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ft VIEWS 'i. jnd J Work Environ Health 12 -(i9S6) 1 --15 drain tumors and occupational risk factors A review by Terry L Thomas, MS,' Richard J Waxweiler. PhD- THOMAS TL, WAXWEILER RJ. Brain minor; and ccverarional risk factors: A review, Sound J Work Era iron Health 12 (19S6) 1 --15. Little is known about the etiology of tumors of the brain and central nervous system (CNS); however, epidemiologic studies have indicated recently that excess brain and CNS tumor risk may be associated with employment in certain occupations or industries. Some studies have shown that certain white-collar professional groups (eg. artists, laboratory' professionals, veterinarians, embalmers) appear to have an elevated risk of brain rumors, and they raise the issue of a diagnostic sensitivity bias. Some blue-collar occupational groups, including rubber workers, oil refinery workers, chemical plant workers, polyvinyl chloride workers, machinists, and others, have been reported to have an elevated risk of brain tumors. Most of these workers are poter.iial'.y exposed to multiple chemicals; nevertheless they have some exposures in common, for example, exposure io organic solvents, lubricating oil, acrylonitrile and vinyl chloride, formaldehyde, polycyclic aromatic hydrocarbons, and phenolic compounds. Key terms: organic solvents, lubricating oils, acrylonitrile, vinyl chloride, formaldehyde, polycyclic aromatic hydrocarbons, phenolic compounds. . <r V-C> The age-adjusted average annual incidence rate for malignancies of the brain and central nervous system tCNS) among white men in the United States (US) dur ing 1973--1977 was 6.7 per 100 000, and the corre sponding mortality rate was 4.9 per 100 000 (104). Mortality rates for malignant brain and CNS tumors among all age groups over 55 years have been steadily increasing since the 1940s (95). Mortality and incidence rates for CNS malignancies in the United States are higher among white men than among women and blacks (45, 104). About half of the brain tumors (be nign and malignant) diagnosed among white men of all ages are glioblastoma multiforme, but this cell type accounts for a much lower percentage of the brain tumors diagnosed among women and blacks (5). There is a dramatic peak in mortality due to brain and CNS malignancies among white men between 45 and 65 years of age (45); the peak corresponds with that in the incidence rate for glioblastoma multiforme between the same ages (74). These patterns imply that some genetic and/or environmental risk factor(s) may be responsible for the elevated rates among white men compared with women and blacks. The age peak and increasing rates over calendar time suggest an environ mental risk factor, possibly occupational. 1 Occupational Studies Section, Environmental Epidemiology Branch, National Cancer Institute. Bethesda, Maryland 20S92, United States. 2 Special Studies Branch, Chronic Diseases Division. C.-mer for Environmental Health, Centers for Disease Ccr.uol. At lanta, Georgia 30333, United States. Reprint requests to: Ms TL Thomas, Occupational Studies Section, Environmental Epidemiology Branch, NCI. Lar.dow Building, Room 4C16, Bethesda, MD 20S92, USA. One of the difficulties in comparing epidemiologic studies of brain and CNS tumors is disease definition and terminology. The term "CNS tumors" includes tumors of the brain, cranial nerves, and cranial meninges; however, because more than 90 `To of CNS tumors are brain tumors (104), we have used the terms brain cancer (malignancies only) and brain tumor to refer to all CNS tumors throughout our review, regard less of the original author's definition or terminology. More confusing is the fact that brain tumors can be coded as malignant (International Classification of Diseases, Eighth Revision (ICDA-S) code 191, 192], benign (ICDA-8 code 225), or unspecified as to malignant or benign (ICDA-8 code 238). Unfortu nately, if a physician records just the words "brain tumor" on a death certificate, as is often the case, the unspecified code (ICDA-S 238) will be assigned as the underlying cause of death. Upon later pathological review, many of these cases may be shown to be primary malignant tumors. In addition, there may be some misclassification on the death certificates between primary brain tumors and those that are metastatic from other cancer sites (62). Thus, if brain tumor risk is to be thoroughly evaluated, it is important to report all 1CD codes for primary brain tumors (ICD 191,192, 225, and 238) separately and combined. In most in stances investigators have reported mortality or in cidence only for tumors of the brain specified as malignant; however, in the accompanying tables, we have indicated which results also include tumors coded as benign or unspecified. Very little is known about the etiology of brain tumors; however several associations with occupational and other environmental and genetic factors have ap peared in the epidemiologic literature (23). Although Table 1. Brain tumors among white-collar and professional occupations in surveys of mortality by occupation. Occupation or type of work* Study period Measure of association 6 Observed brain tumor, events Ratio1 Reference Professional & technical, US Professional & technical, Canada Accountants & auditors, US Financial workers, MA Treasurers, financial managers, bank officers, MA Managers, officials, proprietors, manufacturing, US Managers, officials, proprietors, WA Purchasing agents, buyers, sates managers, WA Sales managers (age 65--74 years), UK Purchasing agents & buyers, sales managers, CA Credit men, WA Insurance agents, brokers, underwriters, & appraisers, WA Engineers, nec, WA Engineers, nec, CA Mechanical engineers, WA Aeronautical engineers, CA Electrical engineers, CA Electrical engineers (age 65--74 years), UK Inspectors, nec, WA Inspectors, nec, CA Checkers, examiners, inspectors, MA Public utility supervisors & officials, WA Clergymen, WA Dentists, CA Teachers, US Artists & art teachers, CA Teachers, except music & art, CA Teachers, elementary 6 secondary, MA Professors & instructors, CA School professions, MA Lawyers & judges, CA Lawyers & judges, WA Lawyers 8. judges, MA Postal clerks, CA Postal clerks, MA Officers, enlisted men, armed forces, nec, CA Armed forces (British & foreign), UK Armed forces (British & foreign), UK 1950 1965-1973 1950 1971-1973 1971--1973 1950 1950-1979 1950-1979 1970--1972 1959--1961 1950--1979 1950-1979 1950--1979 1959-1961 1950-1979 1959--1961 1959-1961 1970-1972 1950--1979 1959-1961 1971 -- 1973 1950-1979 1950-1979 1959-1961 1950 1950-1979 1959-1961 1971-1973 1959-1961 1971-1973 1959-1961 1950--1979 1971 -- 1973 1959-1961 1971-1973 1959-1961 1970-1972 1961 SMR SMR SMR sMOR sMOR SMR PMR PMR PMR PMR PMR PMR PMR PMR PMR PMR PMR PMR PMR PMR SMOR PMR PMR PMR SMR PMR PMR sMOR PMR SMOR PMR PMR sMOR PMR SMOR PMR SMR SMR 169 1.34* 10 1,95 27 1.93* 13 2.29* 5 3.47* 43 1.30 64 1.50* 12 1 78 2.47 5 2 89 6 2.97* 21 1.58 26 1.47 10 2.16* 8 4.22* 4 2.17 5 1.55 2.75 7 2.48 10 2.55* 4 5-57* 10 1.99 14 1.99* 2 1.52 21 1.75* 4 2.98 8 2.41* 7 3.71* 6 2.92* 10 2.54* 5 1.91 13 1.88* 7 5.56* 6 2.76* 5 2.66 27 1.56* 1.83 1.67 Guralnick (25) Howe & Lindsay (33) Guralnick (25) Dubrow & Wegman (17) Dubrow & Wegman (17) Guralnick (25) Milham (43) Milham (48) Registrar General (65) Peterson & Milham (63) Milham (48) Milham (48) Milham (48) Peterson & Milham (63) Milham (48) Peterson & Milham (63) Peterson & Milham (63) Registrar General (65) Milham (48) Peterson & Milham (63) Dubrow & Wegman (17) Milham (48) Milham (48) Peterson & Milham (63) Guralnick (25) Peterson Milham (63) Peterson & Milnam (63) Dubrow & Wegman (17) Peterson & Milham (63) Dubrow & Wegman (17) Peterson & Milham (63) Milham (48) Dubrow & Wegman (17) Peterson & Milham (63) Dubrow & Wegman (17) Peterson & Milham (63) Registrar General (65) Logan (39) US = United States, MA = Massachusetts, WA = Washington, UK = United Kingdom, and nec = not elsewhere classified. b PMR = proportionate mortality ratio, SMR = standardized mortality ratio, PIR = proportionate incidence ratio, SIR = standardized incidence ratio, SRR = standardized rate ratio, sMOR = standardized mortality odds ratio, and OR = odds ratio. c Ratio -. observed expected ratio or odds ratio * Statistically significant (Poisson) at the 0 05 level. no causal industrial exposures have been identified, brain tumors seem to cluster in certain occupational groups. Historically, the first occupational association with brain tumors was reported among workers in the rubber industry (42). Since 1968, clusters of brain tumors have been seen among workers involved in polyvinyl chloride production, oil refining, petrochem ical production, pharmaceutical production, use or production of formaldehyde, and other occupations. This review summarizes the scientific literature on oc cupational risk factors for brain tumors and examines some of the exposures that may be implicated. The measures of association shown in the tables are not directly comparable; thus we have used a test of statistical significance to evaluate the relative impor tance of the results shown. Because the authors of the numerous studies discussed in this review used a va- 2 riety of statistical tests to judge the significance of their results, we have ignored the original significance tests. Instead, we applied a common test statistic to each re sult for which the authors supplied an observed num ber of brain tumor events and an expected number of events or an observed:expected (0:E) ratio. If the OtE ratio was not provided by the original author, we cal culated it from the data published. This calculation in cludes results presented in the form of the propor tionate mortality ratio (PMR), the standardized mor tality ratio (SMR), the standardized incidence ratio (SIR), the proportionate incidence ratio (PIR), the standardized mortality odds ratio (sMOR), and the standardized rate ratio (SRR). The statistical signif icance of each of these results was determined from a table of significance factors for the ratio of a Pois son variable to its expectation (6). Since brain cancer r stuwiwi ASI 00005201 w* accounts for only 2.5 % of all cancer deaths (45), the underlying Poisson assumption of a rare event is satisfied in this case. Because our test is inappropriate for case-referent analyses, the statistical significance of the odds ratios from the case-referent analyses pre sented in the tables was determined with the 95 con fidence intervals provided by the authors. Surveys of mortality by occupation Information from death certificates, registries, or record linkage systems has been used in many surveys to examine disease risks by occupation. Surveys of mortality by industry were not included in tables I and 2 because of a lack of specificity with regard to occu pation; however results from some of these surveys are discussed in relationship with specific hypotheses pre sented later in this review. Because an exhaustive list of occupations reported in these surveys would be too lengthy to show in a single table, we decided to limit the results shown; thus, standardized mortality ratios, standardized incidence ratios, and standardized mor tality odds ratios of less than 1.3 are not shown and proportionate mortality ratios of less than 1.5 are not shown. Results from the Washington state mortality data (48) were obtained from a table of statistically significant results for brain cancer. The data indicated that certain white-collar and pro fessional groups may have an elevated brain cancer risk (table 1). These groups include financial managers and accountants, sales agents, engineers, teachers, lawyers and judges, postal clerks, and persons in the armed forces. These occupational groups presumably have minimal exposure to chemicals and other potentially carcinogenic agents in their jobs. White-collar and pro fessional groups may receive better than average medical and diagnostic services because of their socio economic status and, thus, may be more likely than the population in general to have a brain tumor diagnosed (24). Mortality was elevated among Cali fornia residents in the armed forces (63) and among British members of the armed forces (39, 65), who typically receive regular medical surveillance. Table 2 shows blue-collar worker groups with ele vated brain cancer mortality in occupational surveys. The most interesting are the elevated brain cancer mor tality ratios for electricians and power servicemen in four of the surveys (25, 48, 63, 64). Several of the oc cupations listed in table 2 involve exposure to solvents and organic chemicals, but no prominent patterns of common exposures are evident for particular occupa tions. Several of these surveys obtained the information on occupation from death certificates. Because the "usual occupation" listed on the death certificate may be more representative of last occupation, many of the persons classified in white-collar management occu pations could have begun their employment in bluecollar jobs. Occupations were not cross-classified by industry; thus it is not possible to evaluate whether ele vated risk occurred among white-collar managers in particular industries. Furthermore, relatives of a de ceased individual may tend to "upgrade" the de ceased's occupation socioeconomically. Table 2. Brain tumors among blue-collar occupations in surveys of mortality by occupation. Occupation or type of work* Study period Measure of association 6 Observed brain tumor events Ratio' Operatives A kindred workers, MA Painters, paperhangers, glaziers, US Carpenters (age 20--54 years), MA Brickmasons, stonemasons, tile setters, MA Electricians, US Electricians, WA Electricians, Los Angeles County, CA Linemen & servicemen, telegraph, telephone, power, CA Welders, metal, Sweden Boilermakers. CA Machinists & lob setters, US Machinists (age 20--54 years), MA Airplane mechanics & repairmen, WA Firemen A fire protection workers, WA Crane derrickmen A hoistmen, CA Deliverymen A routemen, CA Glass & ceramic makers, UK Glass workers, Sweden Farmers & farm workers, Canada Railroad clerks, WA 1971 -- 1973 1950 1971--1973 1971-1973 1950 1950-1979 1972-1977 1959-1961 1961 -- 1973 1959--1961 1950 1971-1973 1950-1979 1950--1979 1959--1961 1959-1961 1970-1972 1961-1973 1965-1973 1950-1979 sMOR SMR sMOR sMOR SMR PMR PIR PMR SRR PMR SMR SMOR PMR PMR PMR PMR SMR SRR SMR PMR 4 3.26 32 1.39 7 2.74* 4 3.14 31 2.21* 43 1.60* 11 1.42 5 2.07 44 1.44* 3 2.18 37 1.42 5 3.12* 14 2.01* 14 1.77 3 2.23 6 2.03 1.31 io 2.39* 4 1.77 13 3.48* * See table 1 (footnote a) for a definition of the abbreviations. b See table 1 (footnote b) for a definition of the abbreviations. c Ratio = observedexpected ratio or odds ratio. * Statistically significant (Poisson) at the 0.05 level. Reference Dubrow & Wegman (17) Guralnick (25) Dubrow & Wegman (17) Dubrow A Wegman (17) Guralnick (25) Milham (48) Preston-Martin et al (64) Peterson & Milham (63) Englund et al (18) Peterson A Milham (63) Guralnick (25) Dubrow & Wegman (17) Milham (48) Milham (48) Peterson & Milham (63) Peterson & Milham (63) Registrar General (65) Englund et al (18) Howe A Lindsay (33) Milham (48) 3 ASI 00005202 Production of synthetic rubber Table 3 shows results from studies of workers in the production of synthetic rubber. In 1949, an unusual cluster of deaths from CNS tumors was observed among residents of Summit County, Ohio, and a pos sible link with the rubber industry was suggested (42). Subsequently, a cohort mortality study of workers in a rubber plant in the same county indicated an elevated brain cancer risk among employees in the curing and tire-building department (43). Later studies of the same plant population also implied that men employed in tire assembly and tire building had an elevated brain cancer risk, but brain cancer mortality was less than expected in the entire plant population (51, 52). The elevated risk occurred primarily among men whose at tained age was less than 65 years (0:E = 8:1.3), those who lnd worked less than 15 years (0:E = 7:1,4), and those who started working in the industry after 1925 (0:E = 8:1.8). The findings suggested that the elevated risk may be associated with exposures introduced into the work environment in more recent time periods (51). Exposures in the tire curing, building, and assembly areas included hexamethylenetetramine and drum resins containing coal tar, carbon tetrachloride, and other solvents (51,52). A slightly elevated brain cancer risk was seen among workers in the rubber industry in Sweden (18), but brain cancer mortality was not elevated among US rubber workers in a 1950 survey by industry (26) nor in other cohort studies of US rub ber plants (46, 83) nor among workers in the rubber and cablemaking industries in England (19). Polyvinyl chloride production A cohort was assembled from 34 plants to examine the relationship between polyvinyl chloride (PVC) expo sure and risk of cancer (11,85). Among persons who had worked for at least one year in a job invoK ing ex posure to vinyl chloride, the total number of brain can cers observed was significantly greater than expected (table 4). The twelve brain cancers observed during the study period included four glioblastoma, two astro cytoma, one ependymoma, and five unspecified. A proportionate mortality ratio study of deceased workers in two plants using vinyl chloride monomer indicated an increased relative frequency of brain can cer (53). Five deaths were observed, and only 1.2 were expected (table 4). Three of the five brain cancers were Table 3. Brain lumors among workers in the production of synthetic rubber. Occupation or type of work* Study period Measure of association5 Observed brain tumor events Ratio0 Tire building & curing, Ohio One rubb'-r plant. US Tire building Tire assembly (> 5 years) Rubber industry, Sweden Rubber products industry, US Four US rubber plants -- Men Tire building, US Tire assembly, US Rubber & cablemaking industry, UK Tire sector 1940 -- 1964 1940--1974 1940--1974 1940--1976 1961-1973 1950 1940--1973 1951 -- 1971 1951 -- 1971 1968--1974 1968-1974 SRR SMR SMR SRR SRR SMR SMR OR OR SMR SMR 4 5.63' 20 0,80 7 1 90 7 4,1 * 30 1 23 13 14 0 78 5 1.10 1 0 43 20 0,84 10 1.08 * See table 1 (footnote a) for a definition of the abbreviations. 0 See table 1 (footnote b) for a definition of the abbrevialions. 0 Ratio = observed,expected ratio or odds ratio * Statistically significant (Poisson) at the 0.05 level. Reference M'incuso et at (43) Monson & Nakano (52) Monson & Nakano (52) Monson & Fine (51) Englund et al (18) Guralnick (26) McMichaei et al (46) Symons et al (83) Symons et al (83) Fox & Collier (19) Fox & Collier (19) Table 4. Brain tumors among workers in the production of polyvinyl chloride (PVC). Occupation or type of work* Study period Measure of association0 Observed brain tumor events Ratio0 PVC workers exposed z 1 years, US PVC workers ever exposed, US PVC workers exposed > 5 years, > 15 years latency. US Vinyl chloride monomer & PVC production workers, Sweden PVC workers, Germany PVC workers ever exposed. UK 1930-1972 1947-1973 1942-1973 1940--1974 < 1959--1974 1940--1974 SMR PMR SMR SMR SMR SMR 12 2 03' 5 4,17' 3 4 93' 2 6.12 2 1.62 2 0 55 * US = United States, Germany = Federal Republic Of Germany, UK: United Kingdom. " See table 1 (footnote b) for a definition of the abbreviations. ' Ratio = ob$erved:expected ratio or odds ratio. Statistically significant (Poisson) at the 0.05 level Reference Cooper (11) Monson et al (53) Waxwetler el al (97) Byren et al (9) Weber et al (93) Fox & Collar (20) ASX 0000S203 1 glioblastoma multiforme, and the cell types of the other tuo "ere not specified. Elevated brain cancer risk associated with polyvi nyl chloride production was observed in a cohort study which combined data from four plants (table 4) (97). One major plant was common to this study and those done by Tabershaw (85), Cooper (11), and Monson (53). Among workers with at least five years' ex posure to polyvinyl chloride and surviving 15 years since first exposure, three brain cancers occurred and less than one was expected. Four additional brain tumors occurred among employees who had less than five years' exposure to vinyl chloride. Three persons who worked at the plants under study but never in the vinyl chloride-exposed areas also died from brain tumors. No expected numbers were shown for these categories of workers. Nine of the ten brain tumors were histologically confirmed as glioblastoma multiforme. Age at death for these decedents ranged be tween 33 and 65 years. Other exposures that workers might have encountered included acrylates, acrylo nitrile, and chlorinated solvents (96). Studies of polyvinyl chloride workers in Germany and Sweden suggested an excess brain cancer risk (table 4), but the observed numbers of brain cancer deaths were \erj small (9, 98). Analyses of mortality among 7 000 men potentially exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain indicated no excess brain cancer risk (20). Petroleum refining and petrochemical production The first report of elevated brain tumor risk among oil refinery workers appeared in 1979 (table 5). In a cohort study of 1 205 men employed in a Canadian oil refinery for more than five years, three deaths from brain cancer were observed and only 0.77 was expected (87). This excess was confined to workers for whom less than 20 years had elapsed since first employment (0:E = 3:0.46). The work histories of the three brain cancer cases were vague with regard to occupational exposures. Two died at 41 years of age and one at age 43. A proportionate mortality ratio study of deceased active and retired members of the Oil, Chemical, and Atomic Workers International Union (OCAW) in Texas indicated an elevated frequency of deaths from brain cancer among white male hourly workers em ployed in petroleum refining and petrochemical plants (90, 92). The increased relative frequency of brain tumors occurred primarily among active employees in Table 5. Brain tumors among workers in petroleum refineries and petrochemical production. Occupation or type of work*** Study period Measure of association6 Observed brain tumor events Ratio6 Reference Refinery workers (a 5 years), Canada All OCAW members in refineries A, B. C, TX Active OCAW members in refineries A, B. C OCAW members -- refinery A OCAW members -- refinery B OCAW members -- refinery C OCAW members in refineries A, B. C Lube oil refining Pumping of products Texaco (A) -- salaried A hourly Texaco (A) -- research & quality control labs Texaco (A) -- lube oil refining Gulf (B) -- all hourly workers Gulf (B) -- hourly workers (a 20 years) Mobil (C) -- salaried A hourly Ninteen refineries, US Ninteen refineries, US Petroleum A coal products, US Eight oil refineries, UK Oil distribution centers, UK Exxon -- operator, mechanic, laborer Union Carbide (NIOSH), TX Union Carbide (company) -- > 6 months Petrochemical operators, LA and TX Dow Chemical, TX 1928-1976 1943-1978 1943-1978 1943-1978 1943--1978 1943-1978 1943-1978 1943-1978 1947-1977 1947--1977 1947-1977 1935-1978 1935--1978 1945-1979 1977-1979 1977-1979 1950 1950-1975 1950-1975 1970--1977 1941-1979 1941--1977 1970-1980 1949-1977 SMR PMR PMR PMR PMR PMR OR OR SMR OR OR SMR SMR SMR SMR SIR SMR SMR SMR SMR SMR SMR PMR Samplebased SMR 3 33 d 25 d 16d 10d 7d 5 7 31 8 3 20 d 15 9 8 9 13 36 39 4 22 d 10 12a 25 d 390 2.10' 2.29* 2.14' 1.90 2.35 1.6 2.8 1.08 3.9" 4.1" 0.90 1.40 1.09 1.63 1.29 6.80 1.07 1.11 2.06' 200 3.40* 1.26 Theriault & Goulet (87) Thomas et al (92) Thomas et al (92) Thomas et al (92) Thomas et al (92) Thomas et al (92) Thomas et al (91) Thomas et al (91) Divine et al (15) Divine et al (15) Divine et al (15) Wen et al (99) Wen et al (99) Morgan A Wong (54) Schottenfeld et al (75) Schottenfeld et at (75) Guralnick (26) Rushton A Alderson (70) Rushton A Anderson (71) Hanis et al (28) Waxweiler et al (95) Austin A Schnatter (3) Nicholson et al (56) Reeve et al (66) * OCAW = Oil, Chemical, and Atomic Workers International Union; TX = Texas, US = United States; UK = United Kingdom, NIOSH = National Institute for Occupational Safety and Health; LA = Loutsana b See table 1 (footnote b) lor a definition of the abbreviations. c Ratio = observed-expected ratio or odds ratio. Observed includes benign and unspecified brain tumors. * Statistically significant (Poisson) at the 0.05 level. ** Statistically significant at the 0.05 level using the author's significance test. three oil refineries (A, B, and C) in the Beaumont-Port Arthur area of the Texas gulf coast (table 5). A nested case-referent study comparing work histories of the brain tumor cases with those of persons who died from other causes indicated an elevated brain tumor risk among OCAW members whose jobs involved the intraplant pumping and transporting of bulk liquids (crude oil and products) and the manufacture of lubricating oil, but the odds ratios were not statistically significant (91). Industry-sponsored studies of refineries A, B, and C indicated slightly different results (table 5); however, the study groups differed substantially in terms of hourly/salaried status, average duration employed, and induction-latency period. A cohort mortality study of white male Texaco (refinery A in references 90,91,92) salaried (white-collar) and hourly (blue-collar) em ployees combined indicated no excess mortality from brain cancer (15). A nested case-referent analysis in dicated significantly elevated odds ratios for brain can cer among persons whose longest job was in research and quality control laboratories or in lubricating oil refining (15). All male hourly employees of the Gulf refinery (refinery B in references 90, 91, 92) did not have a significantly elevated standardized mortality ra tio for brain cancer; however, mortality was slightly elevated among those who had worked at the plant for more than 20 years (99). The number of brain cancer deaths observed among white male salaried and hourly employees of the Mobil refinery (refinery C in references 90, 91,92) was almost the same as that expected (54). Among white men employed 10 or more years at the Mobil refinery there were slightly elevated standardized mortality ratios for brain cancer (10--29 years, SMR 142.4; > 30 years, SMR 133.5). In a mortality study of oil refinery workers employed by 19 US companies (table 5), eight deaths from brain cancer were observed, and 4.9 were expected (SMR 1.63) (75). The investigators suggested that there may have been underreporting of deaths because of the short study period (two years) and the lag time between the date of death and receipt of a death certificate. Cancer incidence among actively employed refinery workers during the study period was compared with that for the United States from cancer registry inci dence data. Nine incident cases of brain cancer were reported, and about seven were expected. No analyses by duration of employment or occupation were shown. Brain cancer mortality was not excessive among 35 000 employees of eight British oil refineries between January 1950 and December 1975 (table 5) (70); how ever, about 20 % of the study subjects had scientific, technical, administrative, clerical, or engineering jobs, most of which are presumably low-exposure occupa tions. The same difficulty occurred in a cohort of workers at oil distribution centers in England (71), in which supervisors, managers, administrators, and clerical workers were included in the analyses. Analyses were not shown separately for blue-collar (hourly) employees. In one study of refinery workers, investi gators found no association between brain cancer risk and oil refinery employment (28), and two other groups of investigators did not report the observed and ex pected values for brain cancer (29, 84). The follow up period for several studies (28, 29, 75, 84) was very short (less than 10 years), and risks of fatal disease with long latency periods may have been underestimated. A duster of primary brain cancer deaths among workers at a Union Carbide petrochemical plant in Texas City, Texas, was reported in 1980 (2). All of the decedents were less than 66 years of age at death, and the best medical information available indicated that 15 of 18 tumors were glioblastoma multiforme. A cohort mortality study of workers at this plant showed a significantly elevated standardized mortality ratio for brain tumors among white male hourly workers (table 5) (95). A similar analysis of the same data by the com pany also indicated a significantly elevated brain can cer risk among workers who ever held hourly positions (3), but nested case-referent analyses indicated no sig nificantly elevated odds ratios associated with expo sure to any specific chemicals (4, 35). Operating engineers employed in the petrochemical industry in Texas and Louisiana had an elevated fre quency of brain tumors (observed 18, PMR 1.73) (56). This excess was primarily due to a significantly elevated proportionate mortality ratio for brain tumors among persons employed as operators in oil refineries and petrochemical plants (table 5). A sample-based cohort mortality study of workers at a Dow Chemical petrochemical plant in Freeport, Texas, suggested a slightly increased risk from brain tumors (table 5) (66). Clinical or pathological infor mation was obtained for 19 of 25 brain tumors. Based on the best medical information available, 12 were glio blastoma multiforme, and two others were gliomas. A nested case-referent study failed to identify a signif icantly elevated risk associated with employment in any particular department or with exposure to any specific chemical or other agent (8). Other chemical production Studies of chemical plant workers exposed to formal dehyde showed inconsistent results regarding brain tu mor risk. A cohort mortality study of 2 026 workers at a large formaldehyde-producing plant suggested that workers hired before 1961 had an elevated brain can cer risk (table 6) (103). Two of the three persons w ith brain cancer died after a latency period of 10 years. A proportionate mortality ratio study of workers at another plant involved in the production of formal dehyde and its use in the production of resins did not show an elevated frequency of brain cancer (44); how ever only 136 decedents had been exposed to formal dehyde. Both of these studies included small numbers of exposed workers. No data for observed and ex- MBsas** mm pected numbers of brain cancer deaths were presented in a report of the moi tality experience of 7 680 work ers exposed to formaldehyde in the British chemical industry (1). An elevated relative frequency of brain cancer was seen among plant employees but not among sales rep resentatives of a large pharmaceutical firm (89). Brain cancer mortality was elevated among white male production workers (0:E = 8:1.6) and administrative and clerical workers (O:E = 4:1.0) (table 6). Produc tion workers in this industry are exposed to multiple chemical and biological agents. Acrylonitrile has been reported to cause brain tu mors in animals (41); however only one epidemiologic study of acrylonitrile-exposed workers has shown an excess of brain cancer (table 6). Two brain cancer deaths were observed among acrylonitrile polymeriza tion workers in the United Kingdom, and only 0.7 was expected (100). In other studies, brain tumor risk was not elevated (57) or not shown (14, 88). Nuclear industry A study of w orkers at a nuclear fuels fabrication plant indicated elevated brain cancer mortality and incidence among male plant employees (table 7) (27). It was as sumed that all employees had exposure to low levels of gamma radiation; however other exposures in the plant were similar to those in metal working and fab ricating plants and included metal fumes, metal dusts, and oil mists. Seven of the eight incident brain tumors were gliomas, and one was not specified. All except one of the men with a brain tumor were between the ages of 40 and 56 years at death. White men employed at the Rocky Flats nuclear weapons fabrication facility for at least two years between 1952 and 1979 (102) had a slight excess mor tality from malignant brain tumors (table 7), and there was a significant excess of benign and unspecified tu mors of the brain (0:E= 6: < 1.48). Exposures in the work environment included plutonium, uranium, beryl lium, other metal dusts, oil mists, and other exposures typical of machining operations. Increasing mortality trends by latency were seen for brain tumors; however most of the tumors occurred among persons employed less than 15 years. A hospital record review of 16 cases in persons who had ever worked at the plant indicated that 14 were gliomas. Age at death ranged from 31 to 77 years, with a median age of 50.5. A nested casereferent study failed to identify any particular jobs or exposures associated with unusually high brain tumor risk (67). A cohort mortality study of white men employed at a Union Carbide nuclear weapons facility showed an excess of brain cancer deaths among workers in de partments that did not have exposure to mercury (table 7) (12). The operations in these departments included Table 6. Brain tumors among workers in other chemical plants. Occupation or type of work* Study period Measure of association6 Observed brain tumor events Ratio' Formaldehyde producers, US (hired < 1960) Pharmaceutical production. US Pharmaceutical office workers, US Acrylonitrile polymerization, UK Acrylonitrile polymerization, US Chemicals & allied products, US Chemical workers, Italy 1940-1977 1954-1976 1954--1976 1950-1978 1950-1976 1950 1979-1980 SMR PMR PMR SMR SIR SMR OR 3 2.13 8 5.00* 4 4.00* 2 2.90 1 22 i.oo 4 1.9 * US = United States, UK = United Kingdom. b See table 1 (footnote b) for a definition of the abbreviations. * Ratio = observed:expected ratio or odds ratio. * Statistically significant (Poisson) at the 0.05 level. Reference Wong (103) Thomas & Decoufle (89) Thomas & Decoufle (89) Werner & Carter (100) O'Berg (57) Guralnick (26) Musicco et al (55) Table 7. Brain tumors among workers in the nuclear fuels and weapons fabrication industry. Occupation or type of work Study period Measure Of association* Observed brain tumor events Ratio6 Nuclear fuels fabrication Rocky flats -- employed a 2 years Malignant brain tumors Benign & unspecified Union Carbide -- nonmercury Hantord plant employees 1956-1978 1951-1977 1951--1977 1953-1978 1955-1974 SMR SMR SMR SMR SMR 4 2.40 6 1.49 6 4.05* 13 2.30* 28 0.99 SMR = standardized mortality ratio. Ratio = observed:expected ratio or odds ratio. Statistically significant (Poisson) at the 0.05 level. Reference Hadjimichael et al (27) Wilkinson et al (102) Wilkinson et al (102) Cragle et al (12) Gilbert & Marks (22) 7 ASI 00005206 ju-s: ? separation of a uranium isotope through an electro magnetic process and other engineering and manufac turing processes in the fabrication of nuclear weapons. Workers employed in the manufacture, chemical separation, and purification of plutonium at the Han ford plant in Washington state did not have an elevated brain cancer risk (22) overall (table 7) or in any cumulative radiation dose category. Data for men in metalworking and machining occupations were not shown separately. None of the studies at nuclear weapons fabrication facilities showed an association of elevated brain can cer risk in relation to any particular radiation level. One factor common to all of the facilities was the presence of machining operations in which there was an opportunity for exposure to metal dusts and fumes and lubricating oil mists. Beryllium was machined at one of the facilities (102). Other industrial workers Numerous chemicals, some of which contain formal dehyde, are used in photographic processing opera tions, and high levels of formaldehyde have been mea sured in print laboratories (21). After preliminary stud- , ies indicated a possible brain cancer excess among em ployees of an Eastman Kodak plant, a nested casereferent study of brain cancer by exposure category indicated an elevated risk among photographic pro cessing workers exposed to color developers (24). Risks were slightly elevated among workers exposed to sol vents, animal tissue, and film developers (table S). None of the results were statistically significant. No deaths from brain cancer were observed among 208 deceased white male press photographers who often developed their own film (49). A study of 47 glioma cases diagnosed in 1979 and 1980 in Milan, Italy, indicated a twofold excess risk of glioma among textile workers (55). The odds ratio of 2.1 was not statistically significant (table 8). About 20 Vo of the cases had worked in the textile industry, where formaldehyde and other chemicals were used in processing fabrics. In a 1950 survey, US men employed in yarn, thread, and fabric mills had an elevated standardized mortality ratio for brain cancer (26). White male members of the Pattern Makers League of North America who died between 1972 and 1978 had an increased relative frequency of brain tumor deaths (6S). The proportionate mortality ratios were elevated among pattern makers who worked predom inantly with wood and among those who worked pre dominantly with metal (table S). A cohort analysis of cancer morbidity among automobile pattern makers who worked with wood found no significant excess of brain cancer (79). Machinists employed at an automobile manufactur ing plant for five years or more in jobs with exposure to cutting oil mists did not have a significantly e!ev ated risk of death due to brain cancer (0:E = 5:3.3) (1?). Among men who entered the study group after 1948, Table 8. Brain tumors among other industrial workers. Occupation or type of work* Study period Measure of association6 Observed brain tumor events Ratio' Kodak workers (age 55--59 years), NY Kodak workers -- solvents Kodak workers -- color developers Kodak workers -- animal tissue Kodak workers -- black & white developers Textile workers, Italy Yarn, thread, fabric mills, US Pattern makers -- wood, US Pattern makers -- metal, US Automobile wood pattern makers, Ml Automobile machinists (1948+ ), US Aviation electronics workers, US Aluminum reduction workers, US Bus mechanics, UK Railroad carmen, Canada Railroad -- welding fumes, Canada Railroad workers, US Asbestos insulation workers, US Electricians, linemen, servicemen, engineers, MD Glial tumors Unspecified brain 1964-1975 1956-1975 1956-1975 1956-1975 1956-1975 1979-1980 1950 1972-1978 1972-1978 1970-1978 1937-1967 1950--1980 1946--1976 1967--1975 1965-1977 1965-1977 1967-1979 1967-1976 1969-1982 1969--1982 SIR OR OR OR OR OR SMR PMR PMR SIR SMR PMR SMR SMR SMR SMR SMR SMR OR OR 14 2.8132 1.40 6 2.16 13 1.32 7 1.31 10 2.1 32 1.45 7"* 1.75 5d 2.94 1 1.63 3 3.75 9 3.0r 8" 2.25 4 3.20 7 2.78' 10 3.18- 5 1.32 214 1 59 27 2.15* 15" 1.54 * NY = New York, US = United States, Ml = Michigan, UK = United Kingdom. MO = Maryland. 11 See table 1 (footnote b) (or a definition of the abbreviations. c Ratio = observed.expected ratio or odds ratio. * Observed includes benign and unspecified brain tumors. * Statistically significant (Poisson) at the 0.05 level. 8 Reference Greenwald et al (24) Greenwald et al (24) Greenwald et al (24) Greenwald et al (24) Greenwald et al (24) Musicco et al (55) Guralnick et al (26) Robinson et al (68) Robinson et al (68) Swanson & Belle (79) Decoulle (13) Sweeney & Ahrenholz (80) Milham (47) Rushton et al (72) Howe et a! (321 Howe et al (32) Schenker et al (73) Seidman ei al (76) Lin et al (38) Lin et al (33) ASI 00005207 however, there was a notable excess of brain cancer deaths (table 8). A proportionate mortality ratio analysis indicated that white male hourly and salaried employees of an aviation electronics plant had an elevated frequency of deaths from brain cancer (table 8) (80), Six of the nine brain cancers wrere glioblastoma multiforme, one was neurilemmoma, and two were unspecified. Poten tial workplace exposures included trichlorethylene, be ryllium, and a halogenated aromatic hydrocarbon balancing fluid. All five hourly employees with brain cancer had worked as machinists. A mortality study of aluminum reduction plant workers (table 8) indicated an elevated risk of benign brain tumors (observed 5, SMR 9.09) but not malig nant tumors (observed 3, SMR 0.99) (47). All five per sons with benign brain tumors had worked in "ex posed" jobs in the carbon plant, rodding, potlining, potrooms, or quality control. Exposures included fluo rides, particulate alumina, polycyclic aromatic hydro carbons, and sulfur dioxide. An excess of benign neo plasms was found in another study of workers em ployed in 14 aluminum reduction plants (69); however no details were given regarding the primary site of these tumors. Maintenance workers exposed to hydrocarbons in the form of diesel exhaust in London bus garages had a slightly elevated standardized mortality tatio for brain cancer (SMR 1.21) (72). This excess was prima rily due to the elevated standardized mortality ratio for brain cancer among bus mechanics, who were also exposed to oils, greases, and solvents (table 8). A study of Canadian railroad workers exposed to diesel fumes and coal dust showed an elevated brain cancer risk among carmen (table 8) (32). Railroad workers exposed to welding fumes had a threefold ex cess of brain cancer mortality. A survey of mortality by occupation in Sweden also showed excess brain can cer among welders (table 2) (18). US railroad workers had a slightly elevated standardized mortality ratio for brain cancer (table 8), but no data were shown for those with high levels of exposure to diesel or welding fumes (73). A slightly elevated brain tumor risk was reported in a cohort study of asbestos insulation workers (table 8) (76). These workers were employed primarily in the building construction trades, but they also could have worked in shipyards, chemical plants, and oil refin eries, where there are exposures to numerous sub stances. A case-referent study using the occupation listed on death certificates suggested an elevated risk of glioma and unspecified brain tumors among a category of workers which included electric and telephone com pany servicemen, linemen, foremen, and engineers; railroad and telecommunication engineers; electricians; and electric and electronic engineers (table 8) (38). These findings are consistent with those seen in four surveys of mortality by occupation (table 2) that found elevated brain cancer mortality among electricians and power servicemen. Electrical engineers (table 1) also had elevated brain cancer mortality. These occupations have potential exposure to electromagnetic fields, po lychlorinated biphenyls, solder fluxes, and solvents. Professional and other nonindustrial groups The National Institute for Occupational Safety and Health (NIOSH) evaluated the mortality experience of w'hite men employed as motor vehicle examiners in New Jersey for at least six months between 1944 and 1973 (77), The examiners were exposed daily to mo tor vehicle exhaust consisting of aldehydes, carbon di oxide, carbon monoxide, hydrocarbons, lead com pounds, nitrogen, oxides of nitrogen, oxygen, and sul fur dioxide. Four deaths from brain cancer were ob served, and only 1.7 were expected (table 9). All four brain cancers were malignant gliomas. A proportionate mortality ratio study of profes sional artists indicated a significant threefold excess frequency of brain cancer deaths among white male artists (table 9) (50). The excess deaths were not linked to any particular art specialty. Artists may be exposed to numerous potentially carcinogenic substances in cluding components of pigments, dyes, solvents, metal fumes, and dust. Professional chemists are exposed to numerous chemical agents in the laboratory setting. An elevated standardized mortality ratio for brain cancer was seen among 526 chemists who had been educated at one school in Sweden (58) between 1930 and 1949. No brain cancer deaths occurred among 331 men educated at a second Swedish school (58). Further follow-up of the first cohort indicated a significantly elevated mortality from brain cancer (table 9) (59). Other studies of chemists have not reported elevated brain cancer mor tality (31, 37). Members of the Royal College of Pathologists in 1973 were followed for vital status in 1981 (30). Among 2 300 men, six deaths from brain cancer occurred and less than two were expected (table 9). Hematology was a common subspecialty among the decedents with brain cancer. Pathologists are exposed to formalde hyde and other laboratory chemicals. Anatomists, who are exposed to similar chemicals, had a significantly elevated brain cancer risk (78) compared with the US general population (table 9). When another profes sional group was used for a comparison, the stan dardized mortality ratio was 6.00. Risk appeared to increase by duration of employment, but was also elevated among those employed less than 20 years. Risk was elevated regardless of presumed level of exposure to formaldehyde. Four of the 10 brain cancers were listed as "astrocytoma" on the death certificate, while the remaining six were listed as "glioblastoma." Proportionate mortality ratio analyses of deaths among embalmers and funeral directors in New York ASI 00005208 I Table 9. Brain tumors among professional and other nonindustrial workers. Occupation or type of work* Study period Measure of association0 Observed brain tumor events Ratio0 Reference Moto vehicle examiners, NJ Professional artists, US Chemists -- one school, Sweden DuPont chemists, US Pathologists, UK Anatomists, US Embalmers, NY Embalmers, CA Embalmers, Ontario Female cosmetologists, CT Registered female nurses, WI Veterinarians, US Farmers after i960, Italy Agricultural industry, Canada Agricultural workers, Sweden 1944--1973 1940-1969 1930--1977 1964--1977 1974--1981 1924--1979 1925-1980 1925-1980 1950--1977 1935-1978 1963-1977 1947--1977 1979--1980 1955-1973 1961 -- 1973 SMR PMR SMR SIR SMR SMR PMR PMR SMR SIR PMR PMR OR SMR SMR 4 2.35 8 2 90' 5 4.172 0.67 6 > 3.0010 2.716 2.34 9 1.94 3 1.15 16 1.68 21 1.61 28 1.6313 3.64 2 68 744 1.08- Stern et al (77) Miller et al (50) Olin & Ahlbom (59) Hoar & Pell (31) Harrington & Oakes (30) Stroup et al (78) Watrath & Fraumeni (93) Walrath & Fraumeni (94) Levine et al (36) Teta et al (86) Katz (34) Blair & Hayes (7) Musicco et al (55) Howe & Lindsay (33) Wiklund (101) * NJ = New Jersey, US = United States, UK = United Kingdom, NY = New York, CA = California, CT = Connecticut, Wi = Wisconsin. b See table 1 (footnote b) for a definition of the abbreviations 0 Ratio = observediexpected ratio or odds ratio * Statistically significant (Poisson) at the 0.05 level. (93) and California (94) indicated elevated frequencies of brain cancer deaths (table 9). Among white men in New York licensed only as embalmers, there was a 2.5-fold excess (93). A cohort mortality study of On tario embalmers did not show an excess brain cancer risk, but the study group was small, and no data were shown by latency or duration of exposure (36). Em balming fluids consist primarily of formaldehyde, but also contain phenol and methanol. Professional cosmetologists are occupationally ex posed to numerous chemical substances, including for maldehyde solutions, hair dyes, permanent wave solu tions, and other cosmetic preparations. Female cos metologists in Connecticut had an elevated incidence of brain cancer (table 9) (86). This excess was more prominent among those who began hairdressing school between 1925 and 1934 (observed 6, SIR 2.02). Ten of the 16 cases observed were histologically confirmed glioblastoma multiforme. A significantly elevated frequency of nervous sys tem cancers was seen among registered nurses in Wis consin in a comparison with other gainfully employed women (table 9) (34). The observed number of deaths was also greater than the number expected on the basis of mortality among other female professional workers (PMR 1.47). An analysis of mortality among veterinarians indi cated an excess frequency of deaths from brain can cer (table 9) (7). The increased relative frequency was not confined to any particular veterinary specialty group. Four studies have shown an elevated brain cancer risk among farmers (table 9). Odds ratios for gliomas were statistically significant among Italian farmers who had been farming for more than 10 years and among those who had been engaged in farming since 1960, when the use of phosphoric acid and organochlorine compounds became very common as pesticides in Ita ly (55). A study of primary CNS neoplasms in Minne sota indicated a slightly higher than expected propor tion of farm residents among the brain tumor cases (10). The authors speculated that there may be an as sociation with toxoplasmosis gondii infection. Elevated brain cancer risk was also found in a study of Swed ish agricultural workers (101) and among agricultural workers in Canada (33). Discussion There were several limitations in the presented epide miologic studies. First, there is a paucity of casereferent studies of brain tumors; thus most of the in formation was obtained from mortality studies that lacked sufficient statistical power to evaluate specific occupational risk factors adequately for brain tumors. The observed and expected numbers of brain tumor cases in most of the studies were very small. Exposure information was ascertained from work histories in some of the studies and from interview data in some, but, in others, no specific information on workplace exposures was available. In the nested case-referent studies the numbers were very small, and there were difficulties in relating exposures to specific jobs. In most instances workers had multiple exposures, and risks due to any single exposure could not be ade quately evaluated. Brain tumor diagnosis was ascertained from death certificates in most of the studies; therefore the accu racy of the diagnoses may be questionable. The diag nosis "brain tumor" listed on a death certificate would be nosologically coded as a primary tumor of the brain, unspecified as to whether malignant or benign. Many 10 ASI 00005209 o; these tumors may actually have been primary ma* 1-.mancies of the brain. Alternatively, since the brain a common site for metastases of other primary canr., some death certificate diagnoses may not reflect :kc actual primary site. A study of deceased persons m the Third National Cancer Survey areas indicated hat about 97 Vo of deaths from malignant brain tu mors would be ascertained from death certificates (62), whereas only 89 Vo of all primary brain cancer diag noses on death certificates were confirmed by hospital records. This finding indicates that about 10 Vo of the brain cancer cases ascertained from death certificates ma> be misdiagnosed. The issue of misdiagnosis is not considered a major problem, particularly if the general population is used to calculate expected numbers of death in studies that ascertain cause of death from death certificates. In 1981 Greenwald et al (24) concluded that an ex cess of brain tumors noted among Kodak employees mat have resulted from a "diagnostic sensitivity bias.'' This conclusion was drawn because none of the results of the nested case-referent study were statistically sig nificant and because Kodak employees had brain tu mor diagnoses that were histologically confirmed more often than did other brain tumor patients in New York. This explanation might appear plausible in light of the excess risk noted in several professional and whitecollar groups; however, all of the workers reported to have elesated brain tumor risk in this review were probably not enrolled in comprehensive medical sur veillance programs. Furthermore excess brain tumors w ere seen only among certain subgroups of some plant populations (eg, workers in the tire building sector of rubber production, refinery workers in lubricating oil manufacture). In addition other groups with medical surveillance programs, for example, Du Pont em ployees, do not show an elevated brain tumor risk (61). Despite limitations in study methodology, some si milarities are seen between the findings of these stud ies with respect to age and cell type diagnoses. Ages at death for most of the brain tumor cases ranged between 40 and 65 years. It is not clear whether this pattern reflects the age distribution of the populations studied or a biological phenomenon related to the origin of brain tumors. Age-specific mortality rates for US white males indicate a peak between the ages of 45 and 65 years (45). Very few studies included diagnostic information from sources other than death certificates. Since death certificates do not often indicate the cell type of these tumors, most studies grouped all brain tumors without distinction by ceil type. It is possible that risk factors vary by cell type. In the studies that had diagnostic information from medical records, a high percentage of the diagnoses were gliomas, particularly glioblas toma multiforme; however, no expected numbers could be calculated for this type. Table 10 shows selected categories of exposures com mon to the work environments of the occupational groups that appear to have an elevated brain tumor risk. This list is by no means all-inclusive, and one must keep in mind that most of the occupational groups listed are exposed to multiple agents. Numerous groups with elevated brain tumor risk are likely to be exposed Table 10. Common ocupational exposures among groups with elevated brain tumor risk. Occupational group potentially exposed Organic solvents Lubri cating oils Exposure Acryloni trile or vinyl chloride Formalde hyde Acrylonitrile polymerization workers X X Airplane mechanics and repairmen XX Aluminum reduction plant workers X Anatomists X Artists X Bus mechanics XX Chemists X Cosmetologists X Electricians X Embalmers X Farmers and agricultural workers XX Formaldehyde production workers X Machinists XX Motor vehicle examiners Nuclear fuels & weapons fabrication X X Nurses Oil refinery workers XX Pathologists X Pattern makers -- metal XX Petrochemical plant workers X Pharmaceutical workers X X Photographic process workers X X Polyvinyl chloride production workers X X Rubber workers XX Textile workers X X Veterinarians X Polycyclic aromatic hydro carbons Phenols and phenolic compounds X X X X X X X X X X X X XX X X X X XX X X to organic solvents. This broad category of compounds includes aliphatic hydrocarbons and aliphatic halognated hydrocarbons like methylene chloride, car bon tetrachloride, tetrachloroethylene, and others. It also includes aromatic hydrocarbon solvents like ben zene and toluene. One of the common acute effects of exposure to many of these compounds is CNS de pression (16); however solvents are not known to cause brain tumors experimentally. Oil refinery workers, chemical plant workers, rubber workers, and many other occupational groups are exposed to organic solvents. Exposure to polycyclic aromatic hydrocarbons oc curs in the rubber manufacturing, petroleum refining, and aluminum reduction industries. Motor vehicle ex aminers and bus mechanics may also be exposed to these hydrocarbons in motor vehicle exhaust. Certain polycyclic aromatic hydrocarbons have induced brain tumors in animals by direct implantation and transplacentally, but not by inhalation exposure (81). Lubricating oils produced by oil refineries are used for maintaining mechanical equipment and machines and for lubricating cutting edges. Thus several of the groups with elevated brain cancer mortality are ex posed to various types of lubricating oils. Gliomas have been experimentally induced in ani mals by inhalation exposure to acrylonitrile and vinyl chloride (40, 41). These compounds are similar in chemical structure and are found in plastics depart ments in the rubber industry, in polyvinyl chloride production, and in acrylonitrile polymerization. Formaldehyde has recently been shown to induce nasal cancer in rats (82), a finding implying that it may also be carcinogenic in humans. Several of the groups with elevated mortality from brain cancer were occu pationally exposed to formaldehyde. These groups in clude blue-collar workers involved in formaldehyde production, photographic processing and textile production, professionals who use formaldehyde in the laboratory setting, and embalmers. Phenols and phenolic compounds are used widely in manufacturing industries, and many of the com pounds have commercial uses. These include phenol, chlorophenols, cresol, resorcinol, hydroquinone, and quinone. Phenolic compounds are used in the produc tion of explosives, fertilizers, textiles, paints and paint removers, rubber, wood preservatives, synthetic resins, pharmaceuticals, photographic chemicals, rubber, and organic chemicals. Commercial uses include fungicides and herbicides, disinfectants, laboratory reagants, and photographic processing (60). Acute intoxication of these compounds causes severe CNS effects, including tremors, convulsions, vertigo, and mental disturbances. None of these compounds have induced brain tumors experimentally; however some phenols are known to be tumor promoters and cocarcinogens in certain tis sues (16). Of the broad categories of aforementioned sub stances, only a few have been shown to cause brain tumors in laboratory animals. These include certain polycyclic aromatic hydrocarbons, vinyl chloride, and acrylonitrile. However, several of the substances, spe cifically, formaldehyde, certain solvents, and some phenolic compounds, are known to cause neurotoxic effects after acute high-level exposure. Thus, the brain is obviously a target organ for the toxic effects of these materials. Clearly, further epidemiologic studies are necessa ry to evaluate the relationship between brain tumors and occupational exposures. These studies should in clude large numbers of cases and diagnostic confirma tions so that data may be analyzed by cell type. 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