1 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC.
2 Department of Health Care Epidemiology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
3 Division of Pediatric Hematology/Oncology, School of Medicine, University of North Carolina, Chapel Hill, NC.
4 Department of Epidemiology, M. D. Anderson Cancer Center, University of Texas, Houston, TX.
5 Department of Health Policy and Epidemiology, School of Medicine, University of Florida, Gainesville, FL.
6 Current address: Occupational Epidemiology Branch, National Cancer Institute, Bethesda, MD.
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ABSTRACT |
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child; dust; hydrocarbons; metals; neuroblastoma; occupational exposure
Abbreviations: CI, confidence interval; IH, industrial hygienist; OR, odds ratio
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INTRODUCTION |
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To evaluate the effects of parental occupational exposures on neuroblastoma incidence in offspring, we conducted a large, multicenter case-control study. Our first analysis examined incidence by parental job title (6). It found an increased rate of neuroblastoma for parents working as electrical power installers or power plant operators, for mothers working as hairdressers, and for fathers working as firefighters, landscapers, mechanics, painters, glass and optical goods workers, or broadcast, telephone, and dispatch operators. In this paper, we report results from further analysis of the same study population. We employed detailed exposure assessment that allowed estimation of the effects of specific occupational chemical exposures, using information on job title as well as on self-reported duties and exposures.
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MATERIALS AND METHODS |
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One control was selected for each of 504 cases through random digit dialing. We were unable to identify controls for the remaining 34 cases after multiple attempts. Controls were individually caliper-matched to cases on date of birth (±6 months for cases 3 years of age, ±1 year for cases >3 years of age). The response proportion for the random digit dialing screening was 74 percent, calculated as the percentage of households that participated out of the total number selected for screening (9
), and recruitment among eligible controls was 71 percent.
Data collection
A telephone interview was conducted with each mother, as well as with the father when he was available. We obtained interviews from 472 case fathers (88 percent of enrolled cases; 405 direct interviews and 67 proxy interviews with the mother) and 445 control fathers (88 percent of enrolled controls; 304 direct interviews and 141 proxy interviews with the mother). The interview included questions on demographic characteristics such as parental age, race, education, and income. Information on occupational history was obtained from each parent, including dates of employment, names of employers, occupations, industries, job titles, specific duties, and hours per week. For each job held during the 2-year period prior to the child's date of birth, mothers and fathers were asked if they had been exposed to chemicals, dusts, fumes, gases, vapors, or oils. Respondents could report exposure to any of 65 chemicals, compounds, or broad categories of substances listed in an interview guide that was provided. For each chemical exposure reported in each job, data were collected on the form of exposure (gas or vapor, dust or powder, smoke, liquid, or solid), the route of exposure (air, skin, clothing, swallowing), the work activities being performed during exposure (e.g., working near exposure, cleaning, wiping, cutting), the number of hours of exposure per week, and the dates on which exposure began and ended.
Information on occupational chemical exposure was available for 1,040 mothers (537 case mothers and 503 control mothers; 503 matched pairs) and 707 fathers (405 case fathers and 302 control fathers; 232 matched pairs). These numbers are lower than the total number of interviews completed, primarily because proxy respondents for fathers' interviews were not asked questions from the occupational history section on chemical exposures. Proxy-reported information on occupational exposure is subject to misclassification due to low sensitivity and low positive predictive value (10, 11
); therefore, we did not consider it reliable. Additionally, two mothers and three fathers refused to answer the questions on occupational chemical exposure.
Exposure assessment
Parental occupational chemical exposure was coded in several ways.
Self-reported exposures. A parent was coded as having been exposed to a substance if he or she reported exposure to that substance in any job.
Industrial hygienist's review of self-reported exposures. We reviewed each reported exposure scenario carefully under the supervision of an industrial hygienist (K. Teschke), so that any situation in which exposure was improbable was recoded as unexposed. All exposure coding was conducted without knowledge of subject's disease status or parent's gender. In community-based case-control studies in which the prevalence of most exposures is low (<15 percent), incorrectly classifying even small numbers of individuals as exposed results in bias that substantially attenuates effect estimates toward the null value, if the misclassification is nondifferential and there is a true positive association; whereas an equal proportion of individuals incorrectly classified as unexposed will contribute little bias to the estimate (1214
). In order to minimize bias resulting from exposure misclassification, our industrial hygienist (IH) review focused on increasing the specificity of exposure measures by reducing the number of false-positive exposures. Jobs in which no chemical exposure was reported were not reviewed. All reported information for each exposure was reviewed, including occupation, industry, hours of exposure per week, form of the substance, route of exposure, use of protective equipment or clothing, and specific work activities. A parent was coded as having been exposed to a chemical if the IH review determined probable exposure in any job.
Chemical categories. Chemicals were grouped into five broad categories to allow evaluation of the effect of chemicals with similar physicochemical characteristics and for comparability of results with the findings of previous studies. Data on exposures to sufficiently common specific chemicals were retained for analyses, but these substances were also grouped into the following categories: halogenated hydrocarbons; nonvolatile hydrocarbons; volatile hydrocarbons; paints, inks, and pigments; and metals, alloys, and solders (see table 1).
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Statistical analyses
Separate analyses were conducted for maternal and paternal exposures to each chemical. Where the overall frequency of IH-reviewed exposure among cases and controls was five or greater, we calculated exposure odds ratios to estimate the incidence rate ratios for neuroblastoma associated with self-reported and IH-reviewed exposure. Each chemical exposure was evaluated in a separate model, using persons unexposed to the chemical as the reference group. Exposure odds ratios were calculated using unconditional logistic regression modeling so that all matched and unmatched subjects could be included to enhance precision. Each model included variables for the matching factor, child's age, which was coded as a set of indicator variables (6-month intervals for ages 3 years; 2-year intervals for ages >311 years; one variable for ages >11 years), as well as variables for the set of demographic covariates. We conducted separate analyses to evaluate associations between parental occupational chemical exposures and specific subtypes of neuroblastoma, as defined by age at diagnosis (
1 year vs. >1 year) or N-myc oncogene status (amplified vs. normal).
We considered confounding among certain groups of paternal occupational chemical exposures that frequently occurred together (i.e., 10 or more fathers in the study were exposed to both of two chemicals). Frequent co-occurrence was common among the following groups of chemicals, which were evaluated in three separate models: 1) hydrocarbons with paints; 2) wood dust with paints and hydrocarbons; and 3) four types of steel alloys and solders (not otherwise specified) with lubricating and cutting oils. Confounding was examined by modeling all relevant exposures simultaneously, along with variables for child's age and the demographic covariates. Maternal exposures were too infrequent to allow examination of confounding by specific chemicals.
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RESULTS |
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Paternal occupational exposures to several chemicals were associated with increased incidence of neuroblastoma in offspring (see table 4). Odds ratios for several hydrocarbons were 1.5 or above, including alcohols, benzene, cutting oil, diesel fuel, lacquer thinner, mineral spirits, paint thinner, and turpentine. Odds ratios for the categories of volatile hydrocarbons (odds ratio (OR) = 1.5; 95 percent confidence interval (CI): 1.0, 2.1) and nonvolatile hydrocarbons (OR = 1.5; 95 percent CI: 1.0, 2.2) were elevated as well. The data indicated positive associations between neuroblastoma and paternal exposures to certain metals, alloys, and solders, including stainless steel, mild steel, galvanized steel, high-speed steel, brass, metals (not otherwise specified), and solders (not otherwise specified), although exposure to metals, alloys, and solders as a category was not strongly associated with neuroblastoma. There was a 50 percent increased incidence of neuroblastoma associated with paternal exposure to wood dust. Of the other dust exposures analyzed, odds ratios were elevated for grain dust and rubber dust, although the estimates were extremely imprecise. When separate analyses were conducted by N-myc oncogene status or age at diagnosis, there did not appear to be a specific subtype of neuroblastoma with which paternal occupational chemical exposures were more or less strongly associated (results not shown).
Analyses of paternal exposures that frequently occurred together revealed some confounding between different groups of chemicals. When data were simultaneously adjusted for paternal exposures to frequently co-occurring hydrocarbons and paints, odds ratios for alcohols (OR = 1.6; 95 percent CI: 0.7, 3.4), diesel fuel (OR = 2.0; 95 percent CI: 1.0, 4.3), lacquer thinner (OR = 2.9; 95 percent CI: 1.0, 8.3), mineral spirits (OR = 1.7; 95 percent CI: 0.6, 4.5), and turpentine (OR = 12.0; 95 percent CI: 2.2, 65.9) remained elevated, whereas the odds ratio for paint thinner was diminished (OR = 0.9; 95 percent CI: 0.4, 2.1). The odds ratio for paternal exposure to wood dust was elevated (OR = 1.6; 95 percent CI: 0.8, 3.0), even after adjustment for potential confounding by exposure to hydrocarbons or paints. When four steel alloys and solders (not otherwise specified) were included in the same model as cutting and lubricating oils, the effect estimate for solders remained moderately elevated (OR = 2.5; 95 percent CI: 0.8, 7.6), whereas the estimates for the steel alloys were too imprecise for evaluation of confounding.
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DISCUSSION |
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Several of the paternal exposures associated with elevated effect estimates in our study are hydrocarbons. In a previous study, Spitz and Johnson (3) observed an increased rate of neuroblastoma associated with job clusters linked to moderate exposures to aromatic and aliphatic hydrocarbons. This finding was not confirmed in another population (1
), although more specific self-reported paternal exposure to benzene was associated with neuroblastoma. Although several of the hydrocarbons we studied are suspected carcinogens, the only substance deemed by International Agency for Research on Cancer evaluation to have sufficient evidence of carcinogenicity is benzene (20
). Paternal exposures to certain hydrocarbons, including toluene and xylene, have been associated with the risk of spontaneous abortion (21
), which may indicate a chemical's ability to affect germ cells or fetal development. Exposure to hydrocarbons is common in occupations for which associations with neuroblastoma have previously been observed, including electrician, electrical assembler and repairer, farmer, mechanic, painter, and glass and optical goods worker (2
, 3
, 6
).
Surveillance has shown cytogenetic, mutagenic, and genotoxic effects of working as a painter (2226
), and evidence of the carcinogenicity of occupational painting is considered sufficient by the International Agency for Research on Cancer (24
). In addition, numerous childhood cancer studies have implicated painting as a high-risk occupation (27
34
). In our analysis of occupational groups (6
), paternal occupation as a painter was associated with a twofold increase in the incidence of neuroblastoma in offspring. However, in analysis of specific chemical exposures, there is little evidence that exposure to paints accounts for this association. The increased rate of neuroblastoma associated with painting as an occupation may instead result from the use of solvents such as lacquer thinner, mineral spirits, paint thinner, or turpentine during the painting process. All of the fathers who worked as painters during the period of interest reported exposure to at least one of these solvents. Indeed, when we adjusted for paternal exposure to these four solvents, the effect estimate for oil-based paint was diminished (OR = 1.0; 95 percent CI: 0.4, 2.5).
Paternal exposures to several metals were associated with an increased rate of neuroblastoma; however, exposures to metals were rather uncommon, and effect estimates were very imprecise. Previous studies of paternal occupation and neuroblastoma observed positive associations with self-reported occupational exposure to metal fumes and dusts (1) and melted metal (5
). Potential effects of paternal metal exposures on neuroblastoma are biologically plausible, since several metals are known to be carcinogenic and genotoxic. The International Agency for Research on Cancer has concluded that cadmium, nickel, and hexavalent chromium compounds are definite or probable carcinogens (35
37
), and the potential for these metals to cause genetic alterations is clear from the results of in vitro and in vivo assays (38
). In addition, a transgenerational carcinogenic effect of chromium was observed among offspring of male rats exposed to chromium trichloride (17
). Our previous analysis of paternal occupation did not indicate any increased incidence of neuroblastoma associated with welding occupations that entail high exposure to metal fumes (6
), but any risk associated with metal exposure might be in specific types of welding or in grinding and cutting operations that have metal dust exposure. Unfortunately, small numbers of exposed subjects did not permit precise estimation of effects by specific work task.
We observed a positive association with paternal exposure to wood dust. Wood dust is known to be carcinogenic to nasal epithelium (39); however, the systemic carcinogenic potential of wood dust beyond its effect through direct contact with tissues has not been extensively studied. Woods contain numerous chemical components, including terpenes (the major component of turpentine), phenols, resin acids, and miscellaneous inorganic compounds, and an effect of wood dust could potentially operate by a genotoxic mechanism in which the chemicals within the dust mutate germline DNA. Constituents of beech and oak have been shown to cause DNA damage in mammalian cells (39
). Apart from the inherent constituents of wood, wood used in construction is often treated with preservatives such as chromated copper arsenate and chlorophenol derivatives, which may contribute to the genotoxicity of wood dust. Workers in carpentry or construction are commonly exposed to a variety of solvents, including naphtha, white spirits, toluene, xylene, benzene, alcohols, and glycol ethers (39
). However, the effect estimate for wood dust in our study was unconfounded by exposure to commonly co-occurring solvents and paints.
Our IH review of self-reported exposures allowed us to evaluate the impact of exposure misclassification on calculated effect estimates. If exposure misclassification were nondifferential, the effect estimates reflecting true positive associations should, on average, be biased toward the null for self-reported exposures compared with estimates for IH-reviewed exposures. The estimates for paternal exposures generally followed this expected pattern. However, there is some evidence that exposure misclassification of fathers' reports was differential; exposure reports by control fathers were approximately 70 percent more likely to be recoded as "unexposed" than reports by case fathers. This pattern of differential reporting could account for the generally lower odds ratios observed for self-reported exposures. The results for maternal exposures followed an opposite pattern in that odds ratios for self-reported exposures were generally more elevated than those for IH-reviewed exposures. These results suggest that the exposure misclassification for mothers was perhaps due to recall bias; for example, case mothers may have exaggerated their exposure histories. In fact, exposure reports by case mothers were approximately 60 percent more likely to be recoded as "unexposed" than reports by control mothers.
Because our IH review focused solely on correcting false-positive exposure reports, it is likely that false negatives (i.e., nonreporting) exist in our data. A more extensive review could use information on job duties to correct some of the false negatives. In most cases, however, job duty information is not detailed enough to infer specific exposures and could at best be used to infer exposure to categories of chemicals. For estimation of the prevalence of false negatives and differences in reporting between cases and controls, we conducted a post hoc review to detect unreported exposures to the categories "paints, inks, and dyes" and "metals, alloys, and solders" and to the specific exposure "wood dust." We searched for exposures to paints, inks, and dyes by examining job duties for anyone classified with an occupation of "painter," as well as by searching for the words "paint," "ink," and "dye" in job duties across all occupations. We searched for exposures to metals, alloys, and solders by examining job duties for anyone classified with an occupation of "welder or cutter," as well as by searching for the words "weld," "metal," "steel," "solder," and "alloy" in job duties across all occupations. We searched for wood dust exposures by examining job duties for anyone classified with an occupation of "carpenter" or "construction worker," as well as by searching for the word "wood" in job duties across all occupations. After searching for the above keywords, we used subjective judgment to decide whether the person's job duty description indicated probable exposure. Out of 2,028 jobs reported by mothers and fathers during the period of interest for which there was exposure information, we found examples of potential false negatives for paints, inks, and dyes (10 jobs (seven fathers)), metals, alloys, and solders (14 jobs (four mothers and eight fathers)), and wood dust (22 jobs (one mother and 20 fathers)). Some of these potential false negatives occurred in jobs where we were confident that exposure had occurredsuch as the work of a painter whose job duty was "painting homes" and the work of welders who reported "welding" as their job dutybut some potential false negatives were found among owners, foremen, and laborers whose duties were diverse, so the time spent in the exposed tasks may have been insufficient for us to classify the person as exposed. In many instances, the parents with potential false negatives reported exposure to other chemicals (e.g., a painter reporting exposure to thinner solvents, a welder reporting exposure to cutting oil), providing further indication that their work offered opportunities for exposure (as opposed to simply office work). The majority (75 percent) of fathers with potential false negatives were case fathers, indicating some differential bias. However, when we included these parents in the "exposed" groups of the respective exposure variables, effect estimates were not substantially changed (paternal exposure to paints, inks, and dyes: OR = 1.0; paternal exposure to metals, alloys, and solders: OR = 1.1; paternal exposure to wood dust: OR = 1.7).
An ideal IH review might capture both false-positive and false-negative exposures. It would be fairly simple to capture some false negatives by looking within certain occupations and by searching for keywords; however, there are not many occupations or tasks (such as welding) in which exposure is fairly certain to occur. There is clear exposure variability in most other occupations; for example, dry cleaners may send clothes off-site for cleaning or use nonsolvent cleaning agents, and farmers may not apply their own pesticides or may farm organically. For this reason, a more sensitive data collection system might employ computer-assisted interviews in which certain occupations or keywords would automatically trigger job-specific questions to enhance exposure recall or to elicit information from which specific exposures could be inferred with greater certainty (40).
The data presented here broaden our understanding of the associations between parental occupational chemical exposures and neuroblastoma in offspring in several ways. To our knowledge, this study is the largest study of neuroblastoma conducted to date, with the most detailed information on self-reported occupational exposures. The ability to evaluate actual chemical exposures rather than merely occupations provides guidance for the direction of future research directed toward specific causative agents.
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ACKNOWLEDGMENTS |
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The authors thank Joanna Smith for programming support and Laura Fish for assistance with study coordination. The authors gratefully acknowledge the assistance of the principal investigators, oncologists, and data managers of the participating Children's Cancer Group and Pediatric Oncology Group institutions.
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NOTES |
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REFERENCES |
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