1 Department of Medicine, Vanderbilt-Ingram Cancer Center, and Center for Health Services Research, Vanderbilt University, Nashville, TN
2 Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
3 Cincinnati Children's Hospital and Medical Center, Cincinnati, OH
4 The Children's Hospital, Denver, CO
5 Keck School of Medicine, University of Southern California, Los Angeles, CA
6 Division of Pediatric Pathology, Riley Hospital for Children, Indianapolis, IN
7 Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
Correspondence to Dr. Xiao-Ou Shu, Center for Health Services Research, Vanderbilt University, 6th Floor Medical Center East, Room 6009, Nashville, TN 37232-8300 (e-mail: Xiao-Ou.Shu{at}vanderbilt.edu).
Received for publication June 24, 2004. Accepted for publication June 3, 2005.
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ABSTRACT |
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case-control studies; child; germinoma; occupational exposure; pesticides
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INTRODUCTION |
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From 1996 to 2003, the Children's Oncology Group (COG) conducted a large-scale US case-control study of childhood germ-cell tumors. Occupation-specific questionnaires were used to collect information on various exposures, including maternal and paternal exposures to pesticides before conception, during gestation, and during the early childhood of the index child.
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MATERIALS AND METHODS |
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Of the 496 potentially eligible case children registered with the COG during the study period, 344 met the study eligibility criteria. Seventy case children were excluded because of pathology or age, and 26 were excluded because their tumor was in the brain. Other exclusions were due to physician refusal (n = 20), language (mother did not speak English; n = 32), or the biologic mother's not being available for interview (n = 4). Telephone interviews were completed successfully with the mothers of 278 of the 344 eligible cases (80.8 percent), including the mothers of eight deceased children. Among nonparticipating parents, 44 refused (12.8 percent), 20 had nonworking phone numbers (5.8 percent), and two were unable to schedule an interview.
Controls were selected by random digit dialing and were frequency-matched to cases on the basis of the child's sex, year of birth (±1 year), and geographic location at diagnosis. The matching ratio was approximately 1:2 for males and 1:1 for females. The different matching ratio used for males and females was designed to maximize study power, because the incidence of germ-cell tumors is much lower among boys than among girls. Before the study was implemented, a frequency matrix for control selection (by birth calendar year and sex) was generated on the basis of the age and sex distribution of germ-cell tumor cases using information obtained from the Children's Cancer Group (now part of the COG) database. Geographic matching was implemented only at the state level. Control phone numbers were generated by keeping the area code and exchange (i.e., the first six digits) of the cases' phone numbers and randomly modifying the last four digits. If a randomly selected phone number was not residential, another phone number was randomly selected by the same method. A randomly selected number was dialed until a family with children under age 15 years was identified or until a predetermined number of phone calls had been made (15 calls, five made during the day on weekdays, five made on weekday evenings, and five made on weekends). A detailed description of this method has been given elsewhere (14, 15
).
Of 17,292 randomly selected phone numbers, 5,912 were found to be residential. Of these, 634 were for families who were recruited successfully and had at least one eligible child. The remaining phone numbers were for families who were without eligible children (n = 3,105), refused to be screened (n = 325), or could not be contacted (n = 1,848). This yielded a screening success rate of 63.2 percent. For families with more than one eligible child, only one child was randomly selected to participate in the study. A telephone interview with the mother was completed successfully for 423 of the 634 potential controls (66.7 percent). Nonresponse was due to refusal (n = 182; 28.7 percent), changes in phone numbers (n = 28; 4.4 percent), and other reasons (n = 1).
Information was obtained from each child's mother through a self-administered questionnaire and a telephone interview. The father was also interviewed when available (223 cases and 285 controls; 80.2 percent and 67.4 percent of the participating cases and controls, respectively). Additionally, 35 case mothers (12.6 percent) and 97 control mothers (22.9 percent) provided a surrogate interview for paternal exposures. The questionnaire included questions about demographic factors, medication use, radiographic exposures, personal habits, lifetime occupational history, and family medical history. The occupational data collected consisted of two parts: a self-administered generic work history (job title, type of business, location of employer, job tasks, number of working hours, primary job activities or duties, and chemicals and equipment used for all jobs that parents had held for 6 months or longer since the age of 18) and interviewer-implemented module questionnaires with detailed job-specific questions (16). Module questionnaires in our study were designed by an industrial hygienist (P. A. S.) for a variety of jobs and exposures (17
, 18
). A total of 63 job module questionnaires were used in the study. Based on information obtained from the generic work history, up to five module questionnaires were administered to the parents of each participant. If parents had held more than five jobs, priorities were assigned in the following order: 1) the job held during pregnancy, 2) the job held immediately before and after pregnancy, and 3) the job held for the longest time. Questionnaires specifically involved in pesticide assessments comprised those designed for farmers, farmworkers, gardeners, pesticide applicators, carpenters, firefighters, and janitors.
Occupations and industries were coded using the 1980 US Bureau of the Census classification system of jobs and industries (19). Three broad classes of pesticides (i.e., insecticides, herbicides, and agricultural fungicides) were evaluated using a job exposure matrix approach. This method was developed by our study industrial hygienist (P. A. S.) on the basis of an extensive review of the industrial hygiene literature related to the likelihood of pesticides' being used and their probable quantities, and has been employed in several previous studies (20
22
). Using the detailed work history, module questionnaire, and job exposure matrix information, we assigned a score for the probability, frequency, and intensity of pesticide exposure and a confidence score for the exposures of interest to each study participant, with case-control status masked (21
). The industrial hygiene literature review estimated probability of exposure, frequency of exposure, average intensity of exposure (mg/hour), and confidence in these industry/job combinations. For other industry/job combinations not evaluated in the review, probability, frequency, intensity, and confidence levels were assigned using the original job exposure matrix (21
). The distribution of pesticide-related occupations among parents of cases and controls is provided in appendix table 1.
Probability, defined as the percentage of workers in a particular job/industry combination involving exposure to insecticides, herbicides, or fungicides, was assigned to one of four arbitrary categories: <10 percent, 1049 percent, 5089 percent, and 90 percent. Exposure frequency was assigned a score of 1 to 4 according to the amount of time spent exposed to pesticides: <2, 210, >10
20, or >20 hours/week. Exposure intensity reflected differences roughly corresponding to pesticide exposure levels of <1, 1<10, 10100, and >100 mg/hour, which were then given a weight of 1, 7, 70, or 1,000, respectively, for the calculation of cumulative exposure. Assessment of intensity was restricted to dermal exposure, because approximately 95 percent of total exposure to pesticides comes from deposition on the skin (23
). Duration of exposure for a given job was estimated as the difference between the start date and the end date multiplied by the proportion of all hours spent on the job. Finally, an overall confidence score, reflecting the level of confidence in all three exposure metrics, was developed for each job on a scale of 1 (lowest) to 3 (highest) as a means of interpreting the potential for misclassification.
For each subject, the exposure assessments and job history were used to estimate cumulative exposure for each substance, which was calculated as the sum of the product of the intensity level weight and the duration of exposure across jobs. Cumulative exposure was examined during four time windows relative to the index pregnancy and birth: throughout the entire work history before the reference date (i.e., the diagnosis date for cases); within 1 month before the index pregnancy; during the index pregnancy; and after the birth of the index child. Cumulative exposure for the entire work history was classified into three categories (low, medium, high) based on the 50th and 75th percentiles of exposure among exposed controls. Cumulative exposures in the other time windows of exposure were classified into two categories based on the 50th percentile of exposure among exposed controls, because lower exposure rates were reported. The reference group consisted of parents exposed to none of the three groups of pesticides in all jobs. This report is based on the direct interview data obtained from 647 mothers (253 cases and 394 controls) and 492 fathers (215 cases and 277 controls). We did not include paternal data provided by mothers in this analysis. Fifty-four mothers and 16 fathers were excluded from the analysis because demographic information was inadequate or module questionnaires were not administered.
We used the chi-squared test and Fisher's exact test for categorical comparisons of data. An unconditional logistic regression model with adjustment for age, sex, and relevant confounders was used to calculate odds ratios and 95 percent confidence intervals as estimates of the relative risk (24). Potentially confounding factors included parental education, race, family income, and parental age at pregnancy. This limited set of variables was chosen to capture potential confounding effects broadly related to socioeconomic status (SES). Tests for trend were performed by treating levels of categorical variables as units forming a continuous variable in the logistic model (25
). Analyses were performed with all subjects together and then separately by sex to explore differences in associations between boys and girls. Analyses were also conducted by stratifying the data by the children's age and by the major histologic types of germ-cell tumors. Paternal exposure was analyzed for direct interview data only. Statistical analyses were performed using the statistical package SAS (version 8.0; SAS Institute, Inc., Cary, North Carolina). All tests were two-tailed.
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RESULTS |
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We conducted further analyses after stratifying the data by age at diagnosis (2 years vs. >2 years) and histologic type (mainly dysgerminoma, yolk-sac tumor, and immature teratoma) (table 4). Age at diagnosis did not appear to modify the association with parental exposure. Maternal exposure was associated with an approximately twofold, though statistically nonsignificant, increased risk of dysgerminoma (odds ratio = 1.9, 95 percent CI: 0.9, 4.2). The odds ratios for other types of germ-cell tumors associated with parental occupational exposure to pesticides were all close to unity.
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DISCUSSION |
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To our knowledge, only five studies conducted since 1982 have focused on determining risk factors for germ-cell tumors in children. Two of them were carried out in the United States (9, 36
) and included 73 and 105 germ-cell tumor cases, respectively. Two British studies (8
, 37
) included 41 and 87 cases, respectively, and one Mexican study (38
) included 21 cases. Only two of these studies investigated parental occupational exposure to pesticides and other chemicals, and those assessments mostly defined exposure simply as whether a parent had ever held a job involving pesticide exposure (8
, 9
).
In the current study, we administered both a generic questionnaire and job-specific questionnaires to collect information on job titles and specific information on each job. We evaluated this information for pesticide exposure using a pesticide job exposure matrix while taking into consideration hours of work, duties, protection used, products produced, and duration of employment. Our method of exposure assessment attempted to take into account exposure variability within jobs due to specific tasks, processes, and technology. The intensity and duration of exposure were also estimated, thus allowing a more comprehensive evaluation of occupational exposure to pesticides. In general, we found that parental occupational exposure to pesticides was not related to increased risk of germ-cell tumors in offspring.
Previous studies of germ-cell tumors in adults have suggested that such tumors might be caused by exposures incurred early in life or in utero, most probably before birth (11, 39
, 40
). This study focused on relations between parental pesticide exposure in four time windows (before pregnancy, within 1 month before pregnancy, during pregnancy, and after the birth of the index child) and childhood germ-cell tumor risk. In this study, which to our knowledge is the largest and most comprehensive case-control study of childhood germ-cell tumors to date, we found no strong evidence of an overall association between parental occupational exposure to pesticides and risk of germ-cell tumors among offspring. This is similar to a previous study (9
) that found no association with parental pesticide exposure. Another descriptive epidemiologic study found increased risk of testicular cancer in the offspring of male pesticide applicators (10
). The few positive findings from our study, including a positive association between maternal herbicide exposure during the postnatal period and germ-cell tumors among girls and a nonsignificant positive association between maternal pesticide exposure and dysgerminoma, were based on small samples and need to be confirmed in future studies.
It is interesting that paternal pesticide exposure was inversely associated with germ-cell tumor risk, although the point estimates were mostly nonsignificant. The small number of exposed subjects and the multiple comparisons involved in the analyses suggest a cautious interpretation. Nevertheless, this pattern was also reported in an earlier investigation: A Danish study found that offspring of fathers employed in agriculture had a marginally reduced risk of germ-cell tumors, although the offspring were older than 16 years (11). Pesticide exposure in males has been associated previously with a reduced sperm-cell count (41
, 42
) and an increased number of female offspring (43
, 44
). More studies are needed to investigate the possible gender-specific effects of paternal pesticide exposure on offspring.
Our study had several strengths. First, these findings represent the most recent information available on childhood germ-cell tumors in the United States. Second, detailed exposure information was available for many pesticide-exposed jobs and covered the likely relevant periods of exposure. Third, the exposure information was collected from both mothers and fathers. Fourth, the relatively large sample size allowed us, in the analyses, to stratify the data by gender, age at diagnosis, histologic type, kind of pesticide, and exposure probability and confidence. Fifth, we were able to assess each parental subject's pesticide exposure according to specifics of employment during his/her life, such as industry, job title, hours of work, duties, protection used, products produced, and duration of employment. Thus, the exposure assessment more closely reflected the actual occupational pesticide exposure of our cases and controls. Last, although residential exposure to pesticides was not included in this report, additional adjustment for residential pesticide exposure did not alter the parental occupational exposure associations reported. Detailed results on the association of residential exposure to pesticides and other chemicals with germ-cell tumor risk will be presented in a separate paper (45).
The results of this study must be interpreted by recognizing several limitations. First, the relatively low response rate, particularly among controls (80.8 percent for cases and 66.6 percent for controls), raises a concern about selection bias. Using random digit dialing to identify control households may have excluded families of lower SES (46). In our study, there were fewer controls from lower-SES families than cases. For both cases and controls, we found that the number of module questionnaires implemented and the number of pesticide exposures were inversely related to SES. If participation in the study differed according to SES and case-control status (i.e., if potential control parents with low SES were more likely to refuse participation than case parents with the same SES), the association between parental occupational exposure and childhood germ-cell tumors might have been underestimated. Second, the job information reported by parents could have been subject to misclassification. However, the occupational module questionnaires used in the study were designed to collect detailed information on jobs that each parental subject had held during his/her lifeincluding information on industry, job title, working hours, duties, materials used, products produced, and duration of employmentrather than focus only on specific chemical exposures. The module questionnaire data were then reviewed and exposure levels were assigned with case-control status masked. Although we could not completely exclude the possibility of differential recall by case parents and control parents, the procedure applied in the study should have minimized differential misclassification in the exposure assessment. Third, although considerable effort was made to ensure the quality of the exposure assessment, nondifferential misclassification of exposure undoubtedly occurred and would have biased the risk associations toward the null. Fourth, because of the low rate of exposure to pesticides and the relatively small sample size, this study had more than 80 percent statistical power to detect an odds ratio of 1.5 or higher for ever exposure to pesticides or exposure during the preconception period and an odds ratio of 2.0 or higher for in-utero or postnatal exposure. Last, germ-cell tumors comprise a number of different histologic subtypes; each type derives from distinct cells and may have a distinct etiology, which restricts the ability of any single study to detect significant case-control differences.
In summary, this study failed to find strong evidence in support of a relation between parental exposure to pesticides in the workplace and an increased risk of germ-cell tumors in offspring.
APPENDIX TABLE 1. Distribution of pesticide-related occupations/industries among parents of cases and controls in a case-control study of germ-cell tumors and parental occupational pesticide exposure, Children's Oncology Group, United States, 19932001
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* Jobs were assigned two-digit Standard Occupational Classification codes (19) based on the job title and the type of industry.
Subjects could appear in multiple categories if their parents had held jobs in more than one category. Job categories with fewer than five subjects whose parents were exposed to pesticides were not included in the table. These categories were: management-related occupations; veterinarians; social, recreation, and religious workers; teachers, except those at postsecondary institutions; athletes and related workers; forestry and logging workers; production supervisors, including precision production; plant and system operators; fabricators, assemblers, and hand workers; material movers, except transportation workers; and military personnel.
APPENDIX TABLE 2. Prevalence (%) of paternal occupational pesticide exposure by annual family income in a case-control study of germ-cell tumors and parental pesticide exposure, Children's Oncology Group, United States, 19932001
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ACKNOWLEDGMENTS |
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Dr. Zhi Chen is a visiting scholar from China Medical University (Shenyang, China).
Conflict of interest: none declared.
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References |
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