Document VjjzpmNakJ163g2Nrr1b40r8Z

CM|Z& CHEMICAL MANUFACTURERS ASSOCIATION "1 October 29, 1993 v4^Dear Vinyl Chloride Research Coordinator Members: The following documents are enclosed in preparation for the November 5, 1993 meeting: 1. Agenda for the November 5 meeting. The meeting will be held at the CMA offices in Washington, D.C., beginning at 10:30 a.m.; 2. 1986 Final Report: An Update of An Epidemiologic Study of Vinyl Chloride Workers, 1942-1982; 3. 1989 Reassessment of Liver Cancer Among Vinyl Chloride Workers; 4. 1991 An Industry-Wide Epidemiologic Study of Vinyl Chloride Workers, 1942-1982; 5. 1993 Letter to the Editor, Diagnostic Bias in Occupational Epidemiologic Studies (H. Shah); and, 6. 1993 Response to Letter to the Editor, Diagnostic Bias in " ' Occupational Epidemiologic Studies: An Example Based on the Vinyl Chloride Literature (0. Wong). Items 2 to 6, although previously sent to you, are provided for your ready reference. If you have any questions or need additional information, please call me at (202) 887-1192. Sincerely, Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel R&S 150438 2501 M Street, NW, Washington, DC 20037 TeleDhone 202-887-1100 Fax 202-887-1237 Responsible Care" j A Public Commitment ird H, Reitz, McLaren/Hart a (17)631-7039 BE 3/23/94 <510:39 AM 32/2 SEMINAR TOPIC *1 Predicting Cancer Risk from Vinyl Chloride Exposure with a Physiologically-Based Pharmacokinetic Model. ' Ricnard H. Reitz McLaren/Hart, ChemKisk Division Physiologically-based phanrdcokinoilc (PB -PK) models have been proposed as tools for facilitating the extrapolation of animal cancer tests to humans. For instance, several of us (Reitz, Andersen, Gargas, Clewell) developed a risk assessment for methylene chloride which used PB -PK modeling to extrapolate between species, across different routes of exposure, and from high dose to low dose. This risk assessment predicted considerably less risk to humans than earlier procedures, and the PB -PK risk assessment was consistent with epidemiology studies for methylene chloride (which are generally accepted as negative). Because the epidemiology studies for methylene chloride are negative (as the PB -PK model predicted they would be), they do not provide an opportunity for comparing cancer rates in humans with predictions derived from the PB -PK model. However, there is one industrial compound (vinyl chloride, VC) which has been shown to produce measurable increases in thfe incidence of liver angiosarcoma in both rats and humans. In order to determine whether risk assessments based on PB -PK adjustments of dose adjustments are too conservative, not conservative enough, or about right, we have developed a PB -PK model for VC and predicted the risk to humans based on rat studies. The VC model for rats and humans was developed from several In vivo and in vitro data sets. Both the rat aild human models were then validated with independent studies oi VC metabolism in the appropriate species (i.e. the validation studies were not used in development of the model itself). Then PB -PK model was combined with the multista'ge model of Crump & Howe (GLOBALS3) to predict the incidence of liver angiosacroma produced in humans. The human studies included more than 12,000 workers exposed to VC occupationally over a period of several decades. The risk assessment based on the PB -PK model predicted considerably less risk than would be calculated by default (nonpharmacokinettc) procedures. However, the incidence of angiosarcoma acruailv observed in human subjects was still considerably lower than predicted by the PB -PK/multistage model, suggesting that if the results obtained with VC are typical, risk assessments combining PB -PK and multistage modeling likely overpredict, rather than underpredict, human risk. R&S150439 tv n Vk.^ CHEMICAL MANUFACTURERS ASSOCIATION X> Vinyl Chloride Panel 1/ y Research Coordinators DATE: TIME: PLACE: Tentative Agenda November 5, 1993 10:30 a.m. - 1:30 p.m- CMA Offices 2501 M Street, NW Washington, D.C. iM "2^ J ) iJ^ y <ryr +a l LvVl f n^V'-'VK 1.0 Review of Objective of the Meeting ' V5 ^2.0 Discussion of Panel Activities Since the 1986 EHA RepoVrt^ tZs ^ " J* 3.0 Discussion of Scientific Merits of Updating the 1986 Study ) far z*' 4.0 Difficulties That May be Encountered in Updating the Studyj Including Impact of Changes in Business Ownerships / 5.0 Discussion of Future Course of Action ' &J J\(PO r y>, ----- xzHasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel- Subject to Approval October 25, 1993 luM ^ * Atf 3SC3O* Ooi o American Journal of Industrial Medicine 24:249-250 (1993) LETTER TO THE EDITOR Diagnostic Bias in Occupational Epidemiologic Studies Key words: vinyl chloride exposures, mortality study, emphysema, brain cancer The study of vinyl chloride workers by Wong et al. [1991] is an important contribution to our knowledge of the health of people occupationally exposed to tins substance. However, the discussion of findings with respect to two causes of Heath does not include some results that affect their evaluation. One is the apparent excess of brain cancer. There is a good deal of data in the literature showing that diagnostic bias is important when one tries to attribute death to brain cancer [Greenwald et al., 1981; Helseth et al., 1988; Kurland et al., 1982]. In particular, Greenwald et al. [1981] have shown that an excess of brain cancer in Kodak employees was associated with more thorough diagnostic studies and access to comprehensive medical care, rather than with chemical exposure history. The study by Wong et al. [1991] does not discuss diagnostic bias as a possible explanation of special importance, all the more so since there is no firm confirmation of this finding in other studies [Doll, 1988]. The second finding, the significance of which is affected by other factors, is the excess in emphysema mortality. This is a finding with an inverse dose-response relationship based on duration of employment and an ambiguous relationship with latency, accompanied by a complementary deficit of an almost equal magnitude~for deaths due to other nonmalignant respiratory diseases (which can be confused with emphysema). In 1988, Sir Richard Doll dismissed this excess emphysema mortality as not being an effect of vinyl chloride exposure because of such inconsistencies. Readers who do not know the literature would not be able to put those findings from the Wong et al. [1991] study in perspective without this kind of information. Hasmukh C. Shah, PhD Chemical Manufacturers Association Washington, DC Address reprint requests to Dr. H.C. Shah, Manager, Vinyl Chloride Panel. Chemical Manufacturers Association. 2501 M Street, NW, Washington, DC, 20037. Accepted for publication December 15, 1992. 1993 Wiley-Liss, Inc. R&S150441 250 Shah REFERENCES Doll R (1988): Effects of exposure to vinyl chloride. An assessment of the evidence. Scand J Work Environ Health 14:61-78. Greenwald P, Friedlander BR, Lawrence CE (1981): Diagnostic sensitivity bias--An epidemiologic explanation for an apparent brain tumor excess. J Occup Med 10:690-694. Helseth A, Langmaik F. Mork S (1988): Neoplasms of the central nervous system in Norway. II. Descriptive epidemiology of intracranial neoplasms 1955-1984. APM1S 96:1066-1074. Kurland, L. Schoenberg BS, Annegers JF, Okazaki H, Molgaard CA (1982): The incidence of primary intracranial neoplasms in Rochester, Minnesota, 1935-1977. Ann NY Acad Sci 381:6-16. Wong O, Whorton MD. Follart DE, Ragland D (1991): An industry-wide epidemiologic study of vinyl chloride workers. 1942-1981. Am J Ind Med 20:317-334. R&S150442 ANTITRUST CHECKLIST FOR CMA MEETINGS This antitrust checklist is for use by CMA staff and member representatives in the conduct of CMAsponsored meetings, ftohibitcd discussion topics Apply equally to social gatherings incidental to CMA sponsored meetings. The Checklist is not ex haustive and does not address antitrust issues relating to activities other than CMA meetings. Participants in CMA meetings alsc should be thoroughly familiar with: (1) "Antitrust Guide for CMA Committee Members;" and, (2) "General Principles AppUca ble to the Structure and Operations of Committees." Both of these documents may be found in the CMA Directory. DO Ensure stria performance in areas of: OVERSIGHT/SUPERVISION: Have a CMA staff representative at each CMA-sponsored meet ing (unless an exception has been authorized by the appro priate CMA vice-president); consult with an attorney ofthe CMA Office ofGenera/ Counsel on ail antitrust questions relating to CMA-sponsored meet ings; Unit meeting discussions to agenda topics (unless additional epics have been approved by the appropriate CMA aaff rep resentative). and provide each member company representative and CMA naff representative attending a CMA sponsored meeting with a copy of this checklist, and have a copy available for reference at aO CMA sponsored meetings. RECORDKEEPING: Have in agenda and minutes which accurately reflect the mat ters which occur: \ provide agendas and minutes to the CMA Office of General Counsel for review and approval in advance of distribution, and. fuDy describe the purposes and authorities of all task groups, work groups, ad hoc or other standing committee subgroups in the minutes of the appropriate parent committee. VIGILANCE: Protest against any discussion or meeting activities which ap pear to violate this checklist: disassociate yourself from any such discussion or activities and leave any meeting in which they continue Revised 3'80 (single page versionJ i /ftO MOR DONT Do not, in aa or appearance, rilvuss or exchange infor mation on: PRICES, INCLUDING: Individual company prices, price changes, price differentials, nwinip*, discounts, allowances, credit terms, etc.; individual company data on cans, production, capacity, inventories, tales, etc.; and. Industry pricing policies, price levels, price changes, differen tials. etc. PRODUCTION, INCLUDING: Flans of individual companies concerning the design, produc tion, distribution or marketing of particular products, includ ing proposed territories or cusomets; and, changes in industry production, capacity aHnwntories. TRANSPORTATION RATES: Rates or rate policies for individual shipments, including bas ing point systems, zone prices, freight equalization, etc. . MARKET PROCEDURES. INCLUDING* Company bids on contracts fra parocuiar products: company procedures for responding to bid invitations: and. matters relating to actual or potential individual suppliers or cusromets that might have the effect of exduding them from sty market or influencing the business conduct of firms to ward them. CONSENT DECREE SUBSTANCE: Any matter relating to trisodium phosphate (a restriction re quired by a 1962 consent decree to which CMA is a parry) 3, American Journal of Industrial Medicine 24:251-256 (1993) LETTER TO THE EDITOR Diagnostic Bias in Occupational Epidemiologic Studies: An Example Based on the Vinyl Chloride Literature Key words: vinyl chloride, brain cancer, emphysema, chronic obstructive pulmonary disease, diagnostic bias INTRODUCTION Dr. Shah's Letter [1993] raised several issues of potential diagnostic bias on the brain cancer and emphysema findings in our recent paper of vinyl chloride workers [Wongetal., 1991]. These are important and pertinent questions not only in our study of vinyl chloride exposed workers, but also in occupational epidemiologic studies in general. BRAIN CANCER The first issue was the potential diagnostic bias of brain cancer in occupational studies. As Dr. Shah correctly pointed out in his letter, there are reports in the literature documenting the potential bias resulting from the more complete reportingand/or diagnoses of brain tumors in employees of large corporations than in the general population. Greenwald et al. [1981] reported a significantly higher frequency of brain scans (61.1% vs. 30.0%) and pneumoencephalograms (35.2% vs. 17.1%) than in other brain tumor patients in the same state. They concluded that the "diag nostic sensitivity bias" would appear to pertain to conditions that are difficult to diagnose, such as brain tumors, and to industries where workers have such employee benefits as health insurance and high-quality employee medical services with referral and follow-up. Thus, the apparent excess of brain tumors may have resulted from the diagnostic sensitivity bias arising from the more complete medical evaluation of employees of large corporations. Diagnostic sensitivity bias in brain cancer has also been discussed by other investigators [Wong et al., 1986; Wong and Raabe, 1989]. The participants in our vinyl chloride study were employees of major corpora tions in the chemical industry, and were covered by comprehensive medical care Address reprint requests to Dr. O. Wong, Applied Health Sciences. Inc., 181 Second Avenue, Suite 628, P.O. Box 2078, San Mtueo, CA 94401. Accepted for publication December 15, 1992. 1993 Wiley-Liss, Inc. jj ^ ^oft. GJ 252 Wong and Wborton TAB! E I. Cohort Studies of Workers Exposed to Vinyl Chloride* Auth _,rs and location Cohort size Brain cancer SMR Byren et al. (1976], Sweden Hagmar et al. [1990], Sweden Smulevich et al. [1988], USSR Cooper [1981], USA Waxweiller et al. [1976], USA Wu et al. [1989], USA 771 2,031 3,232 10,173 1,294 4,835 2/0.33 = 6.12 s 6/2.60 = 2.29 ns 4/2.61 = 1.53 ns 12/5.90 = 2.03 a 3/0.90 = 3.29 ns 15/9.20 = 1.62 ns *s b significant at the 0.05 level; ns = nonsignificant at the 0.05 level. programs. Therefore, our finding of a brain cancer excess could very well have been subjected to this diagnostic sensitivity bias. In our 1991 paper, although we reported a statistical significant increase of brain cancer, we did not discuss our finding in relation to findings reported by other investigators; nor did we conclude that the observed brain cancer excess was related to vinyl chloride exposure. Although Dr. Shah did not raise the question explicitly in his letter, it seems to us that the most important question is "does exposure to vinyl chloride increase the risk of brain cancer?" The answer to this question should be based not only on our study but also on all other pertinent studies in the literature. Prior to the publication of our 1991 paper, there were a number of cohort studies of workers exposed to vinyl chloride reporting an increased risk of brain cancer (Table I). Based on a cursory reading of the literature (as Table I suggests), one may be led to believe that there are consistent reports of an increased risk of brain cancer among vinyl chloride workers in this country. In reality, all the American cohort studies were based on the same population. The Tabershaw and Gaffey [1974], the Cooper [1981], and the Wong et al. [1991] reports were all based on the same cohort study sponsored by the Chemical Manufacturers Association (CMA). The workers studied by Waxweiller et al. [1976] and Wu et al. [1989] were employees at plants which also participated in the CMA study. Thus, those who are not familiar with the history of the CMA study can easily be confused and led to assume that there had been mote than one American study reporting a brain cancer excess. Essentially the same excess might be counted more than once. To evaluate the relationship between vinyl chloride and brain cancer in the CMA cohort, we must examine, among other criteria, the strength of association [Hill, 1965]. The overall brain cancer standardized mortality ratio (SMR) reported by Wong et al. [1991] was 1.80 (23/12.76), only a modest increase [e.g., see M nson, 1990], Furthermore, the excess was only marginally significant at the 0.05 level (lower 95% confidence limit of 1.14). Even if the diagnostic sensitivity bias ac counted for only 15% of the excess, the increase would no longer be statistically significant. By way of comparison, the SMR for cancer of the liver, which has been demonstrated to be associated with vinyl chloride exposure, in our study was 6.41 (lower 95% confidence limit of 4.50). With respect to length of exposure, there was no clear upward trend for brain cancer in our study, especially when compared to the striking upward trend observed for cancer of the liver. Perhaps the most remarkable difference between brain cancer and liver cancer (the latter was clearly related to vinyl chloride) is the analysis based R&S150444 Diagnostic Bias 253 on time of first exposure. For liver cancer, the excess was most evident among employees first exposed before 1950, when the exposures were higher, than those in later years. For brain cancer, the reverse was true: significant excess was reported only among those first exposed after 1960. This observation argues against a causal role of vinyl chloride. As we stated in our 1991 paper, the brain cancer excess in the CMA cohort occurred at primarily two plants. Wu et al. [1989] conducted a detailed analysis of both brain cancer and liver cancer at these two plants, and found that the increased brain cancer mortality was not associated with vinyl chloride exposure. On the other hand, these authors demonstrated a significant association between liver cancer and vinyl chloride exposure. Thus, no causal link between brain cancer and vinyl chloride exposure was found in the CMA cohort. This conclusion is supported by other studies. Recently, collaborators from four European countries (Italy, Norway, Sweden, and the United Kingdom) in a cohort of 12,706 vinyl chloride workers reported a brain cancer SMR of 1.07 based on 14 observed deaths [Simonato et al., 1991]. This collaborative study included the tw previous small Swedish studies [Byren et al., 1976; Hagmar et al., 1990], which reported an increase of brain cancer. In addition, this study also included updates of studies which had not reported an excess of brain cancer previously [Jones et al., 1988; Pirastu et al., 1990; Storetvedt Heldaas et al., 1984]. Furthermore, a small Canadian study also reported no excess of brain cancer [Theriault and Allard, 1981]. Therefore, studies from both Europe and Canada support our interpretation of the CMA study in this country that the observed brain cancer excess was not related to vinyl chloride exposure. Sir Richard Doll [1988] in a recent review combined the data from four major studies from the United States, United Kingdom, Canada, and Italy, and reported a small nonsignificant increased risk of brain cancer (29 observed vs. 19.54 expected; summary SMR = 1.48). With the updated International Agency for Research on Cancer (LARC) collaborative study, which includes both the United Kingdom and the Italian studies that Doll relied on, the summary brain cancer SMR will be even lower. In Doll's combined data, our study was the only one reporting a statistically signif icant brain cancer excess. We conclude that our finding of an excess of brain cancer ~~ among U.S. vinyl chloride workers reported earlier was not likely related to the chdtnical. The most likely explanation is that the excess was due either to chance [Do]}, 1988] or to the diagnostic sensitivity bias discussed above [Greenwald et al., 1981], \ EMPHYSEMA/CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) Dr. Shah's second concern about the excess of emphysema/chronic obstructive pulmonary disease (COPD) brings out important issues in evaluating chronic airway obstructive disorders. In our 1991 paper, we were concerned that the term "emphy sema" was too narrow a diagnostic term. The diagnostic term more frequently used in the United States is "chronic obstructive pulmonary disease." Emphysema and COPD are two diagnostic terms for chronic airway obstructive disorders and do not represent different conditions. In his review Doll [1988] noted: ^ we --4 tn oAA tn r \ 254 Wong and Whorton TABLE II. Significant Mortality Excess of Emphysema/COPD Accompanied by Significant Mortality Deficit of Other Nonmalignant Respiratory Disease* Disease category Observed Expected SMR Nonmalignant respiratory disease Emphysema/COPD Other nonmalignant respiratory disease 70 41 29 87.61 22.83 64.78 0.79 1.79 s 0.45 s *s = significant at the 0.0S level. International comparisons of chronic nonmalignant respiratory diseases are complicated by the usage of different terms to describe what is now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in the past tended to be called emphysema in the U.S. and chronic bronchitis in the United Kingdom. It must, therefore, be presumed that the two categories of "emphysema" and "chronic bronchitis" used respec tively in the two large national studies were meant to describe the same thing. Thus, in accordance with Doll's comments, one must include COPD with either chronic bronchitis or emphysema if one is to include all of the diagnostic terms for apparently the same condition in a review or comparison of world literature on vinyl chloride. The Seventh Revision of the International Oassification of Diseases (ICD7), which was used in the original as well as the subsequent updates of the CMA study, does not recognize that these different diagnostic terms for chronic obstructive airway disease describe the same generic condition. In 1037, the code for chronic bronchitis is 502, whereas the codes for emphysema and COPD are found within 527 ("other diseases of the lung and pleural cavity"). Emphysema is coded 527.1 and COPD is coded 527.2. On the other hand, chronic bronchitis with emphysema is coded 502.0. In an historical mortality study, the codes for various subgroups of nonmalignant respiratory disease are further complicated by the changes in nomenclature over time. > In our study we found an overall mortality deficit of nonmalignant respiratory disease (SMR = 0.79), consistent with other studies reviewed by Doll [1988] and the, most recent IARC collaborative study [Simonato et al., 1991]. However, in our study, we found a significant mortality excess of emphysema/COPD, accompanied by a significant mortality deficit of other nonmalignant respiratory disease (see Ta ble II). As Doll [ 1988] pointed out in his comments on the above result in our study, the potential for diagnostic misclassification between emphysema/COPD and other n nmalignant respiratory disease in some patients was certainly possible. This diagnostic problem of COPD based on death certificates in epidemiologic studies has also been discussed in detail recently by Selikoff [1992]. > In addition to this potential diagnostic misclassification, we did not observe any upward trend in emphysema/COPD mortality by length of exposure to vinyl chloride; in fact, we observed an inverse relationship. Thus, this lack of a positive doseresponse relationship argues against the interpretation that the excess was solely occupational in origin. R&S150446 p ' i 4 Diagnostic Bias 255 In our 1991 paper, we stated that we could not explain the emphysema/COPD excess, due to the limited exposure data and, more importantly, the lack of smoking data. Our primary objective in reporting the emphysema/COPD result was to alert other investigators. Geariy, one must include all of the diagnoses used in that par ticular country to make certain that the comparisons are similar. For example, if Jones et al. [1988] had included ICD 527 with ICD 502 in their U.K. study, they might have found a different result. The same is true for the von Greiser et al. [1982] study in Germany cited by Doll [1988]. In summary, although we agree that the excess of emphysema/COPD reported in our study could have been due in part to diagnostic misclassification, we do not believe that the issue of chronic obstructive airway disease in relation to vinyl chlo ride exposure has been examined in sufficient detail. This issue can be assessed best by a comprehensive review of the world literature of epidemiologic studies of vinyl chloride workers, a review that includes the gamut of terminology for chronic airway disorders. Otto Wong, SCD, FACE Applied Health Sciences San Mateo, California M. Donald Whorton, MD, MPH ENSR Health Sciences Alameda, California REFERENCES Byron D. Engholm G, Englund A, Westerhoim P (1976): Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ Health Perspect 17:167-170. Cooper WC (1981): Epidemiologic study of vinyl chloride workers: Mortality through December 31, 1972. Environ Health Perspect 41:101-106. Doll R (1988): Effects of exposure to vinyl chloride; an assessment of the evidence. Scand J Work Environ Health 14:61-78. _ Greenwald P. Friendlander BR, Lawrence CE, Heame T, Earle K (1981): Diagnostic sensitivity bias--an epidemiologic explanation for an apparent brain tumor excess. J Occup Med 23:690-694. Hagmar L, Akesson B, Nielsen J, Andersson C, Linden K, AtteweU R, Moller T (1990): Mortality and cancer morbidity in workers exposed to low levels of vinyl chloride monomer at a polyvinyl chloride processing plant. Am J Ind Med 17:353-363. Hill AB (1965): The environment and health: Association or causation? Proc R Soc Med 38:293-300. Jones RD, Smith DM. Thomas PG (1988): A mortality study of vinyl chloride monomer workers employed in the United Kingdom in 1940-1974. Scand J Work Environ Health 14:153-160. Monson RR (1990): "Occupational Epidemiology," 2nd edition. Boca Raton, FL: CRC Press, Inc. Pirastu R, Combs P, Reggiani A, Foa V, Masina A, Maltoni C (1990): Mortality from liver disease among Italian vinyl chloride monomer/poiyvinyl chloride manufacturers. Am J Ind Med 17:155- 161. Selikoff U (1992): Use of death certificates in epidemiological studies, including occupational hazards: Discordance with clinical and atuopsy findings. Am J Ind Med 22:469-480. Shah HC (1993): Diagnostic bias in occupational epidemiologic studies. Am J Ind Med 24:249-230. Simonato L, Abbe KA, Andersen A, Belli S, Comba P, Engholm G, Ferro G, Hagmar L, Langard S, Lundberg I, Pirastu R, Thomas P, Winkelmann R, Saracci R (1991): A collaborative study of cancer incidence and mortality among vinyl chloride workers. Scand J Work Environ Health 17:159-169. R&S150447 256 Wong and Whorton Smulevich VB, Fedotov* IV, Filatov* VS (1988): Increasing evidence of the rise of cancer in workers exposed to vinyl chloride. Br J Ind Med 45:93-99. Storetvedt Heldaas S, Langard SL, Andersen A (1984): Incidence of cancer among vinyl chloride and polyvinyl chloride workers. Br J Ind Med 41:25-30. Tabershaw IR, Gaffey WR (1974): Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Occup Med 16:509-518. Theriault G, Allard P (1981): Cancer mortality of a group of Canadian workers exposed to vinyl chloride monomer. J Occup Med 23:671-676. von Greiser E, Reinl W, Weber H (1982): Vinyl-chloride exposition und mortalitat deutscher chemiear- beiter im vergleich zur mortalitat nichtexponierter chemiearbeiter und PVC-verarbeiter. Zentialbl Arbeitsmed Arbeitssch Prophyl Ergonomic 32:44-62. Waxweiler RJ, Stringir W, Wagoner JK, Jones J, Falk H, Carter C (1976): Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 271:40-48. Wong 0, Morgan RW, Bailey WJ, Swencicki RE, Claxton K, Kheifets L (1986): An epidemiological study of petroleum refinery employees. Br J Ind Med 43:6-17. Wong O, Raabe GK (1989): Critical review of cancer epidemiology in petroleum industry employees, with a meta-analysis by cancer site. Am J Ind Med 15:283-310. Wong O, Whorton MD, Foliart DE, Ragland D (1991): An industry-wide epidemiologic study of vinyl chloride workers, 1942-1982. Am J Ind Med 20:317-334. Wu W, Steenland K, Brown D, Wells V, Jones J, Schulte P, Halperin W (1989): Cohort and case-control analyses of workers exposed to vinyl chloride: an update. J Occup Med 31:518-523. 33 CfiOo 4oo>i.i CO