Document 4QrKDqLoDxnxyOZeZk3V6OVqa

Fi Chem. Toxic. Vol. 2J, No. 2. pp, 117-202, 1917 printed in Greet Briuin. All right! twerved 027S-69U/S7 13.00 + 0.00 Copyright 1917 Pergunoa Journal! Ltd Review Section VINYL CHLORIDE: AN ASSESSMENT OF THE RISK OF OCCUPATIONAL EXPOSURE* I. F. H. Purchase Central Toxicology Laboratory J, Stafford Plastics and Petrochemicals Division and G. M. Paddle Central Medical Group, Imperial Chemical Industries pic, Alderley Park, Macclesfield. Cheshire, England (Received 14 December 1983; revisions received 13 January 1986) Introduction Vinyl chloride monomer (VCM), more properly named monochlorethane, is a'colourless gas normally handled under pressure as a liquid which boils at -- 14C at normal pressure. Discovered around 1835, VCM's commercialization did not begin until the 1930s and did not reach high volume until after 1945. Present manufacture is around 12 x 10* tonnes per annum, nearly all of which is used to make the polymer polyvinyl chloride (PVC). Until the 1960s, VCM was regarded as a material of low human toxicity and the main concerns were related to the compound's narcotic effect. Indeed there are many reports of employees exposed to VCM monomer in polymer plants becoming dizzy and unconscious. Because VCM was considered to be relatively innocuous, it had a threshold limit value (TLV) of 500 ppm, 8-hr time-weighted average {TWA) for many years (ACGIH, 1974; Lester et al. 1963; Torkelson et al. 1961). Measurements of em ployee exposure were infrequent, since most mea surement and warning systems were designed to ensure that plant atmospheres were beyond the ex plosive limits, lire and explosion being the main hazards of VCM. Retrospective estimates (Barnes, 1976) of typical TWA personal exposures (in ppm) for polymerization workers have been cited as: 1000 in 1945-1955, 400-500 in 1955-1960, 3<XW00 in 1960-1970, 150 in mid-1973 and 5 in 1975. However in some jobs, particularly in the cleaning of the autoclaves in which VCM is polymerized to PVC, very much higher exposures, in thousands of ppm, were undoubtedly experienced for short/medium pe* *A longer version of this paper has been published in Toxicological Risk Assessment, edited by D. B. Clayson, D. Krewski and I. Munro and published by CRC Press, Inc., Boca Raton. FL (1985). Abbreviations: AOL acro-osteolysis; ASL angio sarcoma of the liver; PVC - polyvinyl chloride; TLV - j threshold limit value; TWA - time-weighted average; ' VCM vinyl chloride monomer. riods, since in some plants operators became faint and unconscious from time to time. ' The first clear indication of chronic health prob lems associated with VCM arose in the 1960s in men who entered VCM polymerization autoclaves to re move build-up of polymer from the walls. Some of these men developed acro-osteolysis (AOL; Cook et al. 1971; Harris St Adams, 1967; Suciu et al. 1963). Modification of working practices led to a reduction in the incidence of AOL cases in autoclave cleaners. Although AOL is occasionally seen in people not exposed to VCM (Meyerson St Meier, 1972; Wilson et al. 1967) it is a rare disease. In the late 1960s, studies in rats involving exposure to high concen trations of VCM for long periods (Viola, 1969) failed to produce AOL but showed an increase in the incidence of tumours at various sites. Further studies (Maltoni etal. 1980 At 1981;Maltoni St Rondinetla, 1980) showed the rare tumour angio sarcoma of the liver (ASL) in exposed rats, and confirmed VCM as an animal carcinogen. Three ASL cases in employees at a PVC polymerization plant (Creech St Johnson, 1974) confirmed VCM as a human carcinogen. Other known aetiological agents for ASL in man were thorium dioxide, arsenic and, possibly, anabolic steroids (Maltoni et al. 1980). Since 1974, the health hazards of VCM have been the subject of many investigations, scientific papers, seminars and other presentations (Conference to Reevaluate the Toxicity of Vinyl Chloride Monomer, Poly(vinyl Chloride) and Structural Analogs, 1981; Gauvain, 1976; IARC Working Group, 1979; Selikoff, 1975; Szadkowski St Lehnert, 1982; US DHEW, 1980). The plethora of information (and misinformation) now available suggests that an ob jective historical case study of VCM would be of value. Experimental and human data Experimental studies The principal effect seen in the acute and subacute studies is anaesthesia, which occurs at relatively high 187 OCC 1347 188 I. F. H. Purchase et al. Table 1. Lowest concentrations or doses it which i significant tictn of various tumour types wu observed in fit carcinogenicity studies Tumour Concn (ppm) Dose (mg/kg) Forcstomach papilloma Zymbal-gland carcinoma Neuroblastoma Nephroblastoma Liver angiosarcoma Mammary-gland adenocarcinoma 30,000 10,000 10.000 250 (female) 100 (male) 200 50 5 (female) 50 (male) 16.65 (female) Dan from Malloni et at. (1981). doses (7-10%) in both animals and man. The doses responsible for acute toxicity are about 1000-fold higher than the minimum dose for carcinogenicity and there is frequently no sign of overt organ toxicity prior to the development of the carcinogenic re sponse. VCM is mutagenic in a variety of lest systems including Salmonella typhimurium (Rannug et al. 1976), Saccharomyces (Loprieno et al. 1977) and Drosophila (Verburgt & Vogel, 1977), usuaily with some form of mammalian microsomal metabolizing system to convert VCM into its active metabolites, chloroethylene oxide and chloroacetaldehyde. The data on the mutagenicity of VCM provide useful qualitative information on its mode of action and metabolism, but are not suitable for the quantitative estimation of risk to man. The most useful experimental data are derived from long-term animal carcinogenicity studies. An extensive series of 17 studies (Maltoni et al. 1981) gives a useful database for risk assessment. Other studies (Feron et al. 1981; Lee er al. 1978) tend to confirm the findings of Maltoni. Carcinogenic effects were observed in mice, rats, and hamsters. A complication in the selection of these data for risk assessment is the variety of tumour types observed (Table 1). Some of these occurred at very high exposure levels, but mammary adenocarcinoma in females and ASL in both sexes of both rats and mice occurred at SO ppm or less, exposures similar to those believed to have occurred on manufacturing plants (Bames, 1976). Epidemiological studies Several major epidemiological studies on workers exposed to VCM have been reported (Table 2). The main organs that have been associated with higher incidences of cancer in workers exposed to VCM are the liver, lung and brain. Increases in the standard ized mortality ratios of cancers in the buccal cavity and pharynx, of lymphomas and of cancers of the lymphatic and cardiovascular systems have been re ported in one or two studies. The analysis of cancer of the respiratory system is often confounded by smoking, making quantitative analysis of the con tribution of VCM difficult. The excess of liver cancers is due to an excess of ASL in many of the studies. An analysis of the statistical power of various studies for association between VCM exposure and cancer of the lung, liver and brain (Beaumont & Breslow, 1981) concluded that the results for liver were consistent with an aetiological role for VCM. For brain cancer, where three out of five studies had statistically significant findings, the results were more variable, positive findings occurring in the studies with the greatest statistical power. The most reason able interpretation was that the data were consistent with a causal association between VCM exposure and an excess of brain cancer. Infante (1981), in reaching the same conclusion, points out that the relative risk for brain cancer is much lower than that for liver cancer. Only two out of eight studies on lung cancer (Beaumont & Breslow, 1981) yielded statistically significant results and, because studies with a high power were negative, a causal association was consid ered unlikely. ASL is the most suitable endpoint for analysis of the risk of exposure to VCM for a number of reasons. It is a rare cancer in unexposed populations, making attribution to VCM exposure on the basis of work history a reasonable approach. ASL occurs in both animals and humans exposed to VCM and it is unlikely that any other carcinogenic effect of VCM will be found to occur at lower exposures than the lowest exposures that induce ASL. For these reasons, most work on the quantitative risk assessment of chronic exposure to VCM has used ASL as the endpoint to study. Case register The availability of data from a comprehensive case register of ASL cases with a history of occupational exposure to VCM provides an opportunity to identify risk factors for the induction of ASL. Persons potentially exposed to vinyl chloride Current manufacture and use of VCM and PVC results in the potential exposure of four groups of the population. The highest exposure category covers the workers involved in the manufacture of VCM, its polymerization to PVC and certain other industrial uses of VCM. Within this group, certain occupations, particularly autoclave cleaning, involve higher poten tial exposure than others, although all groups would now be expected to have exposures complying with hygiene standards of 1-5 ppm. The next category covers those exposed as a result of using the PVC. Workers in the compounding and fabrication of PVC products are exposed to residual VCM released from PVC on heating (but PVC does not decompose to VCM when heated). In general the exposure levels for these workers are very low in comparison to those for PVC polymerization workers (from 10 to 100 times lower). Consumers who eat food and drink beverages that have been packed in PVC may ingest unreacted VCM OCC 1348 Vinyl chloride--risk assessment 189 which has migrated into the food or beverage. Since 1974, the amount of VCM in PVC has been reduced to less than 1 mg/kg with the result that the maximum human daily intake of VCM in food and drink is O.lpg/day (Ministry of Agriculture, Fisheries & Food, 1978). The fourth group with potential exposure to VCM are those who live in the vicinity of VCM or PVC manufacturing or fabricating factories. The levels in ambient air around a factory are very low (in the parts per 10' range) but much larger population groups, which include all age groups, are involved. For the workers in VCM manufacture and PVC polymerization and fabrication, the route of exposure is by inhalation. Much of the animal carcinogenicity data are based on inhalation exposure and the human epidemiology is predominantly of populations ex posed occupationally by inhalation. Thus an assess ment of the risk factors and the quantitative risk of inhalation exposure is the main objective. For the consumer exposed to VCM via food and beverages the route is by ingestion. Relatively few experimental studies have used oral administration and only one study used a comparable exposure pattern (Feron el al. 1981). Similarly there are no specific epi demiological data on oral ingestion. Risk assessment for exposure via the oral route must rely on the existing animal data and on extrapolation from epi demiological and experimental studies of inhalation exposure. Risk aaseKment from experimental animal data After administration by gavage or inhalation, part of the dose is exhaled unchanged and the remainder is excreted or retained in the carcass. A general scheme CH----- CHjSCHjCHO NM Gtu / (d) Gly 1 1 C=0 11 CHCHjSCHjCHj I1 1 1 NH OH 11 Glu / % Gly 1 1 (' = 0 i CHCHjSCHjCOjH 1 NH 1 1 Glu Assumptions In carrying out a risk assessment on the basis of animal data, a number of assumptions have to be made. The first of these relates to the overall dosi metry. Experimental animals are exposed to concen trations of vinyl chloride or dosed with amounts of vinyl chloride that allow an estimate of the amount to which they have been exposed. It is possible to calculate a correction factor for these quantities so that they are applicable to man. However, rats and mice live for relatively short periods of time (up to 2 years) during which they develop cancers of a type similar to those seen in man. The latent period for the same tumours in man may be between 20 and 40 years. It is therefore assumed that the lifetime of man is equivalent to the lifetime of an experimental animal species even though the chronological time is sub stantially different. Strictly speaking, mathematical extrapolation of risk on the basis of experimental animal data pro vides an estimate of the risk at low doses to the experimental animal under consideration. A variety of factors, particularly inherent biological sus ceptibility and differences in metabolism, render the extrapolation of the data from animals directly to man subject to numerous errors. It is at this point that scientific judgement is required to decide whether these data are applicable to the human situation. Metabolism In rats, VCM has been shown to be metabolized extensively, producing a range of excretion products. CO,H 11 CHCHjSCHjCHj 11 NH (Ac) OH (*) COjH CHCH jSCH jCOjH 1 NHj t COjH C----- CHjSCHjCOjH II o S(CH.COiH)* * <s> Fig. 1. Scheme showing the metabolism of vinyl chloride monomer (VCM) in rats to ^-containing metabolites. VCM (a) is converted to chloroethylcne oxide (b) which is trans formed spontaneously to chloroacetalcehyde (c). These two metabolites are mutagenic and hence are considered to be the proximate carcinogens. The urinary excretion products -acetyl-S-(2-hydroxyethyl)cysteine (e) S-(carboxymethyl> cysteine (0 and thiodiglycolUc acid (g) are derived from these mutagenic metabolites via (d). Gly and Glu are the glycine and glutamate residues of glutathione. (After Green & Hathway (1977)]. OCC 1349 1. F. H. Purchase et al. OCC 1350 Reference Monsoo et of. (1974) Tabcnhaw A Gaffey (1974) Duck et at. (1975) Nichoboa et at. (1975) Otl et al. (1975) Byrcn et at. (1976) ORC (1976) Rrinl * Weber. 1976; Reinl et al. 1971; Weber tl at. 1981 Wamcikr et al. (1976) For A Collier (1977) FreUd-Beyme et at. (1978) Bcruzzi et al. (1979) BuRler ef at. (1979) Oiimr A Ference (1981) Ouazze et at. (1980) Beaumont A Breslow (1981) Table 2. EpkfemiologkaJ studies of cancer associated with exposure to vinyl chloride monomer No. in study* ------------------............. ...... . {% follow up) Increase Sites (or tumours) with changes in SMR 1 "" 1 No increase 7 Brain -- Comments 8394 (85%) Liver, including ASL Buccal cavity and pharynx Respiratory system Unknown site Lymphoma Angiosarcoma Significant SMR not significant but increases with exposure 2130 257 (99%) 594(99%) 771(97%) 10,173(95%) 11,028(90%) 1151 7409 (99%) None ASL All tumours? Liver/pancreas Cerebral? Cardiovascular Digestive tract Malignant liver Lymphatic system GE trad Brain Respiratory tract Lymphatic system ASL Primary liver ASL 1618(95%) 5441 (86%) 464(100%) 3847 Colon/stomach Proslatic hyperplasia All tumours Respiratory system Digestive system Liver Brain Genital Digestive organs Urinaiy tract Leukaemia Brain Stomach Brain Lymphatic and haemopoietic system Some criticism or conduct of study Arsenical* involved Significant increase (2 ASL) Increase not significant PMR study Related to duration of exposure Mixed exposure, not VCM related Not significant Significant Breast Respiratory tract PMR study of female and mate fabricators Increase in PMR not confirmed by case-controlled study Review of nine studies s Vinyl chloride--risk assessment 191 * 3 Zo of VCM metabolism in rats is given in Fig. 1. On the basis of this scheme, the highly reactive intermediates in the metabolic process (particularly chloroethylene oxide) react with cellular macromolecules, including DNA to produce the critical lesions leading to mu tation or the induction of cancer. Studies on the quantitative aspect of VCM metab olism have shown that there is a dose dependency in the rate of metabolism. After administration of uC-labelIed VCM by gavage at doses between 0.5 and 100 mg/kg to Wistar rats, the amount of l4C excreted in the urine and faeces and retained in the carcass was estimated over 72 hours (Watanabe & Gehring, 1976), As the dose of VCM was increased, the proportion exhaled increased and that excreted in the urine and faeces decreased (Fig. 2). The proportion retained in the carcass also decreased. The same general trend occurred after administration by in halation, although the magnitude of the differences in retention and excretion was less (Watanabe & Gehring, 1976). Studies of the amount of non-volatile material retained in the carcasses of rats exposed to various levels of MC-labelled VCM for 6 hours demonstrated that the metabolism of VCM appeared to be in accordance with Michaelis-Menten kinetics (Gehring et al. 1978). The constants for maximum velocity of metabolism (Vn in fig metabolized/6 hr) and the Michaelis constant (K,, in fig VCM/litre air) accord ing to the formula: Vl, V-S K,, + S (where V - velocity of metabolism in pg/6 hr and S = concentration of VCM being inhaled) were VB8558pg metabolized/6 hr and KB 860 /r g I VCM/litre air. Thus there was a considerable change sS s in the ratio of administered dose to metabolized dose as the exposure concentration increased (Table 3). At ds I the higher doses a smaller proportion of VCM was i metabolized than at low doses. > 'z Review of earlier calculations of risk s%?n e s! s There have been a number of attempts to calculate the risk of ASL development on the basis of extrap o' -- f*> olation from experimental data. These have been reviewed by Barr (1982) and an adaptation of his data is presented in Table 4. The introduction of biotransformation data into the estimation of risk increased the level of exposure calculated to cause a 10 lifetime risk, from parts per I billion to in excess of one part per million. A further 5 1 K. refinement of the technique using DNA binding as the measure of dosimetry (Anderson et al. 1980) provided a similar estimate of the exposure. I A variety of mathematical models can be used for i 5 extrapolating below the experimental dose range, and r it is not possible to select from amongst these math ematical models on the basis of goodness of fit to experimental data. Attempts to do so have shown that most of the models fit the data equally well (Gehring et al. 1979). It is equally difficult to select amongst the models on the basis of the assumed mechanism of action of VCM. Thus a comparison of the lifetime risks calculated using the Armitage-Doll 192 1. F. H. Purchase et at. Table 3. Vinyl chloride do* and incidence of hepatic angiosarcoma in Sprague-Dawley rnu expoaed _______________________________ on i daya/wlt for 52 wk* ______ Concn (ppm) Amount metaboliied pg/4 hr /i | (tout) Angiosarcoma incidence (*/) Male Female Mean Expmt no. 30,000 10.000 6000 2500 500 250 200 150 100 50 25 10 5 1 0 5647 1.47 x 10* 16.6 43,3 30.0 5521 1.44 x 10* 10.0 13.3 11.7 5403 1.41 x 10* 10.3 33.3 22.0 5030 1.3 x 10* 20.0 23.3 21.7 3413 8.8 x 10* 0 20.0 10.0 2435 6.3 x 10* 3.4 6.7 5.1 2129 5.5 x 10' 11.7 8.3 10.0 1761 4.6 x 10' 1.7 8.3 50 1309 3.4 x 10' 0 1.7 0.8 739 1.9 x 10* l.l 7.2 4.2 395 1.0 x 10' 1.7 6.7 4.2 169 4.4 x 10* 0 1.7 0.8 84 2.2 x 10* 0 0 0 17 4.4 x t0* 0 0 0 0 0 000 BT 6t Btl BT 1 BT 1 BT 1 BT 1 BT2 BT 2 BT2 BR 1.9 BT 15 BT 15 BT 15 BT 15 BT 1,2. 9.15 `After Maltoni et al. (1981). tExperiment BT 6 ended after only 68 wk, while the real were all approximately 140 wk: therefore the percentage of tumours in BT 6 ia probably low relative to the real because of the abort latency period available. multistage model by the Food Safety Council (1980) and by Gaylor & Kodell (1980) showed that for the same 10'* lifetime risk, the Food Safety Council estimated the dose as 2 x 10'1ppm whereas Gaylor & Kodell estimated the dose as 5 x 10'* ppm. The difference between these two estimates was due to alternative assumptions on the value of the expansion of the exponential term used. In general, calculations based on the amount of material metabolized or on human data have pro duced exposure values of about 1 ppm for a 10'* lifetime risk. All the other studies have produced exposure values in the ppb range. A large variable appears to be the selection of the mathematical model applied to the experimental data. In the following section two models are used to calculate the exposure for a 10'* risk from a variety of experimental animal data applying the correction for metabolism used by Gchring et al. (1979). Calculation of exposure for 10'* risk A summary of the crude ASL incidence rates for inhalation studies in Sprague-Dawley rats is given in Table 3. Similar data for Wistar rats exposed by Txblc 4. Summiry of quantitative rixk axieumcnu for vinyl chloride monomer* Reference Specter Exporurt for 10'* lifetime risk (ppbf) Comments Schneidennan tt at. (1975) Rat Kusnack * McCaughy (1975) Gchring er al. (1979) Food Safety Council (1980) Rat, man Rat. man Rat Rat Anderson et al. (1980) Gaylor A Kodell (1980) Cariborg (1981) Barr (1982) Thie paper (Table 9) EPA (1980) NAS (1980) Crump A Guess (1980) Rat, man Rat Rat Man Rat Moute Man Rat Mouae Man Rat Rat Man Rat By Inhaledo* 73 119 2 14 140-1400 >1000 <)0->l000 20 20 2.1 x 10'* 3.9 x I0'T >1000 0.7 0.S 2.5 x 10'* >100 0.025-9.16\ 2x 10-'* / 0.63-90 2 x 10"*--2 x 10'* 6 x 10'** 0.067-8.14 By lagcetiaa 4/tg/day 3 x 10',mg/k8/`fy 0.7 pg/day 0.5>ig/day Probit (tlope - 1, Mantel) Logit (elope 3.45) Logit (elope 13, one-hit) Linear through.kto Log-probit Bioinniformation data included Linear or log-probit Depcnda on mathematical model uied One-hit Armitage-Doll Weibull Multi-hit DNA binding uaed for doiimctry Upper 97.5% confidence limit of linear model Armitage-Doll Weibull Derived from Barr'a negative epidemiology Log-probit Log-probit including biotraniformation data for man Weibull Weibull including biotranifonnation for man Food or water Water Applying worker dau to water Upper 95% confidence limit! After Brr (1932). tExcept where itaicd otherwj*. OCC 1352 Vinyl chloride--riik assessment 193 inhalation (Table 5) for rats exposed orally (Table 6) and for mice exposed by inhalation (Table 7) are also presented. Data from experiments with various ex posure periods of short duration are given in Table 8. For calculating the amounts of the dose metabo lized in rats in the inhalation experiments, the con stants calculated (Oehring et al. 1978) have been applied. For Wistar rats, the K,, and Vm values derived for Sprague-Dawley rats have been used. These estimates of metabolized dose have been in cluded in the tables. For the experiment in which VCM was given by gavage, the data from Fig. 2 were used to estimate the amount of VCM exhaled unchanged. As the t1/2 for exhalation of VCM was 14 minutes, these data based on a 72-hour period give a good estimate of the fraction of VCM exhaled in the 24 hours between doses. It has been assumed that the VCM not exhaled was metabolized, an assumption similar to the one used for estimating metabolized dose in the in halation experiments. Green & Hathway (1975 & 1977) showed that VCM administered by gavage to Wistar rats was exhaled and metabolized in a similar manner to that in the Sprague-Dawley rats, and the V,, and K,, values derived for Sprague-Dawley rats have been used. In the experiments by Feron ei al. (1981), who used Wistar rats, the same assumptions about V,, and Km have been made. The quantity of VCM administered has been dealt with as if it had been administered by gavage. Fig. 2. Summary of dose-dependent urinary and pulmonary excretion of vinyl chloride monomer (VCM). Urinary excre tion () represents metabolites of VCM, while pulmonary elimination (A) is unchanged VCM. (After Watanabe 4 Gehring (1976)]. For mice, the data have been combined in Table 7. The estimation of the dose metabolized in mice has been calculated using values for V,, that have been adjusted on the basis that, for a chemical requiring metabolism to its active form, the quantity metabo lized will be proportional to the body surface area and must be expressed in terms of metabolized dose/kg body mass. This technique has also been used by Gehring et al. (1978) for estimating the dose metabolized by man. Table S. Vinyl chloride dose and incidence of hepatic angiosarcoma in male Wistar rats exposed on 3 diyi/wk for 32 wk Concn (ppm) Amount metabolized pg/4hr P (total) Angiosarcoma incidence (*/) Expmi no. 10.000 3321 1.4 x 10* 29.6 BT7 6000 3403 1.4 x 10* 11.5 BT7 2300 3030 1,3 x 10* 12.0 BT7 300 3413 8.S x tOJ 10.7 BT7 230 2433 6.3 x 101 3.7 BT7 30 739 1.9 x 10' 0 BT7 1 17 4.4 x I01 0 BT 17 0 00 0 BT 7. 17 Table 6. Vinyl chloride (VCM) dose and incidence of hepatic angiosarcoma in rats given VCM by gavage or ingestion Dose (mg/kg) Amount (Va of dose) Amount metabolized pg/doact pg (total) Angiosarcoma incidence (%) Male Female Mein no. 30* 16.63 3.33 1.0 0.3 0.03 0 300| 14.11 3.0 1.7 0 30 <230 1.6 x 10 20 22.5 33 2703 7.0 x 10* 10 15.1 10 730 2.0 x 10' 0 0 2 3245 7.26 x 10* 1.3 2.7 1.7 74 2.16 x 10* 0 1.4 1.4 7.4 2.16 x 10* 0 0 -- 00 00 10 15.000 6.2 x 10* 49 53 32 2390 1.65 x 10* 49 16 16.5 1040 7.25 x 10* to 4 2 420 2.9 x 10* 0 0 69 00 00 'Calculated from data derived from Wetenabe 4 Gehring (1976) presented in Fig. 2. tAnumini e 230-g rat. JSprague-Dmwtey rats dosed by gavage with VCM in com oil 3 times/wk for 32 wk. JBT27 dosed for 59 wk. IWistar rata used d controls by Feron tt at. (1981) and dosed for S3wk. lWiater rau receiving a diet containing VCM dissolved in PVC. 21.2 12.! 0 2.C 0.1 0 0 31' 32 7> 0 --1 BT II BT II BT II BT27J BT27 BT27 BT 11, 27 Feron tl al. (19g|) OCC 1353 194 I. F. H. Purchase tl al. Table 7. Vinyl chloride dole nd incidence of hepatic angioearcoma in mice Concn (ppm) 10.000 6000 2300 1000 300 250 250 50 1 0 Amount metabolized Pi/4 hr 11,245 11,007 10.246 8699 6952 4959 4959 1506 1506 0 Pi (tout) 1.7 x 10* 1.7 x 10* 1.5 x 10* 3.4 x 10* 1.0 x 10* 7.4 x 10* 7.4 x 10* 2.2 x 10' 5.9 x 10' 0 Aniioiarcoma incidence (%) Male 3.8 6.7 20.7 39.4 20.0 30.0 24.0 3.3 10.3 0 Female 30 36.7 33.3 30.0 26.7 30.0 47.0 0 0 0 Mean I7.S 21.7 27.1 44.7 23.3 30.0 36.5 1.7 5.2 0 Expint no- BT4* BT4 BT 4 Lee tl o/.t BT 4 BT 4 Lee ii al. t BT 4 Lee it at.l BT 4 k Lee il al. Swiss mice, 81-wk expenment, dosed for 30 wk. fCD, mice, 52-wk experiment, 6hr/day exposure (Lee H al. 1971). These results have not been included in the calculations (or Table 9 because the experimental design incorporated interim kills. Thus: V- <m0USe)" V* ^t) x = S706)tg/4hrx^li = 1395 /a g/4 hr The values of 0.045 m1 and 0.011 m1 are the body surface area of a rat and a mouse, respectively. Since toxicity is a function of the concentration of the toxic metabolite in the tissue, the amount transformed must be normalized for mass to estimate an equiv alent response. Thus Vm must be adjusted on the basis of the body weights of a rat (0.25 kg) and a mouse (0.03 kg) by dividing by 0.03/0.25 -- 0.12. The Vm for the mouse on a mass-equivalent basis is therefore: e 11625 pg/4 hr This value of Vm has been used in calculating the total amount of VCM metabolized (Table 7). From the variety of models (or mathematical ex trapolation techniques) used for low-dose risk extra polation (Table 4), an arbitrary choice of models has been made to test the robustness of the extrapolation from the different animal studies. A log-probit analysis of the dose that would be expected to produce a lifetime risk of ASL of 10'* is presented in Table 9. This calculation can be carried out on the basis of the concentration inhaled, the daily dose metabolized or the total quantity metabo lized during the whole experiment. There is a wide variation in the estimated dose depending on the database used for the calculation. The largest vari ation between doses derived from the rat experiments is 360-fold (0.025 ppb v. 9.1 ppb) when exposure in ppb is considered, but this decreases to 100-fold for other estimates of dose. The results from mice are substantially lower when expressed in ppb (2 x 10"15 ppb) but the difference is less for other expressions of dose. Similar calculations of the dose expected to give a 10'* lifetime risk of ASL have been based on a Weibull analysis (Table 9). This is a more `conserv ative' mathematical model and the estimates of dose are accordingly lower. The variation in estimates of dose is, if anything, larger than that observed with the log-probit analysis (for example, a 10'1 difference between the. S values derived from Wistar and Sprague-Dawley rats). The doses for mice arc so much lower than those calculated for rats or man that the assumptions used in their calculation must be suspect. A further calculation to derive the human dose likely to produce a risk of 10'* is given in Table 9 (S calculated for man). These calculations are based on a V,, for man of 1675 pg/8 hr based on corrections for body surface area and mass. The values are substan- Tiblc S. Vinyl chloride (VCM) doee and hepetic angiosarcoma Incidence in Sprague-Dswley rati exposed lo VCM by inhalation Concn (ppm) Schedukt No. of doee* Amount metabolized} p 1/4 hr p| (total) Angiosarcoma incidence (/.) - Expmt Male Female Mean no. 10.000 1 260 5521 1.4 x 10* 10 13.3 11.7 BT 1 10.000 II 85 3521 4.7 x 10* 0 0 0 BT3 10.000 III 25 3521 1.4 x 10* 1.7 0 0.8 BT 10 10.000 IV 100 1379 1.4 x 10' 1.7 0 0.8 BT 10 10.000 V 25 3521 1.4 x 10* 0 1.7 0.S BT 10 6000 1 260 5403 1.4 x 10* 10.3 33.3 22.0 BT 1 6000 11 85 3403 4.6 x 10> 0 3.3 1.7 BT3 6000 lit 25 5403 1.4 x 10s 0 0 0 BT 10 6000 IV 100 1350 1.4 x I0` 3.4 1.7 2.5 BT 10 6000 V 23 5403 1.4 x 10* 0 1.7 0.8 BTTIO `After Maltoni tl al. (I9SI). tSchedules: 1--4 hr/day, S days/wk for 32 wk; II--4 hr/dey, 3 deyi/wk for 17 wk; III--4 hr/day, 3 daya/wk for 3 wk; IV--| hr/day, 4 dayi/wk for 25 wk; V--4 hr/day, 1 day/wk for 25 wk. {Aiftount meiabolired (v) in 4 hour derived from the formula: V (pg/hr) Va x S/K_ 4- S when Vm is 4/6 of the 4 hr value. cc 1354 Table 9. Quantitative risk estimations derived from iviilabke animal carcinogenicily data and expressed as the amount or concentration of vinyl chloride calculated to give a lifetime risk of ASL of 10'* either on the basis of log-probil analysis or a Weibull distribution Table no. Experimental data Exposure for rodents (S ppb*> Amount metabolized in 6 hr by rodents (V jigfbhr) Total amount metabolized by rodents (TM mg) Exposure (ppfe) calculated from V (S calculated for man)f Vinyl chloride--risk assessment OCC 1355 4 S-D nil, inhalation s Wistar rata, male only, inhalation 6 Rata, ingeMkxt--Wistar --S-D --bmhf n Mice, inhalation 4. S Wistar and S-D rats combined, iohalatioa 8 S-D rats, short-term inhalation 4 S-D rets, inhalation Wistar rats, male only, 5 inhalation 6 Rata, injestion--Wistar --S-D --bothf 71 Mice, inhalation 4.1 Wistar and S-D rata combined, inhalation 8 S-D rats, short-term inhalation 0.02S Lf-prollt aaslyalit 1.23 9.16 3 x I0_* mg/kg 9 k 10 "'mg/kg 6 x 10"'mg/kg 2 m 10-11 119 0.69 mg/dosc 2.19 mg/dose 1.70 tng/dosc 0.60 0.038 -- 2 x I0'1 1.41 0.004 WdbaO fistrihatloat 0.013 2 x ID*1 9 x 10" mg/kg 4 x 10 "`mg/kg 2 x 10'* mg/kg 6x10" 11.7 3 x 10'* mg/dose 0.33 tng/dose 0.001 mg/dose 2 x 10'* 6x10-* -- ,, 0.0172 lx I0-* 0.305 39.3 2.27 0.2 0.88 0.0063 0.31 2.86 0.0032 3.68 0.0002 0.003 0.0015 2 x 10 * 0.0042 0.19 0.63 90 -- 0.03 0.72 -- 0.067 8.14 1 x 10' * 0.009 ASL Angiosarcoma of the liver S-D Sprague-Dawlcy *Except where slated otherwise. tExposure calculated from V (in column 3) using the formula: S*Vx S60/1675 - V, where V. for man is 1675 pg/B hr. | Estimated using maximum likelihood. jWjjur and S-D rats combined. |Study BT 4 only. 196 I, F. H. Purchase et al. tially higher than those calculated for the rat and mouse and there is still a range of over 100-fold in the estimates derived from the different rodent experi ments. When this amount of variability occurs in the extrapolation of the risk of low-dose exposure to VCM based solely on different experiments in the same species, the reliability and hence the utility of these procedures is open to question. The general relationship between the dose adminis tered and the incidence pf angiosarcomas derived from 52-week exposure does not apply to exposures of shorter duration (Table 8). In all experiments a total metabolized dose in excess of 5 x I O'jig was required to produce an incidence of angiosarcoma in excess of 1-2%. This relationship was seen in both rats and mice and in experiments in which VCM was administered by gavage or by inhalation. In long term inhalation studies, a total metabolized dose of 5 x I05 fig is equivalent to about 200 ppm adminis tered over 52 weeks and represents a practical thresh old for this series of experiments. In conclusion there is a wide variation in the estimates of dose for a I0~` lifetime risk. This vari ation is due to the type of mathematical model that is applied, to the assumptions that arc made and to the particular experiment that is used to provide data for the extrapolation. A high level of confidence cannot be placed on low-dose extrapolations when variables that would not be expected to alter the expression of risk have a profound effect on the estimated risk. In addition, the interspecies extrapo lation from experimental animals to man is largely intuitive. It is clear that estimates of risk should take into account all available data, including epi demiology, to provide a degree of reliability. Risk assessment from human studies Register of ASL cases Since 1974, lists of reported ASL cases attributable to VCM exposure in the VCM/PVC industry have been kept by NIOSH (Spirtas & Kaminski, 1978), by IARC and by the VCM Committee of the Association of Plastics Manufacturers in Europe (APME). Details of 99 cases in the APME register at Tibia II. Clustering of ASL cates in individual PVC pUnu Plant* no. i 2 3 4 1 2 J 1 2 1 1 1 2 3 1 1 1 Country Western Emope Weal Germany Weal Germany Weat Germany West Germany France France France UK UK Sweden North America Canada USA USA USA RtatofWotM Japan Yugoslavia Czechoslovakia No. of ASL cases Total... Total.,. 10 4 2 2 3 5 2 J 2 J 42 10 II 9 4 34 2 4 2 Total... s 'For the purposes of this case study, ii ii not neceagary to identify the precise ownership and locauon of Ibex plants. the end of 1982 have been analysed by country and by manufacturing company and plant. The cases have been recorded from all major VCM/PVC manu facturing countries (Table 10), but the incidence has not necessarily been in proportion to the PVC pro duction capacity now or prior to 1962. In the absence of data on the number of workers employed, pro duction capacity is the only available indication of the numbers of people potentially exposed. The majority of the ASL cases are PVC autoclave cleaners or men who have worked in or around autoclaves. There are ASL cases among men who manufactured VCM and a few cases were involved both with monomer and with polymer production. Only one case suffered from both acro-osteolysis and ASL. The ASL cases tended to occur in larger numbers in some plants than in others (Table 11). Of the total of 39 ASL cases recorded in North America, 34 have occurred at four PVC plants, while over 40 Table 10. Distribution of ASL caata by country Country No. of ASL cases USA West Germany France Canada UK Sweden Yugoslavia Italy Czechoslovakia Japan Beltlum Norway Total... Western Europe North America Rett of World Total... 29 21 14 10 7 3 4 3 2 2 1 1 99 32 39 I 99 PVC production nameplate capacity (kiloionnes/yr) 1932 1962 1972 193 704 2090 22 260 1133 11 176 627 3 22 S8 27 177 302 3 20 103 3 1 60 9 212 778 1 23 48 12 3*4 1699 3 23 193 2 20 65 12 931 3930 19S 726 2178 31 709 3334 331 23S6 9462 ASL - Angiosarcoma of the liver OCC 1356 Vinyl chloride--risk assessment Tsble 12. ASL cue numbers by year of death and geographical location (eaduding ITOI*) Ye*r death Western Europe ASL cases! in: North America Rett of world Key publications 1955 6 7 8 9 I960 1 2 3 4 5 6 7 8 9 1970 1 2 3 4 i 6 7 8 9 1980 1 Cl C2 US8 C3 US5 FI Gl Swl G2 Nl, Sw2, UKI, It2 G3t G4, G5, UK3 F2, F3. G6. G7, G8, ItJ Bl. F4, F5. F6, F7, Sw3 F8, F9, GIO, Gil. GI2, Sw4 F10, F1I.G9, GI3, GI5, Git. GI7 FI2. FI3. UK4, UK3, GI8 UK6. UK7, GI9. SwJ, G20, G2I It4, FI4. UK8. G22 C4, CJ, US4, US7. US 10 US 12. USX USII C6. US2 a C8, USI, US3, US23 C9, US 13 US6, US9, US 18, US26 US 19, US20, US22 CIO, US2I. US24J US27, US28 US 17, US29, US30. US32 Cz2 Yl, Y2, Czl Japl Jap2, Y3 Y4 Viola Malloni Creech A Johnson Total.. 32 38| 8 ASL -- Angiosarcoma of the liver Italian cue 01 wu not a typical ASL; hit primary tumour wu probably of the pericardium. This man was eniaicd in extrusion of PVC sacks. tB - Belgium, C*W. Germany; Sw - Sweden; C - Canada; It - Italy; UK - United Kingdom; Cl Czechoslovakia; Jap - Japan: Y - Yugoslavia; F -- France; N - Norway, US - USA. Thus G9 - case no. 9 in West Germany. Cases UK2. GI4, US14, US15 and US2S were shown not to be associated with VCM exposure and hence withdrawn from the list. {Aerosol can filler. {Cholangiosareoma. I Does not include US3I (still alive). 197 North American PVC plants have not recorded an ASL case so far. The average latent period between starting work in an occupation involving VCM exposure and death from ASL for the 99 cases is 21.9 years (in France, Sweden and the USA between 24 and 25 years, in Germany about 18 years). It is still too early to predict whether the annual number of ASL cases amongst VCM workers has reached a peak. ASL cases appeared earlier in North America than in Western Europe and while the occurrence is tending to decrease in North America (Table 12), it is still high in Western Europe. On the basis of the data in this case register, it is possible to draw certain conclusions about risk fac tors associated with ASL. The large number of ASL cases in some factories and the absence of ASL cases in others of similar age indicates that variations in manufacturing practices between factories may be the cause. These variations may reflect both differences in the types ofjob carried out by individual workers and differences in engineering practices. The bulk of the cases have occurred, however, in highly exposed autoclave cleaners, with relatively few in other PVC or VCM production jobs. So far no wellauthenticated cases have occurred in PVC com pounding or fabrication where many more people have been exposed but to a much lovyer dose. Prediction offuture ASL cases as a consequence of pre-1974 exposure The causal relationship between VCM and ASL is proved beyond doubt by the specificity of the tu mour, the high relative incidence of that tumour in highly exposed workers, the consistency of the excess in different parts of the world, the time relationship between exposure and diagnosis and the doseresponse relationship. An intensive analysis of the pre-1974 cohorts should establish the dose-response curve for ASL after VCM exposure and predict the likely outcome for the future. It will be impossible to collect a complete data set on which to calculate risks of ASL for the whole world, but within a single company there may be closer definition of the cohort, the number of cases and the pattern of exposure. Using these data and averaging across the worldwide population exposed to VCM, it is possible to calculate the future inci dence of ASL using relatively crude assumptions which can only be tested in time when the prediction can be judged against the final outcome. OCC 1357 198 I. F. H. PimcHAffi tt at. Table 13, ASL cue numbert by year of lint exposure and geographical location (excluding ITOI*) Year of flnt expoture Weitem Europe ASL caaeat in: North America Rett of world Key events 1939 40 1 Frll 2 3 FrU 4 UKI s Sw2 6 Frl. Fr3, Sw4 7 Sw3 8 Fr9 9 Frl2, Fr4 1930 Fr7, Nl, UK8 1 Swl. UK5 2 G3 3 G1S, It] 4 G7, G8. UK4. GI9 s GII.GI6, GI8 6 FrIO. Gl 7 Fr8, G4. Il2, G2 8 Frf, Bl 9 Fr2, Ii4 I960 G5. GI3 1 G9, GI0, G12. GI7, G20, G22 2 G6, UK6, G2I 3 Frl 3. UK7 4 SwJ s Fr5 6 UK3 7 S 9 1970 1 2 3 Total... 32 US24J C3, US27 US 13, US29 C2, US19 Cl, CS, US5. US7, US28 C4. US3, US9 C7, C9, US8, USU, US2I, US3I{ C6, US22, US26 USI USI2 USI6 US 10, US32 US4 CIO USI8 US2, US17, US20 US23 Y2. Ci2 Japl, Yl Y3 Czl Jap2, Y4 C8 US6 US30 39 1 Viola Maltoni ASL - Angiotarcoma of the liter ItOl it not coniiatent with other ASL cu; the primary tumour may have been of the pericardium. The man extruded PVC ucki IFor explanatory key, ee Table 12. {Cholanfiotartoma. IUS3I i> mil aUve. (Aerowl can filler. The data required are: (1) Annual populations of employees classified by age; (2) Annual exposure estimates for each person in (1); (3) An exposure-response latency model for ASL induced by VCM. The data under item (1) are available in the UK as a result of the data extracted from the relevant occupational records (Fox Sl Collier, 1977). Exposure data for item (2) are more difficult to obtain, but can be gleaned from the records that are used to define the occupational population. The problem of oc cupation changing, which occurred frequently, has been dealt with by using the principal employment category or the highest exposed employment cate gory, The estimation of time-weighted average ex posures for the least exposed employees is straight forward, as the exposures were essentially continuous and constant, but for autoclave cleaners, mainte nance workers and laboratory workers, exposures could vary, from zero to near narcotic levels. In the calculations described below, it has been possible to avoid using the exposure data directly by relying on the similarity in exposure levels in differing locations. The exposure/response/latency data indicated under item (3) can be derived from established cases. The key data for these procedures are the set of cases worldwide, together with the descriptive data (Tables 12-14). It has been possible to calculate an incidence rate for each latency period for each ex posure level for each age group (on the basis of the UK data and assuming that it is representative of the worldwide population) and to use these rates to derive a simple model of dose-response latency that can be applied to the population data. The broad conclusions are that most cases have a latency of about 20 years and cases will continue to occur for the next 10 years. In the calculation used to estimate the future number of ASL cases (Table IS) an assumption has been made that when exposures were reduced to low levels, the future risk of ASL became negligible. Two dates at which the negligible risk levels were attained have been selected: 1964, when levels were reduced to hundreds of ppm and 1974 when the levels were reduced to below 10 ppm following the discovery of OCC 1358 Vinyl chloride--risk assessment Table 14. Annual incidence of ASL cssq (date of death) by geographical area No. of ASL cases dying in: Year Western North Europe America Rest of world Annual total Cumulative total Key events 1955 7 1961 2 4 7 8 9 1970 1 2 3 4 5 6 7 8 9 1980 1 2t Total... i1 i1 i1 i1 i 12 11 55 12 3 l1 2 12 3 41 5 14 3 8 32 5 64 1 II 63 2 II 63 9 72 1 to 55 64 4 10 4 00 0 0 S2t 38* 8 . 98* 1 2 3 4 6 7 12 IS 17 Viola 20 25 33 Maltoni 38 Goodrich 49 60 69 79 84 94 98 98* ASL - Angjotarcom* of the liver 'Does not include US3I (still alive in 1982). |At time of compilation. Jlncludes 003 (aerosol can filler) but omits ItOI (bag extruder). 199 the association between ASL and VCM exposure. A hypothetical exposed population of 100,000 has been used, but this is unimportant (see (a) below). An estimate or the age distribution within the hypothet ical `total' exposed population of 100,000 has been based on UK data (Fox & Collier, 1977). For persons already exposed during the whole of the various latent periods, the numbers with a latency of 30 years or more form only a small proportion of the total. The numbers of persons at risk in the future are calculated by advancing time in 3-year periods taking account of the age-dependent death rates in the population at large. Death rates for an intermediate year for the male population of England and Wales have been used in this calculation and the future cases (column 10) have been obtained by multiplication. The incidence figures for long latent periods (>25 years) are unreliable or non-existent but those for latencies of 15-25 years are fairly constant and values of 0.3 and 0.8 cases/1000 persons have been used for all latency periods over 15 years to calculate the expected number of cases for the 1964 and 1974 assumptions. The calculation is unrealistic in many respects but the simplifications are unlikely to afreet the estimate of future cases by more than a small factor. For example: (a) The population size used for the calculation ' is probably larger than the exposed population, but the calculation depends on the ratio of "person-years to come" and "person-years ex perienced" and this ratio is the same for any population size. (b) Exposure level has been ignored. The calcu lations are based on the overall risk to the cohort and although the incidence figures for sub-cohorts could be higher, the estimate of future cases will change very little. Similarly duration of exposure has been ignored. Table 15. Hypothetic*! calculation of future ASL case* using two different assumptions about the date at which the levels became free of risk ____________ Calculations assuming no risk after 1964 Calculations assuming no risk after 1974 Latency W 1-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 5116- Cases to date 0 1 II 21 28 18 6 6 0 0 0 Person* at risk to date 100,000 98.250 95.500 84,750 61.400 36,750 21.250 6750 600 0 0 5-yr incidence 0.00 . 0.01 0.12 0.33 0.46 0.49 0.28 0.89 7 0.50 Future persons at risk 0 0 0 6750 24.550 41,750 48.100 51,750 45.750 34,500 47,600 300.750 Future cases 0 0 0 2 II 20 13 46 7 7 7 150 Persons at risk to date 100.000 94,500 78,000 46,500 28,750 18,750 10.850 3500 310 0 0 S-yr incidence 0.00 0.01 0.14 0.60 0.97 0.96 0.55 1.71 7 7 * 0.80 Future persons at risk 0 3750 17.500 45.000 57.200 59,750 58,500 55.000 46.350 34.500 47,600 403,900 Future cases 0 0 2 27 57 57 32 94 ? ? 323 For details of the assumptions and methods see text (pp. 197 * 191). OCC 200 I. F. H. Purchase et al. (c) The UK is not typical of the worldwide growth in the exposed population. (d) No account has been taken of plant im provements occurring prior to 1964 and hence fewer cases may occur in, for example, the 1980-2000 period than are estimated from the 1940-1980 experience, An assumption that the risk of ASL ceased in 1964 rather than in 1974 results in a considerable reduction in the estimate of future cases. For either assumption, the number of new cases observed annually should soon begin to decline and the rate of decline will indicate which assumption is nearer to the truth. There have been two other predictions of the number of cases of ASL likely to result from previous exposure to VCM. Nicholson et al. (1984) suggest that there will be a further 1500 cases of ASL, while Forman et al. (1986) conclude that a further 150-200 deaths might be expected over the next 30 years. Our estimates rely on a more sophisticated model than the latter estimate and on a larger data set than the former. Nevertheless, the conclusions of Forman et al. (1986) are similar to ours. Only the experience of the next few years will show which is the best estimate. Summary and conclusions There is little doubt that exposure to high levels of VCM as a consequence of occupation can result in an increased incidence of ASL. A review of 20 epi demiological studies involving about 45,000 workers occupationally exposed to VCM showed that neo plasms of the liver showed an increase in incidence in the majority of studies. For brain cancer the associ ation between exposure to VCM and an increased incidence was less clear because of the lower relative risk. Neoplasms of the respiratory tract, digestive system, lymphatic tnd haemopoietic system, buccal cavity and pharynx, cardiovascular system and colon/stomach were reported to show an increased incidence in one or more studies, but to show no increase, or in some cases a decrease, in incidence in other studies. In view of the increased incidence of breast neoplasms in rodents exposed to VCM, the studies of Chaizzc et al. (1980), who did not confirm these findings in humans, are of importance. The register of ASL cases now contains records of 99 persons with confirmed ASL and occupational exposure to VCM. The average latent period between first exposure to VCM and death from ASL is 21.9 years. The majority of cases occurred in autoclave workers, who are recognized as having been exposed to extremely high levels. Although precise estimates of exposure are not available for the periods of most interest, the pattern of cases roughly suggests that extremely high exposures were necessary for the induction of ASL. For example, ASL cases tended to occur in larger numbers in some plants than in others, a finding that can be explained most easily by differences in exposure patterns. There is an extensive series of animal studies on the carcinogenicity.of VCM. Some of these precede the epidemiological studies confirming the association between VCM exposure and ASL in man. ASL and neoplasms of a number of other organs have been induced in laboratory rodents by VCM. Estimation of the exposure levels likely to cause a lifetime risk of ASL of 10'* on the basis of these data give extremely low levels (down to 3.9 x 10'1 ppb) which appear to be unrealistic estimates for man. Part of the reason for this is that laboratory studies have shown that VCM is metabolized in the liver (and elsewhere in the body) to the reactive metabolites chloroethylene ox ide and chloroacetaldehyde. The rate of conversion, is limited at high levels of exposure giving inaccurate estimates of the slope of the dose-response re lationship. It has not been possible to estimate the rate of conversion in man, and hence extrapolation of these low-risk dose estimates is conjectural. The second part of the problem of extrapolation at low risk is the selection of the most suitable mathematical model for extrapolation. Using Maltoni's data from rats (Maltoni et al. 1981), there is a substantial range (up to 10') of low-risk dose estimates, depending on the mathematical model and the assumptions used in applying the models. Using the same (probit and log-dose) model and different sub-sets of experi mental data, a large range of estimates is again obtained, even after correction for the non-linear kinetics of metabolism at high dose (which reduces this range to about I01). Larger differences are obtained with calculations using the Weibull analysis as a basis of low-dose estimation, suggesting that this is a problem with the use of mathematical models rather than one associated with the log-probit anal ysis. Although there was considerable variability in the dose-response relationship in the different experi ments reported, in all cases a total metabolized dose of 5 x 10!/j? (equivalent to inhalation of 200 ppm) was required to produce an elevation in ASL inci dence. This dose represents a practical threshold in rodents. At this stage in their development, mathe matical models for low-risk dose estimates are not sufficiently reliable or reproducible to engender confidence in their use. , Using negative epidemiological studies of popu lations living in the vicinity of VCM production facilities, an estimate of the dose for a 10'* lifetime risk in man may be made (Barr, 1982). The value (100 ppb) is similar to the highest estimates derived from animal data and taking biotransformation data into account, is substantially larger than the lowest estimates, which are up to 1010 lower (3.9 x 10*' ppb using a multi-hit model). The higher estimates are compatible with occupational experi ence and suggest that the current hygiene standard of around 1 ppm is sufficiently low to protect the health of VCM/PVC workers. The estimates also give a considerable safety factor for the general public consuming PVC-packed food and drink or living near VCM/PVC facilities. It has been possible to provide a crude estimate of the number of cases of ASL that may occur in the future from exposure to VCM prior to 1974. Using the age structure of employees in one company, the total number of cases of ASL reported to dale and the mortality pattern expected from a normal popu lation, the possible future number of ASL cases has been estimated as in the region of 150-300. OCC 1360 Vinyl chloride--risk assessment 201 Acknowledgements--We thank Dr M. Thomas for his help with the calculations and Dr D. M. Conning Tor his help with the manuscript. REFERENCES ACGIH--American Conference of Governmental Indus trial Hygienists (1974). Threshold Limit Values for Chem ical Substances and Physical Agents in the Workroom Environment with Intended Changes for 1974. ACGIH, Cincinnati, OH. Anderson M. W., Hoel D. G. It Kaplan N. L. (1980). A general scheme for the incorporation of pharmacokinetics in low-dose risk estimation for chemical carcinogenesis: example--vinyl chloride. Toxic, appl. Pharmac. 55, 154. Barnes A. W. (1976). Vinyl chloride and the production of PVC. Proc. R. Soc. Med. 69, 277. Barr 1. T. (1982). Risk assessment for vinyl chloride in perspective. Presented at the 75th Annual Meeting of the Air Pollution Control Association, New Orleans, USA, June 1982. Beaumont J. J. St Breslow N. E. (1981). Power consid erations in epidemiologic studies of vinyl chloride work ers. Am. J. Epidem. 114, 725. Bertazri P. A., Villa A., Foa V., Saia B,, Febri L., Mapp C., Marcer C.. Manno M., Marchi M. St Bottasso F. M. (1979). An epidemiological study of vinyl chloride ex posed workers in Italy. Archo higrada toxicol. 30, 379. Buffer P. A., Wood S., Eifler C., Suarez L. St Kilian D. J. (1979). Mortality experience of workers in a vinyl chloride monomer production plant. J. occup. Med. 21, 195. Byren D., Enghol G.. Englund A. St Westerholm P. (1976). Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Envir. Hlth Perspect. 17, 167. Carlborg F. W. (1981). Dose-response functions in carcino genesis and the Weibull model. Fd Cosmel. Toxicol. 19, 255. Chiazze L. St Ference L. D. (1981). Mortality among PVC-fabricating employees. Envir. Hlth Perspect. 41,137. Chiazze L.. Warg O., Nichols W. E. St Ference L. D. (1980). Breast cancer mortality among PVC fabricators. J. occup. Med. 22, 677. Conference to Reevaluate the Toxicity of Vinyl Chloride Monomer, Poly(vinyl Chloride) and Structural Analogs (1981). Conference sponsored by N1EHS/NIOSH/OSHA at NIH, Bethesda, March 1980. Envir. Hlth Perspect, 1981, 41, 1-231. Cook W. A.. Grever P. M., Dinman B. D. St Magnuson H. J. (1971). Occupational acro-osteolysis II. An indus trial hygiene study. Archs envir. Hlth 22, 74. Cooper W. C. (1981). Epidemiological study of vinyl chlo ride workers: mortality through December 31, 1972. Envir. Hlth Perspect. 41, 101. Creech J. L. & Johnson M. N. (1974). Angiosarcoma of the liver in the manufacture of PVC. J. occup. Med. 16, 150. Crump K. S. St Guess H. A. (1980). Drinking Water and Cancer. Report no. PB81-I28I67. NTIS, Washington. Duck B. W,, Carter J. T. St Combes E. J. (1975). Mortality study of workers in a polyvinyl chloride production plant. Lancet U, 1197. EPA (1980). Ambient Water Quality Criteria for Vinyl Chloride. Environmental Protection Agency Report, EPA 440/5-80-078 (October). Feron V. J.. Hendriksen C. F. M., Speck A. J., Til H. P. St Spit B. J. (1981). Lifespan oral toxicity study of vinyl chloride in rats. Fd Cosmet. Toxicol. 19, 317. Filatova V. S., Antonyuzhenko V. A., Smulevich V. B., Fedotova I. V., Kryzhanovskaya N. A., Bochkareva T. V., Goryacheva L. A. St Bul-bulyan M. A. (1982). The blastomogenic hazard of vinyl chloride (a clinico-hygiene and epidemiological study). Gig. Truda prof. Zabol. 26 (I), 28. Food Safety Council (1980). Proposed System for Food Safety Assessment. Final Report. FSC, Washington, DC. (Also in Fd Cosmet. Toxicol. 1980, 18, 711J. Forman D., Bennett B., Stafford J. St Doll R. (1986). Vinyl chloride and angiosarcoma of the liver--a report of the register of cases. Br. J. ind. Med. 42, 750. Fox A. J. St Collier P. F. (1977), Mortality experience of workers exposed to vinyl chloride monomer in the manu facture of polyvinyl chloride in Great Britain. Br. J. Ind. Med. 34, I. Fretzel-Beyme R., Schmitz T. St Thiess A.M. (1978). Mortalitatsstudie bci VC/PVC Arbciteme der BASF. Aktiengesellschaft, Ludwigshafen am Rhein. Arbeitsmed. Sozialmed. Preventivmed. 13, 218. Gauvain S. (1976). Vinyl chloride. Proc. R. Soc. Med. 69, 275. Gaylor D. W. St Kodell R. L. (1980). Linear interpolation algorithm for low-dose risk assessment of toxic sub stances. J. envir. Path. Toxicol. 4, 305. Gehring P. J,, Watanabe P. G. St Park C. N. (1978). Resolution of dose-response toxicity data for chemicals requiring metabolic activation: example--vinyl chloride. Toxic, appl. Pharmac. 44, 581. Gehring P. J., Watanabe P. G. St Park C. N. (1979). Risk of angiosarcoma in workers exposed to vinyl chloride as predicted from studies in rats. Toxic, appl. Pharmac. 49, 15. Green T. St Hathway D. E. (1975). The biological fate in rats of vinyl chloride in relation to its oncogenicity. Chemico -Biol. Interactions 11, 545. Green T. St Hathway D. E. (1977), The chemistry and biogenesis of the S-containing metabolites of vinyl chlo ride in rats. Chemico-Biol. Interactions 17, 137. Harris D. K. & Adams W. G. F. (1967). Acro-osteolysis occurring in men engaged in the polymerisation of vinyl chloride. Br. med. J. 3, 712. IARC Working Group (1979). Monographs on the Evalu ation of the Carcinogenic Risk of Chemicals to Humans. Vol. 19. Some Monomers, Plasties and Synthetic Elas tomers and Acrolein, p. 377. International Agency for Research on Cancer, Lyon. Infante P. F. (1981). Observations of the site specific carcinogenicity of vinyl chloride to humans. Envir. Hlth Perspect. 41, 89. Kuzmack A. M. St McGaughy (1975). Quantitative Risk Assessment Tor Community Exposure to Vinyl Chloride. US EPA Report, 5 December. EPA, Washington, DC. Lee C. G, Bhandari J. C,, Winston J. M.. House W. B.. Dixoti R. C. St Woods J. S. (1978). Carcinogenicity of vinyl chloride and vinylidene chloride. J. Toxic, envir. Hlth 4, 15. Lester D., Greenberg L. A. St Adams W. R. (1963). Effects of single and repeated exposures of humans and rats to vinyl chloride. Am. ind. Hyg. Ass. J. 24, 265. Loprieno N., Bavale R,, Baroncelli S., Bartsch H., Brouzetti G., Gammellini A., Corsi C,, Freza D,, Nieri R., Leporini C,, Roscllini D. St Rossi A. M. (1977). Induction of gene mutagens and gene conversions by vinyl chloride metab olites in yeast. Cancer Res. 36, 253. Maltoni G, Lefemine G., Ciliberti A., Colti G. St Carretti D. (1980). Epidimiologie animate et ipidemiologie hu mane: le cas de chlorure de vinyl monomire. In XXe Riunion de Club de Canetrogenise Chimique. ISBN 2.86315.007.3. p. 15. Publications Essentielles, Paris. Maltoni C., Lefemine G.. Ciliberti A., Cotti G. A Carretti D. (1981). Carcinogenicity bioassays of vinyl chloride monomer a model of risk assessment on an experimental basis. Envir. Hlth Perspect. 41, 3. Maltoni C. & Rondinella R. (1980). Hepatic angiosarcoma in workers exposed to vinyl chloride in Italy. Acta Oncologica 1, 35 (in Italian). Meyerson L. B. & Meier G. C. (1972). Cutaneous lesions in acro-osteolysis. Archs Derm. 106, 224. F.C.T. JJ/l-F OCC 1361 202 I. F. H. PUXCHASE et at. Ministry of Agriculture, Fisheries end Food (1978). Survey of Vinyl Chloride Content of Polyvinyl Chloride for Food Contact and of Foods. HMSO, London. Monson R. R., Peters J. M, A Johnson M. N. (1974). Proportional mortality among vinyl chloride workers. Lancet U, 397. NAS (National Academy of Sciences) (1980). Drinking Water and Health. Vol. 3, p. 38. National Academy Press, Washington. Nicholson W. J,, Hammond E. C.. Seidman H. A Selikoff l. J. (1975). Mortality experience of a cohort of vinyl chloride/polyvinyl chloride workers, lancet 11, 1197. Nicholson W. J., Henneberger P. K. A TarT D. (1984). Trends in cancer mortality among workers in the synthetic polymers industry. In Industrial Hazards of Plastics and Synthetic Elastomers, p. 65. Alan R. Liss, New York. ORC (1976). Mortality data collected by ORC concerning the effects of vinyl chloride exposure in PVC fabrication. Cited by Barr (1982). Ott M. G., Langner R. R. A Holder B. H. (1975). Vinyl chloride exposure in a controlled industrial environment. Archs envir. Hlth 30, 333. Rannug V,, Gothe R. A Wachtmeister C. A. (1976). The mutagenicity of chloroethyiene oxide, chloroacetaldehyde, 2-chlorocthanol and chloroacetic acid, conceivable metabolites of vinyl chloride. Chemico-Biol. Interactions 21, 2SI. Rein! W. A Weber H. (1976). Stand der epidemiotogischen Forschung uber die Vinylchlorid-krankheit. Zentbl. ArbMed. ArbSchutz 26, 97. Reinl W., Weber H. A Greiser E. (1978). Epidemiology study of the mortality of workers exposed to vinyl chloride in FRG. Paper presented at the 19th Inter national Conference for Occupational Health. Dubrovnic, September. Schneiderman M. A., Mantel N. A Brown C. C. (1975). From mouse to man--or how to get from the laboratory to Park Avenue and 59th Street. Ann. N. Y. Acad. Sci. 246, 237. Selikoff I. J. (1975). Toxicity of vinyl chloride/polyvinyl chloride. Ann. H. Y. Acad. Sci. 246. Spinas R. A Kaminski R. (1978). Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. J. occup. Med. 20, 427. Suciu J,, Drejman I. A Valaskii M. (1963). Contributions to the study of disease by vinyl chloride. Med. Interna 15, 967 (in Italian). Szadkowski D. A Lehnert G. (1982), Vinylchlorid ats KrankheiMursacha. Eine Bibliographic. VKE, Frankfurt. Tabershaw J. R. A Gaffcy W. R. (1974), Monality study of workers in the manufacture of vinyl chloride and its polymers. J. occup. Med. 16, 509. Theriault G. (1982). Cancer monality of Canadian workers exposed to VCM: a three-year follow-up. J. occup. Med. 24, 730. Theriault G. A Allard P. (1981). Cancer monality of a group of Canadian workers exposed to vinyl chloride monomer. J. occup. Med. 23, 671. Torkelson T. R., Ogen F. A Rowe V. K. (1961). The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am. ind. Hyg. Ass. J. 22, 354. US DHEW--Depanment of Health, Education and Wel fare (1980). Selected abstracts on the carcinogenicity of VCM. DHEW, Washington. DC. Verburgt F. G. A Vogel E. (1977). Vinyl chloride muta genesis in Drosophila melanogaster. Mutation Res. 48,327. Viola P. L. (1969). Pathology of vinyl chloride. Proceedings of the 16th International Congress on Occupational Health, Tokyo. Watanabe P. G. A Gehring P. J. (1976). Dose-dependent fate of vinyl chloride and its possible relationship to oncogenicity in rats. Envir. Hlth Perspect. 17, 145. Waxweiler R. J.. Stringer W., Wagoner J. K., Jones J., Falk H. A Carter C. (1976). Neoplastic risk among workers exposed to vinyl chloride. Ann. N. Y. Acad. Sci. 271, 40. Weber H., Reinl W, A Grieser E. (1981). German in vestigations on morbidity and mortality of workers ex posed to vinyl chloride. Envir. Hlth Perspect. 41, 95. Wilson R. H,, McCormick W. E., Tatum C. F. A Creech J. L. (1967). Occupational acro-osteolysis. J. Am. med. Ass. 201, 577. OCC 1362