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Individuals are exposed to a large number of diverse environmental chemicals simultaneously and the evaluation of multiple chemical exposures is important for identifying cancer risk factors. The measurement of a large number of chemicals (the exposome) in epidemiologic studies is allowing for a more comprehensive assessment of cancer risk factors than was done in earlier studies that focused on only a few chemicals. Empirical evidence from epidemiologic studies shows that chemicals from different chemical classes have different magnitudes and directions of association with cancers. Given increasing data availability, there is a need for the development and assessment of statistical methods to model environmental cancer risk that considers a large number of diverse chemicals with different effects for different chemical classes. The method of grouped weighted quantile sum (GWQS) regression allows for multiple groups of chemicals to be considered in the model such that different magnitudes and directions of associations are possible for each group of chemicals. In this paper, we assessed the ability of GWQS regression to estimate exposure effects for multiple chemical groups and correctly identify important chemicals in each group using a simulation study. We compared the performance of GWQS regression with WQS regression, the least absolute shrinkage and selection operator (lasso), and the group lasso in estimating exposure effects and identifying important chemicals. The simulation study results demonstrate that GWQS is an effective method for modeling exposure to multiple groups of chemicals and compares favorably with other methods used in mixture analysis. As an application, we used GWQS regression in the California Childhood Leukemia Study (CCLS), a population-based case-control study of childhood leukemia in California to estimate exposure effects for many chemical classes while also adjusting for demographic factors. The CCLS analysis found evidence of a positive association between exposure to the herbicide dacthal and an increased risk of childhood leukemia.

The associations between childhood acute lymphoblastic leukemia (ALL) and several factors related to early stimulation of the immune system, that is, farm residence and regular contacts with farm animals (livestock, poultry) or pets in early childhood, were investigated using data from 13 case-control studies participating in the Childhood Leukemia International Consortium. The sample included 7847 ALL cases and 11,667 controls aged 1-14 years. In all studies, the data were obtained from case and control parents using standardized questionnaires. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Contact with livestock in the first year of life was inversely associated with ALL (OR = 0.65, 95% CI: 0.50, 0.85). Inverse associations were also observed for contact with dogs (OR = 0.92, 95% CI: 0.86, 0.99) and cats (OR = 0.87, 95% CI: 0.80, 0.94) in the first year of life. There was no evidence of a significant association with farm residence in the first year of life. The findings of these large pooled and meta-analyses add additional evidence to the hypothesis that regular contact with animals in early childhood is inversely associated with childhood ALL occurrence which is consistent with Greaves' delayed infection hypothesis., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: We investigated the relationship between the risk of childhood leukemia and home remodeling, a surrogate for indoor chemical exposures., Methods: We collected information on remodeling activities carried out between birth and diagnosis in homes of 609 acute lymphoblastic leukemia (ALL) cases, 89 acute myeloid leukemia (AML) cases, and 893 matched controls participating in the California Childhood Leukemia Study (1995-2008). We used multivariable logistic regression to estimate the risk of ALL and AML associated with six remodeling activities: construction, painting, recarpeting, reflooring, roofing, and weatherproofing. Models were adjusted for age, sex, Hispanic ethnicity, race, household annual income, and residential mobility., Results: Construction in the home between birth and diagnosis was associated with a significant increase in ALL risk (odds ratio [OR]: 1.52, 95% confidence interval [CI]: 1.14-2.02) and a nonsignificant increase in AML risk (OR: 1.75, 95% CI: 0.98-3.15). No other remodeling activities were associated with ALL or AML risk in the main analysis. When stratifying by Hispanic ethnicity, a positive relationship between ALL risk and painting was evident in Hispanic children (OR: 1.47, 95% CI: 1.04-2.07)., Conclusions: Specific home remodeling activities appeared to be associated with increased risk of childhood ALL., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Epidemiologic studies worldwide have provided substantial evidence of the contributions of environmental exposures to the development of childhood cancer, yet this knowledge has not been integrated into the routine practice of clinicians who care for children with this disease. To identify the basis of this deficit, we sought to assess the environmental history-taking behavior and perceptions of environmental health among pediatric hematologists and oncologists., Procedure: A web-based survey was sent from June to October 2012 to 427 pediatric oncologists, fellows, and nurse practitioners from 20 US institutions, with an overall response rate of 45%., Results: Survey responses indicated that environmental exposures are of concern to clinicians. The vast majority of respondents (88%) reported receiving questions from families about the relationship between certain environmental exposures and the cancers they regularly treat. However, a lack of comfort with these topics seems to have limited their discussions with families about the role of environmental exposures in childhood cancer pathogenesis. Although 77% of respondents suspected that some of the cases they saw had an environmental origin, their methods of taking environmental histories varied widely. Over 90% of respondents believed that more knowledge of the associations between environmental exposures and childhood cancer would be helpful in addressing these issues with patients., Conclusions: Although limited in size and representativeness of participating institutions, the results of this survey indicate a need for increased training for hematology/oncology clinicians about environmental health exposures related to cancer and prompt translation of emerging research findings in biomedical journals that clinicians read.

Purpose: It has been suggested that home paint exposure increases the risk of childhood acute lymphoblastic leukemia (ALL)., Methods: We obtained individual level data from eight case-control studies participating in the Childhood Leukemia International Consortium. All studies had home paint exposure data (sometimes including lacquers and varnishes) for the pregnancy period with additional data for the 1-3-month period before conception in five, the year before conception in two, and the period after birth in four studies, respectively. Cytogenetic subtype data were available for some studies. Data were harmonized to a compatible format. Pooled analyses of individual data were undertaken using unconditional logistic regression., Results: Based on 3,002 cases and 3,836 controls, the pooled odds ratio (OR) for home paint exposure in the 1-3 months before conception and risk of ALL was 1.54 [95% confidence interval (CI) 1.28, 1.85], while based on 1,160 cases and 1,641 controls for exposure in the year before conception, it was 1.00 (95% CI 0.86, 1.17). For exposure during pregnancy, using 4,382 cases and 5,747 controls, the pooled OR was 1.14 (95% CI 1.04, 1.25), and for exposure after birth, the OR was 1.22 (95% CI 1.07, 1.39), based on data from 1,962 cases and 2,973 controls. The risk was greater for certain cytogenetic subtypes and if someone other than the parents did the painting., Conclusions: Home paint exposure shortly before conception, during pregnancy, and/or after birth appeared to increase the risk of childhood ALL. It may be prudent to limit exposure during these periods., Competing Interests: The authors declare that they have no conflict of interest.

Background: Recent meta-analyses demonstrate an association between self-reported residential pesticide use and childhood leukemia risk. Self-reports may suffer from recall bias and provide information only on broad pesticide categories. We compared parental self-reported home and garden pest treatments to pesticides measured in carpet dust., Methods: Parents of 277 children with leukemia and 306 controls in Northern and Central California (2001-2007) were asked about insect and weed treatments during the previous year. Carpet dust samples were analyzed for 47 pesticides. We present results for the 7 insecticides (carbaryl, propoxur, chlorpyrifos, diazinon, cyfluthrin, cypermethrin, permethrin), 5 herbicides (2,4-dichlorophenoxyacetic acid [2,4-D], chlorthal, dicamba, mecoprop, simazine), and 1 synergist (piperonyl butoxide) that were present in home and garden products during the study period and were detected in ≥25% of carpet dust samples. We constructed linear regression models for the relative change in pesticide concentrations associated with self-reported treatment of pest types in cases and controls separately and combined, adjusting for demographics, housing characteristics, and nearby agricultural pesticide applications., Results: Several self-reported treatments were associated with pesticide concentrations in dust. For example, households with flea/tick treatments had 2.3 (95% Confidence Interval [CI]: 1.4, 3.7) times higher permethrin concentrations than households not reporting this treatment. Households reporting treatment for ants/cockroaches had 2.5 (95% CI: 1.5, 4.2) times higher cypermethrin levels than households not reporting this treatment. Weed treatment by a household member was associated with 1.9 (1.4, 2.6), 2.2 (1.6, 3.1), and 2.8 (2.1, 3.7) times higher dust concentrations of dicamba, mecoprop, and 2,4-D, respectively. Weed treatments by professional applicators were null/inversely associated with herbicide concentrations in dust. Associations were generally similar between cases and controls and were consistent with pesticide active ingredients in these products during the study time period., Conclusions: Consistency between self-reported pest treatments, concentrations in dust, and pesticides in products lends credibility to the exposure assessment methods and suggests that differential recall by case-control status is minimal.

Background: House dust is a major source of exposure to polybrominated diphenyl ethers (PBDEs), which are found at high levels in U.S. homes., Methods: We studied 167 acute lymphoblastic leukemia (ALL) cases 0-7 years of age and 214 birth certificate controls matched on date of birth, sex, and race/ethnicity from the Northern California Childhood Leukemia Study. In 2001-2007, we sampled carpets in the room where the child spent the most time while awake; we used a high-volume small-surface sampler or we took dust from the home vacuum. We measured concentrations of 14 PBDE congeners including penta (28, 47, 99, 100, 153, 154), octa (183, 196, 197, 203), and decaBDEs (206-209). Odds ratios (ORs) were calculated using logistic regression, adjusting for demographics, income, year of dust collection, and sampling method., Results: BDE-47, BDE-99, and BDE-209 were found at the highest concentrations (medians, 1,173, 1,579, and 938 ng/g, respectively). Comparing the highest to lowest quartile, we found no association with ALL for summed pentaBDEs (OR = 0.7; 95% CI: 0.4, 1.3), octaBDEs (OR = 1.3; 95% CI: 0.7, 2.3), or decaBDEs (OR = 1.0; 95% CI: 0.6, 1.8). Comparing homes in the highest concentration (nanograms per gram) tertile to those with no detections, we observed significantly increased ALL risk for BDE-196 (OR = 2.1; 95% CI: 1.1, 3.8), BDE-203 (OR = 2.0; 95% CI: 1.1, 3.6), BDE-206 (OR = 2.1; 95% CI: 1.1, 3.9), and BDE-207 (OR = 2.0; 95% CI: 1.03, 3.8)., Conclusion: We found no association with ALL for common PBDEs, but we observed positive associations for specific octa and nonaBDEs. Additional studies with repeated sampling and biological measures would be informative.

Objectives: We aimed to (1) evaluate the relation between home age and concentrations of multiple chemical contaminants in settled dust and (2) discuss the feasibility of using lead hazard controls to reduce children's exposure to persistent organic pollutants., Methods: As part of the California Childhood Leukemia Study, from 2001 to 2007, we used a high-volume small surface sampler and household vacuum cleaners to collect dust samples from 583 homes and analyzed the samples for 94 chemicals with gas chromatography-mass spectrometry and inductively coupled plasma mass spectrometry. We evaluated relations between chemical concentrations in dust and home age with Spearman rank correlation coefficients., Results: Dust concentrations of lead, polychlorinated biphenyls, organochlorine insecticides, and polycyclic aromatic hydrocarbons were correlated with home age (ρ > 0.2; P < .001), whereas concentrations of pyrethroid insecticides and polybrominated diphenyl ethers were not., Conclusions: Dust in older homes contains higher levels of multiple, persistent chemicals than does dust in newer homes. Further development of strategies to reduce chemical exposures for children living in older homes is warranted.

We examine the association between exposure to herbicides and childhood acute lymphoblastic leukemia (ALL). Dust samples were collected from homes of 269 ALL cases and 333 healthy controls (<8 years of age at diagnosis/reference date and residing in same home since diagnosis/reference date) in California, using a high-volume surface sampler or household vacuum bags. Amounts of agricultural or professional herbicides (alachlor, metolachlor, bromoxynil, bromoxynil octanoate, pebulate, butylate, prometryn, simazine, ethalfluralin, and pendimethalin) and residential herbicides (cyanazine, trifluralin, 2-methyl-4-chlorophenoxyacetic acid (MCPA), mecoprop, 2,4-dichlorophenoxyacetic acid (2,4-D), chlorthal, and dicamba) were measured. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Models included the herbicide of interest, age, sex, race/ethnicity, household income, year and season of dust sampling, neighborhood type, and residence type. The risk of childhood ALL was associated with dust levels of chlorthal; compared to homes with no detections, ORs for the first, second, and third tertiles were 1.49 (95% CI: 0.82-2.72), 1.49 (95% CI: 0.83-2.67), and 1.57 (95% CI: 0.90-2.73), respectively (P-value for linear trend=0.05). The magnitude of this association appeared to be higher in the presence of alachlor. No other herbicides were identified as risk factors of childhood ALL. The data suggest that home dust levels of chlorthal, and possibly alachlor, are associated with increased risks of childhood ALL.

Polychlorinated biphenyl (PCB) production ceased in the U.S. over 30 years ago, but these persistent chemicals remain ubiquitous contaminants. Here, we evaluate potential determinants of PCB levels in dust from California homes including characteristics of the residence as well as the residents' habits and occupations. Dust was collected from 415 households as part of a large case-control study (the Northern California Childhood Leukaemia Study), using a high-volume small surface sampler. Dust concentrations of 6 PCBs (PCB-105, PCB-118, PCB-138, PCB-153, PCB-170, and PCB-180) were measured using gas chromatography-mass spectrometry. Individual PCB detection rates ranged from 9% to 54% with PCB concentrations ranging from below detection (1 or 2 ng g (-1)) to 270 ng g(-1) and PCB loadings ranging from below detection to 960 ng m (-2). Multivariable linear and logistic regression models were used to identify potential determinants of residential PCB contamination based on in-home interviews and residential geographic locations. We observed that residences built prior to 1980 had higher odds of PCB detection and higher PCB loadings than more recently constructed homes. Households where residents typically did not remove their shoes had higher PCB dust loadings than households where residents did. PCBs were less likely to be detected in carpet dust from households that had frequently vacuumed or replaced carpets compared to other households. Since we used a cross-sectional dust sampling protocol and report significant, but modest, effects of these determinants on levels of PCBs in residential dust, our results should be interpreted with caution. Longitudinal studies to determine optimal strategies for reducing PCBs in homes are warranted.

Background: Recent studies suggest that environmental exposures to pesticides, tobacco, and other xenobiotic chemicals may increase risk of childhood acute lymphoblastic leukemia (ALL). We sought to evaluate the role of genes involved in xenobiotic transport and metabolism in childhood ALL risk, both alone and in conjunction with household chemical exposures previously found to be associated with childhood ALL risk., Methods: We conducted a population-based epidemiologic study of 377 cases and 448 controls in California, utilizing a haplotype-based approach to evaluate 42 xenobiotic transport and metabolism genes in conjunction with data on self-reported household chemical exposures., Results: We identified significant associations of childhood ALL risk with haplotypes of ABCB1, ARNT, CYP2C8, CYP1A2, CYP1B1, and IDH1. In addition, certain haplotypes showed significant joint effects with self-reported household chemical exposures on risk of childhood ALL. Specifically, elevated risks associated with use of paints in the home (ever) and indoor insecticides (pre-birth) were limited to subjects carrying specific haplotypes of CYP2C8 and ABCB1, respectively., Conclusions: Our results provide support for a role of xenobiotic transport and metabolism pathways in risk of childhood ALL and indicate that genes in these pathways may modulate the risk of disease associated with use of common household chemicals. Additional studies are needed to confirm these findings and localize specific causal variants.

The objectives of this study were to examine the association between contact current exposure and the risk of childhood leukemia and to investigate the relationship between residential contact currents and magnetic fields. Indoor and outdoor contact voltage and magnetic-field measurements were collected for the diagnosis residence of 245 cases and 269 controls recruited in the Northern California Childhood Leukemia Study (2000-2007). Logistic regression techniques produced odds ratios (OR) adjusted for age, sex, Hispanic ethnicity, mother's race and household income. No statistically significant associations were seen between childhood leukemia and indoor contact voltage level [exposure ≥90th percentile (10.5 mV): OR  =  0.83, 95% confidence interval (CI): 0.45, 1.54], outdoor contact voltage level [exposure ≥90th percentile (291.2 mV): OR  =  0.89, 95% CI: 0.48, 1.63], or indoor magnetic-field levels (>0.20 µT: OR  =  0.76, 95% CI: 0.30, 1.93). Contact voltage was weakly correlated with magnetic field; correlation coefficients were r  =  0.10 (P  =  0.02) for indoor contact voltage and r  =  0.15 (P  =  0.001) for outdoor contact voltage. In conclusion, in this California population, there was no evidence of an association between childhood leukemia and exposure to contact currents or magnetic fields and a weak correlation between measures of contact current and magnetic fields.

Background: Incidence of childhood leukemia in industrialized countries rose significantly during 1975-2004, and the reasons for the increase are not understood., Objectives: We used carpet dust as an exposure indicator to examine the risk of childhood leukemia in relation to residential exposure to persistent organochlorine chemicals: six polychlorinated biphenyl (PCB) congeners and the pesticides alpha- and gamma-chlordane, p,p'-DDT (dichlorodiphenyltrichloroethane), p,p'-DDE (dichlorodiphenyldichloroethylene), methoxychlor, and pentachlorophenol., Methods: We conducted a population-based case-control study in 35 counties in northern and central California in 2001-2006. The study included 184 acute lymphocytic leukemia (ALL) cases 0-7 years of age and 212 birth certificate controls matched to cases by birth date, sex, race, and Hispanic ethnicity. We collected carpet dust samples from the room where the child spent the most time before diagnosis (similar date for controls) using a specialized vacuum., Results: Detection of any PCB congener in the dust conferred a 2-fold increased risk of ALL [odds ratio (OR) = 1.97; 95% confidence interval (CI), 1.22-3.17]. Compared with those in the lowest quartile of total PCBs, the highest quartile was associated with about a 3-fold risk (OR = 2.78; 95% CI, 1.41-5.48), and the positive trend was significant (p = 0.017). Significant positive trends in ALL risk were apparent with increasing concentrations of PCB congeners 118, 138, and 153. We observed no significant positive associations for chlordane, DDT, DDE, methoxychlor, or pentachlorophenol. The associations with PCBs were stronger among non-Hispanic whites than among Hispanics despite similar distributions of PCB levels among controls in each racial/ethnic group., Conclusions: Our findings suggest that PCBs, which are considered probable human carcinogens and cause perturbations of the immune system, may represent a previously unrecognized risk factor for childhood leukemia.

The literature is inconsistent regarding associations between parental smoking and childhood leukemia, possibly because previous studies used self-reported smoking habits as surrogates for children's true exposures to cigarette smoke. Here, the authors investigated the use of nicotine concentrations in house dust as measures of children's exposure to cigarette smoke in 469 households from the Northern California Childhood Leukemia Study (1999-2007). House dust was collected by using high-volume surface samplers and household vacuum cleaners and was analyzed for nicotine via gas chromatography-mass spectrometry. Using multivariable linear regression, the authors evaluated the effects of self-reported parental smoking, parental demographics, house characteristics, and other covariates on house-dust nicotine concentrations. They observed that nicotine concentrations in house dust were associated with self-reported smoking for periods of months and years before dust collection. Furthermore, the authors found that the relation between nicotine dust levels and self-reported smoking varied by parental age and socioeconomic status. These findings suggest that house-dust nicotine concentrations reflect long-term exposures to cigarette smoke in the home and that they may be less biased surrogates for children's exposures to cigarette smoke than self-reported smoking habits.

Background: Few studies have examined the association between home use of solvents and paint and the risk of childhood leukemia., Objectives: In this case-control study, we examined whether the use of paint and petroleum solvents at home before birth and in early childhood influenced the risk of leukemia in children., Methods: We based our analyses on 550 cases of acute lymphoblastic leukemia (ALL), 100 cases of acute myeloid leukemia (AML), and one or two controls per case individually matched for sex, age, Hispanic status, and race. We conducted further analyses by cytogenetic subtype. We used conditional logistic regression techniques to adjust for income., Results: ALL risk was significantly associated with paint exposure [odds ratio (OR) = 1.65; 95% confidence interval (CI), 1.26-2.15], with a higher risk observed when paint was used postnatally, by a person other than the mother, or frequently. The association was restricted to leukemia with translocations between chromosomes 12 and 21 (OR = 4.16; 95% CI, 1.66-10.4). We found no significant association between solvent use and ALL risk overall (OR = 1.15; 95% CI, 0.87-1.51) or for various cytogenetic subtypes, but we observed a significant association in the 2.0- to 5.9-year age group (OR = 1.55; 95% CI, 1.07-2.25). In contrast, a significant increased risk for AML was associated with solvent (OR = 2.54; 95% CI, 1.19-5.42) but not with paint exposure (OR = 0.64; 95% CI, 0.32-1.25)., Conclusions: The association of ALL risk with paint exposure was strong, consistent with a causal relationship, but further studies are needed to confirm the association of ALL and AML risk with solvent exposure.

Like many chemicals, carcinogenicity of pesticides is poorly characterised in humans, especially in children, so that the present knowledge about childhood leukaemia risk derives primarily from epidemiological studies. Overall, case-control studies published in the last decade have reported positive associations with home use of insecticides, mostly before the child's birth, while findings for herbicides are mixed. Previous studies relied solely on self-reports, therefore lacking information on active ingredients and effects of potential recall bias. Few series to date have examined the influence of children's genetic susceptibility related to transport and metabolism of pesticides. To overcome these limitations, investigators of the Northern California Childhood Leukaemia Study (NCCLS) have undertaken, in collaboration with a multidisciplinary team, a comprehensive assessment of residential pesticide exposure, including: (1) quality control of self-reports; (2) home pesticide inventory and linkage to the Environmental Protection Agency to obtain data on active ingredients; (3) collection and laboratory analyses of approximately 600 home dust samples for over 60 pesticides and (4) geographic information studies using California environmental databases to assess exposure to agricultural pesticides. The NCCLS is also conducting large-scale genotyping to evaluate the role of genes in xenobiotic pathways relevant to the transport and metabolism of pesticides. A better quantification of children's exposures to pesticides at home is critical to the evaluation of childhood leukaemia risk, especially for future gene-environment interaction studies.

Acute promyelocytic leukemia (APL) comprises approximately 5-10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning >60 countries) identified, variation was apparent-de novo APL represented from 2% (Switzerland) to >50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed.