Document 5K2ZzJZDz28XnvK9Z0Mgqkj5

n 1 /-*3?^ - &OJL -J* A Division of The Society of The Plastics Industry, Inc. April 16, 1987 Tos The Vinyl Institute Health, Safety & Environment Committee The Vinyl Institute Legal Committee The attached article "Vinyl Chloride: An Assessment of the Risk of Occupational Exposure" (Fd. Chem. Toxic, Vol. 25, Ho. 2, 1987) is for your information and files. MNS/pmb attachment Meredith N. Scheck Assistant Director BOR 008718 fi Ckem. Talk. Vot 23. No. 2, pp. 117-202. 1917 Printed ia Cnot Briuin. Alt ri|hu nttrmI 0271-0913/17 13.00+0.00 Copyright O 1917 taiaiaoa Joanak ltd Review Section VINYL CHLORIDE: AN ASSESSMENT OF THE RISK * OF OCCUPATIONAL EXPOSURE* I. F. H. Purchase Central Toxicology Laboratory J. Stafford Plastics and Petrochemical] Division and G. M. Paddle Central Medical Group, Imperial Chemical Industrie] pic, Alderley Park, Macclesfield, Cheshire. England (Received 14 December 1983; revisions received 13 January 1986) Introduction Vinyl chloride monomer (VCM), more properly named monochlorethane, is a colourless gas normally handled under pressure as a liquid which boils at - I4C at normal pressure. Discovered around 1835, VCM's commercialization did not begin until the 1930s and did not reach high volume until after 1945. Present manufacture is around 12 x 10* tonnes per annum, nearly all of which is used to make the polymer polyvinyl chloride (PVC). Until the 1960s, VCM was regarded as a material of low human toxicity and the main concerns were related to the compound's narcotic effect. Indeed there are many reports of employees exposed to VCM monomer in polymer plants becoming dizzy and unconscious. Because VCM was considered to be relatively innocuous, it had a threshold limit value (TLV) of 500 ppm, 8-hr time-weighted average [TWA) for many years (ACGIH, 1974; Lester el al. 1963; Torkelson el 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, 300-400 m 1960-1970, 150 in mid-1973 and 5 in 1975. However in some jobs, particularly in the cleaning of the autoclaves in which VCM is polymerized to PVC, very much higher exposures, in thousands of ppm, were undoubtedly experienced for short/medium pe *A longer version of this paper has been published in Toxicological Risk Assessment, edited by D. B. Clayson, D. Krewski and I. Munro and published by CRC Press. Inc.. Boca Raton. FL (1985). Abbreviations: AOL - aero-osteolysis; ASL - angio sarcoma of the liver; PVC - polyvinyl chloride; TLV threshold limit value; TWA time-weighted average; VCM m vinyl chloride monomer. riods, since in some plants operators became faint and unconscious from time to time. ` The first clear indication of chronic health prob lems associated with VCM arose in the 1960s in men who entered VCM polymerization autoclaves to re move build-up of polymer from the walls. Some of these men developed acro-ostcolysis (AOL; Cook el al, 1971; Harris & Adams, 1967; Suciu el 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 ei al. 1967) it is a rare disease. In the late 1960$, studies in rats involving exposure to high concen trations of VCM for long periods (Viola. 1969) failed to produce AOL but showed an increase in the incidence of tumours at various sites. Further studies (Maltoni etal. 1980& 1981; Maitoni Sl 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 ei 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; 1ARC 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 Bor 008719 IM I. F. H. PuxcHAJt et a!. Ttbk I. Lows! cooocnirsiioni or tfosa tt which tttnifcmi txcxu at various turnout typei mi obocrvtd in rat cananoitniciiy studits Tumour Concn (ppm) Dos* (me/kt) Fortttomach papilloma Zymbal-fland carcinoma Neuroblastoma Nephroblutoms Uvct angiosarcoma Mammary-gland adenocarcinoma 30.000 10.000 10,000 250 (female) 100 (male) 100 50 5 (female) 50 (male) 16 65 (femak) Dili from MlKont tt <*l. (1911). 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 ef al. 1976), Saccharomyees (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 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 (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 Tor 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. Cast 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 bor 008720 /myl chloride--rilk assessment 189 which hJ migrated into the food or beverage. Since 1974, the amount of VCM in PVC hat been reduced to lett than I mg/kg with the retult 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 exposed 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 01. 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 gavage or inhalation, part of the dose is exhaled unchanged and the remainder is excreted or retained in the carcass. A general scheme CH----- CHjSCHjCHO --o II Q l CHCHjSCHjCHj 11 NH OH 1 1 Glu i I CHCK,$CH,CO,H 1 1 NH I 1 Glu Assumptions In carrying out a risk assessment on the basis of animal data, a number of assumptions have to be made. The first of these relates to the overall dosi metry. Experimental animals are exposed to concen trations of vinyl chloride or dosed with amounts of vinyl chloride that allow an estimate of the amount to which they have been exposed. It is possible to calculate a correction factor for these quantities so that they are applicable to man. However, rats and mice live for relatively short periods of time (up to 2 years) during which they develop cancers of a type similar to those seen in man. The latent period for the same tumours in man may be between 20 and 40 years. It is therefore assumed that the lifetime of man is equivalent to the lifetime of an experimental animal species even though the chronological time is sub stantially different. Strictly speaking, mathematical extrapolation of risk on the basis of experimental animal data pro vides an estimate of the risk at low doses to the experimental animal under consideration. A variety of factors, particularly inherent biological sus ceptibility and differences in metabolism, render the extrapolation of the data from animals directly to man subject to numerous errors. It is at this point that scientific judgement is required to decide whether these data are applicable to the human situation. Metabolism In rats, VCM has been 'shown to be metabolized extensively, producing a range of excretion products. CO,H 1 CHCH-SCHjCH, 11 NH(ac) OH () ro,H 1 CltCH,SCH,CO,H 11 NH, <n CO,H I C -----CHjSCHjCOjH II 0 (,)S{CH,tO,H>, t Fig. I. Scheme showing the metabolism of vinyl chloride monomer (VCM) in rats to 5-containing metabolites. VCM (a) is converted to chloroethylene oxide (b) which is trans formed spontaneously to chloroacetak'ehydc (c). These two metabolites are mutagenic and hence are considered to be the proximate carcinogens. The urinary excretion products AT-acetyi--(2-bydroxyetbyl)cyiteine (e) 5-(carboxymethyl)cystetne (f) end thiodigiycoliic acid (g) are derived from these mutagenic metabolites via (d). Gly and Glu are the glycine and glutamate residues of glutathione. (After Green A Hathway (1977)). BOR 008721 Table 2. Eptdemtolagical studies of cancer usociild with exposure to vinyl chloride monomer Reference No. in study* ---------------- (% follow up) Increase Sites (or tumours) with changa in SMR , ------------------------------- No increase Comments Monsoa rf of. (1974) 7 Brain Lung Urn, including ASL Tabcnhaw A Galley (1974) 13.4 (13V.) Buccal cavity and pharynx Significant Respiratory system SMR not Unknown site significant Lymphoma but increases Angiosarcoma with exposure and time Genital Digestive organs Urinary tract Leukaemia Duck tt of. (1975) 3120 None Some criticism of conduct of study Nicholson et at. (1975) 257 (99%) ASL On tt of. (1975) 594(94%) All tumours? ArsenicaIs involved Byrcn ft of. (1974) 771 (97%) Livcr/pancrcas Significant increase (I ASL) Cerebral? Increase not Cardiovaacutar significant ORC (1976) 10,173(95%) Digestive tract PMR study Rein! A Weber. 1976; 11,02. (90%) Malignant liver Related to duration of Re.nl tt at. I97S; Lymphatic system exposure Weber tt of. I9BI GI trad Brain Waswriter et at. (1976) 1151 Brain Respiratory tract Mixed exposure, not Lymphatic system VCM related ASL Fos A Collie. (1977) 7409(99%) Primary liver Not significant ASL Significant Stomach Brain Lymphatic and hacmoposetic system FreUel-Beymc tt at. (1971) 1611 (95%) Colonfstomach Proslatic hyperplasia BOR Bertazs tt at. (1979) 5441 (tt%) All tumours BufVkr tt at. (1979) 464 (100%) Respiratory system Chiazze A Fcrcnoe (1911) 3M7 Digestive system PMR study of female and male O o CD Chianc tt at. (1990) Beaumont A Breslow (I9BI) Liver Breast Respiratory trad fabricators Increase in PMR not confirmed by case-controlled study Review of nmc studies N Brain Vinyl chloride--rule assessment 191 l!|s i*l I Jt >* o '* "1 S a *S gX -*I |o.s s g1i i til Hi 1}!!I S 2 V S.V .a . t fl 3 5^ W W sj &^ 9Q '&C M ^V g 1 h. 3 &s u of VCM metabolism in rats is given in Fig. I. On the basis of this scheme, the highly reactive intermediates in the metabolic process (particularly chloroethylene oxide) react with cellular macromolecules, including DNA to produce the critical lesions leading to mu tation or the induction of cancer. Studies on the quantitative aspect of VCM metab olism have shown that there is a dose dependency in the rate of metabolism. After administration of l4C-labelled VCM by gavage at doses between 0.5 and 100 mg/kg to Wistar rats, the amount of "C 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 ,JC-labelled VCM for 6 hours demonstrated that the metabolism of VCM appeared to be in accordance with Michaelis-Menten kinetics (Gehring et al. 1978). The constants for maximum velocity of metabolism (V,, in pg metabolized/6 hr) and the Michaetis constant (Km in fig VCM/litre air) accord ing to the formula: K,, + S (where V velocity of metabolism in pg/6 hr and S concentration of VCM being inhaled) were Vn 8558 fig metabolized/6 hr and K,, - 860 ftg 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 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'* 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 BOR 008723 192 1. F. H. PURCHan at. Tble 3. vinyl chloride dow end incident* of hepatic anfioiafroma In Spraguo-Dewtey i ttpomtf mon <S idliewy/w/wkk ffuorr 92 wwklr* Coach (ppm) 30.000 10.000 6000 2300 300 230 200 130 100 so 23 to 3 1 0 Amount metaboliaod jig/4 hr 5647 5531 5403 30)0 3413 24)3 2129 1761 1309 739 395 169 84 17 0 p| (toul) 1.47 x 10* 1.44 x 10* 1.41 x 10* 1.3 x 10* g.l x 10' 6.3 x 10' 3.3 x 10' 4.6 x 10' 3.4 x 10* 1.9 x 10' 1.0 x 10* 4.4 X 10* 3.2 x 10* 4.4 x 10* 0 Angioiareoma inodenct (V.) Male 16.6 10.0 10.3 20.0 0 3.4 11.7 1.7 0 11 1.7 0 0 0 0 Female 43.3 13.3 33.3 23.3 20.0 6.7 1.3 S3 1.7 7.2 6.7 1.7 0 0 0 Mean 30.0 11.7 22.0 21.7 10.0 5.1 too 3.0 0.1 4.2 4.2 0.8 0 0 0 no. BT 4t Btl BT t BT 1 BT 1 BT 1 BT2 BT2 BT2 BR 1,9 BT IS BT 15 BT 13 BT 15 BT 1.2. 9,15 After MaUoni tt ai (1981). tExpenmcnt BT 6 ended after only 68 wk. while the rest were mil approximately 140 wk; therefore the percentage of ivinoun m BT 6 is probably low relative to the test because of the short latency period available. multistage model by the Food Safety Council (1980) and by Gaylor St Kodell (1980) showed that for the same 10'* lifetime risk, the Food Safety Council estimated the dose as 2 x 10'J ppm whereas Gaylor & Kodell estimated the dose as 5 x 10'* ppm. The difference between these two estimates was due to alternative assumptions on the value of the expansion of the exponential term used. In general, calculations based on the amount of material metabolized or on human data have pro duced exposure values of about I ppm for a 10'* lifetime risk. All the other studies have produced exposure values in the ppb range. A large variable appears to be the selection of the mathematical model applied to the experimental data. In the following section two models are used to calculate the exposure for a 10"* risk from a variety of experimental animal data applying the correction for metabolism used by Gehring et ai (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. Summiry of quantitative riik meaimcnu for vinyl chloride monomer* Reference Specie! Exposure for 10"* lifetime risk (ppbt) Comment! Seboeidennaa et of. (1975) Rat Kuzmack A McGaughy (1975) Gchnng et ai, (1979) Food Safety Council (1980) Rat, mas Rat. man Rat Rat Andcrioo et ol. (1980) Ceylor A Kodell (1910) Cirlbori (I9|) Barr (1982) This paper (Table 9) EPA (1980) NAS (1910) Cramp A Guess (1980) Rjt. man Rat Rat Man Rat Mouse Man Rat Mouse Man Rat Ral Man Ral By Malabo* 73 119 2 14 140-1400 >1000 <10->1000 20 20 2.1 x 10`* 3.9 x 10"' >1000 0,7 0.5 2.5 x 10-' >100 0 023-9.16\ 2* I0'h / 0.63-90 2 x 10*'-2 x I0*` 6 x 10**' 0.067-8.14 By laffeitoa 4pg/day 3 x I0*'m|/k|/day 0.7p|/day 0.3pg/dey Frobit (ilope -- 1. Menial) Logit (slope - 3.45) Lopt (dope - 2.3, one-bit) Liocar through.zero Log-probil BiotraAftformation data included Lisear or log.probit Depend! on mathematical model wed Onc'hit Armitaga-Doll Weibull Multihit DNA binding used for dosimetry Upper 97.5V. confidence limit of linear madd Armila|e*-Dotl Weibull Derived from Btrr't nesetive epidemioloiy Lo|-prnbit Lo|-probit includini biotrentformation data for man Weibull Weibull includini biotraiuformition for man Food or water Water Applying worker data to water Upper 93% confidence limits After Brr (1911). tEacepl where ruled oiherwiic. BOR 008724 \ . chloride--rule assessment 193 inhxlation (Table 5) Tor 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 tt at. 1978) have been applied. For Wistar rats, the K_ and V,, 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 V. and K,, values derived for Sprague-Dawley rats have been used. In the experiments by Feron et at. (1981), who used Wistar rats, the same assumptions about V,, and K.,, 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 WaUnabe A Cehnng (1976)). For mice, the data have been combined in Table 7. The estimation of the dose metabolized in mice has been calculated using values for V,, that have been adjusted on the basis that, for a chemical requiring metabolism to its active form, the quantity metabo lized will be proportional to the body surface area and must be expressed in terms of metabolized dose/kg body mass. This technique has also been used by Gehring tt at. (1978) for estimating the dose metabolized by man. Table S. Vinyl chloride dose >nd incidence of hepatic angiosarcoma in male Wiatar _____________________rats exposed on 5 dayVwk for SI wk Concn (ppm) Amount metabolized Anfiottrcoflii Pg/4 hr pg (lolal) incidence (%) Export no. 10,000 5521 1.4 x 10* 29.6 8T7 6000 5403 1.4 x 10* It.J BT7 2)00 5030 1.3 x to* 12.0 BT7 500 3413 I I x 10' 10 7 BT7 2JO 2435 6 3 x 10* 3.7 BT7 30 739 1.9 x 10* 0 BT7 1 17 4.4 x 10* 0 BT 17 0 00 0 BT 7. 17 Txblc 6 Vinyl chloride (VCM) dose ind incidence of hcpxtie angiosarcoma in rats given VCM by gavage or ingestion Dote 16.65 3.33 10 03 0.03 0 3001 14.11 5.0 . , 1.7 0 Amount (V. of dose) 50 35 10 2 1.7 1.4 -- to 32 16.5 2 69 Amount metabolized pg/doset 6250 2705 750 3245 74 7.4 0 15,000 2390 1040 420 0 pg (total) 1.6 x 10* 70 x 10* 20 x 10* 7.26 x 10* 2.16* 10' 2.16* 10* 0 6.2 * 10* 1.65 x 10* 7.25 x 10* 2.9 * 10* 0 Anfioureoma incidence (V,) Mile 20 10 0 1.3 0 0 0 49 49 10 0 0 Ferrule 22.5 15.1 0 2.7 1-4 0 0 53 16 4 0 0 Mean 21.2 12.5 0 2.0 0,7 0 0 Jt' 32 7 0 Expmt no. BT II BT 11 BT 11 BT27J BT 27 BT 27 BT It. 27 Feron tt o/ (1911) `Calculated from data derived from Wannabe A Cebnog (1976) presented in Fig. 2. tAsaumiog a 2S0-g rat. {Sprague-Dawley rats doted by gavage with VCM in com oil i tima/wk tar S2 wk, IST27 dosed for S9wk. | Wistar rau used a> controls by Faroe it at. (1911) and dosed for S3wk. lWistar rau receiving a diet containing VCM dissolved in PVC. BOR 008725 1. F. H. Purchase tt al. 194 Table 7, Vinyl chloride doK mil t"e*dence of hepatic ih|iOiiraima to mie Coach (ppm) 10.000 4000 3500 1000 500 230 230 50 1 0 Amount rnelaboiind P/4 hr 11,245 11.007 10.246 8699 6952 4959 4959 1504 1306 0 PI (total) 1.7 x 10* 1.7 x 10* 1.5 x 10* 5.4 x 10* 1.0 x 10* 7.4 x 10* 74 x 10* 2.2 x 10' 5.9 x 10' 0 An|ioiareoma modem (%) Male 3-8 4.7 20.7 39.4 20.0 300 24.0 3.3 10.3 0 Female M 34.7 JJJ 50.0 24.7 30.0 47,0 0 0 0 Mean 17.* 11.7 17.1 44.7 23.3 30 0 34.3 1.7 5.2 0 no- BT 4BT4 BT 4 Lai at e/.t BT4 BT 4 Lae ti a/.t BT 4 Lac tl a/.t BT4 A Lae er al. *5wits mice. 8l*wk cipcnment, doted for 30 wk. tCD, mice, 52-wk experiment, 6 hr/dey expofurt (Lee n itl. 1978). These results have not been included in the calculations for Table 9 because the experimental design incorporated interim kills. Thus: ,, v 0.011 m2 -5706^g/4hrx|21i - 1395 /ig/4 hr The values of 0.045 m2 and 0.011 m2 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 V,, 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 V. for the mouse on a mass-equivalent basis is therefore: 11625 /ig/4 hr This value of V,, has been used in calculating the total amount of VCM metabolized (Table 7). From the variety of models (or mathematical ex trapolation techniques) used for low-dose risk extra polation (Table 4), an arbitrary choice of models has been made to test the robustness of the extrapolation from the different animal studies. A log-probit analysis of the dose that would be expected to produce a lifetime risk of ASL of 10'* is presented in Table 9. This calculation can be carried out on the basis of the concentration inhaled, the daily dose metabolized or the total quantity metabo lized during the whole experiment. There is a wide variation in the estimated dose depending on the database used for the calculation. The largest vari ation between doses derived from the rat experiments is 360-fold (0.025 ppb v. 9.1 ppb) when exposure in ppb is considered, but this decreases to 100-fold for other estimates of dose. The results from mice are substantially lower when expressed in ppb (2 x 10~15 ppb) but the difference is less for other expressions of dose. Similar calculations of the dose expected to give a 10'* lifetime risk of ASL have been based on a Weibull analysis (Table 9). This is a more 'conserv ative' mathematical model and the estimates of dose are accordingly lower. The variation in estimates of dose is, if anything, larger than that observed with the log-probit analysis (for example, a I0"J difference between the .S values derived from Wistar and Sprague-Dawlcy 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 V,, for man of 1675 jig/8 hr based on corrections for body surface area and mass. The values are substan- Tibk I. Vinyl chloride (VCM) dote end hepatic tnpojireom. incidence in Sprague-Dewley nil expoiad to VCM by inhiltnon Coitcn (ppm) 10.000 10.000 10,000 10,000 10.000 4000 6000 6000 6000 6000 Schedulet iinii IV V iin1t IV V dotet 240 85 25 100 25 260 85 25 100 25 Amount metabolited} pg/4 hr 5521 5521 5521 1379 3521 5403 5403 5403 1350 5403 p| (total) 1,4 x 10* 4.7 x 10' 1.4 x 10' 1.4 x 10' 1.4 x 10' 1.4 x 10* 4.4 x 10' 1 4 x 10' 1.4 x 10' 1,4 x 10* AapoMreomt incidcitea (%) ' Expmt Male Female Mein no. 10 13.3 11.7 BT 1 0 0 0 BT 3 1.7 0 08 BT 10 0.81.7 0 0.8 BT 10 0 1.7 BT 10 10.3 33.3 22.0 BT 1 0 3.3 1.7 BT 3 0 0 0 BT 10 3.4 1.7 2.5 BT 10 0 1.7 0.8 BT 10 After Miltoni n al. (1911). (Scheduler I--4hr/day, 5 dayi/wk for 53 wk; II--4hr/day, 3 diyi/wk for 17 wk; III--4 hr/dey, J dayi/wk for 5 wk; IV--I hr/dey, 4 dayt/wk for 25 wk; V--4 hr/dey. I dey/wk for 15 wk. tArftount mctabobKd (v) in 4 hour derived from the formula: V (pi/hr) V,, x S/K, + S wham V. it 4/4 of the 4hr value. 08726 Table 9. Quantitative risk estimations derived from available animal caranogentcily data and eiprcsscd as the amount or concentration of vinyl chloride calculated to gjve a lifetime fish of ASt of JO'* dlW on the basis of bg-probil analysis Of a WwbuB distribution______________ ____ Table no. Experimental data Exposure for rodents (S ppb*> Amount metabolized in 6 hr by rodents (V pg/tthrl Total amount metabolized by rodents (TM mg) Exposure (ppb) calculated from V (S calculated for man)| 4 S-D rats, inhalation s Wislar rats, mate only, inhalation 6 Rata, ingestion--Wislar -S-D --both| Mice, inhalation 4. 3 Wislar and S-D rats combined, inhalation 1 S-D rats, short-term inhalation 4 S-D rati, inhalation Wistar rats, male only, 3 inhalation 6 Rats, ingestion--Wistar -S-D --bolhf 7| Mice, inhalation 4.5 Wistar and S-D rati combined, inhalation a S-D rats, short-term inhalation 0.025 Log prmbtt ana)yds( l,U 9.16 3 x 10"* m|/t| 9 m KT'mi/ki 6 x I0~* mg/kg 2 x 10' " 159 0.69 rag/dose 119 mg/doae 1.70 mg/doae 0.60 0.031 -- 2 10 ` 1.41 0.004 WtM dhlribwdaot 0.013 2 x 10-' 9 x 10**mg/kg 4x 10*mtfkf 2 x I0'"mg/kg 6 x 10" I5.T 3 x IO-*mtfdtn* 0.33 mg/dose 0.003 mg/doae .2 x 10 * 6x10-* -- , 0.0172 3x 10 * 0.303 39.3 227 02 0.H 00061 0 35 2.16 0.0012 36* 00002 0001 0.0015 2 x 10 * 0.0042 0.19 0.63 90 -- 0.03 0,72 -- 0.067 1 14 1 x 10 ' 0.009 ASL Ao|kmfcoRU of the fiver S-D Spri|ue-Diky Except where stated otherwise. 1 Exposure calculated from V (in column 3) using the formula: S V x 160/1673 - V, where V. for man is 1673 pg/S hr. (Estimated using maximum likelihood. (Wistar and S-D rats combined. |Study BT 4 only. BOR 0 0 8 7 2 7 196 I. F. H. Purchase el. tiilly 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 x I05pg 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 lO'pg is equivalent to about 200 ppm adminis tered over 52 weeks and represents a practical thresh old for this series of experiments. In conclusion there is a wide variation in the estimates of dose for a 10*` 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 all available data, including epi demiology, to provide a degree of reliability. Risk assessment from human studies Register of ASL casts Since 1974, lists of reported ASL cases attributable to VCM exposure in the VCM/PVC industry have been kept by NIOSH (Spirtas & Kaminski, 1978), by IARC and by the VCM Committee of the Association of Plastics Manufacturers in Europe (APME). Details of 99 cases in the APME register at Table 11, Cleaterint of ASL tuu in indlridual SVC plants Flam* no. Country . No. of ASL CBM WynEnpi 1 Wcu Germany 2 Wi Germany 3 Wtjt Germany 4 Wwt Germany 1 France 2 France 3 France 1 UK 2 UK 1 Sweden Nenk America 1 Canada 1 USA 2 USA 3 USA RcMefWarid 1 Japan 1 Yugoslavia 1 Cnchoelovakia Tout... Tola)... 10 4 2 i i 3 2 3 2 3 42 to II 9 4 34 2 4 2 Total... s For die purposes of this ease study, it is um immiry to iieaufy the pncisc ownership end location of these pleats. the end of 1982 have been analysed by country and by manufacturing company and plant. The cases have been recorded from all major VCM/PVC manu facturing countries (Table 10), but the incidence has not necessarily been in proportion to the PVC pro duction capacity now or prior to 1962. In the absence of data on the number of workers employed, pro duction capacity is the only available indication of the numbers of people potentially exposed. The majority of the ASL cases are PVC autoclave cleaners or men who have worked in or around autoclaves. There are ASL cases among men who manufactured VCM and a few cases were involved both with monomer and with polymer production. Only one case suffered from both acro-osteolysis and ASL. The ASL cases tended to occur in larger numbers in some plants than in others (Table 11). Of the total of 39 ASL cases recorded in North America, 34 have occurred at four PVC plants, while over 40 Table IQ, Distribution of ASL cma by country FVC production nameplate capacity (kilotonnee/yr) Country USA West Germany France Canada UK Sweden Yugoslavia Italy Czechoslovakia Japan Belgium Norway Total... Weftem Europe North America Kelt of World Tout... ASL cater 1932 1962 29 193 704 21 22 260 14 M 176 10 5 22 7 27 177 5 3 20 43 1 3 9 212 2 1 IS 2 12 384 1 3 23 1 2 20 99 32 12 931 39 lS 726 1 31 709 99 331 23S6 ASL Anpottrcomt of iht liver 1972 2090 1133 627 IS 302 103 60 771 41 1699 193 65 3930 2171 3334 9462 Bor 008728 Vinyl chloride--risk aiaeumcnt jrku n act ... number* by year of 4ciH and gngnpkieal location (cacludiai fTOI*) Year of death 1955 6 7 1 9 I960 1 2 3 4 3 6 7 t 9 1970 1 2 3 4 5 6 7 1 9 1980 I Western Europe FI G1 Swl G2 Nl, Sw2. UKI. Il2 OJt 04, G5, UK] F2, F3. GO, G7. GS. It) Bl. F4. F5. F4. F7, Sw] FI. F9. GI0, Gil, GI2. Sw4 FI0, FI 1. G9, GI3. GI5, GI6, GI7 FI2, FI], UK4, UK5. GIS UKS. UK7, G19, $w5, G20. G2I ltd. FI4. UKS, G22 ASL caiaat in: North America Cl C2 uss CJ US5 C4, C5, US4, US7. US 10 US 12. USI6 USII C6. US2 ct Cl. USI. US], US2] C9. USI3 USS, US9. US IS. US2S US 19, US20. US22 CIO, US21, U$24$ US27. US2S USD. U529. US30, US32 -- |Ccy Rat of world publication! * Ci2 Yl. Y2. Cal iapl Jap2, Y3 Y4 Viola Malloni Cratch A Johnson Total.. 52 Jl| s ASL * Angiosarcoma of the liver `Italian caie 01 wn not a typical ASL: hit primary tumour was probably of the pericardium. This man wai cnfeted in eatnriion of PVC inclti. IB - Belgium, C W. Germany; Sw - Sweden; C -- Cenede; It Inly; UK United Kingdom; Cl CuchoiloTikie; Jap - Jeptn; Y m Yugoilevii; F - Fnncc: N - Norwey; US - USA. Thue G9 cue no. 9 in Wat Geimeny. Cua UK2, Git, US14, USD end US25 were shown not to he euocieted with VCM exposure end hence withdrawn from the lilt. (Aerosol enn Siler. fCholengiouicome. | Does not include US] I (still elivr). 197 North American PVC plants have not recorded an ASL case so Tar. The average latent period between starting work in an occupation involving VCM exposure and death from ASL for the 99 cases is 21.9 years (in France, Sweden and the USA between 24 and 25 years, in Germany about 18 years). It is still too early to predict whether the annual number of ASL cases amongst VCM workers has reached a peak. ASL cases appeared earlier in North America than in Western Europe and while the occurrence is tending to decrease in North America (Table 12), it is still high in Western Europe. On the basis of the data in this case register, it is possible to draw certain conclusions about risk fac tors associated with ASL. The large number of ASL cases in some factories and the absence of ASL cases in others of similar age indicates that variations in manufacturing practices between factories may be the cause. These variations may reflect both differences in the types ofjob carried out by individual workers and differences in engineering practices. The bulk of the cases have occurred, however, in highly exposed autoclave cleaners, with relatively few in other PVC or VCM production jobs. So far no wellauthenticated cases have occurred in PVC com pounding or fabrication where many more people have been exposed but to a much lovyer dose. Prediction of future ASL cases as a consequence of pre-1974 exposure The causa) 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. BOR 008729 I9t I. F. H. PuacHASE ei d. Table IJ. ASL caee numbere by etar of Itm npoiiuv and ropiphicaJ localkw (eacfadim ITOf) Year or firvl CfpOftUfY Western Europe ASL caicct m: North America ---------- Key Rtil of world tvcnii 1939 40 1 Frll 2 ) FrI4 4 UKl 5 Sw2 ft Frl. Fr3. Sw4 1 Sw3 8 Fr9 9 FrlI. Ff4 1950 1 2 Ft?. HI. UKS Swl. UKS GJ 3 G15. KJ 4 07, GS. UK4. GI9 s Gil, GI6. Gil 6 FrIO. Gl 7 Frl. G4. UI, G2 8 Ff4, B1 9 Fr2, 1*4 I960 GS. GI3 1 G9, GIO, G12* GI7. G20. GI2 3 G6, UK6. G2I 3 FrU. UK7 4 S*5 5 FrJ 6 UKS 7 8 9 1970 1 2 3 Total... 52 US24J C], US27 USIJ. US29 Cl, USI9 Cl. CS. USX US7. US2I C4, US3, US9 Cl. C9, USI. USU, US2I, US3I| C6. US22. US26 USI USI2 USI6 USI0. US32 US4 CIO USIS US2, USI7, U520 US23 Y2. Cx2 Japl, Y1 Y3 Cal Jap2, Y4 * CS US6 US30 Viola Maltoni 39 S ASL - Anpotarcomi of (he liter *1(01 not continent with other ASL cue*; the primary tumour may heve been of the pericardium. The men extruded PVC tacks. ' tFor explanatory key, *ee Table 12. }Cholanfotareoma. |U531 u nil! alive, j Aerosol 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 (I) 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 that it is representative of the worldwide population) and to use these rates to derive a simple model of dose-response latency that can be applied to the population data. The broad conclusions are that most cases have a latency of about 20 years and cases will continue to occur for the next 10 years. In the calculation used to estimate the future number of ASL cases (Table IS) an assumption has been made that when exposures were reduced to low levels, the future risk of ASL became negligible. Two dates at which the negligible risk levels were attained have been selected: 1964, when levels were reduced to hundreds of ppm and 1974 when the levels were reduced to below 10 ppm following the discovery of BOR 008730 Vinyl chloride-risk assessment Table 14. Annua) inddeecn of ASL cases (dam of death) bT teofinphial area Year Western Europe No. of ASL case* dying m: North America Reft of world AaooiJ total Cumulative total Kty CVOftU 1955 7 1961 2 4 7 a 9 1970 1 2 3 4 5 7 t 9 I9M 1 2t Tout... t 1 1 1 1 1 5 12 11 12 41 \4 32 64 43 63 72 5 64 4* 00 521 3* i1 12 13 i4 12 6 17 5 12 3 15 2 *7 Viola 3 20 5 25 3 1 33 Maltoni 3 31 Goodrich 1 II 49 2 II 60 9 69 1 10 79 5 84 10 94 4 91 00 t 98* 91* A5L Angiosarcoma of the livtr Dm not include US] I (Mill alive in 1911). tAI lime of compilation. {Includes GO) (aerosol con filler) but omit* Ml (hog eitruder). l the association between ASL and VCM exposure. A hypothetical exposed population of 100,000 has been used, but this is unimportant (see (a) below). An estimate or the age distribution within the hypothet ical 'total' exposed population of 100,000 has been based on UK data (Fox & Collier, 1977). For persons already exposed during the whole of the various latent periods, the numbers with a latency of 30 years or more form only a small proportion of the total. The numbers of persons at risk in the future are calculated by advancing time in 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. 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 IS. Hypothetic*! calculation of future ASL cates utinf two different attumptions about the date at which the levels became tree of mk ____ Calculations assuming no nsk alter 1964 Calculations stiumint no risk after 1974 Latency (yr) 1-3 6-10 11-15 16-20 21-25 26-30 31-35 36-40 4MS 46-50 5116- Cases to date Persons at risk to date 0 100.000 1 91.250 M 95.300 21 *4,750 28 61.400 IS 36.750 6 21.250 6 6750 0 600 00 0 -* 0 5-yr incidence 0.00 0.01 0.12 0.33 0.46 049 0.21 0.19 7 7 7 0.50 Future penons ftl risk 0 0 0 6750 24.530 41.730 48,100 51.750 45.750 34.500 47.600 300.750 Future eases 0 0 0 2 11 20 1) 46 7 7 7 150 Person! et risk to date 100.000 94.300 78.000 46.500 28,750 11.750 10.850 3500 310 0 0 5-yr incidence 000 0.01 0.14 0.60 0.97 0.96 0.53 1.71 7 7 7 0.80 Future persons t nsk 0 3750 17.500 45.000 57.200 39,750 31.500 55.000 46.350 34,500 47.600 403.900 Future cases 0 0 2 27 57 37 32 94 7 7 7 32) For detail! of the laaumptiopl and methods see test (pp. 197 A 191). Bor 008731 200 I. F. H. Fukchab a 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. Tor 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 ofcases of ASL likely to result from previous exposure to VCM. Nicholson ei al. (1984) suggest that there will be a further 1500 cases of ASL, while Forman ti al. (1986) conclude that a further 150-200 deaths might be expected over the next 30 yean. 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 ei 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 ind 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 ei 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 I0*` on the basis of these data give extremely low levels (down to 3.9 x |0*'ppb) which appear to be unrealistic estimates for man. Part of the reason for this is that laboratory studies have shown that VCM is metabolized in the liver (and elsewhere in the body) to the reactive metabolites chloroethylene ox ide and chloroaceialdehyde. The rate of conversion is limited at high levels of exposure giving inaccurate estimates of the slope of the dose-response re lationship. It has not been possible to estimate the rate of conversion in man. and hence extrapolation of these low-risk dose estimates is conjectural. The second part of the problem of extrapolation at low risk is the selection of the most suitable mathematical model for extrapolation. Using Maltoni's data from rats (Maltoni ri 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 1(F). Larger differences are obtained with calculations using the Wcibull analysis as a basts 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 10s pg (equivalent to inhalation of 200 ppm) was required to produce an elevation in ASL inci dence. This dose represents a practical threshold in rodents. At this stage in their development, mathe matical models for low-risk dose estimates are not sufficiently reliable or reproducible to engender confidence in their use. , Using negative epidemiological studies of popu lations living in the vicinity of VCM production facilities, an estimate of the dose for a 10'* lifetime risk in man may be made (Barr, 1982). The value (100 ppb) is similar to the highest estimates derived from animal data and taking biotransformation data into account, is substantially larger than the lowest estimates, which are up to 1010 lower (3.9 x 10''ppb using a multi-hit model). The higher estimates are compatible with occupational experi ence and suggest that the current hygiene standard of around I 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. BOR 008732 Vinyl chloride--risk assessment 201 Acknowledgements--We thank Or M. Thomas for his help with the calculations and Or 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,, Hoet D. G. A Kaplan N. L. (1980). A general scheme Tor the incorporation of pharmacokinetics in low-dose risk estimation for chemical carcinogenesis: example--vinyl chloride. Toxic, appl. PHormac. 55, 154. Barnes A. W. (1976). Vinyl chloride and the production of PVC. Proc. X, Soc. 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. A Breslow N. E. (1981). Power consid erations in epidemiologic studies of vinyl chloride work ers. Am. J. Epidcm. 114, 725. Bcrtazzi P. A., Villa A., Foa V., Saia B,, Febri L,, Mapp C, Marccr C., Manno M., Marchi M. A Bottasso F. M. (1979). An epidemiological study of vinyl chloride ex posed workers in Italy. Archo higrada toxicol. 30, 379. Buffler P. A., Wood S., Eider C,, Suarez L. & Kitian O. J. (1979). Mortality experience of workers in a vinyl chloride monomer production plant. J. occup. Med. 21, 195. Byrcn D,, Enghol G., Englund A. A Wcsierhotm P. (1976). Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Envir. HUH Perspeet. 17. 167. Carlborg F. W. (1981). Dose-response functions in carcino genesis and the Weibull model. Pd Cosmet. Toxicol. 19, 255. Chiazze L. A Ference L. D. (1981). Mortality among PVC-rabncating employees. Emir. HUH Perspeet. 41,137. Chiazze L.. Warg O., Nichols W. E. A Ference L. D. (1980). Breast cancer mortality among PVC fabricators. J, occup. Med. 22, 677. Conference to Reevaluate the Toxicity of Vinyl Chloride Monomer. Poly(vinyl Chloride) and Structural Analogs (1981) Conference sponsored by N1EHS/NIOSH/OSHA at NIH, Bcthesda, March 1980. Emir. HUH Perspeet. 1981. 41, 1-231, Cook W. A.. Grever P. M.. Dinman B. D. A Magnuson H. J. (1971). Occupational aero-osteolysis II. An indus trial hygiene study. Archs emir. Hhh 22. 74. Cooper W. C. (1981). Epidemiological study of vinyl chlo ride workers: mortality through December 31, 1972. Envir. HUH Perspeet. 41, 101. Creech J. L. A Johnson M, N. (1974). Angiosarcoma of the liver in the manufacture of PVC. J. occup. Med. 16, ISO. Crump K. S, A Guess H. A. (1980). Drinking Water and Cancer. Report no. PB8I-I28167. NT1S. Washington. Duck B W,, Carter J. T. A Combes E. J. (1975). Mortality study of workers in a polyvinyl chloride production plant. Lancet II, 1197. EPA 11980). 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. A Spit B. J. (1981). Lifespan oral toxicity study of vinyl chloride in rats. Pd Cosmet. Toxicol. 19, 317. Filatova V. S., Anlonyuzhenko V. A.. Smulevich V. B.. Fedotova 1. V.. Kryzhanovakaya N. A., Bochkareva T. V,, Goryacheva L. A. A Bul-bulyan M. A. (1982). The blastomogenic hazard of vinyl chloride (a clinico-bygicne and epidemiological study). Git. Truda prof. Zoboi. 26 (I), 28. ' Food Safety Council (1980). Proposed System for Food Safety Assessment. Final Report. FSC, Washington, DC (Also in Pd Cosmet. Toxicol. 1910. It, 7IIJ. Forman D., Bennett B., Stafford J. A Doll R. (1986). Vinyl chloride and angiosarcoma of die liver--a report of the register of cases. Br. j. btd. Med. 42, 750. Fox A. 1. A Collier P. F. (1977). Mortality experience or workers exposed to vinyl chloride monomer in the manu facture of polyvinyl chloride in Great Britain. Br. J. md. Med. 34, I. Fretxel-Bcyme R,, Schmitz T. A Thiess A.M. (1978). Mortalititsstudie bci VC/PVC Arbeiteme der BASF. Akiiengcsellschaft. Ludwigshafen am Rhein. Arbettsmed. Sosialmed. Preveniivmed. 13, 218. Gauvain S. (1976). Vinyl chloride. Proc. R. Soc. Med. 69, 275. Gaylor D. W. A Kodell R. L. (1980). Linear interpolation algorithm for low-dose risk assessment of toxic sub stances. J. emir. Path. Toxicol. 4, 305. Gehring P. J., Watanabe P. G. A Park C. N. (1978). Resolution of dose-response toxicity data for chemicals requiring metabolic activation: example--vinyl chloride. Toxic, oppl, PHormac. 44, 581. Gehring P. J.. Watanabe P. G. A Park C. N. (1979). Risk of angiosarcoma in workers exposed to vinyl chloride is predicted from studies in tats. Toxic, appl. PHormac. 49, 15. Green T. A Haihway D. E. (1975). The biological fate in rats of vinyl chloride in relation to its oncogenicity. Chemico-Bioi. Interactions II, 545. Green T. A 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. A Adams W, G. F. (1967). Acro-osteolysis occurring in men engaged in the polymerisation of vinyl chloride. Br, med. J. 3, 712. 1ARC Working Group (1979). Monographs on the Evalu ation of the Carcinogenic Risk of Chemicals to Hwnans, Vol. 19. Some Monomers, Plastics and Synthetic Elas tomers and Acrolein, p. 377. International Agency for Research on Cancer, Lyon. Inianie P. F. (1981). Observations of the site specific carcinogenicity of vinyl chloride to humans. Emir. HliH Perspeet. 41, 89. Kuzmack A. M. A McGaughy (1975). Quantitative Risk Assessment for Community Exposure to Vinyl Chloride. US EPA Report, 5 December. EPA. Washington. DC. Lee C. C.. Bhandari J. G. Winston J. M,, House W. B., Dixon R. C. A Woods 1. S. (1978). Carcinogenicity of vinyl chloride and vinylidene chloride. J. Toxic, emir. HUH 4, 15. Lester D., Greenberg L. A. A Adams W. R. (1963). Effects of single and repeated exposures of humans and rats to vinyl chloride. Am. ind Hyg. Ass. J. 24, 265. Loprieno N., Bavale R., Baroncelli S., Bartsch H.. Brouzetti G,, Gxmmctlini A., Corsi C,, Freza D,, Nieri R., Leporini C.. Rosellini D. A Rossi A. M. (1977). Induction of gene mutagens and gene conversions by vinyl chloride metab olites in yeast. Cancer Res. 36, 253. Maltoni G. Lcfeminc G.. Ciliberti A.. Cotti G. A Cxrretti D. (1980). Epidemiologie animate et epidemiologic hu mane: le cas de chlorure de vinyl monomere. In XXe Riunion de Club de Canctrogenese Cktmigue, ISBN 2.86315.007.3. p. IS. Publications Exsentielles, Paris. Maltoni C.. Lefemine G., Ciliberti A.. Cotti G. A Carretti D. (1981). Carcinogenicity bbassays of vinyl chloride monomer: a model of risk assessment on an experimental basii. Envir. HUH Perspeet. 41, 3. Maltoni C. A Rondinella R. (1980). Hepatic angiosarcoma in workers exposed to vinyl chloride in Italy. Acta Oncologica I, 35 (in Italian). Meycrson L. B. A Meier G. C. (1972). Cutaneous lesions in acro-osteolysis. Archs Derm. 106, 224. FCT ll/l-F BOR 008733 302 ]. F. H. Puaoust m of. Ministry of Agriculture. Fisheries and Food (1978). Survey of Vinyl Chloride Content of Polyvinyl Chloride for Food Contact and of Food*. HMSO. London. Monaon R. R., Petcre J. M. ft Johnson M. N. (1974). Proportional mortality among vinyl chloride workers. Lancet U, J97. NAS (National Academy of Sciences) (I9S0). Drinking Wattr and Health. Vol.). p. Jl. National Academy Preu, Washington. Nicholson W. J,, Hammond E. C. Seidman H. & SelikofT ). J. (1975). Mortality experience of a cohort or vinyl chloride/polyvinyl chloride workers. Lonert U, 1197. Nicholson W. J., Henneberger P. K. A Terr D. (19*4), Trends in cancer mortality among workers in the synthetic polymers industry. In Industrial Hazards ef Plastics and Synthetic Elastomers, p. 65. Alan R. Liss, New York. ORC (1976). Mortality data collected by ORC concerning the effects of vinyl chloride exposure in PVC fabrication. Cited by Barr (1982). Oil M. G.. Langner R. R. A Holder B. H. (1975). Vinyl chloride exposure in a controlled industrial environment. Archs emir. Hllh 30, 333. Rannug V., Gothe R. A Waehtmeister C. A. (1976). The mutagenicity of chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroxeetic acid, conceivable metabolites of vinyl chloride. Chemico-Siol. Interactions 21, 251. Reinl W. A Weber H. (1976). Stand der epidemiologischen Forschung uber die Vinylchlorid-krankhen. Zentbl. ArbMed. ArbSchulz 26, 97. Reinl W., Weber H. A Greiser E. (1978). Epidemiology study of the mortality of workers exposed to vinyl chloride in FRG. Paper presented at the 19th Inter national Conference for Occupational Health, Dubrovnic, September. Schneiderman M. A., Mantel N. A Brown C. C. (1975). From mouse to man--or how to get from the laboratory to Park Avenue and 59lh Street. Ann. N.Y. Acad. Set. 246, 237. Selikolf I. J. (1975), Toxicity of vinyl chloride/polyvinyl, chloride. Ann. N.Y. Acad. Sei. 246. Spinas R. A Kaminski R. (1971). Angiosarcoma of the liver in vinyl chloridc/polyvinyl chloride workers. J. occup. Med. 20. 427. Suciu J.. Drejman I. A Valaskii M. (1963). Contributions to the study of disease by vinyl chloride. Med. Interna IS, 967 (in Italian). Szadkowski D. ft Lehnert G. (1982), Vinylehlorid alt Krankhfitsurxecht. Eine Bibliographic. VKE, Frankfurt. Tabershaw j. R. ft Gafley W, 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. ft Allard P. (1981). Cancer mortality of a group of Canadian workers exposed to vtnyl chloride monomer. J. occup. Med. 23, 671. TorkelsonT. R.Ogen F. ft Rowe V. K. (1961). The toxicity of vinyl chloride at 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 carcinogenicity of VCM. DHEW. Washington. DC. Verburgt F. G. ft Vogel E (1977). Vinyl chloride muta genesis in Drosophila melanogasler. Mutation Res. 4S, 327. Viola P. L. (1969). Pathology of vinyl chloride. Proceedings of the 16th International Congress on Occupational Health. Tokyo. Watanabe P. G. ft Gehring P. J. (1976). Dose-dependent fate of vinyl chloride and its possible relationship to oncogenicity in rats. Emir. Hlth Perspect. 17, 145. Waxwciier R. J.. Stringer W., Wagoner J. K.. Jones J., Falk H. ft Carter C. (1976). Neoplastic risk among workers exposed to vinyl chloride. Ann. N. Y. Acad. Sci. 271,40. Weber H,, Reinl W. ft Griescr E. (1981). German in vestigations on morbidity and mortality of workers ex posed to vinyl chloride. Emir. Hllh Perspect. 41, 95. Wilson R. H,, McCormick W. E,, Tatum C. F. ft Creech J. L. (1967). Occupational aero-osteolysis. J. Am. mcd. Ass. 201, 577. BOR 008734