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Reproductive Hazards of Industrial Chemicals An evaluation of animal and human data SUSAN M. BARLOW and FRANK M. SULLIVAN Department of Pharmacology Guy's Hospital Medical School University of London 1982 ACADEMIC PRESS A Subsidiary of Harcouri Brace Jovanovich, Publishers London New York Paris San Diego San Francisco Sao Paulo Sydney Tokyo * Toronto ACADEMIC PRESS INC. (LONDON) LTD. 24/28 Oval Road London NW1 United States Edition published by ACADEMIC PRESS INC. 111 Fifth Avenue New York, New York 10003 Copyright 1982 by ACADEMIC PRESS INC. (LONDON) LTD. All Rights Reserved No part of this book may be reproduced in any form by photostat, microfilm, or any other means, without written permission from the publishers British Library Cataloguing in Publication Data Barlow, S. M. Reproductive hazards of industrial chemicals. 1. Human reproduction 2. Chemicals--Toxicology I. Title II. Sullivan, F. M. 616.6 QP251 Library of Congress Catalog Card Number: 82-71008 ISBN: 0-12-078960-4 R&S 132277 Phototypeset by Latimer Trend & Company Ltd, Plymouth Printed in Great Britain by St Edmundsbury Press w 9P !V MW T J/ R&S 132278 46. Vinyl Chloride TECHNICAL DATA Formula CH2=CHC1 CAS registry number 75-01-4 Chemical abstracts name Chloroethylene Synonyms Chlorethene; chlorethylene; chloroethene; ethylene monochloride; monochloroethene; monochloroethylene. Uses TLV Plastics industry; refrigerant; in organic syntheses; production of vinyl chloride resins, methyl chloroform; component of propellant mixtures. 5 ppm ANIMAL STUDIES A. RELEVANT PHARMACOLOGY AND TOXICOLOGY Elimination of vinyl chloride monomer (VCM) from the body is very rapid; Feron et al. (1975) found over 90% of a dose of 300 mg/kg VCM, given orally by gavage or by i.p. injection, was recovered from exhaled gases within 4 h of administration. In a sub-acute study, where groups of 15 male and female weanling rats were given 30, 100 or 300mg/kg/day VCM by gavage for 6 days/week for 13 weeks, Feron et al. (1975) found no sex differences in toxicity in terms of organ weights and histology, haematological parameters or liver toxicity. Ungvary et al. (1978) have shown placental transfer of maternally inhaled VCM. Groups of 3 rats were exposed to 0,2000,7000 or 12,000 ppm (0,5500, 18,000 or 33,000 mg/m3) for 2-5 h on day 18 of pregnancy, then killed. Levels in maternal blood averaged 19 0-48-4 in VCM-exposed groups, levels 566 Vinyl Chloride 567 in fetal blood 12-8--30*5 ^g/'ml and in amniotic fluid 4-3-13-5 ng/ml, showing substantial transfer ofVCM to the fetus during continuous maternal exposure to relatively high concentrations. In view of the lipophilic nature ofVCM this substantial transfer is not surprising, but since there is rapid excretion ofVCM when given acutely as a single dose, placental transfer following adminis tration by gavage or injection is likely to be much lower than with continuous inhalation. B. ENDOCRINE AND GONADAL EFFECTS No relevant data found. C. FERTILITY Absence ofdominant lethal effects has been shown in mice and rats. Anderson et al. (1977) exposed groups of 20 male mice to 0,3000,10,000 or 30,000 ppm VCM by inhalation for 6h/'day for 5 days and then mated them with 2 untreated females/week for 8 weeks. Survival was significantly reduced to 45% in the highest dose group. There were no significant effects on numbers mating, numbers pregnant, pre- or post-implantation losses except for a reduction in total implants/female in week 4 of mating in the highest dose group. However, this latter finding was due largely to a small number of implants in one female and is not therefore likely to be of any biological significance. Treatment with positive control substances, cyclophosphamide or ethyl methane-sulphonate, showed clear dominant lethal effects. Short et al. (1977) exposed groups of 12 male rats to 0,50,250 or 1000 ppm VCM by inhalation for 6h/day, 5 days/week for 11 weeks. During the eleventh week of exposure, each male was housed between exposures with 2 untreated females for 7 successive evenings or until mating with both females had occurred. There was a significant reduction in the number of males in the 1000 ppm group that mated with 2 females (8/12 compared with 12/12 in controls). Two ofthe males in the 1000 ppm group did not mate at all, whereas in all other groups every male mated at least once. At both 250 and 1000 ppm the ratio of pregnant to mated females was significantly reduced from 24/24 in controls to 16/23 at 250 ppm and 14/18 at 1000 ppm. However, there were no significant effects on total implants/dam or dead implants/dam in those that were pregnant in any group. The authors also mention that in a chronic study in their laboratory, no effects on the testes or accessory organs were found with exposure of male rats to 250 or 1000 ppm VCM for 9-12 months, though carcinomas of the liver and lung were seen. R&S 132280 Reproductive Hazards of Industrial Chemicals Conclusion Dominant lethal effects have not been observed in mice and rats exposed to clearly carcinogenic or near lethal levels of VCM by inhalation. However, in the rat study, findings indicative of reduced mating performance, infertile matings and/or early losses of fertilised ova have been seen with sub-acute exposure to 250 ppm. There have been no studies of the effect of VCM on female fertility. D. PREGNANCY Teratology studies on inhaled VCM have been carried out in the mouse, rat and rabbit. John et at. (1977) exposed all 3 species to VCM during organogenesis in a study on behalf of the Manufacturing Chemists Associ ation, U.S.A. Acceptable teratological methods were used. Groups of 27-37 mice were exposed to 50 or 500 ppm for 7 h/day on days 6-15 of pregnancy, each with concurrent Oppm control groups. At 500 ppm there was some evidence ofmaternal toxicity; food consumption, weight gain and liver weight were all significantly reduced and 5/29 animals in this group died. There were no deaths or signs of maternal toxicity in the 50 ppm group. There were significant decreases in total implants/dam and mean fetal weight and a significant increase in resorption rate in the 500 ppm group in comparison with concurrent controls. However, it should be noted that there was considerable variation between the 2 control groups and differences between the 500 ppm VCM group and the other control group concurrent with the 50 ppm VCM group were not significant. There were no significant effects on malformation or anomaly rates, except for an increase in unfused stemebrae and delayed ossification of the sternebrae and skull in the 500 ppm group. John et al. (1977) exposed groups of 17-33 rats to 500 or 2500 ppm VCM for 7h/day on days 6-15 of pregnancy, each with concurrent Oppm control groups. Maternal weight gain was significantly reduced in the 500 ppm group in comparison with concurrent controls, but was similar to that in the 0 ppm group concurrent with the 2500 ppm group. It was not reduced in the 2500 ppm group. The significant difference observed in the 500 ppm group is probably due to the low body weight of concurrent controls in early pregnancy which was made up during the course of pregnancy. Absolute and relative liver weights were increased in the 2500 ppm group and one of the dams in this group died. There were sporadic significant differences in outcome of pregnancies between VCM and control groups, but, apart from an increase in dilated ureter in fetuses from the 2500 ppm group, none of the changes were dose-related and are therefore unlikely to be treatment-related effects. John et al. (1977) also exposed groups of 7-20 rabbits to 500 or 2500 ppm Vinyl Chloride 569 R&S 132281 VCM for 7h/day on days 6-18 of pregnancy, each with concurrent Oppm control groups. One doe in the 2500 ppm group died. Weight gain and food consumption were highly variable in VCM and control groups. A significant decrease in food consumption in the 500 ppm group in relation to concurrerit controls, but not in the 2500 ppm group, is probably of no biological significance. Likewise, significant decreases in implantation sites/dam and live fetuses/dam in the 500 ppm group are most probably the consequence of the significant decrease in corpora lutea/dam in this group and of no biological importance. There was also a significant increase in delayed ossification of the sternebrae at 500 ppm but not at 2500 ppm. Ungvary ei al. (1978) have confirmed the absence of teratogenicity of VCM in the rat. They exposed groups of 13-28 rats to 0 or 1500 ppm VCM (4000 mg/m3) for 24h/day on days 1-9, 8-14 or 14-21 of pregnancy. Acceptable teratological methods were used. There was no maternal mortality and no significant reduction in weight gain except in those exposed in the third week of pregnancy. Maternal liverbody weight ratio was significantly increased in those exposed in the first or second but not the third week of pregnancy. No histological changes were seen in maternal livers at autopsy. There were no effects on live fetuses/dam, dead fetuses/dam, fetal weight, malformation or anomaly rates due to VCM, but there was a significant increase in resorption rate from 3-4% in untreated controls to 5-5% in those exposed on days 1-9 of pregnancy. Mirkova et al. (1978), however, claim to have found significant embryolethality, teratogenicity and fetotoxicity following exposure to a level as low as 2-5 ppm (6T5mg/m3) continuously throughout gestation in the rat. Adequate numbers of rats (40 treated and control) and acceptable teratologi:al methods were used. Results however are reported in qualitative terms only vith no significance levels or without control comparisons. Embryomortality n the VCM group was doubled in comparison with controls and fetal weight was reduced, but no further information is given. There was an 8-fold rise in "anomalies of a general nature (haematoma)" in comparison with controls. Teratogenic effects were also seen affecting the brain, blood vessel walls and ossification of the sternum; VCM exposed fetuses had 2-5% encephalocoele, 54% hydrocephalus with intracerebral haematomata, 14% isolated haematomata, and 3% additional ossification centres in the sternum. No control abnormality rates are given. Retarded brain development may be mistaken for true internal hydrocephalus; however, the occurrence of such a high incidence of intracerebral haematomas is an unusual finding and cannot be dismissed. Mirkova et al. (1978) also studied postnatal development of offspring born to rats exposed to 2-5 ppm VCM throughout pregnancy. Postnatal weight gain and survival were unaffected but some change in liver function was R&S 132282 570 Reproductive Hazards of Industrial Chemica... evident from increased barbiturate-induced sleeping time and changes in biliary excretion at 1-2 months of age. Bingham et at. (1979) have noted low birth weights in pups bom to rats exposed to 600 or 6000 ppm VCM for 4 h/day on days 9-21 of pregnancy in comparison with controls, but more detailed information on postnatal development in these animals is not yet available. Conclusion Two separate groups of workers, using doses of 500-2500 ppm VCM, have shown absence of teratogenicity and fetotoxicity in the rat, and one of these groups has shown absence ofteratogenicity in the rabbit at 500-2500 ppm and in the mouse at 50-500 ppm. The highest doses were toxic to the dam in all 3 species. There was a suggestion of a small increase (around a doubling) in embryomortality following exposure to 1500 ppm VCM in the rat in early pregnancy (days 1-9), but no increased embryomortality was seen in the mouse, rat or rabbit if exposure was confined to the period of organogenesis. One group of workers claimed to have observed a doubling in em bryomortality, a high incidence of cerebral malformations and fetotoxicity with exposure to only 2-5 ppm throughout pregnancy. The study was poorly reported and in view of the large difference in dose level between this and other negative studies, these results await confirmation. Reports of studies to date on postnatal development after prenatal VCM exposure are inadequate for proper assessment, with the exception of a transplacental carcinogenicity study (see section F for details) which suggests that in utero exposure to VCM may induce a wider variety of tumours more readily than adult exposure. Tumours have been seen in offspring exposed prenatally to 6000 ppm VCM but not in their exposed mothers. It is not known whether, as with adult carcinogens, there is no threshold level for tumour induction for transplacental carcinogens. E. MUTAGENICITY VCM is mutagenic in yeast cells in the host-mediated assay (Loprieno et at., 1976) and in bacteria in the Ames test after metabolic activation by liver enzymes (Bartsch and Montesano, 1975). VCM without metabolic activation is mutagenic in the Ames test but it is not clear whether this may be due to nonenzymatic breakdown products or to VCM per se (Bartsch and Montesano, 1975; Simmon, 1977). The major VCM metabolites formed in vitro by hepatic microsomal enzyme preparations from mice, rats and humans are chloroethylene oxide (an epoxide) and chloroacetaldehyde; these are clearly mutagenic in bacterial systems (Bartsch and Montesano, 1975), and other Vinyl Chloride 571 potential metabolites of VCM, such as the monomer, dimer and trimer hydrates of chloroacetaldehyde, are also Ames-positive (Laumbach et al., 1977), The comparative metabolism of VCM in vivo is not known. R&S 132283 F. CARCINOGENICITY IARC Monograph Vol. 19(1979) reported studies showing that vinyl chloride is carcinogenic in mice, rats and hamsters following oral or inhalational administration. VCM, an adult carcinogen in animals and humans, has been shown to be a transplacental carcinogen in the rat. Maltoni (1976) exposed groups of 30 rats to 6000 or 10,000 ppm for 4 h./day on days 12-18 of pregnancy. By the end of the experiment 143 weeks later, 3 of the breeding females in the 10,000 ppm group had developed tumours (angioma or angiosarcoma), and none in the 6000 ppm group. In their offspring, 6/32 animals from the 6000 ppm group and 8/54 animals from the 10,000 ppm group had tumours of various types (including angiosarcoma) and sites; the earliest tumours developed at 22-24 weeks of age (Maltoni and Lefemine, 1974). HUMAN STUDIES A. RELEVANT PHARMACOLOGY AND TOXICOLOGY No relevant data found. B. ENDOCRINE AND GONADAL EFFECTS Walker (1976) has recorded loss of libido as one of the presenting symptoms in men exposed to high levels (unspecified) of vinyl chloride monomer (VCM) on at least one occasion. She examined a total of 37 men aged 26-59 years (average age 40 years) who had been employed at a polyvinyl chloride (PVC) manufacturing plant for 9 months to 54 years (average 2 years 8 months). Thirty had at some time been reactor operators. Four were maintenance men, 2 worked as "baggers" and 1 was a warehouseman. Presenting symptoms in order of frequency included excessive fatigue, cold hands, aches in bones, dyspnoea, paraesthesia, cold feet, aches in muscles, impaired grip and loss of libido in 13/37 cases. Walker (1975) has elsewhere described the men as suffering from impotence, but no further details have been given. Clinically the men showed signs of Raynaud's phenomenon, severe in some cases, and 572 Reproductive Hazards of Industrial Chemicals circulatory changes which may account for some of the symptoms such as dyspnoea, pains in the limbs, paraesthesia and fatigue. It is not known if such changes might also account for the reported loss of libido or potency. No relevant data found. C. FERTILITY D. PREGNANCY Selikoff, in a personal communication to Infante (1976) first observed stillbirth and miscarriage rates that were thought to be high in the wives of VCM workers. He studied 2 plants and found rates of 140/1000 pregnancies in one plant and 72/1000 pregnancies in the other. Comparison with registered rates for stillbirth and miscarriage in the state of Georgia showed that the rates observed in wives of VCM workers were 2-4 times higher than those for Georgia as a whole. However, reliability of ascertainment in both cases and Georgia registry data is not known. Infante (1976) has studied congenital malformation rates in 3 Ohio, U.S.A. communities that have PVC production facilities: Painesville, Ashtabula and Avon Lake, with populations of 12,000-24,000. Data on specific congenital malformations in Ohio residents have been recorded on birth certificates since 1968. For the entire State, the malformation rate/1000 live births was 10-14 for the years 1970-1973. Rates for these years combined in the 3 study populations were 17-37 (Ashtabula), 18-10 (Painesville) and 20-33 (Avon Lake), significantly higher than expected from the State rate (P<001). Comparison of malformation rates in the study populations compared to those in the balance of the counties in which they were located also showed a significantly higher rate than expected in 2 out of the 3 study populations and if data from all 3 populations and the balance of the counties was combined then the difference was highly significant (P< 0-001). Comparison of rates in the 3 study cities with rates in 10 other cities surrounding the index cities showed lower malformation rates in 8 of them (2-06-- 12-05/1000 live births). The 2 non-index cities with high rates were Geneva (25-4/1000) located 12 miles from Ashtabula, and North Ridgeville (27-3/1000) located 8 miles from Avon Lake. The authors determined that race, maternal age and reporting from different hospitals could not account for the high rates observed in the 3 study populations. Combining the data on malformations from the 3 study areas there appeared to be a significant excess risk for defects of the central nervous system (CNS), upper alimentary tract, genital organs and club foot. R&S 132285 Vinyl Chloride 573 The relative risk of CNS malformations amongst live and stillbirths was increased in Ashtabula (I -95) and Painesville (5-80) but not in Avon Lake (0 00). Painesville has 2 PVC plants and the other 2 areas one each, but vinyl chloride levels in the 3 study areas were not monitored and the authors of the report stressed that these preliminary findings do not link PVC production with the increases in congenital malformations but indicate the need for further study of possible contributing factors. Edmonds et al. (1975), using data collected through the U.S. Public Health Service Center for Disease Control's hospital-based birth defects monitoring programme, studied CNS malformation rates in 2 hospitals located in cities with PVC plants, in Pennsylvania and in Painesville, Ohio. White infants bom in 1970-1974 only were included. An increase, primarily in spina bifida and anencephaly, was noted in Painesville but not in Pennsylvania in comparison with rates for each State as a whole, Anencephaly rates/10,000 births were 14-1 in Painesville compared with 5-7 for Ohio as a whole and for spina bifida 21-2 in Painesville compared with 8-9 in Ohio as a whole. However, the rates are based on a total of only 15 cases of anencephaly and spina bifida in Painesville in 1970-1974. The 15 cases were also compared with 30 controls (the first normal white infant bom before or after each case) to compare parents' occupation and residence at the time of the infant's birth. None of the parents of the 15 cases had ever worked at the PVC plants in Painesville but 2 fathers of controls had worked at one of the plants. None of the parents of cases or controls lived within 2 miles of the plant and a significantly larger proportion of control mothers than case mothers worked (including housewives) within a 10-mile radius of the PVC plant. Thus, although this study confirmed an increase in CNS malformations in Painesville no direct association with PVC production could be shown. Edmonds et al. (1978) have carried out another study in Kanawha County. Of the 40 PVC polymerisation plants in the U.S., 17 were located in counties which in 1974 had at least one hospital participating in the Center for Disease Control's birth defects monitoring programme. Ten were excluded because data were available on fewer than 50% of the births in the county. Of the remaining 7 counties. 2 had CNS malformation rates significantly higher than national rates in 1970-1974. They were Painesville, Ohio and Kanawha County, West Virginia. A detailed epidemiological investigation was there fore undertaken in Kanawha County. All infants bom with a CNS defect in 1970-1974 whose parents were resident in Kanawha County at the time of birth were identified. Controls were taken as the first normal infants bom to parents resident in Kanawha County whose birth certificates preceded or followed each case in the records of the West Virginia State Department of Vital Statistics. Cases and controls were then matched for month of birth, race, paternal education and maternal age. A total of 47 cases of CNS Y K < 574 Reproductive Hazards of Industrial Chemicals malformations were identified, giving an overall rate for 1970-1974 of 28-8/10,000 births, but the vearly rates declined dramatically from 40-6 in 1970, 42-9 in 1971, 37-6 in 1972, 16-3 in 1973 to 3-2 in 1974. Families of 46 infants with defects and 46 matched controls were interviewed. Two fathers of cases and 2 fathers of controls were employed at the PVC plant at the time of conception and fathers of 3 other controls had worked briefly in the plant on a contract basis. None of the case or control mothers had ever worked at the plant. There were no significant differences between case and control parents in either distance of place of residence from the plant or distance of place of work (residence ifhousewife or unemployed). However, it was noted that the 9 case families living within 3 miles of the plant had a different residential distribution (mostly to the north-east) than control families (mostly to the south). For this study data on air pollution with VCM was available. From 1967-1973 annual mean emissions ranged from 235-270 lb/h, declining to 180 lb/h in 1974 and 76 lb/h in 1975. Estimates of abnormal emissions available from 1970 onwards declined steadily from 28 in 1970, 18 in 1971,12 in 1972, 5 in 1973 and 2 in 1974, to 0 in 1975. The largest known single emission produced atmospheric VCM levels of0-1-0-2 ppm to the north-east of the plant. This study provides no support for a relationship between parental occupation in PVC manufacture and CNS malformations, though the numbers actually employed at the plant in the total sample are too small to draw any firm conclusions. The decline in VCM emissions alongside the decline in CNS malformation rates between 1970 and 1974, however, is striking and whilst the greatest decrease in malformation rates occurred in 1973, preceding the marked decline in overall VCM emissions in 1974, the decrease in malformation rates does parallel more closely the estimates of abnormally high emissions. So whilst the study does not provide any clear evidence of an association between atmospheric VCM and CNS malfor mations, it does not permit such an association to be ruled out. The authors of this study have pointed out, however, that there are 7 major chemical plants in the Kanawha River Valley, emitting an estimated 52,457 tons a year of over 100 different organic compounds including VCM. Thus to implicate VCM alone would be difficult. Infante et al. (1976a) have studied the outcome of pregnancy in wives of 95 VCM polymerization workers. They were compared with 2 control groups of 158 wives of PVC fabrication workers or rubber workers, who were known to have little or no VCM exposure, respectively. Data on paternal age, pregnancy outcome, and estimated time of conception for each pregnancy were ascertained by interview of the male workers and wives were not interviewed. Age-adjusted fetal death rates for pregnancies occurring prior to exposure were not significantly different at 6-1% for the VCM-exposed group and 6-9% for controls, but for pregnancies occurring after exposure they were R&S 132286 Vinyl Chloride 575 15-8% in the VCM-exposed group compared with 8-8% in controls (P < 0 05). Mean paternal age at conception was similar for each group before or after exposure but the majority of fetal deaths in the VCM group were from the younger-aged husbands; in those aged 30 years or older fetal mortality rates were 13-0% and 12-0% in VCM and control groups respectively, whilst in those aged less than 30 years, rates were 20-0% and 5-3% in VCM and control groups respectively. It is possible that younger employees had higher VCM exposures, the older workers in more senior jobs being less exposed. Comparison of fetal death rates with the VCM group before (6-1%) and after exposure (15-8%) was also significantly different (P<002) whereas the comparison within controls (6-9% versus 8-8%) was not. The trend to higher fetal death rates after VCM exposure was still maintained when wives with one, more than 2 or more than 3 abortions were successively eliminated. The authors considered that the effects observed were unlikely to be due to direct exposure to VCM since VCM is highly volatile and unlikely to be carried home, for example, on clothing by the father. The effects are more likely to be due to damage to the paterrtal germ cells from VCM exposure, ' A number of criticisms have been made of this study including the use of a questionnaire and the low response rates (62-77% of those selected for interview) and the misleading method of age-adjustment (Paddle, 1976), though the latter criticism has been rebutted to a certain extent (Infante et al. 1976b). Buffler (1979) has also pointed out that there is lack of information on maternal age, parity, socio-economic status and dose and timing of exposure of the husband in relation to each pregnancy, and there is unreliability of husband's recall, particularly of early spontaneous abortions, and possibly response bias since the workers were aware of some health effects of VCM. Buffler (1979) has described the methodology of a more rigorous study on over 200 VCM exposed workers where wives are being interviewed too to collect data on reproductive history. The results of this study are not available at this time. In summary, 3 studies of communities living close to PVC plants suggest there may be an association between such a location and an increased risk of malformation, particularly of the CNS. However, none of the studies produced clear-cut association and other uncontrolled variables, including other industrial pollutants, may account for the differences observed. A single study of VCM-exposed workers showing an increase in fetal death rates in their wives is more convincing but had a number of methodological problems, and further more rigorous studies of PVC workers are required before any definite conclusions may be reached. 576 Reproductive Hazards of Industrial Chemicals E. MUTAGENICITY There have been a number of studies of chromosome aberrations in lymphocytes of workers exposed to VCM, some showing an increased frequency and some showing no increase in comparison with controls. Funes-Cravioto et al. (1975) found a mean frequency of 9-52% cytogeneti cally abnormal cells in cultured lymphocytes from 7 workers exposed to VCM for 9-29 years, compared with 1-94% in 3 controls. VCM levels in the plant in the weeks before collection of blood samples were estimated to be 20-30 ppm. However, there was considerable heterogeneity, 2 VCM workers not differing significantly from controls. Only one case showed any symptoms of vinyl chloride disease; he had slight thrombocytopenia and aj-trypsin deficiency and had the highest chromosome aberration rate in the group (18%). Ducatman et al. (1975) have also found a significantly higher incidence of unstable chromosome aberrations (fragments, dicentrics and rings) in lym phocytes from 11 VCM polymerization workers compared with 10 from the same factory but not knowingly exposed to VCM. Exposure data was not available, but it was assumed levels exceeded 500 ppm from time to time, based on reports of odour, dizziness and headaches. However, there were no significant differences between exposed and control groups in breaks, gaps or stable chromosome changes. Furthermore, the groups were not matched for age; the exposed group averaged 40 years of age, and controls 27 years. It is possible that this age difference might account for the increase in frequency of unstable chromosome changes. Purchase et al. (1975, 1978) have published preliminary and full data on a larger study of 81 VCM-exposed workers employed in PVC manufacture as autoclave workers, maintenance workers and workers associated with VCM manufacture. Exposure averaged 6-15 years in the different sub-groups and exposure levels for autoclave workers (the highest exposed group) were estimated as 300-400 ppm in 1960-1970, 15 ppm in mid-1973 and 5 ppm in 1975. Blood samples for lymphocyte culture were collected in mid-1974. In the 24 controls (19 on site, 5 off site), an average of 1 -08% of cells were abnormal compared with the various exposed groups where averages ranged from 1 -40% in laboratory workers and managers to 318% in autoclave operators. The means for the sub-groups were significantly higher than controls in the case of VC maintenance workers (2-43%), VC operators (2*43%) and autoclave operators (3-18%). Chromosome aberrations were correlated with overall exposure levels, length of employment, with a history of exposure to excursion levels in the year prior to sampling and with smoking habits, but not with liver function tests. Szentesi et al. (1976) have studied chromosome aberrations in lymphocytes from 45 PVC workers exposed to VCM for 1-12 years (mean age 27 years), 44 industrial controls working in other chemical plants (mean age 44 years) and Vinyl Chloride 577 49 normal controls with no occupational exposure to chemicals (mean age 29 years). There were significant increases in chromatid-type aberrations and in unstable chromosome-type aberrations in PVC workers compared with either of the control groups and aberrations were correlated with length of exposure. Kuierova (1976) has published a small study on 9 workers with long-term exposure to VCM at 500 ppm or more ranging from 8-16 years. Blood samples for lymphocyte culture were taken twice, 8 months apart. There was considerable heterogeneity, some workers having aberration rates close to that of controls (1-2%) and other having much higher rates (3-11%). Furthermore workers with a high aberration rate in one sample did not necessarily have a high aberration rate in the other. The authors attributed this to irregular exposure due to the cyclic character of the production process. The overall aberration rate in the exposed group was 3 0% at the first sampling and 2-6% at the second. These same workers were studied again on a third occasion, 2 years after the first sampling (Kuierova et al., 1979) and the aberration rate averaged 5-2% compared with*l -8% in 8 age-matched controls. It was confirmed that there was considerable variability within exposed individuals at the 3 sampling points. They also analysed for sister-chromatid exchange (SCE) and found a significant increase from 9-41 SCE/cell in controls to 13-80 SCE/cell in the exposed group. Mean exposure rates were stated in this paper to be 20-150 ppm VCM. Hansteen et al. (1978) have also found differences in a group of workers sampled twice 2-2-5 years apart. A total of 39 PVC workers were studied, 14 chosen at random, 13 because they had been heavily exposed to VCM and 12 who had shown clinical abnormalities in an earlier health screen but were normal at the time ofcytogenetic analysis, with average length of employment 10-3 years, 13-7 years and 16-5 years respectively. Blood samples were first taken in 1974 when air concentrations of VCM at the plant were estimated to be around 80 ppm. Prior to this levels were estimated as 2000 ppm in 1950-1954, 1000 ppm in 1955-1959, 500 ppm in 1960-1967 and 100 ppm in 1968-1972. Results were compared with 16 controls not connected with the PVC plant. In the first investigation, the mean frequency of chromosome breakage was 3-41% in the exposed groups and 1 -79% in controls (P < 0-025). In the 3 subgroups exposed to VCM it was highest (3-97%) in the heavily exposed workers. At the repeat study, there was no significant difference between exposed and control groups in either frequency of breakage or sisterchromatid exchange (SCE), This decrease in breakage frequency in the exposed group in 1977 was attributed to the marked reduction in VCM exposure occurring from 1974 onwards; in 1974 levels were decreased to 25 ppm and then to I ppm from 1975 onwards. The results on SCE analysis do not agree with those of Kuierova et al. (1979), but recent exposure levels in the latter study were much higher. Fleig and Thiess (1978) have studied aberration rates in 10 workers exposed ro oCD 578 Reproductive Hazards of Industrial Cherry. to VCM but showing no symptoms and in 20 workers showing symptoms of VCM induced illness including one case with angiosarcoma. Exposure levels were not known. Results were compared with 20 age-matched controls working in the same factory but not exposed to VCM. The frequency of aberrations (including gaps) was 5-5% in controls, 7-5% in exposed workers without symptoms and 11-2% in exposed workers with symptoms. In the angiosarcoma case the rate was 16-6% but he had received polychemotherapy 9 months before cytogenetic analysis and it is not known if the aberrations were due partly to drug treatment as well as VCM exposure. There are, however, a number of negative studies on chromosome aberrations in VCM-exposed workers, Fleig and Thiess (1974) in their first study found no increase in aberrations in a group of 10 PVC workers compared with 4 controls (range 0-5% in both groups). Picciano et al. (1977) could also find no increase in aberrations in a large group of 209 workers employed for up to 28 years (mean 4 years) in VCM production. Results were compared with pre-employment examinations of 295 prospective employees with no known history of exposure to clastogenic agents. The mean age of the VCM-exposed group was 39-5 years compared with 25T years in controls, which, if anything, would bias results in the direction of positive findings in the exposed group. The aberration frequency averaged 3-7% in VCM workers and 4-5% in controls. When the exposed groups were broken down into sub groups on the basis of exposure levels (< 1 ppm, 1-5 ppm and > 5 ppm), the aberration rate in those exposed to > 5 ppm was almost identical to that in controls. The authors suggest that their negative findings may be due to the relatively low exposures in their workers compared with that in other positive studies. Heath et al. (1977) have also found no increase in chromosome breaks in VCM-exposed workers compared with controls from other industries. Mean frequency of breaks was 6-7% in 14 workers exposed to high VCM levels (not specified), 7-8% in 4 men exposed to lower VCM levels and 5-9% in 17 industrial controls working in rubber tyre manufacture. However, all 3 of these groups differed significantly from a group of 4 male controls not occupationally exposed to chemicals, where the aberration rate was 3-6%. The negative results in this study may reflect the small sample size and possible inappropriateness of industry controls who may also have been exposed to clastogenic agents. Koizumi et al. (1979) have also shown no significant difference in chromosome aberrations between 15 workers exposed to VCM for 6-24 years (mean 11-5 years) and 15 controls, fairly closely matched for age. In summary, there have been 7 positive studies and 4 negative studies on VCM-exposed workers, but the balance of evidence would seem to indicate that chromosome aberrations are related to level of exposure and duration of JO & CO co to to (o vl Chloride 579 exposure. With a history of average exposures above 20 ppm and intermittent exposure to higher excursion levels most studies have shown an increase in the frequency of chromosome aberrations. It is notable that 3/4 negative studies were published after 1976 when exposure levels in most plants would be considerably lower than in previous years. The fourth negative study had very small sample sizes and the same authors subsequently published a positive study on larger groups of \yorkers. F. CARCINOGENICITY IARC Monograph Vol. 19 (1979) states that vinyl chloride is a human carcinogen and its target organs are liver, brain, lung and haemolymphopoietic system. SUMMARY AND EVALUATION EXPERIMENTAL DATA Vinyl chloride rapidly crosses the placenta and equilibrates in the fetus. No studies on endocrine or gonadal effects were found. Exposure of male mice up to 30,000 ppm and rats to up to 1000 ppm did not produce any evidence of dominant lethal mutations and only a transient effect on fertility was observed in rats at the highest toxic doses. No studies on female fertility were found. Studies in mice, rats and rabbits exposed to up to 2500 ppm during pregnancy showed no adverse effects. One unconfirmed study in rats, however, did report embryolethal and teratogenic effects from exposure as low as 2-5 ppm during pregnancy. Studies on postnatal survival are insufficient for analysis. Vinyl chloride is mutagenic in a variety of in vitro systems with activation. It is carcinogenic in mice, rats and hamsters and is a transplacental carcinogen in rats. Exposure of pregnant rats to 6000 ppm produced no tumours in the dams when assessed 143 weeks later but did produce various tumours including angiosarcomas in 6 of 32 offspring, the earliest of which developed in less than 6 months. HUMAN STUDIES Among the symptoms experienced by men exposed to vinyl chloride occupationally, impotence and loss of libido have been reported commonly. No studies on fertility were found. Three studies of communities living near 2 Vi to to to <0 Ni 580 Reproductive Hazards of Industrial Cnemu-ui* PVC plants have suggested that there may be a higher incidence of CNS defects in children at these sites than expected. None of these studies were conclusive, however, and usually many other industrial chemicals could also have been involved. One study showed an increased fetal death rate in the wives of exposed workers.' More rigorous studies are needed to examine these claims and also to define if the effect is on the pregnant woman or is mediated via the sperm of exposed men. Mutagenicity studies on exposed workers have produced conflicting results but several good studies have shown increases in chromosomal abnormalities related to duration and extent of exposure. Where exposure was greater than 20 ppm most studies showed positive results. It is a human carcinogen with target organs of liver, brain, lung and haemo-lymphopoietic system. EVALUATION Data on endocrines, gonads and fertility are inadequate for evaluation. Limited studies in animals have shown that it is not teratogenic or embryotoxic at otherwise non-toxic doses. It is a transplacental carcinogen and the fetus may be more susceptible than the dam but this requires confirmation. Data on its teratogenic potential in humans are inadequate for evaluation but attention is drawn to the need for further studies to evaluate its embryolethal and teratogenic effects by studies in both exposed women and men. It is a human carcinogen but there are no data on its transplacental carcino genic potential in humans. References Anderson, D., Hodge, M. C. E. and Purchase, I. F. H. (1977). Dominant lethal studies with the halogenated olefins vinyl chloride and vinylidene dichloride in male CD-I mice. Environmental Health Perspectives 21, 71-78. Bartsch, H, and Montesano, R. (1975). Mutagenic and carcinogenic effects of vinyl chloride. Mutation Research 32, 93-114. Bingham, E,, Warkany, J. and Radike, M. (1979). Teratological effects of vinyl chloride and ethanol in rats. Annual Report of Program 1978-1979, pp. 140-143. Center for the Study of the Human Environment, Department of Environmental Health, Kettering Laboratory, University of Cincinnati, U.S.A. Buffler, P. A. (1979). Some problems involved in recognising teratogens used in industry. Contributions to Epidemiology and Biostatistics 1, 118-137, Ducatman, A., Hirschhorn, K. and Selikoff, I. J. (1975). Vinyl chloride exposure and human chromosome aberrations. Mutation Research 31, (3), 163-168. Edmonds, L. D., Falk, H. and Nissim, J. E. (1975). Congenital malformations and vinyl chloride (letter). Lancet ii, 1098. Edmonds, L. D., Anderson, C, E., Flynt, J. W. and James, L. M. (1978). Congenital central nervous system malformations and vinyl chloride monomer exposure: A community study. Teratology 17,137-142. Vinyl Chloride 581 Feron, V. J., Speek, A. J., Willems, M. I,, Battum, D. and DeGroot, A. P. (1975). Observations on the oral administration and toxicity of vinyl chloride in rats. Food and Cosmetics Toxicology 13, (6), 633-638. Flcig, I. and Thiess, A. M. (1974). Chromosomen-Untersuchung bei VinylchloridExposition. Arbeitsmedizin, Sozialmedizin, Praeventivmedizin 9, 280-283. Fleig, I. and Thiess, A. M. (1978). Mutagenicity of vinyl chloride. External chromosome studies on persons with and without VC illness, and on VC exposed animals. Journal of Occupational Medicine 20, (8), 557-561. Funes-Cravioto, F., Lambert, B., Lindsten, J., Ehrenberg, L,, Natarajan, A. T. and Osterman-Golkar, S. (1975). Chromosome aberrations in workers exposed to vinyl chloride. Lancet 1, 459. Hansteen, I., Hillestad, L., Thiis-Evensen, E. and Heldaas, S. S. (1978). Effects ofvinyl chloride in man: a cytogenic follow-up study. Mutation Research 51, (2), 271-278. Heath. C. W,, Dumont, C. R,, Gamble, J. and Waxweiler, R. J. (1977). Chromosomal damage in men occupationally exposed to vinyl chloride monomer and other chemicals. Environmental Research 14, 68-72. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Some monomers, plastics and synthetic elastomers and acrolein (1979). Vol. 19. Lyon, France. Infante, P. F. (1976). Oncogenic and mutagenic risks in communities with polyvinyl chloride production facilities. Annals of the New York Academy of Sciences 271, 49-57. Infante, P, F., McMichael, A. J., Wagoner, J. K., Waxweiler, R. J. and Falk, H. (1976a). Genetic risks of vinyl chloride. Lancet 1, 734-735. Infante, P. F., Wagoner, J. K.., McMichael, A. J., Waxweiler, R. J. and Falk, H. (1976b). Genetic risks of vinyl chloride (letter). Lancet i, 1289-1290. John, J. A., Smith, F. A., Leong, B. K. J. and Schwetz, B. A. (1977). The effects of maternally inhaled vinyl chloride on embryonal and fetal development in mice, rats and rabbits. Toxicology and Applied Pharmacology 39, 497-513. Koizumi. A., Dobashi, Y. and Tachibana, Y. (1979). Chromosome changes induced by industrial chemicals. Japanese Journal of Industrial Health 21, (1), 3-10. KuCerova. M. (1976). Cytogenic analysis of human chromosomes and its value for the estimation of genetic risk. Mutation Research 41. (1), 123-130. Kuierova, M,, Polivkova, Z. and Batora, J, (1979). Comparative evaluation of the frequency of chromosomal aberrations and the SCE numbers in peripheral lymphocytes of workers occupationally exposed to vinyl chloride monomer. Mutation Research 67, 97-100. Laumbach, A. D., Lee, S., Wong, J. and Streips, U. N. (1977). Studies on the mutagenicity of vinyl chloride metabolites and related chemicals. Detection and Prevention of Cancer (Proceedings of the 3rd International Symposium) 1, (1), 155-170. Loprieno, N.. Barale. R., Baroncelli, S., Bauer, C., Bronzetti, G., Cammellini, A., Cercignani. G., Corsi, C., Gervasi. G., Leporini, C,, Nieri, R,, Rossi, A., Stretti, G. and Turchi, G. (1976). Evaluation of the genetic effects induced by vinyl chloride monomer (VCM) under mammalian metabolic activation: studies in vitro and in vivo. Mutation Research 40. (2), 85-96. Maltoni, C. (1976). Occupational chemical carcinogenesis: new facts, priorities and perspectives. IARC Scientific Publications 13, 127-149. Maltoni, C. and Lefemine, G. (1974). Carcinogenicity bioassays of vinyl chloride I. Research plan and early results. Environmental Research 7, 387-405. R&S 132293 582 Reproductive Hazards of Industrial Chemicals Mirkova, E.. Mihailova, A. and Nosko, M. (1978). Embryotoxic and teratogenic action of vinyl chloride. Khigiena i Zdraveopazvane 23, (5), 440-443. Paddle, G. M. (1976). Genetic risks of vinyl chloride (letter). Lancet i, 1079. Picciano, D. J., Flake, R. E,, Gay, P, C. and Killian, D, J. (1977). Vinyl chloride cytogenetics. Journal of Occupational Medicine 19, (8), 527-530. Purchase, I. H. F., Richardson, C. R. and Anderson, D. (1975). Chromosomal and dominant lethal effects of vinyl chloride (letter). Lancet ii, 410-411, Purchase, I. H. F,, Richardson, C. R,, Anderson, D,, Paddle, G, M. and Adams. W. G, (1978). Chromosomal analyses in vinyl chloride-exposed workers. Mutation Re search 57, (3), 325-334. Short, R. D,, Minor, J. L., Winston, J, M. and Lee, C.-C. (1977). A dominant lethal study-in male rats after repeated exposures to vinyl chloride or vinylidene chloride. Journal of Toxicology 3, 965-968. Simmon, V. F. (1977). Structural correlations of carcinogenic and mutagenic alkyl halides. In "Structural Correlates of Carcinogenesis and Mutagenesis" (Eds. Asher, I. M. and Zerros, C.), pp. 163-171. FDA Office of Science. Szentesi, I,, Hornvak, E., Ungvary, G., Czeizel, A,, Bognor, Z. and Trimar, M. (1976). High rate of chromosomal aberration in PVC workers. Mutation Research 37, (2/3), 313-316. Ungvary, G,, Hudak, A., Tatrai, E., Lorincz. M. and Folly, G. (1978). Effects of vinyl chloride exposure alone and in combination with Trypan Blue --applied systemati cally during all thirds of pregnancy on the fetuses of CFY rats. Toxicology 11,45-54. Walker, A. E. (1975). A preliminary report of a vascular abnormality occurring in men engaged in the manufacture ofpolyvinyl chloride. British Journal ofDermatology 93, 22-23. Walker, A. E. (1976). Clinical aspects of vinyl chloride disease: skin. Proceedings ofthe Royal Society of Medicine 69, 286-289. U 99 U) CO to to CO