Document 4vzmymzXkXpQgGxwD0NxkZeMQ

/C -/ 7// S/oj Fd Chem. Vol 25, No 2. pp. 187-202. 1987 Pnnted in Great Bnum. All nfhc* reserved 0278-61315/87 S3 00 r 0 00 Copyright <C 1987 Pergamon Journals Ltd Review Section VINYL CHLORIDE: AN ASSESSMENT OF THE RISK . OF OCCUPATIONAL EXPOSURE* I. F. H. Purchase Central Toxicology Laboratory J. Stafford Plastics and Pclrochcmicais Division and G. M. Paddli; Central Medical Group, Imperial Chemical Industries pic. Alderley Park. Macclesfield, Cheshire, England [Received 14 December 1933, revisions received 13 January 1936) Introduction Vinyl chloride monomer (VCM), more properly named monochlorethanc, is a colourless gas normally handled under pressure as a liquid which boils at -- I4,:C at normal pressure. Discovered around 1S35, VCM-5 commercialization did not begin until the 1930s and did not reach high volume until after 1945. Present manufacture is around 12 x I04 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 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, K-hr time-weighted average [TWA) for many years (ACG1H, 197-4; Lester el at. 1963; Torkclson el at. 1961). Mcasutements 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 polvmerization workers have been cited as; 1000 i,, 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/mcdium pe *A longer version of this paper has been published in Toxicological Risk Assessment, edited by D Ft. Clavson. D. Krewski and I, Muiiro and published hv CRC Press. Inc . Boca Raton. EL (I9S5) Abbreviations: AOL - acro-osteolysis. ASL -- angio sarcoma of the liver; PVC *= polyvinyl chloride; TLV ^ threshold limit value; TWA = time-weighted average; VCM = vinyl chloride monomer. riods, since in some plants operators became faint and unconscious from time to time The first clear indication of chronic health prob lems associated with VCM arose in the 1960s in men who entered VCM polymerization autoclaves to re move build-up of polymer from the walls. Some of these men developed acro-usteolysis (AOL; Cook et at 1971; Harris & Adams, 1967; Suciu et at. 1963) Modification oT v-orking practices led to a reduction in the incidence of AOL cases in autoclave cleaners Although AOL is occasionally seen m people not exposed to VCM (Meycrson & Meier, 1972; Wilson et at. 1967) it is a rare disease. In the late 1960s. studies in rats involving exposure to high concen trations of VCM for long periods (Viola, 1969) failed to produce AOL but showed an increase in the incidence of tumours at various sites. Further studies (Maltoni et at. 19S0& 19Sl;Maltoni & Rondinella, 1980) showed the rare tumour angio sarcoma of the liver (ASL) in exposed rats, and confirmed VCM as an animal carcinogen. Three ASL cases in employees at a PVC polymerization plant (Creech &. Johnson, 1974) confirmed VCM as a human carcinogen. Other known aetiological agents for ASL in man were thorium dioxide, arsenic and, possibly, anabolic steroids (Maltoni et at. 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, Poiy(vmyl Chloride) and Structural Analogs, 1981; Gauvain, 1976; IARC Working Group, 1979; Selikoff, 1975, Szadkowski & Lehncrt, 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 vaiuc. Experimental and human data Experimental studies The principal effect seen in the acute and subacute studies is anaesthesia, which occurs at relatively high 137 R&S 024739 4 $ t t 18* I F ri PVFL'HASf. tl al R&S 024740 Table ! Lovmi cO'^eniMuont Or diKf- at sAhieli a ai^mfic.int c*c<*5 nf various tumour tyjj<4 wat nbtcfNcii :n rat carcinogenicity itudio Tumour C'c.ncn (ppm) D ne (mg Vp rorestomach papilloma 7>mbal'glanc| cartmoma Neuroblastoma Nephroblastoma t.jvcr angiosarcoma Mummary*gland adcnocnrcinoni.t 3U.0OQ 10.000 10.000 250 (female) I0Q (mul'-) 2i*j 50 5 (female) 50 (m;!c) 16 65 {Cciiulc} Data front M.tlioni et a!, U981), doses (7-10%) in boih animals and man. The doses responsible lor acute toxicity arc about 1000-fold higher than the minimum dose for carcinogenicity and there is frequently no sign of overt organ toxicity prior to the development of the carcinogenic re sponse. VCM is mutagenic in a variety of lest systems including Sa'innrtello l)phtnturium (Rannug ft at. 1976). Saccharomyccs (I.opricno er at. 1977) and Drosophila (Vciburgt < Vogel. 1977), usually with some form of mammalian microsomal metabolizing system to convert VCM into its active metabolites, chlorocthylene oxide and chloroace'aldehyde. The data on the mutagenicity oT 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 (Malioni ft / 1981) gives a useful database for risk assessment. Other studies (Feron et al. 1981; Lee et at. 1978) tend to confirm the findings of Malioni. 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 I). Some of these occurred at very high exposure levels, but mammary adenocarcinoma in fcmales'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 mar.ufacturin ; plants (Barnes. 1976). Epidemiological studies Several major epidemiological studies on woikers exposed to VCM have been reported (Table 7) The main organs that have been associated with higher incidences of cancer in workers exposed to VCM are the liver, lung and brain, lncteases 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 oflivcr 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 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 tiic 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, poinis out that tre relative risk for brain cancel is much lower than that 'or liver cancer Only iwo uu; of eight studies on lung cancer (Beaumont &. Breslow, I9S1) 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 r.ue 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 n is unlikely that any other carcinogenic effect of \ CM will be found to occur at lower exposures than the lowest exposures that induce ASL. For these reasons, most work on the quantitative risk assessment of chronic exposure to VCM has used ASL as the endpoint to study Case register The availability of data from a comprehensive ease register of z\SL 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 liny! 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 Olheis, although ail groups would now be expected to have exposures complying win, hygiene standards of 1-5 ppm. Thc next category covers those exposed as a result of using the PVC. Workers in the compounding and fabrication of PVC products arc 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 arc very low in comparison to those for PVC polymerization workers (from 10 to 100 times lower). Consumers who cat food and drink beverages `hat have been packed in PVC may ingest unreacted VC. V v?_ e more studies reasontsistent jrc and taching .ve risk >r liver cancer dically a high :onsidlysis of :asons. flaking f work ?ih k.s an the tasons, cnl of as the k case itional lentify J PVC . of the ers the M, its tistrial ations, potenwould g with result ig and isidual Z docs ral the !ow in orkers ;s that rtf Vinyl chloride--risk assessment 189 which has migrated into the food or beverage. Since 1974, the amount of VCM in PVC has been reduced to less than 1 mg/kg with the result that the maximum human daily intake of VCM in food and drink is 0.1 /ig/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, 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 arc 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 at at. 1981). Similarly there are no specific epi demiological data on oral ingestion. Risk assessment for exposure via the oral route must rely on the existing animal data and on extrapolation from epi demiological and experimental studies of inhalation exposure. Risk assessment from experimental animal data 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 H,C CMC! H) Cly Ml OH | i Glu LHCH,SCHjCO,H 1 Ml 1 1 GJu 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 arc 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 arc 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. COjH 1 CHCH -jiCHjCMj 1` i >H(Ae) Oil CUjIl CHCH,5CH2C02H Ml, T COjM (n C -- CH,$CM,CO,H II o MCH.CO.H), r*2 () Fig. 1. Scheme showing the metabol.sm of vinyl chloride monomer (VCM) in rats to .9-containing metabolites. VCM (a) is converted to chlorocthylcne oxide (b) which is trans formed spontaneously lo chloroacetaldehyde (c). These two mciabolites arc mutagenic and hence are considered to be Ihc proximate carcinogens. The urinary excretion products f/-aceiyl-5-(2-hydroxyeihyl)cysteine (e) S-(carboxymethyl)cysteme (0 and thiodiglycollic acid (g) are derived from these mutagenic metabolites via (si). Gly and Glu are the glycine and glutamate rendues of glutathione (After Green St Hathway (1977)). R&S 024741 i !; i #>, Itei . -i:. d?- Reference Monson et at (1974) Tabershaw & GafTey (1974) Duck ft at. (1975) Nicholson rr al 0975) Ott ei at (1975) Byren er at. (1976) ORC (1976) Rein) A Weber. 1976; Reinl el at. 1978* Weber er at. 1981 Waxwcilcr ti at, (19 76) Fox A Collier 0977) Fret/el-Heyme rt at (1978) Reriaj/i rt at. (1979) Burlier n at (1979) Chia7Jc A Fercitcc (1961) Chiajje rt at (I960) Beaumont A lire slow (1981) Table 2. Epidemiological studies of cancer associated with exposure to vinyl chloride mono' * Sites (or tumours) with changes in SMR No, in study'--------------------------------------------------------------------------------------------------------------------------------------------------- (% follow up) Increase No increase Comments ? 8364(85%) Brain Lung Liver, including ASL Buccal cavity and pharynx Respiratory system Unknown site Lymphoma Angiosarcoma 2120 257(9-9%) 594 (99%) 771 (97%) 10,173 (95%) 11,028 (90%) 1151 7409 (9-9%) None ASL Alf tumours? Lfver/pancreas Cerebral? Cardiovascular Digestive tract Malignant liver Lymphatic system Gl trad Brain Respiratory tract Lymphatic system ASL Primary liver ASL 1618(95%) 5441 (36%) 464(100%) 3347 Cnlon/stomach Prostatic hyperplasi All tumours Respiratory system Digestive system l iver Brain Genital Digestive organs Urinary tract Leukaemia Brain Stomach Brain Lymphatic acid haemoposeik: system Significant SMR not significant bul increases with exposure and time Some criticism or conduct of study Ancniuli involved Significant increase (2 ASL) Increase not significant PMR study Related to duration of exposure Mixed exposure, not VCM related Not signtticant Significant Breast Respiratory trad PMR study of female and male fabricators Inc re use in PMR not con finned by case-con trolled study Review of nine studies ZtLPZO S9U '*i ;S H . Purchase ei ill. i Vinyi chloride--risk assessment 191 5 of VCM metabolism in ruts is given in Fig. 1. On the basis of this scheme, the highly reactive intermediates in the metabolic process (particularly chloroethylcne oxide) react with cellular niacromolcculcs, including DNA to produce the critical icsions 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 |4C excreted in the urine and faeces and retained in the carcass was estimated over 72 hours (Watanabe & Gchring, )u3 5 - . : s 2 jsx - 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 0 5? general trend occurred after administration by in o a".g halation, although the magnitude of ihc differences I0** $ 3 ' O* . . U. o Z in retention and excretion was less (Waianabc & Gchring, IS76). 5tudies of the amount of non-volatile material retained in the carcasses of rats exposed to various levels of `'C-labcllcd VCM for 6 hours demonstrated that the metabolism of VCM appeared to be in accordance with Michaelis-Mentcn kinetics (Gchring ft al. 197S). The constants for maximum velocity of metabolism (Vm in /tg metabolized/6 hr) and the Michaelis constant (K,,, in pg VCM/lilre air) accord IT ct a ra J ing to the formula: 'O K. + S f- *o (where V = velocity of metabolism in ;i g/6 hr and S = concentration of VCM being inhaled) were 6 VI II S Vm = S55Spg mctabolized/6 hr and Km = 860pg 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. 5 R&S 024743 Review of earlier calculations of risk s There have been a number of attcmpls to calculate 3 the risk of ASL development on the basis of extrap olation from experimental data. These have been <s reviewed by Barr (1982) and an adaptation of his data is presented in Tabic 9. VI V3 <= The introduction of biotransformation data into > the estimation of risk increased the level of exposure s calculated to cause a I0~` lifetime risk, from parts per JO u billion to in excess of one part per million. A further S3 refinement of the technique using DNA binding as a c O 0( C the measure of dosimetry (Anderson et al. 1980) s provided a similar estimate of the exposure. 3 3 ta 8. c S V (S js 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 (Gchring et al. 1979). It is equally difficult to select amongst the models on the basis of the assumed mcehanisni of action of VCM. Thus a comparison of the lifetime risks calculated using the Armitage-Doll dp 192 I, F. H. Purchase el al. Tabic 3. Vinyl chloride dose and incidence of hepatic angiosarcoma in Sprague-Dawley ran exposed On 5 days/wk for 52 wk* Concn (ppm) 30,000 10.000 6000 2300 500 250 200 150 100 50 25 10 5 1 0 Amount metabolized H%iA hr 5647 5521 5403 5030 3413 2435 2129 1761 1309 739 393 169 34 17 0 MS (total) J.47 x 10* 1.44 x 10* 1.41 x !0* 1.3 x 10* 8.8 x I0` 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 104 2.2 * !04 4.4 x I0` 0 Angiosarcoma incidence (*/*) Male 16.6 10.0 103 20.0 0 3.4 11.7 1.7 0 U 1.7 0 0 0 0 Female 43.3 13.3 33.3 23.3 20.0 6.7 8.3 8.3 1.7 7.2 6.7 1.7 0 0 0 Mean 30.0 11.7 22.0 21.7 10.0 5.1 to.o 50 0.8 4.2 4.2 0.8 0 0 0 Expmt no. , BT6t BT 1 BT 1 BT 1 BT 1 BT l BT 2 BT 2 BT 2 BR 1,9 BT 15 BT 15 BT 15 BT 15 BTl.2, 9.15 After Maltom et al. 0931). tExperimeni BT 6 ended after only 68 wk, while the reft were ail approximately 140 wk; therefore the percentage of tumours in BT 6 is probably low relative to the rest because of the short latency period available. multistage mode! by the Food Safely Council (19S0) and by Gaylor & Kodcll (1980) showed that for the same 10-4 lifetime risk, the Food Safety Council estimated the dose as 2 x 10_J ppm whereas Gaylor & Kodcll estimated the dose as 5 x lO^ppm. The difference between these two estimates was due to alternative assumptions on the value of the expansion of the exponential term used. In general, calculations based on the amount of material metabolized or on human data have pro duced exposure values of about 1 ppm for a I0~4 lifetime risk. Al! 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 10'4 risk from a variety of experimental animal data applying the correction for metabolism used by Gchring et al. (1979). Calculation of exposure for 10~` risk A summary of the crude ASL incidence rates for inhalation studies in Sprague-Dawley rats is given in Table 3. Similar data for Wistar rats exposed by Reference Schncidcrman a al. (1975) Kuzmack dr McGaughy (1975) Gehring tt al. (1979) Food Safety Council (1980) Anderson et al, (1980) Gaylor 4 Kodcll (1980) Carlborg (1981) Barr (1982) This paper (Table 9) EPA (1980) NAS (1980) Crump & Guess (1980) After Birr (UK), fExcept where jtiled txhenyue. , Summary of quantitative risk assessments for vinyl chloride monomer* Speocs Exposure for 10"1 lifetime risk (ppbf) Comments Rat Rat, man Rat, man Rat Rat Rat, man Rat Rat Man Rat Mouse Man Rat Mouse Man Rat Rat Man Rat By Initiation 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 0.025-9.16 \ 2 x I0-" / Q.63^90 2 x W'-2 x 10"' 6 x I0-41 0.067-8.14 By Ingestion 4Pg/day 3 x 10"' mg/kg/day 0 7 pg/day 0.5 bg/day Probil (slope l, Mantel) Logit (slope - 3.45) Logit (slope - 2.3, one-hit) Linear through zero Log-probit Biotransformation data included Linear or log-probit Depends on mathematical model used One-hit Armitagc-Doll Wejbull Mulu-hit DNA binding used for dosimetry Upper 97.5% confidence limit of linear model Armitagc-Doll Weibull Derived from Barr's negative epidemiology Log-probit Log-probit including biotransformaiion data for man Weibull Weibull including biotransformaiion for man Food or water Water Applying worker data to water Upper 95*4 confidence limits 30 Re CO fo -fe Nl -b ".TxSdtw* `-St *- ' " * - ' V '!<' %V .x-,'./'- .T C, '-.-1 IIIIIJUJIXIMJ HTOWE1 ?. lablc lodcl d lo ricty 3tion as,. *, : is..- ' Vinyl chloride--risk assessment 193 inhalation (Table 5) for rats exposed orally (Table 6) and for mice exposed by inhalation (Table 7) arc also presented. Data from experiments with various ex posure periods of short duration arc given in Table 8. For calculating the amounts of the dose metabo lized in rats in the inhalation experiments, the con stants calculated (Cehring et al. 1978) have been applied. For Wistar rats, the Km and Vm 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 t1/2 for exhalation of VCM was 14 minutes, these data based on a 72-hour period give a good estimate of the fraction of VCM exhaled in the 24 hours between doses. It has been assumed that the VCM not exhaled was metabolized, an assumption similar to the one used for estimating metabolized dose in the in halation experiments. Green & Halhway (1975 & 1977) showed that VCM administered by gavage to Wistar rats was exhaled and metabolized in a similar manner to that in the Sprague-Dawley rats, and the Vm and K,, values derived for Spraguc-Dawley rats have been used. In the experiments by Feron cl al. (1981), who used Wistar rats, the same assumptions about V,,, and Km have been made. The quantity of VCM administered has been dealt with as if it had been administered by gavage. VCM <*< limj/xg) Fig. 2. Summary of dose-dependent urinary and pulmonary excretion of vinyl chloride monomer (VCM). Urin.uy excre tion ' &) represents metabolites of VCM. while pulmonary elimination (A) is unchanged VCM. [Alter Waianabe it 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 cl al. (1978) for estimating the dose metabolized by man. Table 5. Vinyl chloride dose and incidence of hepatic angiosarcoma in male Wistar nils exposed on 5 days/vA for 52 wk Conen (ppm) 10.000 6000 2500 500 250 50 1 0 Amount metabolized ,-------- --------- -------- ---------------. Pg)4 hr F g (ioialj 5521 5403 5030 3413 2435 739 17 0 1.4 x 10" 1 4 x 10* 1.2 x 10* 8.8 x 10' 6 3 V 10' 1.9 a IO> 4,4 v 10' 0 Angiosarcoma incidence (%) 29.6 11.5 12.0 10.7 3,7 0 0 n Expmt no. BT7 BT 7 BT 7 BT 7 BT 7 BT 7 BT 17 BT 7. 17 Table 6. Vinyl chloride (VCM) dose and incidence of hepatic angiosarcoma in rats given VCM by gavage or ingestion Dose (mg/kg) sot 16.65 3.33 1.0 0.3 0.03 0 3001 14.11 5.0 1.7 0 Amount (% of dose) 50 35 10 2 1,7 1.4 __ 80 32 16.5 2 69 Amount metabolized hS/doscT 6250 2705 750 3245 74 7.4 0 15,000 2390 1040 420 0 PS (total) 1.6 a I0` 7.0 a 10' 2.0 v If)1 7.26 y 104 2.16 x to' 2.16 >; 10' 0 6.2 a I0` 1.65 x 10` 7.25 x It)' 2.9 x 10' 0 Anziovevcoma incidence (%) .Male 20 10 0 13 0 0 0 49 49 10 0 0 Female 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 SI 1 327 ) o J Expmt no. BT 11 HT II BT 11 HT 275 BT 27 BT 27 BT 11. 27 Feron ti at. (1981) `Calculated from data derived from Watanabc X Gehring (197<>) presented in Fig. 2. fAssuming a 250-g rat. ISpraguc-Dawley rats dosed by gavage with VCM in corn oil S ttmes/wk for 52 wit. 5BT27 dosed for 59 wit, JWistar rats used as controls by Feron ti al. (1981) and dosed for K3 wk. 1 Wistar rats receiving a diet containing VCM dissolved in PVC. 196 I. F. H. Purchase e< al. dally 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. \V!;en 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-weck exposure does not apply to exposures of shorter duration (Table 3). In all experiments a totai metabolized dose in excess of 5 x 10*ng was required to produce an incidence of angiosarcoma in excess of 1-2%. This relationship was seen in both rats and mice and in experiments in which VCM was administered by gavage or by inhalation. In long term inhalation studies, a total metabolized dose of 5 x 10* /ig is equivalent to about 200 ppm adminis tered over 52 weeks and represents a practical thresh old for this series of experiments. In conclusion there is a wide variation in the cstimaies 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 effect 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 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 H, Clustering of ASL cases in individual PVC plants plant* no Country No. of ASL cases Western Europe 1 Wet Germany 2 West Germany 3 West Germany 4 West Germany 1 Frarce 2 France 3 France 1 UK 2 UK I Sweden North America 1 Canada 1 USA 2 USA 3 USA ftm of World I Japan 1 Yugoslavia 1 Czechoslovakia 10 ,* 2 i 5 5 2 5 2 Total... 5 a; Total... 10 tl 9 4 3- T 4 1 Total.., S For the purposes of this case study, it is not necessary to identify the precise ownership and locution 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 daia 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, whiic over 40 Table 10. Distribution of ASL cases by country Country USA West Germany France Canada UK Sweden Yugoslavia Italy Czechoslovakia Japan Belgium Norway 1 otal... Western Europe North Amenca Rest of World Total... No. of ASL cases 29 21 14 10 7 5 4 3 2 2 1 l 99 32 39 8 99 PVC production nameplate capacity (kilotonncs/yr) 1952 193 22 11 5 3 3 9 1 12 3 1962 704 260 176 22 177 20 8 212 25 3S4 25 20 1972 2090 1155 627 88 502 105 60 77S 48 1699 195 65 S2 951 3950 198 726 2178 51 709 J334 331 2386 9462 ASL - Angiosarcoma of the liver Oro *vl -fe O) si.vslL-i'j identify y and cases nanu- , proon of 3clavc round i who olvcd ction, is and larger 1). Of icrica, rer 40 Vinyl chloride--risk assessment Table 12. ASL case numbers by year of death and geographical location (excluding ITO1 *) Year of death Western Europe ASL cases! in; North America Rest of we .Id Key publications 1955 6 7 8 9 1960 I 2 Cl C2 US8 C3 4 5 6 7 FI 8 9 1970 G1 Swl 1 G2 2 Nl. Sw2. UK1, Il2 3 G3t 4 G4, G5, UK3 5 F2, F3, G6. G7, G8, It3 6 Bl. F4, F5, F6. F7, SwJ 7 F8, F9, GI0. GU. GI2, Sw4 8 FI0, Fit, G9, GI3. GI5. GI6. GI7 9 1980 FI2, F13, UK4, UK5. GI8 UK6. UK7, G19. SwJ. G20. G2I l hi. FI4. UK8, G22 A Total., 52 US5 C4. C5, LS4, US7, USI0 US 12. US 16 USll C6, US2 C7 C8. wSl. US3. US23 C9. US 13 US6. US9, US'S. US2o USI9, U520. US22 CIO. US2I. US24 US27, US2S US17, US29. US30. U532 381 Cz2 Yl. Y2. Czl Jap 1 Jap2. Y3 Y4 8 Viola MallOni Creech &. Johnson ASL " Angiosarcoma of the liver 'Italian case 01 was not a typical aSL; his primary tumour uai probably of the pericardium. Tms man was engaged in extrusion of PVC sacks. tB Belgium. G^W, Germany; Sw SweJen; C ^ Canada. It = Italy; UK = United Kingdom; Cz * Chechoslovakia, Jap Japan; V Yugoslavia; F France. N Norway; US TM USA. Thus G9 * case no. 9 in West Germany. Cases UK2. GU, USM, US15 and US25 were shown not to be associated with VCM exposure and hence withdrawn from the list. {Aerosol Can Alter, Cholangiosarcoma. {Does not include US31 (still alive). 197 North American PVC plants have not recorded an pounding or fabrication where many more people ASL ease so far. have been exposed but to a much lower dose. The average latent period between starting work in an occupation involving VCM exposure and death from ASL for the 99 eases is 21.9 years (in France, Sweden and the USA between 24 and 25 years, in Prediction of future ASL cases as a consequence of pre-1974 exposure Germany about 18 years). It is still too early to The causal relationship between VCM and ASL is predict whether the annual number of ASL eases proved beyond doubt by the specificity of the tu amongst VCM workers has reached a peak. ASL mour, the high relative incidence of that tumour in cases appeared earlier in North America than in highly exposed workers, the consistency of the excess Western Europe and while the occurrence is tending in different parts of the world, the time relationship to decrease in North America (Table 12), it is still between exposure and diagnosis and the dose- high in Western Europe. response relationship. An intensive analysis of the On the basis of the data in this case register, it is pre-1974 cohorts should establish the dose-response possible to draw certain conclusions about risk fac curve for ASL after VCM exposure and predict the tors associated with ASL. The large number of ASL likely outcome for the future. eases in some factories and the absence of ASL cases It will be impossible to collect a complete data set in others of similar age indicates that variations in on which to calculate risks of ASL for the whole manufacturing practices between factories may be the world, but within a single company there may be i cause. These variations may reflect both differences in closer definition of the cohort, the number of cases the types ofjob carried out by individual workers and and the pattern of exposure. Using these data and differences in engineering practices. The bulk of the averaging across the worldwide population exposed cases have occurred, however, in highly exposed to VCM. it is possible to calculate the futuie inci autoclave cleaners, with relatively few in other I'vC dence of ASL using relatively crude assumptions or VCM production jobs. So far no well- which can only be tested in lime when the prediction authenticated cases have occurred in PVC com can be judged against the final outcome. wwSi*; " ' 'v-k'f.'.'jy. "I"?-1*;'.'-A R&S 024747 4 I- ?! tft. |f S>T' .a'iU' - 198 1. F, H. FukcmaSE el oL Table 13. ASL cave number* by year of first exposure and geographical location (excluding ITfll*) Year of first exposure Western Europe ASL cavcst in. North America .... - - - - kry Rest of world event* 1939 40 1 2 3 4 5 6 Frll Frl4 UK I Sw2 Frl. Fr3, Sw4 7 8 9 1950 I 2 3 4 5 6 7 8 9 I960 l 2 3 4 5 6 7 8 9 1970 Sw3 Fr9 FrlZ, Fr4 Fr7, Nl. UK8 Swl. UK5 G3 G15. U3 G7, GS, UK-1. GI9 CM. GI6, G18 FrIO, G! FfS, G4, H2. G2 Frfi. HI Fr2, It4 G5. GI3 G9. G!0, GI2. GI7, G20. G22 G6. UK6, G2l Frl3. UK7 Sw5 Fr5 UK3 US24; C3, US27 US 13. US29 C2, US IV Cl. C5, US5, US2, US2S C-i, US3, US9 C7, C9, US8, USII, US2I, US31 Cfi. US24, US26 USI U$l 2 US 16 USIO. US32 US4 CIO US 18 U52. US 17. us:o US 2 3 Y2, 02 Jflpl. Yl Y3 C/.I Jap2, Y4 CS US6 US30 s Vinla 2 3 Maltoni Total... 52 39 X ASL - Angiosarcoma of ihc liver IlOl j* not consistent with other ASL c.i$cs. the primary tumour may have been of the pericardium The man exiruJcd PVC sacks. tFor explanatory key, see Table 12. jCholangiosareoma. 5US31 ts still alive. (Aerosol can filler. The data required arc: (1) Annual populations of employees classified by age; (2) Annual exposure estimates for each person in (1); (3) An exposure-response latency model for ASL induced by VCM. The data under item (1) are available in the UK as a result of the data extracted from the relevant occupational records (Fox & Collier, 1977). Exposure data for item (2) arc more difficult to obtain, but can be gleaned from the records that arc used to define .`he 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 exposurc/rcsponst/Iatcncy data indicated under item (3) can be derived from established cases. The key data for these procedures arc the set of eases 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 ore that most eases have a latency of about 20 years and eases will continue to occur for the next 10 years. In the calculation used to estimate the future number of ASL cases (Table 15) an assumption has been made that when exposures were reduced to low levels, the future risk of ASL became negligible. Two dales 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 X 09 </> o 10 u ->l Ja. 09 `V f-e >e>raw*./-.. r^> `' "' , \:t ; S ,vt` '.W" 4 hv,:-' ng on tiions, under >. set of i data ate an ;h exof the of the tes to y that broad icy of ur for future an has to low :, Two tained ,-duced i were ery- of Table U. Annual incidence of ASL case* (date of death) by geographical area Year Western Europe No. of ASL cates dying in: North Amend Re*: of world Annuli total Cumulative total Key event* 1955 7 1961 2 4 7 8 9 1970 1 2 3 4 5 6 7 8 9 1980 1 21 TOUl. a 1 lI 1\ 1 13 1 14 1 l2 6 1 \7 5 5 12 12 3 15 l1 12 ; 17 Viola 3 :o 41 5 25 1 4 3 8 33 Maltom 31 5 38 Goodrich 64 I 11 49 63 11 60 63 9 69 72 1 10 79 5 5 84 64 10 94 4* 4 95 00 0 0 52`. 38* 8 98* 98* ASL Anposarcomi of the liver Docs not include US3I (still alive in 1932). |At time of compilation. ^Includes G03 (aerosol can filler) but omits ftOI (bag extruder) 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 large. Death rates (or an intermediate year for the male population of England and Wales have beer, used in this calculation and the future cases (column 10) have been obtained by multiplication. The incidence figures for long 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 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. Tabk 15. Hypothetical calculation of future ASL cases using two deferent assumptions about the date at whten the levels became free of Calculations assuming no nsk after 1964 Latency (yr) 1-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51- 16- Cases to date 0 1 u as IS is 6 6 0 0 0 Persons at risk to date 100,000 98.250 95.500 84,750 61.400 36.750 21,250 6750 600 0 0 incidence 0.00 0,01 0.12 0.33 0.46 0.49 0.28 0 8 9 7 0.50 Future persons at nsk 0 0 0 6750 24.550 41.750 48.100 51.750 45.750 >4.500 47.600 300,750 Future cases 0 0 0 2 II 20 13 46 i 7 150 For detail* of the assumptions and methods see lest (pp. 197 & I9S). Calculation* assuming no nsk after 1974 Persons at nsk to date ->r incidence Future persons at nsk Future cases 100,000 94.500 78.000 46.500 28,750 18,750 10,850 3500 310 0 0 0.00 0.01 0.14 0.60 0.97 0.96 0.55 1.71 ? *> 0.80 0 3750 17.500 45.000 37.200 59.750 58.500 55.000 46.350 34.500 47.600 403.900 0 0 2 27 57 57 32 94 * 7 323 JO fi f C/5 O ro >1 ( u < <0 IS f- i m <7r ;V.V; 11 mm (c) The UK is nol 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 eases may occur in, lor 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 eases. For either assumption, the number of new cases observed annually should soon begin to decline and the rate of decline will indicate which assumption is nearer to the truth. There have been two other predictions of the number of eases of ASL likely to result from previous exposure to VCM. Nicholson et al. (1984) suggest that there will be a further 1500 cases of ASL, while Forman et al. (1986) conclude that a further 150-200 deaths might be expected over the next 30 years. Our estimates rely on a more sophisticated model than the latter estimate and on a larger data set than the former. Nevertheless, the conclusions of Forman et al. (1986) arc similar to ours. Only the experience of the next few years will show which is the best estimate. Summary and conelusions 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 xnd haemopoiclie 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 eases a decrease, in incidence in other studies. In view of the increased incidence of breast neoplasms in rodents exposed to VCM, the studies of Chaizzc et al. (1980), who did not confirm these findings in humans, are of importance. The register of ASL cases now contains records of 99 persons with confirmed ASL and occupational exposure to VCM. The average latent period between first exposure to VCM and death from ASL is 21.9 years. The majority of eases occurred in autoclave workers, who arc recognized as having been exposed to extremely high levels. Although precise estimates of exposure arc not available for the periods of most interest, the pattern of eases roughly suggests that extremely high exposures were necessary for the induction oT ASL. For example, ASL eases 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 scries of animal studies on the carcinogenicity of VCM. Some of these precede the epidemiological studies confirming the association between VCM exposure and ASL in man. ASL and neoplasms of a number of other organs have been induced in laboratory rodents by VCM. Estimation of the exposure levels likely to cause a lifetime risk of ASL of 10"` on the basis of these data give extremely low levels (down to 3.9 x 10": 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 chloroeihylcuc ox ide and chloroacctaldchydc. The rate of conversion is limited at high levels of exposure giving inaccurate estimates of the slope of the dose-response re lationship. It has not been possible to estimate the rate of conversion in man, and hence extrapolation of these low-risk dose estimates is conjectural. The second part of the problem of extrapolation at low risk is the selection of the most suitable mathematical model for extrapolation. Using Maltoni's data from rats (Maltoni et al. 1981), there is a substantial range (up to 10') of low-risk dose estimates, depending on the mathematical model and the assumptions used in applying the models. Using the same (probit and log-dose) model and different sub-sets of experi mental data, a large range of estimates is again obtained, even after coricction for the non-linear kinetics of metabolism at high dose (which reduces this range to about 10:). Larger differences arc obtained with calculations using the Weibuil 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 eases a total metabolized dose of 5 x 10s/<g (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 sulticicntly 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 I0"` 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 biolransformation data into account, is substantially larger than the lowest estimates, which arc up to 1010 lower (3.9 x 10'1 ppb using a multi-hit model). The higher estimates arc 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/I'VC 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 eases 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 eases 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. JO Bo O) o ro Vl oUi . S'XVVtAv'ivi < L*te .. . /&$ -A :'&'*** S^V !L and ; been nation risk of remely icar to neason n that : in the :ne ox- sion is ;curate ise re lic the lion of I. The at low natical a from I range :ing on used in it and experi- again .-linear educes are nalysis tat this models t anal- ility in experi:d dose Oppm) L incitold in matheire not .gender popu i^y lation .ifetime ;A i value derived mation R -B' tan the J^v?? * SV*Cv lower higher experi- dard of health give a public living w -f*,, . J.1 bpf' mate of in the 'KJ?!1 . Using ny, the ltc and popu* ses has `irf''d.^^H^J-f ^w^W,), ^ rmnimitifirinitflii mm Vinyl chloride--risk assessment 201 Acknowledgements--We thank Dr M. 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