Document 930Y1g4115pB3aBG3nKKnyod5

'Environmental Health Perspectives Vol. 88, jrp. 325-387, 1990 Parental Occupation and Childhood Cancer: Review of Epidemiologic Studies by David A. Savitz* and Jianhua Chen* Parental occupational exposures might affect childhood cancer in the offspring through genetic changes in the ovum or sperm or through transplacental carcinogenesis. The 24 published epidemiologic studies ofthis association have all used case-control designs, with controls generally selected from birth certificates or from general population sampling. Occupational exposures were inferred from job titles on birth cer tificates or through interviews. A large number of occupation-cancer associations have been reported, many of which were not addressed or not confirmed in other studies. Several associations have been found with consistency: paternal exposures in hydrocarbon-associated occupations, the petroleum and chemical industries, and especially paint exposures have been associated with brain cancer; paint exposures have also been linked to leukemias. Maternal exposures have received much less attention, but studies have yielded strongly suggestive results linking a variety of occupational exposures to leukemia and brain cancer. The primary limitations in this literature are the inaccuracy inherent in assigning exposure based on job title alone and imprecision due to limited study size. Although no etiologic associations have been firmly established by these studies, the public health concerns and suggestive data warrant continued research. Introduction In spite ofnumerous epidemiologic studies of parental occupation and childhood cancer, no clear causal asso ciations have been established (1,2). In fact, the only established human carcinogen that acts through either parent is diethylstilbestrol, a drug administered during pregnancy that causes vaginal adenocarcinoma in fe male offspring (5). It happens that the resulting vaginal cancer does not appear during childhood, but this agent establishes the plausibility of transplacental exposures affecting human cancer risk. In utero exposure to di agnostic X-rays is strongly suspected of causing leu kemia during childhood (4), but the association remains controversial (5). The evidence that parental occupational exposures can adversely affect reproductive outcomes other than cancer is persuasive (1,6). Exposures to males can cause infertility (7) and possibly miscarriages among wives of exposed workers (8,9). Pregnant women who work with anesthetic gases appear to have an excess of miscar riages (10,11) as do nurses exposed to chemotherapeutic drugs used in cancer treatment (12). Studies of parental occupation and childhood cancer are predicated on the limited evidence linking other parental exposures (drugs, X-rays) to childhood cancer combined with the *Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC 27599. Address reprint requests to D. A. Savitz, Department of Epide miology, CB #7400, School of Public Health, University of North Carolina, Chapel Hill, NC 27599. stronger indications that agents in the workplace can adversely affect reproduction (13). Potential mechanisms for an effect of parental occu pational exposures specifically on childhood cancer are speculative. Preconception maternal exposures might have genetic effects that alter the offspring's suscep tibility to cancer, although the ovum appears to be rel atively protected from exogenous agents (14.). Transplacental carcinogenesis is a more likely mech anism through which in utero exposures would influence the later development of cancer. As noted earlier, di ethylstilbestrol remains the only established human transplacental carcinogen, but extensive laboratory evi dence (15) supports the plausibility of environmental agents operating in this manner and suggests that pre natal exposures may be more potent than postnatal ex posures. The evidence for transplacental toxicity is clear for maternal exposure to teratogens such as lead and alcohol (14). Enhanced susceptibility to cancer during childhood could be viewed as a type of congenital anom aly produced by maternal exposure to workplace terato gens. Nonetheless, a series of assumptions is required to argue for the plausibility of an etiologic role of ma ternal occupational exposures in childhood cancer. The potential mechanisms through which male oc cupational exposures might affect the offspring's risk of cancer are far more tenuous. One possible pathway is for the father to bring toxic exposures into his home (16) and thereby expose his wife and, transplacentally, the fetus. Such an indirect route could only occur for nonvolatile chemical agents such as lead. Whether the 326 SAVITZ AND CHEN dose of a toxic agent would be sufficiently large to reach the wife and then the fetus in appreciable quantities is questionable. A biologically interesting but far more speculative mechanism is a genetic alteration in the father's sperm that would transmit an enhanced cancer susceptibility to his child. Genetic syndromes, which include specific types of childhood malignancies such -as certain forms of retinoblastoma or Wilms' tumor, are well documented (17), and the paternal genome clearly can contribute to this risk. Sperm are genetically susceptible to environ mental agents (18). Epidemiologic evidence for pater nally mediated reproductive effects other than infertil ity, however, is quite limited. No paternal exposure (drugs, tobacco, radiation, or environmental chemicals) has been proven to cause miscarriage, congenital de fects, or childhood cancer (6,13). Laboratory evidence suggests that paternal exposures to rats can affect fetal loss and malformations (19), growth (20), and even sub sequent cancer risk (21) without altering fertility. Ex amination of exposures that might genetically alter sperm to enhance the risk of cancer in the offspring of humans thus has some experimental basis, but a welldefined biological basis for paternal exposures increas ing the risk of childhood cancer is absent. In spite of a somewhat tenuous biological rationale, the association of parental occupation and childhood can cer has received substantial interest. The methods and results of the 24 epidemiologic evaluations of parental occupation and childhood cancer that were found in the literature up to October 1989 (22-45) are reviewed. The literature is essentially a collection of unrelated empir ical observations that are not well-suited to a condensed narrative summary (2), so detailed tables have been provided. Relative to an earlier review (46), the volume of literature has grown and a more systematic approach to the classification of study results was developed. As studies proliferate, it will be important to identify those associations that are sufficiently consistent and plausi ble to deserve the intensive effort that will ultimately be required to establish or refute suggestions of caus ality. Methods of Review All published literature that directly assessed paren tal occupation and any form of childhood cancer in hu mans was included. Although the primary interest was on chemical and physical hazards in the workplace, oc cupations not likely to incur such exposures were also considered. Study methodologies were summarized and results were tabulated according to the exposed parent (father, mother), the type of childhood cancer studied (total, leukemias and lymphomas, nervous system, and urinary tract), and the nature of the occupational ex posure (hydrocarbons, metals, etc.). Odds ratios ad dressing similar associations were tabulated in chron ological order by the year of publication. Results for a specific occupation-cancer association were tabulated whenever one or more of three condi tions was met: a) the odds ratio was 1.5 or greater based on 10 or more exposed cases or 5 or more discordant pairs; b) the odds ratio was statistically significantly elevated (p < 0.05); or c) another study provided an association that met conditions a or b and data pertain ing to that association were reported based on 5 or more exposed cases and 3 or more discordant pairs in another study. The goal was to include suggestive associations, requiring a certain minimum study size and a minimally elevated odds ratio. If such an association was observed in at least one study, the criteria for including potential corroborative or contradictory evidence was relaxed in order to fully examine the consistency of the observa tion. Some studies failed to provide a complete array of results, instead tabulating only those that were statis tically significant (54,45). Unfortunately, the effect es timates for such nonsignificant associations could not be included. In some instances, odds ratios had to be calculated from data provided in the articles (22-24-,28). In these calculations, the occupation of interest was considered exposed and all other occupations were considered unexposed. To minimize redundancy in the tables and provide comparable data across studies, several addi tional rules were imposed. Some studies provided risk estimates based on different time periods of exposure (28,31,32,41), but only occupational data nearest the time of birth are presented. Two studies provided risk estimates for different calendar time periods (25,26), but only the values for the total study period were tab ulated. Most studies considered alternative definitions of occupational exposure based on industry, occupation, aggregated industries or occupations, etc. The narrow est occupational groupings are presented, although this goal was sometimes relaxed to include substantially el evated relative risk estimates and to avoid tabulating closely overlapping categories. Results Study Methods Table 1 summarizes the constitution of the study groups, exposure definitions, and confounders included in these 24 studies. Interest in this topic has recently expanded: only two of the studies were published before 1980 versus 15 in 1984 or later. All of the studies used case-control sampling, with the proportionate mortality analysis of Sanders et al. (26) interpretable as a casecontrol study in which the control group consists of all decedents (47). The age range of cancer cases varied markedly across studies, with upper age limits ranging from 1 (29) to 24 years old (36). Vianna et al. (29) postulated that the earliest cancers are more likely to be affected by in utero exposures. Most studies have been conducted in the United States, with one each in Canada, Finland, Eng land and Wales, the Netherlands, and China (Table 1). Although the biological relationships of interest would not be expected to differ as a function of geographic REVIEW OF PARENTAL OCCUPATION AND CHILDHOOD CANCER 327 Table 1. Case and control groups, exposure definition, and confounders in studies of parental occupation and childhood cancer. Study location and study Reference period Total cancers (22) Quebec, 1965-1970 Case group Cancer deaths (23) Massachusetts, Cancer deaths 1947-1957, 1963-1967 births (24) Houston area, Cancer cases 1976-1977 (25) Finland, 1959-1975 Cancer cases (2S) England and Cancer deaths Wales, 1959-1963, 1970-1972 (27) Houston area, Cancer cases 1976-1977 Upper age limit, years Number of cases Source of controls Source of exposure information Time period of exposure Potential confounders considered 4 386 Birth Father's occupa- At birth certificates tion on birth certificate 14 692 Birth Father's occupa- At birth certificates tion on birth certificate Parents' ages, residence Parents' ages, sex, and race of child 15 296 Clinic records, Parents' occupa- Year before Father's age, case parent tional histories birth through parents' siblings, from interview diagnosis education neighborhood 14 948 Birth Parents' occupa- During Parents' ages, certificates tion in welfare pregnancy birth order, center records birth weight, residence 14 6920 All childhood Father's occupa- At death Social class deaths tion on child's death certificate 15 298 Clinic records, Parents' occupa- Year before None case parent tional histories birth siblings, from interview neighborhood Leukemias and lymphomas (28) Baltimore Brain tumor and SMSA, leukemia cases 1965-1974 (brain), 1969-1974 (leukemia) (29) New York Acute leukemia State (outside cases New York Citv), 1949-1978 (30) California, 1975-1980 Leukemia cases (31) Netherlands, Acute lympho- 1973-1979 cvtic leukemia cases (82) Los Angeles Acute leukemia County, cases 1980-1984 (33) Shanghai, China, 1974-1986 Leukemia cases (34) U.S. and Canada, 1980-1984 Acute nonlymphocytic leukemia cases 19 43 Birth certi- (brain) ficates, other 70 cancer cases (leukemia) 1 65 Birth certificates 15 255 Birth certificates 14 519 Populationbased 10 123 Case friends and random dierit dialing 15 309 Neighborhood 18 204 Random digit dialing Parents' occupational histories from interview Before birth through diagnosis Sex, year of birth, race Parents' occupational histories from interview' Father's occupation on birth certificate Parents' occupational histories from questionnaire Parents' occupational histories from interview Parents' occupational histories from interview's Parents' occupational histories from interview' Before birth At birth During Dregnancy and 1 year before birth 1 vear before conception to 0.5 or 1 year before diagnosis Before conception and during pregnancy Lifetime Year of birth, sex, race, county, parents' ages, birth order, maternal education, Xrays, other exposures Parents' ages, child's race, sex, and birth order Age, sex, residence, birth order, social class Parents' smoking. drinking, diet, mother's medications. child's age, sex, race, ultrasound, X-ray exposure Age, sex, birth W'eight, birth order, residence, X-rays, medications, mother's age at menarche Age, race (continued) 328 SAVITZ AND CHEN Table 1. Continued. Study location and study Reference: period Nervous system (35) Los Angeles County, 1972-1977 Case group Upper age Number limit, of years cases Brain tumor cases 9 98 (35) Los Angeles Brain tumor cases 24 County, 1972-1977 (37) Texas, Neuroblastoma 14 1964-1978 deaths 226 157 (33) Western Brain tumor cases 16 Washington State, 1978-1981 51 m Texas, 1964-1980 Intracranial and spinal cord tumor deaths 15 499 m Ohio, 1959-1978 Brain tumor deaths 19 491 UD New York Central nervous State (outside system tumor New York cases City), 1968-1977 15 338 Source of controls Case friends, neighbors Case friends, neighbors Birth certificates Random digit dialing and area sampling Birth certificates Birth certificates Birth certificates Source of exposure information Time period of exposure Potential confounders considered Parents' occupational histories from interview Parents' exposures from interview Father's occupation on birth certificate Father's occupational exposure from interview Father's occupation on birth certificate Father's occupation on birth certificate Parents' occupation and industry history from interview of mothers Year before birth through diagnosis Before birth to before diagnosis At birth 1 yr. before birth to diagnosis At birth At birth At birth and at diagnosis Mother's smoking, drugs, alcohol, hair dyes, foods during pregnancy Numerous parent and child characteristics Parents' ages, residence, prenatal care, marital status, child's sex, ethnicity Parents' ages, smoking, drinking patterns, mother's expo sure to chemi cals, child's sex, age, race Child's age, sex, race, birth weight, birth or der, gestational age, parents' ages, residence, prenatal care, etc. Sex, race, year of birth, parents' ages, birth weight, birth order, county Child's age, sex, race, parents' ages, religion, education, nativity Urinary system cancers m Connecticut, 1935-1973 Wilms' tumor cases US) Columbus, Ohio area, 1950-1967 Wilms' tumor cases CM) Columbus, Ohio area, 1950-1967 Wilms' tumor cases US) Philadelphia Wilms' tumor area, cases 1970-1983 19 None None 15 149 Birth Father's occupa- At birth Social class, birth- certificates tion on birth place, pregnancy certificate history, parents' ages and birth place, birth weight, length of gestation 62 Birth Father's occupa- At birth Age, sex, race, certificates tion on birth birth weight, certificate linked parents' ages, to exposure birth order, county 62 Birth Father's occupa- At birth Age, sex, race, certificates tion on birth birth weight, certificate parents' ages, birth order, county 88 Random digit Parents' occupa- 18 years old to Age, race dialing tional exposures 6 months from telephone before interview diagnosis REVIEW OF PARENTAL OCCUPATION AND CHILDHOOD CANCER 329 location, the range of occupations covered and the im plications of a given job title for specific exposures might differ. For example, Peters et al. (35) focused on aircraft industry employment in their study of brain tumors due to the concentration of this industry in the Los Angeles area. Their findings could not be addressed in studies in Massachusetts (23), Baltimore (28), or Ohio (kO) be cause of the rarity of such employment in those areas. If work conditions vary, for example, between the United States and China, then the exposure implica tions of a given job title (e.g., machinist, textile worker) could produce discrepant results. The earliest eligibility dates for case diagnoses ranged from 1935 (.1+2) to 1980 (32,3k) with the end of eligibility ranging from 1967 (k3,kk) to 1986 (33) (Table 1). Ex posures associated with a particular occupational title might be expected to differ over time as industrial pro cesses and exposure standards change. In general, work environments have improved over time so that a failure to observe excess risk in more recent periods may not negate the causal implications of excess risks observed in earlier time periods. The cancer type and vital status of cases (incident versus deceased) varied across the studies (Table 1). Variations in the composition of case groups could affect study results since the determinants of childhood cancer may be specific to the cancer type (8). If parental oc cupation influenced survival by affecting access to health care, for instance, then the studies of deceased cases might reach invalid conclusions regarding etiologic associations. Case groups ranged in size from 43 brain tumor cases (2k) to Sanders 6,920 cancer deaths (26) (Table 1). Be cause study group size is as important a determinant of the p-values as the magnitude of effect, a given odds ratio from a large study will attain significance more readily than that from a smaller study. The statistical significance of findings is therefore not emphasized in the interpretation of results. Controls were usually derived from birth certificates or sampled from the general population (Table 1). Con trols who were ill were included in three studies (2k,27,28) in an attempt to minimize reporting bias among parents of children who had severe health prob lems. To adequately reflect the exposure distribution in the underlying population at risk, however, it must be assumed that exposure is unrelated to the controls' dis eases and that those children with illnesses other than cancer come from the same base population. Exposure was established based on occupation in birth certificates (9 studies), interviews (12 studies), medical records (1 study), death certificates (1 study), or questionnaires (1 study). Studies that rely on re corded data from birth certificates, medical records, or death certificates have the virtue of unbiased ascer tainment but provide no control over the accuracy or level of detail of the information provided. Interviews provide an opportunity for more detailed discussion of specific exposures with some potential for respondent or interviewer bias, although it is not likely that parents' suspicions would lead to misreporting of occupation. Given the relative ease of obtaining occupational titles from birth certificates, it is unfortunate that none of the studies that selected controls from birth certificates and conducted personal interviews to ascertain exposure (28,kl) addressed the comparability of exposure infor mation from these two data sources. Relative to the true exposures of interest, both certificates and inter view information are obviously imperfect to an unknown but probably substantial degree. Studies that relied on birth certificates for exposure information could only consider exposures near the time of birth. Interview studies were able to examine ex posures in the period preceding birth (generally 1 year) as well as the period preceding the child's diagnosis. In principle, different mechanisms of effect (i.e., a precon ception genetic effect, in utero exposure, or postnatal exposure to the child) could be identified in the latter studies, but the job stability throughout the interval, especially for fathers, limits such analyses. The potential confounders available for consideration largely reflect the mode of data acquisition (Table 1). Certificate-based studies only had access to demo graphic information, including parental ages, race, res idence, and education, child's sex, and mother's preg nancy history. Interview studies generally obtained information on parental occupation as well as many other potential risk factors, so that other potential de terminants of cancer risk could be examined as confounders. Given the paucity of information on etiologic factors in childhood cancer (k8), it is difficult to argue that confounding occurred in studies with less extensive data on extraneous factors. Adjustments for potential confounders such as parents' ages, child's sex, race, and birth weight generally did not change the results mark edly. Study Results Table 2 summarizes the results of studies of paternal exposures and total childhood cancer, including the in itial report by Fabia and Thuy (22). Most studies have focused on exposures to hydrocarbons and other indus trial chemicals. Two studies reported odds ratios of two or greater for mechanics (22,27), with contradictory re sults from Kwa and Fine (23). Odds ratios of 2 to 5 were observed by Hicks et al. (27) for aircraft workers and radiation-exposed military workers. Sporadic eleva tions in odds ratios were found for machinists, printers, and farmers, based on a single study with nonsupportive results reported in one or more investigations. None of the studies reporting results for hydrocarbons war ranted inclusion based on the criteria defined earlier. A noteworthy finding in Table 2 is the suggestive risk increases associated with occupations in which toxic ex posures are not expected, such as men with an academic degree (25) and professionals, administrators, and cler ical workers (26). These associations may reflect the increased incidence of childhood leukemias in the higher social classes (k8), and serve as a reminder that occu- 330 SAV1TZ AND CHEN Table 2. Results of studies of paternal occupation and total childhood cancer. Occupation Number of exposed cases Mechanic Motor vehicle mechanic Mechanic, gas station attendant Aircraft mechanics 28 35 6 Odds ratio'* 2.2b 1.1 2.3-infinity* Reference (22) (23) (27) Machinist Machinist Machinist Machinist, miner, lumberman Machine repairman 24 1.7 (22) 71 1.1 (23) 9 0.5-1.8 (24) 46 0.9 (2.5) Radiation and military Radiation related Radiation-exposed military Radar related Armed forces 30 13 21 187 1.5-2.0 2.1-5,2* 1.1-2,1 0.8 (27) (27) (27) (26) Electrical Electrician, plumber, carpenter Electrical 12 209 0.9-1.5 1.0 (24) (26) Other industrial exposures Printer Petroleum industry Aircraft workers 15 22 13 1.8 0.7-1.6 3.U-5.2* (23) (24) (27) Agriculture Farmers Farmers 450b 1.2 (25) 274 1.1 (26) No industrial exposures With academic degree Professional, technical workers, artists Administrators and managers Clerical workers Sales workers 61b 687 302 376 539 1.7 (25) 1.4* (26) 1.7* (26) 1.3* (26) 1.3* (26) a Range of odds ratios provided when multiple control groups were used. b Number ofexposed cases not provided; number ofdiscordant pairs listed. *p < 0.05. pational titles may be associated with childhood cancer through mechanisms other than environmental expo sures. Studies of paternal occupation in relation to childhood leukemias and lymphomas are summarized in Table 3. Motor vehicle related occupations (mechanics, drivers) were associated with elevated risks in some studies {22,28,32) but not in others {23,31). Machinists and fac tory workers also showed several associations of 2-fold or greater {22,28,32,34), but the diversity ofjobs makes it difficult to evaluate the consistency of the data. Hy drocarbon exposures were strongly related to leukemia in the study by Vianna et al. {29) of cases age 1 year or less. Sanders et al. {26) and Van Steensel-Moll et al. {31) failed to confirm that finding with cases covering a broader age range. Exposure to paints and pigments yielded the most consistently positive results, with five studies {22, 25,31,32,34) producing odds ratios of 1.5 or greater. Isolated findings implicate plastic and rubber, chlori nated solvents, petroleum products, food and drink manufacturing, and medical and social services. Nervous system cancers, consisting primarily ofbrain tumors and neuroblastomas, were examined in a large number of studies (Table 4). The possibility of site-spec ificity of etiologic agents should be considered in re viewing these results, especially for neuroblastoma compared to brain and central nervous system cancers. Motor vehicle-related occupations were found to be overrepresented among case fathers by Fabia and Thuy {22) and to a lesser extent by Wilkins and Koutras (40), but not by four other investigators {23,25,37,39). An odds ratio of 4.4 for machine repairmen {25) was not replicated {23,28,39,40). Risk elevations were again noted for painters, with strongly positive results from two studies (ORs = 2.6, 7.0) (25,35) and null results from two others (39,4.0). Exposures associated with the chemical and petro leum industries produced reasonably consistent indi cations of a positive association, with odds ratios of 1.5 or greater in three studies (35,39,41) and of 3.0 or greater in two studies (35,39). Hydrocarbon exposures in the aggregate were only associated with nervous sys tem cancers in the study of neuroblastoma (37) and not in the three studies of central nervous system cancers (26,28,41). Metal-related work was associated with brain cancer, but in only one study (40). Three studies (37,40,41) found elevated risks associ ated with assorted electrical occupations. Both Hicks et al. (27) and Nasca et al. (41) found ionizing radiation to be associated with nervous system cancers, with odds ratios around two. Isolated reports implicate metal-re lated occupations, farming, construction, aircraft in dustry, printing, and graphic arts in brain cancer risk, though the associations were either not examined or not confirmed in other studies. The three studies that in cluded data on paper and pulp mill workers (23,39,41) ail noted increased odds ratios, ranging from 1.6 to 4.0. Urinary system cancers were the focus of several studies (42-45) (Table 5). Hydrocarbon exposures were implicated by Kantor et al. (42) and Kwa and Fine (23), but not confirmed in other studies (26,41,42). Similarly, lead was rather strongly linked to Wilms' tumor in one study (42) but not others (43,44)- Radiation exposure was associated with Wilms' tumor risk in two studies (27,45), each reporting odds ratios of two or greater. Boron has also been identified as a risk factor in two studies (43,45). The plausibility of environmental con taminants acting on the kidney encourages further eval uation of the postulated associations. Maternal exposures to occupational hazards (Table 6) were addressed in few of the studies, primarily because of the rarity with which mothers had worked in poten tially hazardous workplaces. Hemminki et al. (25) found total cancer risk to be associated with work as a phar macist, farmer, baker, or in the food industry. REVIEW OF PARENTAL OCCUPATION AND CHILDHOOD CANCER Tabic 3. Results of studies of paternal occupation and childhood leukemias and lymphomas. Occupation Motor vehicle related Motor vehicle mechanic, service station attendant Mechanic, gas station attendant Motor vehicle driver Motor vehicle driver Motor vehicle related Auto mechanic, machinist, gas station attendant, miner Transportation Transportation equipment Transportation equipment operator Cancer site Leukemia/lymphoma Leukemia/lymphoma Leukemia/lymphoma Leukemia Leukemia Acute lymphocytic leukemia Acute leukemia Acute leukemia Leukemia Number of exposed cases 16 21 28 96b 6 18 22b 21b 24 Odds ratio 2.0b 1.1 1.0 1.5 0.8, infinity' 0.8 1.4 2.5' 1.2 Machinist and factory worker Machinist, miner, lumberman Machinist Machine repairmen Factory worker, machinist, and related occupations Operators, fabricators, laborers Manual and mechanical skills Machinery Aircraft manufacturing Blacksmiths, toolmakers, etc. Nonauto mechanic Leukemia/lymphoma Leukemia/lymphoma Leukemia Leukemia Leukemia Acute lymphocytic leukemia Acute leukemia Acute leukemia Leukemia Acute noniymphocytic leukemia 23 49 15b 11 57 188 20b 17b 50 14 2.5* 1.3 0.3 0.8,2.5 1.1 1.0 3.0* 1.8 0.9 3.5* Aggregated hydrocarbon Hydrocarbon related Hydrocarbon related Hydrocarbon, high Hydrocarbon, low Hydrocarbon related Leukemia Leukemia Acute leukemia Acute leukemia Acute lymphocytic leukemia 202,416 7,10b 24,28b 19,25b 37 0.9,1.0 1.0,2.5 2.4*,2.5* 1.3,3.8* 1.0 Paints and pigments Painter, dyer, cleaner Painter Painter Painter, cleaner, dyer Pigments (dves) exposure Spray paint Dyes, pigments Painter Leukemia/lymphoma Leukemia/lymphoma Leukemia Acute lymphocvtic leukemia Acute lymphocytic leukemia Acute leukemia Acute leukemia Acute noniymphocytic leukemia 5 7 12b 8 25 26b 8b 7 1.7 0.9 1.5 1.6 1.6 2.2* 3.0 7.0' Food related Baker, cook, restaurant worker Food preparation Foods and drink manufacturing Leukemia/lymphoma Leukemia Acute leukemia 12 1.4 3b 0.5 13b 2.2 Other chemicals Tar or asphalt exposure Petroleum chemicals manufacturing Petroleum products Plastic or rubber exposure Chemical, rubber, and plastics workers Plastics Chlorinated solvents Solvents Acute lymphocytic leukemia Acute leukemia Acute noniymphocytic leukemia Acute lymphocvtic leukemia Leukemia Acute noniymphocytic leukemia Acute leukemia Acute noniymphocytic leukemia 26 16b NAC 25 12 NA 13b NA 1.1 1.0 2.8* 2.0 1.1 1.5 2.2 2.1* Other occupations Medical and social services Medical and public health workers Acute lymphocvtic leukemia Leukemia '`Range of odds ratios provided when multiple control groups were used. ''Number of exposed cases not provided; number of discordant pairs listed. CNA, not available. 'p < 0.05. 18 5 2.8' 0.6 331 Reference (22) (23) {23) {25) {28) {3D {32) {32) {S3) {22) {23) {25) {28) {30) {3D {32) (32) (33) (34) (26) (28) (29) (29) (31) (22) (23) (25) (31) (31) (32) (32) (34) (23) (30) (32) (31) (32) (34) (31) (33) (34) (32) (34) (31) (33) 332 SAVITZ AND CHEN Table 4. Results of studies of paternal occupation and childhood nervous system cancers. Occupation Motor vehicle related Motor vehicle mechanic, service station attendant Mechanic, gas station attendant Motor vehicle driver Motor vehicle driver Transportation, utilities, communication Motor vehicle mechanic, service station attendant Motor freight and transportation Cancer site Nervous system Nervous system Nervous system Brain Neuroblastoma Nervous system Brain Number of exposed cases Odds ratio3 10 .6 5 84b 12 NAC 37 2.8 1.0 0.6 0.9 0.9 0.7 1.6 Machinist and factory worker Machinist Machine repairman Factory worker, machinist, and related occupations Factory worker, machinist, and steelworker Machine trades occupations Nervous system Brain Brain Nervous system Brain 9 0.7 14b 4.4` 16 0.7,2.5 NA 1.2 66 1.2 Paint Painter Paint exposure Painter Painting, plastering, etc. Brain Brain Nervous system Brain 14b 2.6 7 7.0* NA 1.0 7 1.2 Chemicals Chemical solvent exposure Chemical industry Chemical workers Chemical and petroleum refinery worker Chemical and drug salesman Chemical industry Brain Nervous system Nervous system Nervous system Nervous system CNS tumors 20 2.8 12 1.4 6 0.8 9 3.0 5 10.0* 10 1.5 Petroleum industry Oil and gas extraction Petroleum refinery worker Petroleum industry Neuroblastoma Nervous system CNS tumors 8 1.3 6 2.0 9 3.1 Aggregated hydrocarbon Hydrocarbon related Hydrocarbon related Aromatic hydrocarbons, nonionizing radiation Aromatic and aliphatic hydrocarbons Hydrocarbon related, narrow definition Hydrocarbon related, broad definition Brain Brain Neuroblastoma Neuroblastoma CNS tumors CNS tumors 419 0.9 11 0.5,2.3 5 1.8 10 3.2* 18 1.3 38 1.4 Electrical Electronics workers Electrical assembling, installing, and repairing Electromagnetic fields, narrow definition Electromagnetic fields, broad definition Neuroblastoma Brain CNS tumors CNS tumors 6 11.8* 19 2.7 15 1.7 19 1.6 Ionizing radiation Industrial, less exposure Occupation, less exposure Industrial, more exposure Industrial, less exposure Occupation, more exposure Occupation, less exposure Nervous system Nervous system CNS tumors CNS tumors CNS tumors CNS tumors 10 1.0-1.1 7 1.8-2.1 28 2.2* 61 1.7* 19 1.0 31 1.1 Metals Metal processors and producers Welders, cutters Metal working occupations Brain Brain Brain 62 1.8 11 2.7 14 1.6 Reference (22) (23) (23) (25) (37) (39) m (23) (25) (28) (39) (40) (25) (35) (39) m (35) (39) (39) (39) (39) (4D (37) (39) (4D (26) (28) (37) (37) (4D (4D (37) (40) (4D (41) (27) (27) (41) (41) (41) (4D (40) (40) (40) (continued) REVIEW OF PARENTAL OCCUPATION AND CHILDHOOD CANCER Table 4. Continued. Occupation Agriculture Farmer Farmer Agriculture Farming and agricultural occupations Cancer site Nervous system Brain Neuroblastoma Brain Number of exposed cases 6 107b 6 30 Construction Construction Construction industry Construction occupations Carpenters Neuroblastoma Brain Brain Brain 17 47 26 14 Paper and pulp mill Paper and pulp mill Paper and pulp mill worker Pulp and paper industry Nervous system Nervous system CNS tumors 6 NA 8 Aerospace and aircraft industries Aircraft industry Aerospace occupation Aircraft industry worker Brain Brain Nervous system 12 7 NA Other occupations Printing workers Graphic arts workers Glass, clay, stone industry Nervous system Nervous svstem Brain "Range of odds ratios provided when multiple control groups were used. b Number of exposed cases not provided; number of discordant pairs listed. c NA, not available. ' p < 0.05. 9 5 12 Odds ratio" 0.6 1.2 0.6 2.0b 0.9 2.3* 2.0* 1.9 2.8" 4.0 1.6 Infinity 1.1 1.0 4.5 21.9* 1.5 333 Reference (22) (25) (37) m (37) m m m (23) (39) UD (35) (38) (39) (39) (39) m Table 5. Results of studies of paternal occupation and childhood urinary system cancers. Occupation Cancer site Hydrocarbon related Motor vehicle mechanic Wilms' tumor Machinist Wilms' tumor Mechanic, gas station attendant, machinist Urinary tract Machinist Wilms' tumor Hydrocarbon related Kidney Soot exposure Wilms' tumor Hydrocarbon related Wilms' tumor Benzo(a)pyrene exposure Wilms' tumor Number of exposed cases 6 5 10 9 111 16 10 15 Odds ratio 6.2 1.7 2.6" 3.2 1.2 0.8 1.4 0.8 Lead exposure Lead related Lead exposure Lead related Wilms' tumor Wilms' tumor Wilms' tumor 22 3.7* 18 1.1 11 1.3 Radiation related Radiation-related industry Radiation Radium Wilms' tumor Wilms' tumor Wilms (nongenetic) 13 2.5*-2.6* 15b 2.0 5b 4.0 Other occupational exposures Trichloroethylene exposure Boron exposure Boron Dichloroethyl ether Nitroparaffins Wilms' tumor Wilms' tumor Wilms (genetic) Wilms (genetic) Wilms (genetic) "Range of odds ratios provided when multiple control groups were used. b Number of exposed cases not provided; number of discordant pairs listed, 'p < 0.05. 10 7 5b 5b 6b 1.5 3.5" Infinity 4.0 5.0 Reference U2) m (23) US) (26) US) CM) US) U2) US) (M) (27) U5) US) US) US) US) US) US) 334 SAVITZ AND CHEN Table 6. Results of studies of maternal occupation and childhood cancer. Occupation Total cancers Pharmacist Agriculture, gardening, forestry Food industrv Baker Number of exposed cases 12a 29" 37a 20a Odds ratio 3.2* 1.7 2.1* 2.4 Leukemia Pharmacist Pharmacist Medical and social services Physicians Manual and mechanical skills Blacksmiths, toolmakers, etc. Metal refining and processing Lead Metal dusts Textile industry Textile workers and tailors Chemical exposure Chemical processors Hydrocarbon related Benzene Gasoline Toluene Kerosene Diesel oil Pigment (dyes) exposure Paints and pigments Personal service industries Service workers Domestics, hotel, and catering Agriculture and forestry Pesticides Pesticides 5a NAb 21 NA 15 32 8 5 NA 8 27 25 25 7 24 38 20 16 16 22 Not stated 12 34 24 12 12 NA 2.6 19.7' 1.0 5.7* 2.0 1.1 2.6 2.3 3.0 4.2* 0.7 2.4* 3.3* 2.5 2.0 1.6 1.5 1.6 1.6 1.8 1.5 2.7* 1.4 2.8* 2.3 3.5 6.0* Brain cancer Chemicals on skin Inhaled chemicals or fumes Baker Wore protective clothing or equipment (exposure proxy) 10 13 9a 15a 3.3 3.0 1.6 4.0* Wilms' tumor Aromatic amino compounds 5a "Number of exposed cases not provided; number of discordant pairs listed. bNA, not available. "p < 0.05. Infinity Reference (25) (25) (25) (25) (25) (33) (31) (33) (31) (33) (33) (33) (34) (31) (33) (31) (33) (31) (33) (33) (33) (33) (33) (31) (34) (32) (33) (31) (33) (33) (34) (33) (33) (25) (34) (45) Occupations found more frequently among mothers of children with leukemia included a wide variety of chemical exposures. Notably strong or replicated as sociations were found for work as a pharmacist (25), in metal manufacturing or processing (33,34), textiles (31), pigments (31,34), or unspecified chemicals (31,33). Stud ies of maternal occupation and brain cancer (33,34) pro duced strong positive associations with chemical haz ards in general (ORs of 3.0-4.0), Unfortunately, there is very limited opportunity to have these results cor roborated given the few studies of maternal occupation. Discussion In spite of a large number of studies, no specific pa rental occupational exposure has been established as a cause of childhood cancer. However, several paternal occupations have been found to be associated with child hood leukemias and nervous system tumors and mater nal occupations with several cancers based on the mag nitude of odds ratios and replication in two or more studies. The most promising leads for further study are paternal paint exposure and to a lesser extent paternal hydrocarbon exposure in relation to both childhood leu kemias and brain cancer. Paternal work with ionizing radiation and work in the petroleum, chemical, electri cal, and paper industries should be further evaluated in relation to childhood brain cancer. Maternal exposures have received relatively little attention, but the few studies have yielded strongly suggestive results impli cating a variety of occupational chemicals in leukemia and brain cancer. REVIEW OF PARENTAL OCCUPATION AND CHILDHOOD CANCER 385 There was a tendency for specific studies to produce many elevated or many null odds ratios, with no clear methodological basis given their methodological simi larity (Table 1). The most parsimonious explanation for generating an array of positive associations with indus trial exposures would be having selected an unsuitable control group. False negative results are also readily accounted for by poor exposure assessment or overly broad groupings of disease. Positive results were more common in studies of ner vous system cancers (Table 4) than studies of leukemia (Table 3) or urinary system cancer (Table 5), either reflecting more causal relationships or superior study methods. Again, there is no obvious pattern based on the study attributes summarized in Table 1. There are several important methodological limita tions pervasive in this literature that would tend to obscure associations. Exposure classification is the most critical. The exposures of ultimate interest are specific physical or chemical agents in the workplace that reach the parent. The ability of the surrogates used in these studies (typically a job title alone) to accurately identify exposed and unexposed individuals is highly question able. The associations are virtually all between occu pation and childhood cancer, not actually between an occupational exposure and childhood cancer. Job titles may not accurately identify exposures due to errors in reporting, but especially due to the inherent variability in activities and environments associated with any given job title. Different industrial processes, variable use of protective equipment, and differing activities within a job title contribute to this heterogeneity in exposure. Many studies have chosen to address exposure ag gregates such as hydrocarbons or chemical industry em ployment. If only a subset of those agents actually af fected childhood cancer risk, then the aggregation itself constitutes an additional form of misclassification. The direction of bias from these sources of error is predictable since the same methods of imputing expo sure were applied to cases and controls: the misclassi fication is nondifferential with respect to disease status, resulting in a bias toward the null (no association) (49). Superimposed on any underlying etiologic associations between chemical or physical agents and childhood can cer is this dilution from exposure misclassification. Exposure classification will remain the major chal lenge in this research area because the rarity of child hood cancer precludes conducting true prospective stud ies in which exposures of parents are carefully moni tored from before conception to the time of diagnosis. The challenge of retrospective exposure assignment sometimes occurring years after the time period of in terest must be addressed. The limitations of occupa tional data from death certificates is well known (50,51), but at least some of the problems of using job titles from death certificates as exposure indicators for the study of adult cancer or other chronic diseases are not as great of a concern in using job titles from birth certificates as exposure indicators for the study of childhood cancer. The uncertainty over how recently the job was held or whether the job was held for a sufficiently lengthy pe riod to affect disease are less problematic for studies of childhood cancer. Nonetheless, job titles from inter views with the parents are likely to be superior to job titles reported on birth certificates (52,53). In an inter view, there is an opportunity to probe incomplete an swers and ask about specific work activities. The application of an exposure linkage system to ag gregate occupations into exposure groups (54) as im plemented by Wilkins and Sinks (44), Buckley et al. (34), and Bunin et al. (45) constitutes an improvement over purely subjective aggregations of jobs. The original mo tivation for developing such linkage systems was prin cipally to aggregate diverse jobs with common expo sures (54), a particular problem in studies of limited size. Inaccuracies in assigning exposures based on job titles are not avoided (55), but investigators could at least generate comparable results. A more complete solution is to conduct detailed in terviews to ascertain exposure histories, as illustrated by Guerin et al. (56). In the investigation of occupational cancers developed by Siemiatycki et al. (57), a prelim inary structured interview regarding occupational ex posures is followed by a semistructured interview by an industrial hygienist. This provides an opportunity for querying important aspects of exposure not identi fiable through job title such as industrial processes, en vironmental controls, specific work locations, and re sponsibilities. None of the studies conducted to date have been nearly that ambitious, although an investi gation devoting considerable resources to exposure as sessment would be both justified by the existing liter ature and feasible for studies of parental occupation and childhood cancer. Other methodological considerations are also worth noting. The constitution of the case groups varied across studies and could account for inconsistency in the results since childhood cancers are likely to have etiologic fac tors that vary by age at diagnosis and disease category. The isolation of very young leukemia cases by Vianna et al. (29) may have affected their results relative to other studies, either because etiologic factors are dis tinctive for early cases or because the recall of occu pation is improved with a shorter time period of recall (from pregnancy to diagnosis). The known causal influ ences on childhood cancer are so limited (48) that the suggestion of etiologic specificity is based primarily on an analogy with the specificity often found for adult cancers. Until more is learned about the etiology of childhood cancers, it is preferable to conduct studies in which homogeneous subgroups of cases can be analyzed. The precision of risk estimates remains an important concern. The rarity of childhood cancer makes it difficult for individual investigators to accumulate a sufficiently large case group to form subgroups defined by age or diagnosis with precise estimates of effect. One possible solution to this problems is for collaborative investi gations to be initiated to enable inclusion of adequate numbers of cases (34). Alternatively, investigators should group both exposure and disease in a manner 336 SAV1TZ AND CHEN allowing for aggregation across studies, for example by applying a universal occupational coding system and using a standard cancer classification system. Larger study groups will not eliminate the concerns with the accuracy of exposure definition, but could diminish the impact of random variation on the observed results and allow examination of more homogeneous case groups. In spite of these limitations and the inconclusive re sults of past studies, continued evaluation of parental occupation and childhood cancer is clearly warranted. Childhood cancer exerts a major toll in years of life lost and in the psychological burden borne by the families of victims and by cancer survivors. 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