Document 70bZjJ1bpvQLxYQoZVLbgzpV

52S^ MS'ltfJ 1 -_;--;--:-- '* tt-f s. *% *;.; ;.v *' 'Six (-'<: _ y-fj/t. \ ,lO. , fi Pri'\* f`rint, U i krinih Ooc?) [mo) R&S 027003 MINI REVIEW PHARMACOKINETICS OF VINYL CHLORIDE Mikmasn M I3oi.t InMHuic of Toxicology. University of TUhmpen, WilhclmMraOc 5<\ D-7-UXI I iihm^cn I. Cierm.ii)> [Rcoitvil 5 slutfu^t IS77) AbsimeJ - $n f.ir. all studies on phurmneokinciies of vtnsl chloride m ntn used r;ifs Uoiimmchi cwdencc shous ihut. above ;i concentration of "siuuuliou" wh;cli on mh.il.iiion exposure is replied ;it .ihout 25<lppm wriyl chloride in the atmosphere, non-lmcar klo*e*dcpendeni) pluirnucokmeiics ;tppi\ Two different models describing the plnirm.icokmeijcs of vinyl chloride lu\e been puhh.hed They show that >in\i chloride enn leave the body wry rapidly via espimiion h> lung However, sjvei.d conditions apply if rats arc exposed to atmospheric vinyl chloride; the compound equilibrates with the organism within 15 50 min and from this equilibrium it is removed by metabolism This probably involves formation of the reactive epoxide Along with the biochemical d.d.i on way! chloride's inter,iction with the organism that have been recently elaborated, u ij, apparent that phaim-koLmctie research contributes to the understanding of a variety of properties of this important industrial compound. INTRODUCTION The detection of carcinogenic effects of vinyl chloride on the liver (Poller, 1976) has focussed attention or. metabolism and disposition of this important indus trial chemical in the living organism (Leihman. 1977). Many publications deal with aspects of mutagenicity of this compound (Barisch & Montesano. 1475] or with the molecular mechanisms by which vinyl chlor ide may exert its mutagenic or carcinogenic effects (Van Duurcn. 1975; Barbin el at. 1975; Laib ii Bolt, 1977). However, it has to be considered that biologi cal action of a xcnobiotic docs not only depend on the biochemicul target mechanisms of (he latter, but is also largely influenced by pharmacokinetic factors. The aim of the present mmireview is to present the data for.thc pharmacokinetic behavior of vinyl chlor ide which are available at present. So far all studies have been performed with r.its, DOSF.-DKPF.snF.NCF. OF DISPOSITION OF' VINYL CIU.ORIDK It has been stressed, particularly by Cehrmg and his coworkers (Hefner et iff., 1975: Gehring or til.. 1970; Watanabc i't iff.. 1977). that metabolism of vinyl chloride in run is a saturable process. This has been recently confirmed (Boll er til- 1477). as rats mciaboli?c vinyl chloride according to lirsi-ordcr kinetics only if atmosphei ic concentrations below 250 ppm vinyl chloride arc applied. If this concentration is exceeded, non-linear pharmacokinetics apply which are consistent with the theoretical consideration (Gehring cr iff.. 1470] of sauiration of the metabolizing enzymes. Houevci. Itenschler (1977) did not observe a salnraliou nl sinyl chloride metabolizing enzymes lit the isol.ucd perhtsed rat liu'r ('reparation even if such high concentrations as 20 UK) ppm vinyl chlor ide were applied in ihc caibogen nnslin'c used lor oxygenalmn of ihc jvi fusion medium in the "artilieial lun'g". A reasonable e.vpl.iuaimn for the discrepancy_ between conditions in um and in the isolated per fused liver is difficult to give and will descise further studies. Tliat metabolism of vinyl chloride is ilosc-dcpcn- dent can also he1 nuerred from a comparison of the routes for elimination ui llte compound after differs.": dosage schedules, i.e. comparison of cvltafation of tiirmclabohzed vinyl chloride and excretion of urinary metabolites. Table I compiles the data given in the literature. If a low dose, up lo I mg kg. of vinyl chloride is ad ministered in oily .volution, either via stomach tube or hy j.p. injection, a considerable portion is evereted as urinary metabolites. In contrast, when the dose is increased to liximg kg and over, the bulk of vinyl chloride given is exhaled as the unchanged com pound. This very much favours consideration of a saturable metabolism of vinyl chloride under /'i-rrrvi Conditions Another conclusion can be drawn from ihc figures of Table 1. as the data of Green 5c Hath way (1975) Show that the route of elimination of vinyl chloride depends on the route of administration of ihc sub stance. Administration into the splanchnic area, by p.o. oi i.p. dosing, favours urinary excretion of rnctaholites which is even more pronounced alter oral ad ministration. This very much wiggesls a lir.si-pass effect and is consistent with the poiency of liver to rapidly metabolize vinyl chloride if the latter is present in a comparably low concentration. PIIaRMA( OKINL [ K' MCDt l.N FOR MM t. Ott.OKIPI Pharmokmctie surveys on vinyl chloride have been published by Wuliev (1976) and h\ liolt er at i!4?7). Both approaches, although very different m concept, lead lo similar Conclusions as uv the rale ol exhalation ol vinyl chloride, Wtihev i lu'r.) exposed rais to a gas phase where live concentration of vmyl chloride vv.is Hi.khann M. B'ii.r Table I. Exhalation of unmclaholizcd vinyl chloride and urinary excretion of metabolites after administration of dis solved vinyl chloride to rale by various routes Vinyl chloride dose given 250 uc/ke 50 lOOwg/kg 100 mg/kg 300 mg/kg 450 mg/kg Oral dose exhaled urine (".) (",,) 3.7 75.1 1-7 59-68 67 II 92 91.9 5.4 p.o. dose exhaled urine l"J r,,) 43.2 43.1 ---- ---- ... -- 96.2 2,6 i.v, idose exhaled urine ("J 9*; 0 5 -- " References Green & Maihway (1975) Watanabe el nl. (1976) Watanahe vt <*/-. II97h> heron vl tti *1975) Green At llathway 11975) kept constant, and he monitored blood concen trations of unmetaholized vinyl chloride, Between 51X1 and 14.0IX) ppm in tin; atmosphere, the ratio pg VC/ml blood j pg VC/ml air i which is equivalent to Ostwuld's solubility coellkient. was constant and amounted to 2.61. The equilibrium between vinyl chloride in the atmosphere and in biood was attained after 30 min of exposure. Withey (1976) also determined the kinetics of vinyl chloride in rat blood after i.v, administration of the compound. He obtained a hiphasic plasma conccntration curve which was consistent with a two-corn partmenta! open-ended model shown in Fig. I. The rate constants shown in the figure are the means of 4 experiments described after i.v. dosing. The mean rate constant for the partial process of exhalation was 0.046 min ' \ equivalent to a it , of l.\Kmin. The model docs not take into account metabolism of vinyl chloride whieli is justified as so far as Table I shows lliat. after an i.v. dose, the overwhelming portion of vinyl chloride is exhaled. However, the present bio chemical data strongly suggest that vinyl chloride must be metabolized in order to become effective as a chemical mutagen or carcinogen (sec the review of Baruch and Montcsano. 1975). Also, it has to be con sidered that exposure of an individual to an atmos phere containing vinyl chloride will result in adjust ment of equilibrium between vinyl chloride in the gas phase and in the organism (Wiihey, 1976: Buchier cl al., 1977). Under those steady-state conditions the only way for the organism to remove vinyl chloride from the equilibrium is by metabolic conversion. This has been considered when attempting another approach to the biodynamics of vinyl chloride (Bolt el oL 1977). As shown in Fig. 2. rats were exposed to vinyl chloride in a closed system. The concentration of vinyl chloride was measured in the gas phase and kept below the saturation point v'f 250 ppm. Uy means of new and potent inlubitois of oxidative drug meta bolism (Bolt el ill-. 1976) it was possible to completely block biotransformation ol vinyl chloriue. These ex perimental conditions permitted determination of the equilibrium constant and the rale constants kand t,, of Fig. 2. With animals not pre-treated with in hibitor an exponential decline of atmospheric vinyl chloride in the closed exposure system is observed which is due to metahohsm. The first authors report ing about this parameter of metabolism of vinyl chloride were Hefner ei nl. (1975). From this par ameter the constant k:j of Fig. 2 was derived (Bolt ei iii. 1977). Finally, the rate of appearance of radio activity in urine alter application of |4C*vin\l chlor ide to the system gave constant ki0. The data obtained with the model of Fig. 2 are comparable with Withey's basic results. Tins refers to the rate o! exhalation of vinyl chloride from the animal into the atmosphere (k, of Fig. I = IMUI min'1.' k:i of Fig. 2 = (1.056 min'1), as well as to the distribution between vinyl chloride in the gas phase and in the animal. Withcy (1976). as mentioned above, obtained a ratio between concentration of vinyl chloride in hlood and in the atmosphere of 2.61, whereas the cal culation of the "constant of equilibrium" (Bolt el ill.. 1977) , nl gaseous VC per g body wt nl gaseous VC per ml air = ~ (of Fig. 2) *ji under steady-state conditions resulted in 2.86. CONCi.lSlOVS Different conclusions may be drawn from the phar macokinetics of vinyl chloride. However, it has to he iy of VC (6.70't.O mg/Kg ) VC in totHfr tiStkitl k2l' 0,026 min VC in blood kg 0 046 mm tnKiUlion of unmiUbolij o VC Fig, I. Two-compartmcnt. open-ended model for vi\| chloride in iho rat, according lo the c.ilcuiatiors of Wiihc) For details, see text. Pharmacokinetics of vinyl chloride VC loplicitipn 3 VC xophcibon VC in ttmosphrrc 0 16 mm kJl = O.OSC'nin VC ir> k23 = mffUtx)- 0.0077 min' lit** In 4nirTt4(i k30 hits m 0.0077 min'' 1j1!22---------- Fig. 2. Pharmacokinetics of vin> 1 chloride on exposure in ;i closed system: model of Boll cr of. (1977k The model includes metnholism of vinyl chloride. The r.iie constants are calculated after exposures to initial concentrations below 250ppm vinyl chloride. For details, see lest. kept in mind that disposition of vinyl chloride is dose- dependent and hence the "linear" pharmacokinetic assessment of metabolism (Fig. 2) refers only lo Ihe lower dose range (i.e. below 250 ppm in the gas phase). But this is. from the standpoint of occupa tional medicine, the more interesting one. As has been pointed out by Gchring ri til. (1976). the non-linear pharmacokinetic behaviour in the higher dose range is of basic importance for interpretation of toxicologi cal studies because an increase or the dose of vinyl chloride does not necessarily imply a parallel increase in formation of the ultimately mutagenic or carcino genic metabolites. It has been stressed (Bolt or at.. 1977) that, due to the relatively short half-life of vinyl chloride and its metabolites in the organism, no significant cumula tion of vinyl chloride or its major metabolites is to be expected on repealed administration of vinyl chlor ide. This is in marked contrasts to the behaviour of the closely related trichloroethylene in the organism, where trichlorocthanol and especially trichloroacetic acid arc retained for a considerable period of time (Erlle el /,. 1972; (duller er til.. 197-1). The rapid elim ination of vinyl chloride and its major metabolites from the organisms may be consistent with the eutrent theory that a reactive, short-iivcd metabolite which occurs in low concentrations only, may be re sponsible for the toxic effects of vinyl chloride. The pharmacokinetic model of Fig. 2 also reveals the basic difference which exists between inhalation of vinyl chloride and other experimental routes or ap plication. Exposure to a vinyl chloride-containing at mosphere results in a rapid equilibration of vinyl chloride with the organism. If. for toxicological con siderations. the actual dose of atmospheric vinyl chloride acting on the organism is calculated as the dose which is taken up front the atmosphere, after equilibrium with the organism has been attained, uptake is only "due lo metabolism" (A;J of Fig. 21. and all of Ibis dose is metnbob/ed, probably via the reactive epoxide. The implication of the latter in metabolism or vinyl chloride is very likely according 10 recent biochemical investigations iVan Duuren. l975:Greim cr til.. 1975: House of til.. 1975; Reynolds ft til.. |975: Kappus fl til.. 1975. 1976; Watanabe ft til.. 1976; Norpoth ft ul.. 1976; Henseliler. 1977; Green & Halhwuv. 1977). By contrast, d the animal is not held in a closed system and a vital chloride dose injected, the ratio of A-j.A;, (Fig 2) implies that more Iban 90",, of the dose is exhaled and only a minor portion transformed to (he ultimately toxic metabolites. This fully agrees with the experimental data of Table 1. However, after oral application a first-pass effect for metabolism in 11 ver has lo be considered. These theoretical consider ations are not limited to vinyl chloride, but refer also lo other volatile xenobioiics. Thus, a given oral dose of e.'rhon tetrachloride is much more toxic, if the ani mals arc kept in a closed atmosphere (unpublished results|. Another conclusion may be based on the rate of entry of atmospheric vinyl chloride into the organism, until equilibrium is achieved. Figure 2) shows this process which has been visualized using iitts prc-lrealed with an inhibitor of vinyl chloride metabolism (Bolt it til. 1977), The data are consistent with those obtained hy Withey (1976). It can be seen (hat after lOmin the process is nearly completed. Within the first 3 min nearly 50",, of the equilibrium dose tire taken up; in the first minute, about IN";, are taken up. Although an extrapolation from animal data lo man is dillieult. these figures may be impor tant for assessment of occupational peak concen trations occurring in vinyl chloride plants. As uptake of vinyl chloride from air is a time-dependent process, a very short peak concentration may lie of only lowimpact. but as the elevated concentration is main tained only for a few minutes, considerable amounts of additional vinyl chloride may be taken up by the individual. These few examples serve to show that, in addition to the biocliemically-orientated research that is essential for a more complete understanding and a belter evaluation of the toxicological cITccts of 4 Hermans M. Holt R&S 027006 /V Fig. .1 Uptake of vinyl chloride from (he gas phase by rats prc-trcaied with an inhibitor of vinyl chloride metabolism (6^ni(ro-l.2.3-ben70thiadi,T/olo: sec Bolt ct <//.. )977{. Amount taken up to achieve equilibrium between fas phase ami animals is set to |(XV*#F. vinyl chloride, determination and consideration of the pharmacokinetic behavior of this compound is also necessary and helps to interpret toxicological data. Acknowledgement--The author's experimental work was supported by the Department of Research and Technology of the Federal Republic of Germany (grant No. FV 037119). This support is gratefully acknowledged, references Barbin A_ Bki'-Sil H.. Croisy A.. Jacqognos P_ Mala- vfilll CL Mostijaso R. & BartsOI H. 11975) Liver microsomc mediated formation of alkylating agents from vinyl bromide and vinyl chloride Biochcitt. biophys. Res. Commi/u. 67. 596-603. Bartscii H. & MONTtSANo H. (1975) Mutagenic and car cinogenic effects of vinyl chloride. Mutoo'on Res. 32. 93-114, Bolt H. Kapfos H.. Bumn* A. & Bolt W. (1976) Disposition of L2-|4C-vinyl chloride in the rat. Archs Toxics 35. 153 161 Bolt H. M_ Lair R. J_ Kafpl'S H. & Btcitnn A. (1977) Pharmacokinetics of vinyl chloride in the raL Toxico logy 179-lXii. Bosss: G,, Urban* Tii.. RnoirRT D. & Mlnschur D (1975) Chemical reactivity, metabolic oxiranc formation and biological reactivity of chlorinated ethylenes in the isolated perfused rat liver preparation. Ihocitem. Plwr- lime. 24. IK29-IK.U Bi-omR A.. Bolt 1L M,, Kafpus H. & Bolt W. (1977) Die Gewcbsvertcilung von l.2-uC^fn\lchlorid bei der Ratle hit. Archs tKtitp. Kntinm. filth 39, 27 31 HKTLf T.. Hivsiumk D.. MlU-iH G. & SfassdwsKI M. (1972) Metabolism of trichloroethylene in man 1. The significance ol trtehloroethunol m long-term exposure conditions. .1 nh\ litxieol 29. 17| INK. Fikon V. J.. Stnik A. J,, Wm i ms M J, Van HArtt m D, & Di (imum A. P. (1975) ONn.*rv;itiv'v on the oral administration and toxicity of vmyl chlonJc in rats. td fiwihT, Toxic. 13, 633 63X. Cii hkim; P. J.. Waianaik P. G. Jk Ynt n: J D. (1976) The relevance of Jose-dependent pharmacokinetics m 4, the assessment of carcinogenic hazard of chemicals. In ()riiiin\ of 11uni,in Comer. Cold Spring Harbor Meeting Gkiin T. &. Hatuway D. R. (1975) The biological fate in rats of vinyl chloride in relation to its oncogenicity. Chcin.-Biol. Interact. II. 545 562 Gkiin T. & Hatuway D L`. (1977) The chemistry and biogenesis of the .^containing metabolites of vinyl chlor ide in rats. Cheat -Hud. httenuL 17. 13 7 J S) Gkiim h,, Bonn* G,, Raoww Z^ RrtrmRT D. <$4 Ht.NSOtiCfc D. (1975) Mutagemciiy in ittro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxiranc formation, Biochcnt, Pharmac. 24. 2013-2017. Hi lni r R. E.. VYaIanahi P, G. A Giukinu P. J- (1975) Preliminary studies of the fate of inhaled xmyl chloride monomer in rats .Inn. ,V_l\ Acotl. Sci. 246. 135-I4K. Hi.NViiLnc D. (1977) Metabohsmus von VinylcHIorid. In Ixbersclmdeu ihn\U ) invhhforiii'. I'lnvIvhlornl-kronUiett (Edited by Gitacmr H. W. &. Li.Uiacti W. K.) pp. 27-31, G. Witzsiroek. Baden-Baden. Kafk.s H.. Bolt H. M.. BtatTiR A &. Bolt W. (1975) Rat liver mierosomes catalyse covalent binding of ,4C'Ximl chloride to macromolecules. Mature 257. 134-135. KAPRws Bni t H. M-. Bloittr A. A Bolt W. (1976) Liver microsvini.il uptake or ,JC-vinyl chloride and transformation ti> protein alkyUnng metabolites in dim. Toxic. uppl. Phormac. 37, 461 471, Laih R. J, & Bolt H. M. (1977) Alkylation of RNA by vinyl chloride metabolites in vitro and in rivn: formation of t-AfA-cifieno;uienosinc. 7"n\J? Lhhman K, C 11977) Current literature: metaholism of ^ vinyl chloride Druo Mvtnb. Oi.xp. 5. 93-94. Mulltr Gc Si'atsovkki M. &. Hr.sSOiLin D. 11974) Meta' bolism of trichloroethylene in man II. Pharmacokine tics of metabolites. Archs Toxicol. 32. 2K3-295, Nokpoth K_ Ml i i i k CL Wtrrtst; U, Gottsoialk D. vV: GoTfsciiAt s. J (1976) Untersuchungen uher don StoffwccItNel dv> Vinylchlorid und iiber Wirkunpon der ti%W\C(Al VinylchlornlinhaJaimn auf RcgulutioiVNmcchanixmcn dcs LcbcrstulTwevlueK lYrh Ji. (.'ex, | )mi^ 16. PtiitiR H. R f 1 V7f*j Articles W geiiorui imereti; mhvI chloride. b\I <o^nei. Ta\it\ 14. 347 349 (p;iri 1L 49N 5t>I (part 111 Rixmhds l-\ S,. Mom in U. T,. S^aiio S.. Jakuk R, J. & Mrttmn H I) (f975) licpatottn/c/ty of v^iy) chhwdc and U'diehloioeihylenc Iim, J. Path. H1, 219 236 ) * y Pharmacokinetics of vinyl chloride Van Dti'ki.N I). L. (|V7J| On I lie possible mechanism of carcinogenic action of vinvl chloride. Ann. /V. I Aciul. St i. 246 'SX 2fi7. Watanaiik P. Ci., YiH'Nii ), [7. & Cil iiRiNr; P. J. (I`777) The importance of non-linear Idosc-depemJenl) pharma cokinetics in hazard assessment. J. Em. pinIn Tux. I R&S 027007