Document 10Lnd3BOLQ3KN73nVX7xGykYq

C-C ChrK*f>'r^,J /rf.M J*Asf*- *U) fySf\ Ate/. { fr.fry &///.&* AT Me \fuiuitoti Rt'iCjnh. 98 11982) 97- 100 Elsfuer B>omcdc&l Prc<* RECEIVED APR 1 2 1982 ICPHC^> 97 INTERNATIONAL COKMISSION FOR PROTECTION AGAINST ENVIRONMENTAL MUTAGENS AND CARCINOGENS ICPEMC Working Paper TGl/2 */79 Mutagenicity and teratogenicity of vinyl chloride monomer (VCM) Epidemiological evidence Johannes Clemmesen Slockholmsgadf 43, 2100 Copenhagen. Denmark (Received 16 September 1981) (Accepted 21 September 1981) The rarity and special character of angiosarcoma hepatis and its association with exposure to vinyl chloride monomer (VCM) has occasionally led to the error that a case of this tumor is tantamount to such exposure. Apart from the possibility that a number of such cases may in the past have been taken for cbolangiocarcinomas, the experience of a British team of histopathologists going over cases from Britain during 1963-1973 has revealed some over-estimate of the frequency of this lesion, with the additional experience that only 1 of the agreed 14 cases could be confidently associated with exposure to vinyl chloride (Baxter et al., 1977). It follows that exception must be taken to the conclusion that single cases of angiosarcoma hepatis from the surroundings of polyvinyl factories may be taken as evidence of an escape directly from the plants or otherwise. It would, however, be important if mutagenic or teratogenic effects of VCM be demonstrable either in the surroundings of factories or in the domestic environment of workers employed in PVC-producing facilities, and this possibility is the subject of the following review. * ll has been agreed to publish (his document as a working paper for Task Group ) of the International Commission for Protection against Environmental Mutagens and Carcinogens (ICPEMC), The views expressed are those of the author and do not necessanh represent those of the Commission, Thev are published to stimulate discussion and comments, which will be welcomed b\ the author. All correspondence and repnni requests should be addressed to the secretary of ICPEMC: Paul H M Lohman. Ph. D.. Medical Biological Laboratory TNO. P O. Box 45. 2280 AA Riiswijk (The Nether lands). Tel. 15*138777. telex 38034 pmtno nl (ICPEMC document 158-1981-15.5). 0165-1110/82/0000-0000/502.75 C Elsevier Biomedical Press For Distribution by CM/ ;CIAL PROGRAMS DIV1S .. i/f* No.Jlr-----7 vlaliT. An investigation of a possible increased occurrence of birth defects in the surroundings of PVC plants or among the children of workers has been attempted by Infante (1976) and Infante et al. (1976). The studies were based on data from 4 Ohio communities, of which 3, Ashtabula, Painesville and Avon Lake, had at least 1 polymerization facility in operation, Ashtabula since 1954, Avon Lake since 1946, and Painesville since 1946, with a 2nd plant opened in 1967. The 4th community. North Ridgeville. was near to Avon Lake and was without PVC production. Population numbers ranged from 24000 in Ashtabula to 12000 in Avon Lake. Between the census years 1960 and 1970 the population of Avon Lake increased by 30$. whereas the populations of Ashtabula and Painesville remained about the same. According to birth-certificate data for 1970-1973. it appeared that while the rate of malformations for the entire State per 1000 live births was 10.14. the rates in the index communities were : Ashtabula, 17.37; Painesville, 18.10; and Avon Lake. 30.33. For these 3 cities with PVC production facilities the differences between observed and expected numbers of malformations in each city were significant at the P < 0.01 level according to the x2 test. Nevertheless, the highest rates for malforma tions were found in North Ridgeville, 27.26: and in Geneva, 12 miles from Ashtabula, 25.40, both cities without PVC plants (Infante, 1976.) Infante, furthermore, found an excess of CNS defects among still-births and. live births from the index cities, with the exception of Avon Lake. Most of the excess, however, was attributable primarily to Painesville and secondarily to North Ridge ville. It was therefore obvious that the findings did not link PVC production with the said anomalies. Edmonds et al. (1975), observing that the increase reported was not uniform and appeared more prominent in the Painesville area, analyzed data collected through the Center for Disease Control's hospital-based Birth Defects Monitoring Pro gramme (BDMP). For 2 hospitals located in cities with polymerization plants. Pottstown in Pennsylvania and Painesville in Ohio, they compared CNSmalformation rates for white infants bom during 1970-1974 with the rates for white infants in each State. No increase was seen in the Pennsylvania hospital, but an increase, primarily in anencephaly and spina bifida, was noted in the Painesville hospital amounting to 22 cases, or twice the expected. After inspection of the birth-defect registry for Ohio, 1 more case could be included in the study, bringing the total to 15. Interviews with parents revealed that none of them had worked at either of the 2 PVC plants in Painesville. However. 2 of the fathers of controls had worked at 1 of the plants. A significantly larger proportion of control mothers than case mothers worked (including housewives) within a 10-mile radius of the PVC plant, which was probably a chance occurrence (95$ confidence level). It was concluded that, although the follow-up confirmed a moderate increase in CNS malformations in Painesville. Ohio, no association had been found with vinyl chloride exposure. A further study (Edmonds. 1976) of data from hospitals in Pottstown. Pennsyl vania. and in Painesville. Ohio, revealed no difference between the cases and the controls in possible between the cases ar. plants. In Kanawha Cour cases and controls association with VC1 In a personal com among wives of wor without the use of attempted a compa before and after ex number of rubber-fs A total of 95 VCM workers was intervie Interviews were c pregnancy outcome was the initial item c No data were obtain rates for the primar separately before an It should be men before analysis fine misleadingly. From these data tion with those of t) exposure, the mean and for controls 23. Because fetal los death rates for the group. This reduced Contrarily, the rs for controls was on study group, so tha The asymmetry paralleled with an exposure, numbered 159. respectively, fc Further objectio: for the plastics ind based on age prior adjustment to the does not justify co which requires inde Therefore, when so far of an effect > CMA 007962 birth defects in the ers has been attempted e based on data from 4 son Lake, had at least ) Avon Lake since 1946. 7, The 4th community, hout PVC production. 12000 in Avon Lake, kvon Lake increased by le remained about the ared that while the rate ? 10.14. the rates in the 8.10: and Avon Lake, he differences between >' were significant at the lest rates for malformaeneva. 12 miles from 976.) ong still-births and live ke. Most of the excess, darily to North RidgeVC production with the d was not uniform and data collected through fcffects Monitoring Pro polymerization plants, hey compared CNSwiih the rates for white vania hospital, but an oted in the Painesville 1 more case could be h parents revealed that nesville. However, 2 of A significantly larger including housewives) ly a chance occurrence a moderate increase in been found with vinyl in Pottstown. Pennsyleen the cases and the ov controls in possible exposure to YCM. Residential histories showed no difference between the cases and controls when compared at various distances from the PVC plants. In Kanawha County the author found a difference in the pattern of residents for cases and controls living within 3 miles, but the available data suggested no association with VCM. In a personal communication, Selikoff reported that he had estimated fetal deaths among wives of workers exposed to VCM at 7-14 per 100 pregnancies, although without the use of controls. Referring to this statement. Infante et al. (1976a) attempted a comparison of pregnancy outcome among wives of VCM workers before and after exposure, compared with wives of PVC workers and a similar number of rubber-factory workers matched as a group to the VCM workers by age. A total of 95 VCM-polymerization workers and 158 rubber and PVC-fabrication workers was interviewed in October 1974. Interviews were conducted with workers, not with their wives. Questions about pregnancy outcome were contained in a much larger interview questionnaire, which was the initial item of a cross-sectional health survey including physical examination. No data were obtained on maternal age. but. on the basis of paternal age. fetal death rates for the primary VCM exposure group were age-adjusted to the control group separately before and after the husband's exposure. It should be mentioned that Paddle (1976) asked for tabulation of the raw data before analysis finding that age adjustments appeared to have influenced figures misleadingly. From these data published without delay by Infante et al,, (1976b), in combina tion with those of the first publication, the following observations stand out. Before exposure, the mean paternal age at conception for study pregnancies was 26.4 years and for controls 23.0, with crude fetal death rates of 10.1 aif6.9%, respectively . Because fetal loss is known to increase with increasing parental age. the fetal death rates for the primary VCM exposure group were age-adjusted to the control group. This reduced the rate for the study group, before exposure, from 10.1 to 6.1$. Contrarily. the raw rate, after exposure, of 16.5? for the study group versus 8.8% for controls was only slightly influenced by age adjustment, showing 15.8% for the study group, so that Paddle's objection was fully justified. The asymmetry in age, before exposure, between study group and controls, is paralleled with an asymmetry in numbers of families which, before the husband's exposure, numbered 70 for study families against 62 after exposure, versus 95 and 159. respectively, for control families. Further objections were raised by Downs et al. (1977) in a critical review prepared for the plastics industry. They pointed out that matching by age should have been based on age prior before employment not on age at the interview, and that age adjustment to the controls' standard, made separately before and after exposure, does not justify comparison of these 2 values. The use of Mantel-Haenszels test, w'hich requires independence of the 2 rates being compared, is also found incorrect. Therefore, when the evidence is weighted, it seems that there is no demonstration so far of an effect of VCM as alleged by Infante et al. 100 References Baxter. P J . P P Anthony. Me. Sween et ai. (1977) Angiosarcoma of the liver in Great Britain 1963-1973. Br. Med J.. 2. 919-921. Downs. TD,, R.A, Stallones. R.F. Frankouski et al. (1977) Vinyl Chloride. Birth Defects and Fetal Wastage. The Society of Plastic Industries. 1977 Edmonds. L. 11976) Birth defects and vinyl chloride. Proceed on Women and the Workplace. Conf,. Jan 17-19th. Washington. DC. pp. 114-139. Edmonds. L.D., H. Falk and J F Nissim (1975) Congenital malformations and vinyl chlonde. Lancet. 2. 1098 Infante. P F (1976) Oncogenic and mutagenic risks in communities with polyvinyl chloride production facilities. Ann N V. Acad. Sci. 271, 49-57. Infante. P F.. J K. W agoner. Me Michael et al. (1976a) Genetic risks of vinyl chloride. Lancet. I. 734-735 and 1289-1290. Infante, P.F.. J K. Wagoner and R.J Waxweiler (1976b) Carcinogenic, mutagenic and teratogenic risks associated with unvl chlonde. Mutation Res.. 41, 131-141. Paddle. G.M, (1976) Genetic risks of vinyl chloride. Lancet. I. 1079 MUTATION RESEARC Mutation Research Letters publ considered that the results shoe Mutation Research Letters is aim Manuscripts should not be tongc tables and illustrations. Types* acceptance Contributions --in triplicate--m RrirureA Ltnrrs. or directly to Dr, R.J Preston. Manag.ng Ec P O. Box Y. Oak Ridge. TN 3 Proofs and Reprints Proofread!: acceptance of the paper the s article including the 50 free re MUTATION RESEAR Publication schedule for 1982 MR is published according addition, each section has its Reg (green), 'regular' volume Rev (purple). Reviews in Gt Mutation Research Letters. i Reg Jan. Feb March April Mav June Julv Aug. Sep. Oct. 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