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Ft aem. Toxic. Vol. 25. No. 2, pp. 187-202, 19*7 Pnomd is Oral Bnuin. All right! latrad ORIGINAL 02784915/87 53.00 + 0.00 Copynghi C 19*7 ftrpunoo Jounuli Lul Review Section VINYL CHLORIDE: AN ASSESSMENT OF*THE RISK OF OCCUPATIONAL EXPOSURE* I. F. H. Purchase Central Toxicology Laboratory t* J. Stafford Plastics and Petrochemicals Division and G. M. Paddle Central Medical Group. Imperial Chemical Industries pie. Aiderley Park. Macclesfield, Cheshire, England (Received 14 December 1983; revisions received 13 January 1986) Introduction Vinyl chloride monomer (VCM), more properly named monochiorethane, is a colourless gas normally handled tinder 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 chlonde (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 fTLV) of 500 ppm, 8-hr time-weighted average [TWa) for many years (ACGIH, 1974; Lester et al. 1963; Torkelson ti 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 m 1945-1955. 400-500 in 1955-1960, 300-400 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 - aero-osteolysis; ASL-angio sarcoma of the liver; PVC - polyvinyl chloride; TLV -- threshold limit value; TWA * time-weighted average; VCM -- vinyl chlonde 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 wiih 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 ct al. 1971; Harris & Adams, 1967; Suciu et al. 1963). Modification of working practices led to a reduction in the incidence of AOL cases m 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 (Viola, 1969) failed to produce AOL but showed an increase in the incidence of tumours at various sites. Further studies (Maltoni et al. 1980 & 1981; Maltoni & 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 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 & Lehnen, 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 VC6064 188 I. F. H. Purchase et al. Table 1. Lowest concerttrauoru or dotes at which a significant eaeets of vinous Tumour Fonsiomach paptlloms Zvmotl'gJaftd oremom* Neuroblastoma Nephroblaiiome Liver angiosarcoma Mammary-gland adenocarcinoma Data from Maliont ei el. (1981). Concn (ppm) 30.000 10.000 10.000 :S0 (female) 100 (male) 200 so S (female) Dose (mg/kg) SO (male) I6.6S (fanale) 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 lyphimurium (Rannug ei al. 1976). Saccharomyces (Lopneno ei 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 ei al. 1981) gives a useful database for risk assessment. Other studies (Feron ei al. 1981; Lee et 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 50 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 mam 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, malting 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 vmyl chloride Current manufacture and use of VCM and PVC results m the potential exposure of four groups of the population. "Hie 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 which has migrated 1974, the amount o'to less than 1 mg/kg human daily intake 0.1 jig/day (Minisu Food, 1978). The fourth group are those who live manufacturing or fi ambient air around parts per 10' rang __ groups, which inclu For the workers polymerization and is by inhalation. M i data are based on m epidemiology is pi posed occupational mem of the risk fa inhalation exposun consumer exposed the route is by inge studies have used < study used a comp al. 1981). Simiia' demiological data for exposure via i existing animal dm demiological and <exposure. Risk assessment fr Assumptions In carrying ou( animal data, a m made. Tbe first oi metry. Experimen trations of vinyl t vinyl chloride tha to which they ha calculate a eorret that they are app mice live for reiai years) during whi similar to those sc same tumours in years. It is thercfiis equivalent to th species even thoi stantially differcn Strictly speakr risk on the bash vides an estimai experimental ani< of factors, par ceptibility and d' extrapolation of man subject to i that scientific jml these data are at x,..- Metabolism In rats, VCM extensively, prod VC6065 suits were more : in the studies ne most reasonwere consistent M exposure and JS1), in reaching the relative risk * that for liver t on lung cancer ded statisucally ties with a high uon was consid- : for analysis of .mber of reasons, jiations. making te basis of work l^fcxxurs in both VM and it is : effect 0r VCM oosures than the or these reasons, k assessment of >*d ASL as the mprehensive case of occupational tunitv to identifv 5L. chloride ' VCM and PVC our groups of the uegory covers the ure of VCM. its other industrial "tain occupadons. 3lve higher potenall groups would s complying with xposed as a result .'ompounding and .posed to residual tg (but PVC does id). In general the are very low in ^rizadon workers to; beverages that it unreacted VCM Vinyl chloride--risk assessment 189 which has migrated into the food or beverage. Since After administration by gavage or inhalation, pan of 1974, the amount of VCM in PVC has been reduced the dose is exhaled unchanged and the remainder is to less than 1 mg/kg with the result that the maximum excreted or retained in the carcass. A general scheme human daily intake of VCM in food and drink is 0.1 /rg/day (Ministrv of Agriculture, Fisheries &. Food. 1978). '{C\ The fourth group with potential exposure to VCM CHCI H.C----- CH ClCH.CHO are those who live in the vicinity of VCM or PVC r manufacturing or fabricating factories. The levels in (*) U) 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 inhalauon 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 at. 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 GrC|111lyH=CH.SoCM.CH. / Ni11 H ` 1OVH Clu \C11Gl=y 0 CI1 HCH,SCH,,CO,H N|i H G|1lu | 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 CC11 HOC.HH.SCH.CH, Ni1 H (A'c)VO1 H <> CC11 OH4.CHH.SCH.CO.H NH. (f) 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 1 similar to those seen in man. The latent period for the CO.H same tumours in man may be between 20 and 40 C ----- CH.SCH.COjH 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 II o 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 S(CH.CO.H) f` (l) of factors, particularly inherent biological sus Fig. 1. Scheme showing the metabolism of vinyl chloride 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. monomer (VCM) in rats to S-containing metabolites. VCM (a) is convened to chloroethylene oxide (b) which is trans formed spontaneously to chioroacetatdehyde (c). These two metabolites are mutagenic and hence are considered to be the proximate carcinogens. The urinary excretion products hf-aeetyl-S-(2-hydroxyethyl)eysteine (e) S-fcarboxymethyl)- Metabolism In rats, VCM has been shown to be metabolized extensively, producing a range of excretion products. cysteme (f) and thiodiglyeollic acid (g) are derived from these mutagenic metabolites via (d). Gly and Gtu are the glycine and glutamate residues of glutathione. [After Green A Hathway (1977)). VC6066 I. F. H . Purchase et ol. VC6067 Reference Monson et of. (1974) Tabcrshaw & Gilhjr (1974) Duck tl of. (1975) Nicholson el at (1975) Oil et of. (1975) Ryrcn tt of. (1976) ORC (1974) Rein) * Weber, 1976; Rtinl rf of. 1971; Weber el of. 1911 Wesweiler el of. (1976) Foe A Collier (1977) FtellelBeyme rl of. (1971) BciUni el of. (1979) BulRer el of. (1919) CKioe A Ferenee (1911) Chiazte r of. (1910) Beaumont & Brcilow (1981) Talitc 2 F.pidemiokgical studies of cancer .utocialed with exposure lo vinyl chloride nmnomcf No. in study* ------- ---- (*/ follow up) Increase Sites (or I uniours) wilh changes in SMR No increase Comments 7 8)84(93%) Brain lung liver, including ASL Buccal cavity ami pharynx Respiratory system Unlnown site Lymphoma Angiosarcoma 1170 None 157 (99*4) 594(99%) 771(97%) ASL All tumours? Livcr/pancicas 10,175(95%) 11,011 (90%) 1151 1409 (99%) Cerebral) Cardiovascular Digestive tract MaNgnant liver Lymphatic system Of tract Brain Respiratory Iracl Lymphatic system ASL Primary liver ASL 1611(95%) 5441 (16%) 464(100%) 3141 Coton/slomnch Froftfafic hyperptar AH turnouts Respiratory xyster* Digestive system Liver Brain (irnilal Digestive organs Urinary Iracl Ixultaemia Brain Stomach Brain Lymphatic and haemopoieik system Significant SMR not significant but increases with exposure and time Some criticism of conduct of study Arsenical* involved Significant increase (2 ASI.) Increase nol significant mn study Related to duration or exposure Mixed exposure, not VCM related Not significant Significant Breast Respiratory tract l*MR stmly of female and male fabricator* Increase In PMR nol confirmed by case-controlled study Review of nine studies fk't; j. wgarj* -- r *t -Y % a. Cooper (I9tt) 10.173 (9 SV.) Brain Follow up of Tabersltaw ami (iaITey** study No increase in incidence of brain cancer s ff g I SJ;1 -I?1 e" ?s `5 - * S * | I si * st -s ,, i fc> w ta W V . si. "'S ' *s -= I S S-"- Vinyl chloride--risk assessment 191 .a a. Si - 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 macromofecuies, 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 Wistar rats, the amount of l4C excreted in the urine and faeces and retained in the carcass was estimated over 72 hours fWatanabe &. 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 <fc Gehring, 1976). Studies of the amount of non-volatile material retained in the carcasses of rats exposed to various levels of 14C-labelled VCM for 6 hours demonstrated that the metabolism of VCM appeared to be in accordance with Michaelis-Memen kinetics (Gehring ei at. 1978). The constants for maximum velocity of metabolism (VB in /ig metabolized/6 hr) and the Michaelis constant (K,, m ug VCM/Iitre air) accord ing to the formula: VBS V---2-- KLffl-S (where V velocity of metabolism in ug/6 hr and Sconcentration of VCM being inhaled) were VBi= 855S/ig metabolized/6 hr and K.m = S60ug 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. Review of earlier calculations of risk There have been a number of attempts to calculate the nsk of ASL development on the basis of extrap olation from experimental data. These have been reviewed by Barr (1982) and an adaptauon of hts 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 billion to in excess of one part per million. A further refinement of the technique using DNA binding as the measure of dosimetry (Anderson ei 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 ei 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 VC6068 in I. F. H. Furomse ei-al. Tabic 3. Vinyl chloride doic and modem* rf h-pt----- r------------ --- fr~rr'r T*i Itj mi f T|iihhi1 on 5 day/wk (or S3 w)r* (ppm) 30,000 10.000 6000 2500 soo 250 200 ISO too so 2S to s 1 0 Amount metabobaad q*Mhr 5647 SS21 5403 S030 3413 3435 2129 1761 1309 739 J9S 169 *4 17 0 HI (total) 1.47 x 10* 144 x 10* 1.41 x 10* 1.3 x 10* 8.8 x 10! 6-3 x 10* 5.5 x 10* 4.6 x 10! 3 .4 x 10* 1.9 x 10* 1.0 x 10* 4.4 X 10* 22 x 10" 4.4 x 10* 0 Aopotanoma ny-Ktmrr f%) Male 16.6 10.0 102 20.0 C 34 11.7 1.7 0 1.1 1.7 0 0 0 0 Femak 432 132 332 232 20.0 6.7 S2 12 1.7 72 6.7 1.7 0 0 0 Mean 30.0 11.7 22.0 21.7 10.0 S.l 10.0 5.0 02 42 42 02 0 0 0 Ecpcm BO. BT 61 BT 1 BT I BT 1 BT 1 BT 1 BT2 BT2 BT2 BR1.9 BT 15 BT 15 BT 15 BT 15 BT 1,2 9,1$ 'After Maltofu et cl. 0981). tEapemncm BT 6 coded afier only 68 wk, while the rest were nil Approximately 140 wk: therefore the percentage of tumoun in BT 6 u probably low relative to the rest twnv of the short latency penod available. multistage mode) by the Food Safety Council (1980) and by Gaylor &. Kodell (1980) showed that for the same )0~f lifetime risk, the Food Safety Council estimated the dose as 2 * 10':ppro whereas Gaylor & Kodell estimated the dose as 5 x 10"' ppm. The difference between these two estimates was due to alternative assumptions on tbe value of the expansion of the exponential term used. In general, calculations based on the amount of materia) metabolized ot on human data have produeed 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 tbe selection of the mathematical mode) applied to the experimental data. In the following section two models are used to calculate the exposure for a J0-` risk from a variety of experimental animal data applying the correction for metabolism used by Gehring ei al. (1979). Calculation of exposure for 10~` risk A summary of the crude A5L incidence rates for inhalation studies in Sprague-Dawley rats is given in Table 3. Similar data for Wisiar rats exposed by Tablt 4. Summary of quantitative mk assettmenu for vinyl chloride monomer* Reference Spaces Exposure for 10'* lifetime riik (jrpbt) Commenu Schociderman ti el. (1975) Rat Kusnaek k McGaughy (1975) Gehnng ei el. (1979) Food Safety Council 09*03 Rat, mac Rat, min Rat Rai AxxJertoD tt al. (1980) Gaylor k Kodell (19S0) Carlborg (1981) Bart (1982) This paper (Tabic 9) EPA (19*0) NAS (1980) Crump & Guo* (1980) Rat. man Rat Rat Man Rat Mouse Man Rat Mouse Man Rat Rat Man Rat By frhilartoe 73 119 2 14 140-1400 >1000 <)0->)000 20 20 21 x 10'* 3.9 x 10'1 >1000 0.7 0.5 25 x 10'-` > 100 0.025-9.16\ 2 x 10'l! J 0.63-90 2 x IO'5-2 x 10*` 6 x 10*'* 0.067-6.14 Bj iifcMioD 4 pgfdsy 3 x I0'*mg/kg/dsy 0.7 >jf/day 0.5 fig/day Probit (ilope- 1, Mantel) Logit (elope 3.45) Lop! ()ope 2.3, ooe*bit) Linear through aero Log-probu Bioronsformauon dau included Linear or log-probu Depeodi on mathematical model uied Armiiagt-Doll Weibull DNa binding Uied for dosimetry Upper 97.5'A eonfidcoce limit of lioear model Annitage-Doll Weibull Derived from Bair't negative epidemiology Log-probit Log-probit including bioinniformation data for man Weibull Weibull including bioinniformation for man Food or water Water Applying worker data to water Upper 95V. confidence limits After Barr (1982). TEacept when dated otherwiac njnhsiation (Tab! Tssd for mice exp `' presented. Data L osure periods t ; . For calculate I in rmts in ^srants calculate ^applied. For V ^ derived for Sp; '-These estimates eluded in the u. For tbe expe gavage, the dais _ - amount Of VC.' " `exhalation of V `on a 72-bour fraction of VC doses. It has be. was metabolize used for estirr halation expert 1977) showed i Wisiar rats wa manner to tba' V,, and K* va have been use (1981), who u; about V,, and VCM adminis been adminisu Table 6 * :.. 300 VC6069 A large variable -iiematical model dels are used 10 sk from a variety ng the correction al. (1979). raence rates for ey rats is given in rats exposed by car model jeloc On data for man for ms Vinyl chloride--risk assessment m 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 (Gehnng et al. 1978) have been applied. For Wistar rats, the 1C, and VB 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 i,. 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 m a similar ( manner to that in the Sprague-Dawley rats, and the I Vn and JCB values derived for Sprague-Dawley rats i have been used. In the experiments by Feron ei al. ) (1981), who used Wistar rats, the same assumptions l about V. and K,, have been made. The quantity of j VCM administered has been dealt with as if it had V been administered by gavage. Fig. 2. Summary of dose-dependent unnary and pulmonary excretion of vinyl chloride monomer fVCM). Unnary excre tion () represents metabolites of VCM. while pulmonary elimmauon (A) is unchanged VCM. (After Watanabe k 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 chemicai 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 esumating the dose metabolized by man. Table i Vinyl chloride dose and incidence of hepatic angiosarcoma in male Wistar rats exposed on 3 dsys'wk for 52 wit____________________ Coocn (ppm) Amount metabolized pg/ahr at (total) Anpoureom* incidence (%) Expmi no. 10.000 6000 2500 500 250 50 1 0 5521 5403 5030 3413 2a35 139 17 0 1.4 x 10* 1.4 X 10* 1.3 x 10* 8.8 x 10s 6.3 x JO1 1.9 x 101 4.4 x 10* 0 29.6 11.5 12.0 10.1 3.7 0 0 0 BT 7 BT7 BT7 BT 7 BT7 BT7 BT 17 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 exhaled* (*/ of dose) Amount metabolized xt/dose' eg (tout) Mile Femiie Mean Expmi no. 50; 16.65 3J3 1.0 0.3 0.03 0 3001 14.1* 5.0 1.7 0 50 6250 1.6 x 10* 35 2105 7.0 x 10* 10 750 2.0 x 1(F 3245 1.7 - 7* 7.26 x 10* 2.16 x 10* 1.4 7.4 2.16 x I01 -- 00 80 15.000 6.2 x 10* 32 2390 1.65 x 10* 16.5 1040 7.25 x 10* 2 420 2.9 x 10* 69 0 0 20 22.5 10 15.1 00 1.3 2.1 0 1.4 00 00 49 53 49 16 10 4 00 00 21.2 12.5 0 2.0 0.7 0 0 51' 32 7 0 J BT 11 BT 11 BT 11 BT27 BT 27 BT 27 BT 11. 27 Feron <r al(1981) `Calculated from data derived from Watanabe Gehnng (1916) presented m Fig. 2- tAaeummg a I50-g rat. .Sptague-Dewlcy rata doted by gavage with VCM in corn oil 5 times)'*'k for 52 wit. JBT27 doeed for 59 wit. I Wistar rats used as controls by Feron et al, (1981) aod dosed for 83 wit. lWiatar rats raoavmg a diet containing VCM dissolved in PVC. VC6070 194 1, F. H. Purchase et ol. Tabic 7 Vinyl chloride doer and incidence of hepatic anpoearcoma in mice Conen (ppm) Amount metabolized Mg/4 hr us dotal) Angiosarcoma incidence (%) Mate Female Mean no. 10.000 6000 2500 1000 500 250 250 50 1 0 11,245 11.007 10.244 8699 6952 4959 4959 1506 1506 0 1.7 x 10* 3.S 30 17.8 BT4* 1.7 x 10* 6.7 36.7 21.7 BT4 1.5 x 10* 20.7 33.3 27.1 BT4 3.4 x 10* 39.4 50.0 44.7 Lee el ol.t 1.0 x 10* 20.0 26.7 23.3 BT4 7.4 x 10* 30.0 30.0 30.0 BT 4 7.4 x 10* 24.0 47.0 36.5 Lee el al.t 2.2 x I01 3.3 0 1.7 BT 4 5.9 x 101 10.3 0 5d Lee ri o/.t 0 0 0 0 BT 4 & Lee ri al. *Swm mice. S l-wk eipenmcnt, doted for 30 wk. TCD, mice. 52-wk eipenmeoL 6 hr/day eipoturt (La ti al. 197S). These retulu have not been included in the calculations for Table 9 because the experimental design incorporated interim kills. Thus: .V.,,.(mouse). - .(rat), x --0.01-l--m:: 0.045 nr - 5706M/4hrx|211 = 1395/rg/4hr The values of 0.045 m: and 0.01 lm: 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: 1395 11625 ug/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 c. 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 )0*1Jppb) 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 WeibuII 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 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" 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 S. Vinyl chloride (VCM) dote ind hep*tic tnpotarcomi incidence in Sprague-Dewicy nu expoeed to VCM by inhalation Conen (ppm) 10.000 10.000 10.000 10.000 10.000 6000 6000' 6000 6000 6000 Schedule* i ii ID IV V I 11 111 TV -V No. of do 260 85 25 100 25 260 85 25 100 25 Amount metabolized? U 8/4 hr 5521 5521 5521 1379 5521 5403 5403 5403 1350 5403 MS (total) 1.4 x 10* 4.7 x 10* 1.4 x 10* 1.4 x I01 1.4 X 10* 1.4 X 10* 4.6 X 10* 7.4 x 10* 1.4 X 10* 1.4 x )0* AnpotarcoRia incidence (*/.) Male 10 0 1.7 1.7 0 10.3 0 0 3.4 0 Female 13.3 0 0 0 1.7 33.3 3.3 0 1.7 1.7 Mon 11.7 0 0.8 0.8 0.8 22.0 1.7 0 2J 0.8 no. BT 1 BT 3 BT 10 BT 10 BT 10 BT 1 BT3 BT 10 BT 10 BT 10 'After Milioni t: al. (19SI). tSehedules: 1--* hr/day, i daytfwk for SI wk; 11--4 hr/day, S dayvwk for 17 wk; III--4 br/day, 5 dy/k for S wk: IV--l hr/day. 4 day/wk for 25 wk: V--4 hr/day, I day/wk for 25 wk. JAmount metabolized (v) in 4 hour derived from the formula: V (u*/br) - V,, x S/K. + S where it 4/6 of the 6 hr value. f Vinyl chloride-- risk assessment VC6072 Tilite 9 Qusnlilelive list tslimalions derived horn ivsihiblc animal carcinogenicity data ami e,pressed as Ihe amount or concenlralion of vinyl chloride calculated to give a lifetime risk of A SI. of Id * either on live hasir of lug-prnbil analysis or a Wcihull distribution__________________ Table no. Experimental data Expos ure for rodents (S ppb*| Amount metabolized in 6 hr hy rodents (V )if/t hr) Total amounl metabolized by rodents (TM mg) Exposure (ppb) calculated from V (S calculated for man)f 4 5 6 7| 4. S I S D rail, inludation Wiitar rati, mate only, inhalation Rail, ingeslion--Wislar --SO --both} Mice, inhalation Wistar and S 1) Tat* combined, inhalation S-D sals, short-term inhalation 4 S-D rati, inhalation Wiitar rats, male only, s inhahtiofl 6 Rats. ingestion--Wiilar --SO --both) ti Mice, inhalation 4.1 Wiitar and S D rats combined, inhalation 1 S-D rati, short-term inhalation ooi) l.ot ptobEl mlyshl 1 7.1 9 16 ) x 10 ' mg/Vg 9 k 10* mg/kg 6 x 10 * tng/kg 2 k 10 *' 159 0.69 mg/dosc 2.19 mg/dote 1.70 ing/dose 0.60 OO--Sfl 1 X 10 ' Ml 0 004 Wrlhull dhtrlbnlinnt 0013 1 X 10 ' 9 X 10 '* mg/Vg 4 x 10 mgAg 1 x 10 'mg/kg 6 x 10 *' 1ST 3 x 10 `mg/dose 0.33 mg/dose 0 005 mg/dose I x 10 1 6 x 10 ' -- 00171 ) to 0 305 39.) 2 37 02 OSS DOOM ft 35 1.(6 00032 it* 00001 0.003 0 0015 1 X 10 ' 00041 0.19 0 A) 90 0 0J 0 71 0 067 (.14 1 x 10 9 0009 A SI. - Angiosarcoma of Ibe liver S 1) * Sprague Hawley Eaccpt where Haled otlicrwiie. tEiposme calculated front V (in column 3) using the formula S lEslunaled using nidtlinuin liteNhood. (Wiitar and S f) rdli combined ]Sludy BT 4 only. V a gbO/1675 - V, where V,, for man is lftlSpg/8 hr. I JM I. F. H. Purchase et al. ually 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 exirapolauon of the risk of low-oose 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 x )0!/ig 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 iota! metabolized dose of 5 x 10-'fig is equivalent to about 200ppm 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 10-*" lifetime nsk. This vari ation is due to the type of mathematical model that is applied, to the assumptions that are made and to int 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 animats to man is largely intuitive. It is clear thai 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 LARC 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 Cluttcnnt of ASL easel in individual PVC plants Plant* BC. Country No. of ASL cues Waters Europe 1 Wg*i Germany Wsi Gtrmtnv 3 Wert Gtrmenv i Wei Germany \ France 2 France 3 France 1 UK 2 UK 1 Sweden North America i Cantdi 1 USA 2 USA 5 USA RcetofWerM 1 Japan 1 Yugoslavia ] Czechoslovakia Total... Toul... 10 4 A 2 s 5 2 j 2 5 42 10 11 9 4 34 2 42 Total... ._ _ `For the purposes of this cue study. it tt not necessary to identify the precise ind location of these planu. the end of 19S2 have been analysed by country and by manufacturing company and plant. The cases have been recorded from al) major VCM/PVC manu facturing countries (Table JO), 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 cues by country Country No. of ASL cues USA Wen Germany France Canada UK Sweden Yufoilavia lialv Czechoslovakia Japan Belgium Norway Tout.. Wcaurtt urope North America Rut of World Total... 29 21 14 10 7 J 4 3 2 2 l 1 99 52 39 8 99 PVC production nameplate capacity (kiloionncs'yr) 1952 1962 1972 193 704 2090 22 260 1155 n 176 627 5 22 88 27 177 502 3 20 105 3 8 60 9 212 778 I 25 48 12 384 1699 3 25 195 2 20 65 82 951 3950 198 726 2178 51 709 3334 331 2386 94*2 ASL * Anposareoma of the liver 4c 1* ; } - 1 r * 1\ > Ta: Year of death IMS S 7 S 9 I960 1 2 3 4 5 6 7 S 9 1970 1 2 4 < 6 I 1 I 1 1 I 1 TotaL North American ASL case so far. The average lav an occupation in from ASL for the Sweden and the Germany about predict whether amongst VCM v cases appeared t Western Europe : to decrease in N high in Western On the basis o possible to draw tors associated w cases in some fac in others of sim; manufacturing p; cause. These van the types ofjob c differences in en cases have occi autoclave cleane or VCM pros authenticated c VC6073 Total. Total. 10 a 2 t 3 3 2 5 2 S 42 10 II 9 4 54 2 4 Total. not necessary to identify inese plants. sed by country and i plant. The cases r VCM/PVC manuit the incidence has in to the PVC pro- 962. In the absence ^ers employed, proliable indication of y exposed. : are PVC autoclave rked in or around rs among men who cases were involved oolymer production, acro-osteolysis and to occur in larger Mien (Table 11). Of ; in North America, -lants, while over 40 Vinyl chloride--risk assessment Tabic 12. ASL case numbers by year of death and feopaphieal location (excluding ITOI") Year death Westera Europe ASL asest in: North America Rest of world itey publictii<ms 1955 Cl 7 8 9 I960 1 2 5 4 5 6 7 g 9 1970 1 * 5 4 5 6 8 9 1980 1 C2 US8 C3 USJ Fl Gl Swl G2 Nl. Sw2. UKl, It2 G3: G4. G5. UK3 Fl F3, G6. G7. G8, IO Bl. F4, Fi, F6, FT, Sw3 F8, F9, G10, Gl 1, Gil Sw4 F10. FI 1, G9, G13. GI3. GI6, GIT Fll F13. UK4. UKl CIS UK6. UK', GI9, SwJ, G20, G21 It4. FH, UK8, GI2 C4, C5, US4. U$7, US10 US 12. US 16 US II C6. US2 C7 CS. USI, US3. US23 C9, US 13 US6, US9. USI8. US26 US 19. US20. US22 CIO. US21. US246 US27. US28 US 17. US29. USM. US32 Cz2 Yl. Y1 Cxi Jtpl Japl Y3 Y4 Viola MthonJ Creech k Johnson Total., 52 38f 8 ASL Angiosarcoma of the liver `Italian case 01 was not a typical ASL; his primary tumour was probably of the pericardium. This man was enpased in extrusion of PVC sacks. tB -- Belgium, C W. Germany; Sw " Sweden; C -- Canada: It Italy; UK -- United Kingdom: Ct * Czechoslovakia; Jap Japan; Y * Yugoslavia. F France; N * Norway; US -- USA. Thus G9 * case no. 9 tn Weal Germany. Cases UK2. GIF USM, US13 and US23 were shown not to be associated with VCM exposure and hence withdrawn from the list. XAerosol can filler. $Cholang)osarcoma. I Does not include US31 (still alive). 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 2i 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 rases 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 fses in some factories and the absence of ASL cases m others of similar age indicates that variations in manufacturing practices between factories may be the rause. These variations may reflect both differences in toe types of job carried out by individual workers and differences in engineering practices. The bulk of the e^ses have occurred, however, in highly exposed autoclave cleaners, with relatively few in other PVC or VCM production jobs. So far no wellsutbenticated 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. VC6074 198 1. F. H. PuRCHAffi el al- Tibk 13. ASL caie number! by ygi of firtt exposure and geographical location (excluding ITDI*) Yr of ASL caaeat in: exposure Western Europe "North Amend Rcti of world event* 1939 40 l Frl 1 2 3 Frla 4 UK1 5 Sw2 6 FrI. Fr3, Sw4 7 Sw3 s Fr9 9 Ffl2, Fr4 1950 Fr7. Nl, UK8 1 Swl, UK5 G3 3 GlS, U3 4 G7, G8, UK4, G19 s Gil. GI6. G18 6 FrIO, G1 7 FrB, Ga, li2. G2 S Fr6, B) 9 Fr2. Iia I960 GS. C15 1 G9, G10. G12. GI7, G20. G22 i G6. UK6. G21 3 Frl3, UK7 4 Sw5 s FrS 6 UK3 7 8 9 1970 1 2 3 Total... US2a; C3, US27 US 13. US29 C2. US 19 Cl. CS. US5, US7, US28 C*. USJ. US9 C7, C9. US8, US11, US21, US3lf C6, US22, US26 USI US12 US16 US 10. US32 usa CIO US18 US2. US 17, US20 Y2, Ci2 iapl, Y1 Y3 US23 Czl Jap2, Yd CS US6 US30 39 8 Viola Maltoni ASL Anpoureom* of the liver *h01 is not consistent with other ASL cue*; the pnnrury tumour may have been of the pericardium. The man extruded PVC sacks. tFor explanatory ke), see Table 12. ;Cholanpottrcom*. ?US3I is ni)l alive. lAerosol 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 &. 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 ihat 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 15) 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 r%L- i .> * the association be hypothetical expo used, but this is estimate of the ag ical `total' expose based on UK data already exposed latent periods, the or more form on! The numbers of ; calculated by acvx account of the a population at largr year for the male ; have been used in v (column 10) have The incidence figu years) are unreliat latencies of 15-25 y of 0.5 and 0.8 case: Table IS. Hypothetical c. Latency <yr) 1-5 6-10 11-15 16-JO 21-25 26-30 31-35 36-40 4M5 46-50 5116- Caiei to date 0 1 II 2S 28 18 6 6 0 0 0 Fr details of the aananr Pi*) 'iey mu Vinyl chloride--risk assessment Table 14, Annual ioddctxx of ASL cwa (data of death) by geographical area Year Wttiern Europe No. of ASL taxes dying to: North America Rest of world Annual total Cumulative total Key evcou 1933 7 1961 2 4 7 s 9 1970 1 2 3 4 5 6 7 * 9 1980 I 3+ Toul.., i 11 i 12 i ]3 i 14 i I3 6 1 17 3 3 13 13 11 3 13 3 17 Viola 13 3 20 41 3 23 i 4 3 8 33 Maitoni 32 5 38 Goodrich 64 1 11 49 63 3 11 60 6 7 3> 9 69 1 10 79 5 3 84 64 4# 10 94 4 98 00 0 0 si: 38" s 98* 98* ASL Angiosarcoma of tbe liver *Does not include US3I (still alive in 1982). tAi time of compilation. Jlodudes G03 (aerosol can filler) but omits ItOI (bag extruder). 199 talioiu iiutn. Tbe .irectly by relying on n differing locations, data indicated under published cases, sdures are the set of the descriptive data ssible to calculate an period for each ex> (on the basis of the - representative of the d use these rates to response latency that ion data. The broad es have a latency of continue to occur for estimate the future 5) an assumption has i were reduced to low j scame negligible. Two _ Mt levels were attained j. Blevels were reduced. when tbe levels were ? wing the discovery oC JC 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 of the age distribution within the hypothet ical `tour exposed population of 100,000 has been based on UK dau (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 toul. The numbers of persons at risk in the future are calculated by advancing time in 5-year periods uking account of tbe 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 obuined 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 0.5 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 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 13, Hypothetical calculation of future ASL taxes using two different aasumptions sbout the dxtx M which the levels became free of _________________________________________________ ______ nslt Calculations assuming no risk after 1964 Calculations assuming no nsk after 193* Latency lyf) 1-5 6-10 11-13 16-20 21-25 26-30 31-33 36-40 41-45 46-50 51* 16* Cases to date 0 1 11 28 28 18 6 6 0 0 0 Persons at risk to date 100.000 98.250 95.300 84,750 61.400 36.730 21.230 6750 600 0 0 S-yr incidence 0.00 0.01 0.12 0.33 0.46 0.49 0.28 0.89 * y 0.50 Future persons at risk 0 0 0 6750 24.550 41,750 48.100 51.750 43.730 34,300 47,600 300,730 Future cases 0 0 0 2 11 20 13 46 7 n iso Persons at risk to date 100,000 94.300 78.000 46.300 28.750 18.730 10.830 3300 310 0 0 J-yr incidence 0.00 0.01 0.14 0.60 0.97 0.96 0.55 1.71 <7 0.80 Future persons at risk 0 3750 17,500 45.000 57,200 59,750 58,300 55,000 46,350 34.500 47,600 403.900 Future eases 0 0 2 27 57 57 32 94 i V 323 For details of the ssaumptions and methods see text (pp. 197 A 191). VC6076 200 1. 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 aod 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 \nd 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 roost 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 m larger numbers in some plants than in others, a finding that can be explained most easily by differences in exposure patients. There is an extensive senes of animal studies on the carcinogenicity of VCM. Some of these precede ihe 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"7ppb) which appear to be unrealistic estimates for man. Pan 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-nsk dose esumates 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 Mahoni'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 (probu 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-probii 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!|ig (equivalent to inhalation of 200ppm) 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*: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 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. 1& $ Si Adatm iraf with the ca_ wuh the su i > ) T 1 1 t I r ( ( r v, - > u V* * A COIH--Ac trial Hype: icai Subsu Envirocme Cinannau. Anderson M general sebe is low-dose example--v Barnes A. W. PVC. Proc. Bare J. T. (If perspective. Air Polluno June I9S2. Beaumont 1 (rations is r era. Am. J. i Benaxzi P. a.. ' Marcer C., ) (1979). An t posed worker Buffler P. A- Vr (1979).Mona moDomer pro Byren D,, Enghc Mortality anc VCM and PV( 17. 167. Carlborg F. '. ( genesis and tb 255. Chiarzt L. * F PVC-fabncawi Chitat L_ Warg Breast canoa 3 Med. 22. 677. Conference to R< Monomer. Pots (1981). Confer: at NIH. Brtber 1981. 41, 1-231 Cook W. A.. Gre H. J. (1971). Oc trial hygiene sni Cooper W. C. (I9i ride workers: r. Emir, Htth Pen Creech J. L. & Jon liver in the mast Crump K. S. & G Cancer. Report r Duck B, W,, Carter study of workers Lancet it, 1197. EPA (1980). Ambi Chloride. Envtrc EPA 440/5-80-07: Feroo V. J,, Hendrii Spit B. J. (1981). chloride in rats, i Filatova V. S., Ac: Fedotov* I. V., T. V,, Goryachev; blastomogenic ha. and epidenuoiog: M (1). 28. r.CT. ao--r . in man. ASL and - organs have been v VCM. Estimation use a lifetime risk or data give extremely ob) which appear to . Pan of the reason s have shown that and elsewhere in the s cfaloroethylene ox* rate of conversion is .it giving inaccurate dose-response reable to estimate the met extrapolation of is conjectural. The extrapolation at low .ntable mathematical Maltoni's data from s a substantial range mates, depending on assumptions used in ie same (probit and sub-sets of expertf estimates is again n for the non-linear dose (which reduces _retr differences are : the Weibull analysis n. suggesting that this atbemarical models oe log-probit analderable variability in n the different experiMal metabolized dose halation of -00 ppm) evadon in ASL indpracticai threshold in development, matheose estimates are not ducible to engender teal studies of popuof VCM production ise for a 10'* lifetime art, 1982). The value jest estimates derived ng biotransformarion -.ually larger than the t up to 1010 lower nit model). The higher ?? : occupational expertat hygiene standard of ,5 * to protect the health estimates also give aj -v the general public, i and dnnk or living ij&j, .de a crude estimate of, " `hat may occur in the 1 prior to 1974. 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The toxidty of vinyl chloride as determined by repeated exposure of laboratory animals. Am. tnd. Hyg. Ass. J. 22. 354. US DHEW--Department of Health, Education and Wel fare (1980). Selected abstracts on the cardnogenidtv of VCM. DHEW, Washington. DC. Verburgt F. G. A Vogei 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. Witanibe P. G. A Gehring P. J. (1976). Dose-dependent fate of vinyl chloride and iu posable relationship to oncogenicity in tits. Encir. 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. A'.Y. Acad. Sci. 2171, 40. Weber H.. Reinl W. A Griescr 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. A Creech J. L. (1967). Occupational acro-osteolysis. J. Am. med. Ass. 201, 577. U Chem. Tone PWRUDOS JOTRU Interpretation for Caressoge International 1985. pp, vii Epidemiolr public confic effectively pr sympathy sin the data they iniepret is so roots in the who are pror have expetisi' in which a de group of wor and haul it r< that a reoent; carcinogen p man. Public i next month,: data on ano: regulatory m likely to be j This a not Director of epidemioiogs that an expc developing c mental evide real difficult demiological enougbt to number of l invitation fr Shubik to sp summer of 1 what might c five epidemi The present The agent which there justify the significant 1 eeived. and; carcinogenic bon. On the dishes as `pill' and fot For each ag brief returngenic actiw viewed, in doniolopcs reviews, ea report of if hors d'oeuv volume, is t VC6079