1 Institut National de la Santé et de Recherche Médicale, Unité 625, Rennes, France.
2 Neuroepidemiology Research Unit, Istituto Nazionale Neurologico "C Besta," Milan, Italy.
3 Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.
4 Department of Clinical Epidemiology, Chaim Sheba Medical Center, Sackler School of Medicine, Tel-Hashomer, Israel.
5 Public Health Sciences Division, Fred Hutchison Cancer Research Center, Seattle, WA.
6 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
7 Unidad de Informacion y Documentacion Medicosanitaria, Instituto Lopez Pinero, Consejo Superior de Investigaciones Cientificas, Universitat de Valencia, Valencia, Spain.
8 Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand.
9 Manitoba Cancer Treatment and Research Foundation, Winnipeg, Manitoba, Canada.
10 University of Aberdeen Medical School, Aberdeen, Scotland.
11 International Agency for Research on Cancer, Lyon, France.
Received for publication July 31, 2003; accepted for publication January 5, 2004.
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ABSTRACT |
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brain neoplasms; child; germ cells; mutation; paternal exposure; polycyclic hydrocarbons, aromatic
Abbreviations: Abbreviations: CI, confidence interval; ISCO, International Standard Classification of Occupations; ISIC, International Standard Industrial Classification of All Economic Activities; OR, odds ratio; PAH, polycyclic aromatic hydrocarbons; SEARCH, Surveillance of Environmental Aspects Related to Cancer in Humans.
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INTRODUCTION |
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The international case-control study coordinated by the International Agency for Research on Cancer as part of the SEARCH (Surveillance of Environmental Aspects Related to Cancer in Humans) Program offered us the opportunity to test the hypothesis that parental occupational exposure to PAH affects childrens risk of brain tumors.
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MATERIALS AND METHODS |
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Randomly selected controls from the general population were either pair-matched (six centers) or frequency-matched (three centers) to cases by sex and birth year (or by age at one center). The different study centers used several different sampling frames to contact and recruit control participants; these included census data, telephone directories, and random digit dialing methods. Eligible families were those known to have at least one eligible child according to the protocol applied in each center. Of the 2,950 eligible control families contacted, 2,223 (75 percent) were interviewed.
Mothers, and fathers whenever possible, were interviewed in their homes (or by telephone for some fathers) according to a structured questionnaire. Questionnaires used were similar at all centers. A number of suspected risk factors for childhood brain tumors were investigated, including exposure to tobacco smoke and parental occupational history. Specifically, all jobs held for at least 1 month during the 5-year period before the childs birth were recorded, and parents were asked to describe the tasks performed at each job site and to report the type of industry, the number of hours worked weekly, and the products handled. Overall, 48 percent of the fathers who were employed during the 5-year period participated in the occupational interviews (55 percent among cases, 45 percent among controls). This percentage was much higher at the US centers (81 percent), where fathers were usually interviewed by telephone after the interview with the mother. When fathers did not participate, answers about paternal occupational history provided by the mothers were used in the analysis.
Occupations were coded according to the International Standard Industrial Classification of All Economic Activities (ISIC) (17) and the International Standard Classification of Occupations (ISCO) (18). Exposure to PAH was estimated with a job exposure matrix first developed for an international collaborative study of laryngeal cancer in Southern Europe (19). Because the original job exposure matrix did not contain all of the ISIC-ISCO combinations found in our study, the group of experts who created it prepared an extension so that every industry-occupation combination in our study had a PAH exposure level. The calendar period considered was 1974 onward. Exposure categories were defined as followslevel 1: job-related exposure is not higher than that for the general population; level 2: the job may entail a cumulative exposure higher than that for the general population; level 3: the job may entail exposure to levels definitely higher than those for the general population, but an imprecise job description does not permit discrimination between the exposed and those not exposed. This category was further subdivided according to the a priori probability of exposure (level 3a: probability less than one third; level 3b: probability between one third and two thirds; level 3c: probability greater than two thirds). There were two additional categorieslevel 4: the job entails exposure to the specific agent at levels clearly higher than those of the general population; and level 5: the job entails exposure to the specific agent, and exposure is known to be particularly high. Exposure levels were thus defined by both the probability of exposure and the intensity of exposure. That is, as the category level increases, the likelihood of misclassification decreases and the intensity of exposure increases. If a causal association exists, risk should increase for each category. To obtain sufficient numbers in each category, we combined the original classifications into three groups: no exposure (level 1), medium exposure (levels 23b), and high exposure (levels 3c). Persons employed in several occupations during the 5-year period were classified according to their highest level of exposure.
Statistical analysis
Because different matching strategies were used at the different study centers, odds ratios were estimated by unconditional logistic regression, which allowed more efficient use of all of the controls in the histologic subgroup analysis. Post hoc matched strata were created for centers that used frequency matching by generation of a reference date for controls, defined as the date on which the control child attained the age of the corresponding case at diagnosis. A comparison of results from matched conditional analyses and unmatched analyses for the same subset of study participants allowed us to evaluate the influence of matching variables that could not be taken into account in the unmatched analysis, such as area of residence. Since risk estimates were similar, we decided to report only the results from unmatched analyses.
Analysis was restricted to parents who reported having had at least one occupation outside the home during the 5-year period before the birth. Adjustment for risk estimates was made for the matching variables: center, sex, and age at diagnosis of the child (04, 59, 1014, or 15 years). Other potential confounders such as parental age or number of years of schooling did not modify risk estimates by more than a few percentage points and were not retained in the adjustment.
Tobacco smoking was introduced into the analysis either as a confounder or as an additional source of exposure to PAH for estimation of the joint effects of tobacco smoke and occupational exposure. Both paternal and maternal smoking were defined as dichotomous variables for each period considered because of the absence of quantitative information for the father. The period of interest for paternal exposure to PAH (from occupation or from smoking) was the period before conception, whereas maternal exposure was defined as exposure before conception or during pregnancy.
Analyses were performed for all brain tumors and for the histologic subgroups for which we had adequate numbers of cases: astroglial tumors (International Classification of Diseases for Oncology codes 93809382, 9384, 94009421, 94249429, 94319440, and 9442); primitive neuroectodermal tumors (codes 94709473 and 9501); and other glial tumors, including ependymoma (codes 9391 and 9392), oligodendroglioma (code 9450), and ganglioglioma (code 9505). The subgroup analyses used all control participants.
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RESULTS |
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Maternal occupational exposure to PAH during pregnancy was rare and was not associated with a significant excess of any type of childhood brain tumor (table 2). Odds ratios were greater than 1 for every tumor group among mothers who smoked and were occupationally exposed in comparison with nonsmoking, non-occupationally-exposed mothers, but these increases disappeared after adjustment for paternal preconceptional exposure to PAH (from smoking or from the occupation). When maternal occupational exposure before conception was considered, no increase in risk was observed for any tumor group.
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We also restricted the analysis to US centers, from which 44 percent of the cases originated and which used similar control selection and interview procedures. The risk estimates obtained (OR = 1.3, 95 percent CI: 1.0, 1.7) were very close to those observed in the rest of the study population (OR = 1.4, 95 percent CI: 1.1, 1.7) for paternal exposure to PAH.
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DISCUSSION |
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These results from a large representative sample corroborate our previous findings from European centers (20). They accredit, for a narrower class of chemicals (the PAHs), the hypothesis proposed by Fabia and Thuy (21) in 1974 and confirmed (2227) and refuted (28, 29) by subsequent studies. Since then, experimental findings have suggested mechanisms for these associations in humans.
Much of this evidence is based on biologic markers of PAH binding to DNA. Such markers were not available in our epidemiologic study. The absence of direct measurements of PAH exposure from all possible sources precludes too strong an interpretation of our findings. Of the three principal sources of PAH exposure in industrialized countriestobacco smoke, occupational exposure, and air pollutionwe could estimate exposure for only the first two.
Our estimate of occupational exposure to PAH was indirect. Exposure to PAH in the workplace typically occurs via products or combustion fumes originating from incomplete combustion, pyrolysis, or pyrosynthesis of organic matter. The list of occupations entailing PAH exposure higher than that in the general population was identified some time ago, but individual assessment of exposure requires detailed workplace descriptions or ad hoc measurements. Self-reports could identify circumstances of exposure to oil or coal products or combustion products, but they are limited by the lack of relative or objective benchmarks against which to judge ones working conditions (30); this results in very variable sensitivities. An additional problem in our data is that only 48 percent of working fathers provided answers about their own occupational exposures. This explains why our assessment was preferably based on the evaluation provided by a job exposure matrix, assuming that answers from the mothers would be of better quality with regard to the fathers occupational history than when mothers were reporting specific exposures present in the fathers workplace. Use of job exposure matrices introduces a high level of misclassification, since the heterogeneity within job and industry and individual exposure determinants are not accounted for, but this misclassification would be expected to be similar among cases and controls. We used different levels of exposure corresponding to increasing levels of both probability of exposure in a given job and intensity of exposure. However, there was no suggestion of increasing risk with increasing exposure levels. The absence of a dose-response pattern may have several alternative explanations: exposure misclassification, no association between PAH exposure and cancer risk, or a nonlinear shape in the relation, as discussed below.
One may also question the validity of applying a job exposure matrix originally developed in Southern Europe to other parts of the world such as Australia, Israel, or the US West Coast. However, these countries have similar levels of industrial development and similar occupational processes, and all circumstances of occupational exposure to PAH have been considered by experts when updating the job exposure matrix.
Using a validation subsample, we could verify that the use of maternal reports for paternal occupational history had only a minimal impact on the overall risk estimate.
Occupational exposure to PAH was frequent: overall, 40 percent of the control fathers were classified as probably exposed and 19 percent as more highly exposed; these percentages are similar to those estimated with this job exposure matrix in previous applications (20, 31). Exposure to PAH occurred mainly among blue-collar workers, and the higher proportion of case fathers exposed might have been related to a lower educational level among cases than among controls. Nonetheless, adjustment for parental education did not modify the estimates.
The link observed between the risk of childhood brain tumors (mainly astroglial) and paternal exposure to PAH, either occupational or from smoking, together with the absence of an association with maternal smoking before or during pregnancy (11), tends to suggest that paternal preconceptional exposure rather than maternal passive exposure to tobacco smoke is the risk factor involved. It also corroborates the observation by Ji et al. (32) that the risk of childhood cancer, including brain tumors, increases with duration of paternal smoking in the absence of maternal smoking. This was also confirmed in a review of papers on parental smoking and childhood cancers conducted by Boffetta et al. (33). Postnatal and prenatal exposures from parental smoking or occupations are very correlated. Previous reports from situations where different periods of exposure could be studied did not show an impact of postnatal exposures (32); a role of these exposures in our study could not be assessed but cannot be excluded.
Several reports based on PAH adducts provide indirect support for the hypothesis of a role of paternal preconceptional exposure. A recent paper shows a correlation between molecular markers of PAH exposure and sperm damage among men with occupational exposure (5). Finette et al. (34) examined T lymphocytes in the umbilical cord blood of newborns and reported an increase in "illegitimate" genomic mutations in the hypoxanthine-guanine phosphoribosyltransferase reporter gene; they attributed it to maternal exposure to passive cigarette smoke, but it may have had paternal causes. Benzo[a]pyrene diol epoxide-DNA adducts have been detected in preimplantation embryos from couples in which both parents smoked but also in cases where only the father smoked (2). In addition, animal evidence shows an increased incidence of brain tumors in the progeny of male rats exposed to chemicals such as ethylnitrosourea before mating (35). Paternal but not maternal germ-line mutations were recently observed among laboratory mice exposed in situ to air pollution around steel mills (which release large amounts of PAH) (4). These correlations suggest that mutational events occurring during spermatogenesis may be the cause of the increased tumor incidence in the offspring. However, none of the studies in the published literature explored the likelihood of epigenetic tumor causation after PAH exposure; hence, this possibility cannot be ruled out (6, 7).
In our study, the risk of brain tumors in children was greater among fathers who were occupationally exposed than among fathers who smoked, in comparison with fathers who had neither exposure. However, this risk did not increase when fathers were exposed both occupationally and through smoking or when the level of estimated occupational exposure increased. Ji et al. (32), in studying paternal smoking, noted that patterns of increase in risks of childhood cancer were less consistent with the number of cigarettes smoked per day (analogous to intensity) than with the duration of smoking. These observations may well be related to the saturation in DNA adduct formation that has been demonstrated at high levels of PAH exposure (36).
In summary, the findings of our large study support the hypothesis that paternal preconceptional exposure to PAH may increase the risk of brain tumors in humans. Moreover, several reports linking PAH exposure and germ-cell damage provide indirect support for this association. It would be difficult to obtain large-scale confirmation that this mechanism operates in a portion of childhood brain tumorsby measuring PAH-DNA adducts, for example. Nonetheless, attempts at this sort of biologic confirmation must be incorporated into future studies.
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ACKNOWLEDGMENTS |
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The authors thank P. Pisani, L. Troschel, and I. Belletti, who kindly provided updated information for the job exposure matrix, and J. A. Cahn for skillful assistance in revising the manuscript.
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NOTES |
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REFERENCES |
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