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Review Section VINYL CHLORIDE:: AN ASSESSMENT OF THE RISK OF OCC J PATIONAL EXPOSURE* I. F. H. Purchase Central Toxicology Laboratory J. Stafford Plas .lcs and Petrochemicals DiMsion and G. M. Paddle Central Medical Group. Imperial Che: nical Industries pic, Alderley Park. Macclesfield. Cheshire. England (Received 14 Deep nber 1983: revisions received 13 January 1986) Introduction Vinyl chloride monomer (VCM), mor: properly named monochlorethane, is a colourless g; s normally bandied under pressure as a liquid which boils at -- 14=C at normal pressure. Discovered ar >und 1835, VCM's commercialization did not begir until the 1930s and did not reach high volume until after 19-15. Present manufacture is around 12 x 106 onnes 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 con :ems were related to the compound's narcotic effe :t. Indeed there are many reports of employees expost d to VCM dizzy and unconscious. Because VCM was considered to be relatively innocuous, it had a threshold 1 mit value (TLV) of 500 ppm, 8-hr time-weighte<! average [TWA) for many years (ACGIH, 1974; L ster et al. 1963; Torkelson et al. 1961). Measurements of em ployee exposure were infrequent, since r lost mea surement and warning systems were d< signed to ensure that plant atmospheres were beyond the ex plosive limits, fire and explosion being the main hazards of VCM. Retrospective estimate (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. 3< '0--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 thousand of ppm. were undoubtedly experienced for short/m :dium pe *A longer version of this paper has been p Jblished in Toxicological Risk Assessment, edited by D. . Clavson. D. Krewski and 1. Munro and published by (JRC Press, Inc.. Boca Raton. FL (1985). Abbreviations: AOL = acro-osieolysts; AS . = angiosarcoma of the liver: PVC = polyvinyl chlorl TLV = threshold limit value; TWA = ume-weightet averase; VCM = vinvl 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-osieolvsis (AOL: Cook et al. 1971; Hams &. Adams, 1967; Suciu et al. 1963). Modification of working practices led to a reduction m the incidence of AOL cases in autoclave cleaners. Although AOL is occasionally seen in people not exposed to VCM (Meyerson & Meier. 1972; Wilson et al. 1967) it is a rare disease. In the late 1960s, studies in rats involving exposure to high concen trations of VCM for long periods (Viola. 1969) failed to produce AOL but showed an increase in the incidence of tumours at various sites. Further studies (Maltom etal. 1980& 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 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. Polyfvmyl Chloride) and Structural Analogs, 1981; Gauvain. 1976; IARC Working Group, 1979; Selikoff, 1975; Szadkowski & Lehnert, 1982; US DHEW, 1980). The plethora of information (and misinformation) now available suggests that an ob jective historical case study of VCM would be of value. Experimental and human data Experimental studies Tne principal effect seen in the acute and subacute studies is anaesthesia, which occurs at relatively high 187 SPI-00993 188 I F H Pi rchvse ei at Table Lowest ci mirations or doses at which a significant eicess of various tumou pes was observed m rat carcmogemcuv studies Concn (ppmi Dose img kg) Forestomach papilloma Z>mbai-gland ca anoma Neuroblastoma Nephroblastoma Liver angiosarcor ta Mammarygland idenocaranoma >0.000 in ox) 10.000 150 (female) I (.0 \ male) :oo 50 5 (female) 50 imale) 16 65 tfemale) Data from Maltom al. (1981). doses (7-10%) in both animals and i nan. The doses responsible for acute toxicity are axmt 1000-fold higher than the minimum dose for carcinogenicity and there is frequently no sign of over: organ toxicity prior to the development of the carcinogenic response. VCM is mutagenic in a variety < f test systems including Salmonella typhimurium ( kannug et al. 1976), Saccharomyces (Loprieno et al. 1977) and Drosophila (Verburgt & Vogel, 19771, usually with some form of mammalian microsomal metabolizing system to convert VCM into its metabolites, chloroethylene oxide and chloroacetfej dehyde. The data on the mutagenicity of VCM provide useful qualitative information on its mode of action and metabolism, but are not suitable for liie quantitative estimation of risk to man. The most useful experimental dan are derived from long-term animal carcinogenicity studies. An extensive senes of 17 studies (Maltoti et al. 1981) gives a useful database for risk ass*ejsment. Other studies (Feron et al. 1981: Lee et al. 1978) tend to confirm the findings of Maitoni. Carcinogenic effects were observed in mice, rats, 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 nsk for brain cancer is much lower than that for liver cancer. Only two out of eight studies on lung cancer (Beaumont & Breslow, 1981) yielded statistically significant results and. because studies with a high power were negative, a causal association was consid ered unlikely. .ASL is the most suitable endpoint for analysis of the nsk of exposure to VCM for a number of reasons. It is a rare cancer in unexposed populations, making attribution to VCM exposure on the basts 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 and hamsters. A complication in the; sel ction of these data for risk assessment is the variety of tumour types observed (Table I). Some of these o*ctjurred at very high exposure levels, but mammary ad ocarctnoma endpoint to study. Case register The availability of data from a comprehensive case in females and ASL in both sexes of >oth rats and register of ASL cases with a history of occupational mice occurred at 50 ppm or less, expostfries similar to exposure to VCM provides an opportunity to identify those beiieved to have occurred on nlanufacturine risk factors for the induction of ASL. plants (Barnes. 1976). Persons potentially exposed to vinyl chloride Epidemiological studies Current manufacture and use of VCM and PVC Several major epidemiological studied on workers exposed to VCM have been reported (Table 2). The main organs that have been associate with higher incidences of cancer in workers exposec to VCM are the liver. lung and brain. Increases in he standard- lzed mortality ratios of cancers in the luccal cavity and pharynx, of lymphomas and of ers of the lymphatic and cardiovascular systems Have been re- ported in one or two studies. The analylsi:is of cancer of the respiratory system is often ntfounded by smoking, making quantitative analysis of the con- iribution of VCM difficult. The excess; of liver cancers is due to an excess of ASL in many ol the studies, An analysis of the statistical powei of various studies for association between VCM ekposure and cancer of the lung, liver and brain fjeaumont & Breslow. 1981) concluded that the re Its for liver were consistent with an aetiological ro! : for VCM. results in the potential exposure of four groups of the population. The highest exposure category covers the workers involved in the manufacture of VCM. its polymerization to PVC and certain other industrial uses of VCM. Within this group, certain occupations, particularly autoclave cleaning, involve higher poten tial exposure than others, although all groups would now be expected to have exposures complying with hygiene standards of 1-5 ppm. The next category covers those exposed as a result of using the PVC. Workers in the compounding and fabrication of PVC products are exposed to residual VCM released from PVC on heating (but PVC does not decompose to VCM when heated). In general the exposure levels for these workers are very low in comparison to those for PVC polymerization workers (from 10 to 100 umes lower). Consumers who eat food and drink beverages that For brain cancer, where three out of fiv studies had have been packed in PVC may ingest unreacted VCM SPI-00994 nyl chloride--risk assessment 189 which has migrated into the food or bev rage. Since 1974, the amount of VCM in PVC has b :en reduced to less than I mg, kg with the result that th maximum human daily intake of VCM in food a id drink is 0.1 yg day (Ministry of Agriculture. sheries & Food, 197$). The fourth group with potential exposure to VCM are those who live in the vicinity of V CM or PVC manufacturing or fabricating factories, The levels in ambient air around a factory are very ow (in the pans per 10* range) but much larger population groups, which include all age groups, ait involved, For the workers in VCM manufacture and PVC polymerization and fabrication, the route >f exposure is by inhalation. Much of the animal car ogenicitv data are based on inhalation exposure and the human epidemiology is predominantly of popu attons exposed occupationally by inhalation. Thus an assessment of the risk factors and the quantita ive risk of inhalation exposure is the main objectiv For the consumer exposed to VCM via food and beverages the route is by ingestion. Relatively few ex|xrimental studies have used oral administration and only one study used a comparable exposure patten (Feron et at. 1981). Similarly there are no sp anific cpi- demiological data on oral ingestion. Risk tssessment for exposure via the oral route must rilv on the existing animal data and on extrapolation from cpi- demiological and experimental studies of nhaiauon exposure. 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 = CHC1 111 CH.St H.CHO Id) dy CHCH.SCH.CH, 1 *| 11 OH [ CHCH,SCH,CO,H SH Risk assessment from experimental animal data Assumptions In carrying out a risk assessment on th: basis of animal data, a number of assumptions h ivree to be made. The first of these relates to the ov trail dosimetry. Experimental animals are exposed concentrations of vinyl chloride or dosed with aifiounts of vinyl chloride that allow an estimate of th: amount to which they have been exposed. It is possible to calculate a correction factor for these au;entities so that they are applicable to man. However, rats and mice live for relatively short periods of urn : (up to 2 years) during which they develop cancers of a type similar to those seen in man. The latent pe;ri >d fI or the same tumours in man may be between ) and 40 years. It is therefore assumed that the lifetinje of man is equivalent to the lifetime of an experime;ntal ai nimal species even though the chronological ttrr(e is substantiallv different. Strictly speaking, mathematical e.xtrapo ation of risk on the basis of experimental animal 4ata pro vides an estimate of the risk at low dos^s to the experimental animal under consideration, variety of factors, particularly inherent biological susceptibility and differences in metabolism, ri nder the extrapolation of the data from animals d; rcctly to man subject to numerous errors. It is at tis point that scientific judgement is required to decidt whether these data are applicable to the human siittlation. Metabolism In rats. VCM has been shown to be me; abolized extensively, producing a range of excretion products. Glu co2h T chch;sch;ch2 SH(AC) Oh (e ) Glu 1 J CO:H ii 1 CHCH,SCH,CO,H | 1 SH. (M CO.H I' c -- ch.sch2co,h II 0 S(CH^COjH), () Fig. 1. Scheme showing the metabolism of vinyl chloride monomer (VCM) in rats to S-containing metabolites. VCM (a) is convened to chloroethylene oxide (b) which is trans formed spontaneously to chloroacetaldehyde (c). These two metabolites are mutagenic and hence are considered to be ihe proximate carcinogens. The urinary excretion products iV-acetyl-5-(2-hvdroxyethyl)cysteine (e) S-(carboxymethyl)cysteine (f) and thiodiglycollic acid (g) are derived from these mutagenic metabolites via (d). Gly and Glu are the glycine and glutamate residues of gjutathione. [After Green & Hathway (1977)]. SPI-00995 SPI-00996 >- a au j*s H ^> <"v= ^=15 =i0 to< = = /2 * a &Oo Vinvl chloride--risk assessment 191 60 < o Z 3 of VCM metabolism in rats is given in Fig. I On the basis of this scheme, the highly reactive intermediates in the metabolic process (particularly chloroethylene oxide) react with cellular macromolecules, including DNA to produce the critical lesions leading to mu tation or the induction of cancer. Studies on the quantitative aspect of VCM metab olism have shown that there is a dose dependency in the rate of metabolism. After administration of l4C-labelled VCM by gavage at doses betw een 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 & 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 & Gehnng. 1976). Studies of the amount of non-volatile material retained in the carcasses of rats exposed to various levels of l4C-labelled VCM for 6 hours demonstrated that the metabolism of VCM appeared to be in accordance with Michaelis-Menten kinetics (Gehring et al. 1978). The constants for maximum velocity of metabolism (Vm in tig metabolized.6hr) and the Michaelis constant (K,, in tig VCM litre air) accord ing to the formula: (where V = velocity of metabolism in tug 6 hr and S = concentrauon of VCM being inhaled) were Vx = 8558 tig metabolized'6 hr and Km = S60tig 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. On < .2 3 .sw Review of earlier calculations of risk There have been a number of attempts to calculate the risk of ASL development on the basis of extrap olation from experimental data. These have been reviewed by Barr (1982) and an adaptation of his data is presented in Table 4. The introduction of biotransformation data into the estimation of risk increased the level of exposure calculated to cause a 10~6 lifetime risk, from parts per billion to in excess of one part per million. A further refinement of the technique using DNA binding as the measure of dosimetry (Anderson et al. 1980) provided a similar estimate of the exposure. A variety of mathematical models can be used for extrapolating below the experimental dose range, and it is not possible to select from amongst these math ematical modeis on the basis of goodness of fit to experimental data. Attempts to do so have shown that most of the models fit the data equally well (Gehring et al. 1979). It is equally difficult to select amongst the models on the basis of the assumed mechanism of action of VCM. Thus a comparison of the lifetime risks calculated using the Armitage-Doll SPI-00997 192 I F H Purchase et ai Table 3 Vinyl chionde dose and icidcncc of hepanc angiosarcoma in Sprague-Da*le> rats exposed on 5 da'.s for 52 *k* Concn (ppm i 50.000 10,000 6000 2500 500 250 200 150 100 50 25 10 0 Amount me' ug 4 hr 5647 5521 5403 5030 3413 2435 2129 1761 1309 739 395 169 $4 17 0 Mg (total) .47 * I0# 44 x 10* 41 x 10* 1.3 * 10* 8 8 x 10' 6 3 * I05 5.5 * IQJ 4 6* i05 3 4 x 10s 19 x 105 1.0 X io} t 4 x 104 2.2 * I04 k 4 x 101 0 \ngiosarcoma incidence ( Female Mean 16 6 43 3 30 0 100 13 ! 11 1 10 3 33 3 :: o 20 0 23 3 21 ' 0 200 100 34 67 5 1 U 7 8 3 100 1.7 S 3 5 0 0 1 ' 08 1 ! -2 4; I 7 6 ~ 4: 0 t ' 08 000 000 000 Expmt BT 6* BT 1 BT t BT 1 BT 1 BT 1 bt: BT 2 BT 2 BR 1.9 BT 15 BT 15 BT 15 BT 15 BT L 2. 9. 15 After Mallow et ai. (1981). f Experiment BT 6 ended after ool) 68 wk. while the rest were ail approximately 140 wk; therefore the percentage of tumours in B7|6 is probably low relative to the rest because of the short latency penod available. multistage model by the Food Safety Coun nl (1980) and by Gaylor & Kodeli (1980) showed th; t for the same t0~` lifetime risk, the Food Safety Council estimated the dose as 2 x 10"' ppm wherea; Gavlor & KodeQ estimated the dose as 5 x 10 ppm. The difference between these two estimates wafc due to alternative assumptions on the value of the expansion of the exponential term used. In general, calculations based on the an)ourn of material metabolized or on human data h ive produced exposure values of about 1 ppm fo: a 10-* lifetime risk. All the other studies have droduced 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 !0"` risk from a variety of experimental animal data applying the correction for metabolism used by Gearing et al. (1979). Calculation of exposure for 10 risk A summary of the crude ASL incidence rates for inhalation studies in Sprague-Dawlev rats is given in Table 3. Similar data for Wistar rats exposed by Table 4. Summary' of quant iuuve mlc assesstneou far vinyl chionde monomer" Reference Species Exposure for I0~` lifetime nsk (ppb*) Comments Schoeidermao et ai. (1975) Rat Kuxmack & McGaughy (1975) Gebring et ai. (1979) Food Safety Council (1980) Rat, man Rat. man Rat Rat .Anderson et ai. (1980) Gaylor <fc Kodeli (1980) Cariborg 11981) Barr (1982) This paper iTable 9) EPA 11980) NAS (1980) Crump Jc Guess (1980) Rat, man Rat Rat Man Rat Mouse Man Rat Mouse Man Rat Rat Man Rat B inhalation 73 119 2 14 140-1400 > 1000 < 10-> 1000 20 20 2.1 x 10-* 3.9 x 10~7 >1000 0.7 0.5 2.5 x 10"' >100 0.025-9.l6\ 2 x 10-,J / 0.63-90 2 KT1-: x io-' 6 x 10- 0.067-8.14 Bv ingestion 4ug day 3 x 10'J mg, kg/day Q.7 ug.day 0.5 u g day Probit (slope 1. Mantel) Logit (slope * 3.45) Logit (slope - 2.3, one-hit) Linear through zero Log-probu Biotransformauon data included Linear or log-probu Depends on mathematical model used One-hit Armuage-DoU Wejbull Multi-hit DNA binding used for dosimetrv Upper 97.5V* confidence limit of linear model Amu tage-Do11 Weibull Derived from Barr s negative epidemiology Log-probit Log-probu including biotransformauon data for man Weibull Weibull including biotransformauon for man Food or water Water Applying worker data to water Upper 95# confidence limits After Barr (1982). Except where suied otherwise. SPI-00998 P^' ap: der Th ga'. arr. on fra. do5 was use hai. 19" Wis mar V. hat (19r a be VC' beer Vinvl chit ride--risk assessment 193 inhalation (Table 5) for rats exposed orally (Tat le 6) and for mice exposed by inhalation (Table 7) are also presented. Data from experiments with vanoui ex posure periods of short duration are given in "able 8. For calculating the amounts of the dose me abo- lized in rat', in the inhalation experiments, the con stants calculated (Gehnng el al. 1978) have been applied. For Wistar rats, the and Vm v dues derived for Sprague-Dawley rats have been ised. These estimates of metabolized dose have beep in cluded in the tables. For the experiment in which VCM was givei by gavage, the data from Fig. 2 were used to estimat: the amount of VCM exhaled unchanged. As the t, . for exhalation of VCM was 14 minutes, these data based on a 72-hour period give a good estimate ol the fraction of VCM exhaled in the 24 hours bet veen doses. It has been assumed that the VCM not exf aled was metabolized, an assumption similar to the one used for estimating metabolized dose in the in halation experiments. Green & Hathway (197 5 & 1977) showed that VCM administered by gavage to Wistar rats was exhaled and metabolized in a sir lilar manner to that in the Sprague-Dawley rats, ant the Vm and values derived for Sprague-Dawley rats have been used. In the experiments by Feron < r al. (1981). who used Wistar rats, the same assump ions about Vm and K.m have been made. The quantii y of VCM administered has been dealt with as if it had been administered bv zavaee. VCM dose (mg/kg) Fie 2. Summary of dose-dependent urinary and pulmonary excreuon of vinyl chloride monomer (VCM). Urinary excreuon i i represents metabolites of VCM, while pulmonary elirainauon (A) is unchanged VCM. [After Watanabe Sc Gehnng (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 Vm 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 7kg body mass. This technique has also been used by Gehnng et al. (1978) for estimating the dose metabolized by man. Table 5. Vir.yl chloride dose and i: cidence of hepatic angiosarcoma in male Wistar rats expose* wk for 52 wk >. -3 oP Concn (ppm) Amount met bolized ug 4 hr ig (total) Angiosarcoma incidence (/#) Expmt no. 10.000 6000 2500 500 250 50 1 0 5521 5403 5030 3413 2435 739 17 0 1.4 x 10* 1.4 X 10* 1.3 X 10` 8.8 x I0J 6.3 x 10J 1.9 x I0! 4.4 x I0J 0 29.6 11.5 12.0 10.7 3.7 0 0 0 BT 7 BT7 BT 7 BT 7 BT 7 BT 7 BT 17 BT 7. ! 7 Table 6. Vinyl chloride (VCM) dose and incidence o' hepatic angiosarcoma in rats given VCM b> gavage or mgesuon Dose (mg kg) Amount exhaled* (S of dose) Amount meiab< iized ug dose* Ui (total) Angiosarcoma incidence (*/) Male Female Mean Expmt no. ;o: 16.65 3.33 1.0 0.3 0.03 0 30011 I4.l 5.0 1.7 0 50 35 10 2 1.7 _4 SO 32 16.5 69 6250 2705 750 3245 74 7.4 0 15.000 2390 1040 420 0 1. ) x 10* 7. ) x 10' 2_ 1 X 10! r *t i x 10* 2.1 I X 104 2.1 i X 10J 0 6. : x io` 1.6 i X 10* 7.2 1 x 10* ' X lO* 0 20 10 0 1.3 0 0 0 49 49 10 0 0 22.5 15.1 0 2.7 1.4 0 0 53 16 4 0 0 21.2 12.5 0 2.0 0.7 0 0 511 32 7> 0 J BT 11 BT 11 BT 11 BT27 BT 27 BT 27 BTll, 27 Feron et al. (1981) Calculated from data derived from Watanabe & G rhnng (1976) presented in Fig. 2. Assuming a 250-g rat. Sprague-Dawley rats dosed by gavage with VCM a corn oil 5 umes/wk for 52 wk. BT27 dosed for 59 wk. "Wutar rats used as controls by Feron et al. (1981) and dosed for 83 wk. "Wisur rats receiving a diet reclaming VCM dissol -ed m PVC. SPI-00999 I F H Pi. rchase et al Table Vm\l chloride J >e anc incidence 'f hepatic ang losarcoma in mice Concn (ppmj Amount meiabol :ed u% 4 hr ug ( oui) Angiosarcoma incidence i%i --- - - - - Male Female Mean Exprm no 10.000 6000 2500 1000 500 250 250 50 1 0 11.245 1 1.007 10.246 8699 6952 4959 4959 1506 1506 0 l 7 10* 17 10* 1 5 10* 3 4 10* 1 0 10* 7.4 10* 7 4 10* 2.2 I05 5.9 )03 38 67 20 ^ 39 4 20 0 30 0 24 0 33 10.3 0 30 36 7 33 3 50 0 26 7 30 0 47 0 0 0 0 r 8 BT421.7 BT 4 Z" l BT 4 44 " Lee et aft 23.3 BT 4 30 0 BT 4 36.5 Lee et al * 1.7 BT 4 Lee et aJ 0 BT 4 A Lee et al. Swiss mice 81-wk experiment, dose 1 for 30 w k. *CD, mice. 52-wk experiment. 6 hr av exposure (Lee et al )9"8). These results have not been included in the calculations for T able 9 because the experimental design ncorporated interim kills. Thus: 0.011 m2 Vm (mouse) = Vm (rat) x 0.045 nr 0.011 = 5706 /ig/4 hr x 0.045 = 1395 #tg/4hr The values of 0.045 nr and 0.011 nr are tl e body surface area of a rat and a mouse, respective! t. Since toxicity is a function of the concentration of tie toxic metabolite in the tissue, the amount tran: formed must be normalized for mass to estimate ar equivalent response. Thus V= must be adjusted on t le basis of the body weights of a rat (0.25 kg) and a mouse (0.03 kg) by dividing by 0.03'0.25 = 0.12. The Vm for the mouse on a mass-equivale|it basis is therefore: 1395 -- = 11625/i g/4 hr This value of Vm has been used in calculating the total amount of VCM metabolized (Table 7). From the variety of models (or mathemat cal ex trapolation techniques) used for low-dose ris!: extra polation (Table 4), an arbitrary choice of models has been made to test the robustness of the extrap olation from the different animal studies. A log-probit analysis of the dose that wiuld be expected to produce a lifetime risk of ASL of 10'* is presented in Table 9. This calculation can be earned out on the basis of the concentration inhaled, the daily dose metabolized or the total quantity metabo lized dunng the whole experiment. There is a wide variation in the estimated dose depending on the database used for the calculation. The largest vari ation between doses derived from the rat experiments is 360-fold (0.025 ppb r. 9.1 ppb) when exposure in ppb is considered, but this decreases to 100-fold for other estimates of dose. The results from mice are substantially lower when expressed in ppb (2 x 10'15 ppb) but the difference is less for other expressions of dose. Similar calculations of the dose expected to give a 10"* lifetime risk of ASL have been based on a Weibull analysis (Table 9). This is a more 'conserv ative' mathematical model and the estimates of dose are accordingly lower. The variation in estimates of dose is, if anything, larger than that observed with the log-probit analysis (for example, a 10's difference between the S values derived from Wistar and Sprague-Dawlev rats). The doses for mice are so much lower than those calculated for rats or man that the assumptions used in their calculation must be suspect. A further calculation to derive the human dose likely to produce a risk of 10'* is given in Table 9 (S calculated for man). These calculations are based on a Vm for man of 1675 pig, 8 hr based on corrections for body surface area and mass. The values are substan- Table S. Vinyl chlonde (VCM) dose and hepat c angiosarcoma incidence in Sprague-Dawley rats exposed lo VCM by inhalauon Concn (ppm) 10.000 10.000 10.000 10.000 10.000 6000 6000 6000 6000 6000 Schedule* I II III IV V I II III [V V doses 260 85 2f 100 25 260 85 25 100 25 Ar ount metabolized; Mg' 4 hr <5 21 44 2l 55 :i 13 79 < :i 54 33 54 33 54 33 13 '0 54 33 yg (total) 1.4 x 10* 4.7 * 10! 1.4 X I0! 14 x 101 1.4 x t05 1 4 x 10* 4 6 x 10' i 4 * I0! 1 4 * 10s 1 4 10s Angiosarcoma incidence (%) Male 10 0 1.7 1.7 0 10.3 0 0 34 0 Female 13.3 0 0 0 1.7 33.3 3.3 0 1.7 1? Mean 11.7 0 0.8 0.8 0.8 22.0 1.7 0 2.5 0.8 Expmt no. BT I BT 3 BT 10 BT 10 BT 10 BT 1 BT 3 BT 10 BT 10 BT 10 After Maltom et al. (1981). Schedules: I--4 hr day. 5 days wk for 52 wk; 1--4 hr.day. 5 days w k for IT wit Ill--4 hr'day. 5 days wk for 5 wk; IV--l hr day. 4 days.wk for 25 wk; V- day. I aay wk for 25 wk. *Amount metabolized (v) m 4 hour derived frefcn the formula. V (^g hrj Vw * S K*, -- S where u 4/6 of the 6 hr value. SPI-01000 196 F. H Purchase ei a! lially 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 roden: experi ments. When this amount of variability occt rs in the extrapolation of the risk of low-dose exp jsure to VCM based solely on different experimems in the same species, the reliability and hence the Utility of these procedures is open to question. The general relationship between the dose idmimstered and the incidence of angiosarcomas derived Table 11 Clustering of ASL cases m individual PVC plants Plant* no Country No of ASL cases W wtern Europe l Wt Germany : 'Vest Germany \ \*est Germany 4 West Germany 1 France : France 2 France 10 4 > 5 5 : from 52-week exposure does not apply to ei posures ! UK 5 I of shorter duration (Table 8). In all experinents a : UK i Sweden 2 5 total metabolized dose in excess of 5 x 10'pg was Total. .. 42 required to produce an incidence of aneiosarioma in North America excess of 1-2%. This relationship was seen in both rats and mice and in experiments in w hich VOl was administered by gavage or by inhalation. In longterm inhalation studies, a total metabolized dose of 5 x lO-'/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 i Canada i USA 2 USA 3 USA Resi of World 1 Japan l Yugoslav** 1 Czechoslovakia Total. .. 10 11 9 4 34 2 4ri estimates of dose for a 10~` lifetime risk. This vari Total... 8 i ation is due to the type of mathematical mo< el that For the purposes of this case study, it is not necessary to identify is applied, to the assumptions that are made and to the preaje ownership and location of these plants. the particular experiment that is used to provi le data for the extrapolation. A high level of confidence the end of I9S2 have been analysed by country and cannot be placed on low-dose extrapolation when by manufacturing company and plant. The cases \ variables that would not be expected to at er the have been recorded from all major VCM/PVC manu expression of risk have a profound effect jn the facturing countries (Table 10). but the incidence has estimated risk. In addition, the interspecies e: trapo not necessarily been in proportion to the PVC pro ! lation from experimental animals to man is arEtlv duction capacity now or prior to 1962. In the absence intuitive. It is clear that estimates of risk shou d take of data on the number of workers employed, pro into account all available data, includin epi- duction capacity is the only available indication of demiology. to provide a degree of reliability. the cumbers of people potentially exposed. Tne majority of the ASL cases are PVC autoclave Risk assessment from human studies cleaners or men who have worked in or around Register of ASL cases autoclaves. There are ASL cases among men who manufactured VCM and a few cases were involved Since 1974. lists of reported ASL cases attribptable to VCM exposure in the VCM PVC industry have been kept by NIOSH (Spirtas & Kaminski 1978). by IARC and by the VCM Committee the Association of Plastics Manufacturers in Europe (APME). Details of 99 cases in the APME regi ter at both with monomer and with polymer production. Only one case suffered from both acro-osteolysis and ASL. The ASL cases tended to occur in larger numbers in some plants than in others (Table 11). Of the total of 39 ASL cases recorded in North America. 34 have occurred at four PVC plants, while over 40 North ASL ca.- The a an occu from A; Sweden Country Table 10. Distr bution of ASL cases by country No. of ASL cases PVC production nameplate capacity (ktiotonnes vr) 1932 1962 1972 German predict amongst cases ar Western USA 29 193 704 2090 West Germany :i 22 260 . i 155 to decre,, high in t- ! France Canada UK Sweden 14 11 176 627 10 ; T*> 38 7 27 177 502 5 3 20 105 On thr I possible tors assoc Yugoslavia 4 3 8 60 cases in s Italv Czechoslovakia Japan Beipum Norway 3 2 1 1 9 212 778 1 25 48 12 384 1699 3 25 195 2 20 65 in others manufac: cause. Th the types Toul... Western Europe North .America Rest of World TouJ. .. 99 52 39 8 99 82 951 3950 198 *'26 2178 51 709 3334 331 2386 9462 difference cases ha. autoclave or VC.Y ASL - A lgiosarcoma of tne liver authentic^ chloride--risk assessment Table 1: ASL Lase numrvers b\ Year of death Western Europe 1955 6 7 1 9 I960 ) 2 3 4 5 6 7 8 9 1970 1 3 4 5 6 7 9 1960 FI Gl Swl g: Nl, Sw2, UK I. Ii2 cn G4, G5, UK3 F2. F3. G6, G7, G8. It3 BI. F4. F5. F6. F7. S*3 F8, F9. GIO. Oil. Gl! Sw4 F10. FU, G9. G13, G15, GI6. GI7 Fli F13, UK4, UK5* G18 UK6, UK7, G19, $w5. G20, G2I It4. FI4. UKS, G22 ar of death and geographical location (excluding ITOI'l ASL cases'1 in. North America Cl Rest of world Kev publications C2 US8 C3 US5 Cz2 C4. C5. US4. US7. US10 US 12. US 16 US 11 C6, us: C7 Cl. US1. US3. US23 C9. US 13 JS6. US9. US 18. US26 JS19. US20. US22 riO. US21. US24 JS27. US28 Yl. Y2. Czl Japt Jap2, Y3 SI7. US29. US30. US32 Maltooi Creech & Johnson Tout . ASL - Angiosarcoma of the iiver `Italian case 01 was not a typical ASL. his Y tumour was probably of the pericardium. This man * engaged m extrusion of PVC sacks. 7B Belgium, G * W. Germany; SwSw:dea; C Canada; It = Italy; UK = United Kingdom; Cz Czechoslovakia; Jap = Japan: V * Yugoslavia, F * France; N Norway; US USA. Thus G9 * case no. 9 in West Germany. Cases UK2, G* USI4. US15 and US15 were shown not to be associated with V'CM exposure and hence withdrawn frjjm the iist. ^Aerosol can filler. fCholangiosarcoma. `Does not include US31 (still alive). N7 North American PVC plants have not record! d pounding or fabrication where many more people ASL case so far. have been exposed but to a much lower dose. The average latent period between starting w c rk in an occupation involving VCM exposure and death from ASL for the 99 cases is 21.9 years (in Frince. Sweden and the USA between 24 and 25 veais m Prediction of future ASL cases as a consequence of pre-1974 exposure Germany about 18 years). It is still too eariy to The causal relationship between VCM and ASL is predict whether the annual number of ASL i ases proved beyond doubt by the specificity of the tu amongst VCM workers has reached a peak, X.SL mour. the high relative incidence of that tumour in cases appeared earlier in North America tha 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 i 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 nsk fac- curve for ASL after VCM exposure and predict the ! tors associated with ASL. The large number of ySL likely outcome for the future. cases in some factories and the absence of ASL cases It will be impossible to collect a complete data set t in others of similar age indicates that variations in on which to calculate risks of ASL for the whole manufacturing practices between factories may fcx world, but within a single company there may be cause. These variations may reflect both differenci s 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 exp< sed to VCM. it is possible to calculate the future inci autoclave cleaners, wuh relatively few in other F VC dence of ASL using relatively crude assumptions or VCM production jobs. So far no ell- w hich can only be tested in time when the prediction authenticated cases have occurred in PVC can be judged against the final outcome. SPl-01003 198 1 F H. Purchase ei j/ Tabic 13. ASL ca numbers by ye ir of first exposure and geographical location (excluding 1T0I*> Year of first exposure Western Europe ASL cases* in North Amertca Rest of *orld Key events 1939 40 1 2 3 4 5 6 Frl I Frl4 UK1 Sw2 Frl, Fr3, Sw4 7 8 9 1950 \ 2 3 4 5 6 7 8 9 I960 1 2 3 4 5 6 7 Sw3 Fr9 Frl2. Fr4 Fr7. Nl, UK8 Swl, UX5 G3 G15, 10 G7, G8, UK4. G19 GII.G16, G18 FrlO, Gl Fr8. G4. ia G2 Frf, B1 Fr2, 1(4 G5, G13 G9, G10, G12, GI7, G20. G22 G6, UK6, G2I Frl 3, UK7 Sw5 Fr5 UK3 us:4; C3. us:? US 13. US29 C2. US 19 Cl. C5. US5. US7. US28 C4. US3. US9 C7. C9. US8, US 11. us: l US3I C6. us::. us:6 LSI US 12 US 16 US 10. US32 US4 CIO US 18 US2, US 17, US20 US23 Y2. Czl Japl. Yl Y3 OI Jap2. Y4 a US6 US30 the as hypo; 9 used, 1970 Viola estitna !i 3 Maltoni Total. 39 8 ical 'tc based aireac ASL -- Angiosarcoma of the liver ItOI is not consistent with other ASL c ises; the primary tumour may have been of the pericardium. The iatent or me man extruded PVC sacks. For explanatory key. see Table 12. t Ch olan p osarco ma. US31 is still alive. ; Aerosol can filler. The r, caJcuia accour popuia year fc The data required are: (1) Annual populations of employees classified by age; (2) Annual exposure estimates for each person in (1); (3) An exposure-response latency model for ASL induced by VCM. avoid using the exposure data directly by relying on the similarity in exposure levels in differing locations. The exposure; response/latency data indicated under item (3) can be derived from established cases. The key data for these procedures are the set of cases worldwide, together with the descriptive data (Tables 12-14). It has been possible to calculate an incidence rate for each latency period for each ex have N. (colurr. The ir. years i latent:; of 0.5 a Tabic 15 Tne data under item (1) are available in the UK as posure level for each age group (on the basis of the < a result of the data extracted from the tlevant UK data and assuming that it is representative of the occupational records (Fox & Collier, 1977). E: posure worldwide population) and to use these rates to data for item (2) are more difficult to obtain, jut can derive a simple model of dose-response latency that Latenc be gleaned from the records that are used tc define can be applied to the population data. The broad (yr' the occupational population. The problem of oc- conclusions are that most cases have a latency of 1-5 cupation changing, which occurred frequen^fly, has been dealt with by using the principal empl lyment category or the highest exposed employmei t category. The estimation of time-weighted aver . ge ex- 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 6-10 11-15 16-20 21-25 26-30 posures for the least exposed employees is s|ra:zht- forward, as the exposures were essentially confi nuous and constant, but for autoclave cleaners, ifiainte- been made that when exposures were reduced to low levels, the future risk of ASL became negligible. Two dates at which the negligible risk levels were attained 31-35 36-40 Jj-45 46-50 nance workers and laboratory workers, ex[ iosures have been selected: 1964, when levels were reduced 51- could vary from zero to near narcotic levels In the to hundreds of ppm and 1974 when the levels were 16- calculations described below, it has been possible to reduced to below 10 ppm following the discovery of For details l SPI-01004 Vinyl ' blond risk assessment Table 14 Annual incidence c * ASL cases (date of death) by geographical area Western Europe North America of ASL cases dying i Rest of world Annual total Cumulative total Key events 199 9 1: 3 1970 li 2 l2 2 X1 3 5 3 \4 3 8 4 3 -> 5 64 1 11 6 .6 3 2 II 76 9 8 72 1 10 95 5 1980 64 10 l 4 4 2t 0 0 0 0 Total. . 52; 38* 8 98* ASL * Axt jposarcoma of tbe liver Does oot include US3I (still alive ini :1 82). tAt moe of compilation, tlodudes G03 (aerosol can filler) bui oduts 1x01 ("bag extruder). 6 ? i: 15 1? Viola :o 2< 33 Maltorn 38 Goodneb 49 60 69 79 84 94 98 98* the association between ASL and VCM exposure A hypothetical exposed population of 100,000 has tx en used, but this is unimportant (see (a) below). . tn estimate of the age distribution within the hvpoth :tical 'total' exposed population of 100.000 has be m based on UK data (Fox &. Collier. 1977). For perso is already exposed during the whole of the vario js latent periods, the numbers with a latency of 30 yea rs or more form only a small proportion of the lou 1. The numbers of persons at risk in the future a e calculated by advancing time in 5-year periods takii g account of the age-dependent death rates in tl e population at large. Death rates for an intermedia e year for the male population of England and Wall s have been used in this calculation and the future cast s (column 10) have been obtained by multipiicatioi. The incidence figures for long latent periods (> 2 > years) are unreliable or non-existent but those folatencies of 15-25 years are fairly constant and value of 0.5 and 0.8 cases 1000 persons have been used fo 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 exampie: (a) The population size used for the calculation is probably larger than the exposed population, but the calculation depends on the ratio of "person-years to come" and "person-years ex perienced" and this ratio is the same for any population size. (b) Exposure level has been ignored. The calcu lations are based on the overall risk to the cohort and although the incidence figures for sub-cohorts could be higher, the estimate of future cases will change very little. Similarly duration of exposure has been ignored. Table 15. Hypothetical calculation of future ASL cases using two .ifferent assumptions about the date at which the levels became free of nsk Calculations assuming no nsk afu 1964 Calculations assuming no nsk after 19"4 Latency i.vr) Cases to date Persons at 5-vr nsk to date incidence Future persons at nsk Future cases Persons at nsk to date 5-yr incidence Future persons at nsk Future cases 1-5 6-10 11 -- 15 16-20 2!-25 26-30 31-35 J6--*0 4| --45 4o-50 5!16- 0 100.000 0.00 00 1 98.250 0.01 00 11 95.500 0.12 00 28 84.^50 0.33 6750 28 61.400 0.46 24.550 11 18 36.750 049 41.750 20 6 21.250 0.28 48.100 13 6 6`50 0.89 51.750 46 0 600 45.750 00 03 34.500 47.600 050 300.750 150 100.000 94.500 78.000 46.500 28.750 18.^50 10.850 3500 310 0 0 0.00 0.01 0.14 060 0.97 0.96 055 l.7| ? "i 0.30 0 3750 17.500 45.000 57.200 59,750 58.500 55.000 46.350 34.500 47.600 403.900 0 0 T 27 57 57 32 94 > *> * 323 For details of tbe auunpuons aad methods see text {pp. 197 & 191). SPI-01005 200 I. F H Pxkchxse ft Jl (c) The UK is not typical of the worldwide between VCM exposure and ASL in man ASL and growth in the exposed population. neoplasms of a number of oiher organs have been -i. Id) No account has been taken of plant im induced in laboratory rodents by VCM Estimation provements occurring prior to 1964 and hence of the exposure levels likely to cause a lifetime nsk of fewer cases may occur in, for ext mple. the ASL of 10 " on the basis of these data give extremely '98C-2000 period than are estimate! from the 1940-1980 experience. An assumption that the nsk of ASL ceas ;d in 1964 rather than in 1974 results in a considerable reduction in the estimate of future cases. For either as lumption. the number of new cases observed annua ly should soon begin to decline and the rate of d<cline will indicate which assumption is nearer to th< truth. There have been two other predictiot s of the number of cases of ASL likely to result frort prev ious exposure to VCM. Nicholson et al. (198-) suggest that there will be a further 1500 cases of A >L, w hile Forman et al. (1986) conclude that a furthe 150-200 deaths might be expected over the next 30 v :ars. Our estimates rely on a more sophisticated mode than the latter estimate and on a larger data set than the former. Nevertheless, the conclusions of F irman et al. (1986) are similar to ours. Only the exp< rience of the next few years will show which is the best estimate. Summary and conclusions 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 chloroethvlene ox ide and chloroacetaldehyde. The rate of conv ersion is limited at high levels of exposure giving inaccurate estimates of the slope ot the dose-response re lationship. It has not been possible to estimate the rate of conversion in man. and hence extrapolation of these low-nsk dose estimates is conjectural. The second part of the problem of extrapolation at low nsk is the selection of the most suitable mathematical model for extrapolation. Using Maltoni's data from rats (Maltom 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 in applying the models. Using the same (probit and log-dose) model and different sub-sets of experi mental data, a large range of estimates is again obtained, even after correction for the non-linear kinetics of metabolism at high dose (which reduces tins range to about ICE). Larger differences are obtained with calculations using the Weibull analysis as a basis of low-dose estimation, suggesting that this A Cu ir. C A no gr :r c\ Bar- ?\ Bar- P* A. Jur Beau era ers Berta M, <1- Buie; lIT cc BNrtr. Me There is little doubt that exposure to high le'veis of is a problem with the use of mathematical models VCM as a consequence of occupation can re;s alt in an rather than one associated with the iog-probit anal VC r. increased incidence of ASL. A review of 20 epi- ysis. Although there was considerable variability in { Car!: demiological studies involving about 45.000 workers the dose-response relationship in the different experi occupationally exposed to VCM showed tl .at neoplasms of the liver showed an increase in ii:nn ieince in the majority of studies. For brain cancer thi association between exposure to VCM and an it c:reased incidence was less clear because of the lower relative ments reported, in all cases a total metabolized dose of 5 x 10\ug (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 Chiuo. P\ Chtaz B-; St. risk. Neoplasms of the respiratory tract, digestive matical models for low-nsk dose estimates are not Cor.:: system, lymphatic tnd haemopoietic system buccal sufficiently reliable or reproducible to engender Me cavity and pharynx, cardiovascular system and colon stomach were reported to show an increased incidence in one or more studies, but to S low no increase, or tn some cases a decrease, in in nee in other studies. In view of the increased inciid :nce of 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 lO'6 lifetime risk in man may be made (Barr. 1982). The value \ i ^' a; ` (Cx Cook H. breast neoplasms in rodents exposed to VC M. the (100 ppb) is similar to the highest estimates derived Coorc studies of C'naizze et al. (1980). who did not i onnrm from animal data and taking biotransformation re; these findings in humans, are of importance data into account, is substantially larger than the Er.: The register of ASL cases now contains reic srds of 99 persons with confirmed ASL and occu:,p ational 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 au oclave workers, who are recognized as having been ekposed to extremely high levels. Although precise eis imates lowest estimates, which are up to 10' lower (3.9 x 10"'ppb using a multi-hit model). The higher estimates are compatible with occupational experi ence and suggest that the current hygiene standard of around 1 ppm is sufficiently low to protect the health of VCM/PVC workers. The estimates also give a considerable safety factor for the general public In*: Crurr.r Car.. Duck ; stuc Ur. EPA of exposure are not available for the periods ( f rmost consuming PVC-packed food and drink or living Chic interest, the pattern of cases roughly sueges that near VCM PVC facilities. EPA extremely high exposures were necessary fir the induction of ASL. For example. ASL cases tier ded to occur m larger numbers in some plants than in ithers. a finding that can be explained most eas Iv bv differences in exposure patterns. There is an extensive series of animal studies on the 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 Feron Spit chic- Filatcv. Fee: I. V bias: carcinogenicity of VCM. Some of these preice ie the lation. the possible future number of ASL cases has anc epidemiological studies confirming the assioblation been estimated as in the region of 150-300. 26 . SPI-01006 fCT 12 Vinyl chloride--risk assessment :oi Acknowledgments -- We thank Dr M The mas for his help with the calculations and Dr D M. Connng for his help with the manuscript. REFERENCES ACOIH--American Conference of GoverHme;ntal Indus* mat Hygienists (1974). Threshold Limit V due:s for Chem- ical Substances and Physical Agents in Workroom Environment with Intended Changes for 1974. ACGIH. Cincinnati, OH. Anderson M. W,, Hoel D. G. & Kaplan 11 L. (1980). A general scheme for the incorporation of pt arml;acokmeucs in low-dose risk esumation for chemical carcinogenesis: example--vinyl chloride. Toxic, appl. Phknmac. 55, 154. Barnes A. W. (1976). Vinyl chloride and th< production of PVC. Proc. R. Soc. Med. 69, 277 Barr J. T. (1982). Risk assessment for vi^yl chloride in perspective. 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