Document kDNjJj5a4wqQ5Oj74eLdJxKab

f f"l W ' . |< , 11 r 4-e.r( .i -il %ilv_<.l o* '''O' ''tV ftMUinJrvjic*'1 MuOH'S on ;i.ut 'ol*`v.in( m tli" r*tt":witiun r-f nifr.Ai Mudi*lX M t realm effects *udv`og topics mentioned above 'itted to the journal should con 4j> tor Authois" and should be of the editors .* back cover V-. a '*'.) On^tr.ji 1`a/u`i i Occupational Chemicals Tesled for Teratogenicity uraJ descnpfw* namr-s. trade ws etc , iri th*s (ut)lication. oven -ot soecil'O.aHv identified is not jM.ii suet' names ar c^cn'ji: protective laws and regulations 'gJy l>o used freely by anyone tv offprints Of each article will .. authors free of Charge Add<- be ordered at cost price at the S are returned formation 49 (4 issues each) will appear n back volume* are available on Mion. we also offer microfonr tun and 35 mm microform anc 'pondence concerning subscrip iddressed to the publisher. . Subscription rate US * 385 00 and handling Subscriptions i prepayment only Orders shoufc ^ Springer Verlag NewYofk InC New York. 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Sitninurt. i mcmiimc w,i* mhuuU unik.'iiii:!': tilt 'yr.C'.hj^K.il kM.n*: of chcmid.iK. to which Lirttc numbers nj workc,"\ .ire owup.uiomilK exposed. 1hc> include metals. plastics muiini)H-i. .md additives. snlwnts. .mu! oilier OfLMMu' them/Calv Ilk* elJeeic.c u'l'si'N met* in the s!ud;cs were CrimpjrcJ (<> the potential exposures in ihe occupational environment as regulated In hxuicnic standards, In Icahi id the animal experiments. the 11 \`s for some organic ehennenls, parhcularlv im ac :> Imninle. methaerviate esters, sixrene. Carbon disulfide. ehlorolot m. met In k ne chloride. toluene and \\ lene. appeared loo Inch to provide .1 I'm >lute sa`etv !"t piecuian 1 u0: kers I lie nuxhattisms ol ler.itocenesiN and the \silidnv *! die .1:11111,1! experiiuents were .iKn eotu .side retJ Kcs words: Teratoeenie testing - (Lenpaliona! eheniu.ils - I:\irapoLuion u> humans - 'I l.Vs - l'rei:nani wotkeis Epiddmioloiiic:il Minin.", Irinii M-icr.il .'mmlues luie indn'iil.nl ililloren.'.'s in ill.incidence m am^.'inUil nniluirin.mmi, li. p.ircnt.1 Mi.inl tla.s (Lck 1977). ami by paremnl occupation (FcUnck 1976; Uicrkcil.il ami l.uml 197,X; Occupaiumal Mortality I97N: Lnckson cl al. 1979. Mcmmmki cl al. 19X11). Such ihllcrcncc. may be accounted lor by a number o!'social and occupational factors. However, in a multivariate analyMs on the association ol ilic maicrn.il occupaiion viiih malformalion. in die olTsprini:. earned out in Finland, a number ol social factors were controlled, and a siipiilicunl association still remained between the maternal occupation m industry and mallorm.itions in the oll'spnni; (Henuninki et al. 1981). Spccilic occupational acems have also been impheaied as leraloiiens in cpidciniolocical studies (Hcmminki el al. 1979). In view ol such results ami ihe variety of harmful chemicals used in the working environment, the possible relationship of ihe occupational exposures lo leraiojtemeiiy in the olfsprinii deserves further exploration. Epidemiological methods have certain limitations which call lor die use of experimental methods to provide additional evaluation on the teratogenic O.UO-0131 /N()/0l)47/0191 /$ 3.40 K 1 It rl'.'lt.llo f H t up I lit >" il Iff, 1 jMv* t Aiunul - in in.|M O impound R&S 024150 I" ij 1. 1 ' pi. 11 tli I'S'.el It, t, 1 11 !.t* it iit.li:[-. til Isi ,i it "js Itts 11 \ ;. ,,,i*: .f. '".'tltlit'ii ir.ttit llttk .mil [If I i 1'"' t .nit! W iim'II I I'l" ''l AUohol(nm) Ammopierjo Androgens Cahai.iIic drug's ~- IJlIMlIl.lfl --- Chlnrjmbucd -- Csvlnphinph.ini OivilnhidKcsirol properties ol ehcmieals. I lie limit.moils i'l ilie epnltiiiinliMjic.il methods in [he H.iloiluni; investigation ol occupational risks include dillieulties m the idvniilication til sufficiently exposed populations. rehabilny ol lilt exposiite daiu, incomplciencss fVkthlonn.iied hip . of registration. bias by tlie confounding factors, and tlie pc i hoc nature ot the Ih.'didnnndc information obtained. Several hundred chemicals have been tested lor ter.itogeiiicity in cspcrimem.il U'.irUrm animals (Shephard 197b). In ilu.s paper. I m.ill review the tcrutoecnicity tests carried out with compounds to which large numbers ol workers .ire exposed occupationally. I'reviously, occupational clivnucals h.iie been surveyed only shortly (Wilson |977h. /.eulhen Heid.nn 197N). However, data on medicines and ' Humiin cvkJchvs* cst.ihlidicd. + - * * D.iu ;ts collects' Reduced Idler st pesticides will mu he assessed as comprehensive reviews on these topics are available l Wilson 1977a. b). The doses used m the annual tests are compared to the possible human exposures as regulated by hygienic stamlaids, Additionally, mechanism of teratogenicity, dose-response relationships, and the general valid ity of the animal tests In relation to humans are shortly considered, * chemicals m esp reviewed by ses ! onlv wav to vah.' I investigate Die . I teratogenic in in. Dose-Response Relationships ' were based on i` The teratogenic responses are thought to follow' a tlosc-respon.se relationship as ( collected from b: illustrated in Fig. I (Wilson 19771. The actual shape of the dose-response curve i man. all but o depends on whether the malformations are scored per live fetuses or per experimental u.i implantations, as the increasing concentrations of lorctgn compounds always warfarin, apply n confer cmbryotoxicity and fetal deaths. In most teratogenic systems u is thought suggest a rcas." that a threshold dose giving a /cro-rcspoitsc can be determined. This is in and data in bin contrast to mutagenic responses in general, where any dose may cooler a probability of mutation (Auerbach 1976). It is conceivable that mutagenic The qualiia particularly hclj properties of chemicals on the germ cells may cause malformations (Harhison I97S: Hcinminki et al. 1979). In such cases, the dose-response relationships may any compound establish quanti resemble those of mutagenic responses in general. Unfortunately, . the quantitativs Validity of Animal Tests estimate the inn data on the rej The application of animal tests in the testing of teratogenic compounds implies frequently I'ailu. that a qualitative correlation exists between the teratogenic properties of observed). Alio. K. I U'lllinillt.1 Oteup.ili.in.il I er.it.'tens 'ii.il (tow-ctrix:l 11|' ill tCMIOgClliCliy iiunJilicd from Heck jihI i'1'l jml W il-on l m7.li i;ic;iI methods in the the identification of data, incompleteness ost hoe nature of the iitcity in experimental ic teratogenicity tests workers are exposed been sun eyed only `ala on medicines and on these topics are tests are compared lo ulards. Additionally, md the general validntsidered. ponse relationship as , dose-response curve lixc Ictuses or per compounds always systems it is thought termined. This is in Jose may confer a able that mutagenic .-nuuiions (Harbison use relationships may e compounds implies .genic properties of Talilc I. Aniiii.il tests u nli ei'nip.Minds Ui.iueht n. he ierai..eem. to man Compound M.i.r Alcoholism) Aminopterin Androgens C)lOMatic Urug'i -* * -- Chlorambucil -- CyclopluKpluumdc Diclh}lshlbc*troI - Diphenvllndantoin * Halolhanc 4- Mercury f* Polychlorinated biphernl* * Thalidomide -+ Warfarin - \nun il Specie* Onto une Chick. mouse * Chick, rat Several * H.ti rtai Hal. motive * + Rat Motive, numkev Rat Rat. mouse * Hog. ral Scseral Mouvc. rabbii - * Human evidence as discussed by Wilson ( 1977a. hi, . = established. + = suspected * Data as collected Irom the catalogue of Shephard (I97U) 1 Reduced litter si/e (Wilson I977h) I chemicals in experimental animals and m man. This appears to be largely true as reviewed by several authors (Wilson 197.1; Fraser 1977). One and perhaps the only way to validate the qualitative correlations-between man and animals is to investigate the outcome or the animal testing results with compounds found to be teratogenic in man. Such a comparison is presented in Tabic I. The human data were based on the evaluations of Wilson (1977a, b). The animal testing data were collected from Shephard (1976). Of 13 chemicals considered to be teratogenic to man, all but one (warfarin) have been found to be positive in one or more experimental animals. Two negative experiments have been carried out with warfarin, applying doses up to 100 times the effective human dose. The data suggest a reasonably good qualitative correlation between experimental results and data in humans. The qualitative correlation between experimental and human data arc not particularly helpful for practical risk evaluations, as very high doses of almost any compound arc likely to be effective (Fig. I). Thus, it would be desirable to establish quantitative correlations between the experimental and human data. Unfortunately, no dose-response data are available from human studies, making the quantitative analysis rather arbitrary. It is particularly difficult even to estimate the true human risk of malformations in a given exposure, because some data on the reported teratogenicity of medicines are derived front case reports, frequently failing to state the denominator (i.c., how many pregnancies were observed). Allowing for such errors, the literature on the teratogenic properties of K ) ! iTi itHMki | fXi u;' <' ,i <i '! J , r , 300 ii ii3 200 ! `J iI / lOO ;/ c_ _ _ Trimesters I Weeks Months Birth Fig. 2. Devcfupmcnt ul druii-rnei.iholi/ini,' en/\ me ,.e i> v tne\in l.ih, imtorv .. nim.il* .nui in hununi (Pelt,men IU79), ,*l. C'= e\ wieluotne J*--lbli-11 iV.cl! en/wne* in .imm.il* ;ind nun. H, l) - hmchrome t*--1-SS-lmtcil en/vmes m .imm.il* -nut nun, re-neimsel*. Smc the c.irlv aciiciiv nf cvmehrume 1*-'I50-Imketi amines in nun chemicals in humans and in experimental animals was analxsed m ve terms liable 2). I he reported dailv (.lose (mg/kg bodv wtj in human** was compared io 'he do.se*. applied in aniinal studies. The observed risk in the treated humans was indicated, d available in the original reports. It mav he assumed that the animal experiments reported relate to risks in the linear portion of the dose- response curve (Fig. J). The most extensive data were available for thalidomide. The human embryo appeared to be as sensitive as the most sensitive animal species, chick, rabbit, cat, and monkey, but the human was about 50 times more Sensitive than the common laboratory animals, rat and mouse. In each ease certain inbread strains were used and n is possible that the strains as well as species differ in their sensitivity. Relatively complete data were also available for antinoptcrin, diphcnylhydantoin. and halothane. if linlothanc is assumed to be the effective teratogen in operation rooms, Man appeared to be more sensitive to aminoplcrin and halothane than rat. while the sensitivity of man to tliphenyl- hydamoin appeared to be roughly equal to mouse and monkey. The data on the other drugs and chemicals did not allow exact evaluation on the species differ ences. The only observation to be made suggested the humans described in the case reports were generally exposed to lower or much lower conccntrations.than those used in the animal experiments. As a conclusion, the limited data suggest that man appears to be at least as sensitive, if not more sensitive, to the terato genic effects of chemicals as compared to the experimental animals. The biological basis for the differential species sensitivity may depend, among other parameters, on the feio-placental transfer of the chemicals (Mtrkin 1973: IK < -sU "If'v>r -:i V .Vnu', 1*1,1 lfU?> I! "I II H.IIUjyyM'l <-- -Iinms. a1-*', " ' I 1.11 R&S 024153 U rp: tfe \*H\ K iU'mr.mi. Pvlknrcn >v > l < ii i he nu t.ih* iIn:i . >' th-_ t: ^; > ; \u is \. it let me* lui*' (llcm.nntki 1979, i nutr cl ,|! |9"9, Ml ,ssni Mu..: :v 1. iimi.iIIs iL-t|is:tsilt Cil/yules c>t<> 1-1111 >n;I'-.tyti,,: i1- t-ls a-. ,M M'ih, ! he ,:.-i.i/ipmvii; i/I the 1 n/y me -ivif. .`if*. 111 the cn:h:y u .m.l ,m tfh.- p!.1 * nt.i ,:i: lit ill it< relate tu [lie teratogenic hazard-, ol the compon!,,!-- I iaurv 2 cltoa i!,k\ciop:iPvin.il appear ance Ol (/re fun enzyme attnna,-' in liurrurn and in , ',. /;i,.:.:oc,J laboratory nonpfim.jte ,pvcic\ (e.g.. r.it imee) (IVIkoiien 1979) 11:.- .u_tivj;\ ol cytochrome P-450 enzyme-. appeal scry caily. during the tir-.t trui.-.-Met. 111 tlie developing liiinitin embryo as computed to the laboratory ;imti..:i- I his may suggest th;n the human ctt. Mi n mote susceptible ilia 11 the luboi an ,r\ animals to the teratogenic action ol the compound* oxidized by cytoehroim P-45u I eraiogcnieity lests on Industrial Chemicals I he liter.iUtre on chemicals tested lor 1er.1ioeeni1.11y was surveyed lor the compounds thtn .ire in extcitsnc industrial use. Onls those compounds lor which some positive results tire ttvttil.ible. were leported. I-'or some compounds, seser.il test results hose been reported, and in those eases mils one or a less illustrative reports base been considered. The teports ssere listed in Tables a-6 giving the species, doses, ellccts noted, relerenees. and the calculated human daily intake lor women working ai Tl.V eoneeiur.ilions. The doses wcie calculated as mg/kg body w 1. as given in a single injection or hs gasage. I lie inhalation concentrations are indicated specifically. The human doses ate calculated assuming a Tl.V (OSIIA 1974) concentration of die ehemieal. pei'on <5l)kg hs sseight) inhaling III in' of air during the working day and absorbing 5u' i ol the dose. All the para meters are rough estimations of the true esposure. 'I he outcome of the testing is indicated as M (= malformations) lor the muior malformations described given as per cent ofihe live fetuses. In some cases, particularly when low concentrations of chemicals were used, "minor skeletal" malformations or delayed ossification ssere reported. In the tables such findings are stated specifically. In a lew cases no malformations were noted but instead embryolOMcny (embryonic deaths) was found. Such findings are also indicated in the tables. Mauls Several metals base been tested for teratogenicity in experimental animals (Table 3). Aluminium chloride has been shown to cause malformations at relatively high doses 411-200 mg/kg. Several tests have been carried out with arsenates. Four different tests are listed in Table 3. each conducted with different species. The doses range from less than 6 to 45 mg/kg. In the chick, growth inhibition was reported, while in the mammals the indicated concentration caused a high frequency of malformations. The daily human dose for persons working at TLV would amount to about 0.05 mg/kg, far below the effective experimental dose. Cadmium salts have been tested in several species. In the injections, the teratogenic doses have been 2-6 mg/kg. The TLV concentration would lead to a total daily dose of 0.01 mg/kg in the humans. Chromium salts have been tested in the chick (< 1.2 mg/kg) and in the hamster (15 mg/kg), both < >, ll{> illMll.ll fl'I.lU JO fio (/> O to 4* mi CJl < s5. n3 c*2i H?. ! ' ? " =" "--, C5 =c. V,,- - -~r. n sS<-|o = 5 3 rig ?3 ? - -- ^ !L ^ r - - .5 Q < . 9 a3 -S3 n2O TJ n - _ K3 --;, c. = -- = s 2f,. o5 --; ^3 r. i; r. o' ?, % =- C- s H. K^rff-'.F'C' *".>.'.1 S : C-2 =. c3 2` -- j? n m '5 =; = S 5. ^ _ C'H c. - si = s 5 %tr I <r*235!355>Ss 4 . r2rK353n'5S-<S=5=';-S2=3-'Smm. Soj;'T <?w2rtnE=- ft <J R O mX:- \i.SmSd:e- I 1 ?--J. *7' x*g: S<X hi?. i tv., Compound Almiunhmi chloride )lhlultull) Mll|H>ll.tlil 11 KM*!> Sprtift' T D..SC-* (me/kjff K.it 111 :<KI * Ulcers* Ucl ere nee f \I -- iii.tlltiim.i(Miis| M Ileum ee et .it. PJ~4 Afsenioxxliimi arscmue -sodium ursciuilc -xxlium urseiuie sodium arseiule Chick 1 homier Mouse Rat Cudiiiiimi-MiU'utc -chlorulc 1 Lirustcr Mome R.n Cl i ft mi i u i ii- uxti u m die 111n in. 11 e Cluck uiovidc UmuMct - ( 2IJ 45 in s 10 |p;im. mat) fi *_ | i 15 (omsih mlidmum M M (r.v; j M KudetVsit ,trd k.iuioi vk> t'JV 1 ei m ;md C.ii|vnlei l4)r^a n,,.si .in.i i`ikc I'c: Ik'.iiuhnn JM7-J Nl lt.51. 1 MlNM \l t 15 . 1 1 ei m ,md l .o pcolei SJmvdei ,ind MiuIi Ulk! 14] Oivith'i! |uM M M <M r > H ideu .iv ,sihJ K j i rii'l sk s t4\ l.de l')?s CnKiTK'hloijde Cllli'l tdc Chick Cliuk in Id U \i i: :. i 1" ul ju .o .nul k.o ti. As I')*. k ut t .i ihI Cii'sht 1 lU -s Coppor-sulpluie \ l.niKier 1 C.id-lilUalC niliale. -chkHide. accintc -1 cl i ;i c 111 \ 1 IcliaCtlljl Cliik.li. 1 launder Mouse it.u 7 _ 5(1 55 (ppm. or,ill 7.5(orali 1 mhi \f (*/*.'r 1 M 1'iu imr, i M (`J511 l 1 lllt't tOUlVK 1 Clin ..ml II .11 .m n'"4 Is'iklett.it and kainof ,ii I`15. ] k i nt and t \o;u nia r pin* Ssliovdei and Mmh ^t.ki !4 NU l. tain a ml tk s kei ee.' MffCtm mcilit liikicuiv dtessiuidaiiude i lie l h > 1 me/e ii ry clilimile iiie!Ii > 1 me re u r\ el 111 u ule Moiue 1 Isimstei Cal s u:5(,h.iIi M l5H', 1 M M i.'ir 11 'sptkei anti SmidiJn i c 1"'.' ............. .1 .ii i'c: KImj Niclckiccfcitc e.ubomt -chloride ll.im.ic! Ka! Mouse III .HI 11 511^1/1 ait 15 mm l,(i l ml>t Mtltivkuv ,\1 OS'i 1 M I5IM 1 Cl 111 l`/\' Smuteniuti el al I'J- 4 ! n ct .it. I`l "" .v Tablet C.klllJK d luUU.111 A* at I I \ fill- U* das i'5.VN W nu: t.,> <. o 1*1 ( i u m uin r,' (Uidl laAtl 11: i If t (.is NiT ssitzo s'sa .................. . tl M lii#M ?* $V >?.; >*>;v .? r -?^f . * ?,% - . ' '.||4r. '^L^r .Ts-^ffe** \ m K Hcmmmki species exitibiting malli'rmuimnv "I he dad' iiur.i.in occupational dove would be Tar less, about 11.01 mg/kg Cobalt and topper have only exhibited weak terato genic properties at concentrations tar higher titan the calculated human exposures at TLV. Several tests hate been conducted with lead salts and organic lead compounds. The coneentranons used haxe caused a high incidence ol mal formations. and the safety evaluation is difficult as the results may apply to the extreme right-hand portion of the dose-response curve (Fig. I). Several lest results arc available on the teratogenicity of organic mercury derivatives, which are relatively potent teratogens ns compared to many other metals. An acute occupational exposure would amount to a far lower tinily dose. However, mercury is known to accumulate in the fetal tissues, particularly in the brain (Vang ct al. 1972). and a chronic occupational exposure may result in tissue concentrations much higher than those predictable alter an acute exposure. Three nickel salts have been tested for teratogenicity. Nickel carbonyl appeared to be a particularly potent teratogen as a transient 15mm exposure lo l).3ml/l in the air caused malformation, particularly eye malformation in 2i<`7 of the rat fetuses. Tf M4-3 Plastics Monomers and Additives Tite production of plastics monomers has increased markedly during the past decades and today the most w idelv used monomers, cthcnc and vinly chloride, arc among the major organic compounds produced. The plastics monomers arc reactive because of their chemical application in forming large polymers. Plastics production-has created new occupational safety problems which have been objects of intense toxicological research in recent years. Several plasties monomers have been tested for mallormations m experi mental animals (Table 4). Acrylonitrile was tested in the rat using an oral dose of 25 mg/kg and an inhalation dose of SO ppm for 6h. Both types ol exposures caused malformations. The TLV lor acrylonitrile is so high (40 ppm) that the daily exposure of llte workers may he as high as the one used in the animal experiment. Only one published repon on the teratogenic properties of epoxy resins has been v. `.found. In this report an undefined dose caused fetotoxieity. NIOSH (1978) has , referred'loan,, unpublished study on the teratogenicity of phenyl glycidyl ether, ,4'hieh is a component in some epoxy resins. The result of this study was reported ' ' To be negative. Methylacrylate esters are used in industry, as well as in dentistry and medicine for prosthetic devices and artificial eyes. Methacrylates were tested , in the rat with a large concentration range and found to be teratogenic. The test J. concentration covered the potential extent of exposure in the workplaces. Pluhalate esters arc common additives in plasties products, and they may account for a large proportion of the weight of the products. Pluhalate esters have been found to be teratogenic to chick and rat embryos. Styrene is one of the major monomers produced in the plasties industry. Jn industrial hygiene styrene is of special importance as it is used in the reinforced ; plastics industry, where exposures are frequently high. Styrene is teratogenic lo ..the chick embryo. It has produced minor skeletal malformations (called variants by the authors) in rats and rabbits'when exposed to 300-600 ppm by inhalation. ,`T In mice and hamsters fetotoxieity was observed at concentrations of 250 and 44^; Oitup.inoriiif Ivr.rU^vm is "4. ifc vwmmm Ilirs m\ Mf;. -y: --r>. :' -:,:!rtfv?;sagv^ itsk r. C. C. =.3 o c 5. 5 ? g "* rnJ, -"r2ri0*;i-.yre*..f*rrcia:` ~ft *g0 3 5 rv fi t x >-' " ' si.'-ut ' v&4 -<V'2M" ^*_^j f'r*-2% "0=r-s*3"3 *^-< - 5-5 r-/**lC33rn. izcZ:S E-. ^ 3 S S. 5 E = = S 3 s o- .iSJorsar'rtftv'-oVCL^Tn - :'"> >V~fl ^rfU'A'V-^ ,-l - .* i -J Talilc.4._Tcnnolo*>cal testing oT plasticjmonomeri and adJilive. v,---' ,<X^-~'~ - - -.- .- " ' ^>mp^H ;v iK^to-}V'. 0&& ,v-.----::=---- 3jr.^V? ?c-^ A i*r\ fonitrilv ; ' Spcclci'; " >' Rill . Dose* (mp/kpl 25 ' KOppm/Mi, inluil, IKwls* Rctovovc |M - nialioirnatioust M Murray vl al. 197Sa M Mmtav vl ill. 197* o CnlvulnUxl himvm i?.->sV' at 1 l.V f mp/kgAl.ii V 5 (2l* ppml tijHi.xv^Vvsin ll:piUi:m 5) -/: ttiiinca pip SVin fuiiminp Sfli.f t'A-: ' -------- :--------------------------------------------;------- ---------------------------- N1 vl 1we r\ blv vstc rs ^ Rat 5-7110 l-clolox'MH M Wmion vl ;il* 1975 Sinpli cl at. 1972 a I Ife-^: . SR'1. \0r-y I'htlial.itc olvrs Styrene | -TiWp,-'.i? - -v * Chick Ral Unspecified 500 dlXKI l cc VI ;il. 197-1 Sinptt vt al I9??n 2.5 M |7rJ) JUKI-WX)ppm/71i iohal M (minor skdvt.il 1 5(JO-fO(l ppm/7 Innlwt. M (minor skvk tal) 25<)ppni/M5 inlv.il. l vtoti>xivit> I IXH> ppm/6 i\ intul, ! vtinmiciit V.iinio vl al, 197 7 Muiu\ vl al. 19'Sh Muit.ix vl j! 197Sh K.mV.i,mj\M vi al. I9S1I KanV.wii|W.i vl al E9MI 5*5 110 ppml 92 {IOtl ppml 11ivilia1 iv VNifKowttv* Mouse M Siik lair 19<ll \ md chtoiiilv Mouse Kill KaMiil 5ll ppm/7 li iulul. 5lXlppm/7ii inlul 5(Hlppm/7li inlw! M M (minor sk.vfcl.il| M (minor skvlvtalj .lolui vt al 197? .lolm cl al 197? John vl al 197? 0 1 \\ j*pml Dose rvlarinp to ilic injwivil amount tin lev. m.hciI othvr\%isv h 1;ipurcs in piirciuhvsvs iiulivalc ihv pvrcvniapv ol mallothkvI ammaU *t' si.ual in iho utvivncc Human ilosc as isilculalvil In laktnj! the TIA' vonvein ration lilvluwJ by OS HA 197-1),out iissimmc .1 J.ot> mlwlaiion ,>|l(lm' jmvI ah>oiption oi 50** nl tlox' In ills' limps of a pvison wciphmp 5<lVp ImT ; V' ;-:A : .'-'? - ?S f 'K'.5fh> \I *m\ ' *'/jf r -*)Ur- L .w is lWO SSU ; -5^ 1 m 11 w5U*1vk*IU\U;*w 'K'lfai ltIiinKilui 1 e 11jt111 uriK-llij Itnc Toluene Hi ill ft..! IMKImnu'Mi >1.1. .1 > Minna. n| I Km...... Il.i ,1 jl. I'lt'J n.a...,t.i ,-i ..1 vr.'i 1,1,1 M t'f - f Vlm.hli I'J't. 17 M|V,| I I..1.1.11.1 VI ,il I'lM IMltf iu/fit/'.|tiiutta|. M tm.noi \Vclvi.il) llu.Lit .i'u( V n S`' .n. IV7> |l>Hlm,:/in`/.Ml.,,iKil M Itnunn vl.l.i.ill 11n.l.iK nihil . 1U IS M ( U* |fpcnI t5j 6? (l(*/ pj'rnf 75 .14 rJ n> } , |Hblr ft. `JcraUilupCiil nl ........................ iijmuiut-. S|3jV'2^. ."t *--V' - ;r Compound , fcr Amimu/obciwcflc fey'- A/o Jjo. li>|i:inli)ik' civ. &:-> SJpipSK IKUTiicnK f: -- :ilV\1bcivcnc Milplum.ik* -- alcohol vulphau* '- n -- oWlVl) Mllplltnwlc -. -- Trhon N Specif* Miuim* Et.it IW Imji/ti:) 'IK) 7|*I <*\ Mi HIM.* Inti MiHIM* HX> Mihjm'.K.iHHh '|J0 NJO Mmiw 2m Ikii(O' (M M Mi Sr ,) Kck'ICJK*tf >IIJ`'l,,1HM |'l ,ll Hi i is aiisl l U\k| M rmiiHEt H , | M i mi ........ ir , i M( (Ui-, \ M H.iIuhy til .it 1^' 1 *t .il N P.llllM'j t | ,|J l*> Kmuk^I Jlui \iw R& Yi ii | J ; 7,12-Pimcllivllvti t\ ;i KmihiiKOu* Et.il Kill} ls`K*tllioUKM K,.t It .ii ltu!r.i/nv C'likt 11 :*> 11 V./I5K : Ml | IN, ] ' mill >t .li 1't* M | x-v . | .................... M I Klst.il V t ' ,] \<i h \ H 4..h*| nut i,. ^ii'U ^ iVnuchliUolwn/iitc it .u 2m M i in . | Kl.. i.i .n.l \ .jl 1ctr.whK*t vxiitxMwwjv^iuMn M.W n om M t-'i.ll .1.11 'll , | Si Ill'll! *1 ,3 I- It _. V-'' I i. *1 ciuclilmophcno) Ihmimm -- ilm.im -- tint,tin -- JiMillir.tm 4 * ' *cc TabW 4 lt.il lit Haimtci. Kai MiUkC 1 K.im>lcr .'Mi 'no 'on |i> 1 ' t *t ' % *t ||l , Si tl. 1 -L *.1 "SSlIi, 111, HI 1- M i 0.1 M 1 Ur. ) Mt wr, i ll.ilsn. 5'ii.n u.>u *-: i It.'Ik us |.||,'l CalviilHcil lnmt,m i .M Il.V | Tif! -^k ii.'vl.i iv.rfw n i i I " f. . 0 5 l> nii' IteS.-V ------ '\ix *' ` yp?*X"' " 6SVW<> SW -? V.e^l v '' f K V '=> . nf(1 :r*| 1. ,' K I U nimii^i l.Uiltppm. respectively. l.Tetliaiic at .1 dosi <>l lynig^kg I'-i' been l"'uu! to be positive in the rat. Vsrnl chloride h.i.. been icocd in mice l>y mli.i!.,110:1 esposure in 5<>ppm and found to produce iii.illoruiutions. higher 'luemi.iiii'in were lonnd to cause skeletal anomalies t:i rats and 1 .dibits Solvents Solvents area group ol organic compounds, to wlueh large numbers ol employees are heavily exposed in many types of industries. Literature on the teratogenicity of the industrial solvents in laboratory animals was compiled m Table 5. Hen/cnc was found 10 be positive ur the mouse alter a large injected dose. Minor skeletal malformation* were observed in an inhalation evposme to 5ddppm. 1 hesc doses are higher than the expected human exposures at Tl.V. Carbon disulfide, a solvent extensively used in the viscose rayon mJii'irv, was lound to produce malformations at a relatively low dose ol MXlmg'm in the rat. Chloroform, previously used even in anaesthetics, was loutul to be teratogenic m rats at a UK)ppm concentration, a concentration only twice as high as the Tl.V ol OSMA 11974). Dimethyl formamide. dimethyl sulfoxide, and propylene glycol have been tested at very high concentrations. Chlorinated hydrocarbons make a large group of industrial solvents, which have been of concern because of the carcinogenic properties of some derivatives in this series. Methylene chloride. l.I.I-irichloroethane. 1.1.2-trichloroeihanc. trichloroethylene, and tetradtloroethylene were found to cause mallormations in chick embryos. Methylene chloride, thrichlorocihylenc. and tetinchlorocihylene were tested m mammals, and a weak teratogenic activity was noted at relatively high doses. Toluene and .xylene are among the most widely used industrial solvents, and the exposures in painting and printing are quite high Minor skeletal defects were noted in rats exposed to toluene and .xylene at 1.500 and 1.000 mg/m. respectively. Oilier Organic Compounds . This section includes a number of compounds with large but versatile use. For most of these compounds no industrial standards have been set. Aniinoazobenzene and other azo dyes, used on a large scale, have produced malformation in mice and rats. Detergents have a large application as washing powder and as industrial emulsifiers. Some detergents, such as alkylbcnzene sulphonatc. alcohol sulphate, olefin sulphonate. and Triton, were found to cause mallormations or minor defects at high doses. 7,l2-Dimcthylben/.(a)anthraeene. one representative of a large group of polycyclic aromatic hydrocarbons, was found.to be a potent teratogen in the rat. Ethyleneihiottrea is used in the rubber industry and it is also a degradation product of the cthyknebisthiocarbamatc group of fungicides. It was found to be teratogenic in rats at a dose of 40 mg/kg. Halothanc caused skeletal malformations in rats inhaling it at Q.89c concentration. Hydrazine is commonly used as an oxygen trapping agent in water containers. It was found to be teratogenic in the chick. Pciuuehloroben/.cne is used as lire retardant and 1 fungicide. A dose ol" 200 mg/kg of pemacbloroben/ene caused skeletal mal* (Xv up.il liiiiul 1 efjiiigeii. lormaimns in the rat contaminant in cmn . such as 2.4.5-T. TCIi tions at a dose ufO.OUo: the fat. and fciotoxiciq 30 mg/kg. The preparai. and the authors conclu chlorophcnol. The twi. the rubber industry, thit were shown to be icr.n Cuncltisions The most hygienic slam! the workers from acute 1 industrial compounds h.* of the hygienic standard studies are available to exposure and malformal test* has not been firm "I he present analysis literature, that the hum common laboratory amn even more conservative more sensitive to this do should be taken into . metabolic heterogeneity . rhe humans. The metals individuals may vary extv. absolute safety have to rto humans may lead to the animal experiment cann . The review of the tcrat of the metals in animal by about 100 times or mm such high TLV values th., developing human embryt of acrylonitrile, methaer; methylene chloride, and ; absolute safely of the him animal experiments. Even pounded by uncertainties. : pregnant worker appears - r &S 024160 H Vis ?%r \ * V. - -.if* -4'' . * ;'.k , if).i v jV-1? ' 4 K.HcmmirAi '/kg has been found 10 be >iJe by inhalation exposure tgher concentrations were is. urge numbers of employees alure on the teratogenicity mpilcd in Table S. Benzene iceted dose. Minor skeletal tc to 500ppm. These doses TLV. Carbon disulfide, a tv, was I'ound to produce i in the rat. Chloroform, he teratogenic in rats at a high as the'TLV of OSHA propylene glycol have been industrial solvents, which perlies of some derivatives me. 1,1.2-trichlorocthane. to cause malformations in and icirachlorocthylcne ny was noted at relatively d widely used industrial i|uite high. Minor skeletal k: at 1.500 and 1,000 mg/m! urge but versatile use. For tave been set. Aminoazo- vc produced malformation as washing powder and as ; -Mt/cne sulphonate. alcohol < cause malformations or laeene, on epresentative uavlbii't be a potent r.-.mt. nd it is also : jrinip angicidcs. It ^ijv'zg. H., a:nanc caused cemratio;.'. Hydrazine is untaincrs. |t was found to >.'d as lire retardant and vac caused skeletal mal* Occup.ition.il teratogens formations in the rat. 2.1.7..S-Tcir:ii-hlufiidiben/n-p-di<>\in (TODD) is a common contaminant in commercial poh chlorinated phenols and chlorinated pesticides, such as 2.4,5-T. TCDD is an extremely potent teratogen producing malforma tions at a dose of 0.006 mg/kg. Tetraehlorophcnol was teslcd lor teratogenicity in the rat, and fetoioxicity and delayed ossification were observed with a dose of 30 mg/kg. The preparations were assayed for TCDD contamination (<0.05 ppm), and the authors concluded that the observed effects were mainly due to tetrachlorophenol. The two thiuram compounds, thiram and disulfiram, arc used in the rubber industry, thiram also as a pesticide and disulfiram as a medicine. They were shown to be teratogenic to several species at high doses. Conclusions The most hygienic standards and norms have been established lo proicct most of the workers from acute toxicity of industrial exposures. Teratogenic properties of industrial compounds have not been an important factor influencing the setting .of the hygienic standards. This is understandable as very few epidemiological studies arc available to show an association bciwecn a parental occupational exposure and malformations in the offspring. Moreover, the power of the animal tests has not been firmly established. The present analysis suggested, based on the limited data available in the literature, that the human embryo is at least as sensitive as the embryos of the common laboratory animals. However, the thalidomide studies appear to justify even more conservative safety factors as the human embryo was about 50 times more sensitive to this drug than the rat and mouse embryo. Other factors that , should be taken into account in the setting of hygienic standards are the metabolic heterogeneity of the human populations and the chronic exposure of the humans. The metabolic heterogeneity implies that the sensitivity of the individuals may vary extensively. Thus, hygienic standards attempting to provide absolute safety have to take such variation into account. Chronic exposure of the humans may lead to the accumulation of the compound and the short-term animal experiment cannot predict the levels attained. The review of the teratogenicity tests indicated that the effective concentration of the metals in animal tests generally exceeded the calculated human exposures by about 100 times or more. By contrast, many organic compounds had generally such high TLV values that they probably do not guarantee the safety of the developing human embryo exposed in ulcro. Pariicularly. ihc present standards .^of, acrylonitrile. methacrylate esters, styrene, carbon disulfide, chloroform. Jfmethylcne chloride, and possibly of toluene and xylene may not provide an ^absolute safety of the human embryo, as extrapolated from the results of the ' animal experiments.' Even though the extrapolation from animal tests is com pounded by uncertainties, the revision of the hygienic standards concerning the pregnant worker appears justifiable in such cases. ;tPss- VlS/7`5 O) < ; f. sm fe.;,. V * Vv" '"vft ' I'fsStte* ly^'V^V^iS :.`.. y!v,1, II ,% I '*. > Jiifir,v':''>4ssj 1 "-'Vi'S i'^3 . .' >3 !*kf I ivsta^l biiiSftg KuMT K.Hemnunkj References ' kV tvr^l. ! ?; Auerbach C(I976) Mutation research Problems. re.-ilts. and perspectives Oiapman xnd Mall, London tiaranov VS fl966) Oi.irac!cri'iics of the teratogenic effect of aminopterin compared with that of other teratogenic agents, Bull Exp Biol 61-77-81 Bastard AR. Fink UR (1968) The teratogenicity of halothane in the rat, Anesthesiology 29; 1167 --f17J Beaudoin AR (1974) Teratogenicity of indium arsenate in rate. Teratology 10; 153-158 Beck F. Lloyd JB (1966) Teratogenic effects of aio dye*. In Woollam DHM (ed) Advances in teratology, vol I. Logon Prrss/Academic Press. Dublin, pp 131-197 Bennett RW. Persaud TVN, Moore KL (1974) Tcratological studies with aluminium in the rat. Teratology 9:A-4 Iljcrkcdul I. Lurid Tf; (1978) Occupation and b.rth (in Norwegian) llygicnisk Instnuil. 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