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Breast Cancer Mortality Among PVC Fabricators Leonard Chiazze, Jr., Sc.D.; Otto Wong, ScD.; William E. Nichols, Ph.D,and Lorraine D. Ference, MS. A case-control analysis of breast cancer deaths among PVC fabricators is presented. This study is an extension of a cross-sectional mortality study of deaths occurring among 17 PVC fabricators during the years 1964 to 1973. Relative risk estimates were derived and tested using the ManteiHaenszef procedure Although no statistically significant relative risks were found, a least significant relative risk analysis indicated that the underlying relative risk would have to be on the order of three to one in order to be detected. There does seem to be reasonable assurance that very large increases in risk for breast cancer do not exist among these PVC fabricators. The authors have previously reported the results of a cross-sectional mortality study of deaths occurring among current and former employees of 17 PVC fabricators during the years 1964 to 1973.' That study identified 44 deaths among white women for which the underlying cause of death was cancer of the breast Those 44 deaths attributed to cancer of the breast occurred among employees of eight of the 17 participating.com panies. On the basis of a proportionate mortality ratio (PMR) analysis, the observed number of deaths from breast cancer was found to exceed the number expected based upon the distribution of deaths by cause and age among all U.S. white women in 1968. The original mortali ty study focused on deceased employees who worked anywhere in the study plants where PVC fabrication was carried on. A decision was reached to investigate further by carrying out a case-control study which would attempt to determine whether either the cases or controls could have been exposed to PVC during their employment and to estimate the relative risk for breast cancer among those exposed to PVC and those not exposed. Materials and MeOrods Controls were to be selected from among deaths from diseases of the circulatory system (ICDA 390-458. Eighth Revision) and accidents (ICDA E800-E999) since no in creased mortality was found for these conditions. An at tempt was made to match cases and controls by com pany (plant, if passible) and age plus or minus five years. Thirty-five of 0k cases could be matched on both criteria. There were nine breast cancer deaths which could not be matched both on company and age. Con trols for these cases were drawn at random from the pool of potential controls with matching on age alone in order that every breast cancer death have at least one matching control. The basis for this report is a total of 44 breast cancer deaths (cases) and 134 controls matched for age and distributed among five companies. In planning the fieldwork, emphasis was placed on ob taining employment histories on the cases and matched controls. A variety of jobs were held by both cases and controls, ranging from office and clerical work to produc tion jobs such as bench inspector, press operator, trim mer, assembler and sweeper. The wide range of job con tent and location made it impossible to determine precisely whether there was PVC exposure in every case or the precise length of that exposure. Therefore, a sub jective ranking system was developed to classify expo sures. Work histories were reviewed with knowledgeable plant personnel and PVC exposure potential was cate gorized into fh* classes -- no exposure, improbable ex posure, possible exposure, definite exposure, and unknown expoare. The various categories of exposure potential through employment and examples of each, are as follows: Classification of Exposure Potential Examples From the Division of Biostatistics and epidemiology. Georgetown University School of Medicine, Washington. DC 20007 (Dr Chiaize and Ms. Ference), T*berhaw Occupational Medicine Associates (Dr. Wongl and International Harvester Company (Dr Nichols, formerly with Organization Resources Counselors. Inc.). No exposure Employment terminated before PVC use PVC processed in a separate building from decedent's work station Journal of Occupational Medicine/Vol. 22, No. 10/0ctober 1980 677 BFGQ6999 20815001 BFG07000 L Improbable Possible Definite Unknown PVC processed in the same building but removed from decedent's work station Decedent handled only fabricated products Work station in vicinity of PVC resins; periods of no monitoring or with no detectable level of VCM Direct work with PVC resins. Moni toring indicated a detectable level of VCM Employment records not complete enough to determine potential for exposure Results A total of 44 breast cancer deaths and 134 controls matched for age and distributed among five companies was available for analysis. Comparison of cases and con trols on a variety of variables where information was available, including length of employment with the com pany, continuous vs. intermittent employment; ever mar ried vs. never married, and child-bearing history, reveals no statistically significant differences (p > 0.05) between cases and controls for any of these variables. The distribution of cases and controls by exposure category is given in Table 1. This classification scheme enabled some definitive exposure statement in 80% of the cases and 92% of the controls. After matching by age and company, 38 matched sets of cases and controls were developed from the 44 cases and 134 controls. There are fewer matched sets than cases because, in six instances, it was necessary to com bine cases of similar age within the same set in order to have at least one control per matched set The MantelHaenszel procedure was used to derive a summary estimate of relative risk and to test for significant depar tures from unity.11 In this procedure, each of the 38 sets can be viewed as a 2 x 2 contingency table. Thus the i* set can be represented as follows: Cases Controls Total PVC Exposure Yes No Total A, B, N-,1 c, D, Na M T, Relative risk is defined as the ratio of the probability of dying from cancer of the breast among women exposed to PVC to the probability for women not exposed. Estimates of these individual probabilities are not avail able from a case-control study. However, a measure of estimated relative risk from case control studies as sug gested by Mantel and Haensze! has been calculated as: Z a,d, T, R = I~ET i T, To assess whether the departure from unity of an ob served relative risk is too great to have occurred by chance alone, a summary chi-square test corrected for continuity was performed using the Mantel-Haenszel pro cedure. The calculated chi-square must be 3.84 or larger in order to conclude with 95% assurance that the ob served relative risk did not differ from unity by chance alone. Combining the five exposure categories into two may be accomplished in a variety of ways resulting in several possible relative risk measures. For example: 1. Yes = Definite exposure only No = No exposure only (Ignore improbable, possible, unknown) R = 1-81 = 0.0189 (not significant) 2. Yes = Definite + improbable possible + unknown No = No R * 1.94 x'mh = 1.119 (riot significant) 3. Yes = Definite + possible No = No + improbable (Ignore unknowns) R * 0.624 x*mh = 0.0194 (not significant) 4. Yes = Definite + possible + unknown No = No + improbable R = 2.73 = 1-548 (not significant) None of the above calculated relative risks, including number 2, which treats anything other than no exposure as definitely exposed, are statistically significant; i.e., they may have occurred by chance alone. Similar analyses were carried out on a company-bycompany basis. None of the relative risks so calculated is significantly different from unity. Conclusions The results presented here must be interpreted with caution. Absence of a statistically significant relative risk does not demonstrate that there is not an excess risk of death from breast cancer among white women employ ees with PVC exposure. In fact when no statistically significant relative risks are found, it is pertinent to ask what the chances are of detecting an increase of a given magnitude from the available data. Using the method described by Walter,4 the authors have subjected each of Tibia 1. -- Distribution of 44 Braast Cancer Deaths and 134 Matched Controls by Exposure Category. Exposur* Category No exposure Improbable exposure Possible exposure Definite exposure Unknown exposure Total Cases No. X 27 61.4 6 13.6 00 2 4.5 9 20.5 44 100 Casoe No. X 97 72.4 17 12.6 4 3.0 6 4.5 10 7.5 134 100 678 Breast Cancer Mortality Among PCV Fabricators/Chiazze et al 2081500; I i the relative risk estimates to a least significant relative risk analysis under the conditions that they desired 95% assurance that a risk of such magnitude, if observed, did not occur by chance alone and 80% probability of detecting the least significant relative risk if it exists. Results of that analysis are as follows: 1. Definite exposure only vs. no exposure only Relative risk estimate = 1.81 Least significant relative risk = 6.77 2. Definite + improbable + possible + unknown vs. no exposure Relative risk estimate = 1.94 Least significant relative risk = 2.92 3. Definite + possible.vs. no exposure + improbable Relative risk estimate = 0.624 Least significant relative risk = 5.02 4. Definite + possible + unknown vs. no exposure + improbable Relative risk estimate = 2.73 Least significant relative risk = 3.41 Even in case number 2, where all but "no exposure" are counted as exposed, the smallest relative risk which could be detected from these data is nearly 3:1. In this instance. over 130 cases and 130 controls would have been necessary to detect a true doubling of the risk under the specified conditions. In order to achieve 95% probability of detecting a true twofold risk, if it in fact existed, well over 200 cases and 200 controls would have been re quired. Given the sample size in this study and the percentage of controls exposed (a percentage which was unknown at the start of the study), it would be possible to detect only very large increases in risk. There seems reasonable assurance, therefore, that such very large in creases in the risk for breast cancer do not exist among these PVC fabricators. References 1. Chiazze L Nichols WE, and Wong O: Mortality among employ ees of PVC fabricators. I Occup Med 19:623-628.1977. 2. Mantel N and Haemzel W: Statistical aspects of the analysis of data from retrospective studies of diseases. I Natl Cancer Inst 22:719-748,1959. 3. Pike MD and Morrow RH: Statistical analysis of patient-control studies in epidemiology: Factor under investigation an alt-or-none variable. Br I PrevSoc Med 24:42-44.1970. 4. Walter SD: Determination of significant relative risks and op timal sampling procedures in prospective and retrospective com parative studies of various sizes. Am / Epidemiol 105:387-397,1977. Light in Darkness I am not tragic or desponding by nature. Temperamentally I am buoyant and hope ful. Through the darkness I always see a light -- a bright star that no misfortune ever quite hides from me... With an embossed book on my knee, or seated at my typewriter, I am not conscious of any handicap. In spirit and mind I am untrammelled, imagination rides Olympian horses. Once my foot is in the stirrup, 1 am off to the uttermost isles of thought I ought to say also that I have received the most wonderful kindness from my fellow creatures. Everyone has given me of his best in proportion to the richness of his nature and the goodness of his heart -- Helen Keller, as quoted m Heten and Teacher by Joseph P. lash. Published by DelacoAe Press, New York, N.Y. Journal of Occupational Medicine/Vol. 22, No. 10/0ctober 1980 679