Document evXydekgZ6VapjBm3V7vzdDN9

`V rt CA*m. TVw/c. Vo], 25, No. 2, pp, 187-202, 1987 Printed in Great Britain. All rights reserved '/L -Q;7S.fi9l5 87 J3 00 + 0.00 Copyright \19S7 Fcrgamcn Journals 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, Alderles Park, Macclesfield, Cheshire, England (Received 14 December 1983; revisions received 13 January 1986) ** ^.`9' Introduction Vinyl chloride monomer (VCM), more properly named monochlorethane, is a'colourless gas normally handled under pressure as a liquid which boils at -- \4C,C 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 106 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 w'ere related to the compound's narcotic effect. Indeed there arc 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 el ill. 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, fire 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, 3OCM00 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 1. 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 = 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 walis. Some of these men developed acro-osteolysis (AOL; Cook et al. 1971; Harris & 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 & 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 IViola. 1969) failed to produce AOL but showed an increase in the incidence of tumours at various sites. Further studies (Maltoni etal. 1980 6; 1981;Ma!toni & Rondinella, 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 & Johnson. 1974) confirmed VCM as a human carcinogen. Other knowT. 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 & 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 ASX 00005580 I 188 1. F. H. Purchase ci al Table I. Lowest concentrations or doses at which a significant excess of various tumour types was observed in rat carcinogenicity studies Tumour Forestomach papilloma Zymbal-gland carcinoma Neuroblastoma Nephroblastoma Liver angiosarcoma Mammary-gland adenocarcinoma Conen (ppm1 30.000 10,000 10.000 250 (female) 100 craiei . 200 50 5 (fer.alei Dose (mg/kg) 50 (male) 16.65 (female) Data from Maltom ft al. (I9SI). 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 test systems including Salmonella typhimurium (Rannug et al. 1976), Saccharomyces (Loprieno et al. 1977) and Drosophila (Verburgt & Vogel, 1977), usually 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 cl. 1981; Lee et al. 1978) tend to conhrm. 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 50 ppm or less, exposures similar to those believed to have occurred on manufacturing plants (Barnes, 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 ASI 00005581 f 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 0.1 pg/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 et 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 assessment from experimental animal data After administration by gaxage or inhalation, part of the dose is exhaled unchanged and the remainder is excreted or retained in the carcass. A general scheme Gly 1 1 C=0 Glu / / ( HCHjSCHjCH, 1 1` NH OH 1 1 Glu U) \V, 1i f=0 1 CHCH.SCH.CO,H 1 NH 1 1 Giu 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. co2h CHCHjSCHjCHj 11 NH (Ac) OH fe) C'C.t I' '1 IHf.H.SCH.COjH 1 \H, (: t C0,H C -- CHjSCH:CO.H II 0 S(CH.COjH)j t (st Fig. 1. Scheme showing the metabolism of vinyl chloride monomer (VCM) in rats to S-containing metabolites. VCM (a) is converted to chloroethylene oxide (b) which is trans formed spontaneously to chloroacetaldehyde (c). These two metabolites are mutagenic and hence are considered to be the proximate carcinogens. The urinary excretion products #-acetyl-S-(2-hydroxyethyl)cysieine (e) 5'-(carboxymcthyi)cysteine (f) and thiodiglycollic 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)]. ? i, $ ;r i 2> -; y(H> o o o 0 01 yi go (*) i Referenee Momon rf rif. (1974) Tabcrshaw A Galley (1974) Duck rial. (1975) Nicholson rial. (1975) Oil el at. (1975) Byrcn et ul. (1976) Otic (1976) Reinl A Weber, 1976; Rein! et at. I97H; Weber ft at. 19(11 Wuxwcilcr r/ ttf. (1976) Fox & Collier (1977) Frdrel-Beyme et a!. (1978) Rcrliizxi rt at. (1979) UuIRcr ft al. (1979) Cliia/zc A FerencC (1981) Chiuzxc el al. (19S0) Dcuumont & Brtslow (1981) Table 2. Fpidcmiulogicaf si u< lies of cancel associated with exposure lo vinyl chloride monomer No. in study* (*/ follow up) I ue lease Sites (or liumnirs} with changes in SMR No mcicasr Comments 7 8384 (85%) Ihaiil Lung Liver, including ASL tluccal cavity and pharynx Respiratory system Unknown site Lymphoma Angiosarcoma 2170 257(99%) 594 (99%) 771 (97%) 10.173 (95%) 11,02K (90%) 1151 7409 (99%) None A SI. All tumours? Livcr/pancrcas Cerebral? Cardiovascular Digestive tract Malignant liver Lymphatic system til tract Brain Respiratory tract Lymphatic system ASL Primary liver ASL 1618(95%) 5441 (86%) 464 (100%) 3847 Colon/stomach Proslatic hyperplasia All tumours Respiratory system Digest ive system Liver Drain Genital Digestive organs Urinary tract Leukaemia Drain Stomach Drain Lymphatic and hucmopoictic system llreusl Respiratory tract Significant SMIt not significant but increases with exposure and time Some criticism of cotulucl of xludy Arscnicals involved Significant increase (2 ASL) Incie.isc not significant PMK sludy Related to duration of exposure Mixed exposure, not VCM rvhlH-ll Not significant Significant PMR study of female and male fabricators Increase in PMR not confirmed by case-conl rolled study Review of nine studies i K ti 213 2 % t 7o hp UX i5Z. a .- >S A fi 22 frV8-S jC t=! c j.Ss tO.SS ! t> g5 * CL'S > t T? c, ? eS* -QSEda j -tS5 ox I Vinyl chloride--risk assessment 191 Vi i c 4^ II o o 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 chloroethvlene 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 l4C-labelled VCM by gavage at doses between 0.5 and 100 mg/kg to YVistar rats, the amount of |JC 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 ,4C-tabelled 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 (Vm in pg metabolized 6 hr) and the Michaelis constant (Km in /tg VCM/litre air) accord ing to the formula: V =5 V,,S m K-u + S (where V = velocity of metabolism in /ig.6hr and S = concentration of VCM being ir.haled) were Vm = 8558/jg metabolized'6 hr and K._ = 860/rg VCM/litre air. Thus there was a considerable change in the ratio of administered dose to metabolized dose as the exposure concentration increased (Table 3). At the higher doses a smaller proportion of VCM was metabolized than at low doses. 0 c *: <u i5S J(A XB <c rt & u s Review of earlier calculations of risk There have been a number of attempts to calculate the risk of ASL development on the basis of extrap 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 10~6 lifetime risk, from parts per billion to in excess of one part per million. A further refinement of the technique using DNA binding as the measure of dosimetry (Anderson et al. 1980) provided a similar estimate of the exposure. A variety of mathematical models can be used for extrapolating below the experimental dose range, and 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 ASI 00005584 192 I. F. H. Purchase et al. Tabic 3. Vinyl chloride dose and incidence of hepatic angiosarcoma in Sprague-Dawley rats exposed on 5 days/wk for 52 wk* Concn (ppm) Amount metabolized pg/4 hr et <totit) Angiosarcoma incident* (%) Male Female Mean Expmt no. 30.000 10,000 6000 2500 500 250 200 150 100 50 25 10 5 1 0 5647 5521 5403 5030 3413 2435 2129 1761 1309 739 395 169 84 17 0 1.47* 10* 1.44* 10* 1.41 * 10* 1.3 * 10* 8.8 * 10* 6,3 * I0! 5.5 * 101 4.6 * I0! 3.4 x 10* 1 9 * 10s 1.0* I0J 4.4 * 10* 2.2 x 10* 4.4 x 10* 0 16,6 10.0 10.3 20.0 0 3.4 11.7 1.7 0 1.1 1.7 0 0 0 0 43.3 13.3 33.3 23.3 20.0 6.7 8.3 8.3 1.7 7.2 67 1.7 0 0 0 30.0 11.7 22.0 21.7 10.0 5.1 too 50 0.8 42 4.2 0.8 0 0 0 BT6T BT I BT 1 BT 1 BT 1 BT 1 BT2 BT2 BT2 BR 1,9 BT 15 BT 15 BT IS BT 15 BTI.2. 9.15 'After Maltonj et al. (1981). f Experiment BT 6 ended after only 68 wk, while the rest were all approximately 140 wk; therefore the percentage of tumours in BT 6 is probably low relative to the rest because of the short latency period asailable. multistage model by the Food Safety Council (1980) and by Gaylor & Kodell (1980) showed that for the same 10~B lifetime risk, the Food Safety Council estimated the dose as 2 x KT:ppm whereas Gaylor & Kodell estimated the dose as 5 x 10"4ppm. 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"6 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 10'6 risk from a variety of experimental animal data applying the correction for metabolism used by Gehring et at. (1979). Calculation of exposure for I0~( 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 Table 4. Summary of quantitative risk assessments for vinyl chlondc monomer* Reference Species Exposure for 10"* lifetime risk (ppbt) Comments Schneiderman et cl. (19?5) Rat Kuzmaek & McGaughy (1975) Gthrir.g el al. (1979) Food Safer/ Council (1980) Rat, man Rat, man Rat Rat Anderson el cl. (1980) Gaylor & Kodell (1980) Carlborg (1981) Barr (1982) This paper (Table 9) EPA (1980) NAS (1980) Crump &. Guess (1930) 'After Ban- (1982), tExcept where stated otherwise. Rat, man Rat Rat Man Rat Mouse Man Rat Mouse Man Rat Rat Man Rat By inhalation 73 119 2 14 140-1400 >1000 <10->I000 20 20 2.1 x JO"* 3.9* 10-' >1000 0.7 0.J 2.5 x 10-3 >100 0 025-9.16\ 2 x 10~13 / 0.63-90 2 x I0"3-2 x 10"* 6 x 10-*3 0.067-8.14 By ingestion 4pg/dav 3 x 10"3mg/kg day 0.7 pg'day 0 5 pg'day Probit (slope -- 1, Mantel) Logit (slope - 3.45) Logil (slope " 2.3, one-hit) Linear through zero Log-probit Biotransformaiion data included Linear or log*probit Depends on mathematical model used One-bit Armitage-Doll Wetbull Multi-hit DNA binding used for dosimetry Upper 97.5% confidence limit of linear model Armitage-Doll Weibull Derived from Barr's negative epidemiology Log-probit Log-probit including biotransformaiion data for man Weibull Weibull mdudme biotransformaiion for man Food or uater Water Applying worker data to water Upper 95% confidence limits 00005&85 Vinyl chloride--risk assessment 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 (Gehring 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 t,, 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 Vm and Km values derived for Sprague-Dawley rats have been used. In the experiments by Feron et al. (1981), who used Wistar rats, the same assumptions about Vm and K3 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 Watanabc & 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 Vn 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 5 days wk for 52 wk Concn (ppm) Amount metabolized -- - Angiosarcoma /is 4 hr fig (total) incidence (Vo) Expmt no. 10,000 6000 2500 500 250 50 1 0 5521 5403 5030 3-H3 2435 759 P 0 1.4 x 10* 1.4 x 10' 1.3 x 10f 8.8 x 306.3 x 10* 1.9 x Hf 4,4 x IQ-1 0 29.6 11.5 12.0 10.7 3.7 0 0 0 BT 7 BT 7 BT 7 BT 7 BT 7 BT7 BT 17 BT 7, 1' Table 6, \ :n\ I chloride (VCM) dose and incidence of hepatic angiosarcoma in rats given VCM b> 2 age or ingestion Dose <m| Amount exhaled* (*/* of dose) Amount metabolized do*e+ tig (total! Angiosarcoma incidence (/o) Male Female Mean Expmt no. so: 16 65 5 55 1.0 03 0.03 0 300 14 l* 5.0 1.7 0 50 35 10 2 \1 1.4 -- 80 32 16.5 2 69 6250 2^05 750 3245 74 7.4 0 15.000 2390 1040 420 0 1 6 x 10' 70 x 10: 2.0 x I0f 7.26 x 10` 2.16 x 101 2.16 x 10: 0 6-2 x 10* 1.65 x 10` 7.25 x 10! 2.9 x 103 0 20 10 0 1.3 0 0 0 49 49 10 0 0 22.5 15 1 0 2.7 1,4 0 0 53 16 4 0 0 21.2 12.5 0 2.0 0.7 0 0 51' 32 7 0 oj BT 11 BT 11 BT 11 BT27 BT 27 BT 27 BT 11, 27 Feron rr al. (1981) 'Calculated from data derived from Watanabc & Gehring (1976) presented in Fig 2. tAssummg a 250-g rat. fSprague-Dawley rati dosed by gavage with VCM in corn oil S limes/wk for S2 wk, {BT27 dosed for S9 wk. (Wistar rats used as controls by Feron et at, (1981) and dosed for 83 wk. ^Wistar rats receiving a diet containing VCM dissolved in PVC. ASI 00005586 r ? 194 1. F. H. Purchase el al. Tabic 7. Vinyl chlonde dose and incidence of hepatic angiosarcoma in mice Concn (ppm) Amount metabolized jig4 hr jig (total) Angiosarcoma incidence (%) Male Female Mean Expmt no. 10.000 6000 2500 1000 500 250 250 50 1 0 11,245 11,007 10,246 8699 6952 4959 4959 1506 1506 0 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 10s 5.9 x 10' 0 38 6.7 20.7 39.4 20,0 30.0 24,0 3.3 10.3 0 30 36.7 33.3 50.0 26.7 30.0 47 0 0 0 0 17.8 21.7 27.1 44.7 23.3 30.0 36.5 1.7 5.2 0 BT 4* BT 4 BT 4 Lee e; at. t BT 4 BT 4 Lee ti all BT 4 Lee tl al * BT 4 & Lee ei al. Swiss mice, 81-wk experiment, dosed for 30 wk. +CD, mice, 52-wk experiment, 6 hr,day exposure (Lee et at." I97S). These results have not been included in the calculations fot Table 9 because the experimental design incorporated interim kills. Thus: 0.011 nr Vm (mouse)-V, (rat) x 0.011 = 576/tg:4hrx -- = 1395 /eg,4 hr The values of 0.045 m3 and 0.011 m: 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 VE for the mouse on a mass-equivalent basis is therefore: 1395 -- = 11625 /tg/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 analysts of the dose that would be expected to produce a lifetime risk of ASL of 10'6 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 10~1 ? ppb) but the difference is less for other expressions of dose. Similar calculations of the dose expected to give a 10*6 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 10~5 difference between the S values derived from Wistar and Sprague-Dawley rats). The doses for mice are 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 10-6 is given in Table 9 (S calculated for man). These calculations are based on a Vm for man of 1675 pg/8 hr based on corrections for body surface area and mass. The values are substan- Table 8 Vinyl chlonde (VCM) dose and hepatic angiosarcoma incidence in Sprague-Dawley rats exposed to VCM by inhalation Concn (ppm) Schedulet No. of doses Amount metaboliiedj ji g/4 hr jig (total) Angiosarcoma incidence (%) Male Female Mean no. 10.000 i 260 5521 1.4 x 10* 10 133 11.7 BT 1 10.000 ii 85 5521 4.7 x 10' 0 0 0 BT3 10.000 in 25 5521 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 5521 1.4 x 10' 0 1.7 08 BT 10 6000 i 260 5403 1.4 x 10* 10.3 33.3 22.0 BT I 6000 ii 85 5403 4.6 x 10' 0 3.3 1.7 BT 3 6000 in 25 5403- 1,4 x 10' 0 0 0 BT 10 6000 IV 100 1350 1.4 x 10' 3.4 1.7 2.5 BT 10 6000 V 25 5403 1.4 x 10' 0 1.7 0.8 BT 10 After Makoni r al. (1981). +Schedu!es; I--4hr'day* 5 dayswk for 52 wk; II--4hr/day, 5 days wk for 17 wk; III--4 hr/day, 5 days wk for 5 wk; IV--1 hr da>, 4 dayswk for 25 wk; V--4 hr/day, 1 day/wk for 25 wk. tAmount metabolized (v) in 4 hour derived from the formula; V (^g/hr) - Vn x S/K* + S where Vff is 4/6 of the 6 hr value. ASI 0o05587 ASX 0 0 0 0 5 5 8 8 Table 9. Quantitative risk estimations derived from available animal carcinogenicity data and expressed as the amount or concentration or vinyl chloride calcutalcd to give a lifetime risk of ASL of 10 1 cilhcr on the hasis of log-probit analysis or a Wcibull distribution Table no. Experimental data Exposure for rodents (S ppb*) Amounl mclabohicd in 6 hr by rodents (V /ig/6 hr) Total amounl metabolized by rodents (TM mg) Exposure fppb) calculated from V (S calculated for man)t 4 S D rals, inhalation 5 Wislar rats, male onfy, inhalation 6 Rats, ingestion--Wistar --S-D --bolh 71 Mice, inhalation 4, 5 Wislar and S D rals combined, inhalation 8 S-D rats, short-term inhalalion 4 S-D rats, inhalation Wislar rats, mate only, 5 inhalation 6 Rats, ingestion--Wistar --S-D --both( 71 Mire, in.Vil.itum 4,5 Wislar and S D rals combtned, inhalation, s S-D rats, short-term inhalation 0.025 I.ng-probit analysis] 1.23 9.1ft 3 x 10 ! mg/Vg 9 x IQ-'mg/ltg 6 x lO 'mg/kg 2 x 10 159 0.69 mg/dose 2.19 mg/dose l .70 mg/dose 0.60 0.038 -- 2 x 10 * 1.41 0.004 Wcibull distribution] 0.013 2 x 10 1 9 x 10-'`mg/kg 4 x 10~6mg/lsg 2x 10 "mgAg ft x 10 *' 15.7 3 x 10 mg/dose 0.33 mg/dose 0.005 mg/dosc 2x10' 6 x 10 ' -- o.o n: 3 x 10 0.305 39 3 2.27 0.2 0.S 0.0063 0.35 2.86 0.0032 3.68 0.0002 0.003 0.0015 2x10' 0.0042 0.19 0.63 90 -- 0.03 0_.72 0 067 8.14 1 x 10 ' 0 009 Except where staled otherwise. ASL = Angiosarcoma of the User S-D = Spraguc-Dawlcy tExposure calculated from V (in column 3) using the formula: S ~ V x *60/1675 -V, where Vw Tor man is 1675 jig/B hr. } Estimated using maximum likelihood. Wislar and S-D rals combined. ijShuly OT 4 only. < 5' o a 'COA 196 1. F. H. Purchase el 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 of 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 * 10'ftg 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 10'^ig is equivalent to about 200 ppm adminis tered oxer 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 10-6 lifetime risk. This vari ation is due to the type of mathematical model that is applied, to the assumptions that are 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 al! 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 IAR.C and by the VCM Committee of the Association of Plastics Manufacturers in Europe (APME). Details of 99 cases in the APME register at Table 11. Clustering of ASL cases in individual PVC plants Plant* no- Country No. of ASL cases Western Europe 1 West Germany 1 West Germany 3 West Germany 4 West Germany 1 France 2 France 3 France l UK 2 UK 1 Sweden North .America 1 Canada 1 USA 2 USA 3 USA Rest of World 1 Japan l Yugoslavia 1 Czechoslovakia Total. . Total . 10 4 2 2 5 s 2 5 5 42 10 U 9 4 34 2 4 Total... s For the purposes of this case study, it is not necessary to iJentify the precise ownership and location of these 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 Tabic 10. Distribution of ASL cases by country Country No. of ASL cases PVC production nameplate capacity (kilotonnes, yr) 1952 1962 1972 USA West Germany France Canada UK Sweden Yugoslavia Italv Czechoslovakia Japan Belgium Norway Total. .. 'Western Europe North America Rest of World Total... 29 21 14 10 7 5 4 3 2 2 1 1 99 52 39 8 99 193 704 2090 22 260 1155 11 176 627 5 22 88 27 177 502 3 20 105 3 8 60 9 212 778 1 25 48 12 384 1699 3 25 195 2 20 65 82 951 3950 198 726 2178 51 709 3334 331 2386 9462 ASL -- Angiosarcoma of the liver 00005589 ASl Vinyl chloride--risk assessment Tabic 12. ASL case numbers by year of death and geographical location (excluding ITOi*) Year of death Western Europe ASL casest in: North America Rest of world Key publications 1955 6 7 8 9 1960 1 2 3 4 5 6 7 8 9 1970 i 2 3 4 5 6 7 8 9 1980 1 Cl C2 US8 C3 US5 FI G1 Swl G2 Nl. Sw2, UK1, Il2 G3J G4, G5, UK3 F2, F3, G6, G7, G8, It3 Bl, F4. F5. F6, F7, Sw3 F8, F9, G10, Gil, GI2, Sw4 F10, Fll, G9, G13. G15, G16, G17 F12, F13, UK4, UK 5, G18 UK6, UK7, G19, Sw5. G20, G21 It4, F14, UK8, G22 C4, C5, US4, US7, US10 US 12, US16 US11 C6, US2 Cl C8. US1, US3, US23 C9, US 13 US6, US9, US18, US26 US 19, US20, US22 CIO, US21, US24| US27, US28 US 17, US29. US30. US32 Cz2 Yl, Y2, Czl Japl Jap2, Y3 Y4 Viola Maltoni Creech & Johnson Total.. 52 38,| 8 ASL =* Angiosarcoma of the liver 'Italian case 01 was not s typical ASL; his primary tumour was probably of the pericardium. This-man was engaged in extrusion of PVC sacks. +B = Belgium, G = W. Germany; Sw = Sweden; C " Canada: It = Italy. UK - United Kingdom; Cz = Czechoslovakia; Jap " Japan; Y = Yugoslavia; F ** France; N - Norway; US = USA. Thus G9 = case no. 9 in West Germany. Cases UK2, G14, US14, US 15 and US25 were shown not to be associated with VCM exposure and hence withdrawn from the list. J Aerosol can filler. jCholangiosarcoma. Docs not include US31 (still alive). Norlh 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 mthie types ofjob carried out by individual workers and iifjferences in engineering practices. The bulk of the S:ses 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 lower dose. Prediction of future 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. ASI 00005590 198 1. F. H. Purchase et al. Table 13. ASLease numbers by year of first exposure and geographical location (excluding IT01*) Year of first exposure Western Europe ASL cases* in: North America Rest of world Key events 1939 40 1 2 3 4 5 6 Frll Frl4 UK1 Sw2 Frl( Fr3* $w4 7 8 9 1950 1 2 3 4 < 6 7 8 9 i960 1 * 3 4 5 6 Sw3 Fr9 Frl2. Fr4 Fr7, Nl, UK8 Swl, UK5 G3 G15, It3 G7, G8. UK4, G19 Gil. G16. GI8 FrlO, G1 Fr8, G4. 1(2, G2 Fr6. B1 Fr2, 114 G5, G13 G9, GIO. GI2, G17. G20, G22 G6, UK6, G2I Frl3, UK7 S5 Fr5 UK3 US24J C3. US27 US13. US29 C2, US 19 Cl. C5. L'S5. US7, US28 C4, US3, US9 C7. C9. US8. USU.US21, US31 C6, US22. US26 US1 usi: US 16 USIO. US32 US4 CIO US1S US2. usr. US20 US23 YI, Cz2 Japl, Yl Y3 Czl Jp2, Y4 C8 US6 US30 8 9 1970 Viola 1 2 5 Maltoni Total... 52 39 8 ASL = Angiosarcoma of the liver MiOi is not consistent with other ASL cases; the primary tumour may have been of the pericardium. The mar. extruded PVC sacks. For explanatory key, see Table 12. 2Cho!angiosarcoma. jt'Sjl is still alive. Aerosol can filler. The data required are: (1) Annua! 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 & 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 cn 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 teat 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 15) an assumption has been made that when exposures were reduced to lowlevels, the future risk of ASL became negligible. Tw o 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 ASI 00005591 Vinyl chloride--risk assessment Table 14. Annual incidence of ASL cases (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 S 6 7 8 9 1980 1 2t Total... i i i 1 i 1 5 i2 i1 i2 41 i4 32 64 63 63 72 5 64 4 00 52: 38* 1i t2 i3 14 1 2' 6 17 5 12 3 15 2 17 Viola 3 20 5 25 3 8 33 Maltoni 5 38 Goodrich 1n 49 2 ii 60 9 69 1 10 79 5 84 10 94 4 98 00 8 98* 98* ASL -- Angiosarcoma of the liver 'Does not include US31 (still alive in 19S2). tAt time of compilation. {Includes G03 (aerosol can filler) but omits ItOl (bag extruder). 199 lie; association between ASL and VCM exposure. A hypothetical exposed population of 100.000 has been u=cd, but this is unimportant (see (a) below). An esdmaie of the age distribution within the hypothetloil `total' exposed population of 100,000 has been fcised on UK data (Fox & Collier, 1977). For persons aready exposed during the whole of the various ktent periods, the numbers with a latency of 30 years cv more form only a small proportion of the total. Tie numbers of persons at risk in the future are circulated by advancing time in 5-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. Tne incidence figures for long latent periods (>25 y;srs) are unreliable or non-existent but those for latencies of 15-25 years are fairly constant and values c-: 0.5 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 affect 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 incider.ee figures for sub-cohorts could be higher, the estimate of future cases will change very little. Similarly duration of exposure has been ignored. "i_rie If Hypoifce*..cal calculation of future ASL cases using two different assumptions about the date at which the Joels became free of nsk Calculations assuming no nsk after 1964 Calculations assuming no risk after 1974 LltCSC* Cases to date Persons at 5-yr risk to date incidence Future persons at risk Future cases Persons at risk to date 5*yr incidence Future persons at risk Future cases ^-10 : i-i5 16-20 2J--- 26-30 31-3* 36--!0 41-45 46-50 1- 0 100,000 0.00 00 1 98,250 0.01 00 11 95,500 0.12 00 28 84,750 0.33 6750 2 28 61,400 0.46 24.550 11 18 36,750 0.49 41,750 20 6 21,250 0.28 48,100 13 6 6750 0.89 51.750 46 0 600 7 45,750 7 0 0 7 34,500 7 0 0 1 47,600 7 0.50 300,750 150 100,000 94,500 78,000 46,500 28,750 18,750 10,850 3500 310 0 0 0.00 0.01 0.14 060 0.97 0.96 0.55 1.71 9 7 7 0.80 0 3750 17,500 45,000 57.200 59,750 58.500 55,000 46,350 34,500 47,600 403,900 0 0 2 27 57 57 32 94 7 7 7 323 rcr A***!* of the assumptions and methods sec text (pp. 197 & 198). ASI 00005592 1 200 1. F. H. Purchase et at. (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 ei 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 Chaizze 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 10'6 on the basis of these data give extremely low levels (down to 3.9 x 10_7ppb) 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 or 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 101) 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 10:). 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 105/jg (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 10 lower (3.9 x 10~7ppb 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 genera! 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 date 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. ~ *---- rin .___,___ , ASI 00005593 l Vinyl chloride--risk assessment 201 Acknowledgements--We thank Dr M. Thomas for his help with the calculations and Dr D. M. Conning for 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. & Kaplan N. L. (1980). A general scheme for the incorporation of pharmacokinetics in low-dose risk estimation for chemical carcinogenesis: example--vinyl chloride. Toxic, oppl, Pharmac. 55, 154. Barnes A. W. (1976). Vinyl chloride and the production of PVC. Proc. R. Soe. Med. 69, 277. Barr J. 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. & Breslow N. E. (1981). Power consid erations in epidemiologic studies of vinyl chloride work ers. Am. J. Epidem. 114, 725. Bertazzi P. A., Villa A., Foa V., Saia B., Febri L-, Mapp C., Marcer C., Manno M., Marchi M. & Bottasso F. M. (1979). An epidemiological study of vinyl chloride ex posed workers in Italy. Archo higroda toxicol. 30, 379. Buffler P. A., Wood S., Eifler C., Suarez L. & 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. & Westerholm P. (1976), Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Em ir. Hith Perspect. 17, 167. Carlborg F. W. (1981). Dose-response functions in carcino genesis and the Weibull model. Fd Cosmet. Toxicol. 19, 255. Chiazze L. & Ferencc L. D. (19S1). Mortality among PV'C-fabricatmg employees. Em ir. Hhh Perspect. 41, 137. Chiazze L.. Warg O., Nichols W. E. &. Ference L. D. (1980). Breast cancer mortality among PVC fabricators. J. occup. Med. 22, 677. Conference to Reevaluate the Toxicity of Vinyl Chloride Monomer. Po!y(vinyl Chloride) and Structural Analogs (1981) Conference sponsored by NIEHS NIOSH,OSHA at NIH. Bethesda. March 1980. Emir. Hltli Perspect. 1981. 41, 1-231. Cook w; A.. Grever P. M., Dinman B. D. & Magnuson H. J (1971) Occupational acro-osteolysis II. An indus trial hygiene study. Archs emir. Hith 22, 74. Cooper . C. (lySl). Epidemiological study of vinyl chlo ride workers: mortality through December 31, 1972. Emir. Hith 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, &. Guess H. A. (1980). Drinking Water and Cancer. Report no. PB81-12S167. NTIS, Washington. Duck B. W.. Carter J. T. & Combes E. J. (1975). Mortality study of workers in a polyvinyl chloride production plant. Lancet ii. 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. & 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. & 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, 711], Forman D., Bennett B., Stafford J. & 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 & Collier P. F. (1977). Mortality experience of workers exposed to vinyl chloride monomer >n the manu facture of polyvinvl chloride in Great Britain. Br. J. ir,d. Med. 34, 1. Fretzcl-Beyme R,, Schmitz T. & Thiess A M. (1978) Mortalitatsstudie bei VC/PVC Arbeuerne dcr BASF Aktiengesellschaft, Ludwigshafen am Rhein. Arbeusmed. Sosialmed. Preventirmed. 13, 218. Gauvain S. (1976). Vinyl chloride. Proc. R. Soe. Med. 69, 275. Gaylor D. W. & Kodell R. L. (I9S0). Linear interpolation algorithm for low-dose risk assessment of toxic sub stances. J. emir. Path. Toxicol. 4, 305. Gehring P. J., Watanabe P. G. & Park C. N. (1978). Resolution of dose-response toxicity data for chemicals requiring metabolic activation: example--vinyl chloride. Toxic, appt. Pharmac. 44, 581. Gehring P. J., Watanabe P. G. & Park C. N. (1979). Risk of angiosarcoma in workers exposed to vinyl chloride as predicted from studies in rats. Toxic, oppl. Pharmac. 49, 15. Green T. & Hathway D. E. (1975). Tne biological fate in rats of vinyl chloride in relation to its oncogenicity. Chemico-Biol. Interactions 11, 545. Green T. & 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 \V. 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, Plastics 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. Emir. Hith Perspect. 41, 89. Kuzmack A. M. & McGaughy (1975). Quantitative Risk Assessment for Community Exposure to Vinyl Chloride. US EPA Report. 5 December. EPA, Washington. DC. Lee C. C., Bhandari J. C., Winston J. M.. House W, B.. Dixon R. C. & Woods J. S. (1978). Carcinogenicity of vinvl chloride and vinvlidene chloride. J. Toxic, em ir. Hith 4, 15. Lester D.. Greenberg L- A. & Adams W, R. (1963). Effects of single and repeated exposures of humans and rats to vinyl chloride. Am. md. Hyg. Ass. J. 24, 265, Loprieno N.. Bavale R.. Baroncelli S,. Bartsch H., Brouzetti G., Gammellini A . Corsi C., Freza D., Nieri R.. Leponni C., Rosellini D. & Rossi A. M. (1977). Induction of gene mutagens and gene conversions by vinyl chloride metab olites in yeast. Cancer Res. 36, 253. Maltoni C., Lefemine G., Ciliberti A., Cotti G. & Carretti D. (1980). Epidemiologie animale et epidemiologic hu mane: le cas de chlorure de vinyl monomere. In XXe Reunion de Club de Cancerogenese Chimique. ISBN 2.86315.007.3. p. 15. Publications Essentielles, Paris. Maltoni C., Lefemine G., Ciliberti A., Cotti G. & Carretti D. (1981). Carcinogenicity bioassays of vinyl chloride monomer, a model of risk assessment on an experimental basis. Emir. Hith Perspect. 41, 3. Maltoni C. & Rondinella R. (1980). Hepatic angiosarcoma in workers exposed to vinyl chloride in Italy. Acta Oncologica 1, 35 (in Ilalian). Meyerson L. B. & Meier G. C. (1972). Cutaneous lesions in acro-osteolysis. Archs Derm. 106, 224. r c t ;j :_f ASI 00005594 202 i, F. H. Purchase et al. Ministry of Agriculture, Fisheries and Food (1978). Survey of Vinyl Chloride Content of Polyvinyl Chloride for Food Contact and of Foods. HMSO, London Monson R. R., Peters J. M. & 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- & Selikoff I. J. (1975). Mortality experience of a cohort of vinyl chloride/polyvinyl chloride workers. Lancet ii, 1197. Nicholson W. J., Henneberger P, K. & Tarr 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 (19'6). Mortality data collected by ORC concerning the effects of vinyl chloride exposure in PVC fabrication. Cited by Barr (1982) Ott M. C.. Langner R, R. & Holder B H. (1975). Vinyl chloride exposure ir. a controlled industrial environment. Archs ; ;r. Hit' 30. 333. Rannug V., Gothe R & Wachtmeister C A. (1976). The mutagenicity of chloroethylene oxide. chloroacetaldehyde. 2-chloroethanol and ch oroacetic acid, conceivable metabolites of vinyl chloride Chemico-Biol. Interactions 21. 251. Rein! W. i Weber H. (1976). Stand der epidemiologischen Forschur; Ober die Vinylchlorid-krankheit. Zentbi ArhMeJ .a rb~Schu!z 26, 97. Reinl W._ Vseber H. & Greiser E. (19"5i Epidemiology study of the mortality of workers exposed to vinyl chloride ir. FRG. Paper presented at the 19th Inter national Centertnce for Occupational Health, Dubrovnic. September. Schneiderman V. A, Mantel N. & Brown C. C. (1975). From mouse :o man--or how- to get from the laboratory to Park Avenue and 59th Street. Ann V }' Acad. Set. 246, 237. Selikoff I. J. (iS'5). Toxicity of vinyl chloride/polyvinyl chloride. Anr. X.Y. Acad. Sci. 246. Spirtas R. & Kaminski R. (1978). Angiosarcoma of the liver in vinyl chloride polyvinyl chloride workers. J. occup. Med. 20. 427. Suciu J., Drejman I. & Valaskii M. (1963). Contributions to the study of disease by vinyl chloride. Med. Interna 15, 967 (in Italian). Szadkowski D. & Lehnert G. (1982). Vinylchlorid als Krankheitsursache. Eine Bibliographie. VKE, Frankfurt. Tabcrshaw J. R. & Gaffey \V. R. (1974). Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. occup. Med. 16, 509. Theriault G. (1982). Cancer mortality of Canadian workers exposed to VCM. a three-year follow-up. J. occup. Med. 24, 730. Theriault G. & .Allard P (1981). Cancer mortality of a group of Canadian workers exposed to vinyl chloride monomer. J. occup. Med. 23, 671. Torkelson T. R.. Ogen F- & 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--Department of Health, Education and Wel fare (1980). Selected abstracts on the carcinoEeruciix of VCM. DHEW. Washington, DC. Verburgt F. G. & Vogel E (1977). Vinyl chloride muta genesis in Drosophila melonogaster. 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. & Gearing P. J. (1976). Dose-dependent fate of vinyl chloride and its possible relationship to oncogenicity in rats. Emir. Hlth Perspea. 17, 145. Waxweiler R. J.. Stringer W,, Wagoner J. K.. Jones J., Falk H. & Carter C. (!976>. Neoplastic risk among workers exposed to vinyl chloride. Ann. X.Y. Acad. Sci. 271, 40. Weber H., Reini W Sc Grieser E. (1981). German in vestigations on morbidity and mortality of workers ex posed to vinyl chloride. Emir. Hlth Perspect.-41, 95. Wilson R. H., McCormick W. E., Tatum C. F. & Creech J. L. (1967). Occupational acro-osteolysis. J. Am. med. Ass. 201, 577. ASI 00005595