Document yrZ73nndnbpyOaYV8GRqzmxo6

i QUANTITATIVE RISK ASSESSMENT FOR COMMUNITY EXPOSURE TO VINYL CHLORIDE Arnold M. Kuzmack Office of Planning and Evaluation U. S. Environmental Protection Agency Washington, 0. C. 20460 and Robert E. McGaughy Office of Health and Ecological Effects U . S . Environmental Protection Agency Washington, D. C. 20460 December 5, 1975 <gr see 2-0822 " Vinyl chloride has produced liver angiosarcoma, a very rare form of cancer, as well ,as other cancers and serious liver damage in occupationally exposed populations. Since it is generally considered - prudent to assume that there is no threshold for chemical carcinogens7~ . .the small concentrations of vinyl cnioride observed in the ambient air -in the vicinity of plants producing vinyl chloride monomer (VCM) or poly merizing it to polyvinyl chloride (PVC) involve some public health risk. This paper reports the results of.an analysis to estimate quantitatively the risk resulting from vinyl chloride emissions and assess the re liability of the estimates. In addition, a search was initiated of the residence of people who have died of liver angiosarcoma in order to detect evidence of adverse effects among people living near plants. ' The analysis involves three steps: estimation of the number of people exposed, the concentrations of vinyl chloride to which they are exposed, and the number of cancers and other health effects resulting from this exposure. Of these, the last is by far the most difficult to make and involves the most conceptual problems. The number of people living at various distances -from each VCM and' PVC plant was determined by an analysis of census data-. All told, seme 4.5 m'i1 i:on people live within 5 miles cf these plants. Ambient concentrations of vinyl chloride in the vicinity of plants were determined using standard methods of diffusion modeling. Exposures at each location were adjusted to allow for the types, numbers and sizes of plants present and the meteorological conditions which affect the dispersion of pollutants. It was found that the 4.6 million people living within 5 miles of uncontrolled VCM or PVC plants are exposed an average concentration ot about 17 parts per billion. Quantitative estimates of health effects likely to result from this exposure were made by predicting from animal data the probability that highly-exposed workers would get angiosarcoma, checking that prediction by calculating the same probability using epidemiological studies of workers, and then projecting the results to ambient concentrations around plants._ Cancers other than liver angiosarcoma were assumed to occur at the same relative rate as at the higher doses, Birth defects have been reported in communities with VC and VCM plants. These effects are not onsidered in detail here because quantitative"estimates of these effects can not be made at this time. Projections from incidence rates in rats to incidence rates in highly-exposed workers were made by assuming that a lifetime exposure to rats would produce the same number of effects as a lifetime of exposure to humans, which means roughly that one year of exposure to rats fields the same incidence rate as 30 years of exposure to people. svJL am&jL to. a ir U*^|t /VsSuuuffW m see 2-0823 ! was found, using a linear dose-response model extrapolating to zero, that the probabi1ity of getting angiosarcoma due to a year of continuous exposure is 71 casas-zoer year of continyous exposure per ppm of vinyl chloride per million people exposed. I The corresponding probability of getting cancer of all sites is 150 cases per year of continuous exposure per per ppm of vinyl chloride per million people. tin's basis the probability of getting liver angiosarcoma in workers On .^4^1 " exposed to 350 ppm for per person per year^f 7 hours per day, exposurei' ' ` 5. days per. week .. would be 0.0052 5I . From epidemiological studies~of exposed workers, it was estimated that the probability of getting angiosarcoma at some time in the r worker's life per year of exposure is 0.0031. To arrive at this rate, the analysis considered the distribution of exposure durations among tie 14 known occupational cases of angiosarcoma, as well as the time distribution of man-years of exposure in the industry. Tv/o other important facts about vinyl chloride carcinogenesis resulted from this aralysis: 1) at some time in their lives about 7.5% of all highly- exposed workers are expected to get liver angiosarcomas due to vinyl chloride exposure with double this rate of primary cancer at all sites combined. 2) Of all the cases of liver angiosarcoma wTtich have this far been produced by vinyl chloride, only 33% of them have been diaonoses as of 1974. " JLtXcc. lA< Wo. ` After considering the error associated with the separate estimates based on animal and human data, it is concluded that the two approaches give results that are indistinguishable. The projection to low doses was done using two separate mathematical models of the animal data: 1) the linear model, v/hich assumes that the response rates are directly proportional to dose with no threshold; 2} the log-probit model, which assumes that the susceptibility of the population is log-normally distributed with dose. The former model is widely used for low-dose extrapolation in radiation carcinogenesis and is generally considered to be conservative for chemical carcinogens, and the latter is usually used for describing the dose-response relationship -j Jr in the dosage range of animal experiments. n .J . T4 -fenck-*^ It was found that the rate of initiat^off of liver angiosarcoma among people living around VCM-PVC plants/is expected to range from less thin one to ten cases of liver angiosarcoma per year of exposure to vinyl chloride. The log-probit model gives predictions that are 0.1 to 0.01 times this rate. This wide range is an indication of the uncertainties in extrapolation to low doses. The cases initiated by exposure this year will not be diagnosed until 1991 or 1995. Vinyl chinridp is also expected to produce an equal number of primary cancers at other sites. for a^total of somewhere between less tnan one and twenty cases of cancer pe'' yefcr of exposure among residents around plants. The number of these effects is expected to be reduced in proportion to the reduction in the ambient annual average vinyl chloride concentration, which is expected see ?-0824 % .. . .- . . - ..; -- .. - .. '' . ... ..*. . - : ... . xxx ; : .. '.. .. . , . ^ ;- ,. - -../ V-. to be 5% of current levels after the proposed EPA regulations are_ - implemented. . ...... . / *I J&ctix. _7 ^:rC As Jpart of this'analysis a 'survey of the known cases of 1iver angiosarcoma diagnosed in the last 10 years was initiated in order to see whether any evidence could be found that living near VCM or PVC ; ,plants results -in higher-rates than expected for the general U. S. ; population. No" conclusion can be drawn from the survey at its present ^ s t a g e of,completion. -It isrexpected-that if the true rate is as_high as~10 cases per year of exposure among residents near plants, which is - t h e highest rate our analysis would predict, higher than average rates' of case occurrence might not yet be observable in such a survey but . should become detectable in the next 5-10 years, due to the increase in vinyl chloride production rates since 1955-1960. . VL*-'*. o *<> l - H jpf go r/U ^ u _ 1 "Ct b i a s u ^ <awJAqgP JU <T see 2-0025 :;-- v ' : ;' . -- J Table -of Contents : .j : - Executive Summary ; i. Quantitative Risk Assessment for Community . Exposure to Vin y l Chloride ! '.. ^ s i ^ / ^ S l z ^ o f -Exposed Population *" - Ambient Vinyl -Chloride Concentrations > " .Health Effects Resulting from Exposure. V 1. ~ -1 -2 3.... Appendix A., Population and Exposure Estimates v-.-- . population Estimates . Ambient Concentration Estimates Overall Exposure Estimates A-l 7 A-l A-2 A-l Appendix B. Estimates of Effect Rates from Animal Data . . The Animal Data on Cancer Extrapolation to Low Doses Extrapolation to Human Exposure Incidence of Non-Cancer Effects Overall Effect Rates Error Analysis ' w .. B-l B-l B-2 B-l B-5 B-5 B-6* Appendix C. .Mathematical Treatment of Dose-Response Data- Equations for ML Estimators Asymptotic Variances Newton's Method-for One Variable Newton's Method for Two Variables " C-l C-l C-2 C-3 C-3 Appendix D. Use of Human Data to Estimate Risks Interspecies Comparison- of Lifd Expectancy and Angiosarcoma Latent Times Comparison of Angiosarcoma Incidence Alternative Approach to Calculating - Incidence Rate Comparison with Animal Data Ratio of All Cancers to Liver Angiosarcoma Frequency of Non-Cancer Effects Relative to . Liver Angiosarcoma D-l D-l D--2 . . D-l D-6 D-7 D-B Appendix E. Is Residence Near Vinyl Chloride Plants a Risk actor in Frequency of Deaths Due to Liver , Angiosarcoma? . E-l see 2-0826 m ( w SCC 2-0827 ( Thus, a total of 4.6 million people live in-the vicinity.of these plants. To calculate the average exposure, detailed population data around each individual plant was weighted'to-rflect .differences in the type of plant (PVC or.VCM), size of plant (average or-large) and meteorological conditions at the plant site. '. v* u*- The use of residence data involves some error, of course, since people spend part of their time away from their homes and hence exposed to varying levels of vinyl chloride: There does not seem to be any practical way around this problem, short of a detailed study of_travel ...patterns of 4 million people in over 40 separate communities.- : Ambient vinyl chloride concentrations Annual average, ambient concentrations of vinyl chloride were _ v-l'I .-v... calculated by standard diffusion modeling techniques. Two independent studies were made, one by EPA's Office of Air Quality Planning and Standards (OAQPS) and one by Teknekron, Inc. The agreement among the two studies was good, with differences generally less than 25%. It was decided to use the Teknekron results in the actual calculations since they included data on variations in meteorological conditions from location to location. .. For an average uncontrolled PVC or VCM plantin an area with average meteorological conditions, the annual average concentration of vinyl chloride in each annulus around the plant is shown in the following table: Distance (mi) v1 Vinyl chloride concentration (ppb) Uyj. 4.iooo >ioo tyytete poc 0-1/2 ^ 1/2 - 1 1 - 3 Hfeif 3-5 pvc plant 323 57 4 2- 15 . 5.7 VCM plant 113 f Z 20 O 5.2 0 2.0 It can be seen that concentrations around VC plants are significantly smaller than around PVC plants. This fact combined with the much smaller population living near VC plants, implies that by far the greatest part of the public health risk is from emissions from PVC plants. In calculating total population exposure, it is necessary to take account of factors that lead to variations from the average. Information from OAQPS and from the APHA study was used to determine areas where more than one plant was located, and OAQPS characterized the size of each plant as "average" or "large." The Teknekron study was used to categorize the meteorological and topographic conditions at each location. Oetails are <^ven in Appendix A. * * see 2-0828 jillilf I ! m Quantitative Risk Assessment for Community Exposure to Vinyl Chloride . Vinyl chloride is a known human carcinogen; i,tShas produced liver angiosarcoma, a very rare form of cancer, as w e > r a s other cancers and . non-cancer effects in occupationally exposed copulations. It is also . ' ' ' known to be emitted into the`atmosphere frpm plants which produce.vinyl chloride, monomer --(VCM-piants) ;and piants/iiith^polymerize the monomer to . - ` ` polyvinyl chloride (PVC plants). Although concentrations of vinyl - . . chloride in the ambient air are much^iess than those which caused cancer . . ' " in workers, it is generally considered prudent to assume that there is *I - - - no threshold for chemical carcinogens; so that anv exposure involves t some' '^n with EPA consideration of rulemaking action 'T ':- to regulate emissions of vinyl chloride from VCM and PVC plants, the Administrator of EPA requested that an analysis be performed which would estimate quantitatively the risk resulting from VC emissions and assess the reliability of the estimates. This paper reports the results of that analysis. The details are presented in the Appendices A through E. The analysis involves.three steps which are discussed in turn below: an estimate of the size of the exposed population, an estimate of the concentrations of vinyl chloride to which they are exposed, and an estimate of the number of liver angiosarcomas and other health effects which would result from this exposure. Of these, the last estimate is by far the most difficult to make. In addition an investigation was made of the places of residence of all people known to die of liver angiosarcoma in, the last ten years in an attempt to detect clustering around PVC and VC plants. Size of exposed population A study by the American Public Health Association (APHA), performed under contract to EPA's Office of Toxic Substances, determined the number of people living within various distances, up to 5 miles, from each VCM or PVC plant. The study was based primarily on census tract information. The validity of the methodology used was confirmed by a more detailed analysis of the population living around a few plants, performed by EPA's Office of Planning and Evaluation. The total population living within 5 miles of all PVC and VCM plants is shown in the following table: Distance (mi) Population . 01/2- 11/2 - 47,000 203,000 ( 1-3 1.491.000 2.838.000 TOTAL 4,579,000 see 2-0829 within 5 mi 1es of Dlants is i7 ooh> --- : . - Unfortunately, it has not been nnssihla. tn make a systematic com parison of the diffusion jpodeTing results with data obtained from actual monitoring, although thpy apppay generally consistent, tt is"therefore "difficult to estimate the uncertainty of these estimates. Lacking .^anything ..better,- we can take the difference between the two diffusion " modeling efforts of up to 25% as an estimate of that uncertainty. ' Health effects resulting from exposure- What' arerthe resul ts of exp^s4tfg4. 6 million people to an average of -17 ppb of vinyl chloride?^The first major decision to face in answering this question is w arrive at some combination of two basic approaches. One approach is to rely largely on human data (which exists for vinyl chloride but not for many other chemicals of concern to EPA): the secons is to make orojections from animal experiments. Both involve difficulties. Use of human data eliminates the uncertainties that result because we do not know the differences in response between the test animals and humans. On the other hand, with the'Uata on human (occupational) exposure, it is necessary t.o guess at exposure levels over the past 30 years and approximate the total number of workers involved and the number of cancers caused by past exposures for which symptoms may not appear until many years in the future. By using animal data v/e can avoid these problems, but only at the prirp of jincA&tai-p-tv in the relevance of an imal experiments to human exposures. The approach taken in this analysis is to use animal data to predict tne probability of human liver angiosarcoma, and then use the human data to the greatest extent possible to interpret those predictions. . A second major decision that must be made is how to project the results observed at high doses in animal experiments (and in the occupa tional exposures) to the much lower doses encountered in the environment. Two alternative assumptions are frequently made in the scientific litera ture. The first is a straight-line projection to zero dose, assuming no threshold (the "linear model"). This is also referred to as the "one hit" model, since it would follow logically from the assumption that each minute increment of exposure to a carcinogen has the same independent y probability of causing a cancer, regardless of the dose level. This y assumption is generally accepted as prudent in radiation carcinogenesis.! For chemical carcinogenesis, the model i; gsn^llv considered to provide I an upper limit_to the level of effects likely at extremely low doses, J because the existence of detoxification mechanisms would render small doses less effective in causing cancer and would therefore result in a threshold of at least fewer effects. 9he second commonly used projection method is based on the assump tion that the observed changes in response with dose are the result see 2-0S30 . ; - ; . ." ; ./. . : -; / 4. of variations of susceptibility: in'Vthe population, which -is assumed T to be log-normally distributed with'dose. . For convenience* we refer to this as .the "log-probit". model, because it forms a straight line when the logarithm of the dose is plotted^against the proportion of; responses expressed in probability units (probits). The log-probit model is cloSely related to the Mantel-Bryan procedure. . \ ' In this analysis, both models are used. For technical reasons, ;r.r^;.7 . ^the'Jog-pro.bit..model.v.is.:difficult .to, apply-to this case. t "the:basicvcalculations were done using the linear7 model, Therefore, but a sett sitivity analysis was done-to show how the results would change under. ,the log-probit assumption. . ...A third decision that must be made is how to predict human incidence rates from animal data. Again, there is little hard data to provide guidance. The assumption used here is that a lifetime exposure of humans to a given concentration of vinyl chloride would ? produce the same number of effects as a lifetime exposure of rats. the one-year exposure in the animal experiments would be equivalent Thus to ' T l / a . W ; abouf~TT years of exposure~fo?~humanrs~: . A fourth decision to make is how to use the available human data on liver angiosarcoma cases among highly-exposed workers to calculate the probability per year of exposure that cases will eventually develop in people. This calculation is needed for comparisons with the animal model. There are three aspects to this problem: 1) to find in the literatjre a realistic estimate for the fraction of highly-exposed workers who have contracted liver angiosarcoma at some time in their lives; 2) to account for the fact that the currently-observed rates underestimate the actual incidence because they do not include ~ who have been exposed more recently than 15 to 20 years ago; account for the fact that people can die from other causes latent case of liver angiosarcoma becomes manifest. v f ' -7` ioT These issues were'treated as follows: Of the four occupational epidemiology studies from which it is possible to estimate an incidence rate, the two with the smallest number of subjects and the best separation of highly-exposed workers from the group of all workerXs had the largest incidence of angiosarcoma. .This incidence was assumed to be valid for all highly-exposed workers. The latency time for liver angiosarcoma and the growth in the number of person-years of exposure since 1940 are two factors which affect the number of cases we have observed through 1974. These factors, along with the distribution of exposure: durations for people who have been diagnosed with liver ' angiosarcoma, were included in an analysis presented in Appendix D. The result of the analysis is an estimate of the probability per year of. exposure that a person will get angiosarcoma sometime in his life. The remaining problem of multiple risks competing for mortality was not treated because of its complexity. ' m see 0831 A fifth decision which had to be made was how to quantatively describe the nthpr pffprt.s of yinvl chloride exposure besides .liver ; . angiosarcoma. This problem was handled by estimating from the literature ratios of the number of people with other cancers and the number of people'with liver damage compared to the number with angio sarcoma. As an index of liver damage, the bromsulphalein (BSP) test is used because it, among all liver function tests that have been used, correlates best with vinyl chloride exposure and because an abnormal . BSP test indicates that severe damage has occurred in the. liver, either because-the liver cells are not able to assimilate the intravenously ' injected BSP dye from the blood and excrete it into the bile passages, or that the bile" passages'are no longer structurally intact enough to carry the dye out of the l i v e r . ..... ....... . ' -- The results of these five aspects of the problem are presented below in reverse order. The approximate ratio of severe liver damage cases to liver angiosarcoma cases is about 30, the result being con- 7 ;sisteni for two independent occupational studies. It was also found that about twice as many cases of cancer of all sites are caused bv vinyl ch lo rjnp as raseL.nr n vg?~amifMrrt'oma" alone. "The ani!mal! experiments have shown approximately the same ratio of all cancers to liver ongiosarcoma, after background incidence is taken into account. Ii calculating the probability per year of exposure that a highlyexposer worker will get angiosarcoma some time in his life, we found that tl e fraction of highly-exposed workers who have been currently diagnoied is 0.02; they have been exposed for an average of 17 years before diagnoses. The analysis,which required assumptions about s the tii e distribution of man-years of exposure and the distribution of ,,exposuie durations preceding diagnosis, showed that only 38% of the lly- exposed workers who are expected to get angiosarcoma some time in tmi''*Oives have been already diagnosed. Therefore the probability that or e oi is 0.01/(17 1keople will get angiosarcoma some time in their lives * 0.0031 per year of exposure, In Appendix D the Calcul< tion ained in greater detail. ?W Tie 17--year average concentration to which these workers were exposer was estimated to be 3_5_0___p_p_m on the basis of one study. Only one cor.oanv. has reported measurements of vinyl chloride for the jobs in their flant. These measurements, started in 1950, showed the highest exposure jobs ranged from 120 to 385 ppm before 1960, when the exposures were reduced because of suspected toxicological problems with & vinyl chloride. In estimating the average, it was assumed that the other lactories, most of which probably did not monitor the concentra tion o1 vinyl chloride, v/ere less concerned about industrial hygeine and therefore took fewer pains to keep the levels low. . * Ir predicting the human angiosarcoma rate from the animal doseresp^ise data, it was projected, from the linear model, that exposure to vinyl chloride would cause 0.071 cases of liver angiosarcoma and & 0.15 cases of all types of cancer per million people per year per ppb of continuous exposure. Details of these calculations are given in Appendix B. Converting to a 7-hour per day, 5 days per week work schedule of .exposure to 350 ppm, the model predicts an incidence rate of 0.0052 per person-year exposure. It is shown in Appendix D that this rate is numerically indistinguishable from the rate of 0.0031 calculated from the human data, considering the known quantifiable errors of estimating the parameters of the animal and human data. It -can be concluded;that the slope of the-1inear animal dose-response relationship for angiosarcomas is consistent with the human data. The extrapolation of the animal dose-response relationship to a concentration of 17 ppb (the average concentration around the uncon trolled plants) yields the following predicted number of cases in the 4.6 million people living within 5 miles of the plants. For details see Appendix B. Cases per year of exposure Type of effect Linear model tog-probit model All cancer 11 ^ Q.l - 1.0 Liver angiosarcoma . 5.5 0.05 - 0.5 /. M '`J . This is the expected number of cases. .pr. ojected to be caused per year at current levels of emissions; tyie people exposed now will rot bfc <3ia"hosea tor another 15-20 years/ Similarly, any cases observed now would have been caused 15-20 years ago (if they were in fact caused by vinyl chloride) when production was about 10% of current levels. In order to arrive at a final estimate of the number of people adversely affected by vinyl chloride emissions, the important results of this analysis to consider are as follows: 1) the number of careers at all sites caused by vinyl chloride is twice the number of liver angiosarcomas; 2) the number of people with severe liver damage is 30 times the number of liver angiosarcomas; 3) the animal model predicts that the number of liver angiosarcomas in the population around plants is 5.5 cases per year of exposure; 4) the number of cases calculated from the human data is 60 of the number predicted from the animal model; 5) the use of a log-probit model for extrapolation to low doses gives predictions of 0.1 to 0.01 times the number predicted by the linear model; 6) the error in the estimate of 5.5 cases per year ranges from + 55% to -10%. This error includes statistical uncertainty in estimating the dose-response, uncertainty in ambient concentration estimates, and errors resulting from not considering exposures beyond 5 miles or decomposition of vinyl chloride in the atmosphere. It is-^-- not symmetrical because it includes possible effects beyond 5 mile5'>'from the plants, which were not explicitly considered in the analysis. It does ( not Recount for our uncertainty about the appropriateness of using a cr see 2-0833 J l i 1ineor: model extrapolated to zero dose; or of extrapolation from animal da ;a ; 7) the quanti fiable error in the rate calculated from the human da :a is about +_ 67%. This includes uncertainties in the 17-year, averaqe .do::e received by the workers, uncertainty in the number 01* hours per* flay of actual high exposure, and uncertainty in the fraction of highly-exposed workers who have been diagnosed with liver angiosarcoma. Other errors can not be quantified, and are discussed in Appendix D. , .When all' these uncertainties are considered, our judgement is that- ; the; number of liver angiosarcoma cases produced per year of exposure in people residing near vinyl chloride plants is somewhere between less- than one and~ln" rasps. Ihe "cises produced by this year's exposure will' not. be diagnosed until 15 to 20 years `from now. " If the EPA regulationsare implemented, th,e number of cases is expected to be reduced in preportion to the reduction in the ambient annual average concentration, which is expected to be 5% of the present level. . ' The vinyl chloride exposure around plants is also producing sonewhere between less than 1 and 10 cases of primary cancer at other sites, mainly lung, brain and bone. Assuming no threshold for liver damage somewhere between less than 1 and 300 cases of-serious liver damage would be predicted. The number of liver damage cases Ys likely to be less than this because the assumption of no threshold is likely to be wrong. * ---- In order to find out whether people living near VC-PVC plants-have, as of 1574, had higher rates of liver angiosarcoma diagnosis than the overall U. S. population, a search of the residence records of all known liver angiosarcoma cases in the last 10 years was performed. Out of 176 ^ cases where residence at time of death was known, 3 people lived within "5 mifes of a plant. Unfortunately, the diagnosis of these cases has not yet been confirmed by the National Cancer Institute. In addition one infant whose parents lived within one mile of a plant died of a relatively common liver tumor. It was shown in Appendix E that this rate of occur rence is not higher than the national average. However, the survey is too incomplete to draw any conclusions at the current time. t7 ( Considering the results of the foregoing analysis, one would only now expect to be seeing some evidence of vinyl chloride exposure. If the highest rate in our range were actually occurring, 10 cases of liver angiosarcoma per year of exposure are being produced; 15-20 years ago when the vinyl chloride production 3as 102 of current levels, one case would be expected per year of exposure (with constant population). This is to be compared to a background rate of 0.6 cases per year that are occurring now. ' The survey of liver angiosarcoma cases would probably-xfetect the exist^jjee of 10 cases over the 10 year period. Sice"this was not observed we can conclude that the real incidence'Is not significantly gre.iter than the predicted upper limit of 10 cases initiated per year see 2-0834 II ';V^ vbf. exposure unless migration .of people in-and'Out;;ofvthe regions around .. >jp]ants has been e x c e s s i v e . t h e . lower rates in the range of/the above " e analysis were to be .true, increased incidence of angiosarcoma would not ^"be o b s e r v a b l " : X'-* 1 m i r * & see 2-0835 Appendix A. Population and E xposure E stim ates . ' T his appendix d e scr ib e s the approach taken in estim ating the .. imputation at risk and the le v e ls of exposure. The task is made e a sie r ' by . the use of a lin ea r d o se -r esp o n se m od el to project health effects at very low exp osu res. T his m od el.im p lies th a t..for example, a given number of people exposed to em issio n s from two plants, each at the sam e distance from the people, would su ffer the sam e number of health- effects as tw ice as many people at the sam e distance from one plant. ' M ore form ally,, with a lin ea r d o s e - r e sp o n se relation sh ip , .the number of health effects is proportional to the sum , over all plants, : distances, e t c ., o f population tim es dose. This discussion shows - how this quantity was estim ated. ; Populaiion E stim ates -. . - The population estim a tes used in this analysis are all based on a study perform ed by the A m erican Public Health A ssociation under contract to the O ffice of T oxic Substances (APHA, Population R esiding Near Plants Producing Vinyl Chloride, Aug. 1975, hereinafter cited as t,AP11A Study1'). ^ . The APHA Study is based on the 1 9 7 0 C ensus. Fr each PVC or VCM plant (or group of plants located c lo se together), APHA determ ined the number of people resid in g within 0 - 1 / 2 m i, 1 /2 - 1 m i, 1-3 m i and 3- 5 m i. Further breakdowns by age and s e x and by direction from the plant w ere a lso determ ined; how ever, as is d iscu ssed below, these detailed breakdowns w ere not used in this analysis. For those plants located in Standard M etropolitan Statistical A reas (SMSAs), wher C ensus T ract data is available, APHA asked a local respondent to a llo ca te each tract to one of the distan ce ranges. C ensus tracts were not sp lit. Independently, the O ffice o f Planning and Evaluation, EPA, m ade a sim ila r analysis for sev era l selected plants in which Census tracts, w ere sp lit and one for which city block data was used. A com parison with the APHA data for those plants indicates that no significant erro rs w ere introduced by the APHA procedure. F or untraclcd a rea s, population w as assu m ed to be uniform ly distributed over the area. F or a m ore detailed description of the m ethodology used to estim a te population, the reader is referred to the APHA report. The total population residing at the indicated distances from PVC or VCM plants is shown in the following table: D istance (m i) Population - 0 -1/2 1/ 2-1 1-3 3-5 4 7 ,0 0 0 203,000 1 ,4 9 1 ,0 0 0 2 ,8 3 8 ,0 0 0 . . Total 4. 579, 000 A-2 .i : , . Of c o u r se , so m e o f these ind ividu als a re ex p o sed to VC from ..more than otic plant o r arc exposed to e m issio n s from plants that are la rg er than - average. ; T hese variations are taken into account in calculating exposure estim ates, as described below. - . " ' .' '' ' ' -\ :. T here are sev era l sou rces of erro r which resu lt from the methodology used here. F irst, by estim ating the exposed population from C ensus s ta tis tic s on place of resid en ce, we do not take into account the . . .5?.- . d a ily m o b ility o f people, som e of whom tr a v e l into a r e a s of higher VC concentrations than their resid en ces while' oth ers do the opposite. . . . - - T here does not seem to be any way of estim ating the net effect of such 1 - travel or even whether it in creases or d ecreases overall exposure,, sh ort v o f an a n a ly sis of com m uting and tra v el'p a ttern s in the 42 com m unities included in th is study. In g en era l, it m ight be noted, h ow ever, th ese plants do not appear to be located in large cen tral b u sin ess d istr ic ts to which large number of non-factory w orkers com m ute. Given the much g rea ter u n certain ties that are inherent in the estim ation of d ose-resp on se rela tio n sh ip s, it does not appear to be worth the effort to do such anaylsos. ! V: - ,- . i . ^ ... L; , ' Second, the overall U. S. population has grown about 5% sin ce the 1970 C ensus, but it is not known whether the a rea s covered in this study have grown sim ila rly . The error here again se e m s sm a ll com pared with other uncertainties. - $$ I j ; Third, people living further than 5 m i from plants are not included. The effects of this error are considered below in the context of the overall calculation. i ; | Fourth, even though inform ation was availab le on the distribution of exposed populations by age, sex , and direction from the plant, this data was not u sed . The data on age and s e x w as not u sed b eca u se there is no inform ation on how su scep tib ility to the effe cts o f exposure to VC would vary with these factors. The data on distributionn o f population by direction from the plants could have been used, together with data on the distribution of the am bient'VC concentration by direction, to develop a m ore accu rate estim ate of the o v e ra ll population exposure to VC. An exam ination of sev era l com m unities with largeexposed populations su g g ested , how ever, that the populations w ere eith er distributed in many d ir e ctio n s o r did not appear to be c o rrela ted with the angular distribution of VC concentration. Since the m ore detailed a n a ly sis would require 16 tim es as much calculation, it was judged not be worth the effort, parti- cularly given the much greater uncertainties in other partsof theanalysis. . Ambient Concentration Estimates j| I . : : I ; : ; i;* ; j i , a. ` It w as decided ea rly that the m ea su re of exp osu re to be used is the long-term (annual) average ambient concentration. At one level, this assum ption is a consequence of the lin ear (single shot) d ose-respon se relationship. But regard less of the sp ecific form ot the d ose-respon se r e la tio n sh ip , it app ears reason ab le to a ssu m e that the probability that see 2-0837 ( -. .. . ' . A-3 any given individual su ffe r s an a d v erse health e ffe c t would depend on the Ion/'-term integrated exposure of the individual, independently of the . functional relationship between the probability and the exposure level. Indpcndent of the actual truth of this assum ption, how ever, is the absence of any data oh r e s p o n se s to peak e x p o su r es, e ith e r from the occupational experience or anim al experim ents. Thus, there is no alternative to.this assum ption if a quantitative projection of effects is to be made. ; The estim ates of average annual concentrations were derived from , , diffusion-m odeling^ usirig standard techniques. Two independent modeling e ffo r ts w ere made! - The fir s t was perform ed by the M onitoring and Data A n a ly sis D ivision o f E P A 's O ffice of A ir Q uality Planning and Standards in R esearch T rian gle Park, N. C. T his a n a ly sis took one rep resen tative se t of m e teo ro lo g ica l conditions and devoted con sid erab le effort to investigating tne e u e c ts of different plant so u rce configurations fer con tr o lled and un con trolled W (J and VCM plants. In gen era l, for average ~ ^. a n n u a l concentrations, the resu lts for uncontrolled PVC plants w ere r quite sim ila r'fo r the plant configurations analyzed, as w ere those for uncontrolled VCM plants (although, of course, em issio n s from PVC plants are very different than those from VCM plants). The resu lts for typical PVC and VCM plants are shown in F ig s. A -l through A-4. The second independent effort was perform ed by Teknekron, Inc. under the contract with E P A 's O ffice o f Planning and Evaluation. In this a n a ly sis, plant configurations w ere fixed (excep t for s iz e and the d iffer ence in pattern of em issio n s between PVC and VCM plants), but an effort w as m ade to estim a te the distribution of m ete o ro lo g ica l conditions and, to som e extent, topography for each site . The resu lts of the two sets of calculations w ere extrem ely clo se. The following table shows the average annual concentration of VC emitted from a typical PVC plant as a function of distance (that is, averaged ' radially through a ll direction s), as determ ined by the two stu d ies. Distance (m i) 0. 25 0. 75 .1.00 1. 50 2 00 3. 00 4. 00 4. 50 5.00 Vinyl Chloride Concentration (ppb) OAQPS Teknekron" 301 76 . 26 -- 10 -- 5. 6 -- : ` 323 57 37 -- 15 8 5.7 -- 4.0 i j- A dash (--) in the table indicates that a value was not determ ined for precrSely that range. The resu lts appear gen erally to be within 25% of each other, with the OAQPS resu lts low er than the Teknekron resu lts at very c lo se ranges and higher at longer ranges. see 2-0839 r; ( 1 i r In g e n e r a l, the c lo s e n e s s of the two s e ts of independent r e su lts . ser v o s as a eonfirm ation of both. Of course, sin ce both use sim ila r m ethodologies, it is possible that they Share som e of the'sam e errors. It lias, not proved p o s s ib le to com pare th ese m od eling r e su lts with actual m onitoring data in a sy ste m a tic way, and this is an im portant shortcom ing of the an a ly sis as it stands at present. Sum m aries of the am bient m ea su re m en ts have been exam ined; how ever, and they appear to be g en era lly con siste n t with-the m odeling resu lts. F or the actual calculations, it was decided to u se the Teknekron r e s u lts , sin c e th e se show:ed how am bient co n cen tra tio n s would vary with . m e te o r o lo g ic a l con d ition s (although, :in r e tr o sp e c t, it turned out that th ese v a ria tio n s m ade little .d iffe r e n c e in the fin a l r e su lt). The s it e s liste d in the Teknekron report divided naturally into four categories, which we' . designate as Low (L), .A verage (A), High (H), and V ery High (VH), based on the am bient concentration projected.to result from the sam e lev el of " e m issio n s. (V ariation am ong s ite s due to the num ber and s iz e of the plants are factored into the analysis sep arately and are d iscu ssed below). Table A -l shows the category to which each location is assign ed . The relative am bient concentrations for the four categories are: Low Average High V ery High 0. 56 1. 00 1.55 2. 55 "uAa J c (a / A - 5 ,0' 'A v OAQ erage P"IISo,, rp,, rI"oTLv ided arge .inI"If o rL T m aL l i d he tUioU nU typi cwWa lhl l ii""LcAHh vceartaeggeo""ri.i^VzCeC.' UdMCeT dapLc-liahI nptpi Alhat alnLdt UbJ y OsiiizCe ad O s a productio n J of 70 0 m illion lb /y r, and the typical "Large" VCM plant 1300 m illion lb /yr. F or PVC plants, the typ ical "Average" plant used 150 m illio n lb /y r and the typical "Large" plant 350 m illion lb /yr. It was assu m ed that large plants would have proportionately greater e m issio n s. It is estim ated that u n con trolled PVC plants e m it about 4% of the vinyl ch lo rid e p r o c e sse d and VCM plants, about 0 .3 % . T able A -l a lso show s, for each location, the number and siz e ca teg o ries of plants located there. The letter "L" in d ica tes a "L arge" plant; thus, for exam ple, the designation "2" m eans two "A verage" plants afid "2 & 2L" m eans two "A verage" and two "Large" plants. S O verall Exposure Estim ates T able A -l a lso show s the populations resid in g at the indicated distances from individual plants. To determ ine the equivalent exposure (com pared to exposure from a sin gle average siz e plant at a location with average m eteorological conditions), each of the population figures m ust be m ultiplied by two factors, one reflectin g m eteorological conditions at that location and one reflectin g the number and s iz e of plants at the lo c a tion. Thus, for exam ple, in T exas City, T exas, each individual is exposed to e m issio n s from two average s iz e plants and one large plant^ (equivalent to 2. 3 a verage plants) but under "Low" m eteo ro lo g ica l condi tions (heading to 0. 56 of the concentration that would be expected under a v e r a g e conditions). Thus, these individuals are exposed to the equiva lent of 0. 56 x 4. 3 = 2. 4 average plants' em ission s under average ' see ';" MiriiliLirtns."n'JSin'ilar :V:al<-ulalions w o r o p e r f o r m e d for:carli location in ;Tal>l<` A - l and the r e s u lts sum m ed to obtain the v a lu es shown as.-'W eighted - lolaj population'' in T able A - 2 .: - \` 7 The weighted total population figu res are then m ultiplied by the a v er -age annual concentration of vinyl chloride, as derived from the diffusion m odeling. The sum of th ese figu res is the total population exposure. - Thcise- r e s u lts a r e show n in T a b le A -2. The total exposure is estim ated ^ t o b c (7 6 . 4 m illion people x ppb. Thus, the total exposure o f the U. Sr fiT ^jju iiT ti^n -to ^v ih y i^h io ri^e "due 'to' e m is s io n s from th ese plants is eq u ivyalen t to 7C .4 m illio n people exp osed to 1 ppb* or 7. 64 m illio n people i expoisedto 10 ppb, etc. Probably the sim p le st way to understand this . figure is in term s .of.the ^average exposure of those who are exposed. : . . - S in ce th ere a r e ' i:total o f 4. 6 m illio n people e x p o s e d ^w tth in ^ m i o f plants-, ^ the average, ex p o su re of th e se people is 7 6 . 4 / 4 . 6 r>^J7 pph We can a ls c u s e th ese fig u re s to gain so m e in sig h t into the d istrib u tion of the aggregate exposure (and hence of the resulting adverse health e ffe c ts ). We c a \ s e e from T able A -2 that only about 3% of the exposure is-a r e s u lt of err is s io n s from VCM plans, with the rem aining 97% com ing from PVC plant?;. It a ls o ap p ears that the bulk of the health e ffe cts w ill be occurring frem 1 to 5 m iles from the plants, rather-than within one . m ile, sin ce much la rg er num bers of people live at the greater distances. : 7 -- 0* q- see 2-0840 octo cnno  : ,f. : Kilometers >. .0 ; : v'- ..: .4 .:; . I n 1 1 1 i . i i . n n n i n I tiVii i . i 111 m 11 . J r ;j ' i vr . : <l ' *. *!":l` ' Figure A -1. Estimated annual concentrations (ppm) of VCM from average PVC plant. ' i ; 'Sit'-- i !' # S : 'K vlJ'tei-.. ; ' *jp: - ,?ii i fir f c :;l | | w f t v .v ' W ; :`: A i l i n ' V*b v.-i'iV- ;v . - ;: ' ' Wit: K * i d rt^jgaesil M -i 4 SCC -0842 Kilometort 0 , 3v , 6 L t.i_uj.il u n n i m i i l i n i u m i l i li i i ij : ': 1 '* Figuro A -2. Erti mated annual concontratiora (ppm) of VCM from eran g s : . PVC plants.  3 w SCC -084 a 9 -0844 Kilometer* 0 31 1-- ____ i -________________ I____ Figure A -4. Estimated annual concentration* (ppm) of VCM from average size VCM plant. TABLE A -l Population Exposed by Location l ,o ralio n No. & Size M e t e o r o l o g i c a l of Plants Conditions (a) PVC Plants C arson City, CA Saugus, CA D elaw are C ity, DE Pace, FL Henry, IL Illio p o lis, IL C alvert City. KV L ouisville, KY . Plaquem ine, LA Baton Rouge, LA P e r ry v ille , MD Fitchburg, MA Springfield, MA M idland. MI A berdeen, .MS Burlington, NJ Pedriekton, NJ P? ~aic. NJ ' 5.' .earny, NJ Flcm ington, NJ H icksville. NY W illiam sville, NY A sh tabu la, OH Huron, OH Avon Lake, OH P a in e s v ille , OH O klahom a C ity, OK Potts town, PA Deer Park, TX Freeport, TX Texas City, TX P t. P le a s a n t, WV S. C h a rlesto n . WV 2 1 1&1L 1 IL 1. 1 IL 1 1. IL 3 -1 1 . IL .2 1 1 1 1 1 1 1 1 IL 1&1L IL IL IL 1&1L 2&1L 1 1 A H A A A LA A A A H A A L VH L A L L A L L A L L A L H H L L H VH Population vs* Distance (m i) 0 - 1/2 1 / 2-1 --- ITT---- -- 16.541 - - 10.935 -- -- -- -- 37 , 146 30 117 102 398 6, 315 177 673 -- -- -- 2. 091 34,395 8. 258 492 1,899 114 442 .8, 159 - - W"" 22, 512 29.458 18,656 81 306 5, 900 20 ,70 2 11,522 12,552 434 1, 671 98 380 827 5, 511 - - ' -- .-- -- -- 2. 447 -- 12.820 -- -- 3,440 -- 263 1. 007 5, 698 259, 309 -6, 970 -- 1, 161 922 3, 134 1 1 1 ,146 5, 328 25. 615 11.091 67.767 40, 671 15, 045 3, 504 122,419 9,113 194,601 214.594 2. 394 143,760 51,872 13,239 2. 988 16. 398 21.550 25.526 36,121 32,151 4,746 19.460 7,984 .40. 685 405.461 12,029 9, 218 7, 071 2. 013 1, 597 5,436 146,000 9. 237 54.193 9,791 114,489 108,966 26, 067 6, 073 230.361 98,992 269,259 696,928 4. 153 215,230 113.422 22,937 5.175 8, 022 16,434 73.581 30, 382 86,508 15.879 34,751 13,836 53,432 (b) VCM Plants G eism ar, LA Baton R ouge, LA Lake C harles, LA Plaquem ine, LA N orco. LA Dec Park, TX Fri. port, TX C a lv ert C ity. KY GuaN'kmilla, PR 3 1 2 /\ 1 0^2 * 2 - 1. 1. IL 1 A A A A A H L A A 62 -- -- 177 215 .- 102 202 233 -- -- 673 823 1 2 .8 2 0 -- 398 780 1.852 25. 615 11. 601 5. 328 6. 525 32.151 4,746 3. 134 6,173 3,211 54.193 44,100 9,237 11,306 86.508 15,879 5,436 10.692 tj - see 2-0845 . FOOTNOTES: - r a / N um bers follow ed by "L" ind icate "L arge" plaints as defined ., .. in the text. Other num bers indicate "A verage" siz e plants. : - -. b l Ratio of am bient concen tration to e m is s io n s is ch a ra cterized as Low (L), A verage (A). High (H). or V ery High (VH). : - / Adjusted to show effect of m ultiple exposures at varying "' ; distances from plants. Not to be m ultiplied by number of . plants. ' V e .. - ' ` ; II i see 2-0846 ( TABLE A-2 Aggregate VC Exposure 0 -1 7 T Distance From Plant (mi) T m --------n oe~ (a) PVC Plants W eighted total population VC concentration (ppb) Total exposure (m illio n population x ppb) 34,000 323 11.0 228, 000 57 13. 0 2, 0 1 3,0 00 15 30.2 3, 43 9,0 00 5.7 19. 6 Total 73.8 (b) VCM Plants W eighted total population VC concentration (ppb) Total exposure (m illio n population x ppb T\ a.1 for a ll plants 1, 200 113 0.1 37,000 20 0. 7 169,000 5. 2 0. 9 434,000 2.0 0.9 2. 6 76.4 xW \ l / a' /r^ /> - ^ ( v|^' 0 `10 .v 7 / * - jT ' / > <* ^` r 7 a see 2-0847 ( ! ' ^ y- - y Appendix B. 'E stim a tes of E ffect R ates from A nim al Data In an alyzin g the e ffe c ts of v in y l ch lo rid e, ,w e a r e fortunate to w. . : liave at le a s t sem i-quantitative data for both human and anim al expo- > - . su r es. -C h o ices had to be made concerning how to u se this data. .. " ' ; V inyl chloride is known to cause both cancer and non-cancer effects . , in hum ans. With resp ect to cancer effe cts; we have anim al ex p eri- ' T. rnents in which rats-w ere exposed ,to-known co n cen tra tio n s for known p eriod s of tim e '. We a ls o have the human occu p a tio n a l ex p e rie n c e , in ' ' - which increased incidence.of liver angiosarcom as and other cancers - w ere observed in exposed w orkers. Ideally, we should u se human data \ r . throughout and avoid the problem of extrapolating from an anim al m odel - ;io human, b ein g s. U nfortunately, we do not have good data on the le v e l - - of ex p o su re of w ork ers. In a rriv in g at a s p e c if ic num ber to w rite down and u se in the calcu lation s, it would be n e c e ssa r y to gu ess at th ese fa c to r s. We d ecid ed , th erefo re, to d eriv e a d o s e - r e s p o n se rela tio n sh ip from the anim al data, for cancer effects, but to u se the human data to the g r e a te st extent p o ssib le to confirm o r deny the validity of the relation- ship. T hese checks are described in Appendix D. Since both the human and the anim al data involve exposure at high le v e ls , the difficulty in extra- polation from high to low exposure le v els would be the'sam e in either case. . .. . ! = .I >; | ;j ' .. ! - |-;i| :t * 'f ' i i : && With r e sp e c t to e ffe c ts other than ca n c er , the an im al data is too fragm entary to e stim a te quantitatively the ra tio betw een ca n cer and non-cancer effects caused by exposure to vinyl chloride. However, the human data does perm it an estim ate of this ratio, and this estim ate can then be used together with the d o se-resp o n se estim a te for cancer to p lace so m e lim its on the m agnitude o f the n o n -ca n cer e ffe c ts. ! ' * The A nim al Data on Cancer . The basic experim ent is M altoni's experim ent BT1. SpragueDawley rats w ere exposed by inhalation to a sp ecified concentration of vinyl chloride for 4 lir/day, 5 days/w eek for 52 w eeks. After the 52 w eeks, the anim als w ere not exposed to vinyl chloride but w ere observed for the rem ainder of their lifetim es. The resu lts o f the experim ent w ere as follows: , ' j i j ; | j ; j VC Concentration (ppm) L iv er Angiosarcom as A il Tumors 10, 000 6, 000 2, 500 500 250 50 &0 9/61 (15%) 13/60 (22%) 13/59 (22%) 7/59 (12%) 4/59 ( 7%) 1/59 ( 2%) 0/58 ( 0%) 38/61 (62%) 3 1 /6 0 (52%) 3 2 /5 9 (54%) 2 2 /5 9 (37%) 16/59 (27%) 10 /59 (17%) 6/ 58 (10%) see 2-0848 Two conclusions can be drawn im m ediately from these resu lts. . . . . Fi rst, the rate of.occu rren ce of both liv er angiosarcom as and total can cers..in creases much m ore slow ly with dose above 500 ppm than ' below this concentration. The cause of this phenomenon is not under stood , but,; w h atever it.m ay be, it does not appear to be relev a n t to -: extrapolation to low er d oses in the p artsrp er-b illion range. H ence, .- a ll the c u r v e- fittin g reported h ere is done only for the data fo r 5 0 0 .. ppm and b e lo w .. . . .% : .. - Second, the control group had no liv er angiosarcom as, but about 10% of them did have other types of ca n cers, as is to be expected. T h erefo re,' in estim ating the d ose-respon se relationship for total ca n cers, it w ill b e ,n e c e ssa r y to u se a m ethod which allow s for a ' positive respon se at zero dose.* Extrapolation to Low D oses ' It is w idely understood in the scien tific com m unity that no f ir m ' lo g ica l b a sis can e x ist for extrapolating data to le v e ls many o rd ers of m agnitude beyond the range of ex p erim en ta l o b serv a tio n . In spite of this, two alternative assum ptions are frequently .made in the literature. The fir st of these is that the respon se is lin ear in dose, e. g . , half as many effects are produced at half the dose. This is a lso referred to a s the "one-hit" m odel, sin ce it would follow lo g ica lly from the assum ption that each minute increm ent of expo su re to a carcinogen has the sam e independent probability of causing a cancer r eg a rd less of the dose level. This assum ption is generally accepted as prudent in radiation carcin ogen esis. F or carcin ogen esis in gen eral, this m odel is usu ally considered to provide an upper lim it to the le v el of e ffe c ts lik ely at extrem ely low d o se s, b ecau se the possible existen ce of detoxification m echanism s might render sm all d o ses in effectiv e in contributing to can cer effe cts and thus r e su lt in a threshold below which no effects would occur. The second assu m p tion frequently m ade is that the response is lin ear when the logarithm of the dose is plotted against the proportion of resp o n ses ex p ressed in a probit sca le (i. e . , the value of the argum ent of the cum ulative norm alized G aussian distribution function corresponding to that proportion); for convenience, we refer to this as the "log-probit" m odel. This m odel is derived from the assum ption that individuals in the population have a sta tistic a l d istr ib u tio n of su scep tib ility to ' cancer effects which is norm ally distributed with log dose. The lin ear m odel is much ea sier to apply, sin ce the number of effects depend only on the number of individuals exposed and their average dose. The log-probit model, on the other hand, requires data as to the distribu tion of d o ses in the population and is th erefo re m ore lik ely to be influenced by anom alies in the m ethods for e stim a t ing population exp osu re. F or this reason and because of the c o n se r v a tiv en ess of the lin ear m odel, the calculations w ere made using the lin ea r m odel, but a sen sitiv ity an a ly sis was perform ed to show how the resu lts would vary w ere the log-probit m odel used. see 2-0849 Straight lin es were fitted to M altoni's data using a maxim um- ` \ .; , likelihood method. E s s e n tia lly , th is m ethod a ssu m e s that the prob-> ^ . ahilitii'S oil can cer at the d ifferen t d o se s w ere related by a lin ea r June-" , ; ; tion and detem in es the valu es of the slo p e and intercept that would . inako the likelihood of the o b served r esu lts as high as possible. ;1 - ' ,V:: M athem atical d eta ils are provided in Appendix C. . .. ' - ... V ; ' F o r the data on liv e r angiosarcom a, the line was constrained . . - to go through the origin . (Without this, constraint, a slightly nega- . ^ tive in tercep t was obtained. ) With the constraint, the following " relationship is "obtained: "^ \ ' w.: ;o P = 2. 53x10 * 4d . . .where P-is the probability o f a liv e r an giosarcom a and d is the dose . -- .. in ppmT" F o r a ll tu m ors, the co rresp o n d in g lin e i s . P = 0. 123 + 5. 26x10* ^d rTcrc, the in tercep t is the b e s t e stim a te from a ll data at 500 ppm and b.elow of the can cer rate in the a b se n c e of vin yl chloride; the slop e is the best estim ate of the rate at which tum ors are caused by exposure to. vinyl ch lo rid e. T hus, inn the a n im a ls, vin yl chloiude appears to cause about one other cancer for each liver angiosarcom a. Estim ates of the total number of ca n cers caused by vinyl chloride are based on the slope of this line, not on the intercept. The standard d eviation s o f the e s tim a te s of the slope w ere found to be 6 .9 x 10* for liv e r an giosarcom a and 1 .1 x 1 0 '^ for a ll tum ors. (T h ese e stim a te s are d eriv ed from la r g e - sa m p le theory). It cannot be c m p h a siz e d ;too much that the standard d eviation s r e fle c t only that uncertainty in the estim a tes that is due to lim ited sam ple size; they arc derived from the linear m odel and cannot reflect the much greater uncertainty due to our ignorance o f w hether the lin ear m odel is correct. They a lso do not r e fle c t the e ffe c ts of the p art-tim e exposure used in the experim en ts or, most- im portantly, of the difference between human beings and Sprague-D aw ley rats; th ese are d iscu ssed below. The goodness of fit is shown in the follow ing table, which com pares the actual data obtained in the experim en ts with the values expected from the above equations. D ose (ppm) Liver A ngiosarcom a A ctu al Expected All Tumors Actual Expected 0 0 0.00 50 1 0.7 5 250 4 3.74 500 7 7.47 6 7.16 10 8 . 8 4 16 15. 05 22 2 2 .8 1 In ord er to te s t the s e n s itiv ity of th ese projection s to the assu m ed t lin e a r form of the d o s e - r e s p o n se rela tio n sh ip , the data for liv e r angio sa r c o m a was a lso fitted to a lo g -p ro b it equation. U sing an unweighted . see ' 2-0850 B-4 , v lesLSt-squarGS fit to the data for d o se s of 5 0 0 ppm or le s s , the '/ ~ follow in g equation is obtained: . 1 ; - : ' ; . . .*. . probit = --3. 71 + 0 .9 3 2 lo g d o se =' . - ; / w here log indicates common (base 10) logarithm and dose is in ppm. " ... ' . The fit is e x tr e m e ly clo se: the m axim um d iffe re n c e betw een predicted . . . ; .. and actual valu es is 0. 02 probits. . : -. v V . ' . ; Both.the lin ea r and log-probit fitted cu rv es a re plotted in F ig. B - l - on a log-p rob it s c a le . It can be se e n from th is graph that, in the ' .. . ... range of con cen tration s of in te r e s t (sa y , 5 to 3 0 0 ppb), the log-probit ; projection y ield s risk s of one to three ord ers of magnitude low er . . . " than the lin ear projection. Since the resu lt o f a com plete log-probit a n a ly sis of human effects due to exp osu re to vinyl chloride in the am bient air near plants would tend to be dom inated by the high concen trations clo se to the plants (unlike the lin ea r a n a ly sis), the log-probit an a ly sis would yield final resu lts one to two ord ers of magnitude low er than the linear m odel. Extrapolation to Human Exposure > The equations derived above can be used to project what the resp on se of rats would be in sim ila r experim ents at much low er d o se s. To apply th ese resu lts to human com m unity exposures, it is n e c e ssa r y to m odify the resu lts to r e fle c t 24-h ou r exposure and, m ost im portantly, the difference between humans and r a ts. The latter is particularly problem atical. The rem ainder of this Appendix w ill be based on anim al data. Human data w ill be d is c u s s e d in Appendix D. . In the ex p erim en ts, the an im als w ere e x o se d to vinyl chloride for 4 h r/d ay, 5 d ays/w eek . In the com m unity, the exp osu re would be continual for 24 hr/day, 7 days/w eek. This effect can be corrected for by dividing the continuous dose receiv ed by people by (7x 24)/ (5x4) = 8. 4 and u sin g the sam e lin ea r d o se -r esp o n se function to c a l culate the risk . T his is m athem atically equivalent to m ultiplying the slope by the sam e amount. - Adjusting for the difference betw een humans and rats is much m ore ' difficult. As in the extrapolation to low d o ses, very little evidence is ' available. Furtherm ore, controlled experim ents involving human c a r c in o g e n e s is are unlikely to be c a r r ie d out. In sp ite of the lack of evidence, the consensus of the scien tific com m unity appears to be that, if an assum ption m ust be m ade, it should be assum ed that the sam e number of cancers would be induced in humans over their lif e tim es a s are induced in rats over their life tim e s . With this assum p. tion, the one-year exposure of the exp erim en tal is expected to cause ^ the sam e probability of cancer (i. e . , the sam e incidence rate) as about 0 y e a rs of exposure to humans at the sam e concentration. * Thus, to d eterm ine the annual rates of can cer induction in humans. sec 2-0851 vWv/' II I | *,L#,. ' - ' r**^* the rates derived above should be divided by 30. B-5 '* Y ' Yo"~:Y:2 -Y-Y'-Y.Y--'YY .- ^ - Making th ese adjustm ents and a lso converting the units to c a s e s : ' 0 ' per m illio n population per ppb per y e a r , we obtain a rate of 0. 0 7 i liv e r angiosarcom as and 0 .1 4 7 total cancers (in e x ce ss of background rates) pei* m llio n population per ppb vinyl ch lorid e per y ea r. The standard - d eviation s of the e s tim a te s , which, again, r e fle c t only the s ta tis tic a l ^ u n certain ty due to lim ited sam p le s iz e s , a re 0 . 0 1 9 and 0. 0 3 1 , - ` ?v r r e sp e c tiv e ly . .. Incidence of N on-cancer E ffects ' . ; ; L iver dam age has been a frequent observation in anim als exposed to vinyl chloride. The low est dose in chronic experim ents (tim es longer than 3 m onths) at which non-cancerous liv er effects are observed is 100 ppm (Torkelson, et a l . , 1961). The effect observed was liv er enlarge m ent which cannot be called damage sin ce the m icroscop ic structure was norm al, but it is an indication that the liv er is affected in som e way by' vinyl chloride. Of all reports-on anim als the low est dose causing liv er c e llu la r d egen eration is 5 0 0 ppm (7 h r s/d a y , 5 days/.w eek, fo r 4 - 5 months). A Russian report of bone resorption, cardiovascular im pair m ent and neu rological changes in the hypothalm us of rats and rabbits at concentrations of 12-16 ppm for 6 months (B asalaev, 1972) has also appeared. It is unfortunate that we currently have no published reports of pre-eancerous liv er damage occurring in the sam e experim ental group of anim als in which cancer la ter develops. T herefore there is no way to e stim a te the in cid en ce ra tio o f n o n -ca n cer to liv e r . angiosarcom a effects in anim als. The human data on non-cancer effects is d iscu ssed in Appendix D. I O verall Effect Rates In Appendix A. it w as estim a te d that the 4. 6 m illio n people liv in g within 5 m i of PVC or VCM plants would be exposed, on the average, to 17 pnb of vinvl c h lo r id e . C om bining th is inform ation with the d o se - respon se estim ates.d erived above, we can calculate that, for exam ple, vinyl chloride e m isssio n s in the absence of control would cause 4. 6 x 17 x 0. 071 = 5. 5 c a se s of liv er angiosarcom a per year in the U. S . , using the lin ear m odel. S im ilar calculations for all cancer yield the following results: . . Type of Effect C ases Caused per Year Cancer Liver angiosarcom a . 5 1/2 All cancer 11 ' . .. It should be r ea lized that can cers caused by vinyl chloride have about a 20-year latent period. Thus, we would not expect to ob serve th ese num bers of ca n cers occu rring now; rather, th ese are the num bers - 2-0852 that .are estim ate?! to .be in itia te d now but which w ill produce sym ptom s ^" perhaps 20 years from now if em ission s rem ain unchanged from current u n con trolled le v e ls . S im ila r ly , .we would e x p e ct that ca n c er s caused by .. vinyl chloridc thatjare showing sym ptom s now would have been caused ' . by e m is s io n s d v e r fth e p a st:2 0 .y ea rs',' during which to ta l vinyl chloride : T- production in c r e a se d from about 10% o f its c u rren t le v e e l. .. ; :: E r r o r Anal ys i s . . ,1 . .- -The follow ing d is c u s sio n attem p ts to e stim a te the e r r o r s involved in this an alysis other than the erro rs introduced by extrapolation from . high to low d o se s and from anim als to man,' which a re d iscu ssed in ~ Appendix D. Quantitative estim a tes are provided below for the . . following sources of error: , (1) E rro rs in the slo p es of the d o se-resp o n se lin es due to the lim ited sam ple s iz e s in the experim ents. (2) E rrors in estim ating the am bient concentrations around plants. . (3) E rro rs resu ltin g from not considering effects^on the ` population liv in g fu rth er than 5 m i from plan ts. -- ' (4) E rrors resulting from not considering the decom position of vinyl chloride in the atm osphere. The standard deviations of the estim a tes for the slopes of the dose- response lines w ere calculated from m axim um -likelihood large-sam ple theory, a s described in Appendix C. As m entioned above, the resu lts are 27% and 21% of the estim ated slo p es for liv e r angiosarcom a and all cancer, respectively. - \ Ideally, an estim ate of the e rr o r s in the diffusion m odeling could be derived from a com parison with actual m onitoring data. Unfortunately, such a com pa r iso n is not availab le . In its a b se n c e, w e u se the d ifferen ce "between tne two independent estim a tes as a m ea su re o f the degree of uncertainty in the e stim a te s. As w as noted in Appendix A, the two se ts of resu lts w ere generally within 25% of each other. We can estim a te the m agnitude o f the e r r o r s due to the 5-m ile cut off and vinyl chloride decom position as follow s. Suppose that, say, 10 m illion people liv e between 5 and 10 m i from the plants where they would be exposed to an average concentration of VC of about 2. 4 ppb, based so lely on the diffusion m odeling. (The figure o f 10 m illion people is chosen to show the sen sitiv ity of the calcu lation to the 5-m ile cut-off. The 5-10 m ile annulus contains 3 tim es the area of the 5-m ile circle, but would probably contain le s s than 3 tim es the population, sin ce in manyjjpases the bulk of the urban area would be within the 5 m i d ista n ce .) T his exposure would cau se 3. 5 c a s e s of can cer of a ll types per y ea r and corresponding num bers of other health effects, according to the linear m od el. H ow ever, vinyl chloride is b elieved to decom pose in the . B-7 r;rtnVosphprp%ith~a h a lf -life ^e s tim a te d `at^about'S'hniifsr^Assumin'tT an oVcrnl l ;a; <vrag<v A\ incl spocd ol 10 m i/h r/, the a v era g e con cen tration . 0 the. 5 Im lO'mil* annulus would be red uced by d eco m p o sitio n by -about 8 % ; s o ^ b o u 0 3 . 2 . c a s e s of cancer would be o c cu rr in g th ere. . 'At the sia'n e 'tim e ,^ d ecom p osition would red uce the a v e ra g e co n c en tr a tion withi a 5 m iles as w ell, by about 3. 4%. The o v era ll effect of these com pensating e r r o r s 'would be to in crea se the estim ate by about 25%. -A ssuj ung..thal_the fir s t two so u rces of erro r a r e independent,- the ; ; ^'eVtimatei^ cah'Tbe"com bined u sin g a :P ythagorean form u la. - T h u s/ the ' ..com bined e rro r estim a te would be the square root of .; (.21)2 + (.25)2 o r about :-3% o f the estim ated 11 c a s e s of ca n cer per y e a r pred icted by the lin tar m od el. T his is about 3. 6 c a s e s per y e a r. Since the second two so u r c e s of erro r listed above are estim ated to lead to an undcresti nate by about 2. 8 cases per year, a total error estim ate m ight be tlus about 6 or minus about 1 ca se s out of 11 per year. (N ote under the log-p rob it m odel, the e ffe c t of the "&mi cu t-off would be tegligib le. ) ." a see 2-0854 rtobit Probability SCC -0055 ( - . . AppendiXiC- M athem atical T reatm ent of D ose-R esponse Data ~ Tho dose-resp on se curves given in Appendix B w ere derived from the anim al experim ents using an extension of the standard maximum- likelihood (ML) method of sta tistic a l estim ation . The resu lts at " d ifferen t d o ses are combined and the lin e chosen is the one for which the likelihood of the observed resu lts is the greatest. - A discussion of . the standard ML method may be found in any elem en tary text on -T m athem atical statistics. - Equations for ML E stim ators - A ssu m e that M experim ents (including the controls, if any) are" p erfo rm ed . In theW-th exp erim en t, n,- a n im a ls a re exp osed to a d ose d,* and x{ resp o n ses are observed. We assu m e that the response of each anim al is independent of the others, so each experim ent is a set of B ern ou illi tria ls in which the probability of respon se pi is a function of d,* with unknown jjaram eters. In p a rticu la r, we co n sid er two functional form s here: p. * P d > w A^ T he method is readily adapted to other functional form s. (1) (2 ) Eq. (1) w ill be called the "no zero resp on se" ca se and is appropriate when there is no m easurable resp on se at zero dose. Eq. (2) w ill be called the "positive zero response" ca se and is appropriate when a m easurable response occurs at zero dose. (The m athem atics allows * < C , o f c o u r se , which would im p ly at th resh o ld below which no resp o n se would occu r. Inferring the ex isten ce of a threshold is fraught with d ifficu lty .) . . F or the p o sitive-zero-resp on se ca se, the joint probability of the resu lts obtained is i. K.}. - IT (.*)( -*&-V (3) (all su m s and products are assu m ed to be o v er the range l = 1 , . . . , M u n le s s o th er w ise in d icated ). The v a lu e s o f n and (i which m a x im ize L (u n le s s they fall on the boundary c>f C* i I. for som e i ) satisfy the equations y log L = 0 r i lo& L = 0 (4) (5) see 0856 I i A fter sim p lific a tio n , E q s. (4) and (5) red u ce to ky (** Jr). a-'-pA). o (6) >,v ; x;th -- 6* +'gc/; );*}: J: 6<+-(3Ji )(>-<- (37/ ) (7) ,, T h ere.are a set of two sim ultaneous 2M-th order algebraic equations for which no closed-form -solution is p ossib le. However, a num erical solution can be obtained by, for exam ple, N ewton's method for two v a r ia b le s w hich is described below. . F o r the n o - z e r o - r e s p o n se c a se , Eq. (5) a p p lies and is equivalent to Eq. (7) with oc = 0. T his s im p lifie s to S'^-*1 mo (8) T his is , again, a 2M-th order algebraic equation which can be solved n u m erica lly by the standard N ew ton's m ethod, d escrib ed below . \ Asym ptotic V ariances . With the M l. m ethod, asym p totic v a r ia n c es of the ML e stim a to r s are readily obtained. (See S. S. Wilks , M athem atical Statistics (W iley, 1962), pp. 3 7 9 - 8 1 . ) T h e se a re given by * pC . <9> i - `{ [ M T (10) for the p o sitiv e-zero -resp o n se case. E qs. (9) and (10) reduce to -`Fi*2- * I_ r J ? < y- n ; ____ c-- 71,* <ni; * ' / ( (<X + (?, cf, ) ( l - <*" P d ' ) ' (U ) (12) . see 2-0857 iVirfSv.' C -3 P A g a in ,'-for.,ih e ; n o -z e ro - e sp o n s e le a s e , tth e c o rre s p o n d in g r e s u lt is o b ta in e d by s e t t i n g -oc. = 0 in E q . (1 2 ), w hich g iv e s ' : ;. -I _ 5#. -n, 2: ( i- (5^0 ; (13) v r E q s . (1 2 ) and (1 3 ) w e re u se d in A ppendix B to ''c a lc u la te `th e '-sta n d a rd ; deviations of the slopes of the d o se-resp o n se lin e s. N ew ton's M ethcd fo r One V ariable . . . .... Wc w ish to solve the equation f(x ) = 0, w here f has a continuous f ir s t d eriv ativ e." S tartin g with an in itia l e stim ate x 0 , we approxim ate the curve y = f(x) by its tangent at x = x 0 ; the point w here the tangent in te rse c ts the x - axis is an im proved estim ate of the root. The equation of the tangent is y - f(Xp ) = f'Xp) (x - (14) S ettin g y = o in E q. (1 4 ) y ie ld s (*o) x = x,. -- 'iO (15) Eq. (15) can be iterated until sufficient accuracy is obtained. N ew ton's M ethod fo r Two V a ria b les . H ere, we wish to solve the equations . f< x.y)V 0 g(x.y) = 0 ` (16) i ( and have an initial estim ate a t ( x . , y \ , , f(x t. ,y , )) is x 0. y0 . T he plane tan g en t to f (x .y ) . (fA, f j ,- 1 ) (x - xa,y-ycz.- f ) = 0 or (x -x 0 )fy + (y-y, )fT - (z -f) = 0 (18) w here the su b scrip ts indicate differentiation and all functions are . evaluated at ( Xcy, t. ). S im ila r ly , the p la n e ta n g e n t to g (x , y ) - z = 0 . a t (x , , y t. , g (x e , )) is (x - x c )g + (y - y,. )gu - ( z - f ) = 0 (19) see 2-0858 ( C-4 - The planes given by E qs.. (l'8) and (19) intersect'xn 'arlin e7;lw hich'in v. : .turn in te r se c ts z.= O in a point which is an im proved estim ate.of.th e - ,root,-v'`T his 'point^ari be obtained i ' ' ' <ou sly with z --0. - T h is g iv e s . (2 0 ) - (21) E qs. (20) and (21) lean be iterated until sufficient accuracy is obtained. iga r I see 2-0859 ( ' A P P E N D I X . USE OF HUMAN DATA TO ESTIMATE RISKS . '' In Appendix 8 the linear model describing the dose-response curve : for the incidence of liver angiosarcoma in rats was modified by two factors in order to estimate the number of cases of human angiosarcoma in human populations. These two (multiplicative) factors were 8.4, to convert the 4 hrs/days, 5 days/week rat exposures to continuous exposures, and 1/30 = 0.033, to convert the annual rates in rats to in humans. In this appendix the available human data on liver angiosarcoma were examined to validate these factors, revised estimates of the number of human cases per year of exposure to ambient vinyl chloride concentrations around plants are made, and the number of people incurring effects other .than liver angiosarcoma is estimated. The emphasis is placed on the quantitative comparison of data in rats and humans. . -i ! : ! '! '' ; ; ' - is;? ; Intersoecies Comparison of Life Expectancy and Angiosarcoma Latent Times The most obvious difference between rats and people is their relative size and attendant metabolic rate and life expectancy. Both life expectancy and the time required for tumors to develop are independent manifestations of the basic differences in metabolfc rates. . ; ^ ;' According to the 1970 U.S. census data, the life expectancy of oneyear old infants in the U.S. is 75.6 years for females and 68.3 years for males. This is to be compared to about 100 weeks or 1.93 years for rats. The ratio of life expectancies is therefore about 1.9/72 = 0.026. The time required for tumor development in people can be estimated from the case histories of 14 confirmed cases of liver.angiosarcoma, all of whom are highly-exposed workers in the vinyl chloride industry ^ (reference 2). The average time between first exposure to vinyl chloride and diagnosis is 19.6 years, and the average duration of exposure is & 17.2 years. The distribution of exposure durations preceding diagnosis among these cases is approximately log normal, i.e. it is a normal distribution when plotted against the logarithm of latent time. The median time is 17 years, and the variance is 0.15 units of log (time) per one standard deviation. By contrast, Mai torn' found that the average time in rats between onset of exposure and appearance of tumors was 80 weeks (after a 52-week exposure), regardless of dose between^ 10,000 ppm and 250 ppm. The one liver angiosarcoma which appeared in the 50 ppm group occurred 135 weeks after onset of exposure, but this one case is regarded as insufficient information to disprove the conclusion that the latent time in rats is independent of dose. The approximate ratio of times required for tumor development in humans and rats is 1.54/19.6 = 0.078. r This estimate contains considerable error. One error is that the see 2-0B60 . ; ./ ' - ; . - .. D2 . - observed average: exposure duration preceding diagnosis in :the.workers - ` is anunderestimate of the true biological latency. There are two ., reasons for this statement: '. a . - M h e number of people in the industry has increased steadily ' since 1940. therefore the current work force .contains an over representation of people with short exposure times, and the cases which have appeared are systematically biased toward . . short exposure times.,t . ... " . . b. Even -if the number of exposed people had not increased in the past, the disease could still develop in those people in the . ... . future, which would result in a longer average exposure . ' duration before diagnosis.7 ; 7 7 ' 77 A more fundamental difficulty in attempting a comparison of exposure times for rats and humans is the uncertainty whether the disease is caused by a gradual build-up of some type of tissue irrita tion which requires constant intake of vinyl chloride or whether it is caused by an event occurring randomly in the exposure history and progressing to angiosarcoma independent of subsequent exposures. Intuitively, we think the latter mechanism may be happening in animals because of the independence of latency time with respect-to dose. However, in people, there is evidence of latency time variation with dosage (see reference 7). If there are indeed different mechanisms in rats and people the ratio of exposure durations computed above has no valid interpretation. Latent time considerations would dictate that the annual incidence of human cases should be 0.0-78 times the annual incidence of rat tumors. The model in Appendix B assumed a factor 0.033, so that exposure duration considerations would dictate that the rates calculated from the model should be multiplied by 2.4. * One intuitive measure of the sensitivity of a species is to compare for similar doses, the time it takes to get cancer, expressed as a fraction of total lifespan. For rats this is 80/100 = 0.8 of a lifetime irrespective of dose and for humans it is 19.6/72 = 0.27 of a lifetime. By this measure, humans are over three times more sensitive than rats. Comparison of Angiosarcoma Incidence The estimation of liver angiosarcoma incidence in workers is possible from several epidemiology studies, but unfortunately the only study in which it was possible to define the vinyl chloride exposure (reference 4) had too small a sample size to detect liver angiosarcoma cases. (Tjln this pi ant, measurements of vinyl chloride sampled in the breathing zone of the workers were begun in 1950, and continued until the see 2-0861 I t (; ; . '.; v ` ' ' ; . . D3 ; ,-v: ; : 'present... It was found that'in :an old section^'"of the pliiht^ lexpoSure f in the wet end operations averaged 120-385 ppm, over an 8 hour/day .'"'5 day/week-time period, with documented excursions up to 4000 ppm. The ' measured excursions coincided with reports of workers feeling dizzy on ' , 1 the job. In 1959, following reports of toxicological effects of vinyl.' _ ; chloride, the operations were improved,a continuous monitor was installed ... and subsequent exposuresfor the same job were reduced to 20-80 ppm with excursions of 500 ppm. In a newer-section of this plant the highest . ^ exposure job was 135-825 ppm before 1959 and 30-240 ppm thereafter. ._ ' ' - : - Since this is one of the largest companies and one of those most - - concerned with worker exposure, it is likely that these are lower than ' .'.the industry average, so that -one might assume from this that -the cases - : :of angiosarcoma occurring among workers in the last 5-10 years were, the result of past chronic exposures of 200-500 ppm.- -` . In Table 1 the incidence of angiosarcoma from several industrial studies is summarized. The Tabershaw-Gaffey study (reference 5) of records of 8384 men in the entire vinyl chloride industry classified 1817 of them in the high exposure, high duration category. Since the study encompassed 33 plants, it was not possible to define objectively, wha.t `'high" exposure was, but instead each plant classified cases high ' or low considering only its own experience. The term "high' duration" here means more than 60 months on the job. They found two angiosarcomas in the 1817 people, but from detailed studies by other investigators an additional four v/ere found to be misclassified as other diseases, so that the incidence of angiosarcoma among the high exposure, high duration workers was found to be 6/1817 = 3.3 x 10-3. The average exposure duration for this group was 15.9 years. Nicholson et. al. (reference 6) studied 255 workers employed in one plant for more than 5 years. Of these, 151 worked in direct PVC production and 3 cases of liver angiosarcoma were found in this group for an incidence of 20 X 10-3. They were exposed for 14, 17, and 23 years respectively. The exposure duration for the entire 255 workers ranged from 5 to 28 years, and most of them were exposed for more than 23 years. . - In the Heath and Falk study (reference 7) of angiosarcoma cases in the Louisville plant, 7 cases were seen among 270 people working directly in polymerization activities, for an incidence of 26 X 10-3. The mean duration of exposure (employment) was 17 years in the seven cases. The authors stated that these 270 workers represent about 20X of the plant employees. The study of 0. K. Wagoner (reference 8 ) of 745 male workers in two plants, 31 cancer deaths, 6 of them liver cancer were reported. This population of workers had been engaged in the polymerization of vinyl chloride for at least 15 years. The type of liver cancer was not . specified, so that this study can yield only an upper limit of the liver *. ' see '. ' 2-0S62 it | angiosarcoma incidence it is 1ess.,that 6/745 = 8 X 10-3 Since no break down of job categories was made in this study it is likely than many of the-745 people did not have the highest exposure tasks. _ . - In comparing the incidence in table 1, it is significant that . . studies- with the larger number ;of people have the lowest incidence and ^ the studies with the most.complete definition of worker, exposure have the highest rate. '-It-can be.concluded that the incidence among just -the most highly -exposed workers. is about 0 .02. The-incidence-numbers in Table 1 represent the number of cases - .. diagnosed before 1974 divided by population exposed before 1974. These numbers,: however, do not really represent the true incidence of the - disease because all. members of the population exposed before 1974 have not had time to develop angiosarcoma because of its 17-year average exposure duration. At least two alternative approaches are available to adjust for latency time effects. The first approach described in this paragraph assumes a fixed exposure duration and considers only the popula tion exposed earlier than this time. The second approach described in the next section considers the entire exposure duration distribution. In the first approach the incidence is expressed in terms of the population exposed before 1974-17 = 1957, which is only a fraction of the popula tion exposed before 1974. To calculate this fraction, information concerning the number of people entering the work force as a function of time from reference 5, table 2 has been used. It is found that the ratio of people whose exposure began before 1974 to the number whose exposure began before 1957 is 3.8. Therefore the population in which cases of angiosarcoma have appeared is 1/3.8 as much as the population in table 1, and,the incidence among workers is 3.8 times that given in table 1, or 0.02 X 3.8 = 0.076. This means that sometime in their lives, over 7.5% of all highly-exposed workers are expected to get liver angiosarcoma. . . The average exposure time for high duration workers reported in the industry-wide Tabershavi-Gaffey report (reference 5) is 16 years. There fore, the incidence rate, defined as the number of cases per person-year of exposure, is 0.076/16 = 0.00475 per person-year. ' Alternative Approach to Calculating Incidence Rate The difficulty with the previous approach is that a fixed exposure duration was assumed whereas the actual distribution of exposure durations is approximately normally distributed in log (duration) for the 14 reported occupationally-exposed cases. For each year, t, of exposure, n(t) person-years of exposure have occurred, and the number of cases, c(t), that have occurred before 1974 due to the exposure at time t is c(t) = n(t) p L(74-t) where p is the probability per person-year of exposure that a person .. - , . . D5 . -will get angiosarcoma sometime in his life after, being exposed: for -one~V. year; and l(74-t)i s the'probabi 1ity that the exposure occurred a 1ong ' ' .enough time aoo to'appear by 1974 if he was exposed in year t. The - ; function _L (x) is the cumulative distribution of latency times and is . ;f " equal to the probability that.the latent time is less than or equal to X years. .The total number of.cases is the sum of c(t) over all times ..from-the beginning of exposure to times-so recent that L (74-t) is ' vanishingly smal1. For. convenience we shall write n(t) as the product ... of the total number of person-years of exposure, N, and a distribution . :.v ^function , q ^ fraction of the N person-years that occurred " " in year t. With these quantities defined, the probability p can b e ' -v - calculated.from . . . - . :- .... . P = 2 1 c(t) H ^ , q ( t ) x L(74-t) .. ... ; ; (1) - . For this calculation the function q(t) was derived from table 2 of the Tabershaw study (reference 5), where the distribution of man-years of employment is presented as a function of the year in which exposure started. It is assumed that the distribution of man-years is the same for highly-exposed employees as for all 7128 workers in his study. The distribution of exposure durations for the 14 known occupational cases of liver angiosarcoma was taken from reference 2 and used for L(74-t). With these functions, the cumulative product in the denominator of equation (1) is 0.378. This is the fraction of cases which have been initiated by exposure through 1974 which have been diagnosed. . Therefore the overall effect of this more exact treatment, where the exposure duration distribution is explicitly considered, is to multiply the calculated probability by 1/0.378 * 2.65. This turns out to be not much different than the earlier approach, where the factor was 3.8. We consider the alternative approach to be conceptually more firmly based. Therefore we obtain 0.02/(17 X 0.378) = 0.0031 as the probability per year of exposure that a highly-exposed worker will get angiosarcoma some time in his life. The errors in this calculation are of two types: (a) uncertainties in the numerical estimates of parameters; and (b) con ceptual errors in the assumptions of the model. The first type can be quantified in the following way. The chronic dose experienced by highlyexposed workers is estimated to be somewhere between 200 ppm and 500 ppm. The value of 350 ppm was chosen as the mid-point of that range, so the variation could be 1 5 0 ppm, or + 43%. Although this error does not _ strictly enter into the calculation of the 0.0031 value, it does contribute to the error when this is compared with the animal data, as discussed on page D-6. The incidence of angiosarcoma in highly-exposed workers was 0.02 (table 1) and by intuition the author would guess that it should be within the range of 0.01 or 0.03, for a variation of 50%. The number of hours of daily exposure in the workers is almost certainly not as much as 8 , but may well be over 6 hours, so one may say it is 7 + 1 or 7 + 14%. If we assume that these errors are random, the error in the product of these factors is a cr* </(0.43)2 + (0.50)2 + (0.14)2 = 0.67 see 2-0864 i t I The conceptual errors in the assumptions of the model- are. not directly quantifiable. One error is that we assumed no breaks in exposure once employment began. People who left the job and returned later have contributed their man-hours of exposure more recently than we assumed, and would therefore not contribute as much to the occurrence of cases observed today. This has caused us to over-estimate the incidence. A "second error-is that, as discussed on page D-2, the distribution of latent times is biased toward shorter exposure intervals than is likely to be the actual case. The error acts in the same - direction as the first, and would cause aTfurther over-estimate of the ; incidence. . A third error is that the true biological, latent time is not . directly observable, since the process leading to irreversable disease may have been initiated some unknown time after the first year of exposure. By using the duration of total exposure, we tend to over estimate the true biological latent time. This error operates in a direction opposite to the preceding two errors. The net result of these of these three errors is unknown in direction or size. The overall conclusion is that the incidence rate .is 0.0031 per person-year of exposure with a quantifiable error due 0 uncertainties in'estimation of parameters of 67% and an additional unknown conceptual error in the precise assumptions. It is important to point out that the incidence rates calculated in this Appendix are probabilities based on the duration of exposure to vinyl chloride, rather than on the number of cases which happen to be diagnosed in a population each year. In descriptive epidemiology the latter concept-is called the incidence rate. The epidemiological incidence in the general United States population is discussed in Appendix E. _ Comparison Kith Animal Data ' At this point we are in a position to compare the human annual incidence rate (0.0031) with that predicted from the animal model in Appendix B. For continuous exposure to 350 ppm, Appendix B would predict an \ncidence rate of (0.071 X 10^) x 3.5 x 10^) = 0.0249 per person-year of exposure. If this is adjusted to occupational exposure conditions by dividing by (24 x 1 Y J x 5) = 4.8, the incidence rate for highly-exposed occupational groups is predicted to be 0.0052 per person-year of exposure. This is a factor of 1.68 higher than the human rate. Therefore all of the estimates in Appendix B should be multiplied by 1/1.68 = 0.60 to be consistent with the human data. When the error estimates are explicitly taken into account, w e `find for the aniral model, that the range encompassed by plus or minus one standard error is (0.0052 + 27%) = 0.0033 to 0.0066 and for the human data Ctt is (0.0031 + 67%) = 0.0010 to 0.0052. Therefore, within the accuracy of our procedures, the two approaches for calculating the incidence are in agreement. \ ; The rationale for comparing human incidence data with the rat " . experiments is considered more firm than the alternative approach of : :; . comparing latency times, as discussed on page 0-1 , because of the ' - 1. conceptual difficulties already pointed out.-. ; ;` . - The other effects of vinyl chloride besides liver angiosarcoma are V evaluated in the remainder of this appendix. . : " Ratio of all cancers to liver angiosarcoma - . _ ; . ~ The study of"Nicholson, et alV (reference 6 ) showed that, out of 255 workers 24 deaths were recorded, 9 of them were due to cancer, 3~of which were liver angiosarcoma. Unfortunately this study cannot be used - . to estimate the"number of non-angiosarcoma cancers caused by vinyl chloride because if the 3 angiosarcomas were not in the population, there would be 6 cancers out of 21 deaths, which is not different than one would expect in the general population. Reference 15, p. 2 indicates that of all deaths in the general population, 1/5 of them are due to cancer. . In the Tabershaw study of mortality in the VC-PVC industry (reference 5) the cancer mortality of the high exposure group is only slightly higher than the overall cancer mortality for*the entire group. Although this slight excess could be due to vinyl chloride exposure, . it is not enough to enable one to estimate how many cancers of all sites are induced relative to liver angiosarcoma. Studies by Ott, et al. (reference 4) and Wagoner (reference 8) have shown statistically significant excesses in mortality from many primary cancer_sites, including brain, respiratory system, and lymphomas. However, angiosarcomas were not observed, so that the ratios of . total/angiosarccma incidence cannot be estimated from these studies. In a proportional mortality study of 161 workers in the Louisvi-lle plant, Monson, et. a l . (reference 16) found a larger rate of cancers than expected for U. S- white males at the following sites: digestive tract (excluding liver), liver and biliary tract, lung and brain. They found 41 deaths due to all cancers Compared with 27.9 expected) for an excess of 13 cases. In the same population there were 5 deaths due to liver angiosarcoma (compared with a vanishingly small number expected). Therefore the total number of cancer deaths is 13/5 = 2.6 times the number of liver angiosarcoma deaths. One cannot be absolutely sure that all of the cancers in this population are due to exposure to vinyl chloride, but in view of the other studies cited above, it can be said that vinvl chloride is a strong risk factor in the development ot otner* ^anrpr*_in the rat experiments of Mai torn*, a total of 76 animals had Zymbal gland carcinomas and liver angiosarcoma combined, compared with 47 with liver angiosarcoma, for a ratio of total cancer/liver angiosarcoma of 1.62. V/hen all tumors were considered in the Appendix B, the ratio was 32,0. Therefore, both the human and animal data show that vinyl chloride induces about twice as many total number of cancers as liver cr ` angiosarcomas alone. . . : t . ` . scu 2-0866 'v-:\. e . : ; : :0 8 ; . _ . . " Frequency of ^on-Cancer Effects Relative to Liver Angiosarcoma. ...... > ' ' . ; i In a. literature review of 12,724 vinyl chloride workers; in the. ^ i -United States and Europe (reference 12) Marsteller, et al. found 118 - .^ cases of acroosteolysis (a gradual erosion of bone at the fingertips), 9 7 people with symptoms of Raynaud's syndrome (cold hands and feet), '' 40; people, with skin legions,-and 73 with liver, disturbances. We might: assume that,,of these 328 cases of reported symptoms, 207: of the people ' :vvi K ;^had^/-symptoms^each and the other 80%. had one each, so that the total. ' ."number o f 'people reporting'symptoms in 328/1 .2 = 273 people. This ~ .. .. ' incidence;of overt symptoms .(273/12,724 = 21 X 10-^) is to be compared ... with the incidence of angiosarcoma in a similar large worker population- ` - such as is seen in reference 5, Table 1, which is 3.3 X 10~3.- The ratio is 7 people with symptoms for every liver angiosarcoma case. ! -j .j . ; 1! -i i .-- I 1 i |j -; In detailed clinical observations of 50 highly exposed people currently working in plants, Marsteller (reference 12) finds that only one had a history of liver disease and 8 had experienced Raynaud's " syndrome. Despite this lack of overt symptoms, he found that 38 of the 50 had pathologically high BSP retention times (a measure of serious cellular liver damage), 31 had marked liver enlargement, which could be palpated, and 42 had abnormally low blood platelet counts.. Therefore for every person with clinical symptoms of vinyl chloride exposure there is expected to be 38/9 = 4.2 people with liver malfunction serious enough to cause abnormal BSP retention times. This brings the ratio of serious liver malfunction to angiosarcoma to 4.2 X 7 = 30. i ! ' - The frequencies of abnormal BSP measurements and low platelet counts seen by.Veltman (reference 13) in 70 vinyl chloride workers are almost identical to those found by Marsteller, but Veltman found only half the frequency of Reynaud's syndrome. In a liver function screening program among 1183 workers at Louisville, Creech and. Makk (reference 14) used a large battery of blood chemistry tests of liver function followed by more elaborate diagnosis of people who were abnormal in the initial screen. In this series of tests, 59 people were found to have liver function ^ abnormalities; 17 of them major abnormalities which required biopsies and other elaborate tests. The plant physicians considered the 59 cases abnormal enough to justify moving the people to work areas where there were no hepatic toxins. Of the 17 serious cases, 2 turned out to be liver angiosarcoma. Therefore from this study, the ratio of definitive liver toxicity to liver angiosarcoma cases is 59/2 = 30, a ratio which agrees with the literature survey of Marsteller, et al. (reference 12). . . see 2-0867 i-i .f'Vv: & TABLE 1 - LIVER ANGIOSARCOMA INCIDENCE AMONG HIGHLY EXPOSED WORKERS Reference 5 6 7 8 Number of Angiosarcoma Cases 6 3 7 <6 Number of People Surveyed : 1,817 151 270 745 Incidence (X 10~^) ;3.3 ;m f- ' '(1. : lX s \ : ;;i '' ; f*i . *, i " wp 1 :: ii Mpr :ii8 1 a .VlSV' ... mm- :'-V;n'ii la't-eiMi*'-ivi'i' -dV O f O .a. /:$$$ '.a-: ;-a' ','a,%'i'"Sa 'Vil-V-O ut see 0868 REFERENCES FOR APPENDIX D I. ' "Statistical Abstract of the United States," U. .S. Department of ' Commerce, Bureau of Census (1974). T ; 2. "Scientific and Technical Assessment Report on Vinyl Chloride and Polyvinyl; Chloride," EPA/ORD report, p. .143-145,'Oune .1975. r - -3. -- "Annual Report of U. S. Vinyl Chloride Production," P. Tarasoff^ EPA Memo July 15, 1975. ... .4. "Vinyl Chloride Exposure in a Controlled Industrial Environment," M. 6 . Ott, et al, Arch. Environ. Health 3 333-339 (1975) 5. "Mortality Study of Workers in the Manufacture of Vinyl Chloride and its Polymers," I. R. Tabershaw and W. R. Gaffey, J. Occupational Medicine 15 509-518 (1974). 6 . "Mortality Experience of a Cohort of Vinyl Ch1orie--Polyvinyl ` Chloride Workers," W. J. Nicholson, E. C. Hammond, H. Seidman, I. J. Selikoff, Ann. N. Y. Acad. Sciences, 246 225-230 (1975). 7. "Characteristics of Cases of Angiosarcoma of the Liver among Vinyl Chloride Workers in the United States," C. W. Heath, Or. and H. Falk, Ann. N. Y. Acad. Sciences 246 231-236 (1975). 8 . J. K. Wagoner, testimony at Senate Subcommittee on Environment, Commerce Committee, 93 Congress, 2nd Session; Aug. 21, 1974, Serial No. 93-110 p. 59. 9. "Third National Car.cer Survey: Incidence Data," National Cancer Institute Monograph 41 (March 1975). 10. "Carcinogenicity Bioassays of Vinyl Chloride: Current Results," C. Maltoni and G. Lefimine, Ann. N. Y. Acad. Sciences 246 195-218 (1975). II. "The Correlation of Clinical and Environmental Measurements for Workers Exposed to Vinyl Chloride," C. G. Kramer and 0. E. Mutchler, Amer. Industrial Hygiene Assoc. Jour. 33 19-30 (1971). 12. "Unusual Splenomegalic Liver Disease as Evidenced by Peritoneoscopy and Guided Liver Biopsy among Polyvinyl Chloride Production Workers," H. J. Marsteller, W. K. Lelbach, R. Muller, P. Gedigk, ( Ann. N. Y. Acad. Sci. 246 95-134 (1975). 't * sec 2-0869 { 2 13. "Clinical Manifestations and Course of Vinyl Chloride Disease," 6 . Veltman; E. E. Lange, S. Juhe.G. Stein, and U./Bachner, Ann. ... ... - N. Y. Acad. Sci 246 6-17. (1975). - :^ . 14. "Liver Disease Among Polyvinyl Chloride Production Workers," - .v - . J. L. Creech, Jr., and L. Makk, Ann. N. Y. Acad. Sciences . ; ; 246 88-9441975) r ' ^ ; : - ' .............. / . ' 15. "Cancer Rates and Risks," 6 . L. Levin, et al., U. S. Department of Health, Education and Welfare, 2nd Edition, 1975. - . ^ t 1 ti-* see 0870 Appendix E Is Residence Near Vinyl Chloride Plants a Risk Factor . In Frequency Of Deaths Due To Liver Angiosarcoma? - V '' ' I. Introduction *<-r j : *-- . 1 ' ... .. ..... ' - Abundant evidence exists that vinyl chloride is one of the chief ... causative factors for the high frequency of liver angiosarcoma among > : highly-exposed workers in the vinyl chloride-polyvinyl chloride industry ---In proposing to regulate air emissions around these plants on the basis of health hazards to people living near factories, it is important to look for evidence that this disease occurs more frequently among people living near plants than those living at random places in the United States. Accordingly an investigation was made of the place of residence, relative to the vinyl chloride and polyvinyl chloride plants which are covered by the proposed regulation, of the people who thus far are known to have contacted liver angiosarcoma. .II.- Sources of Data A. Plants and Locations . . ...... The list of plants and their addresses which was used in the investigation is shown in Table I. It was compiled from the APHA report (reference 1) and the EPA Air Programs Office document (reference 2). -*This list includes some plants that are no longer in operation and at least one plant which is reported (by APHA) to involve no current work with vinyl chloride. Some of the plants make co-polymers with vinyl chloride and other monomers. The list is believed to include all plants in the contiguous states which make vinyl chloride monomer or polyvinyl chloride resin. The fact that it contains extra plants does not detract from this study; in fact it might be desirable to expand the investigation to all plants known to fabricate plastics if it were not for difficulty that such an expansion would excessively broaden the list of chemicals which could be implicated as causal agents.* In several cases street addresses of the plants are not available. In these cases it was assumed that the plant was somewhere within the city limits of the postal address (for large cities) or was exactly at the center of town (for small towns or suburbs with no definite boundaries). B. Liver Angiosarcoma Cases . . i. n- * In September 1974, Dr. Henry Falk of the Cancer and Birth Defects Sectwn, Center for Disease Control (CDC) initiated an extensive case finding national survey of all liver angiosarcomas which have been ' sec 2~0Q71 I I I / \ E-2 . diagnosed between -1964 and 1974. He obtained the information from three sources : (1) A systematic examination of death certificates filed at the National Center for.Health Statistics, Research Triangle Park,.N. C. - - Copies of death certificates viere obtained for those deaths where the . diagnosis vas similar to, or could easily be confused with, liver angio sarcoma. Death certificates always give date and place of death, age, sex and race, date (and frequently place) of birth, residence and occupation at time of death, occasionally the time lived at the residence, the _ immediate and underlaying cause of death and a statement of whether an * -autopsy was performed. : .; " .. . (2) Case records on file with the Armed Forces Institute of Pathology. These included cases diagnosed at military hospitals. Usually residence and occupational information were not provided, and for the most part only age, sex, hospital location, autopsy number and a minimum amount of clinical information were available from this source. . (3) Response to requests for information originally sent out by Dr. Falk to state public health departments and hospital pathologists throughout the nation. Typically a letter from a state official would list cases on record and Dr. Falk would send letters to the pathologists identified by the state requesting further information and permission to contact physicians and patients. This process invariably results in complete clinical histories of the patients, (dates of hospital admission, description of methods of diagnosis, detailed surgical and autopsy reports) but rarely includes more than a bare minimum of personal information such as residence and occupation. Currently Dr. John Herbert at CDC is continuing the investigation by interviewing next of kin and physicians in order to get residence, occupational and medical histories, family members with cancer, possible exposure to other chemicals through home hobbies, drinking and smoking histories and any other personal information which could indicate causal connection with the disease. As of early October, Dr. Herbert has followed up about 20 cases in this way. In order to confirm the initial diagnosis of liver angiosarcoma, Dr. Louis B. Thomas, Director, Pathology Laboratory, National Cancer Institute has agreed to examine the sections of tissue which CDC obtained from the hospitals. This confirmation is regarded to be absolutely essential, especially when attempting to draw conclusions from a small number of cases. The information currently on hand is far from complete. As of early October 1975, a large backlog of slides was awaiting confirma tion at the NCI and over 90% of the cases have not yet been followed up by C^C. C? * 1 see 2-0872 III. Procedures of-this Study : With the cooperation of Dr. Herbert, the author, assisted by Or. Kenneth Cantor, v/ent to CDC arid extracted the available information ' on liver angiosarcoma cases. The form shown on Attachment A was filled out to the extent possible for each case in the files. To maintain confidentiality of personal information,"the names of the deceased were not copied from CDC records. Instead the cases are identified in our . files by state and initial letters of the name. A total of 286 cases were identified. Out of this total the cases' with information on place of residence at time of death were selected; . this group was further examined and cases with known or suspected exposure to arsenicals or thorotrast and cases f known occupational . exposure to plastics fabrication and VC-PVC favrications were eliminated. A subsample of the entire group of 286 cases was analyzed for age and sex distribution and tested on a state-wide basis for clustering to a greater degree than expected on the basis of population concentration. Following the case selection procedure, the place of residence of all selected cases was identified using maps and atlases of various scales. ,,' The initial survey of residences was done by locating cities and towns in an encyclopaedia atlas (reference 3). This was found to be adequate to locate residences to within 10 miles from plant locations. In cases that were suspected to be within 10 miles of the plant, indexed street maps were consulted at the Geography and Map Division, Library of Congress, Alexandria, Virginia. The plant locations had been identified on a series of U.S. Geoloaical Survey topological maps (scale of 1: 250,000, or 10 statute miles = 6.4 cm) by Teknekron, Inc. under contract with EPA's Office of Planning and Evaluation. These plant locations were verified by detailed street maps at the Library of Congress, for those plants where residence of cases *as less than 10 miles from the plants. IV. Results of the Survey: Of the 286 case records obtained from CDC, all cases from the states alphabetically from A through M (a total of 166 cases where age and sex is known) were analyzed for age distribution and sex ratio and a test of gross clustering was performed. Such analysis for the entire population of 286 cases will be performed at a later time. It was found that of the 166 cases, 119 were males and 47 females, for a sex ratio of 2.5 males/1 female. The age distribution for females is approximately constant for all ages. It is more variable for males, but there are not obvious bimodalities. When the male/female sex ratio is examined at a function of age, it isfound that for all cases less than age 44, the ratio is about 1.0 (27 males/20 females), but for ages above 45 it is larger than a factor of three. An test was performed to test the hypothesis that the number of . cases in each state is proportional to the 1970 population of the state. . .IT the data should disprove the hypothesis, we would .have evidence of large-scale (state-wide) clustering of cases which cannot be explained -by population concentrations. The results were that (for the states A through M) was no larger than chance variation would predict, so that . there is no evidence of clustering on a state-wide scale. - .' '` Of the ,286 case ..records obtained from CDC, 176 cases remained after elimination.of those with no residence-information and possible .thora trast, arsenical, and occupational VC exposures. The rejected cases ^ included 12 possible thoratrast exposures, two possible arsenical exposures, one person exposed occupationally to plastics, and six cases from Alaska and Hawaii. After locating the residence cities and towns of the 176 cases using an United States Atlas, there were only a handful of cases close enough to the plants to justify searching the detailed maps at the Library of Congress. Cases of distances larger than 20 miles from the plant were only rarely recorded, and to date a complete tabulation of number of people versus distance in the range of 5 to 20 miles of all plants has not been made. However, for distances lessjthan five miles, there were only six cases, as shown in Table II. Case number 1 of Louisville, Kentucky appears on this list through a clerical error because by mistake his work address was traced and found to be less than 5 miles from the plant, whereas the home address is the subject of this study. This accident does cause one to speculate whether a systematic investigation of employees working near vinyl chloride plants would reveal some larger than expected rates of angiosarcoma. It also emphasizes the importance of locating place of occupation in the case of follow-up. Cases 2 and 4 must be eliminated as candidates for vinyl chloride induced liver angiosarcoma caused by living close to factories. Case 2 . .moved from Egypt to Jersey City just two years before his death. Cases 5 V| and 5 turned out to.be other types of cancer, according to NCI path ologists. A . lt is still possible that Cases 1, 3, 5 and 6 can be attributed to A residence near vinyl chloride plants, but we will not know until NCI confirms or denies the diagnosis, and until there is more complete ' follow-up of the residence history of Case 6 . . . i . ~ Case 6 is a special situation because he was an infant who died at 5 months of age from a liver cancer which is relatively common among infants. This case must be eliminated from the formal study because it is not a liver angiosarcoma. It could have been caused by vinyl chloride, but we have no knowledge of any facts about the parents except residence at thF time of their son's death. Since transplacental carcinogenesis has been observed in animal studies, it is possible that Case 5 is a case of cancer caused by residence close to a vinyl chloride plant. see . _ '->-007a ti i t : : "il. V " V-'- . -----.-~ - - 4^'^:/ ^V .^'VttsVr*'f' :Vrr--*-~~y^.h*1.-v^2;.*^-? -y**?; E-5 ,-, V . Discussion of Results . - Liver angiosarcoma is an extremely rare disease among the United States population. According to data in the Third National Cancer Survey (reference 4) the incidence rate averaged over the nation is 0.0128 per 100,000 population per year. At this rate, the expected yearly incidence in the United States population (203 million people) is 26 per year, and - - . . the. expected incidence among the 4,580,000 people living within 5 miles . of the plants listed in Table I is 0.59 cases per year. Therefore for the 10 year collection of cases in the-CDC files we would expect 5.9 . . cases .to occur within .5 miles of all plants if the presence of the vinyl chloride plant contributed no risk factor pre-disposing people to the disease. ' ' The number of cases in our s>1tudy, 286, is close to the expected year total of 260, and the 3 poss>iibbllte anr__p_n_s_a_r_r_n_m_a_ r a ^ < within fivft miles of vinyl chloride plants wdujd proDaoiy match well with the 5.9 cases expected if we could get residence information and trace addresses for the cases in which we have no information. Since we could only trace 176 of the 286 cases, the approximate number of cases close to the plant would total 3 X (286/176) * 4.9 if all were traced. Fo> these reasons our files probably contain most of the cases actually recorded in these ten years. The high male/female sex ratio and the striking manner in which it increases above age 45 are indications that this is an occupationally- exposed population, and there may be other factors in addition to vinyl chloride. ; This survey has produced no evidence that living around vinyl chloride plants is a risk factor in the occurence of liver angiosarcoma. This conclusion is far different than saying that living around plants is not a risk factor fo.r several reasons: 1) this type of survey of' a disease with a latent time from first exposure to diagnosis of 17 years reflects exposures that started at some time before 1957, when the quantities of vinyl chloride produced were much smaller than the current production levels. 2) This survey did not include the place of occupation of the currently-suspected collection of liver angiosarcoma cases. There fore it underestimates the risk of being near a vinyl chloride plant. 3) This survey might not have detected all existing liver angiosarcoma cases, although the number we have is consistent with the national statistics. The circumstantial evidence for this is that there was not substantial overlap between the three sources of case information. If the data sources had been complete, the information collected by COC from the National Center for Health Statistics would contain all the cases . i " f JC . * see 2-0875 reported by both the. Armed Forces Institute of Pathology and the state . health departments. 4) In over 90%;of the cases traced in this survey, the only information available Was the residence at the time of death, and in some cases, the residrice of'the spouse or'parent only. This ' information is only a crude indication of where the .individuals spent. .. most of their lives. 5) In contrast with our expectation when the survey was started, there is a significant rate of changes in diagnosis after the slides were confirmed by the National Cancer Institute. The 286 cases currently on file cannot be regarded as definitely-established liver angiosarcomas. In view of these limitations of the survey, positive statements cannot be made about residence near plants being or not being a risk factor. The only interpretation of these results that is justified is that a search was made of the residence information which exists and this search revealed no evidence that residence near plants us a risk factor. In view of the long 17-year latent time it is expected that any survey of current cases would underestimate the actual risk. --- Tabie-4:.VList of VC-PVC.Plants and their.-Locations . Company .' . :- - ' - : Type VC/PVC): Location ' ;, 1. Air Products and Chemicals, Inc. PVC . . Pace, Florida I. 2 . Air Products and Chemicals, Inc. PVC - Highway 95 Calvert City, Ky. . .^ 3. Allied Chemica1 Corp. ; '' near River Mile 2355 ' Gulf State Road - - Baton Rouge, La. ' 4. Allied Chemical Corp. 7 VC . . Geismar, La. 5. American Chemical Corp. V C , PVC Long Beach, Calif.* 6. Atlantic Tubing & Rubber PVC Cranston, R.I.* 7. AST Wyandotte 500 Central Ave. S^ Kearney, N. J. 8 . Borden, Inc. 9. Borden, Inc. 0. Borden, Inc. Geismar, La. Bainbridge, N.Y.* _ Compton, Calif.* 11. Borden, Inc. ' 12. Bofden, Inc. 13. Borden, Inc. 14. Borden, Inc. Demopolis, Ala.* PVC Illiopolis, 111. PVC Leominster, Mass.* near 59th & Interspace St Oklahoma City, Okla. - 15. Continental Oil Co. 16. Continental Oil Co. Lake Charles, La. VC Old Spanish Trail Westlake, La. 17. Continental Oil Co. 18. Diamond Shamrock Corp. PVC PVC Aberdeen, Miss. . River Road Delaware City, Dela. 19. Diamond Shamrock Corp. i VC, PVC La Porte Highway Deer Park, Texas . see 2- 0S77 .^ . ', --.-lO;- " :V V - \t . . . ...-.- . .. Table I - P. 2 '" 0(npany- - : ; - - .- - Type (VC/PVC) ' Location - : ' ^; 20. Diamond Shamrock Corp. 21. Dow Chemical Co. 22. Dow Chemical Col , 23. Dow Chemical Co. .,,.. 24. Dow Chemical Co. 25. Ethyl Corp. VC vc vc PVC VC, PVC * Plaquemine, La.* ' Freeport, Tex. ' .. Oyster Creek, Tex.* PI aquemine, La.. , . ; Midland, Mich. - Gulf State Road Baton Rouge, La. . 25. Ethyl Corp. 27. Firestone Tire & Rubber Co. . vc PVC Deer Park, Tex. Firestone Blvd. Pottstown, Pa. 28. Firestone Tire & Rubber Co. 29. Foster Grant Co. PVC 30. General Tire Co. 31. B. F. Goodrich Co. PVC . PVC Perryville, Md. w 389 N. Main Street Leominster, Mass. Ashtabula, Ohio Walker & Moore Road Avon Lake, Ohio i 32. B. F. Goodrich Co. PVC 2104 E. 23rd Street Carson City, Calif. 33. B. F. Goodrich Co. ^ PVC 41st Street & Bells Lane Louisville, Ky. 34. B. F. Goodrich Co. 188 Presidio Place Williamsville, N. Y. : 35. B. F. Goodrich Co. vc near River Mile 17 Tennessee River Calvert City, Ky. 36. B. F. Goodrich Co. ' 37. B. F. Goodrich Co. 38. Goodyear Tire' & Rubber Co. vc PVC PVC Henry, 111. ; Pedrickstown, N. J. Plaquemine, La. ct:* scc 2-0878 ; : .*1* 7T & i K '\ .. *">*.-.*V-`*<->*< .* - \ .*:'< : ,4^ ^ ^ .-%<- ^ - ^ **^..7 *v ,* i r r * ^ ' *J *;>*"Jic""-*TviirV?1'3 ?v*.5 * Table T - P. 3 Compa n y x 4 ^ A.wv-35.t-v?*-L;%.-:-v.---; Type (VC/PVC) T- r-Location r - 39. Goodyear Tire & Rubber Co. i;] ;' 5408 Baker Avenue . Niagara Falls, N. Y .* 40. W. R. Grace & Co. .Owensboro, Ky.* .. ... 41. W. R. Grace & Co. South Acton, Mass.* 42. Great American "Chemical Corp. PVC:V:;l i::. '.rSit'TitchburgMass.* "" 43. Keysor-Century Corp. PVC 2600 Springbrook Avenue Saugus, Calif. 44. Monochem, Inc. ` VC Geismer, La.* 45. Monsanto Co. PVC 730 Worchester Street Indian Orchard, Mass. 46. Monsanto Co. . Texas City, Tex. 47. Morton Norwich Co. Ringwood, 111.* 43. National Starch & Chemical Co rp. PVC Meredosia, 111.* 49. Occidental Petroleum Corp. PVC River Road Burlington, N. Y. 50. Occidental Petroli urn Corp. (Hooker Chemical) PVC New South Road Hicksville, N. Y. 51. Olin Corporation PVC 238 S. Main St. Assonet, Mass.* 52. Pantasote Co. . PVC 26 Jefferson Street Passiac, N. J. 53. Pantasote Co. PVC 54. Pittsburgh Plate Glass VC Industries, Inc. 55. Robintech, Inc. PVC Point Pleasant, W. Va.* Columbia Southern Road Lake Charles, La. 786 Hardy Road Painsville, Ohio 56. Shell Oil Co. VC State Highway 225 Deer Park, Tex. 57. SK811 Oil Co. VC Norco, La.* SCC 0879 Table 1 - P. 4 Company .... ..Type (VC/PVC) , Location 58. Schintech . \ ' :; PVC Freeport, Tex.* 59. SCM Corp, (Huron Plastics) Huron, Ohio 60. Stauffer Chemical Co. . 2112 E. 223rd Street Carson City, Calif. 61. Stauffer Chemical Co. . - PVC . : 62. Stauffer Chemical Co. Delaware City, Del.* School House Road Burlington, N. J.' 63. Tenneco Chemicals* Inc. 64. Tenneco Chemicals, Inc. 65. Tenneco Chemicals, Inc. 66. Tenneco Chemicals, Inc. 67. Union Carbide Co. PVC PVC VC . VC PVC Beverly Road Burlington, N. J. Flemington, N. 0.* Painesville, Ohio 4403 La Porte Road Pasadena, Tex. ' 4337 McCorkle, South Charleston, VI. 68. Union Carbide Co. 69. Union Carbide Co. 70. Union Carbide Co. ; 71. Uni royal Inc. 72. Vulcan Materials Co. 73. Vulcan. Materials Co. PVC . Highway 146 & Texas Avenue ............. Texas City, Texas / ' Taft, La. Reported Closed . Niagara Falls, N. Y.* PVC J 720 Fairport Nursery Road Painesville, Ohio Geismar, La. . VC Deer Park, Texas* *location not included in APHA estimate of total population.- i see 2-0890 Age (at autopsy): Age at Death: _____________ _ _ Date of Diagnosis: _ _ _____________ Age Diagnosis: ________ Residence at Time of Death: _____________________ _____________ ;_____ Occupation at Time of Death: ______________________ _______________ -- Family: Married: Yes /__ / No /__ / . Children: Number: _________ Ages at Death: Pathology Reviews: Specimens Received: 'Yes /___/ No /___ / Unavailable / / Specimens Reviewed: Yes /___/ No /___ / / NIH. Report: _ _ _ ----------_--------------- ----- -------------------- AFIP Feport: _________ * ____________ ' --- ---- ------------------- CDS Report: _________ _ ______________ -- _____ _________________ -- -- Followed up by CDC: Yes /__ / ft - * No /__ / ` t see 2 --08 81 SCC -osa Table II Case Summary Case Identification 1. JLK, Louisville Kentucky Distance from Plant ' Horae: 6.7 mi. SSW of B. F. Goodrich Work: 4.3 m i . ESE of B. F. Goodrich Time in Area 32-1/2 years 2. IN, Jersey City, New Jersey ' Home: 2.0-2.4 mi. SE of BAST Wyandotte 2 years 3. HCM, Buffalo ' Home: Age_ Distance 68 years 0-20 7-9.2 mi SW of B.F. Goodrich ... . 20-40 2.6-4.4 mi WSW of B.F Goodrich 40-58 8-9.5 mi. SSW of B.F Goodrich 4. CF, Niagara Falls . 58-68 3.8-5.2 mi SW of B.F. Goodrich Home: 0.25 to 1.1 ml. SSE of Goodyear f. 30 years 5. GB, Niagara Falls Home: 0.25 to 1.0 mi. NNW of Goodyear 5 months 6. RJ, Niagara Falls Home: 2.1-2-2.3 mi. W of Goodyear Age at Oeath ' ;* 33 . ; NCI .: 1r Confirmation.: . ,` - 1 ` .i 1 ' - h1 .N ; : 41 '' 68 : ^ No . - , ' 7 Y. No j\ 63 : ; . 5 mo. 41 - Yes, not anglosarcoma Yes, not angiosarcoma : No Appendix E References ^ _ 1. Landau, E., ."Population Residing Near Plants Producing Polyvinyl Chloride," American Public Health Association, Contract report* - EPA/OTS (August 1975). - . ... . . . ' 2. EPA, OAQPS, Emission Standards and Engineering Division, r "Standard Support-Environmental Impact Statement, Voi. II (draft)." April 1975. .: ` 3. Encyclopaedia Britannica, "Britannica Junior, Voi. 15" (1959). ' 4. National Cancer Institute Monograph 41, "Third,National Cancer " Survey: " Incidence Data," March 1975; :. .. > -- .. .^ fit see 2-0884