Document MJEJqn6eYdoRM68ZnDjgBj9Dj

R&S 024717 Volume 25 Number 2 K--1711 -- (100) 119871 February 1987 (formerly Food and Cosmetics Toxicology) An International Journal published for the British Industrial Biological Research Association Research Section T. Detahunty. L Rrcber and D. Hollander M3 Intestinal permeability changes in rodents: a possible mechanism for degraded carrageenan-induced colitis A. Ogata, Sf. Yonevama, M. Sasaki, K. Suzuki and T. imormch: 119 Effects of pretreaimtm with SKF-525A or sodium phcnobarbilal on thiabendazole-induced teratogenicity in ICR mice S, . Smith, p, R, hicl-lhotton and F. M. Sutiwan 125 Effects of administering caffeine to pregnant rats eiiher as a single daily dose or as divided doses four times a day C.-L, Yu and B, Suatninaihan 135 Mutagenicity of proanthocyanidins W. M F. Jongen, W. A. J. S. van Boekel erd L. W. van Brotkhoven 141 Inhibitory effect of cheese and some food constituents on mutagenicity generated in Fieic /aba after trealmer-. with nitrile S, Ohyatna, T. Inamasu, M, Ishizawa, N. Ishinishi and K, Malruura 147 Mutagenicity of human unne after the consumption of fried sailed salmon J. H. Forsell. R. Jensen, J.-JI. Tai, M, IFill, W. S, Lin and J. J. Pesika 155 Comparison of acute toxicides of deoxynivalenol (vomitoxin) and 15-acet/ldcoxynivalcaol in the 36C3F, mouse J. J. Welsh, T. F. X. Collins. T. N. Black, S. L. Graham and M. W. O 'Donnell, Jr 163 Teratogenic potential of purified p-mtachlorophenol and oerttachnroanisole ~ ' in subchrontcally exposed Sprague-Dawley rats C, L. Kennedy, Jr, M.-Ji, Lu and J, W, MeAlack t S j. Williams, B. B. Baker and K.-P. Lee 173 Teratogenic evaluation cf l,1.3.3-tetrabu:ylurea in the tat following dermal exposure 177 Formation of acute pulmonary toxicants following thermal degradation or perfiuoricated polymers: evidence for a critical atmospheric reaction Fd Chem. Toxic, is indexed/abstracled in Current Contents, Excerpta Medica, Index Medicus, MEDLINE, CABS and B10S1S Database, [continued on inside back cover ISSN 0278-6915 FCTOD7 25(2) 113-210 (1987) I V, R&S 024718 i- ^ GY & icesler, UK lauld Walk, zlude ^^P/stems iij ous system X :eptors, v 3ases $ a ases ;eases CONTENTS--<onttnucd from outside front cover] Review Section A /. /A Purchases J- Stafford and C. hf. Paddle RVirW5 OF RECENT PUBLICATIONS Information Section Announcements Forthcoming Papers Software Surrey Section rig?) Vinyl chloride an assessment of the risk of occupational exposure \) ? 203 (207yPEGs and other chcrricnli a biohazard? Mushroom carcinogenicity 209 210 I rnon 10X3 OBW, UK >fk 10513. USA '' Some other Pergamon Journals which may interest readers of Food and Chemical Toxicology-. Annals of Occupational Hygiene Archives of Oral Biology Atmospheric Environment Biochemical Pharmacology Chronic Diseases European Journal of Cancer and Clinical Oncology Health Physics Journal of Aerosol Science Life Sciences Toxicology in Vitro Toxicon Each journal has an individual Information and Index Leaflet giving full details, Write now for any leaflet that interests you. -.V.^ .. K-nn-Ow^ Fd Ch*m. Toxic. Vol 23. No, 2. pp. JS7-2C2, 1987 Pnr.ted in Gri Bnum. All n*hu rwcrved 0278-6915/*7 S3 00 + 0.00 Copyn&hi 'C 1987 PeTgamon JounuU Ud Review Section VINYL CHLORIDE: AN ASSESSMENT OF THE RISK' OF OCCUPATIONAL EXPOSURE* I. F. H. Purchase Central Toxicology Laboratory J. Stafford Plastics and Petrochemicals Division and G. M. Paddle Central Medical Croup. Imperial Chemical Industries pic, Alderley Parle. Macclesfield. Cheshire. England (Received 14 December 1983; revisions received 13 January 1986) Introduction Vinyl chloride monomer (VCM), more properly named monochlorethanc, is a colourless gas normally handled under pressure as a liquid which boils at -- 14C at normal pressure. Discovered around 1835, VCM's commercialization did not begin until the 1930s and did not reach high volume until after 1945. Present manufacture is around 12 x 10* tonnes per annum, nearly all of which is used to make the polymer polyvinyl chloride (PVC). Until `he 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 arc many reports of employees exposed to VCM monomer in polymer plants becoming dizzy and unconscious. Because VCM was considered to be relatively innocuous, it had a threshold limit value (TLV) of 500 ppm, S-hr time-weighted average (TWA) for many years (ACGIH. 1974; Lester et al. 1963; Torkelson et al. 1961). Measurements of em ployee exposure were infrequent, since most mea surement and warning systems were designed to , ensure that plant atmospheres were beyond the cxj 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 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. Qayson. D. Krtwski 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 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 wails. Some of these men developed acro-ostcolysis (AOL; Cook et al. 1971; Harris &. Adams. 1967; Suciu et al. 1963). Modification of working practices led to a reduction in the incidence of AOL cases in autoclave cleaners. Although AOL is occasionally seen in people not exposed to VCM (Mcycrson & Meier, 1972; Wilson et al. 1967) it is a rare disease. In the late 1960s, studies in rats involving exposure to high concen trations of VCM for long periods (Viola. 1969) failed to produce AOL but showed an increase in the incidence of tumours at various sites. Further studies (Maltoni etal. 1980 &. 1981;Maltoni &. Rondinella, 1980) showed the rare tumour angio sarcoma of the liver (ASL) in exposed rats, and confirmed VCM as an animal carcinogen. Tnree 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; 1ARC Working Group. 1979; Selikoff, 1975; Szadkowski & Lehncrt, 1982; US DHEVV, 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 R&S 024719 t r | / j 188 I. F. H. Purchase ei al. Tabic 1. Lowest concentrations or doses at which a significant excess of vanou. tumour typo was observed in rat carcinogenicity studies_____________ Tumour Concn (ppm) Dow <m* t(> Foreiiomach papilloma Zymbal-fland carcinoma Neuroblastoma Nephroblastoma Livrr anpourcoma Mammary-gland adenccarcinom* 30,000 10.000 10.000 250 (female) 100 (male) 200 J0 5 (female) 50 (male) 16.65 (female) Data from Maitoni ei of- (1981) doses (7-10%) in both animals and man. The doses responsible for acute toxicity arc about 1000-fold higher than the minimum dose for carcinogenicity and there is frequently no sign of oven organ toxicity prior to the development of the carcinogenic re sponse. VCM is mutagenic in a variety of test systems including Salmonella typhimurium (Rannug et al. 1976), Saccharomyces (Lopricno et al. 1977) and Drosophila (Vcrburgt & Vogel, 1977), usually with some form of mammalian microsomal metabolizing system to convert VCM into its active metabolites, chloroethylcnc oxide and chloroacetaldehydc. 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 arc derived from long-term animal carcinogenicity studies. An extensive series of 17 studies (Maitoni ei al. 1981) gives a useful database for risk assessment. Other studies (Fcron et al. 1981; Lee et al. 1978) tend to confirm the findings of Maitoni. Carcinogenic effects were observed in mice, rats, and hamsters. A complication in the selection of these data for risk assessment is the variety of tumour types observed (Table 1). Some of these occurred at very high exposure levels, but mammary adenocarcinoma in females and ASL in both sexes of both rats and mice occurred at SO ppm or less, exposures similar to those believed to have occurred On manufacturing plants (Barnes, 1976). Epidemiological studies Several major epidemiological studies on workers exposed to VCM have been reported (Table 2). The main organs that have been assoc' Med with higher incidences of cancer in workers exposed to VCM arc the liver, lung and brain. Increases in the standard ized mortality ratios of cancers iu 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 &. Brcslow, 1981) concluded that the results for liver were consistent with an actiological 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 & Brcslow, 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 rei xter 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 cf PVC products are exposed to residual VCM released from PVC on heating (but PVC does not decompose to VCM when healed). 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 cal food and dnnk beverages that have been packed in PVC may ingest unrcaclcd VCM * ft V-~ ere more 0 ilncJicf 1 muon' wsiitait sure tmd leitcliing tilvc risk (or liver V* tt*:} it ameer mtiailly I u high . eurtsid- .ilynis of reawMi. milking ,,C work tit both il ii i* 1VCM Twin ilie .iuhiih. rill of lie (lie ec cn*c illiililil : leniify i |*VC II! Ilic .is (lie M. il fc, MSHIIll 41 lIKIIII. linleil- wilill`1 , Willi insii/l g mill *: iiliml lines ,,l (lie w in -ileis (hill Vinyl chloride--rule assessment 189 which has migrated into the food or beverage. Since IJ74, the amount of VCM in PVC has been reduced to less than 1 mg/kg with the result that the maximum human daily intake of VCM in food and drink is 0.1 pg/day (Ministry of Agriculture, Fisheries & Food, 1978). The fourth group with potential exposure to VCM tie 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, arc involved. For the workers in VCM manufacture and PVC polymerization and fabrication, the route of exposure is by inhalation. Much of the animal carcinogenicity data are based on inhalation exposure and the human epidemiology is predominantly of populations ex posed occupationally by inhalation. Thus an assess ment of the risk factors and the quantitative risk of inhalation exposure is the main objective For the consumer exposed to VCM via food and beverages the route is by ingestion. Relatively few experimental studies have used oral administration and only one study used a comparable exposure pattern (Fcron ti at, 1981). Similarly there arc 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 (i) Glu / Cly I 1 C =O 11 7 t'M( M,S( hjCH, I1 MI OH I1 CJu Id) \ \ Cly 1 1 1=0 1 K. Mt'M ,SC"H*CO,H 1 NH 11 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 lime (up to 2 years) during which they develop cancers of a type similar to those seer, in man. The latent period for the same tumours in man may be between 20 and 40 years. It is therefore assumed that the iifeiime 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 factois, 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 dau arc app'icabie to the human situation. Metabolism In rats, VCM has been shown to be metabolized extensively, producing a range of excretion products. co3h CHCHjSCKwCH' 1 "l SH(Ai) OH (c) t'O-M ! UiCH:5CH;CO;K sh3 (M CO,H I' C ------ CH,SCH3CC,H 0 S(CH.CO.H), r '* (.) Fig. I. Scheme showing the metabolism of vinyl ehlonde monomer (VCM) in rats to ^-containing metabolites. VCM (a) is convened to ehloroethylene oxide (b) which is trans formed spontaneously to chioroacctaldehyde (e). These two metabolites are mutagenic and hence arc considered to be the prosimate carcinogens. The unnary excretion products A'-acetyl-5-{2-hydroxyetliyl)cyste:ne (e) J-fcarbotymethyl)- eyttdrte (0 and thiodiglycoliic add (g) art denied from these mutagenic metabolites via (d). Gly and Glu arc the glycine and glutamate residues of glutathione. [After Green Hathway (1977)1. R&S 024721 Reference Monton a al. (1974) Ttbcnhiw A Gilley (1974) Duck tt al. (1971) Nicholton tt al, (1975) Otl ri al. (1971) Byren tt al. (1976) ORC (1976) Rcinl ft Weber. 1976: Rein) tl al. 1978: Weber tt al. 1981 Wixwrikr it al. (1976) Foe A Collier (1977) Frcteel-Bcymc tt al. (1978) Betuni tt al. (1979) Bufiler tl a1, (1979) Chirac ft Ferencs (1981) Chirac tt at. (1980) Beaumont A Brcslow (1981) Table 2. Epidemiological studies of cancer associated wiih exposure to vinyl chloride monomer No. in study* (% follow up) Inc rex ie Sites (or tumours) with changes in SMR No increase Comments 7 8384(85*/.) Brain Lung Liver, including ASL Buccal cavity and pharynx Respiratory system Unknown site Lymphoma Angiosarcoma 2120 257 (99%) 594 (99V.) 771(97%) 10,173 (93%) 11.028 (90%) 1151 7409(99%) None v ASL All tumours? Liver/pancreas Cerebral? Cardiovascular Digestive tract Malignant liver Lymphatic system 6l Iran Dram Respiratory tract Lymphatic system ASL Primary liver ASL 1618(95%) M4| (86%) 464(100%) 3847 Colon/stomach Proiiatic hyperplasia All tumours Respiratory system Digestive system Liver Drain Genital Digestive organs Urinary tract Leukaemia Brain Stomach Brain Lymphatic aod baemopoieuc system Bruit Respiratory tract Significant SMR not significant but increases with exposure and lime Some criticism of Conduct of study Arsenical* involved Significant increase (2 ASL) Increase not significant PMR study Related to duration of exposure Mixed exposure, not VCM related Not significant Significant PMR study Of female and male fabricators Increase in PMR not confirmed by case-controlled study Review of mne studies I |m 4 5 E o o. & 3 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 chlorocthylene oxide) react with cellular macromolccules. 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 MC-labellcd VCM by gavage at doses between 0.5 and 100 mg/kg to Wistar rats, the amount of l4C excreted in the urine and faeces and retained in the carcass was estimated over 72 hours (Watanabe & Gehring, 1976). As the dose of VCM was increased, the proportion exhaled increased and that excreted in the urine and faeces decreased (Fig. 2). The proportion retained in the carcass also decreased. The same general trend occurred after administration by in halation, although the magnitude of the differences in retention and excretion was less (Watanabe & Gehring. 1976). Studies of the amount of non-volatile material retained in the carcasses of rats exposed to various levels of uC-labellcd VCM for 6 hours demonstrated that the metabolism of VCM appeared to be in accordance with Michaelis-Mcnten kinetics (Gehring et at. 1978). The constants for maximum velocity of metabolism (V,, in fig mctabolizcd/6 hr) and the Michaclis constant (K.,, in /ig VCM/litre air) accord ing to the formula: V: VS " (where V = velocity of metabolism in jig/6 hr and S = concentration of VCM being inhaled) were V,, -- 8558 )tg mctabolizcd/6 hr and K.,, * 860 /<g 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 Armitagc-Doll l f I R&S 024723 192 I. F. H. Purchase ti al. ( Tsble 3. Vinyl chlondc dose *nd incidence of iepeix .ngiourcomi in Sprague-Dkwlcy nil npoicd on 5 diyt-wk for 53 wk* R&S 024724 Conca (ppm) Amount metabolized figj^hr m (tout) Angiosarcoma incidence (*/) Male Female Man Expmt no. 30.000 5647 1,47 * 10* 166 43.3 30.0 BT 6) 10.000 5521 1.44 v 10* 10.0 13.3 11.7 BT 1 6000 5403 1.41 x 10* 10.3 33.3 22.0 BT 1 2500 5030 1.3 x 10* 20.0 23.3 21.7 BT 1 500 341J 8.8 x 10' 0 2J0 10.0 BT 1 L. 250 2435 6.3 X |0` 3.4 6.7 5.1 BT 1 200 2129 s.s x io' 11.7 13 tO.u BT2 .- ISO I76 4,6 x 10' 1.7 8.3 SO , BT 2 100 1309 3.4 x 10' 0 1.7 o.s BT 2 50 739 1.9 X 10' l.l 7.2 4: DR 1.9 25 m 1.0 X (O' l 7 67 4.2 BT 15 10 i*9 4.4 X 10* 0 1.7 0.8 BT IS 5 84 2.3 X 10* 0 0 0 BT 15 I 17 4.4 x 10* 0 0 0 BT 15 0 0 0 000 BT1.2. 9. IS After Maltoni tt al. (1981). t Experiment BT 6 ended after only 68 wk. while the real were all approximately 140 wk: therefore the percentage of tumour* in BT 6 is probably low relative to the rest because of the short latency i period available. r I multistage model by the Food Safety Council (1980) exposure values in the ppb range. A large variable and by Gaylor & Kodell (1980) showed that for the appears to be the selection of the mathematical model l same 10'* lifetime risk, the Food Safety Council applied to the experimental data. ( estimated the dose as 2 x 10'1ppm whereas Gaylor In the following section two models are used to i Si Kodell estimated the dose as 5 x 1 O'* ppm. The calculate the exposure for a 10'* risk from a variety difference between these two estimates was due to of experimental animal data applying the correction alternative assumptions on the value of the expansion for metabolism used by Gehring et al. (1979). of the exponential term used. In general, calculations based on the amount of Calculation of exposure for 10~* risk material metabolized or on human data have pro A summary of the crude ASL incidence rates for duced exposure values of about 1 ppm for a 10'* inhalation studies in Sprague-Oawley rats is given in lifetime risk. All the other studies have produced Table 3. Similar data for Wistar rats exposed by i v h~ Table 4. Summary of quantitative nsk iuqutkiiu for vinyl chloride monomer* Reference * ** 5pedes Exposure for IO** lifetime risk (ppbt) Comments 1 - Scbnctdcrmxti tt al. (1975) Rat Kuzxnack & McGaughy (1975) Gehring et al. (1979) Food Safety Council (1980) Rat, man Rat, mac Rat Rat Anderson ft al, (1980) Gtylor A Koridl (1980) Carlborg (1981) Barr (1982) This paper (Table 9) EPA (1980) NAS (1980) Cramp & Guos (1980) Rati man Rat Rat Man Rat Mouse Man Rat Mouse Man Rat Rat Mao Rat By Inhalation 73 119 2 14 140-1400 >1000 <io->tooo 20 20 2.1 x 10'* 3.9 x 10-' >1000 0.7 0.5 2.S x 10"' >100 0.025-9.16 \ 2 x 10"`* / 0.65-90 : x io-'-2 x io-* 6 x 10-*' 0.067-8.14 By ifrtloi 4 a g/day 3 x lO^mi'kg/day 0.7>ig/day 0.5 jig/day Probit (slope -- 1. Mantel) Logit (slope * 3.45) Logit (slope - 2.3. one-hit) Linear through zero Log-probit Biotraoaforauuoc data ipclurird Linear or log-probit Depends on mathematical modd used Otc*hit ArmiUge-Doll Weibull Multi-hit DNA binding used for dosimetry Upper 97.5*4 confidence limit of linear modd Armiugt-Doll Weibull Denved from Barr's negative epidemiology Log-probit Log-probit including biotranaformation data for man Wcibutt Wcbull including baotransformitipn for man Food or water Water Applying worker data to water Upper 95% confidence limns *After Barr (1982). tExcept where stated otherwise. riabic node! ed to lriety ction s for en in d by Vinyl chloride--risk assessment 193 inhalation (Table S) for rata 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 Spraguc-Dawley rats have been used. These estimates of metabolized dose have been in cluded in the tables. For the experiment in which VCM was given by gavage, the data from Fig. 2 were used to estimate the amount of VCM exhaled unchanged. As the t1(- 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 Spraguc-Dawley rats, and the V. and K,, values derived for Spraguc-Dawley rats have been used. In the experiments by Fcron ei 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. 0.01 i i 100 1000 VCM MM (mg/kj) Fig. 2. Summary of dose-dependent urinary and pulmonary excretion of vinyl chloride monomer (VCM). Urinary excre tion () represents metabolites of VCM. while pulmonary elimination (A) is unchanged VCM. (After Watanabc & Gehring (1976)]. For mice, the data have been combined in Table 7. The estimation of the dose metabolized in mice has been calculated using values for 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 el at. (1978) for estimating the dose metabolized by man. Table 5, Vinyl chloride dose and incidence of hepatic angiosarcoma in male Wirtar rata exposed on 5 days/wk for 52 wk Concn (ppm) 10.000 6000 2500 soo 250 50 1 0 Amount metabolized jig/4 hr 5521 5403 5030 3413 2435 739 17 0 Pg (tout) " 1.4x10* 1.4 x 10* 1.3 x 10* 8.8 x 10' 6.3 x 10' 1.9 x 10* 4.4 x 101 0 Angiosarcoma incidence (V*) 29.6 11.5 110 10.7 3.7 0 0 0 Ex pint no. BT7 BT7 BT7 BT7 BT7 BT7 BT 17 BT 7, 17 Table 6. Vinyl chlonde (VCM) dose and incidence of hepatic angiosarcoma in ms given VCM by gavage or ingestion Dose (mg/kg) Amount exhaled* (% of dose) Amount metabolized jig/doset pg (total) Angiosarcoma incidence (% Male Female Mean Expml no. 50: 16.65 3.33 1.0 0.3 0.03 0 3001 14.11 5.0 1.7 0 50 35 10 2 1.7 1.4 -- 80 32 16.5 2 69 6250 2705 750 3245 74 7.4 0 15.000 2390 1040 420 0 1.6 x 10* 7.0 x 10* 10 x 10* 7.26 x 10* 116 x 10* 116 x I01 0 6.2 x 10* 1.65 x 10* 7.25 x 10* 19 x 10* 0 20 10 0 1.3 0 0 0 49 49 10 0 0 22.5 15-t 0 2.7 1.4 0 0 53 16 4 0 0 21.2 12.5 0 2.0 0.7 0 0 51 32 7* 0 Oj BT 11 BT 11 BT 11 BT 27 BT 27 BT 27 BTll. 27 Fcron at a/. (1981) "Calculated from data derived from Waunabc A Gehring (1976) pmemed in Fig. 2. fAssuming a 230-g rat. isprague-Dawley rati dosed by gavage with VCM in corn oil 5 umes/wk for 52 wk. |ST27 doacd for S9 wk. IWistar rats used as controll by Fcron n ai. (1981) and dosed for S3 wk. ^Wisur rats receiving a diet containing VCM dissolved in PVC. 20 8 0) o N> >1 (O (71 1. F. H. Purchase et al. Table 7 Vinyl chloride drive .md incidence of hepatic anciotarcoma in mice Concn (ppm) Amount meubohzed pg/4 hr ft8 (loul) Angiosarcoma incidence (*/*) Male Female Mean no 10.000 6000 2500 1000 500 250 230 50 I 0 11.245 11.007 10.246 8699 6952 4959 4959 1506 1506 0 1.7 x 10* 1.7 x 10* 1.3 x 10* 3.4 x 10* 1.0 X 10* 7.4 x 10* 7.4 x 10* 2Jx 10' 3.9 x 10' 0 3.8 6,7 20 7 39 4 20.0 300 24.0 3.3 10.3 0 30 36.7 33.3 50,0 26.7 30.0 47,0 0 0 0 17.8 21.7 27,1 44.7 23.3 30.0 34.3 1.7 5>2 0 BT 4# BT 4 BT 4 Lee el al. t BT 4 BT 4 Lee et al * BT4 Lee et ai.t BT 4 A Lee et ol. Swim mice. 8l*wk eipenmem, doled for 30wk. tCD| mice. 52-wk eapenment. 6hr/day cxpoiur. {Lee et ol. 1978). These remlit have not been included in the calculaiioni for Table 9 because ihe experimental design incorporated interim kills. Thus: .V.,,.(mouse,) - ,V, ,, ,(rat), x 0.011 nr. 0.04 7 nr 0.011 = 5706,i s/4 hr x -- = 1395 pg/4 hr The values of 0.045 m2 and 0.011 m: are the body surface area of a rat and a mouse, respectively. Since toxicity is a function of the concentration of the toxic metabolite in the tissue, the amount transformed must be normalized for mass to estimate an equiv alent response. Thus 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 VK for the mouse on a mass-equivalent basis is therefore: 1395 0^2 = 11625 pg/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 Tabic 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 vac 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 arc substantially lower when expressed in ppb (2 x 10"11 ppb) but the difference is less for other expressions of dose. `- Similar calculations of the dose expected to give a I0~` lifetime risk of ASL have been based on a Wcibull analysis (Table 9). This is a more 'conserv ative' mathematical model and the estimates of dose arc accordingly lower. The variation in estimates of dose is, if anything, larger than that observed with the log-probit analysis (for example, a 10"5 difference between the S values derived from Wistar and Sprague-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 calcu'ation to derive the human dose likely to p'oduce :: risk of 10~` is given in Tabic 9 (S calculated for man). These cumulations are based on a V,, for man of 1675 pg/S hr based on corrections for body surface area and mass. The values are substan- Table 8. Vinyl chloride (VCM) dose and hepatic ingiciarcomi incidence in Sprague-Dawley rata expotod to VCM tj inhalation Concn (ppm) Sehcdulet No, of doses Amount metabolized; it */4 hr jg (total) Anpoiwma incidence (%) Male Female Mean DO. 10,000 I 260 5521 1.4 x 10* 10 13.3 11.7 BT 1 10.000 II 83 5521 4.7 x I0J 0 0 0 BT 3 1G.00C in ?5 5521 1.4 x 101 1-7 0 0.8 BT 10 10.000 IV too 1379 1.4 X 10* 1.7 0 0.8 BT 10 10,000 V 25 5521 1.4 x 10' 0 1.7 0.8 BT 10 6000 I 260 5403 1.4 x 10* 10.3 33.3 22.0 BT 1 6000 11 83 5403 4.6 X 10' 0 3.3 1.7 BT 3 6000 III 25 5403 1.4 x 10' 0 0 0 BT 10 6000 IV 100 1350 1.4 x 10' 3.4 1.7 2.5 BT 10 6000 V 25 5403 1.4 x 10' 0 1.7 0.8 BT 10 After Maltoni et al. (1981). tSchedulcs: I--4hr/day, 5 dayi/wk for 52 wL; II--4hr/day, 5 day/wk for 17 wit; 111--4hr/day, 5 dayi/wk for 5 wk; IV-- I hr/day, 4 days/wk for 25 wk; V---t hr,'day. I day/wfc for 25 wk. ^Amount metabolized (v) in 4 hour derived from the formula; V (/ig/hr) -- V* x S/K^ + S where VB is 4/6 of the & hr value. Tabk V. Quantitative risk cslirr Mltons derived from available animal carcinogenicity data and expressed as the amount or concentration of vinyl chloride calculated t| give a lifetime nsk of A5L of 10 '* either on the bans of log-probn analysis or a Weibult distribution Table *n. Experiment* 1 dala Exposure for rodents fS ppb*) Amount metabolized m 6 hr by rodents (V /ig/6hr) Total amount metabolized by rodents (TM mg) Exposure (ppb) cakulated from V (S calculated for man)t 4 S-D rats, inhalation 5 Wixiar rals, male or y. inhalation 6 Rats, ingestion--Wi. tar -SI I -- bol >s n Mice, inhalation 4, 5 Wislar and S P rat combined, inhabit on 8 S P rats, short'lcnr inhalation 4 S D rats, inhalation Wislar rats, mak or iy. 3 inhalation 6 Rats, ingestion--WL tar ~S-I > --bol n Mice, inhalation 4,5 Wislar and 5*0 rat combined, inhabit on 8 S P rats. short*teni inhalation 0,025 La>g*probil analysis! 1.23 9.16 3 * 10 1 mg/kg 9 x 10 '4 mg/kg 6 x I0`4mg/kg 2 x 10 " 159 0 69 mg/dosc 2 19 mg/dose 1.70 mg/dose 0 60 0 038 2 x 10 1 41 0 004 Welbull distribution! 0013 2 x 10 > 9 x I0 "m*/k 4 x IO"*mgAg 2 x I0``mg/kg 6 x 10" 15.7 3 x 10mg/dosc 0.33 mg/dose 0 005 mg/dosc 2 x in 1 6 x 10 1 -- 0.0172 3 x 10 ` 0.305 39.3 2 27 0.2 0 88 00063 0 35 2 86 0 0032 3 68 0 0002 0 003 0 0015 2 x 10 0 0042 0 19 0 63 90 -- 0 03 0.72 -- 0 067 y i4 1 . 10 ` 0009 *fcxccpt where staled otherwise ) Exposure calculated from V (i column 3) using the formula: S V x 860/1675 - V, where } llaumutcd using maximum lik;c lihood jWislar and S D rats combine*: |Sludy UT 4 only. for man is l675/ig/8hr. t M i 31 fio CO o IO fe N IO "J 196 I. F. H. Purchase ti at. daily higher than [hose calculated for ihe 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 lO'/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 longterm inhalation studies, a total metabolized dose of 5 x 10'pg is equivalent to about 200ppm adminis tered over 52 weeks aod 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 arc made and to the particular experiment that is used to provide data for the extrapolation. A high level of confidence cannot be placed on low-dose extrapolations when variables that would not be expected to alter the expression of risk have a profound cfTcct on the estimated risk. In addition, the intcrspccies extrapo lation from experimental animals to man is largely intuitive. It is clear that estimates of risk should take into account all available data, including epi demiology, to provide a degree of reliability. Risk assessment from human studies Register of ASL cases " '' Since 1974, lists of reported ASL cases attributable to VCM exposure fn the VCM/PVC industry have been kept by NIOSH (Spirtas & Kaminski, 1978), by IARC and by the VCM Committee of the Association ol Plastics Manufacturers in Europe (APME). Details of 99 cases in the APME register at Title II. Gmienng of ASL cai-i in individual PVC pltnu Plant" no- Country No- of ASL eases Western Europe 1 West Germany West Germany 3 West Germany 4 West Germany 1 France France 3 France 1 UK 2 UK 1 Sweden North America 1 Canada 1 USA 2 USA 3 USA Rnt of WorW l Japan 1 Yugoslavia 1 Chechoslovakia Tqtal.., Total... 10 4 2 2 5 3 2 5 n 5 42 10 II 9 4 34 2 A 2 Tout.., 8 For the purpose) of this case study. H is not necessary to identify (he precise ownership and location of these plants. the end of 1982 have been analysed by country and by manufacturing company and plant. The cases have been recorded from all major VCM/PVC manu facturing countries (Table 10). but the incidence has not necessarily been in proportion to the PVC pro duction capacity now or prior to 1962, In the absence of data on the number of workers employed, pro duction capacity is the only available indication of the numbers of people potentially exposed. The majority of the ASL cases are PVC ai 'oclavc 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-ostcolysis and ASL. The ASL cases tended to occur in larger numbers in some plants than in others (Table 11). Of the total of 39 ASL cases recorded in North America, 34 have occurred at four PVC plants, while over 40 Tabic 10. Distribution of ASL cases by country PVC production nameplate capacity (kiloionncs/yr) Country ASL cusei 1952 1962 USA West Germany France Canada UK Sweden Yugoslavia Inly Chechoslovakia Japan Belgium Norway Total... Western Europe North America Rest of World Tola!-.. 19 21 w 10 7 5 4 3 2 2 1 1 99 52 39 8 99 193 704 *2 260 11 176 3 22 27 177 3 20 38 9 212 l 25 12 384 3 25 2 20 82 951 198 726 31 709 331 2386 ASL Angiosarcoma of the liver 1972 2090 1155 627 88 502 105 60 778 48 1699 195 65 3950 2178 3334 9462 R&S 024728 k <***: - pitnii No. of SL did [o identify ury and ic cases ' manu- absence d, proition of itociave around :n who ivolved luction. sis and larger 11). Of mcrica. iver 40 Vinyl chloride--risk assessment Table J2 ASL case numbers by year of death and geographical location (excluding 1T01*1 Year pf death Western Europe ASL caiett in. North America Rest of worlJ publication* 1953 Cl 7 C2 9 I960 1 2 3 4 5 6 7 8 9 1970 1 2 3 4 5 6 7 8 9 1980 1 US8 C3 US5 FI Gl sw 02 NI, Sw2. UKI, It2 G3J C4. GJ. UK 3 F2. F3. G6, G7, G8. !t3 Bl, F4, F5. F6, F7. Sw3 F8. F9. GIO, Gil. GI2. Sw4 FI0. Fit. G9, 013. GI3. GI6. G17 Ft2, FI3. UK4. UKJ. GI8 UK6. UK7. GI9, Sw3. G20. G21 U4. F14. UKB. G22 C4. C5, US4. US7. US10 USI2, US16 usn C6. US2 C7 C8. USt, US3. US23 at. usi3 US6. U59. USI8. US26 US 19. US20, US22 CIO. US2I. US244 US27. U52S US 17, US29. USjO. US32 a: VI, Y2, Cil Jipl Jip2. Y3 Y4 Viola Multoni Creech < Johnson Toul.. 52 383 8 ASL " Angjoiarcoma of the liver Italian case 01 was not a typical ASL; his primary tumour was probably of the pericardium. This man was engaged in extrusion of PVC sacks. tB ** Belgium, G ** W, Germany; Sw Sweden: C Canada. ItItaly; UK United Kingdom; Czechoslovakia; Jap > Japan: Y - Yugoslavia; F France; N Norway, US - USA Thus G9 - case no. 9 in West Germany. Cases UK2, GU, USU, US IS and US25 were shown not to be associated with VCM exposure and hence withdrawn from the list. {Aerosol can filler. (Cholingiosarcoma. |Docx not include US31 (still alive). 197 North American PVC plants have not recorded an ASL case so far. The average latent period between starting work in an occupation involving VCM exposure and death from ASL for the 99 cases is 21.9 years (in France, Sweden and the USA between 24 and 25 .years, in Germany about 18 years). It is still too early to predict whether the annual number of ASL cases amongst VCM workers has reached a peak. ASL cases appeared earlier in North America than in Western Europe and while the occurrence is tending to decrease in North America (Table 12). it is still high in Western Europe. On the basis of the data in this case register, it is possible to draw certain conclusions about risk fac tors associated with ASL. The large number of ASL cases in some factories and the absence of ASL cases in others of similar age indicates that variations in manufacturing practices between factories may be the cause. These variations may reflect both differences in the types ofjob earned 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 wcllauthcnticatcd 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-197-4 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 nsks 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 VC.M. 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. R&S 024729 198 I. F. H. Pluchase *t at. Tibfc 13. ASL cue numbers by ynr of first exposure and tcographml location (escMine ITOI*) Year of firvl exposure Western Europe J939 40 1 2 3 4 5 6 Frll FrU UKl Sw2 Fr|, Fr3. Sw4 7 8 9 1930 1 2 3 4 S 6 7 S 9 I960 l 2 3 4 3 6 7 Sw3 Fr9 FrI2. Frt Fr7, Nl. UK8 Swl. UK5 G3 GIS. ID G7, G8. UK4, C19 Gil. GIS. GIS FrIO. Gl FrS. G4. Il2. G2 Frt. Bl Fr2. Il4 G3, G13 G9, GI0, G12. G17. C20, G22 G6, UK6. G21 Frl3. UK7 SwS FrS 17KJ ASL oieit in: North America US24J C3, US27 US 13. US29 C2, US19 Cl. C5, US5. US7. US2S C4, U53. US9 C7. C9. US8. USU. US2I, US3I5 C6. US22. US26 USI US12 US 16 US10, U532 US4 CIO US1S USX US!7, US20 USX! Re*i of world Y2. Ci2 Jxpl, Yl Y3 Ctl Jap2, Y4 Key event* C3 US6 US30 9 1970 Viola 2 3 Tout... 52 Maltoni 39 8 * ASL * Anposarcoma of the liver *It01 not consistent with other ASL cases; the primary tumour may have been of the pericardium. The man extruded PVC sacks. fFor explanatory key, see Tabic IX JCho anpoufeotna. JUS31 i* tut! alive. lAcrool 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-resp mse 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 wore difficult to obtain, but can be gleaned from the records that arc 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 cxposure/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 lev?'; for t-.eh 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 15) an assumption has been made that when exposures were reduced to low lcveis, 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 tc hundreds of ppm and 1974 when the levels were reduced to below 10 ppm following the discovery of lying on xatioos. d under ses. ic set of ive dau ulate an each exis of the ve of the rates to ncy lb*1 e broad eney of ccur for I : future tion has 1 to low ile. Two attained reduced :1s were >very of Vinyl chloride--risk assessment Table 14 Annuel incidence of ASL cua (date of dca'h) by gcogaphical area Year Western Europe No. of ASL cun dying m: Noah Ajttera Rest of world Annual total Cumulative ioul Key evnu 199 1 1 2 1 3 3 2 3 3 8 5 11 11 9 10 5 10 4 00 38* 98* ASL - Angiosarcoma of the liver *Doci not include US31 (stall alive in 1982), tAt Ume of compilation. 1 Includes G03 (aerosol An Alter) but omits ftOI (bag ciimdct). 3 4 6 7 12 13 17 Viola 1*0 25 33 Maltom 38 Goodrich 49 60 69 79 84 94 n 98* 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 `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-ycar periods taking account of the age-dependent death rates in the population at targe. 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 iong latent periods (>25 years) arc 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 1904 and 1974 assumptions. The calculation is unrealistic in many respects but the simplifications arc 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-yea's 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 arc based on the overall risk to the cohort and although the incidence figures for sub-cohorts could be higher, the estimate of future cases will change very little. Similarly duration of exposure has been ignored. Table 15. Hypothetical calculation of future ASL caiei ming two different ajrumptionj about the date at which the levels became free of mit Latency (yr) 1-5 6-10 11-15 21-25 26-30 31*05 16-40 41a*45 46-50 3116- Cues io dale 0 1 II 28 28 18 6 6 0 0 0 Calculations assuming no nsk aficr 1964 Person* at mk to date 100.000 98.250 95.500 84.750 61,400 26.750 21.250 6750 600 0 0 5-yr incidence 0.00 0.01 0.12 0.33 0.46 0.49 0.28 0.89 7 7 7 0.50 Future persons at nik 0 0 0 6750 24,550 41.750 48.100 51.750 45.730 34.500 47.600 300.750 Future cases 0 0 0 2 11 20 13 46 7 7 7 150 Calculation* assuming no mk after 1974 Persons at risk to date 5-yr incidence Future person* at risk Future cases 100.000 94.500 78.000 46.500 2..750 18.750 10.850 3500 310 0 0 0.00 0.01 0.U 0.60 0.97 0.96 0.55 1.71 7 7 7 0.80 0 3750 17,500 45.000 57.200 59.750 58.500 55.000 46.350 34.500 47.600 403.900 0 0 2 27 57 57 32 94 7 j23 For detain of the auumpuom and methods lee text (pp. 197 & 19S). SSH n 200 J. F. H. PuxCHtSZ et at. (c) The UK is not typical of the worldwide growth in the exposed population. (d) No account has been taken of plant im provements occurring prior to 1964 and hence fewer cases may occur in, tor example, the 1980-2000 period than arc 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 cither assumption, the number of new cases observed annually should soon begin to decline and the rate of decline wilt 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 cs'imate and on a larger data set than the former. Nevertheless, the conclusions of Forman et al. (1986) arc 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 iower relative risk. Neoplasms of the respiratory tract, digestive system, lymphatic tnd hacmopoietic system, buccal cavity and pharynx, cardiovascular system and colon/stomach were reported to show an increased incidence in one or more studies, but to show no increase, or in some cases a decrease, in incidence in other studies. In view of the increased incidence of breast neoplasms in rodents exposed to VCM. the studies of Chaizzc et al. (1980). who did not confirm these findings in humans, arc 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 cf animal studies on the carcinogenicity of VCM. Some of these precede the epidemiological studies confiiming 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 lO'^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 chlorocthylenc ox ide and chloroacctaldehyde. The rate of conversion is limned 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 (Malioni et al. 1981), there is a substantial range (up to 10*) of low-nsk dose estimates, depending on the mathematical model and the assumptions used m 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 agun obtained, even after correction for the non-linear kinetics of metabolism at high dose (which reduces this range to aoout 101). Larger differences arc obtained with calculations using the Weibull analysis as a basis of low-dose estimation, suggesting that this is a problem with the use of mathematical models rather than one associated with the log-probit anal ysis. Although there was considerable variability in the dose-response relationship in the different experi ments reported, in all cases a total metabolized dose of 5 x 10*/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 Tor 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 (Ban1. 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 arc up to 1010 lower (3.9 x 10':ppb using a multi-hit model). The higher estimates are compatible with occupational experi ence and suggest that the current hygiene standard of around 1 ppm is sufficiently low to protect the health of VCM/PVC workers. The estimates also give a considerable safety factor for the general public consuming PVC-packed food and drink or living near VCM/PVC facilities. It has been possible to provide a crude estimate of the number of cases of ASL that may occur in the future from exposure to VCM prior to 1974. Using the age structure of employees in one company, the total number of cases of ASL reported to 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. R&S 024732 I n a i \SL and ] ivc been titmtion ie risk of xtremcly ppear to c reason >wn that ;re in the /lene oxersion is accurate mse re- nate the lation of ral. The n at low emalieal ua from ial range ding on t used in tbit and experi ls again in-lincar reduces tees are analysis that this models analiility in t expertcd dose 00 ppm) SL incithoid in matheare not ngender . f popu!) eduction lifetime ie value derived I rotation han the ' lower : higher experildard of ; health give a public r living mate of r in the . Using ny, the ate and H *I pPopu* set has v Vinyl chloride--risk assessment 201 Acknowledgements--We thank Dr M. Thomas for his help with the calculations and Dr D. M. Conning for his help with the manuscript. 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