Document NErOqOO48zKwJ39j88dkOOd2y

hi. J, Cancer: IS, 429^37 (1975) |{fpflMrd fumi Il*r intrrnnthtmti C*mrrr (g> ItHdiMiNHul Union AwwM Cancer PitnUil in itoKitrliitd HUMAN, RAT AND MOUSE LIVER-MEDIATED MUTAGENICITY OF VINYL CHLORIDE IN S. TYPUIMURIUM STRAINS by JUf! o H. Baktscii, C. Malavcjlle and R. Monttsano r\ International Agency for Research on CahCcr, Unit of Chemical Carcinogen?sis, ISO Conn Albert Thomas, 69003 Lyons, France >9/S Exposure of S. lyphimuriutn strains TA 1530, TA 1535 and G-4C to vinyl chloride increased the number of Ilis* revertants/pTate J6, 12 or 5 times over the. spontaneous mutation rate. After 6 h of exposure to vinyl chloride, the mutagenic response for TA 1530 strain was enhanced 7-, 4- or 5-fold when fortified postmitochondrial liver fractions from humans, rats or mice were added. The enzyme-mediated vinyl chloride mutagenicity iraj dependent on on NADPH generating system and the enzyme activity was localized in a liver microsomal fraction: 9,000 / liver supernatant was three times more active than microsomes, while liver cytosol or alcohol dehydrogenase did not affect the mutagenicity. Phenobarbitone pretreatment of rats and mice increased the mutagenic response by up to 15-40% as compared to untreated controls. The relative mutagenic activities of VCM, taking the value from manse liver as 100, for TA 1530 strain mediated by 9,000 x g tissue fractions were: rat liver, SO; mouse and rat kidney, 20 / ;>>*>,>*<j /tvrr t trnm tour mao.sv specimensj, 170, 64, 70 and 46. Chloroacetaldehyde and chloraacetic acid, a urinary metabolite of VCM, showed toxic effects, while chloroethanol was weakly mutagenic for TA 1530 strain. Vinyl chloride monomer (VCM) is extensively used for the production of polyvinyl chloride and other plastic material, and also as a propellant for aerosols. Carcinogenicity in rats, when exposed to 30,000 ppm VCM in air, was first reported by Viola et al. (I97J). Subsequently, Maltoni and Lcfcmine (1974) showed that angio sarcomas of the liver, as well as other tumours, were induced in rats and mice exposed to various doses of VCM by inhalation. Recently, eases of angiosarcoma of the liver have been found in workers exposed to VCM during the polymeriza tion process and a causal relationship Ixdwccn VCM exposure and this type of tumour in man has been established (Creech and Johnson, 1974; Heath et at., 1974; Lee and Harry, 1974; IARC, 1974). Tlic systemic action of this carcinogen and its low chemical reactivity suggest that the biological effects of VCM arc dependent upon its metabolic activation. In these studies, we report the muini'cnicity of VCM and its presumed metabolites in S. typhimnrium strains, mediated by liver and other tissue fractions of rat, mouse and human origin. MATERIAL AND METHODS Chemicals VCM (purity 99.9"') was generously provided by Rhonc-l'rogil, Lyons, France, contaminated with ethanol (30 ppm), water (20 ppm), methylchloride (<20 ppm) and non-volatile substances Rewived: October 16, 1974. 429 RSV 0012326 TYPE ABSTRACT 1 IE lit Tuiajiicq, m.jgiikko:j, c.V;Hi;Trro:!i-, c. Minor, lied. IJniv.S.C., Charleston, B.F,Goodrich,.Akron, ami Conoco, Inc., Ponca City. In vivo skin capillary abnormaljtics in vinvl chloride workers. Rtw,,, v t u RESEARCH & UIVCLQPMENT, JUL 2 3 1975 W. M. SMiT^ Workers (V.'s) exposed to vinyl chloride (VC) have proliferative small blood vessel and interstitial fibrotic lesions of peripheral (aero-osteolysis [AO!.], Raynaud's phenomenon [RP| and scleroderma [Sn]-like skin changes) and visceral (angiosarco ma [A.5] and hepatic fibrosis [Hp] of Uanti type) areasi In the present study in vivo widc-field capillary microscopy (which has demonstrated a distinctive pathologic pattern whose severity correlates with visceral involvement in idiopa thic SU) lias been used to examine IS2 VC V.'s and SO control non-VC manual lvs. WI VC v.'s selected on the basis of known pathology (RP,A0L,I1F,AS and si;in lesions) revealed a high proportion with SD-like capillary abnormalities (CA) Since man) VC ft 5 had been reactor cleaners (RC) , the trauma and cold exposure of RC could explain the CA seen. Comparison between ICS VC Us (including those who had never been RC) and 50 non-VC V.'s showed that CA were significantly more common in r\Ar\ f/vyve usz^ a* -- ^ivc C*$u and SP"iikt* changes hau more CA than j \ those with healed AOL, various skin rashes and RP alone (p <0.001). Among 108 VC Ws no corre lation was found between and history of RC. Further studies early in VC exposure are needed to determine whether a subpopulation ''susccpt- iblcn to the mj.crovasculnr effects of VC can be detected. Capillary observations arc proposed a a non-invasivo technique to monitor VC and pos sibly identify more serious VC related vascular and visceral disease at a preventable stage. Aulhor: Name and full address _______ Telephone ____________ Copied by MCA 7/30/75 for VC Technical Panel .distribution RSV 0012327