Document GmEy4oLyxde3mvzK6Vjy690Lq

r% m 0 1 <0 N> 00 t, : r. \l iik J7;i Lj LIBRARY ETIiYL CORP., DETROIT T I Kimvi 11/ 5 August f977| Abstract Si (ir alf studio on plurmacolmclicx of v*nvl ttitonA^m ru used rjtv Consistent evidence shows shut, jhou1 .1 sontLiJiMlitiTi uf "sjiur.iln>n~ winch m> inluJalion exposure is reached at about -5o ppm ximl l NI.ji mJc in ihc atmosphere. non-linear Idosc-dcpindcnll plurmacokmclics apply. Two different mitdcL describing the pharmacokinetics of unxf chloride have been publislicd They show lh.it vim. I chloride can lease the hodj sen rapidly via expiration by lung However special conditions a|vp]v ir rats arc exposed to jiinnspliinc vim I chh<ride, the compound c\|uilihrates wilh rhe organism witfnn J 5 Ao urn. and from this equilibrium it j? removed by metabolism This probably involve* formj(n in of the lead ne epoxide Along with the hind ifmica1 data on vinyl eMorrde's mieraction with 1 be organism thai have been recently elaborated it is apparent I hat pharmacokinetic research coniiirules to ihe understanding nt a variety of prupcrlics id llus important industrial compound % a o o Ci 2. CP ') 6 > c INI ROIIL`17 KIN The delect I c>n of carcinogenic effects of vinyl chloride on the liter I Kilter. 19"6t has focussed alien him on melabolism and dispi>silion ol this important indus trial chemical in the living organism (Leibman. 19771 Manx publications deal with aspects of mu 1 a genial x of this compound (Bart sell & Ntonlcsano. 1975) or xvilh Ihe molecular mechanisms hy which Mini chlor ide max exert its muiaecnu: or carcinogenic cflccts (Van Lhiurcn. 1975, Liurhm cr ol.. 1975: Laib & Holt, 1977) However. it has to tie considered that biologi cal action of a xenohioiic does not only denenJ~on iheTnochc irnc.il tatcei tnechani>ms ol the latier. hut is also largely influenced h> pharmacukinelk. factors', 1 he aim ol l he presenl' mini rev tew is to present ihe data for the pharmacokinetic behavior of vinyl chlor ide which arc available at present. So far all studies have been performed with rats. . DOSE-DEPEN DEM E Of DISPOSITION Ol tINVI (IITORim. It has been stressed. particularly by Gchring and his coworkcis Hlclner <r ill. 1975; Ciehrtng er ot.. |97fi: Walanabc it ol. W77j. that metabolism of vinyl chloride w in.* is ;t sat ut a hie prwess, lhi< lta> tven lecvnlJy continued |Boll r ol. 1977\ as ut>. melaboli/c vinyl chloride accoiding to first order kinetics only il atmospheric c on een I rat 1011s below 250 ppm vinyl chloride are applied If this concentralion is exceeded, non-linear pharmacokinetics apply which are consistent wilh the iheoretical consideration iCielmng er . 197t>|ol salination ol ihe me l a boll zing cn/vines However. Hensettler |I977) did not observe a saturation of vinyl chloride metabolizing enzymes in ihe isolated perfused ial liver prcp.irjiion. even if such high cixtjcentT.ilions as 201X10 ppm wuyl chlor ide wetc applied tn the caibogcn miv lure used lor iu\geii.i(ion of ihe perfuston medium in the "arliliei.il A reasonable explanation for the discrepancy between con Jit urns m mo ,md tn the tsolaled per used liver is drfficuh to give and will deserve further studies That metabolism of vinyf chloride is dose-dependent can also be inferred from a comparison of the routes for dimmalum of the compound uficr diflcrent dosage schedules. 1 e. comparison of exhalation of unmctaboli/ed vinyl chloride and excretion of urinary mctubohlcs. Table I compiles the data given in the literature. If a low dose, up to 1 mg Ig. of vinyl chloride is adin inisieved in oily solution, either vra stomach lube or by i.p injection, a considerable portion is excreted as urinary metabolites. In contrail*, when the dose rs increased to It Kim gig and over, the bull of vinyl chloride given is exhaled as the unchanged com pound. Mus very much favours consideration of a SUluT.iblc metabolism of vinyl chloride under in-Tito conditions Anolher conclusion can be drawn from the figures of Table 1. a* the data of <Srecn & Hathway {1975) show that the route (if elimination of vru*l chloride dc|vnds on tlsc route of administration of the subsumo;. Administration into Ihc splanchnic area, by p.o or t p. dosing, favours urinary excretion of roetaholilo which is even more pronounced after oral admimsir.itnHi, This very much suggests a lirst-puss cfTecl and is conxisient wilh the potency ol liver to rapidly ftielaKdurc vinyl chloride if the Isttcr it present in a comparably tow concentration. rmRMiraMMttCMniieu for VINH (lILOtttllK INi.irtmAmciic surveys on vinyl chkifidr have K -n publisltcd hy ^ (they and hy fhift cr ot (IV7 '1 Itoih approaches, although very different m conceit, lead to similar conclustonv as to lhe rate <9 cvhwUu.-n of vinyl chloride Wnhey il97o expo-ed >at\ to a h y 1 E c~ 1929 92 III kyiw \1 ti>n i Table I, Evtidhiixm of untnclaboli/cil vhK>nJt* and U unary cviTclion ol n^!.h^ipu% ,,i(iu .idiiiinisir.ifi.Mi ..| .!%- soheJ Mil)k iHlaridc In rais bv sarum* rome- Vinyl chl.YHle dose given :ju m t* Si too pa kg liVfTIg kg kg 45i.Emg kg Oral dose cxhakd t'j nr me r ti 3.7 75 1 t 2 59 6k h? 11 92 91 9 54 p v dose exli.iti.iJ unnc J32 winded lJ Poll, renter <iccn X flaihway 119751 \X Jiitn.ihc tf ni. i IIV'I Wj|;m,llK' il if/, |19~0| heron i-; if' *ly75> Cnueii A, Iljtlmav 11`>7^i kept constant. jin! he monilofcd 1 'ration* of umnctjboltscd vinyJ chloride Met ween 5<<Ct and I4.t*xippm rn ihe atmosphere. the ratio VOmt Wood Mg VC, ml air which is equivalent to Oswald's solubility coefficient, wasconstant and amounted to 2bl, Tlic equilibrium between vinyl chloride tn ihe atmosphere smd in blood wjs nil allied after 30 mm of exposure. Wuhey tl9"M also determined live kinetic* of vinyl chloride in rat blood after i v. .ulmmistralinn of die com pound He obtained a hrphaxc pLi*mii concen tration corse which was consistent with a iwo-compadmental open-ended model shown in Fie. 1 The rate constants shown in the figure are the means of 4 experiments described after i.v. dosing. Die mean rjic constant for the pjriial process of cxhalaium was 004bmin1, equivalent lo j i, or I5i<ii>iii. The model does not take into account metabolism of vinyl chloride which is justilied as so far as Table I shows that, after an iv dose, the overwhelming portion of vinyl chloride *> exhaled However, the preset)I bitchemicul data strongly suggest ihat vim I chloride must be metabolized in order to become effective as a chemical mutagen or carcinogen (see the review of Rartsch and Monlcsano. 19751. Also, n has iu he con sidered that exposure of an individual lo an atmos phere containing vinyl chloride will result m ndnMmcm of equilibrium between vtnyl chloride m the gas phase and in the organism tWithev, 1976; Huchter et at. 1977). l/nder those steady-state condrlions the only wav for the organism lo remove vinyl chloride from ihe equilibrium is by metabolic conversion. This has been considered when attempting another approach to the butch mimics of vim.I chloride |Fiofi ft aL 1977)i As shown in Fig. 2, mis were exposed to vim I chlornle in a dosed system. The com.cn ira I ton of vinyl chloride hum mi ret I iu ihe gas phase and kepi below l Ik* saturation point ol 25* i ppm IIv means or new and polenl mfuFitors of uvidafoc ding uicia- bdlismtllult ft ai. 1976) ti was po.ssiHi tn tompfctelv block. bioirjnsfotni.ition of vinyJ cliEonde These ex perimental vondil tons permuted determination ol the equilibrium constant and the rale constants A,. and JU, of big 2 With .ijnrrtafs nol pre-trealed uilh in hibitor an exponential decline of atm..spheric vinyl iblonde in liiv closed tvposiire sol-ih is observed which is due to metabolism The lirsi anl!>or> report - mg al-HWiI this p.ir.iin-.ier oi mcl.ib. .fisrn of x ii.y T shli>nde weri H.-incr 11 ,t! ipi~<i from Ibis p.u- amctcr ihe ionst.ini A:, ol I ig 2 w.o denied tllolt cl al.. 1977). ) mallv. the ule ol .ippcjiamc ol radm- uctivm m urine utter application ol `"(.-vinyl chlor ide lo ihe system gaii constant Ilk data obtained wiiJi ihe imdj ol Fig 2 are comparable with Wirhey's hasu rtsoils Hits ukrs lo ihe rate of exhalation of nn-.l cldonJe Irom the .imm.il into the atmosphere is of f ig I = im4J mm 1 A - of I ig 2 -- Oo5brnm .o well .is to ir.e distribution Ktween mis I tidonde m ihe gas pJiase and m die animal. Wid.ev (l^'io as mentioned .inmi obi.nncd j ratio between eoncentr.iuoti of vinvl chlorrde m hliud .ukI in the at mo sphere of 2 fl. uhere.ix the cal culation of ihe "eoii^lanl of equilibrium" (Hofi e; of. I977i Is = nl gaseous VC per c IxhIv wi nl gaseous VC per ml air _ A,, ts't Fie. 2t under s leads-si ate eondinons resulted in 2>b < OMll si(\s Different conclusions may be drawn from the phar macokinetics ol \m\l tblonde. Ifiiwevei. ii has to he WC m rr totntf o of vc ti 70'l4]mglbgf ft ky! CiD min l,,* 0 OJS fnin*1 VC n blood k,*0(U6 fnm"T i Ll4lll.on ol wnmfUbOliitd I Ml I f wiwi'inp.irTniciM otvn-i'nflt'il TMisJd fni trn f t hfoi .h- in r1 . f'l.jrmjuAmeiicv vf s in - T ehlon-f' 91 <C .n l j lb 1------------------ ar.irrjrs O.C5t wti' *iy- \[ n,ii&00.0037 mm'1 f m" ,n *K . OtijJJ wji*1 rfV*bo- | hits n urrnt | T ilt 2 Plurni^.fi.iraiies v:n>I <or.de on e' pinure in j eh sed sj.tera' m del t< Rah ti at i !9`,"i. Hie n.'J.'t it.vluJvs tki r.-lwr si kWo".iic The cori'1 jr:*.s ,ire valetiUled after exposure* ii' ini!j.,l Cl ncem rations ht.ow 25(<ppm ijm. chlunJe for Jctj.S. see icvt kept :n nnuJ ilul dopusiiion of \ -nyl ^fftoriOe h dose- d^p.nd.nl aijJ hcr.ve llic Inn...'"' pli Tnjjvokinelic asst^snicnt oj mefarvdism d ic 2t refers ('rd} lo th* lower dose range tie belov 2^0ppm in the ga> phjsei Hut dis is. from i!:e si^r.Jpomt of .saipj* ti.'ii if mvdtcate. ihe more intvrcqv. e on^ \s f;a been pointed on m fi. bring ; a. '^`hi, the r..'n-h.nca: ph.trnuut'kn.eik ntHa\!o.jr in ihe higher Jose rare-.- ivt.i Kt>,e impoi-,tm.e U " ai3erpret. l.on ol loxicofog.- c.ii siudies lxcji.se an intrude me co'-e ol vtnyi ddor.de dik's not recessjru> rntrh j parallel increase in lortrijtjon oi the afttm^leh nt_tagemc or carcino gen re metabolites Il has been -fc;scd tHolt .' al. H"-! ih.it. due to the rekmveh short k.h-hfe o; vmyj chh'nde and its metabolites in the orgamsm. no >ign:1kaTjl cumula tion of vinyi chF nJe or rts ma'or irct.ihohtes j to K' exp.xtcd on i\ peeled ad minima non o! chlor ide fins is rn marked corura>i% lo the heh. woi:r o- ihe elosely related injilo.-ocitvftene in the o-aunism. where Tricl'forocthanol and es]ve:-ili> irkhlo*-oacetJs acid are retained lor a eonsidei.iMe period ot tim- iLitloir.i.' 1972. \Iuller t/ a1.. I9"4i The rjptd elim ination oi vinyl chloride and u> major metabolites from the- organisms may K- consistent with the cur rent theory that a rejetoe short-lived metabolite whkh nkcurs rti low vorie-nt ran oris only, mat be re- spoTisibk' fi'r the to\k effcvis of vinyl chloride [he ph.iini kokir.etk' rn.sJef of Fig 2 abo ieie.J> the basic difference which exists beiwesn mh.ilairoit ol vinyl dilonde and olher exper.mi.niat ioutes ot jp- phs.ition I xpvwure to n vuuf chloride-cort niang at mosphere rcstilH in a rapid cujilibration of vinyl chloride with the organism If. lor losicological con suls rations ihv aciu.d low of almosphenc vinyf ihtonJc .uitng on live oigamsm i> Mltul.iied us the dose uinj' is taken up mmi the uim.ispliere. after equihbruini with the organism has been attained, uptake is .-illy "due to metabolism"1 |sof Hg 2). ,n .1 .ill ol rhis d i>e is itu-iliol'-.d nro1'tf't- mei.il ofivm of uiul d fonde ix verv hkdy aeciirdin. l> fiieni buxr.enifcjl investtgaiio.'iv t\ar Maurer |9"'5. Cireim *; jf. 197y. Boitac 11 al. !9'5, Revnnkiv ct al 19^5: Kappus ti at.. 1975. !976: Wj tana be i.' tu.. N.-pi.tih or jf. 1976, Hen.xchler, 1977. Oreer/ Ja Ha:hwa>. 19`,~i R.. eonirast. X the a mm a I is not held in a closed system and a urnf ehior.de dove injected, the ratio of A- tFig 2> implies ttui more than 9(1,, of the dosi .so ha leu and only j minor portion transformed ti-i 11 c ult-maT^'; toxic Dieijhohtes Thi* futiy agrees uilh ihe exper.-.-ent.i! dalj of Tjble I. However, after nra! arpl.ciikn a lirsi -pass effect for met.-.rkvhsTT in liver ha> to be con side red These iheoreticul corisideraturns arc nci 1 mned to vtnvi chloride. Hut reler jk> to ether volatile xeuobioiics Thus, a pven oral dose of sarK-n letuc.'londe is much more loxtc. if it?e animaix ure kepi in a sloswd atmosphere MmpuhlisheJ result si An at he: conclus^sn n.av he based on the rate of -mrv o: ainuKohe.-.c vinyl chloride into the organism. : in. eqt: librium is achieved Figure ? shows this "toccss winch ha> been visualized usma: ruts pre-ircatcu witn an inhibitor of vinyl diktr.Je meinShiism cMoh <n . Isppt The data are consitunt with those obtained by Wuhey (|976| It can be seen that uticr Iftmm the procos rv nearly conipfettd Witlnn the lint a min nearly 51**^ of the equ*librium dose me la ken up. in the first minute. Ail 147, arc 1.1Vcn up -Vthough an extrapolation from anmul data io man is difficult, these figures may bt imporutii t 'r assessinent of occupational peak concen trations iKcuri ng in vinyl chloride plants. As uptake of mi! chloride Irom air *sa time-dependent i'toccsc. a very sliort jx-ak conccntratron may be of o *ly low impact, but u> the e lev j ted concvnirution is main* mined only for a Tew minutes, considerable amounts of additional vinil chloride may be ULcn up hi the individual. Jhcv.* lew examples *crve to show- (hat, in addition to the bnchcmlullyr-stfkintalcd resca th lh<l -s i-s^-niiil I ir i rn.sti ..irunVii- t.. .1, t ,,t, -i.1 - v 94 HtHMANS M. (ill T VC tnp PliaimacnViriclies <4 vinyl clilonde Van. I>t i his |t | On ifn. pmsihk meihanism of s.lienilLine jlIkhi il xjinJ JdiMiJc I*n x > Ifi*/ ,S., 24lt. 2^6 W AlAssiir f* i,. Mt f hux VS r, R A (,1 iikim, |* J ((9761 fate ol '*t -xnivi ililcaidk idler smjfle oral sulnumurj turn in r,i(s 7omi- Kji/if I'tun mm 36, TJ9 352. Waianahi P ti, Vm'Mi J t) A Ginhis'i, p J. ti^T) 1 he imporlar.ee of non-line.ir fdoncHlcperdviHl (banna cokmetics in hazard tsvewmeni J. t-.m perfi /.m. I tm press). Fig. 3. Uptake of vinyl chlonde from the gas phase by rats pre-rrcaied xxiih an inhibitor of vinyl chWde metabolism 16-nilro-1.2 3-bcnzoihiadraxolc; see Hull rf of. I977y Amount taken up lo achieve equilibrium bcitveen gas phase and animals is vcl lo lOtF,. vinyl chlorute, determination and consider;!lion of the pharmacokinetic behavior of this compound is also necessary and helps lo interpret toxicological data. Acknowledgement--The author's experimental work xsjs supperled by the IteponmeM of Research and IcJinnlogy of ilic 1 cderal Republic of tiermam fgunl No FV U37|J9|. This support is gratefully atKnow lodged RLF1 RCMKS Baamn A.. Barm If. Catusv A.. -Unit igno'v P. M vla- vjiLLr C, Mivs.TtSANo K. & Baris*ii If (I975| laser rmcrosonie mcdiaied Icrmalton orally luting agents from vmyl bromide and vinyl chloride. Bn* hem. f<iopb\%. /fn. riMrwmn 67. 5lff> Mil Baarse if If A Womisano R <I975) Mutagenic and car cinogenic effects of vinyl ililondc. Mururtcw Ref. 32, 93 114 Boti M M. Kaws If.. Bmma A & Umr W (J9761 Disposition of I.Wvin)J chWtdc m The rut. ,-lri/is To\ji . 35, 153-161 Bolt H. M. Lair R. J. Kawi sH & Butm* A (11771 Pharmacokinetic* nf vinyl chloride in llie ral rnxmo- byi 7, ITRIW Bonse Cm Urban Th, Rucmlkt D & Hissrmtx D {1975| Chemical reacitviiy. metabolic ox mine Immation and biological reactivity of chlorinated eth>tents iri the isolated perfused rjl liver preparation BnaAcmi PAut- moi. 24, IH29Ih.U Btriifr* A.. Bolt H M, Kapm s H Jt Boir W. J19771 Die Gewebsvertertung von 1.2-,4C-Vmykrlilorid bei dT Raite. tm. A'ch* ncrup / nriron. HUH 39. '7 32. Ex nr T. Hi-ssoiux l)., Muux G & Spaxvowsm M |1972l Metabolism nf trichloroethylene m man- f Tlvc significance of irtchloroeihanol in long-term exposure conditions. Archx Toxic. 29, 171-MtH. FtxoN V. J. Sv\ik A. J, Witumx M. J.. Van Saiiih D & IH Groot A P. (19TM Observations on the oial administration and toucil) of vm>1 chloride in rais. Yd cov/iti- rvie. 13, 613-63B GittRi*** P J, Waianahi PGA Vtu Mt J. D (1976) The relevance i*t dose-di'pcndent pharmjcokincttcv in lVii* i,. i^f .'imrivnii hii.iuf of rlinMii.ik In Gails T. A Hatiiway I) H (11751 The biological fate in rais of vinxl chloride in relation lo its oncogenicity Cfrcni -Hud fuuratl II, 545-562- Griis T. & IIatii'aat IJ L 119T7| The chemistry ami biogenesis ol the S-cont tuning meij hoi lies of vinyl chlor ide in rats ( Jnr<rif 17, 13 I ^lt (HUM II.. Itossi (i.. R Aim an Z. Kiichih.1 I> A Hi w hi ta IJ |I975i Muijgcmcity ttt t itro and potential carcinogenicity of elitorinaled elhylrnes a> a fumtion of metabolic nvirane formation, /fan hem Wutrmui 24, 2013 20|7 Husik R. f . W*tASAt P G & Glintisc P J (I9"5l Preliminary studies of the fjle of inhaled vinyl chloride monomer in rats. -bin. \ Y AtaJ. S<j. 246. 135 I4K. Htssotua 1) |I077| Mcljholisrmis son Vmvlchlond In sc hitdi n dun ii I in i Ji hi<* hi, I'm\ h h /ond- K ran Utril I Id ik'd hx <il I,OVIK H w A lllAsai W Kl PP- 27 3? <r 'Au/'itrock. Haden-Hadcn Kavpi s U. Bihi H M.. Bi.cimi.k A. A Bolt Wr. tiy`5/ Ral liver microsomes cjiafyse covalent binding of r*4'-iiit)f vlilundi: lo macrumoleeules Auric re- 257. 134 135 Kahs IJ, Bnt i If M. Bit mi a A A Bolt W. 119761 Liver micrmomol uptake of l4<"-vmyl chloride and trnnsfor ma non lo prokin alky lai mg nk- label lies w i;rrtp Tow. opft t'hornbit- J7. 4t> I 471 Laiii R I. A Bot r II. \t (1977) Alkylation or RNA by vinyl chlcuidc metabolites in titro and in i iio. formation of l-V'-clheiioadcnotinc. 1oxkfoiyi 8, 1S5-195 Llihman K. C. (1977) Current literature metabolism ol vmv I chloride. !>ruy Meisih Disp 5, 93-94 Mllllh G. Spa-Vuis ski M A Hissritiix 1) JI974) Mda- htdism of tnehlorsiclhykne in man--11 Phurmacokine- licx of metabolites 1r<6' Ftr.Mi l 32, 2S3-295 Nor pm ii k. Mi Lira G.. Wittim. U. Gottmiialk IX A Gollvi Hsi K i. (19761 Uiitersuchungen uher den Sioflwechsel ds*s VinykhUmd und lihcc Wirkungen der VmylchlofHlmluilation auf Rrgulationsmechunismen des Lebcrviollweehsels. 1 crh. dr. (u-j. .J^hcirsnn-Ji'Ni 16, 1K7 W Poriiv H R (I97(>) Aniclcx of general tnleresl vinyl chloride. Ft/toxHh'r toxic 14. 347-349 (part lk 49s-501 IpaM ML Riinoii*\ |- S. Mosiin If T, S/Ami A. Jam.ir R J- A 5'i urns V O il'^si Hep.iloi.isn itx ,4 vmvt t filinnh' EC- 1930