propensity to a noclurnal (rats. mice) or a diurnal (quails) respiratory and aclicily maximum; other^(Fuinea pies) shoa• rto- narked differences related to a light periodicity. 3fore precisely,lhese circadi;m h)thms are s)nchroniZed indep<ndently from environment factars Ilighting, I em- peralure, noises. feeding, elea. It makes little sense to study nocturnal rodents mly in daylight. \4ith the possi6ilij, ofc(rcannual .'ariations in carbon monoxide toxicily, the time of the years.hen Ihe expeomenls are performed should be ,oted. Furthermore, (he large differenecs in the life spans of different species rats, micc 2-3 )ears: dogs: 17-15 )ears) must be considered when the age ofthe animal is taken into consideration. ?foreover, in many species, the life span under aboratory conditions is unl.nown. . In addition to these general staiements inherent to animal models, more specific )roblems are ecident. We refer to carboxyhemoclobin, hemoglobin dissociation, ar.d endocenous carbon monoxide formation in different senebrate species. The studies of carboayhemoglobin dissociation curves and the reaction rates of he uptake of carbon monoxide in a limited number of laboraton' species hase . ,hown inlraspcciGc di(ferences (5--7). The displacement to,cards Ihe left of the H/d. dissociation curve by' carbon monoxide decreaves P;r. Thoueh the meaning >( the relationship behceen P„ and body weiehts (1a) is debatahle (8). it is ecident hat inlerspecies differences in Hb-Hb0_ combination do exist and are inp,uenced >) many factors. It should be noted that carbon monoxide affects '_.3]iphosphoglitfcate in rats (6) but not in rabbifs (IJ). Endoe_ecovs carbon monoxide pro ucion appears to be related to body a'eicht and to ox%ceaa con- ;umPtion, as noted abo,e. in groups of male SPF Spraeue-IlawIey of different agcs (Figs 2 and 3) and in a Cew individuals of different species (Fie. 4), It is not <nown uhether this zndogenous production of carbon monoxide. which is tela- ti~ely important in small rodents. influence5 the uptake and release of carhon -~Lf T 30 Lto ISp }J] 730 >]J Fe 1. Onren m mp~mn - E-bon mm.a.6fe mns- n ymups of _<p;eruc-Da~lry-le ...: ormsrrrr :cPdr.3 „r /~ "Hb0 z- ~ r r- ~ ~e%l. IIII L' l [ t 1`?S I /k;lV t

STCPFEL CT AL. TABLE ! Pf.[L~laG[ $L'.,lR .L FnLLO..:IG - AC, Ir [wc60~ \1nI o\IDEI11DLIrallO' - Are IE,1+1 4.!n F.rtin N l >5 ,.pe.ur. .... % 16 69 F: )l 101 61 ICU l6 IC) n, 6 )I ;nF.e-D,.Iq U, le 'FE b_ . Bed) .eir6' 1.) }lak, !<mak Nin 111 _ 16 1)1 _ 16 SIC6 4. e.l .) 4 2)3 e08 )C1cLf ]0.-0.1 `5cI-3 136`. ]61R 11J~03 `J }I6ell a6_1U Jl _ la nPCll 1`6 .:) .n) )I ~b = 56 l1! _ )) ]6 s' 5u-.)1`:I F.calo P• FS • Su .:al ,.pnTun,e ufl.nl.al 4rls~a. tei.een rvl., „A rroaln. n_vinE u,lq ILe q ,L S5. Castration of males and females at lhe ze_e of 3 s.eeks decreases bul does not suppress the difference heNCCn seIes of survival to an acute carbon monoxide Intoxication (Table 3). - Adrenafectomy, performed in youne OF, male and female mice 14 days before Ihey wert submitted to an acute carbon monovide iwoxication. decreased sur viva7 in males and in femalcs ITable 4). A similar response to adrtnateclomy vas Dbsen<d in both sexes of that same ftrain of mi<e submitted to an acute hypoxic challcnce. . - Precnancy decreases surcil'aI ofOF, female mice. as shos,n in Tahle 5. females (precnant and nonpreenanq left .ith males are compareda~sircin females and males of the same a_ee. A comparable decrease in survival due to pregnanay uas obtained in OF, mice. The eaislenre of a Fenetic faclnr in acule nitrogen h}pocia resiaanee ,as drmonstra;ed in quzils flll. We hal'e also found dilTerences in resistance to h.poxia in different strains of SPF-mice tOF.. CBA~ C571YBI Ssisbl. but hace found no dala in the literzture concernine_ genefrc_ varialions of acute czrbon monoxide inloxic3tiUn. TABLE ) Er rscls or C.srnenu. o+ : rf Suxclr.L or 6FI)n-Oi u OF, ]hce FoL a>c ERw=LxL lo a AccTC Dues ar C.eso1 Jlo1omloL•- StL Kombnr Bod. ~el_cM1U 1€I Sunl.al P' - curval Al 6' )I T :0 )1 i 2. _ ~` a Gcrmcd M 6` . 19.] 69.}6 fnW~ ' 1r C_rl:ol F - ts.3- 9o )S Cae:.-a:ed F .r6 27.6 66 96 ' Ml;e .ne o,zled w her.'I dal s old atLl{L`cy'InLNS.n ~~aol TABLE ) E/nCnsnrCu:n.no1 11 vrtSLC.n.LCZrSD,I A,DOF,''. _FOL:+:~cF.cr - AcL:[Dnc rrC.-an..`. . i ' StR 1--.~.: Irir CI Ccnuol A1 N al T / Cacu:<d hl M1- -9 ) Cenl:ol F ! , Gl:ra~.a F ~~ : -6 c 1i`. ` . nr r .icp Ihv R ` FS. m 1. .a .p'-- 1 :I ]' '031 69 ±6 ---' -44~ '°5 9o `s s6s-~ K~

\COR[SIIOP: CAR9ON >IOSO\IDE \\D Cb'D 19. SlupkL IJ.. 51nrJdcr, D.mhnne U.. and P,«ol. J..L. The.a -, or+ue.m.~Klc e.haua Fa, and ir s comPoncros on iui nca Pip vachcal pro-su.c. T..rir A`ArPl. PL,. ...:e• .d. IJ. ul l-f I I 11915). 20. 5lupfrl. \I , hlnerel.l- P._ and StaFnler. \L An aCrvrrnrll ('+raLC.ical acllca nf nF:ng. Drvo•e nrarure hppo.ic nonaLr) in nole aS"d pr:.l. Gr..•m.•1. !0. I V-I)611V11b ]I. 5 Y! 1. \I. H Ibr F F>1 d 1, D - 4i and fl " \f. P p ;n cbr nbinl p fpollu'.Ch A- • i. _.1119]. /~L~r 7 25..SU1rl.U_te. ,A.1_Der e\L.ad\lzseHH- . I l andrema/o :~rw:rnn orlnronolo~ralanden.no.,-en„Irannn.A,a:.sr,~•r&n•, ; lt4a.~'tEr~ ~ ~04 I 11n1 aQ 10 -I[4t1[9]BI U. Sm;fd.\f"f.5~c(u 4..ROman-,R.Tnn.>LH.a-.d?fouu.J-P.Llfdon,r•;ucweofSPF\~/ u au m.ol e achauea Cas di!mion comai mF ]0 pP'a C. m a o L~ArJr Fiu r.•. n. Xr nY4 26 D261b'69I19IJ1~ !a. $wpfd. AL Pcrranun. A.. oasp J. \L )Ignicr. p1.. an] Do..a. ]I. Bod• d:-cpM1i•m.and ca GRttc,ze of rnislancc m an acwe Yc;n\IC challc-.cr in rNCnu and baJ• n' d Rrnnl +_ . ves - L.&..d•r.n. PM1-d. A 59. y:-ay r 19'SI. 25. Theodcre.l. O Dunncll. R. D. and 9acL i.. \_ To.r.olra_, evmlim m caen monovJc m ' humane and alM1rr, mammahan epedec.l. Oru,ry Jlyd. 13. ]: -'S:119c11. 26. Thom t\I. F., and Penner. D. 0. H~IeF,c rasyon. n m c.rNn mono.n•c and sLh.dr A ~ A hemaT0~04/C ompanluesmd)'.I.APy/.PM1n~n/ 33.3b<-36911Y 11. 2). RFnslnn, L~f , a..d Robem, R 1. Gluco.e eantnlnra felo.inp earbon monu.ida or M1•po.+c 6)poJa c.po•ure. HbrrFrm. PM1nr•nnrrl. 27. SP-:F0119:61 28. q'ins;nn. J. M.. and Rntene, R. 1. £Rec1 af po!ar.ium o a-a:e nn carbon rronoude and h.pnJe hlpoua-mGucM IClhalny.l. Tnricul. £c•von. HrOIrA 2. M1`c-6311191i1. PI! `~ G.-Im

I I SxOFASHOP: CARBON VO]O£IDE xFDCVO TABLE I SOnwu nr OF, >f in or BOrx SGre Esrna D tn OIr o. Tao Sr ttnv-r CO oa H+ravr Pu~ons .r I. u.c.u ar 2-3 hr Or.rc,rO,urc ' T.o c.rosures Con rals- - Prt urosu Srcend c.pnsu Scr Arc Nn.e So.• rl Fo. s nl rdapsl Imal tmal ul ~ _ L~uvnca P AI .CO. CO CO )1 -1] T0.fi) ]0'S3 31J! 74 laT ICP9 F T _ 1 41 47 - 89.36 e!e3 IC0.00 +963 -'/1.-6 N5 • DI 99 co H oa CO _so am <9.` 'aPl.9r Ir59 18" ~F I 99 C Jl 89.)6 E9 II 95.83 6170 9' N+ >u5 ' to 76 Ht .6 II.L `J9 10'_0 F 76 34 49 69.39 ]a'J IoO.Po .- J ]0R - ry+ r / ~ f- 'P<0.03:••P<001~ / ~NS,MT^frr}'MA'y~L~A PreriousexposuresofOF;rS,V~micetnahighconcenlrationofcarhonmonoside (J +r or to h7 poxia increase the reslstance lu a lethal concenteslion ol carbon monoxide _ (Table I). This con6rms the report of 33inston and Roberts 1281 ssho shos. a ~ F S {~ [= sienificant decrease in death rate in rmale Sa'iss 31eF4cr mice induced b, expo- /~ ~ sure lo'_500 ppm of carbon munoxid: follotsinc exposure to 500 or IfiCO ppm of r I CO for 4 hr. This protection could revLk either from a selection (uur datal or from ~s an adaptation (]8) . . i In addition to theie en.ironmemal factors. intrinsi: factors are capable of in- fluencin5 carbon monoxide toxicitp. J~'e have studied Ihe effect of seti, hodx si'e, age, preenancy. castratioe, and adrenelectomy. - A sex difference in survival from an acute carbon monoxide challence •.as _ noted in mice and rals that at comparable ace differ io bud)'s.'eight. The mortality is greater in the ma)es. whichare the lareer animals. >foreu.er, rhis sex-relr.'.ed diRerence in carbun monoside toxicilc increases uilh aeine-- resullirc from the increasing difference in bod}' ..eieht s.ilh ace belween the sexes 1Table ?I. In Japanese quails ICwurni* rou,rnir japanica). uhere there is but a small - difference in bod)- ueight benreen sezes. there is no sex-rdaled differecce in carbon monoxide monalitv ITable 2/. A similar sex-related dimorphism in toxiciry uas observed in rzts, mice, and quails submiued to an acute nitrocen h~poxic ehallengc QSI. - As shown in Table '_. in order to stud, the eeTect of zee, Spraeue Da..Icy rals of both sexes.and of three diflcrent aces (98. 334. and 56] days) s.ere c(sen the i same carbon munosid<concemralion. It can he seen that, in rets. ec:ne inaeases , significantly survixa4 after thls CO challenee- Simila: resuln were oS;ained in senescent male Sprxgue-Daw lep rets r<hich are more resistant to an acute nilro- ! gen challenge than smmc and adult ones. This results in pan from a selec-ion due ~ to spontaneous monality due to ag_Ine ('-0!. I

.. t)yb-_-._ Srcl'FELCrIC. TAHLE 6 bi~ rm C.aen• 51o•nar r E.ro . A-Dm1nF alblife eaposure. \lale ratslSr'ra[uc-Da.ley) 8oL1 "<c[61s. fcoJi and v inla4cs,9,,,.--- Hon n. QRSt amplhude. artb.rhmlas. FCG abnormalilies - A•oidance ennditlnnint Ifm: <Ir, Wc sM1ocA) Necrovries: Ndner.. aor,a. wope. wmors IM1istoW€y) - ~Durin: and afmr a!-non16 esporura >late rals (5prap-Da.lry) Or6an ~<ighls and percenaFe .a.er brain, hezn, lldnry., IunFS, ri.er, epleenl reno, sAin. BieeTemic.at blood dvz. CO. hemedobin, Flueovr. proin.+s.liplda, ebnlevernl. Ca. Ng, SGOT. SGlrf H<rnamlr~Gy: bemrncrir «d Nood c<Ils, plar<krt, s.hlle b!nnd cdle. nnnrephds. II mphocpres, <osinopbh. montts es - C-Aher a Jbda)' esposur<' >la:e ras (SPaeue-Da~tq1 LDafa , /rulcnt.naio of5nrm:.i rnarrrarrnr IG. eoulcyl _ Hamoh6e <ornelrmcnl tisr 10 Nau!e/ l - 6-Duriny . iDdaY eaposure: ]we a~r !GVrosue-mwl<>! l -slumnrtsranedl - E-_ DwinF and an<r s 11.9y e.pofur<: Femalr mic<OFr . - Fee-dns.dead fn....... in, - AsphYnie s.l un adu!I mi<e durinF me'LdaY evp.,sure ASSOCIATION OF CARBON 67ONOXIDE WITH OTHER ENVIROM AENTAL - AGGRESSIONS The sludv of the action bc carbon monoaide alone, hos~e.er, is unrralisne,- since carbon monoxide cene!allc is associatrd vith other producls of comhu~'on, euch xs carbon dioxide or a decrease in oxygen concentration. etc. Lowar con:entrations of carbun monoxide assodzled witholLer roxic compo- nenls occur in cieareue smoke and aulomotisa exhaust. Ciearel!e smoke and aulomotive exhaust contain both gaseous and solid compounds of comparab;e concentralions (17). «'e have studied the effects ofdlfierent dilutions of automotivic exhaust and the eRects at diRerenl diluliens of secer 1 individual enmpon<nts (carbon mmroxide. carbon dioaide. ni«ous oaides. and oxaeen) on urethanized and arti5cizlle tenti- la!ed male guincx pigs. Chanecs in pulmonary resis!ance ftrachral presswc), blood pressure,and histamine-indnced hronchospasm ware delermined. Results indicale that carbon dioxide and hypoxia srere at least as active as carbun monovide. and Ihal these compocenls in automohile exheust can either potenliale or antagonize the concentration threshold required by individual gases to induce chaoges in pulmonary resis!ance ( 19). Using this technique, are also observed that cervical blsaeolomy decreases pulmonary resistance caria:lons provoAed by a ninh cnncentration of carbon monoxide as uell as br a severe nitrogen h.poxia. 6r zno!her sefies af expenmrnts..ve exposed SF F mzle Spr,reue- llauIey rats r !wodilctionsofavtomoticeexhaustgas.Theexpovlrescas8hrperdap(durine the photoperiod), 5 days per eeek. The length of time of the exposure ar.d the cuNents of!he two dilutions of ar^omoti,e exhausl gas (60 or 45 ppm of carbon 50 ffm i ~ O C^ i

N'ORF:SHOP: CARBON MONOXIDE xND CVD TABLE 7 AuTOMOTISE E\HACST GAS E]Y[xCAE _ 0.fale rars (Sprarue-Da, lcy) _ A. OurorR nfFLfr rspnarrc Dilution B contair.ing: 60 ppm CO. 0.037.^. CO;, 14 ppm NO'. I ppm A'O_, '- p,;m atdehydes. <0.5 mgliien codrocarbons. I ppm \]4s. 8.5 yg'm' lead Body ueighrs. food and water intake. '6'c,,. Heart rate. QRSu amplitude. arnc%ihmias. ECG ahnorma)ities A.oidance conditioning (foot electric shock) Kecropsies: S,{dneys. aona. lungs. turnors. histology Bone (tiFia) Radford: Ca. Mg. Mn. Zn. Fe. Cd, Pb B. .Urr n S-ranruh rtpuvve: Diluwion A containing: 45 ppm CO. 0-0fi5i CO-. 0_' ppm NO'.0.1 ppm atdeh)des. <0-5 mgliter h.droc3rbons. I ppm NH,. 8 ygm' lead . Bods ..eichts - Organ ueichts and percentages ~•'aler. suprarenals. brain- hea«, kidncys.lungs, livcr. splcen, testes, skin. carcass - Biochemical blood data: CO. hemoglobin. glucose, proleins. lipids. choleslerol. Iaciic~ SOOT. SGPt. LD (sH Hemaioloe.: hematocril, red blood eells, platefets, uhite blood ce)Is, neuirophils, lymphrr . ecles. ensinophils. mor.ocytes C. Afler a?.S-rrrunrh r.epnsu.c Dilution B(composieion above) Bodc uei^hls Organ ..eiFSrs and percentages kamr: suprarenals, brain. hean. kidnecs.lungs. licer. spleen, testes.skin. carcass Blood pH. blood Fuffering capacity - - monoxide) also differed in their other components, as shown in Table Z This table also-shows the parameters measured. Most of the results previously published (?3) show an increase in suprarenal .~eights and blood neutrophils. Dilution B which contained 23 ppm NhO_ in addition to the 45 ppm CO produced a decrease in body weight. a dimfnlinon of sound-avoidine reflexes. and an increase in the number of spontaneous tumors. In addition (12), a sienificant increase in lead was observed in the tibias. The hieher incidence in spontaneous tumors with no spe- cific location mieht be ascribed to the great concentration (23 ppm) of inhaled nitrogen oxides, although longerity «as unaltered. As previously shown (Table 6). ue have associated bacteriological action (Ser- rnlio inarcescens) and grafis of Guerin's tumor to a 56- or 42-day exposure to 50 ppm carbon monoxide. Hotiecer, no signi5cant difference was obtained. DISCUSSION The validity of animal models in studying the effect of acute and long-term car- bon monoxide intoxication must be stated with qualifications. First, it is difficult to compare one mammal species with another- This is due to size variations which reculate heat losses, and thus oxygen consumption, and hence respiratory ventila- tion. The latter influences the intake and the elimination of carbon monoxide in the ambient air. Such a stntlation difference, resulung from a sex body dimor- phism, may explain most of the sex sur.ival difference in mice and rat inhalation studies with lethal concentrations of carbon monoxide or nitrogen hypoxia. I Second, circadian rhythms must be taken -into account to define toxicological 'ej

a~fe _ srurFELLTAL. A lUhal concentration of carbon monoxide appears to be the most easily esti- i E mamd paramucr, but for accurzcy this must be determined a[ Anown barometric pressure. temperature, hygrometry conditions, and a specific time oflday. The lituxture does not gis'e sufficient data concemiac different species in on- anesthetieed animals due to-the diffculty of blood sampling in these animals. Figure I shous circadian .ariation in the action of 330 ppm carbon monoxide on respiratory aaivity when inhaled at three different.times of the day by a group of 17 Spracue-Oawley male rats. Their respiratory metabolism is gauged by the continuous recordin¢ of the carbon dioxide that thec expire in a chamber venti- ~S lated with a conslant air Oo.v. This rtpiratory activity as ts ell as their displacement ~ activity (LFB Animex actometer) are less during the photoperiod IX400-IN00) X •shen the animals rest and.'or sleep. A concentration of 730 ppm carbon monoxide X ~ in the atmo~.here of the chamber does not change the Vr,4when inveduced in sJ the phofopenod (from 1700 to 1700 and from 1100 to 1309) but sicniGcantlc dc crcases t'ou_ uhen introduced from'300 to I00during the dark period. Similarly; a \~ concentration of 50 ppm carbon monoxide does nor chance t'cn. tehen introduced 1; during the photoperiod but decreases Vco_ svhanintrnduced during the dark pe V- riod. Accordingly, in groups of male or female SPF Spracue-6auiey rats it has .~ J been demonstrated that vanations of L'r, are proportional to the concentrations / of the inhaled carbon monoxide and are g~eater in the eircadian dark period than^ t~ ~~ Iicht photoperiod ('_ 1). These results can be explained mainly by ventilati6n, as the absorption of carbon monoxide is greaterduring anicity than in Ihe rest period. We are unauare of anv studies describing.seasonal variatiuns in carbon _ monoxide tocieity, but sae found in.OF.. SPF male and feniale mice. sienifmant •easonal cariations in acuie nitrogen hypoxia survi%al O]L In man, epidemiolopi- cal data has related cardiac and respiratory death rate in Lns Angeles County Iu yearly atmospheric carbon monoxide varianons (3). ~ xnb,co os e e o c e n a e v a n e v e o a v u a Fie. 1. Culen [lo.lee c caa.a a pro.y nr Il SPF S, ra,.r-D..~'et ml.. n<M1rcnied F. f pM1t I Wn- INNI ara du rlncse t 16C9-NNU penods: C0.. , anudon /s frcaRrdi, d, tEc ~IiAres.i v!„ch rnrtc5runas r., &'e a c per+oE d LSe _ir..a.. Con;<ri ns or uU ca-}m . dCe erh ztuMee Ar:ereniL ndunnE~ne a t:er.zraar.v~dae,mmicuz T+n2no!_a ~,e.rinF~he6¢Mpedodb~dna.nccrcutzn{nF•ztxiloneunreacazrACCn.dlzreuna ±annqroern,d.:-wmeorlhee,rtbri d,-dev _ - I I G.oS~ Clx \f .L r

: n.• \YOF/:S/IOP; CARnON MONOXIDE A;tit) C\'U TABLE 4 EFFrcrs Or ADers.ucsovr n.- n/r St'ar.Ar OF Atel r A.n FT.ut r OI', M u1 . 49 D+ss OF AcE Fottout.y AcuTE Exs•DSUaE 10 C+RBO. sfO~ovDL- ~ Bodywcights Suni.al -p• Scx Numbcr 161 /'.%1 a' Cortrol !d 52 29 32 51.9'- . <0_01 I Adrerutcclo:,y hl 50 29.'-2 32.00 Control F 52 94 ?? s-1 56 - . <0.01 Adrer•a:ectomy F 49 23.18 6122 ' The earFrn r..vooxide chaacnce was-performed 14 days after xdrenateclom). • Using the z' test. - LONG-TERM EXPOSURE Long-term toxicity of small concentrations of carbon monoxide is of a paramount interest since epidemiological and experimental studies ('_) suggest that a concentration of 20-50 ppm may potentiate vascular diseases in man, and that such concen:rtions may he reached t%hen smoking or exposed to air pollution. Lone-term studies use rats and mice because of their short life span ('_-3 years). Several studies (6. 9, 10, 25. ?6) indicate that even if a concentration of 50 ppm_ is tolerated, 100. 200 and 500 ppm increase heart tceiehts and enhanceF ercth- ropoicsis. Tahie 6 shot.s the eaposure.penods (5 days per ttcek) du:in, uhich tTc e.posrd Spraeue-Da+rley. SPF rats, and OF„ SPF mice to 50 ppm carbon monoxide, and the phpsioli,~eical and biochemical parameters that ste measured. The results. ti.hich have been published pretiouslv ( IS). shoit no effect eNccpt an increase in b!oad carbon monoxide. Of parlicularinterestisthe ab>znce of effect on loncetiv. - The sienificance of the conclusions of these previously mentioned loe-tetm eaposures is li mited by the small numbers (eroups of 5. 10, 30 animals) of animals used by many of these experimenters. Thus, they-enable one to apprcciate onlc gross and freq-ent phpsiopL:holoeical reactions. RoTSexer, the mer,nine of thcse previous data is reinforced b}the fact that they tcere generallc carried our inde- pendently in dlffercnt laboratories and u-ith different strains of rodents. T.ABLE 5 PsEC>.. cT A,D.icolE C.a:.ol NtOSOaIDE IIio\lurnn~ OF OF, Vlcc. 10> Das OtD• N'u^:Ser (F) 5o:•.i.al I :1 CO_:rot fe^: 4) 2-1 :,.19 Fcc.J<s Icfl 15 d2_ss \Cl!h feru.cs 57 '9.6 -:.'6 wilh nzcs \t';;hout feluses 43 19_ '0 Males I CI0 T.f6 0 N • Fe^atcs •'.crc left ith mxtes li malc for 5 fem-lcs) during 15 dais. • Using the x= test. _I _- __ I . _-- . - - _ ~ re:.n TABLE 5 PREGNA]CS AND ACI:TE CAFBO1 M0~0\IDE 1Ci0%ICIT10\ OF OF, NlICE. 10 D~15 OLD' r~.,~~ - B.1s weiFhts Sur•i•'al P' W N lumber Igl 1~1 x' N Control fcmalcs 43 27.2 44.19 M.l < O•os' ~ Females left 15 days K'ilh fetuses ' 3 s9;s 19 ;o w with males ilhout fctn•es N I.A • Fcmales were IefCaith males (1 male for 5 fen'•alesl during IS da)s. • Using the ;' test.

SrL'PFELSrAI_ Our results sho- fie impertance cf emironmental and chronobioingical factors for both 1)pes of imo.ic:ltion and the influence of body size, exercise, aee, se:, and endocrine factors on this intonication. Our long-term <.periments s.ith 50 ppm concentration of carbon monoxide. in :ombination +ith other environmenlal factors (compnnents of automolive eshaust. e.perimental infeclion, or Guerin's tumor), have shoscn no physiopatholecical effrtcls- This raises the question of the choice of the animal mod% Possibl)', rats and mice are relatively insensilive to carbon monovide or ndoeenout carhon monocide producliono or, more simply, perhaps ca~r-:':..~a-0e r_- caea ha.e been inopprupriato. Consequentl)'. se+erxl apecies should be studled c,~dar specific en• ironmental conditions and Ihese vodies should then be used in =onjunetion .ith epidemiolooical and clinical studies in man: REFERENCES I. Baler, G. }L_ and N'richr. E A. ERra+ of earbon monnaide on Insras. BrJL [m don. Corn•rrn. 1n.nal. f/.93-IM119T. - . Gordem•.h. 1. R.. and Aronnu, N. 5. Ca•Fan mono.ide and coronary Ecan disrase A re.ir..~. E~•rnn. Rrr. 10.'_3R-VS/IWA. - Gald+mith.l. R_ Terrachi.l.. and V/adnp'.1. D. E.alua!ion ofnuclualingCO eapow.e.. A•rh. EnJron. 3/rclm 1.61]-663 u96I). - '. HaJ`crg. E. Chm:.aMalnRr. Ann. Rn. PhradA. 31.6'•-]?51IS691. _ Hol uod. R. A-B. Reacuon ramsofcarbon monoaide and hrmogluGn.Ann.6 Y. AcaJ. Sri. 1]9. IV-1]1119-01. 5. looe+. R. A_ 9ric\land, J. A.. S:umlard. 1. A.. and S'.aeel. 1. Effraa on e.Frnnenial ammms uf lorylttn in..aanon upomrr m ca.-Nm -nnaidc Tnrlral. AP'!1. Pharnarnl. 19. =6-11 fl9]H 7. Khmiuh. HJ. CTe+al'se H I. HarAC H. P_nnd Dumen.il 'A'. Cpla4e o(ca~bon mono.ide in FInoE orn,nhrure plgs and omer mammals rndrne,c, 3.301-3m/19]5). l.Lzbri.S.Blaado na/Lnl ardal.ml.u.erll611nninrala•mnloM.dywaghrinmamnxle. A ./P' -af. 9_9 _619"_I. ~ 9->I 1. \.P G R u.A \ M1 P.la KlLsA.F.T. lr A V.H. .dO^<nLF.N' _ Col. of labcn n n mu\s lo lo mncen,ral om of c rb n nade. Arrr. +vurr Vrd. 30^! ]1 `5]9 11959, D lo. Prnerf. G. G_ Pao!.am. E_ and 5enian'Jn. M1I Corone car1,,n menoJdc e,p.nere 1ln+e mune nf Ecnoc~ehn-he.m . dchr ani lauas deh• dm_er.a.e isoa. cv changas. L•urnl. Al'PI Pl:nr- nrr! S8,l91- 19]119]L. L P {, Ncn P S Pf I ll.1 r 1 JR. a d V VSf !'d ce cYea I. e ///1 1 fv. c e d fr - ge cq 1 n ee I- rhVry -. C R Acod. Srr. D 2g~ pl 131 /19 61 : R d d E P. Pcn al . r-.m 9]a 3. R /.1 .1., and [ per P. N'. E9 ofevFen mono d eqv es .6 i- IDMJ ra`-hs. f. .l; pl. PM1 r ru,l. Al. 689-692 119'6). I< SchnldlS.elsen. K Energq ncutcliem. body elzr and proFlem, of acaGnS Frd. Pme ]9, 133a-1611 1 ITaI It S:e;!ct. N. Bm .:hn culcgf and pha acoingy. I.Oenerelltin . utadian znd uezdan EorE.: v RL.~ 13, Ig-J<119]51 - 16. S:urfrl. 4. B.e:l.nhma r in or mlog~ II. InfraCnn b.orhlil.mt and general d'uo.nsion. B•nr:rJ~ci,rr !J I0S-I11119]51 ~e - onsofau.oesbauuma vF•;vrnn./IrcM1hPrny. Ir.Sm-ld.\IFm-ad+nneeso.+rAe m Il.'_`1-]fl5119-61. 18 Y.~pfel. V.. a d Bouln, O. PE15inlo;lcal and tnochemiaal eneeca on ra ard r',;e,MseJ lo n.er.n. ion, of carFom mxnoaide for lung period:. Aen..V. J'. Ared Sri. 1]a, 1C-168 rrl9alOr rn 1 /"- Irizrv"" lF 13 T 0