Document G5bzVyb9Kj4gKkDKGbN68v14N

' m*-- s r M0 6c/lf/i*"7 /r *7* 0D4 t/wuyf ddojjj. Mutation Research, 98 11982) 97-100 I Elsevier Biomedical Press RECEIVED APR 1 2 1982 dCPSHC^ 97 INTERNATIONAL COMMISSION FOR PROTECTION AGAINST ENVIRONMENTAL MUTAGENS ANO CARCINOGENS ICPEMC Working Paper TGI /2 V79 Mutagenicity and teratogenicity of vinyl chloride monomer (VCM) Epidemiological evidence Johannes Clemmesen Stockholmgad* 4$, 2100 Coptnhagtn. Denmark (Received 16 September 1981} (Accepted 2) Sepiembcr 1981) The rarity and special character of angiosarcoma bepatis 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 Ihe 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 bepatis 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. r~ Cn *"J It has been agreed to publish this document as a working paper for Task Croup > of the International Commission for Protection against Environmental Mutagens and Carcinogens (ICPEMC). The 'iew expressed are those of the author and do not necessarily represent those of the Commission. The> art published to stimulate discussion and comments, which will be welcomed b> the author. All correspondence and reprint requests should be addressed to the secretary of ICPEMC: Paul H.M. Lohman. Ph. D.. Medical Biological Laboratory TNO. P.O. Bo* *5. 2280 AA Rijswijk (The Nether lands). Tel. 15-138777. tele* 38034 psuoonl (ICPEMC document 158*1981-15.5). 0165-1110/82/0000-0000/80175 G Elsevier Biomedical Press For Distribution by CMA SPECIAL PROGRAMS DlVISiO 9* 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 ah (1976). The studies were based on data from 4 Ohio communities, of which 3, Ashtabula. Painesville and Avon Lake, had at least f 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 sthe 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. Pottstow-n 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 l 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 (he 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 is possible e? betw een the cases and plants. In Kanawha count cases and controls li association with! VCM In a personal comir .among wives Without the us ^tempted a rfore and after exp> number of rubber-fac: AVotal of 95 VCM-p workers was i iterview Interviews were co pregnancy oulcome w was the initial item of No data were obtained rates f< >r the primary <Z DO sep&ra sly before and It be mesti <cn before lysis findix UD CO mislead fgiy- Fro [these data p tion wi those of the exposu the mean p and f mtrols 23.0. B fetal loss death! rat for the p grou reduced t mtra y, the raw for Control was only stu y. group! so that e asymmetry ir. paralleled w*h an as exposure, numbered 1^9. respectively, for Further objections for the plastics indu^ ased on age prior ' djustment to flhe c- 'does not justifyAcoir which requires inoep Therefore, when t so far of an effect'of birth defects in ih< has been attemptec leased on data from .Lake, had at least v* Lake since 1941, je 4th community, out\J>VC production. 12000 in Avon Lake, von Ljake increased b e remained about th : red thatt while the rait 10.14. the rates in tne `10; and\ Avon Lye, e differences between were significant ar the t rates for malfcxmaneva. 12 jniles ftrom ng still-births a4d live e. Most of the/excess, iarily to North* RidgeC production /vith the I was not uniform and lata collectedithrough ects Monitoring Pro>olymerizatipn \plants, iey compared \CNSnth the rates fon white ama hosprtal. bin an ted in the Painaville more case could be parents revealed mat tesville. However, 2\of \ significantly larger including housewives) v a chance occurrence moderate increase it >een found with viny n PotistowTi. Pennsvl ten the cases and th< ifg liniifnirirr 99 controls in possible exposure to VCM. 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-poIymerkation 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 ah, (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 air6.9%, 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, which 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 URL 15499 100 References Baxter. PJ.. P.P. Antbonv. Me. Sweo et al. <1977) Angjosarvomaof the liver in Great Britain 1963-1973. Br. Med. J.. 2. 919-9*21. Down*, T.D.. R.A. Stallone*. R.F. Frankowski et ai (1977) Vinyl Chloride. Birth Defects and Feta/ Wastage, The Society of Plastic Industries. 1977. Edmonds. L. (I9?6 Birth defects and vinyl ehlonde. Proceed on Women and the Workplace. Con/.. Jan 17-- 19th, Washington. DC. pp. I i4--139. Edmonds. LD., H. Falk and J.F. Ni&sim (1975) Congenital malformations and vinvl chloride. Lancet. 2. 1098. Infante. P.F. (19761 Oncogenic and mutagenic risks in communities with polyvinvl chloride production facilities. Ann. N Y. Acad. Sci. 271. 49-57. Infante. P.F.. J.K. Wagoner. Me. Michael et aL (1976a) Generic risks of vinvl chloride. Lancet. I. 734-73$ and 1289-1290. Infante. P.F.. J.K. Wagoner and R.J. Waxweiler < 1976b) Carcinogenic, mutagenic and teratogenic risks associated with vinyl chloride. Mutation Res.. 41. 131 --141. Paddle. G.M. (1976) Genetic risks of vinyl chloride. Lancet. I. >079. MUTATION RESEARCH Mutation lUniwt Letm publish considered that the results sbouk MmiUm RMtitk Latter* a munis Mnwaripi should not be longer tables and illustration*. Typcser acceptance. ConfrfbiMteM--in trplicata--may Ltttwrt. or directly to tl Dr. RJ. Presion. Managing Edu P O. Box Y. Oak Ridge. TN 37* Proofs and Reprints Proofreading acceptance of the paper the sub article including the $0 free rtpr c: 30 MUTATION RESEARC OOV7 Publication schedule for 19 MR is published according to addition, each section has its O' Reg (green), 'regular' volumes: Rev (purple). Reviews jo Gen Mutation Research Letters. i Rn Jan. Feb. March April Mav June | July Aug. Sep Oct. Nov Dtv. Total 13 Vols. 92-104 92/1 93/1 93/2 94 1 94/2 95 / 1 95/2 95/3 96/1 96/2 96/3 5 Vels. 93-96 The publication schedule of c. In particular, an extra \ciumc