Document mBVmnp0ybGdG6dd2g7BQ6azb

MtCUlA roft Y TOXICOLOGY ANO PHARMACOLOGY 7,120-127(1917) A Scientific Basis for the Risk Assessment of Vinyl Chloride Developedjointly by the Members ofthe Committee on the Evaluation of Carcinogenic Substances. National Health Council ofThe Netherlands' ttrcnvtJOcuberU. IMi In July 1964 (he Minuter of Wclbie, Public Htilth ud Culture, representing the Dutch government, sent a request to the Health Council of The Netherlands to advise on the health risks presented by environmental capoaure to several carcinogenic tubatanccs. One of these substances was vinyl chlonde (VQ. On the basis of a worfciag document prepared by the Na tional Institute of Public Health and Environmental Hygiene, a committee ofthe Health Coun cil of The Netherlands prepared a report concerning a health risk asscatmeat of VC which was published in May 1916. A short review is presented ofthe available dau and the considerations that formed the basts lor the nsk assessment ofthe cardnogenioty ofVC to humans. The advice was based mainly on human data from epidemiological studies of workers occupationally ex posed to VC. The committee concludes that continuous exposure to 0.001 mg/m1 VC corre sponds to an additional cancer mortality nsk of 10"* per hfcume. The Dutch government con siders this additional nsk to the general population to be acceptable, e iM) iiamuu run iu INTRODUCTION Man is continuously exposed lo a multitude of substances that are present in the environment in which he lives. A number of these substances possess the capability to induce malignant tumors in animals, humans, or both. Some carcinogens are natu rally occurring chemicals and exposure to these can hardly be prevented. Others are man-made, emitted into the environment as a consequence ofhuman activities, and thus exposure can, at least in principle, be reduced to an acceptable level. Reduction of the emission of carcinogens can be achieved by governmental regulation. One of the instruments for such regulation is to set upper limits for pollutants in the environ- ' Committee on the Evaluation of Carcinogenic Substance*. G M H Swacn, Department of Occupa tional Medialie. University of Limburg. P.O Box 616 6200 MD Maastricht, The Netherlands (to whom correspondence should be addressed); A. E. M. te Hollander, Secretary. Health Council of The Nether lands. The Hague. The Netherlands. R. K/ocs, Chairman ufthe Commuter. National Institute of Public Health. Bilthoven, The Netherlands; L. den Engcbe. Dutch Cancer Institute, Amsterdam, The Nether lands. V. J Feron.TNO-ClVO, Toxicology and Nutrition Institute. Zeist. The Netherlands, G ) Mulder, Department of Toxicology. University of Leiden. Leiden. The Netherlands. A. L M Vcrbcek. Department ofSocial Medicine. University of Nijmegen. Nijmegen. The Netherlands. H G. Verschuuren. Dow Chemi cal Europe. Horgen. Swiucriand. E. W. Vogel, Department of Radiation Genetics. University of Leiden. Uidcn, The Netherlands; A W van der Wielen. Ministry of Housing. Physical Planning and Environmcni.^hc Hague. The Netherlands. l)?7)-2700/67 SJ00 I t l*ar h(!L li AH n^hti ul im i* tr lum m 120 This item mrViTed by Ohio Northern University, Helerick Vertori;" l 'b'i'v without profit in lieu of loan, r"r " r -rr<t of research. The per son rt r ' -'icale is responsible for ait, Uic copyright law. RISK ASSESSMENT OE VINYL CHLORIDE 121 menl that may nol be exceeded. These limits are in principle based on qualitative and quantitative information about Ihe carcinogenicity of the specific substance. A particular health risk is then defined as an acceptable risk, which is frequently given as one additional cancer death per one million lives after a lifetime of continuous exposure. This risk will funher be referred to as the I0"` risk level The actual low exposure levels that result in this risk cannot be directly determined and must there fore be estimated by extrapolation. The extrapolation of tumor incidence at high exposure levels to the incidence at low exposure levels is one of the principle problems connected with carcinogenic risk assessment. Several mathematical models have been developed to describe the relationship between the level ofexposure to a carcin ogen and the probability of developing cancer, none of which have been verified in real life circumstances. In principle two types of data can be used in an extrapolation model for carcinogenic risk assessment: Data on the carcinogenic response in species other than man from experiments in which animals arc exposed to high levels ofa carcinogen. Data on the carcinogenic response in humans circumstantially exposed lo high levels of a carcinogen, e.g., industrial epidemiologic studies. Animal studies should be performed in a rigorously controlled environment and thus ideally are not necessarily subject lo bias or confounding by extraneous influences. However, the results must be extrapolated from the animal model to man, which introduces a considerable degree of uncertainly. Epidemiology can only study the health effects of environmental or occupational exposures as they actually occur or have occurred. Moreover, epidemiological studies are more likely to be subject ta bias or confounding due lo uncontrolled differences between the exposed and nonexposed groups that have not been investigated In addi tion epidemiological studies generally lack precision with respect to exposure data However, they have the advantage of being actual health effects in humans and thus could provide more relevant information for human risk assessment. Relatively high human exposures to carcinogens may occur in Ihe occupational environment. Epidemiological studies that evaluate the carcinogenic elfecls of occu pational exposure to particular substances may provide the most significant human data for carcinogenic risk assessment (Cook, 1982; Day, 1985). The purpose of this article is to compare two approaches for carcinogenic nsk assessment, taking expo sure to vinyl chloride (VC) as Ihe exposure of interest. Long-term health effects of occupational exposure to VC have been enlcnsivcly studied, thus VC is a chemical for which a good comparison can be made between the (wo approaches. An extensive review on the health hazards of VC has been compiled by the Dutch National Insti tute of Public Health and Environmental Hygiene (1984). We will first assess the carcinogenic nsk of VC on the basis of animal data Then we will conduct a nsk assessment for VC using human data collected by means of epidemiological studies of workers occupationally exposed to VC. In both types of risk assessment a linear dose-response model has been applied. A linear dose-response relationship is sup ported by the one-hit stochastic model for carcmogciusis, recommended by the American Food and Drug Administration (1971) and by the Dutch National llealili Council (1978). The application of a lineai dose-response model was also supponed by the occupational mortality study conducted by Weber et ul (1981). In this study a subanalysis was undertaken in which the VC exposed cohort was subdivided into CTL017444 122 COMMITTEE ON CARCINOGENIC SUBSTANCES Tablei Inodi ni ls of Angiosarcomas in rut Exferimentsof Maltoni tt al. (I9SI) with SfragueDawley Rats after Various Concentrations of VC Ea(M ur i Hr 2 BT 2 BT2 BTI BT 9 BT BT 1) VC conccnlraiMM (ppm) 2 SO 200 ISO 100 SO SO 2S 10 * Hepatic Md eiinhcpiiic iniioMrconuu. liddcaceof MMMC0MAS* <%> 1.5 101 5.0 0.1 5.4 ?. 4J 2.5 Ratio of concentration to incidence 29 19 30 I2S IS 6 6 4 several dose groups, in terms ofduration ofexposure. The results or this subanalysis are indicative for the existence of a linear dose-response relationship between the duration of occupational exposure to VC and the subsequent risk of liver cancer mortality. The pharmacokinetics of VC in animals and humans are still not understood well enough to incorporate an estimation of the "biologically effective dose," based on a pharmacokinetic model for saturable metabolism, in the dose-response extrapola tion model, as was proposed by Gehring el al. (1978,1979). Thus this model was not used in the risk assessment of VC. RISK ASSESSMENT BASED ON ANIMAL DATA VC is a procarcinogen which requires metabolic activation through the cyto chrome P-4SO system to exert genotoxic properties (Ivanelich el al.. 1977). Muta genic activity of VC has been demonstrated in both in vitro and in vivo assays (Bartsch and Monlesano, 1975; IARC, 1979). In several animal studies the animals exposed to VC by oral dosing developed more tumors than the control populations (Maltoni ei al. 1981; Feron el al.. 1981). There can be no doubt that VC is a carcinogen in animals. In several studies with mice and rats a clear dose-response relationship was noted between VC exposure and frequency ofangiosarcomas of the liver. A series of studies with Sprague-Dawley rats, performed by Maltoni el al (1981), was selected to form the scientific basis for the risk assessment based on animal data because in these studies VC was applied by means ofinhalation and because the results suggested a clear dose-response relationship for angiosarcoma of the liver. The results of the experiments conducted by Maltoni with mice and rats are presented in Table I. A linear, nonthreshold model was applied for risk extrapolation to lower dose levels. The results ofeach separate dose experiment were combined by taking the arithme tic mean of the incidence per mg/m1 of VC applied in each experiment. The arithme tic mean of the ratios was 29, which indicates that in order to increase the incidence of angiosarcoma by 1% an additional concentration 29 ppm VC must be applied. RISK. ASSESSMENT OF VINYL CHLORIDE 123 table 2 Results of Seven Occufational Mortality of Workers with Past Exi-osuketg VC Reference Number of exposed workers Total mortality obs/exp SMR Cancer mortality obs/exp SMR Liver cancer mortality obs/exp SMR Tibcnhaw and Gaflcy. 1974 (United States) 8384 3S2/467 0 75 79/77 1 10 7/0 S' 140 Weber nui. 1911 (West Germany) 7021 414/4)5 7 0 95 94/90 6 1 12 12/0 09 15.2 Fox and Collier, 1977 (United Kingdom) 7717 393/521 0.75 115/127 091 4/1 64 24 Waiwcilerrro/. 1976 (United States) 1294 136/126 1 08 35/23 5 1 49 7/0 6 II 5 Otirta/. 1975 (United States) 594 89/100 0 89 20/17 9 1 12 0/0 1.0 Theriault and Allard, 1911 (Canada) 451 59/55 1 07 20/13 5 1 48 8/0 14 57 1 Nicholson and Hcnncbcrgcr, 1984 (United Stales) 257 80/85 6 093 28/19 7 l 42 10/0 42 238 Estimated. which equals 74 mg/m1 VC. Taking the inverse of this ratio, it can be concluded that an average increase of risk of0.000135 of angiosarcoma per animal will be the result ofan increase of I mg/m1 VC. In order to adapt the experimental situation to human lifetime exposure, two conversion factors were introduced. The animals in the experi ment were exposed to VC during 20 hr a week. Human exposure to environmental concentrations of VC occur during 168 hr per week, giving a conversion factor of 168/20 - 8.4. A second conversion factor was necessary because the rats were not exposed for 143 weeks, the average life span of a rat, but only 52 weeks, giving a conversion factor of 143/52 = 2.75. The additional risk ofangiosarcoma per mg/m1 VC concentration for a continuous lifetime exposure for one individual was calculated to be 0.000135 x 8.4 x 2.75 - 0.0031 per mg/m1 VC. The proposed maximum level for environmental exposure to a particular carcinogen as formulated by the committee is one additional death of cancer per one million lives, giving a lifetime environmental exposure of 0.00032 mg/m1 VC (I0'*/0 003I). Thus the committee would consider an environmental exposure to 0.00032 mg/m1 VC to correspond to a 10'* risk level on the basis of animal data. RISK ASSESSMENT BASED ON HUMAN DATA The risk for humans of occupational exposure to VC in industry has been investi gated by epidemiologists for groups of workers. All studies used the design ol a retro spective cohort study. A group of workers exposed to VC in the past was identified and followed through time to observe the occurrence ofcancer in the exposed group CTL017445 124 COMMITTtE ON CARCINOGENIC SUBS IANCES Based on national statistics an expected number of deaths from a particular disease was calculated, taking into account the age distribution, length of follow-up, and calender period. By dividing the observed number by the expected number, the stan dardized mortality ratio (SMR) was calculated, which is a measure of the relative risk for a particular cause ofdeath resulting from VC exposure. Table 2 summarizes the results of the seven largest epidemiological studies on workers exposed to VC. All studies except one indicate an excess mortality from cancer of the liver and in particular of ingirmirniiil of the liver (ASL). Other types ofcancer also showed a tendency to be wcnaaad in incidence, but these increases are not consistent. Total cancer mortality, however, is higher in four out of the seven, studies. In order to carry out a risk assessment the results of these epidemiological studies had to be combined to obtain an overall estimate of the relative risk. Prior to combining the results, the studies indicating the highest and the lowest relative risk were omitted, because these studies were considered to be extreme results due to random variation. Three studies were regarded as unbiased estimates ofthe true stan dardized mortality ratio. Although the cohort studied by Waxwcilcr el al.( 1076) was probably completely included in the study conducted by Tabershaw and Galley (1974), both studies were regarded as being independent estimates of the risk of liver cancer after exposure to VC. An alternative analysis aAer omission of the study con ducted by Waxwcilcr et at. revealed similar conclusions. Because the three studies were not of the same size, a weight was given to each study according to its size, based on the standard error of the observed SMR. This weight was the expected number squared divided by the observed number, being the inverse of the variance. The over all SMR was subsequently calculated by dividing the sum of the products ofthe indi vidual weight and the SMR by the total sum ofthe weights. The overall SMR for liver cancer mortality obtained in this manner was 13.07, meaning that workers occupa tionally exposed to VC experienced a 13.07-fold risk of dying of liver cancer. The overall SMR for total cancer mortality is 1.14. VC concentrations that have occurred at the workplace have varied greatly through time. Barnes (1980) retrospectively estimated these exposures to have been approxi mately 1000 ppm between 1943 and 1933. between 400 and 300 ppm, from 1933 to 1963; between 300 and 400 from 1966 to 1972; 130 ppm by 1973; and 3 ppm after 1973. Based on these numbers a time-weighted average of 300 ppm for the total exposure period was applied in the nsk assessment. An important aspect of the occupational exposure to VC and its long term health effects as described in the epidemiological studies, is the average duration ofexposure. In the report of the large cohort study of VC exposed workers, conducted in the United States by Tabershaw and Galley (1974), n was staled lhal the average duration of VC exposure was 8.7 years. The committee decided that for the risk assessment for the duration ofexposure of all three cohorts 8.7 years would be taken. In summary, epidemiological studies of workers occupationally exposed to an average concentra tion of 300 ppm for an average duration of 8.7 years indicated lhal these workers experienced a 13-fold risk of liver cancer as compared to the general population. Total cancer mortality was 1.14 times the cancer mortality in the general population. Extrapolation to Lifetime, Continuous Exposure A number of steps must be taken before the risks existing for workers exposed to 300 ppm VC for a period of 8.7 years can be convened into estimated risks of lifetime, RISK ASSESSMENI OF VINYL ClllOKIUE 25 continuous exposure to low concentrations. The first step is to convert the intermit tent exposure occulting for 8 hr/workday to a continuous lil'etiine exposure A work week usually consists of40 working hr. whereas a total week consists of 168 hr. There fore a conversion factor of 168/40 * 4 must be applied. This mejns that an exposure encountered only at the workplace corresponds to one-fourth of the dose resulting from a continuous exposure to the same concentration. The second step is the calculation of the conversion factor for the duration of the lime-limited VC exposure experienced by the workers to lifetime exposure to ambi ent air concentrations of VC. The workers studied by epidemiological methods were exposed for an average duration of 8.7 years. Given an average Itfeiinie of 70 years, lifetime exposure results in a 70/8.7 - 8-fold higher dose at equal concentrations. The conversion from 500 ppm during 40 hr per week, for 8.7 years (500 X j X | ppm), leads to a lifetime exposure of 15.6 ppm. An estimated SMR of 13.07 will result from lifetime exposure to 15.6 ppm. Extrapolation to the 10"4 Risk Level Extrapolating the effects of high exposures to low concentrations can only be done if certain assumptions are made regarding the dose-response relationship. We will assume a linear dose-response relationship. This straight line is defined by two points. Having identified two points on the straight line, it is possible to express this line by means of a mathematical equation: SMR = 1 + b X c (in which c is the lifetime exposure concentration). Calculate b front the model: SMR = I + b x c, if c = 15.6 and SMR 13.07. Thus, b " 0.774. The dose-response relationship is SMR = l + 0.774 X c. The next step is to express the 10'* risk level in terms of an SMR. The accepted risk is expressed as one additional death by cancer per one million lives. In The Netherlands 1484 per million people die of liver cancer (CBS, 1980). One addi tional case would be 1485, giving an SMR of 1485/1484 = I 00067. By means ofthe above equation for the linear dose-response relationship, the con centration of VC for lifetime exposure can be calculated, resulting in this SMR of 1.00067: SMR 1 + fi X c, c -= 0.0008 ppm. A lifetime exposure to a concentration of 0.0008 ppm = 0.002 mg/m' VC is ex pected to lead to an additional I0'4 risk. However, it can not be excluded that there are other cancer types related to VC exposure, or perhaps cancer unrelated to specific sites. In fact four of the seven epidemiological studies presented in Table I showed elevated cancer mortality. The overall SMR of the three studies used earlier for cancer mortality is 1.14 for all types ofcancer. The lifetime exposure concentration remains 15 6 ppm SMR =1 + 6Xc if c " 15.6 and SMR = 1.4, then b - 0.009. giving SMR = I + 0 009 x r. In The Netherlands about 250,000 per one million deaths are due to cancer (CBS, 1980). One additional death will then result in an SMR of 250.001/250.000 = I 000004 SMR - M 0 009 l c I CTL017446 i 126 COMMITTEE ON CARCINOGENIC SUBSTANCES thus, c " 0.000004/0.009 - 0.00044 ppm " 0.001 mg/m1 VC. H was concluded that a lifetime exposure to 0 001 mg/m1 VC results in an additional risk to the general population ofone death per million lives. DISCUSSION Epidemiological data have rarely been in environmental nsk assessment. Extrapolation on the basis ofexperimental dfttt as well as epidemiological data suffers from a number ofshortcomings. The Main uncertainty of a risk assessment based on* animal experiments is extrapolation to humans. Differences in body size, metabo lism, DNA-rcpair mechanisms, and immunological responses can lead to differences in response to exposures to carcinogens between animals and humans. As pointed out by many researchers on many occasions, the linear, nonthreshold dose-response model is likely to be an oversimplification of the complex process ofcarcinogenesis. However, no ideal model incorporating relevant biological mechanisms is yet avail able, or will be in the near future. Therefore a simple model ofa conservative nature was considered to be most appropriate for environmental carcinogen risk assessment of VC. The main uncertainty of a risk assessment based on human data is the lack of exact information with respect to the actual past exposures. Application of a linear extrapolation to these two different types of data resulted in two different environ mental exposure limits, being 0.00032 mg/m1 VC based on the experimental data and 0.001 mg/m1 VC based on human data, which differ only by a factor of 3. Be cause of the existence ofextensive human data the committee decided to base its risk assessment on human data. Conseqently, the Dutch Government was advised to uke 0.001 mg/m1 VC as an exposure corresponding to an additional risk ofone death per million individals exposed for a lifetime as the scientific basis for the development of air quality standards. REFERENCES Barnes, A. W.( 1976). Vinylchlondcandthe production of PVC. Proc RSoc.Med **,277-211. Baxtsch. H. and Montssamo, R. (1973). Mutagen* and caroongen* cfccts of vinyl chlondc. Mutot Res 32,93-114. Central Bureau voor dc Sutistick (CBS) (1910) Atlas mu Jr Konkeruetfte ui Nederlami Staatsuitgcvcnj Den Haag. Coon, RR(I9I2>. The role ofepidemiology in nsk assessment. Drug Metab Rev 13.90-921 Day, N. E. (1913). Epidemiological methods for the assessment of human cancer nsk. In Toxicological Xut (D. B. Clanm, D. Kimti, and I Muoio. Eds.). Vol II. CRC Pima, Boca Raton, Ft. Dutch National Health Couoctl(Gezodhcidsrad)(l978). Advies intakede Beoordeimg van Carcinogenr- leit run Chemtiche Staffer No 19. Rijswijk fenUN. V. i . HtKO*i*SN, C. F. M., SKW. A Til, H aHO ST. B. J. (19t|). Lifespan oral loaicity study of vinyl chlondc in rats FoodCotmet Toxuot 19,117-133. pod and Drug Administration Advisory Committee on Protocols for Safely Evaluation (1971) Panel on carcinogenesis report on cancer testing in the safely evaluation offood additives and pesticides Tuxievi Appi Pharmacol 20,419-411 Fox. A J . ANoCoiut*. p F (1977). Mortality experience ofworkers exposed to vinyl chloride monomer in the manufacture of polyvinyl chlondc in Great Bniatn Bm J Iml Med 34, I --10 RISK. ASSESSMENT OF VINYL CHLORIDE 127 GchkinG, P. J , WaTaNaRE, P G , aNO Pack. C N (1978) Resolution ol dosc-rcspunse toxicity data for chemicals requiring metabolic activation: Example vinyl chloride Toxnol Appi Phurmatul 44, 581-591 GEIirinG, P J , WaTanarl, P. G , and Park, C N (1979) Risk of angiosarcoma in workers exposed to vinyl chloride as prcdiacd from studies in rats Toxuol Appi Phunnmoi 49, 15-21 HOLMIttC. 8 , Kjionevi, T., and Winlll, M (1976) The pathology of vinyl chlondc exposed mice Acta Vet Scant! 17,228-142 Hong.C B, Winston, J M. Thornburg. L P.andLle.C C (1981) Follow-up study on the carcino genicity of vinyl chlondc and vmylidcne chlondc in rats and mice. J /usual tnvuon Health 7, 909924 JARC|I979).Monogr EvaI Carcinogen Risk Chent Humans 19, 377-348. IVANETtCH, K. M , Aronson, I, and Katz, 1 D (1977) The interaction of vinyl chloride with rat hepatic microsomal cytochrome P-450 in vttro Btochem Biophys Res Common 74, 14II-J4I8. Maltoni.C., Lefemine.G .CiuatRii. A . Com. G . ANoCAktnt, D (I98J) Carcinogenicity bioassays of vinyl chlondc monomer. A model of risk assessment on an experimental basis Environ Health Perspect 41,1-29. Nicholson, W. j., and Hennererger. P K (1984) Trends in cancer mortality among workers in the syniheue polymers industry Prof Clin Biol Res 141,65-78. Ott, M. G , LaNGENR, R. R , AND Holder. B B (1976). Vinyl chlondc caposurc in a controlled mduv Inal environment. Arch Environ Health 10,311-139 State Institute ofPublic Health and Environmental Hygiene (1984) Cnienadtnument over Vinyl Chloride. Lucht, 24. Staaudrukkenj Den Haag. Tarershaw, ( R . ano GaFFEY, W R. (1974) Mortality study of workers in the manufacture of vinyl chlondc and its polymers. J Occup Med 16,509-518 Theriault, G.. and Allard. P. (1981). Cancer mortality of a group of Canadian workcis exposed to vmylchlondc monomers. J Occup Med 23,671-676. Waxweiler, R. J, Stringer. W, Wagoner, J K. JoNtns, J, Falk. H , and Cam it*. C (1976) Neoplastic nsk among workers exposed to vinyl chlondc Ann NYAxad Sti 271,40-48 Werer, H., Rxinl, W, and GreiseR, E (1981). German investigation on morbidity and mortality of workers exposed 10 vinyl chloride. Environ Health Perspect 41,95-99. \ i i CTT017447