American Journal of Epidemiology Advance Access originally published online on June 7, 2006
American Journal of Epidemiology 2006 164(3):212-221; doi:10.1093/aje/kwj203
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Original Contribution |
Child and Maternal Household Chemical Exposure and the Risk of Acute Leukemia in Children with Down's Syndrome: A Report from the Children's Oncology Group
1 Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, MN
2 Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
3 University of Minnesota Cancer Center, Minneapolis, MN
4 Department of Epidemiology, University of North Carolina, Chapel Hill, NC
Correspondence to Dr. Logan G. Spector, Division of Epidemiology/Clinical Research, Department of Pediatrics and Cancer Center, University of Minnesota, 420 Delaware Street, SE, MMC 715, Minneapolis, MN 55455 (e-mail: spector{at}epi.umn.edu).
Received for publication September 7, 2005. Accepted for publication February 17, 2006.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Compared with the general pediatric population, children with Down's syndrome have a much higher risk of acute leukemia. This case-control study was designed to explore potential risk factors for acute lymphoblastic leukemia and acute myeloid leukemia in children with Down's syndrome living in the United States or Canada. Mothers of 158 children with Down's syndrome and acute leukemia (97 acute lymphoblastic leukemia, 61 acute myeloid leukemia) diagnosed between January 1997 and October 2002 and mothers of 173 children with Down's syndrome but without leukemia were interviewed by telephone. Positive associations were found between acute lymphoblastic leukemia and maternal exposure to professional pest exterminations (odds ratio = 2.25, 95% confidence interval: 1.13, 4.49), to any pesticide (odds ratio = 2.18, 95% confidence interval: 1.08, 4.39), and to any chemical (odds ratio = 2.72, 95% confidence interval: 1.17, 6.35). Most of the associations with acute myeloid leukemia were nonsignificant, and odds ratios were generally near or below 1.0. This exploratory study suggests that household chemical exposure may play a role in the development of acute lymphoblastic leukemia in children with Down's syndrome.
Down syndrome; environmental exposure; leukemia; maternal exposure
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Leukemias comprise about 24 percent of cancers in children aged 0–19 years and are the most frequent type of cancer in this population (1
). Compared with children without Down's syndrome, children with Down's syndrome have a roughly 20-fold increased risk of developing leukemia (2, 3). It is uncertain why children with Down's syndrome are at increased risk of leukemia, but several hypotheses have been proposed. Chromosomal instability and gene expression dysregulation due to trisomy of chromosome 21 may be involved in this increased risk (3). Already established or hypothesized environmental risk factors for leukemia may also contribute to leukemia oncogenesis in children with Down's syndrome (4). Some in vitro experiments indicate that DNA damage in response to application of mutagens is greater in Down's syndrome compared with normal cells (5–8). Thus, children with Down's syndrome may experience a greater risk of leukemia in response to an environmental exposure.
Many investigations of childhood leukemia, apart from Down's syndrome, have examined exposure to chemicals. Positive associations between parental or child exposure to diverse chemicals and the occurrence of childhood leukemia have been found, although the results are inconsistent (9–12). These chemical exposures include pesticides, petroleum products, solvents, and paints. A larger number of studies have evaluated paternal exposure, which may affect childhood cancer risk directly by altering sperm or indirectly by increasing maternal and child exposure to chemicals (9–14). In light of these investigations, we explored whether maternal or child exposure to household chemicals is associated with acute leukemia in children with Down's syndrome.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Subject selection and recruitment
Details of this study have been published elsewhere (15
, 16) and are described here briefly. Incident cases of acute leukemia diagnosed in children with Down's syndrome between January 1997 and October 2002 were identified through the registration files of the Children's Oncology Group. Eligibility criteria were diagnosis of incident acute leukemia at age 19 years or younger, residence in the United States or Canada at the time of diagnosis, a telephone in the household, and a biologic mother who spoke English and who could be interviewed. Requirements also included permission from the child's primary care physician to contact the parents and written consent from the mother for the interview. Mothers of children with Down's syndrome and leukemia were asked to provide the names and addresses of their child's primary care physician prior to diagnosis of leukemia. The physicians were asked to provide a list of pediatric patients from their practice who had Down's syndrome but no leukemia. Potential controls were randomly selected from this list and were frequency matched to cases by age at diagnosis of leukemia (within the age strata of 0, 1–3, 4–6, 7–10, 11–14, 15–19 years). All mothers were interviewed by using a structured, computer-assisted telephone questionnaire. This study was approved by the institutional review boards of the University of Minnesota and participating Children's Oncology Group institutions.
Variable specification
Mothers were asked about their exposure to household chemicals during the month before the index pregnancy, during the index pregnancy, and while nursing the index child. Exposures of cases were recorded up to a reference date, which was 6 months prior to the date of leukemia diagnosis. Controls were assigned a randomly selected reference date in the 12 months surrounding their birthdays of that year. All mothers were asked about their chemical exposures prior to their child's assigned reference date. Mothers of children whose reference age was less than 1 year were not asked about their child's chemical exposures.
Mothers were asked to specify, for each time period of interest, the number of times she or the index child was exposed to the following substances: products to control household insects; products for moth control; rodenticides; products for flea or tick control; herbicides, including those used to control insects that infest plants; insect repellants; petroleum products such as gasoline, kerosene, lubricating products, and spot removers; and paints, stains, or lacquers. For each of these groups of substances, there was an option for mothers to answer that they "have product around always/usually," which, to rank exposure frequency, was assigned a value of 100.
Dichotomous (i.e., ever/never) exposure variables were created for individual chemicals for each time period of maternal exposure, overall maternal exposure, and child exposure. Categorical and ordinal variables were also defined for the individual chemical categories by determining the median frequencies of exposure without regard to case-control status and comparing individual subjects' values with this combined distribution. Frequency of exposure was designated "high" if equal to or above the median and "low" if below. If the distribution of exposure was highly skewed, then only dichotomous (ever/never) exposure was analyzed. The ordinal variables were assigned values of 0, 1, and 2 for no, low, and high chemical exposure, respectively.
Groups of chemicals designed to kill or repel insects, mammals, or plants, including the use of professional extermination, were combined to form a pesticide index variable. Petroleum products, paints, stains, and lacquers were also combined into an index variable. Finally, all groups were combined into an index of any chemical exposure. These indices were created by summing the ordinal variables for individual chemicals. For instance, for a child with no exposure to petroleum products and high exposure to paints, stains, and lacquers, the ordinal values would be 0 and 2, respectively, and the index would have a value of 2. As with the individual chemicals, categorical and ordinal index variables were created based on the distribution of exposure frequencies in cases and controls combined.
Demographic data, as well as information on the mother's family characteristics, medical history, and personal habits, were collected. From these data, several potential confounders were decided upon a priori. Included were the child's age, the child's sex, and the mother's educational level. Feeding method was also thought to be a potential confounder. Child's age was represented categorically to distinguish cases at the peak incidence of the acute lymphoblastic leukemia (ALL) subtype. Breastfeeding was categorized into breastfed, bottle-fed, or both. The following additional potential confounders were evaluated: child's race (White or non-White), gestational age (
38 weeks or >38 weeks), birth weight (3,500 g or >3,500 g), maternal age at delivery (35 years or >35 years), mother's educational level (<high school, high school graduate, or >high school), and smoking during pregnancy (any or none).
Statistical analyses
The distributions of chemical exposure variables and covariates among cases and controls were compared by using the t test for two proportions or the chi-square test, as appropriate. The correlation (r) of chemical exposures across maternal exposure periods and between individual chemicals within exposure periods was also calculated.
Odds ratios and 95 percent confidence intervals that estimated the association of maternal and child household chemical exposure with the risk of leukemia in children with Down's syndrome were calculated by using unconditional logistic regression (SAS, version 9.1 software; SAS Institute, Inc., Cary, North Carolina). Odds ratios were calculated for the stratified subgroups of ALL and acute myeloid leukemia (AML). Dichotomous, categorical, and ordinal chemical exposure variables were each modeled separately and were adjusted for potential confounders. All exposure category models were adjusted for child's age, child's sex, and mother's educational level. Age was adjusted for as a continuous variable for all exposure analyses. The models for the exposure period of maternal exposure while nursing were adjusted for feeding method as well. The indices were also adjusted for child's race, mother's age at delivery, child's birth weight, gestational age, and maternal smoking during pregnancy if the potential confounder changed the parameter estimate by more than 10 percent. The p values for linear trend test were obtained from models of chemical exposure frequency as ordinal variables. In the tables in this paper, odds ratios are not reported when cell sizes were less than 3.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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A total of 116 Children's Oncology Group institutions identified 210 potential cases for inclusion in this study. Mothers of 158 (75 percent) cases contacted completed the telephone interview. Of these cases, 97 had ALL and 61 had AML. The mean duration between diagnosis of cases and interview of their mothers was 21 months.
To identify Down's syndrome controls, 151 clinics were contacted. In response, 77 (51 percent) of the clinics provided lists of 726 children with Down's syndrome; 27 (18 percent) other clinics reported no other age-eligible children, and 47 (31 percent) clinics declined or were unable to provide rosters. Of the 726 children, 329 potential Down's syndrome controls were selected based on their date of birth. Clinics provided names and addresses for mothers of 215 (65 percent) potential controls; a name and address was not supplied for 114 children for the following reasons: the families could not be located or were no longer seen by the clinic (n = 46), the families refused the clinic's request (n = 19), the clinic determined that the child was not eligible (n = 18), the clinic chose not to contact them (n = 8), or reasons that the clinics did not report (n = 23). Telephone interviews were successfully completed with 173 (81 percent) mothers whose contact information was provided, an average 2 months after assessing their child's eligibility.
Descriptive characteristics of cases and controls are presented in table 1. The two groups were similar with respect to child's sex, gestational age, birth weight, breastfeeding, family income at child's birth, and maternal smoking during the index pregnancy. ALL cases were more likely than controls to be aged 2–6 years (p < 0.0001). AML cases were more likely than controls to be less than age 2 years, and none of the AML cases were older than age 6 years (p < 0.0001). Compared with controls, AML cases were more often non-White (p = 0.04), and, at delivery, mothers of AML cases were older than mothers of controls (p = 0.03). Mothers of cases were also less educated than mothers of controls (p = 0.003).
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Maternal exposure
Correlations of maternal chemical exposures during pregnancy with those during the month before pregnancy and while nursing are shown in table 2. These correlations were generally strong (r > 0.50). Thus, in the interest of simplification, we report the results of overall maternal chemical exposure in table 3. Positive associations of any versus no exposure with ALL were apparent for most categories of chemical exposures. However, associations were significant for only exposure to professional pest exterminations (odds ratio = 2.25, 95 percent confidence interval: 1.13, 4.49), the all-pesticides index (odds ratio = 2.18, 95 percent confidence interval: 1.08, 4.39), and exposure to any chemical (odds ratio = 2.72, 95 percent confidence interval: 1.17, 6.35). Significant linear trends were noted for exposure to insecticides (p = 0.05), for the all-pesticides index (p = 0.05), and for the any-chemical index (p = 0.02). Period-specific results did not clearly indicate a window of greatest risk (data not shown). The associations of overall maternal chemical exposure with leukemia incidence for AML cases were nonsignificant with one exception, and odds ratios were generally near or below 1.00 with wide confidence intervals.
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Child exposure
No statistically significant results were found regarding child exposure for ALL cases compared with controls (table 4). For AML cases, a near-significant negative association was found for any insecticide exposure (odds ratio = 0.34, 95 percent confidence interval: 0.11, 1.03) and a near-significant decreasing test for linear trend was found for exposure to this chemical class (p = 0.07). Other odds ratios for AML featured very wide confidence intervals.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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This case-control study is the largest known to examine risk factors for acute leukemia in children with Down's syndrome. In this exploratory analysis, we looked specifically at household chemical exposure. For ALL, we found a positive association for overall maternal exposure to insecticides, professional pest exterminations, the all-pesticides index, and the any-chemical index. Household chemical exposure was not significantly positively associated with AML. Rather, there was a near statistically significant negative association of AML with child exposure to any and high frequencies of insecticides.
To our knowledge, only one other comparable case-control study of acute leukemia in children with Down's syndrome exists. Mejia-Arangure et al. (17) examined in utero exposure to alcohol and tobacco and the incidence of leukemia in children with Down's syndrome, but they did not consider household chemical exposure. Thus, there is no body of literature with which to directly compare our results. However, significant associations have been found between prenatal chemical exposure and congenital heart disease in children with Down's syndrome (18, 19), which may be biologically relevant given the similar periods of risk. In addition, there are a number of reports on the relation between chemical exposure and acute leukemia in children without Down's syndrome. Unlike a previous Children's Oncology Group study of ALL that found positive associations for ALL cases with ras mutations to household and occupational maternal exposure to petroleum products and solvents, these exposures were not significantly associated with an increased risk of ALL in our study of children with Down's syndrome (20). Several other studies have also found significant positive associations with leukemia and exposure to paints, stains, lacquers, and petroleum products, but no such association was found in this investigation, and, in fact, a negative association was found with petroleum products (12, 21–27). Many of these earlier studies examined paternal exposures in occupations where exposures were frequent. In this study, we examined maternal and child home exposures, and exposures to these chemicals were low. However, studies have examined maternal exposure to solvents with relatively infrequent exposures and have found positive associations (24–27). The positive associations we found between acute leukemia and exposure to professional pest exterminations and to insecticides were also reported by others (22, 26, 28).
This study examined exposure of the mother and child, rather than of the father, who represents a less direct route of exposure (12). It also examined ALL and AML separately. A review by Daniels et al. (10) indicated that previous studies have not found a difference in exposure-disease associations of ALL and AML with pesticide exposure, but, in this study, we did find a difference. Significant positive associations were found for ALL cases, and null or protective associations were found for AML cases.
This study also looked at different time exposure periods: before pregnancy, during pregnancy, and after birth. These divisions were designed to differentiate exposure periods of greatest risk and to distinguish between germline and somatic mutations. However, the correlation of maternal chemical exposure across windows of exposure precluded a detailed assessment of period-specific risk. We also assessed the frequency of exposure, allowing for a dose-response analysis of the chemical groups.
As with most case-control studies, there is a potential for recall bias. Mothers of cases may have scrutinized their past pregnancy more thoroughly than did mothers of controls. That positive odds ratios were found for ALL and not for AML indicates that recall bias was likely not a strong factor in this study. However, that interviewees had to recall events taking place up to 20 years in the past may have been a source of reporting bias.
Selection bias among controls is also commonly a concern with case-control studies. A third of the clinics declined to provide rosters of potential controls, and contact information was not available for roughly a third of the children selected. It was not possible to calculate the overall participation rate for controls because doing so depended on the number of potential controls at nonparticipating clinics, which could not be determined. However, participation was certainly less than ideal, and there was some indication of selection by socioeconomic status since, as shown in table 1, mothers of controls had attained significantly more years of education than mothers of cases. Although we adjusted for maternal educational level, selective nonparticipation of children with household chemical exposure would lead to overestimation of odds ratios. Enrollment of controls with a substantially different geographic distribution than that of cases might also bias results since pesticide use varies by region (29). We found that region of residence did not differ significantly between cases and controls and, moreover, that adjustment for regions of residence did not materially affect our results (data not shown). There was minimal potential for selection bias among cases because case participation was high and the Children's Oncology Group treats 94 percent of leukemia cases in children aged 0–14 years and 21 percent of cases in children aged 15–19 years (30, 31).
Many exposure-disease associations were assessed in this analysis. Thus, our results may have been due to multiple comparisons. However, many of the positive associations found were supported by results from previous studies, as noted above.
The significant negative association of childhood insect repellant exposure with AML is novel. One possible explanation is that AML cases were younger than controls and thus had a shorter duration of postnatal exposure, although age was adjusted for as a continuous variable. The result is counterintuitive but persisted after adjustment for possible explanatory factors.
Although this is the largest known case-control study of acute leukemia in children with Down's syndrome, the sample size was relatively small, especially for AML. Thus, some exposures were very infrequent, and their relation to leukemia could not be assessed reliably.
The chemical exposure categories defined in this study were broad and did not provide details on specific chemicals to pinpoint specific carcinogenic pathways. Products in different categories may mean overlapping carcinogenic exposures; for example, pesticides contain solvents. In addition, a correlation analysis showed overlapping exposures across time periods. The self-reported data were also not validated, although validation was not feasible with this study design or population.
To help identify specific chemicals that may be associated with leukemia incidence in children with Down's syndrome, future studies of this population could seek paternal participation and ask for specific names of products to which mothers and children are exposed. Once the spectrum of possible chemicals has been narrowed, research into the biologic mechanisms of leukemia oncongenesis in children with Down's syndrome possibly associated with these chemicals can occur. As part of this research, those chemicals that cause aneuploidy on chromosome 21 and are known to occur in the positively associated chemical classes could be targeted.
In conclusion, this study is the first known to look at the association of chemical exposure with acute leukemia in children with Down's syndrome. Positive associations were found between professional pest exterminations, insecticides, any pesticide, and any chemical and childhood ALL, and with any chemical and combined leukemia types. However, the magnitudes of the odds ratios and the test for trend did not strongly support the hypothesis that household chemical exposure contributes to the disparity of leukemia risk in children with and without Down's syndrome.
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ACKNOWLEDGMENTS |
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This study was funded by a grant from the National Cancer Institute (R01-CA75169) and by the University of Minnesota Children's Cancer Research Fund. Dr. Olshan was supported in part by a grant from the National Institute of Environmental Health Sciences (P30ES10126).
Conflict of interest: none declared.
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