Document KGMy78dJozRLmwOd0L1rY2O0Q

R&S 109555 68 69 76 File number [Right justify [Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAHA preceeded -by.one blank space 1 ' 20 "21 1 -cnr i - /,(-- | /Veuse*4 MT K n. < / 2 >- S f~ I /.4>-r5//7 ' 40 41 ) 1 i" - 77 78 l/c^ Sub-Index Code 60 61 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terns, separated from each other with -comma-space. Avoid other punctuation; 12 do 'not abbreviate. * 61 '62 ^ ^ L-r ^ ' j r* o7 7 7? toe// (- /V<C <//<'- /y?~ z^-/ /s? ^//Z. //?_/ 21 22 C, , / ' r'. /7 o <7 /> -/ C / '\zr:J<.r /t-S 23 u 24 (Journal, Vol Number, Pages, Date) 12 Zs>- /7 7 J1 ...... U ///Tf 61 62.31 32 Brief Summary' 12 10 SU1-2-IARY: 61 62 61 62 63 64 In:. Arch, Occup. hr.v'jon. Kith. 41, 199-235 (i97S) >:nti l I5 R&S 109556 0000234 Determination of Thiodiglycolic Acid in Urine .. Specimens of Vinyl Chloride Exposed Workers G. Muller1. K, Norpoth1 , li. Rasters2. K. tlerwcg3 and E, Versir,2 ' I;wh:i.: fir Saatlik-.rc-r.t'nufhan.i.' and .Arbe;;'n;e.ii2:n der \Ve>:i.V, V.'?,:i.r.rlr.v;;;::::. D-uriO Minster. Federal Republic of Germany : tVefiv-.ar/.ilici'.e Abidina;: uer B \5,F, Antwerp-..",, Beigu'r. 3 Werk'-.ir/iliche Abteilur.;: dcr Chcmiscl-.en V/erke Hals AG. Marl-!-GIs. Feder.-.t Republic of Giro -.ay Summary. A strong correlation was found between vinyl chloride concentrations at woiking places and the increased excretion of thiediglycoi.e acid of IS exposed wot kens. The mean air concentration of cirn I chloride was calculated referring to peison.il exposure. Tiie \alucs obtained were in the range of 0.14 -- 7,0 opm. The excretion of thiodiglycolic acid -- measured by GC-.MS analysis -- amounted to 0.5 hi) nig/L. It could be demonstrated that significant increases of the meta bolite excretion occur c-.eu at VC-con,.-enir.ttio:i>. below 5 ppm. Key words: Vinyl chloride - ThiodL-Ivcolic ,ic;d -- vinyl chloride metabolism in man Vinyl chloride ur.ne metabolites -jiioiogical ex no sure control Today the air concent; itions. jt.icV't i iiituuw:iv ig. wu. in-only due to its cm. iiioecnlc Ut and mutagenic ffc. S. 9. :4. 15. I.s . 1 51) j nrone;: '-es. !1\ '-n!y b..scd on air analyses by ine.ina ;>i hlrhlv sCiwtere. but f.c Jnalynca! methods, 'll-leret'ore. vre emphasi/Cv ual oirccsmcal expos-ire controls |d4. d-' '! ib ariim.i! cxneir.'.'.fn'i v.a ah! dem.nrc.'r.-te the poislbili's c-t determining the exert tioii tit tliiodip.v .oil aci.i and S-c.irbu-xi,-metl'A Icy steine, 'we ttriite rnatar-vhtei ol v;!:\| tl.ioriuc j lit, d-i, Ho. d?. 351 Data ot thiudii.dycuhc acid itt the urm.a ot war.-ters slightly expo'c.i to \ iuvI cidt'i.i.c _nd the unproved analytical method used for tietcriiimation are rersiriei: here. Materials and Methods ' Cham, uk Tiiio.JiylvcntK- a.id (Os - pariis , win puTea.isv;: from Jar.swr, Pnarmaceiuieu. Depl. Alir.ch I H-2 A-VO |{i-.-rv. Ivcaiao. D./n:aetli:.a.- two yen.-nited n-i ia N'-tnc:!;>l-.'--r.:trO' .-p- |olm'n*-Miiiiin -1".idi- o'-dir,'-, *o C-- ,I, a r ::a! It u k>-r | I {, All u; a.r miIi-s on .** w a: w pa'.*;:.i,.eJ a! anal', l a ,tl cra.ii* ; 1 , M o C .Vi Doin') Dative nil. o.'Od oi5i-7.'s'i'r;i Gdoi/s 1.40 i 2UH *. -' i CM hm(* epilates Determinations of Individual i.xpustire by personal A i Sampling R&S 109557 > S*ripltnz Sjmpin.c `1 iib* '1 ra*cs oi u:y.iim puilatauts lunior.c w inch vinyl vliiorme) in the factory air were .oiIe.icd b; alas. tune -- mpuiw `'li, - Lngth ui ! 1 cm m.u ,;.i ,;u.rua4 'J.nm:;.r uL 3 mm. 1'iiied w ith 25 `50 me'it euarcuni j 7 j. I base eiureoai u. je> hud - ureakt'u'yugh volume. for % my! chloride at 20 CVuf aiv*ui 5 luefs i 33 J. l';<T * X, : i Jhijjij). lo ihe uir through ;:.e lube sample:s we eseo a U p.mm imi.icc personal sampler i 1 matiutULluicd by An.itoic J. Sipm Co. I he 'urnp.ed Uw' volume tu;i he vjl_uL:ted irum the rancher ! 01 pistonpiuy* of the pump. i aeistcred by a bail: u\ counter. t I A' the amount of Lhuri.ojJ .md the density of p.ukinc vurud trom sampling tube to .n.i15p!uijj tube. we had to cal.bmte the pump before c.u h experiment. ! he relationship bciwuer. 1 pNoupbiy > ana normal gas volume v;a easily rneas-LVd will: a gasbubbie meter and a stopwatch. i 1M Atulyui . ,J- x.. SS*-. t .eel C.mdii.on'v. A spe-.e! :me*iiu:L p..rt i!.,,t u;i`\ s to. J.res r :." ,l.u_:,o:i ot the :oml v.i.tplc, w-rtiMije mAuded. was uscu tor toe Luermal d.-swipt.".1. >jI ths. trapped smyi ..munCe j i, 2 |. I he vjjoi;/-d vm\ I eui.;; wle was ; j..md `.o .. a.i^ ii.o::;.:' w\.p.,:v eulI1* separate the vmyi vlUoraic hujii other sam; sea ura-h :c xap^r j atiui-uts we `a-e,: e, 25 m xmii ^u-ted a-i how u\ 2l) M c-pida; y a: vS;i ' v '. t ,.e Jet eel or a -ed was, u^ su-rse. a tij.'ie lonarauon Jet eel c*. i I..' Nutu.ee ot u`.e 'if.; i e 1 norida pu.% \s'ji meesurej *'v ,,n im'vjfainij **u*onier r.U?' ' JT .f^r Cdhbration. A eab.br-t.o:'. w-x dyuiuuaahy p;e:j,,,ea b> p,.ssir.e h.iov. n gas,sifea:n over a ii ttiion pcm.eatjuii Labe iiiied wit:, h.p.sd v:r.s i wiilorue |2h. 51 i ihe toueentr.uon oi v.nyl (.iiid.'ide v.js waLulaiea ny t.;e losi u: wvi^nr oi tiu p-f.ua-tis. r. Lube o'., r several dav s. A i h:uiv.ii \'A.:;iooi Lin. lji v.as d;-wr, 4.'a'0'jen a li--;v. j. u.be an^ ..i.s Lane w.:s -.'^.vaed | dev..J'.\J above, i.ie aasi.n,r/n;^Loprwp.ue result's >icre rejofted as tne .ir*".OkU.L ct absorbed i by t.ie e:.,.reoui tube sampler I' 1 m I l ,v.,|:ut ion oi ;ije !'.i .wh,i.` l.xj v u.:e U..fa, : i.e mean e.indentr,.t*ou ot v m;.! wi:!orae j:: Liie a:: rrM l it;:i n.p llie exp. rnneni was \ .ilet.L.Lest iiui.i the au.ou.u (*l .nwn i*n vh.v! wMi.ruie a,:ai> / eJ by jms.'Ijoi !.:nsuaphy ind Lmn iiu s^mpied a.r \uun:ie ealv;.i,*n;s: trum the ;iumber ot pi .umpli/s ji llie pump Jiuiin; sun.pun^. \ t -L/eteruMU tivi* m Lla A if V* orks.m * i lie : ivas..ret;:ent > u yvftoi::: ,d m :ay .11 I cndtipomt t Lone u*i,, jo Jete I i L ), \ pe i<, v 1>. 1 e> i f. ' pre.s J m L . * w or M,.e .;:i, I ota! hydrocarbons in the ...r o! e.uJi o:.,p.m,: point were ana^/.d u:we u inmate * been siiown by (iC-mx-'ureinuutx ilmt approxunateiy 1 ppn; ot ll'.e tot^l l;yuroe*.roo:`.s u\ I ,}l this werhtnaarea Lie ".^t \`CM. C`o:;s:a*;.; a tl is a.'i.ou.d of 2 ppm :io: \C>1 - h>droeu;bo:;s Il tiie (me air concentration ot * n> l widoriwe \..is calculated. 1 lie personal e.xcosjre of Caen v. orker \vj s ev.i ! i.ited. 1! .a s i. o. u reuss t rw t ions La >ed u'l t ne u ur - ueo t way at dit ef or. i v.orkmi; places, *o values ui \ CM aw' coiieeutmuOMs eiven m Uu> paper, which are not obtained by personal a:r samplii.3't refer aisO to personal exposure. D*:e::,*,Matiuu ui 11. a#u !_. cu u c A mu b y f ii *.*\ ti.i b. st,, j n a 10 m 1 e la ss t ubo i ml ot urine a nd U.3 ml ol cone. HC1 were evam-ratca ttm.r * ness m s.uuo at r. om temp era lure. T he rfsjdue J S w*s suspenued in metiia.iol .i;.J tla* suspension w.u Lvmp.eivty met!\\ j,;ied by means ot (1 ;u/ >met he:ic <11 *. i iiv! eL iier [ a J. w! i er 1 x in \i`.,it as 5hi i me *..!' va 11> ju . \. fij nuc re*.**?'. < D-^w c\ 5( ` vv'X a, ! i1 ) w era adsts u, I iuoa. atye>r I.e tie id dime; m. I e^i *; \;,,s Jet s mme j by rcru m-to- . J prapine sep,.r,ition and w.-^ie ion dcu'ctioii of the mass fragment M No. it is r.eccsvu'y to uij the standard audition lechmuue to obtain exact measurements. i l .A .t i -s.A l niadiplyeolie A till in siio l rule ol \ ;::yi ('"Oiri.X- / vpi.Mst V\ orSi.T' 201 Fig. 1. t-nnciMtrjtions .'iiotfietyeol.e :>;;d (TDGAi. CuV.up A: 2'i nnr,-:\pn\.-d r-V.!.'' Grcui" H: ucrk.'n exposed t.. <*. 1 -r 2,2' VCM r-.M' iri'.i by I !u ,:ir ur.ib.Mv <i.'.'n;) f: s .* i.rki."', i`>,pi.oi; O' ! .02 2,0 ppm Vi~v; m.U'iired ' \ lb- m per-ory;; .nr v.rr.plei' i1 i t i; !' [ I'tii. 2. urine i.PpiytSlir-lent * ! IX.Ai .::v.r ei.ii-iiiiji.on 01 >7 .Lr.; .I.v urdme !7> I.*:r Lo/eeuvei uliii.. .-.-e re!Ur,; to -per d./Are:-.! \ f expo'jre .'.i.'.ar' A = 0/ ppm, C = l.'iL -2i0 pp; C " 2,5 ;- 5.00 ppm. .0 - 5I ~.5.j ppm CVi-.diiiorts C : ieir r rmitne:.i-.;i 0500 em 7: rr' 1 v .i!, trust - ere: ruyre'.e: 7700 <1 : r.'i'. i tPO. O i .:r 1.5 m S ibOii'i.i. (A I nil M). !;\0 S ( .Vu:,,1.-,': V.. C j.'rie.y.j'et1 re! m.u. Cbierm trmprr.ut.Lre 1 Hi'' C. Ir,(er:i;in port iL-mp.v.!ere 201/' C. 5. r-.-onr re.--..p.'.'..:,ir7 200' C\ Results The ru'iily'ie:1.! proeedur; v.iuJi '.ve deveiup-.'ii for JufficieniA prcei.-e deierrr.indttcin o; snip.!; .iruc-un's of l!und;ii!vvoiic aeut ;n u.r',1: i.iuipU-i allow eu 11s to eompnrc data oi f.'.o ;'rtin|'i ill' V( -workei1 willi tlunc <>l ,1 nnn-e\ p.isod pinup A' ile.-ur-ii'.i 1 .iled Iiv I e;. 1. 1! i\ pox'ii.l,- it 1 .liv1pmi ei v.een iioiuki! values (eri'uj) -\) .mil 'iivli oblainyil iron; sliphtiv c\y i 'vi-'!: 1 r.' 1.; .nip H i.iul C) a: i!ie 1 sigr.ilitiiiiee level. As \> : ealenl.iieu bnr, in:r i.i.rin.,; u.uis. in ./! e.ise-s cnr.edn- I R&S 109558 `5.1 202 | toga [ ^'hj i 4001 I' 3coi: w. Makar et iL J VCfppm.'lt R&S 109559 i ir ! i" n V *I ;-h fig. 3. Kes.etsoi a eoinparivii ir-.vamaa'.iou on VCM oxpoxura it-t.-liinj tea CAcreuor: c; iniodiglycmiC m.U (1 DGAJ/uoer ir\ the ansa 01 j worker, wi;o wjs observed during s three-day period tratioux ot Uuouglycohc a-ud exceeding 2.1 ug/ni! urine can bo distinguished trorvt nornia! concentrations a; the 1 significance love! (99 fA probability of confidence). 'I hose values were found iv/ice in group li mid five tunes :n group C. The mean values of the [luce group., suggest a correlation betv.eei'. rite extent of exposure and the amount of tided.gtycohc :.etd cxcreteJ. 'l Ins correlation cu.nJ be proved by ciassitlcation of the auaivncai data according it) lour classes ufuilieieut exposure. As shown in Fig. 2, .tit increase of mciaboiite conceu'.iatioiis in the uiiue is Icnud with in creasing expomie, 'tt.e am retutiem was tesied by a d.suibatiun tree statistical proce dure [ I 7 j and cn.dd be continued at tne levei o: p < U,0I. Since individual exposure cnniioi b> means u; personal .nr sampling seerrtS to provide more precise data than $,.'obJ air analysis, v.e stalled exact examinations of single v.oikers imninnlmg the personal expo,ore darmg tune period, of two or three days. In this period all urine portions were collected separate!} and in each of tncr.i the concentration of tmodiclycouc ac;J w,;5 measured. The results uf one investigation are shown m lug. 3. It can be seen that the increase of metabolite excretion, begirt shortly alter starting the exposure c-ch d.:\ -ml tin.; tt.e highest concentrations were found in tl;e first or second mine sample obtained alter the highest possible YC-epttike. Kirtiierni.ne, it v;.i,., romt or tins un. csug.uiviii ti.^t lire merubohic excretion exceeded ti'.e normal range significantly even alter ti mean exposure level of about 1,5 ppm but no; aider an individual exposure uf less than 1,0 ppm. t*tl' r.,:: ,v/n Tii:Ow:^!;,\Mii. Aeie iw l nine of \ .">i C'ii nn.'.i Fxgos;:; W.v trots 203 DiSCUssim; Ma:;: meiabolues ofvinsi wforije wimh a.e excreted .r the urine of laboratory animcix are thiniiigh, cohc w b ; iI-'-. 2m 'V 35 ;, S-wrbmxv-n'ieihy icyiteme [II.:;. :<>. :7J and !r> Jt4".y cri::-1 mercaptune ac.d | ! i . 55 j Previously, we proposed qua; tuuiive deiernmatrons o: ihmdiglycolic acid and S-e;:rho\' -inciinl e;. deine m the i.rriw of v.rq 1 ci.ionde exposed workers for biolo gical ox unsure control [ : - 2&|. in the meantime. v.e could demonstrate by anime! experiments that S-c,irbo\y-m;rr.y 1 cysteine, a precursor of :h: final ruetaboiite thiodinlycolic aeid. accumulates on,!'.' in the ease of wm, i chloride air concentrations higher than 500 ppm in the exposure chamber [ 25 j. which arc unusual today ar working places. Concerning hydroxy ethyl rr.ereactunc acid measurements where performed using an ammo acts! analyzer. No amounts a hero found in the urine of IS workers slightly exposed tow; \l cihorile which exceeded the corresnondins \ .slues of thmiiialycuhc acid. I; m.w i'c taker, mm cou.si,ieratam that :i;e contribution of jStenuiti'.e metahohe routes to the huntransformimor, c.f v.ny! chloride depends on the exposure leva! f 13, 25, 3S]. Tims it is on: yet clear, whether hvdroxyethv! mercapturic acid is the main urine metabolite of VCM m man or whether it is thiodiglycoiie acid, i w.es.ncnrir.g the rent concentration of the letter metabolite, a more precis; procedure was needed than in our aru.me! experiments performed prewoiidy [ 13, 2Pd because its increase after VCM exposure is apnareuriy less marked in man liian in the rat. furthermore, it has been shown that thicdmiycobc acid is also a naturnily occurring urine metabolite in man [ 25 J. I whig an unmoved analytical meth.od then, we couki clearly demons;rate that the metabolite concentrations in tise urine of winkers expect: the normal level significantly even after VC-exposuros between 1.5 ami 5 ppm. This increase of urine concentrations ieprnds Nearly or. the exposure level. Neglecting oilier eliruination routes than urinary excretion theoretical values of the daily amnunrs ( i i oi excreted tiiiodmlycol.c acid may be calcinated according to the following concerning1 If = "vSh X C\-(' x Rye x Q x MwTQGa MCiVC ~ " The explanation of me symbols is1 = him; scTi'.iiano-, tinring nr. h hour interval] C\,'f = mean air corn entratior of XT' RVC " rcsorpiiou a ,.e. whii.it h.:' 'n found ni animal; as about O.d l~) Q - rclti; !' .'mount "f imobighvniir acid as compared v> ilie total art aunt of VC- metahoiires. winch ha; been found between 25 '' (55) ami 50 C i U;i. '^TDAA = molecular weight of ;h.. .digiycolic acid MGvfWj = molocniar weigh: of Vf M. The inns determined thec.ratK.ul values cor:expo;-;i w;l! to tne measured excretion rates u. ;he rat. They are. however, hewed', 2 and 10 limes higher than the excretion values as shown in Figs. I ami 2. Tins mnv be due in dut.tvtu Fuuiransformation rates in ra! and man. On I lie c niter hand, i Iw vain w < >hta .ncd I'v personal air sampling are mote hi accord.ii.ci- with ilv 1icuro11..i v im than ih.u,: i.-lamed by dr.ect air aitalc s>-s using I ID d.-icslors. In the I uier c..si:. as m:,c.ac.cd presloiwlv. other liydroc ii hnus are me ,'stired togetiier a ill: \\ M .imoc.uting u> .m average level of R&S 109560 t 3J 9f> CP O < .1 ! t ii i t i s i i ! i i i '! ii `i i j i 1 .1 i I 204 G, Maher et aJ. about 2,0 ppm. 'I hi* average may have been exceeded during Mime ofuur measurements. Thus, more evidence is needed tor the true si.me of the tune'.iot: between VCM exposure and excretion of ihiodiglycoiic acid. Therefoie. we started a new study to reinvestigate this slope by measuring live personal VCM -exposure using the personal air sampling tech nique in direct comparison with the use of FIL)-detecrors for air afialyses. As shown in Fig. 3. ever a slight VCM exposure cat: cause characteristic fluctuations of tluodigiycolic acid excretion ,,ud this can be revealed by continuous urine analysis. Conducting tire excreted amo-.ints of tire VCM metabolite per hour, it seems possible tu prove a penodicai uptake of very low amounts of VCM b> single workers. Such measurementv could aiio provide some informations about inter- and intreindividual differences of V'CM metabolism in man. ' - `V >- /,V *f r}$ :j,T -.a.-' ,ltf now/-Jiymem. I hit u u J > u, v.ipported by a grant of the beruGger.Osjer.sehaft dvr Cr.inu-chen Inciu't.'io, i>6960 Heicelarrg !. iiR10. References 1. Aue, W. A., il,."ii.;!g>-'.,uL;:ii. C. k.. Yui.uUar, la It.'. A srji.iu'onuii.geapiue iwrrr.dgc de-or p - -o u port. j. t. :irum. t i 4, 1 IS-, -159 (: 9 . r I 2. liart.seii, ih- MjLiveihe, C . '.ioeie-anu, Ru iiaw.'.r., rai and r:;uuv liver mediated iniitageiucity -! vinyl chl-irmc in viL'nuneiLi ;> puiUiarM.-;: lU.un.s. in;.' J. Ca.ee. 15, 429-437 11 *>75 i J. Doer, 'In. J- tie, li-whcr. ,i. i t lOi.i.euiiw;C:g. 5';. tu;:. JO. 16 :1953) * 4. Holt. II. Laic, k. J.t Aapeai. ifiaci'.te:, a.: Fkarmaaokinciics o:' v;r.y! chloride in the rat. Tc\.eulogy 7. 17si -- lA(1977) 5. Cre.-eh. J. L.. Jolm-on, M. Mu Ane.t -areon.a o'.' hve; in tn-e ii'.a.it.ia.;o: r.u i y ,uyI eiilondc. J, Ocai-p. Med. Hi, 150 il974t" 6. Hoig, I . I ilicw. A. Me !' \!r. ;:..l elamtiusoine '.'.mliei undertaken 0:1 f.ertotu and anirruli with VC ihnc-,,. K a j w' r: je.u: a nteri: Conf-.re:iee on Lirrironineuiai Mui-gens, Isdinburgi), July 11 15, I 077, Conference Ab .-reGs, page 21 9 7. l-'raut't, C. L,, Hermann L it.: t LaraC-al >ai;in..:ig u.lie., lor organic vapor analyse: by g..vcieotic;logi^piiy, Am. lire, /vt-ui-Ia-l,. J. 27. {,!> -- 74 i IVjo) o'. I-'-.ir.evv'r.ivioto, lx, L.a:,ie.n. 1) . i.ind-tei;i, J., Liire.iberg, L.. Natarap-n, A. T-, O.iermannGolkar, 5.: Chromosome aii-rr.iiion.- in worker- expovcJ tu vinyl -hl-Mide. Lancet 459, (1975) 9. (larro, A. J., Gull - ::;'U.i. J It.. i'. M ,.vj : V-uyl -uioride depenile.it mutagenesi., efiecti of liver esltevti and fiev radie.u- MuU'.i-m Rev. 35.x I-ho t i 9 71>> 10. Green, '1'.. lhth'.vay. D. 1: . I he i.'!ul-,enai f-te m wt- of vi;.> | chloride in relation to us or.eo- tenieuy. Che.-.i, [>iul. Intct.niion- I I. 545 -5h2 11975) I I. Green. T.. I!athw_y. D. I... i..: Ci.e.-iusirv anu Ih-.geuv-i- ni riie S-eontait::r.g Mei.bdbtei of vmyl Chloride u: Kat\. Chem.-bi-sl. inler.enon- I 7. ! 37 - 1 j(J ' I 9771 12. Greim. 11.. Uonve. G Itadwa;;. Z., Reichert, IX. iieii-elder G.: Mutagenicity m vitro ar.J p-Menti.il e.reu.ueviueiry et tr.ioni.ated etlr-'lenev j.-. a tun.tior; of metabolic oxtrane fortiiation. liioeiiem. I'hcr.n.ieol 24. 2013-2017 t 1975) 13. Heftier, k L., Watai-.abe, k. G., Gelu.r.e, ?. H : ihelunmary sta-lie- of the fate of vmyl iblonde monomer m raH. Ann. N. Y. Ae.id. 5ei. 24f>. 1 35-1 3S 11975) 14. Infante. 1'.. Wagoner. J. IC. V.axweiier. R. J.: C.-retr.ogatue. M.itaceme ar.d teratogenic risks , aMOeiate-l w u ii vinyl thlurice. Xturu11 jn Res. 4 1, 1 31 -142 (1976) 15. 1 Mia me i'.. Wj.rtii.er, J. R . M..uel, A. J., Vvavucder, k. J.. l;a!x, Hu Genetic riic s of v.nyl cuior.tle. I.a -eel 754. ! 2l) ti97n) lb. Lee, i:.) . Hatty. I). 5.: Atviosareoma of the liver in a vinyl chloride worker. Lancet 1 31 o-- 1 316 (1974) ,&:y. V: i J i. ,!! - <.1 -A a: VMS. r-.~ie >11 iA. i JC ' ' fc-r l`o ; 5 i * V- l \ ) X l \ f 'k > i iitr . xi o; Thiedistly colic Acid >r. tue L'ia: Vinyl Chloride Expand Workers 205 12. Lirneri. li. A.: Verteiainc-trcie Metkodcn in da: iliostatistik, Mcisenheim am Clan. S. 120-124 ti 4n2) 13. M a lav-. 1C:t'dii, H\, fiarlnn, A., "arm:<, A. M.. Mnnte.scno. R.: Mutagenicity of vir.s 1 cklnr.lc. chlnrvi-.'tl'.yKneoN.'dc. , f:i-nr.-*:ita!rlc?.yctr, and t i.lnroetha.-.oi. Finchem. Hiophys. P.cs. Co.-mum 6 5, 56.5- a?'"' > 1575 19. M dtuni. ('.. 1 vleraae, G.: i a puti'iv/rd t:> dei saggi 'penmerinli r.clh predixinne del ri'Ch: nn.'iTfr. n .*::!> u-::: Co. etiiplev.; cl di vjniie. A do!. Mai.urai Dei I.unci, Ser. VI-I. 56.1 1 I 119 7 4 i 20. Ma!;om. C.. 1 cferii.no, G.: Carcinogen.cits bioassays of vinyl chloride, t. Research plan and early results. Environ. Res. 7, 337 -405 (1974) 21. Mahon'. C., 1 etemir.e.C,.: I.a cancempene'i ambi-mlnta e professionals-, r.uovc prospettive aile !uc della eance.-oeenesi de clorura di vimlo. Gli 0,p. delia v ita 1,5 -6 (1974) 22. Malioni, C. l.cfcnnna. G.: Carcir.ogeniuty bioassays of vinyl chloride: current results. An.-.. N. Y. Acad. Sci 248, 195-2! 3 <1375 23. M.iltom. G.: Predictive value of rtircini'per.esis bioas-ays. Ann N. Y. Acad. Sci. 271. 43! -447 (197b > 24. Muiicr. C-, Nnrpor!.. R.: Bestimmiirig c.cicr E'rinmetal-ohte dcs Vi.nylchlorid'. Niturvvissenschaften 52, 5-11 (1975) 25. Midler, G,, Mnrpoin. K.: Spezifitat der llrmanalytik atir biologisehen t herv.aehur.g be; V'iny!- - chlorid-Fvpositior.cn. In: Arbcitfmodirm'.schc Risikoheiirtejlurg. Herainasg. von Dr. Saadkewski, S. 237-241, Stutr-eart, Canine: 1977. 26. Muller, 0.. Norpoth, R., F.ekard, R.: Identification of two urine metabolite,, of vinyl chloride by (iC-MS-invcstivations. Ir.t, Arah.-Oecup. Environ, filth. 3S, 69-75 (19761 27. Norpoth, R.-. Wodurch cmAehl bci PVC-Ari'e.'.ern Krebs1' 1 mtchmi 76, 634 -636 (197f) 2S. n'Keoife. A. li., Unman, G. C.: Prin-.jrv standards for trace gas analysis, Anal. Cham. 33, 760-763 11 966i 29. Pclluari. li. D., Carpenter, H. II., Nunrh, J. V..: Collection and analysis of trace organic vapor poiiurar.ts ir, ambient air. - Thermal desorption of organic vapors from sorbent media. Env, Sc. Tcehn. 9,556-560 (1975; 30. Purrh i'-j, 1. F, H., Richardson, C. R.. Anderson, D.: Chromosomal and dominant lethal effect j ofviryl chloride. (.meet, 410 -41 l 111 >75} 31. Purdue. I,, J., Thompson, R. J.: A rapid, .-ensitive method for calibration of permeation devices. Ant!. Cham. 44, 1074-1056 (19721 32. Rarmu!!, C.. Johuns-on, A., Ramel, C.. Wachtmeister, C. Ad The mutagenicity of vinyl chloride alter metabolic ast.vation. Ambio 3, 1 9.;- 197 (19741 33. R i\ mnnd. A.. Gcku.lion, G.: The i>\e of praphdired carbon Mack as a tripping material for erg m.ic compounds m light .yves befnr- a gaschromatopraphic analysis. I. Chrom. Sc. 1 3, 1 75-177 (1975) 34. 7 bn mas. 1.. .'I., Popper. If., j'erk, P. D,, Scb.k.'.-ff, 1., Falk. !!, V;r,y! chloride-induced ,;ver (Incase - From, idi< pathic portal h> perte.nsiou (ilar.ti'.s >> Mlrome) to angle sarcomas. .New I'm:!. J Med. 292. 17 22(1975) 3 Waian.'.l-e, P. G.. 'd cGnv;an. G. R,. t lehnnu, P, J.: Fare 01 j '"Cj Vinyl Chloride after S.uelc Ot i> Adniinistrainu> in li.iis. Ti.xiv<>!. Appi. Rearm icrd. 36. 559--552 l!975i 36 V ::!:ey. i. R.. Plvrmacodynamics nrd .'p'.'.ke of vi.iyi s-hi sri (a monomer administered by various routes to mis. J. Toxicol Envirc.nm. Health 1, 331 -39 ( (1976) Received November 29. <977 / Accepted January IS, 1973 R&S 109562 i / f i < R&S 109563 Determination of ThiociigiycoMc Acid in Urine Specimens of Vinyl Chloride Exposed Workers G. Miilier', K. Norpoth1, E. Kusters2. K. Herweg3 ar.d E. Vorsin2 1 Institut Cur Staublungenforsehiinp ur.d Arbeits--ej:'m tier Wcstf. V-'iihct'ns-tJniversjtct. J-4400 Murkier, Federal Republic of Germany ' V/erksarrtlieho Abie,lung dor CAST, Antwerpen, Bclgicn * Werksiirzilieiiu Ahtcilung dcr Chomischen V/orke Kills AG. Marl-Huls. Federal Republic of Germany Summary. A strong correlation was found between vinyl chloride concentrations at working places and the increased excretion of ihiodigiyaoiic acid of IS exposed workers. The mean air e meentration of vinyl chloride was calculated referring to personal exposure. The values obtained were in the range of 0.14 - 7.0 ppm. The excretion of thiodiglycolic acid - measured by GC-MS analysis - amounted to 0,3 -- 4,0 mg/L. It could be demonstrated that significant increases of the meta bolite excretion occur even at VC-concentrations below- 5 ppm. Key words: Vinyl chloride -- Thiodiglycolic acid -- vinyl chloride metabolism in man - Vinyl chloride urine metabolites - Biological exposure control Today the air concentrations of vinyi chloride at working places are rigorously reduced mainly clue to its caicinogcnic [5. 14. 16, id, 30-23. 34] and mutagenic (6. S. 9, l-i. o. 18.19. 30] properties. Exposute controls are commonly based on air analyses by means of highly sensitive, but not always strongly specific analytical methods. Therefore, we emphasized the useful.',css of additional' biological exposure controls 134. 26], By animal experiments we couid demonstrate the possibility of determining the excretion of thiodiglycolic acid and S-curunxy-methyicysteinc. two urine metabolites nf vinyl chloride f 10. 24, 26, 27, 35] D.ila of thiodiglycolic acid in the urine of workers slightly exposed to vinyl chloride and the improved analytical method used for determination are reported here. Materials ar.d Methods (lictnimis . uioUiplyeulic :;cei (9?) t; purity) was purchased trom Janssen Rharn'.aceutiej, Dept, Atctriel. I uropc. P.O.'cf) li.vrsi-. Belgium Dia/ometiiar,.' was generated from N'-metiu l-N'-nitrosn-p'.'luene-s'ilfunaiimle .wsordinc 'o tie Boer ,uui Backer (3J. At! other sui-start.-es were purchased at an.ilyur.il .made from l,, Merck ACi, D-'>l()0 Darmstadt. 0304-0131/7$,'0041/0201/ S 1.40 , hi: ij h':I , 2> I VC* zo :cj hrtjfiduns Determinations of I:idiv 1 duu 1 Exposure by 1'ersonal An Sampling O. .`.-.He. C, Jl, i I 1" ; 4' - rr\y f XA ' t * Sampin.y Sampling Tube. Traces of organic pollutants (among which vinyl chloride} in the factory ait were collected by glass ti-iic s.-mpiers v.uhu length of 12 eni and an internal diameter of 3 mm. fitlesl with 35-50 mesh ,,hat coal!?). These charcoal tubes had a break t.'trough volume, for vinyl thlunde at all'' C, of about 5 liters 1331- Pump. To draw the air tlirough the tube samplers we Used a small pump named personal sampler manufactured by Auatoie J. Sipin Co. The sampled air volume can be calculate.! irom tlie number of pistonpiays ol the pump, registered by a bunt in counter. As the amount of ciutcoal and the density of packing varied front sample.^ : dye to sarni.'fmg tube, we had 10 calibrate the pump before each e.vper;1- mi. The relationship between pistoupLiys and norntal gas volume was easily measured with a gc.'jubble meter mid a stopwatch. j i I ; j | ; j 3 JO fio C/7 I lO CO in 03 u 1 1 ae Analysis | Analytical Conditions. A special injection port that allows for direct introduction of the total [ >s I3GA !\ sample, cartridge included, was used for the thermal desorption of the trapped vinyl chloride j (1, 2S f The vaporised vinyl chloride was routed to a guschromategraphic column. To separate j the vinyl chloride from other sampled organic vapor pollutants we used a 25 m wall coated j curbowax 20 M capillary at S01C. Tiie detector Used was. of course, a flame ionization detector. The surface of the vhiy! chloride peak was measured by an integrating computer. J1 I Cdibrutioi' A calibration gas was dynamically prepared by passing a known gasstream over a )i teflon permeation tube filled with liquid vinyl eldoride |2S. 31 J. fho concentration of vinyl chloride was calculated by the loss of weigh: of the permeation tube over several days. A known volume of this gas was drawn through a charcoal tube and this tube was analysed as described above. The gascliromatographic results were reported as the amount of pg absorbed by the charcoal tube sampler. Evaluation of the Personal Exposure Data. The mean concentration of vinyl chloride in the air during (he experiment was calculated from the amount of absorbed vinyl chloride analyzed hy gaschmiiutogranhy and from the sampled air volume calculated from the number of pmonpLiys of the pump during .sampling. j | !, S 1 i ; ! ? A H VC-Derermination in the .Air of Working Places. The measurements were performed using multipoint flame ionisation detectors (ITDl, type RADFISH, spread in the working area. Total hydioearhons in the air of each sampling point were analyzed once a minute. It has been shown by GC-mcasurenisnts that approximately 2 ppm of the total hydrocarbons in this working area are not VCM. Considering tins amount of 2 ppm not - VCM - hydrocarbons the true air concentration of vinyl chloride monomer was calculated. The personal exposure of each worker was evaluated. Thus, from registrations based on the duration of stay at different working places, all values of VCM air concentrations given in this paper, which are not obtained by pel ..Oiial air sampling, refer also to personal exposure. Determination of Thiodiglycotic Acid by GO-MS-Analysis. In a 10 ml glass tube 1 ml of urine and 0,3 ml of conr. 11C1 were evaporated to dryness in vacuo at room temperature. The restJue was suspended in methanol and the suspension u'as completely methylated by means of diuzomethj.ue in ethyl ether j.'j. .-.Iter 15 rnmuius 500 mg diy wit: m exchange resign (Dowes 50 \VX 5: l-M were added, fliiodtglycoltcacid dimetltyl ester was determined by gaschromatograpiac sepamr.'on and shade ion detection of ti:c mass fragment M 146. It is necessary to use the stamLud addition iee!ir.ti|ue to obtain exact measurements. Conditions A *' Casclirornatograp 0,3 cm 3 OV 1 1 130 C. Injection ; Results t Thu analytical j : small amounts < I two gtoup;of\ \ As demons' (group A) and s 1 1 % significance '_I r . * " yr^i' /i y;^`_ "%';>Fiyi.-: vwTSi^Tifii-jigg'Afr^;r^. -v.v.V',;"' ---' . UO.r~.-Wvyc:.-e.s.rrj-i~ -1 g^ft' i - ' - :~ '- '-.-' y^:ry\;. _ -"' '.J -,.; ----- .".y` _.'y ' t? , .' rr^vUVl Muller ct j! flv.odglycolic Acid in the Urine of Vinyl Chloride Ksposed Worker :oi actorv nr 30 W ibcr o CO cn o> tn eh. . Ml the tot d :- | dilori.le ... I o separate .til eotttetl ,Mtior. detector. '-.uni over a : 111 of nn\ I Jays. A malyzed as ; iis absorbed ride in the air t analsve-t by , r in pistonplays r.ed usit g f.e area. .:o. It has , ttbons ut hsdroeatbotis eat expo-ure of . is- at diftetotit :,e not ol't lined > nil ot urine and . The residue mean - ol resign ID"'.veS > jraschrnrmtoeesxars io use Fig. I. Urine cor.eentrtitiorts of 'tvodigiycoti. acl.l (TDGAU Group A: 20 nor.-exposeJ male., Group If: work .'?$ expose^ to. 0.14 -- 3.3a ppm VCM mcutitred by FID air r.-a lysis. Group C: S workers exposed 'o i .02 - 7.0 ppm VCM measured by use of personal a:: sump'ers Fig. 2. Urine eor.eentr.uions of thiodicl.colic acid (TDGA) after classification of 37 data according to four collectives sshieh are related re four different VCM exposure r.iraes: A = f>.0 ppi:. U = n.Oi '.CC) ppr C= 2.51- 5.00 pern, D = 5.01 7.50 ppm Conditions i'.aschromatograph 0500 combined with mass spectrometer 3200 tFinnigan). Column 1.5 m x u.t cm i" OV 1 on f'D.'bO DMCS Cliromosorh V . Garriereas 30 mUntin. Goliims temperature I .:0" C. Injeetri'ii port temperature 200" 0. Separator uvnpeu'ure 200" C. Results The analytical procedure which we developed for sufficiently precise determination of stttali .imounts of thiodivtivcolic ticisl ip. wine samples allowed us to compare data of two u(v,ups of VC-wotkers with, those ofu non-exposed croup. As demonstrated by Fig. i, it is pos'ibie to distinguish between noi.nn: values (group A) and such obtained from slighih exposed e.rkers fgroup 3 and C) at the l '/r significance level. As we calculated from our normal values, in all cases concert- 7 y 0*v>r. yt-'i.'rr?" - - i, -55S'. '.Upie si'-fzyr, "P I*ieTi-' , f.-c*<.-' m UV! rv* n 202 TOGA I fjglh]! 400 C, Muller i:\jI C I VClptiml 300! Sft * --- TO no 1 > --, - - II 24" gee 24" tr ie" Fig. 3. Remits of a comparison ii-.w-Miitation on VCM o\pos.irs loveli an-2 the excretion of thioeiglycolic acid (TDCJAJ/liour in the c.i;_> of a single worker, who was observed during a lltrce-iiay period [rations of thiodiglycolic acid exceeding 2,1 ngjml urine can be distinguished from norma! concentrations at the I % significance level (99 % probability of confidence). fho.se values were found twice in group 13 and five times in group C. The mean values of the three groups suggest a correlation between the extent of exposure and the amount of thiodiglyoolic acid excreted. This correlation could be proved by classifi cation of the analytical data according to four classes of different exposure. As shown in Fig. 2, an increase of metabolite concentrations in the urine is found with in creasing exposure. The correlation was tested by a distribution free statistical proce dure I! 7J and could be confirmed at the level of p < 0,01. Since individual exposure control bv means of personal air sampling seems to provide more precise data than global air analysis, we started exact examinations of single workers controlling the personal exposure during lime periods of two or three days. In tin's period all urine portions were collected separately and in each of them the concentration of thiodiglycolie acid was measured. The results of otic investigation are shown in Fig. 3. It can be seen that die inciease of metabolite excretion began shortly after starting the exposure each day and that the highest concentrations were found in the first or second urine sample obtained after the highest possible VC-untake. Furthermore, it war, a remit of this investigation tiiat the metaboli'e excretion exceeded the norma! range significantly even after a mean exposure level of about 1,5 ppm but not alter an individual exposure of loss than 1,0 ppm. Thio^u-iy t; Diseased Main me animals. [11,24, Prev S-carbo\ gical exp experirnt tluodigly higher th working; performe IS worke of thiodi: alternativ the expos mercaptu: thiodiglye more prec previously in man th; a natural!} method tli urine of w 1.5 and 5 ; level. me la no mgtdaa= MGyCM=1 The thu rates in the r -values as she in rat and m. more in acce analyses usir hydrocarbon (>. MulJcr el nl. CJ VCfpp^IV4 [3 1 |I 1 - r`"r-*T---i---i--r---Q it,** or* wrvtion of . .iJ (lurin'; a ashed from s;`confidence). ;ie mean values re and the by classifi- <urc. "n \v\l) Aiic JO So O) "J so --i o iwt to , Ol 0) 10 1 ion ilo rj -- re ible VC-up- :e excretion ! of about Tliiodiglycolic Acid in the Urine of Vinyl Chloride Exposed Workers 203 Discussion Main metabolites of vinyl chloride which are excreted in the urine of laboratory animals are thiodiglycolic acid [10, 24, 26, 27, 35], S-carfco,\y-methylcysteine '[11,24, 26, 27] and hydroxyethy! mercapturie acid [11.35]. Previously, we proposed quantitative determinations of thiodiglycoiic acid and S-carboxy-methyl cysteine in the urine of vinyl chloride exposed workers for biolo gical exposure control [24, 26|. In the meantime, we ccuid demonstrate by animal experiments that S-carboxy-methyl cysteine, a precursor of the final metabolite thiodiglycoiic acid, accumulates only in the case of vinyl chloride air concentrations higher than 500 ppm in the exposure chamber [25], which are unusual today at working places. Concerning hydroxycthyl mercapturie acid measurements where periormed using an amino acid analyzer. No amounts where found in the urine of IS workers slightly exposed to vinyl chloride which exceeded the corresponding values of thiodiglycoiic acid. It may be taken into consideration that the contribution of alternative metabolic routes to the biotransformation of vinyl chloride depends on the exposure level [13, 25, 36], Thus it is not yet clear, whether hydroxyethy! mercapturie acid is the main urine metabolite of VCM in man or whether it is thiodiglycoiic acid. Investigating the real concentration of the latter metabolite, a more precise procedure was needed than in our animal experiments performed previously [ IS, 20] because its increase after VCM exposure is apparently less marked in man than in the rat. Furthermore, it has been shown that thiodiglycoiic acid is also a naturally occurring urine metabolite in man [25], Using an improved analytical method then, wc could clearly demonstrate that the metabolite concentrations in the urine of workers exceed the norma! level significantly even after VC-cxposures between 1.5 and 5 ppm. This increase of urine concentrations depends clearly on the exposure level. Neglecting other elimination routes than urinary excretion theoretical values of the daily amounts (E) of excreted thiodiglycoiic acid may be calculated according to the following concerning: H = v8h X Cyc x Ry-p x Q x MCtdGA MG vc The explanation of the symbols is: v8h 3 lung ventilation during an 8 hour interval! C'vc = mean air concentration of VC R\'(7 ~ resorption value, which has been found in animals as about 0,^ (4) Q = relative amount of thiodiglycoiic acid as compared to the total amount of VC- metabolitcs. which has been found between 25 V. (35; and 50 % (10). MGTDAA = molecular weight of thiodiglycoiic acid MGv'CM ~ molecular weight of VCM. The thus determined theoretical values correspond weii co the measured excretion rates in the rat. They are, however, between 2 and 10 times higher than the excretion values as shown in Figs. 1 and 2. This may be due to different biotrunsformation rates in rat and man. On the Other hand, the values obtained by personal air sampling are more in accordance with the theoretical values than those obtained by direct air analyses using FID-detectors. In the latter case, as mentioned previously, other hydrocarbons are measured together with VCM amounting to an average level of (i ---if f; r? SIS J *- t- * t- U Vi * - C, j v'iJrVr \ij-.-* fV. ri--'n**, -=h i- : . . .''I v.: r> i r' y ' **' -7 :: ir- i V.- ~T .c-u 204 G. Midler et-fll. * about 2,0 ppm. This average may have been exceeded during some of our measurements. Thus, more evidence is needed for the true slope of the function between VCM exposure and excretion of thiodiglycolic acid. Therefore, we started a new study to reinvestigate this slope by measuring the personal VCM exposure using the personal air sampling tech nique in direct comparison with the use of FID-detectors for air analyses. As shown in Fig. 3, even a slight VCM exposure can cause characteristic fluctuations of thiodiglycolic acid excretion and this can be revealed by continuous urine analysis. Considering the excreted amounts of the VCM metabolite per hour, it seems possible to prove a periodical uptake of very low amounts of VCM by single workers. Such measurements could also provide some informations about inter- and iiUraindividua! differences of VCM metabolism in man. Acknowledgement. 'iliis si inly was supported by a grant of the Berufsgenossenschuft der Chemisehen Industrie, D-6900 Heidelberg i, BRD. References 1. Aue, W. A., Hostings-Voght, C. R., Younger, D. R.: A gasehromatogruphic cartridge desorption port. J, Chrom. 114, 184-189 (1975) 2. Bartsch, H., N.lalaveillc, C., Montesino, R.: Human, rat and mouse liver mediated mutagenicity of vinyl chloride in salmonella typliimurium strains. Int. J. Cane. 15, 429 -447 (1975) 3. Boet. 'lit. J. de, Backer, H. J.: Dieaomatliune. Org. Synth. 30, !5 (1950) 4. Bolt, H. M., Laib, R. J., Kappus, II., Buchtei, A.: Pliarmacokinetics of vinyl chloride in the rat. Toxicology 7, 179-1SS (1977) 5. Creech. J. L., Johnson, M. N.: Angiosarcoma of liver in the manufacture of polyvinyl cldoride. J. Occup. Med. 16, 150 (1974) 6. Fleig, I., Thiess, A. M.t External cliromosome studies undertaken on persons and animals with VC illness. Report second intern. Conference on Environmental Mutagens, Edinburgh, July 11-15, 1977. Conference Abstracts, page 219 7. Fraust, C. L., Hermann, E. R,: Charcoal sampling tubes for organic vapor analysis by gaschromatography. Am. Hyg. Assinduslt. J. 27. 63-74 (1966) 8. Funcs-Cravioto, F., Lambert, B., Lindstcin, J., Ehrcnberg. L., Natarajan, A. T., OsterniannGoikar, S.: Chromosome aberrations in workers exposed to vinyl chloride. Lancet 459, (1915) 9. Garro, A. J., GuttcnpLin, J. B., P. Milvy: Vinyl chloride dependent mutagenesis effects of liver extracts and free radicals. Mutation Res. 3S, SI -S8 (1976; 10. Green, T., Hathway, D. E.: The biological fate in rats of vinyl chloride in relation to its onco genicity. Client. Biol. Interactions II, 545-562 (1975) 11. Croon. T.. Hathway, D. E.: The Chemistry and Biogenesis of the S-containing Metabolites of vinyl Chloride in Rats. ("lem.-Bioi. interactions 17, 137-150 (1977) 12. Greim, H-, Bonse, G. Radwan, Z,, Reicliert, D.. Henscltler D.: Mutagenicity in vitro and potential carcinogenicity of chlorinated ethyienes as a function of metabolic oxiranc for mation. Bioclicm. Pharmacol, 24, 2013-2017 (1975) 13. Hefner, R. ., Watanabe, P. G., Gehring, P. H.: Preliminary studies of the fate of vinyl chloride monomer in rats. Ann, N. Y. Acad. Sci. 246, 135-138 (1975) 14. Infante, P., Wagoner, J, K., Waxweiler. M. J.: Carcinogenic, Mutagenic and teratogenic risks associated with vinyl chloride. Mutation Res. 41, 131-142 (1976) 15. Infante, P,, Wagoner, J. V... McMichael, A. J., Waxweiler, R. J., Faik, H.: Genetic risks of vinyl chloride. Lancet 754, 120 (1976) 16. Lee, F. J., Harry. D. S,: Angiosarcoma of the Ever in a vinyl chloride svotker. Lancet 1316-1 318 (1974) TlliOdiglyi 17. Lioner 0962 18 x(a|JV horn ts. C 30 ft ilto: (O cog , 1o Itoi to ly i CJ1 itoi 07 00 k*c! on (1976) 24. Miiller, schafte 25. Miiller, chlorid S. 23726. Miilter, by GC27. Norpo: 28. o'Keeft 760-7 29. Pellire: pollute Techn. 30. Purehaof viny. 31. Purdue, Anal, C 32. Rar.nug after rr.33. Ray mo: organic 173-17 34. Thomas disease Engl, J. 3 WataiU' Oral Ad 36. Withey, various; Received No-  -t-: ' 7-* * " . -- -'..-k'4*' ' ^ , .' . . - 'VV4. ` *, - V C>. Muller ct aI : our rn'-vnireoienn. osn VCM exposure Ly to Tcinvesiigato :i air nmnliilj tCCh- > ;5 ::eri .by lilt C.v hot 33 fio ujs W r, it -J. lo O CO tnd -ch cartridge . J cited .'anc. 15, 't chloride in the polyvinyl '.ns and animals 'gens, analysis by - T.. 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Maltoni, C,, Lcfemine, G.: La canccrogenesi anbientale e professional: nuove p-ospettive alle luc della cancerogcnesi dc cioruio di viniie. Gii CRp. della vita 1,5-6 (1974) 22. Maltoni, C-, Lcfemine, G.: Carcinogenicity bioassays of vinyl chloride: current results. Ann. N. Y. Acad. Sci 246, 195-218(1975) 23. Maltoni, C.: Predictive value of carcinogenesis bioassays. Ann. N. Y. Acad. Sci. 271.431-447 (1976) 24. Muller, G., Norpoth. K.,: Destimmung zweier Urinmetatolite des Vinylchlorids. Natur.vi..scn- schaften 62, 541 (1975) 25. MtiUer, G., Norpoth, K.; Spezifitat der L'rinanalytik zur hioiogischen (jT'erwachting bei Vinyl- chlorid-Expositionen. It:: Arbeitsmedizinbche Ristkobeurteilunit. Herausgeg. von Dr. Szadkowski, S. 237-241, SutUgart. Centner 1977. 26. Miiller, G.. Norpoth, K., Eck.ard, R.: Identification of two urine metabolites of vinyl chloride by GC-MS-investigaiions. Int. Arch. Occup, Environ. Hlth. 33, 69-75 (1976) 27. Norpoth, K.: Wodurch entstchl bei PVC-Arbeitern Krebs? 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