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yTi4-. y/si^t c4/or.is. /^o /y CA/onX/o.__ 7r. CUa~Ucm-->^.<^ .A --XXke<i*w^ -ynii-i 'r>-'tvXj 1 *Ut , Dig Occupational CancGWS-RifElVED the Nervous System aUG 121932 Ellen Kessler, M.D., M.P.H." TMTMTM and Paul W. Brandt-Rauf, Sc.D., M.D., Dr.P.H.f The occurrence of nervous systems cancers has in creased markedly over the past 40 years, particularly brain tumors among white males over the age of 55, which has raised the possibility of occupational contri butions to etiology. In fact, there has accumulated enough evidence to suggest that a link may exist be tween the incidence of brain tumors and certain occu pations and chemical exposures. The first inkling of this came from animal studies in the early 1940s that dem onstrated the induction of brain tumors in rats by direct intracranial implantation of known carcinogens. Subse quent studies in rats demonstrated that gliomas could be induced by inhalation or ingestion of acrylonitrile, whereas neuroblastomas developed with vinyl chlo ride inhalation. These and similar compounds have been used extensively in the plastics and rubber indus tries. Later epidemiologic studies, particularly in rub ber workers, suggested that humans with certain indus trial exposures may indeed be at increased risk for developing brain tumors These investigations prompted research in other industries and there are now studies raising concern of a potential excess risk for brain tumors in a number of work-related environments in cluding rubber manufacturing, polyvinyl chloride pro*, duction, oil refining and petrochemical production, and nuclear fuels and weapons fabrication. Unfor tunately, in many cases the evidence is conflicting and inconclusive, and further study is necessary, but epi demiologic analysis has been complicated by lack of complete exposure data, prolonged latency periods, and difficulty in obtaining and accounting for different histologic cell types.1-2 RUBBER MANUFACTURING Mancuso's studies on synthetic rubber workers arose following his observation that the 1947 death certifi cates among white males between the ages of 25 and 64 in Summit County, Ohio (the location of most of the U S. tire manufacturing at the time) revealed an excess pro portional mortality for brain cancer.3 Mancuso went on to determine that men employed in tire assembly and tire curing had a particularly elevated risk for develop ing brain/CNS malignancies, although a lower than ex pected risk existed for the entire plant populations.3 Although potentially toxic chemicals including coal tar, carbon disulfide, benzene, and other solvents had been used in the tire manufacturing process, none of these compounds could be directly linked to CNS carcino genesis. Nevertheless, subsequent studies by Monson et al. supported Mancuso's original observations.4-5 However, later investigations, including a large coop erative study that used a cohort of active and retired male workers between 1963 and 1973 from 48 different plants, failed to support the earlier findings.6 Other cohort studies after 1964 were also unrevealing.7 8 It has been argued that the earlier studies were representa tive of exposures initially found in the rubber tire manufacturing process that have since been removed. `Medical Director, Corporate Healthcare Services Inc., Springfield, Virginia 'Director, Occupational Medicine, Columbia University, New York, New York Reprint requests: Dr. Brandt-Rauf, Occupational Medicine, Columbia University, 60 Haven Ave, B-l, New York, NY 10032 1987 by Thieme Medical Publishers, Inc, 381 Park Avenue South, New York, NY 10016. All rights reserved. WARNING: This material may b OLI 3435 by eopyrioM 3U SEMINARS i.N ocCLP.\n<J.\AL MEDICINE \blume 2, Number 4. December 1987 POLYVINYL CHLORIDE PRODUCTION the same Union Carbide plant.14 In addition, Reeve al. from NIOSH found that residents of Brazoria Countv When it was ftrat reported that workers exposed to the site of Dow Chemical, had a twofold risk of dvin high levels of vinyl chloride were at increased risk for from a brain tumor if, at any time, they had worked * developing angiosarcoma of the liver, an otherwise rare the Dow petrochemical plant.16 However, Ralph Cook tumor, NIOSH and otner study groups intensified their the director of epidemiology at Dow, and his groun investigations in order to identify other possible haz failed to find an association between a specific job ards from exposure. Waxweiler et al. reported that category or exposure with an elevated risk for develop among a cohort of workers exposed to vinyl chloride ing brain tumors among employees at Dow.17 for greater than 15 years, a significant risk for the devel Subsequendy, Thomas et al. from the National Can- opment of brain cancer existed with three observed cer Institute calculated a proportional mortality ratio and 0.6 expected,9 Overall, a total of ten brain cancers for brain tumors of 2.28 in deceased active and retired were identified among vinyl chloride workers on the members of the Oil, Chemical and Atomic Workers basis of death certificates, pathology reports, and/or Union among hourly workers employed at Mobil, Gulf tissue evaluation, and nine of the ten brain tumors were and Texaco petroleum plants in the Beaumont-Pon histologically identified as glioblastoma multiforme; no Arthur area of Texas.18 However, a series of industry, histologic diagnosis was available on the tenth.9 Al based studies of the same three refineries found no though glioblastoma multiforme is a brain tumor that increased risk.19-21 No association between brain tu occurs in a relatively high proportion of adult cases, this mors and specific work categories was demonstrated in percentage is considerably higher than would be ex a follow-up case-control study by Thomas et al.22 pected. Furthermore, a proportional mortality ratio of In 1980, J. William Lloyd of OSHA and Irving Selikoff 4.2 was calculated from a study by Monson on deceased of the Mount Sinai School of Medicine organized a workers from two plants with vinyl chloride monomer conference through the offices of the New York Acad exposure.10 At about the same time, Maltoni et al. were emy of Sciences in order to evaluate the rapidly grow- able to show that brain tumors could be induced in rats ing but conflicting evidence on brain tumors and expo when exposed to vinyl chloride by inhalation at levels sure to petrochemical production. Several studies were resembling the human exposure data.11-12 presented including four by epidemiologists from In Britain, Fox and Collier observed two brain cancer OSHA, NIOSH, and NCI and four by investigators with deaths as compared to 3.7 expected for a cohort of vinyl industry-backed support (Dow Chemical, Gulf Oil, Du chloride exposed workers.15 However, of the cohort Pont, and a group representing some of the United members that were considered to have a high expo Kingdom oil refineries). The disparities were marked sure, one brain cancer death was observed versus 0.4 with the government studies invariably indicating a expected. Although the number of brain tumor cases in twofold increased risk and the industrially supported all these studies is relatively small, the results are gener studies showing no elevation of risk. The industry- ally regarded to be indicative of an association between backed studies were criticized for including all em vinyl chloride exposure and the development of brain ployees such as office workers who were most likely malignancy, in particular glioblastoma multiforme. not significantly exposed. By diluting the study popula tion, certain subgroups who actually had significant exposures and potential risks may not have been identi OIL REFINING AND PETROCHEMICAL fied. On the other hand, some of the criticisms pertain PRODUCTION ing to the government studies that were brought out included the use of PMR methodologywhich can inflate There has been considerable effort by numerous the calculated risk for cancer. Some of the problems study groups to determine if oil refining and pe Faced by all the investigators included the relatively low trochemical production could be linked to brain can number of identified cases, the varied degree of expo cer. Although the potential carcinogenicity of certain sures among employees, and the retrospective analysis petroleum products is well established, the cancer risk that involved tracing employee records back through among refinery workers is less clear-cut. In the United 40 or more years.23 States, the focus came about when representatives of Most recently, a five-year follow-up of a previous Union Carbide and the Oil, Chemical and Atomic mortality study on 1,207 men employed in a Canadian Workers Union together identified 18 cases of brain oil refinery again revealed an excess risk of brain malig cancer among deceased and living former employees nancies (SMR = 519) among men who died within 20 of the Union Carbide plant in Texas City, Texas.14 Epi years of first exposure.24 The study, however, failed to demiologists from OSHA/NIOSH joined-the effort with identify any hazardous exposures in the workplace a cohort mortality study on workers employed at Union Although conflicting results exist concerning the in Carbide and consequently found a significantly in creased risks for brain malignancies in the oil refining creased SMR of 2.06 for white male hourly workers at and petrochemical production process, there is enough 312 OLI 3436 CANCERS OF THE NERVOl'S SYSTEM--Kessler, Brandt-Raul evidence to suggest such a risk. The extremely large possible role of animal viruses)2; and occupational or Mze of the work force together with the controversial environmental exposure to power frequency magnetic studv results place a great demand on investigators to fields and brain tumors.'0-11 proceed with further research. One of the most serious problems with occupational studies of nervous system tumors in the past has been the failure to segregate out the various and diverse OTHER INDUSTRIAL AND histologic types owing to lack of adequate pathologic NONINDUSTRIAL STUDIES evidence and the small numbers involved. However, it is probably erroneous to consider all primary nervous The results of some of the above studies have svsiem tumors as a single disease in terms of suscep prompted investigations in other industries including tibility to induction by occupational exposures The the nuclear fuels and weapons fabrication industry. In most recent studies have attempted to address this one study, the mortality risk was found to be elevated issue. For example, a case-control study of 78 astro ISMR = 2.40) and the incidence rate was found to be cytoma patients showed an elevated risk for working at significantly elevated (SIR = 2.67) for brain tumors an airfield or living near a petrochemical plant, sewage among male employees at a nuclear fuel fabrication treatment plant, or paper or saw mill.32 A study based plant. However, radiation, industrial, or previous em on the Swedish Cancer-Environment Registry exam ployment exposures could not be correlated.'' Ura ined 1,092 cases of meningioma and found statistically nium fuel is contained in a controlled area and the significant standardized incidence ratios between 4? radiation levels are assumed to be lory however, the and 6.0 for glass, porcelain or ceramic workers of both exposures to metal dust, fumes, and oil mists are not sexes, and for male workers in headgear fabrication unlike a metal fabrication plant and have to be consid and book publishing. Significant SIRs between 1.7 and ered as well as possible sources of carcinogen expo 3 0 were observed for men employed in health care, sure in nuclear fuel fabrication. At the Rocks' Flats Nu railroad and trolley construction, sheet and plate metal clear Plant, Wilkenson et al. noted an increased risk for fabrication, moving equipment operations, and ele brain tumors, however, when tumors of benign and mentary schools.33 These findings were consistent with unspecified classifications were excluded, the increased previous studies 2834-3' In a parallel study of intra risk was no longer statistically significant.2*1 Other cranial gliomas, a significant twofold excess risk was studies of plutonium processing workers failed to dem also found for glass, porcelain, and ceramic workers 38 onstrate an excess brain cancer risk among employees.27 This group is of interest because of potential exposure However, because the nuclear industry is still relatively to arsenic, chromium, and lead, and hat makers are of new, the latency period may be insufficient to accurately interest because of potential exposure to mercury, a examine the risks in these cohorts. Follow-up investiga well-known neurotoxin. tions on already studied cohorts would certainly be Finally, note should be made of the concern for the worthwhile, particularly because studies of other potential development of childhood brain tumors due groups nonoccupationallv exposed to radiation for to parental occupational exposures,39 It has been medical-diagnostic and therapeutic purposes support clearly demonstrated in animal models that carcinogen the concept of radiation-induced nervous system tu exposure in the mothers can cause brain tumors in the mors.2 offspring. For example, the offspring of pregnant rats Several other occupationally or environmentally ex injected intravenously with ethyl nitrosourea during posed groups have been targeted as potential risks for the latter halfof pregnancy' have an increased incidence brain malignancies Professional artists, pathologists, ofgliomas and neuromas; in fact, the nervous systems of embalmers, and farmers are examples of the nonin- fetal rats have a 50-times-greater sensitivity to the carci dustrially exposed groups with suspected brain tumor nogenic effects of ethyl nitrosourea compared to risks.28 Chemicals common to these groups include adults.90 The first indication of a possible effect in hu formaldehyde and organic solvents although definitive mans was provided by the study of Fabia and Thuy correlations with exposure have not been established. which raised the possibility that children of fathers in In addition, farmers are exposed to pesticides, and hydrocarbon-related occupations were at elevated risk Italian studies have suggested that this may be contribu for childhood cancer, a large fraction of which occur in tory to the increasing incidence ofgliomas in this occu the nervous system.41 Hemminki et al. found an associa pational group.29 Other potential associations that have tion between brain cancer in children under 15 years been noted include: trauma and the development of old and specific jobs held by the father, including ma brain tumors, particularly meningiomas; lead exposure - chine repairmen (relative risk = 4.4) and painters (rela and the development of astrocytic gliomas in children tive risk = 2.6), once again raising the possibility of a and animals; dietary consumption of nitrites and me link to hydrocarbon and other chemical exposures.42 ningiomas in women; exposure to farm animals and the Other studies have supported an association with paren development of childhood brain tumors (suggesting a tal chemical exposure or work in particular industries OLI 3437 313 SEMINARS IN OCCUPATIONAL MEDICINE Volume 2, Number 4 December 1987 (metal and construction work) with the development of childhood tumors.Design problems common to these studies have included confounders, histologic diagnosis and the vagueness of job category. The inde pendent risk factors not addressed have included preor postnatal radiation exposure, cancer in siblings, viral diseases, and congenital defects. Although none of the findings warrant a firm conclusion, clearly, as is true with occupational associations for nervous system can cers in general, further investigation is warranted REFERENCES 1 Kessler E, Brundt-Rauf PW Occupational cancers of the brain and bone Occup Med 198", 2 155-- 163 2. Schoenberg BS Nervous system, in Schottenfeld D, Fraumeni IF Jr teds)' Cancer Epideniiolog}' and Preiennon Phila delphia, V B saunders Co. 1982, pp 968-983 3. Mancuso T Epidemiologic study of tumors of the central ner vous svsiem in Ohio Ann NY Acad Set 1982, 381.1'-39 4 Monson RR. Nakjno KK. Mortality among rubber workers. Am J Epidemiol 19'6, 103 28-1-296 5. Monson RR. Fine LJ Cancer mortalirv and morbidity among rubber workers J Nat Cancer Inst 19'8. 61.1047-1053 6. Symons MJ, Andielkovich DA Spirtas R. Herman DR. 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Preston-Martin S, Yu MC, Benton B, Henderson BE N-uiir"'' compounds and childhood brain tumors A case-contr. .1 '|,JU' Cancer Res. 1982; 42-5240-5245 45. WilkinsJR III, Koutras RA Parental occupation and hrum m offspring Joint Conference on Occupational Health, v-e" can Academy of Occupational Medicine, 1983 314 OLI 3438