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Child Leukemia

• Environmental Pollution and Risk of Childhood Cancer: A Scoping Review of Evidence from the Last Decade
  The long-term effects of environmental pollution have been of concern as several pollutants are carcinogenic, potentially inducing a variety of cancers, including childhood cancer, which is a leading cause of death around the world and, thus, is a public health issue. The present scoping review aimed to update and summarize the available literature to detect specific environmental pollutants and their association with certain types of childhood cancer. Studies published from 2013 to 2023 regarding environmental pollution and childhood cancer were retrieved from the PubMed database. A total of 174 studies were eligible for this review and were analyzed. Our search strategy brought up most of the articles that evaluated air pollution (29%) and pesticides (28%). Indoor exposure to chemicals (11%), alcohol and tobacco use during pregnancy (16%), electromagnetic fields (12%), and radon (4%) were the subjects of less research. We found a particularly high percentage of positive associations between prenatal and postnatal exposure to indoor (84%) and outdoor (79%) air pollution, as well as to pesticides (82%), and childhood cancer. Positive associations were found between leukemia and pesticides and air pollution (33% and 27%); CNS tumors and neuroblastoma and pesticides (53% and 43%); and Wilms tumor and other rare cancers were found in association with air pollution (50%). Indoor air pollution was mostly reported in studies assessing several types of cancer (26%). Further studies are needed to investigate the mechanisms underlying the potential associations between indoor/outdoor air pollution and pesticide exposure with childhood cancer risk as more preventable measures could be taken.
  [Navarrete-Meneses, M.D.P. et al. (2024) Environmental pollution and risk of childhood cancer: A scoping review of evidence from the last decade, International journal of molecular sciences. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10970446/. ]
• Association between Residential Proximity to Viticultural Areas and Childhood Acute Leukemia Risk in Mainland France: GEOCAP Case-Control Study, 2006-2013
  Pesticide exposures are suspected of being a risk factor for several childhood cancers, particularly acute leukemia (AL). Most of the evidence is based on self-reported parental domestic use of pesticides, but some studies have also addressed associations with agricultural use of pesticides near the place of residence. The objective of the study was to evaluate the risk of AL in children living close to vines, a crop subject to intensive pesticide use. Data were drawn from the national registry-based GEOCAP study. We included all of the AL cases under the age of 15 years diagnosed in 2006-2013 (n = 3,711) and 40,196 contemporary controls representative of the childhood population in France. The proximity of the vines (probability of presence within 200, 500, and 1,000m) and the viticulture density (area devoted to vines within 1,000 m) were evaluated around the geocoded addresses in a geographic information system combining three national land use maps. Logistic regression models were used to estimate odds ratios (ORs) for all AL and for the lymphoblastic (ALL) and myeloid (AML) subtypes. Heterogeneity between regions was studied by stratified analyses. Sensitivity analyses were carried out to take into account, in particular, geocoding uncertainty, density of other crops and potential demographic and environmental confounders. In all, about 10% of the controls lived within 1 km of vines. While no evidence of association between proximity to vines and AL was found, viticulture density was positively associated with ALL [OR=1.05 (1.00-1.09) for a 10% increase in density], with a statistically significant heterogeneity across regions. No association with AML was observed. The results remained stable in all the sensitivity analyses. We evidenced a slight increase in the risk of ALL in children living in areas with high viticulture density. This finding supports the hypothesis that environmental exposure to pesticides may be associated with childhood ALL. 
  [Mancini, M., Hémon, D., de Crouy-Chanel, P., Guldner, L., Faure, L., Clavel, J. and Goujon, S., 2023. Environmental Health Perspectives, 131(10), p.107008.]
• Occupational exposure to pesticides in mothers and fathers and risk of cancer in the offspring: A register-based case-control study from Sweden (1960–2015)
  Maternal and paternal occupational exposure to pesticides was linked to leukemia in the offspring in some previous studies. Risks for other cancers, particularly from maternal exposure, are largely unknown. We examined the association between maternal and paternal exposure to pesticides and childhood cancer in a Swedish register-based case-control study (1960–2015). Cancer cases
  [Rossides, M. et al. (2022) Occupational exposure to pesticides in mothers and fathers and risk of cancer in The offspring: A register-based case-control study from Sweden (1960–2015), Environmental Research. Available at: https://www.sciencedirect.com/science/article/pii/S0013935122011471?via%3Dihub. ]
• Residential proximity to croplands at birth and childhood leukemia
  Domestic and parental occupational pesticide exposures are suspected of involvement in the occurrence of childhood acute leukaemia (AL), but the role of exposure to agricultural activities is little known. In a previous ecological study conducted in France, we observed an increase in acute lymphoblastic leukaemia (ALL) incidence rate with increasing viticulture density in the municipalities of residence at diagnosis. This study aimed to test the hypothesis that residential proximity to croplands at birth increases the risk of childhood AL, with a particular focus on vineyards. We identified all the primary AL cases diagnosed before the age of 15 years in the cohorts of children born in the French municipalities between 1990 and 2015. We estimated crop densities in each municipality of residence at birth using agricultural census data, for ten crop types. Variations in standardized incidence ratios (SIR) were evaluated with Poisson regression models, for all AL, ALL and acute myeloid leukaemia (AML), separately. Among the 19,809,700 children born and residing in mainland France at birth in 1990–2015, 8,747 AL cases (7,236 ALL and 1,335 AML) were diagnosed over the period. We did not evidence any statistically significant positive association between total crop density or any specific crop density in the municipality of residence at birth and all AL, ALL or AML. Interestingly, we observed a higher ALL incidence rate in the municipalities with the highest viticulture densities (SIR = 1.25 95%CI [1.01–1.54]). Adjusting for the main potential confounders did not change the results. Our study does not support the hypothesis that residential proximity to croplands, particularly vineyards, around birth plays a role in childhood leukaemia. The slightly higher ALL incidence rate in children born in the municipalities with the highest viticulture densities may reflect the previously-observed association at diagnosis.
  [Bamouni, S., Hémon, D., Faure, L., Clavel, J. and Goujon, S., 2022. Environ Health 21, 103 (2022). ]
• Exposure to pesticides and childhood leukemia risk: A systematic review and meta-analysis
  Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15–3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39–4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00–1.99) and insecticide (OR: 1.60, 95%CI: 1.11–2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12–0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44–3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98–5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (ORparental: 1.75, 95%CI: 1.08–2.85; ORpaternal: 1.20, 95%CI: 1.07–1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure.

  Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15–3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39–4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00–1.99) and insecticide (OR: 1.60, 95%CI: 1.11–2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12–0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44–3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98–5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (ORparental: 1.75, 95%CI: 1.08–2.85; ORpaternal: 1.20, 95%CI: 1.07–1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure.
  [Karalexi, M.A., Tagkas, C.F., Markozannes, G., Tseretopoulou, X., Hernández, A.F., Schüz, J., Halldorsson, T.I., Psaltopoulou, T., Petridou, E.T., Tzoulaki, I. and Ntzani, E.E. Environmental Pollution, p.117376.]

• Agricultural crop density in the municipalities of France and incidence of childhood leukemia: An ecological study
  Pesticide exposure is suspected to play a role in the etiology of childhood leukemia (AL). Various sources of exposure have been explored, but few studies have investigated the risk of childhood AL in relation to residential exposure to agricultural pesticides. Since around 50% of France is agricultural land, with marked pesticide use, France is a suitable location to investigate for an association. We aimed to analyze the association between the agricultural crop density in the municipalities of France and the incidence of childhood AL between 1990 and 2014. 11,487 cases of AL diagnosed in children aged 0–14 years were registered by the French National Registry of Childhood Hematological Malignancies over 1990–2014. National agricultural census data for 1990, 2000 and 2010 were used to estimate the densities of the most common crops in France. The incidence of AL was estimated in the 35,512 municipalities, by age and gender, and 3 observation periods, and expressed as the standardized incidence ratio (SIR). We observed a moderate log-linear association between viticulture density and the incidence of AL, with a 3% increase in SIR for a 10% increase in viticulture density (SIRR = 1.03; 95%CI [1.00–1.06]). The association remained for lymphoblastic AL but not for myeloid AL. The association was stable after stratification by geographic area, age and period, and after adjustment on UV radiation and a French deprivation index. No consistent association was observed for other crop types. This nationwide study shows a moderate increase in incidence of childhood AL in municipalities where viticulture is common. Future individual studies are needed to know whether this observation is confirmed and related to particular use of pesticides.
  [Coste, A., Goujon, S., Faure, L., Hémon, D. and Clavel, J., 2020. Environmental Research, p.109517.]
• Prenatal pesticide exposure and childhood leukemia - A California statewide case-control study
  A number of epidemiologic studies with a variety of exposure assessment approaches have implicated pesticides as risk factors for childhood cancers. Here we explore the association of pesticide exposure in pregnancy and early childhood with childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) utilizing land use and pesticide use data in a sophisticated GIS tool. We identified cancer cases less than 6 years of age from the California Cancer Registry and cancer-free controls from birth certificates. Analyses were restricted to those living in rural areas and born 1998-2011, resulting in 162 cases of childhood leukemia and 9,805 controls. Possible carcinogens were selected from the Environmental Protection Agency's classifications and pesticide use was collected from the California Department of Pesticide Regulation's (CDPR) Pesticide Use Reporting (PUR) system and linked to land-use surveys. Exposures for subjects were assessed using a 4000m buffer around the geocoded residential addresses at birth. Unconditional logistic and hierarchical regression models were used to assess individual pesticide and pesticide class associations. We observed elevated risks for ALL with exposure to any carcinogenic pesticide (adjusted Odds Ratio (aOR): 2.83, 95% CI: 1.67-4.82), diuron (Single-pesticide model, adjusted (OR): 2.38, 95% CI: 1.57-3.60), phosmet (OR: 2.10, 95% CI: 1.46-3.02), kresoxim-methyl (OR: 1.77, 95% CI: 1.14-2.75), and propanil (OR: 2.58, 95% CI: 1.44-4.63). Analyses based on chemical classes showed elevated risks for the group of 2,6-dinitroanilines (OR: 2.50, 95% CI: 1.56-3.99), anilides (OR: 2.16, 95% CI: 1.38-3.36), and ureas (OR: 2.18, 95% CI: 1.42-3.34). Our findings suggest that in rural areas of California exposure to certain pesticides or pesticide classes during pregnancy due to residential proximity to agricultural applications may increase the risk of childhood ALL and AML. Future studies into the mechanisms of carcinogenicity of these pesticides may be beneficial.
  [Park, A.S., Ritz, B., Yu, F., Cockburn, M. and Heck, J.E., 2020. International journal of hygiene and environmental health, 226, p.113486.]
• Prenatal pesticide exposure and childhood leukemia – A California statewide case-control study
  A number of epidemiologic studies with a variety of exposure assessment approaches have implicated pesticides as risk factors for childhood cancers. Here we explore the association of pesticide exposure in pregnancy and early childhood with childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) utilizing land use and pesticide use data in a sophisticated GIS tool. We identified cancer cases less than 6 years of age from the California Cancer Registry and cancer-free controls from birth certificates. Analyses were restricted to those living in rural areas and born 1998–2011, resulting in 162 cases of childhood leukemia and 9,805 controls. Possible carcinogens were selected from the Environmental Protection Agency's classifications and pesticide use was collected from the California Department of Pesticide Regulation's (CDPR) Pesticide Use Reporting (PUR) system and linked to land-use surveys. Exposures for subjects were assessed using a 4000m buffer around the geocoded residential addresses at birth. Unconditional logistic and hierarchical regression models were used to assess individual pesticide and pesticide class associations. We observed elevated risks for ALL with exposure to any carcinogenic pesticide (adjusted Odds Ratio (aOR): 2.83, 95% CI: 1.67–4.82), diuron (Single-pesticide model, adjusted (OR): 2.38, 95% CI: 1.57–3.60), phosmet (OR: 2.10, 95% CI: 1.46–3.02), kresoxim-methyl (OR: 1.77, 95% CI: 1.14–2.75), and propanil (OR: 2.58, 95% CI: 1.44–4.63). Analyses based on chemical classes showed elevated risks for the group of 2,6-dinitroanilines (OR: 2.50, 95% CI: 1.56–3.99), anilides (OR: 2.16, 95% CI: 1.38–3.36), and ureas (OR: 2.18, 95% CI: 1.42–3.34). Our findings suggest that in rural areas of California exposure to certain pesticides or pesticide classes during pregnancy due to residential proximity to agricultural applications may increase the risk of childhood ALL and AML. Future studies into the mechanisms of carcinogenicity of these pesticides may be beneficial.
  [Park, A.S., Ritz, B., Yu, F., Cockburn, M. and Heck, J.E., 2020. International journal of hygiene and environmental health, 226, p.113486.]
• A task-based assessment of parental occupational exposure to pesticides and childhood acute lymphoblastic leukemia.
  Associations between parental occupational pesticide exposure and childhood acute lymphoblastic leukemia (ALL) vary across studies, likely due to different exposure assessment methodologies. This study assessed parental occupational pesticide exposure from the year before pregnancy to the child's third year of life for 669 children diagnosed with ALL and 1021 controls. Authors conducted expert rating using task-based job modules (JM) to estimate exposure to pesticides among farmer workers, gardeners, agricultural packers, and pesticide applicators. Compared to complete JMs, partial JMs and JEM led to 3.1% and 9.4% of parents with pesticide exposure misclassified, respectively. Misclassification was similar in cases and controls. Using complete JMs, we observed an increased risk of ALL for paternal occupational exposure to any pesticides (OR=1.7; 95% CI=1.2, 2.5), with higher risks reported for pesticides to treat nut crops (OR=4.5; 95% CI=0.9, 23.0), and for children diagnosed before five years of age (OR=2.3; 95% CI: 1.3, 4.1). Exposure misclassification from JEM attenuated these associations by about 57%. Maternal occupational pesticide exposure before and after birth was not associated with ALL. The risk of ALL was elevated in young children with paternal occupational pesticide exposure during the perinatal period, using more detailed occupational information for exposure classification.
  [Gunier RB, Kang A, Hammond SK, Reinier K, et al. 2017. Environ Res. 156:57-62.]
• Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research.
  Infant leukaemia (less 1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease-secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide-and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future.
  [Pelkonen O, Terron A, Hernandez AF, et al. 2017. Arch Toxicol. 91(8):2763-2780.]
• Spatial clustering of childhood leukaemia with the integration of the Paediatric Environmental History.
  Leukaemia remains the most common type of paediatric cancer and its aetiology remains unknown, but considered to be multifactorial. It is suggested that the initiation in utero by relevant exposures and/or inherited genetic variants and, other promotional postnatal exposures are probably required to develop leukaemia. This study aimed to map the incidence and analyse possible clusters in the geographical distribution of childhood acute leukaemia during the critical periods and to evaluate the factors that may be involved in the aetiology by conducting community and individual risk assessments. Researchers analysed all incident cases of acute childhood leukaemia diagnosed in a Spanish region during the period 1998-2013. At diagnosis, the addresses during pregnancy, early childhood and diagnosis were collected and codified to analyse the spatial distribution of acute leukaemia. A total of 158 cases of acute leukaemia were analysed. The crude rate for the period was 42.7 cases per million children. Among subtypes, acute lymphoblastic leukaemia had the highest incidence (31.9 per million children). A spatial cluster of acute lymphoblastic leukaemia was detected using the pregnancy address (p<0.05). The most common environmental risk factors related with the aetiology of acute lymphoblastic leukaemia, identified by the Paediatric Environmental History were: prenatal exposure to tobacco (75%) and alcohol (50%); residential and community exposure to pesticides (62.5%); prenatal or neonatal ionizing radiation (42.8%); and parental workplace exposure (37.5%). Study suggests that environmental exposures in utero may be important in the development of childhood leukaemia. Due to the presence of high-incidence clusters using pregnancy address, it is necessary to introduce this address into the childhood cancer registers. The Paediatric Environmental History which includes pregnancy address and a careful and comprehensive evaluation of the environmental exposures will allow us to build the knowledge of the causes of childhood leukaemia.
  [Cárceles-Álvarez A, Ortega-García JA, López-Hernández FA, et al. 2017. Environ Res. 156:605-612]
• A review of risk factors for childhood leukemia.
  Leukemia is the most common cancer of childhood, with AML, CML, ALL and CLL being the most common. Environmental and genetic factors have been studied extensively in children with childhood leukemia. Other factors, such as the prenatal parental use of controlled substances, have not been investigated to the same degree. We review what is currently known about environmental and parental factors and the occurrence of leukemia in children.Electronic databases were searched for studies correlated pediatric leukemia with (1) ionizing radiation; (2) benzene; (3) parental drug use (4) parental alcohol use; (5) genetic factors.The two known significant environment risk factors for the occurrence leukemia are ionizing radiation and benzene. However, at least 4 studies have been published over the last century have looked at other environmental factors such as pesticides and drug and alcohol use as well as genetic factors such as gene fusions and translocations. We determined the risk of environmental and genetic factors that could be the cause of childhood leukemia in an effort to reduce the incidence of this disease.
  [Jin MW, Xu SM, An Q, Wang P. 2016. Eur Rev Med Pharmacol Sci. 20(18):3760-3764.]
• Childhood Leukemia and Primary Prevention.
  Leukemia is the most common pediatric cancer, affecting 3800 children per year in the United States. Its annual incidence has increased over the last decades, especially among Latinos. Although most children diagnosed with leukemia are now cured, many suffer long-term complications, and primary prevention efforts are urgently needed. The early onset of leukemia-usually before 5 years of age-and the presence at birth of "pre-leukemic" genetic signatures indicate that pre- and postnatal events are critical to the development of the disease. In contrast to most pediatric cancers, there is a growing body of literature-in the United States and internationally-that has implicated several environmental, infectious, and dietary risk factors in the etiology of childhood leukemia, mainly for acute lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In contrast, intake of vitamins and folate supplementation during the preconception period or pregnancy, breastfeeding, and exposure to routine childhood infections have been shown to reduce the risk of childhood leukemia. Some children may be especially vulnerable to these risk factors, as demonstrated by a disproportionate burden of childhood leukemia in the Latino population of California. The evidence supporting the associations between childhood leukemia and its risk factors-including pooled analyses from around the world and systematic reviews-is strong; however, the dissemination of this knowledge to clinicians has been limited. To protect children's health, it is prudent to initiate programs designed to alter exposure to well-established leukemia risk factors rather than to suspend judgment until no uncertainty remains. Primary prevention programs for childhood leukemia would also result in the significant co-benefits of reductions in other adverse health outcomes that are common in children, such as detriments to neurocognitive development.
  [Whitehead TP, Metayer C, Wiemels JL, et al. 2016. Curr Probl Pediatr Adolesc Health Care. 46(10):317-352.]
• Childhood Leukemia: A Preventable Disease.
  In contrast to most pediatric cancers, there is a growing body of literature, nationally and internationally, that has implicated the role of several environmental indoor and outdoor hazards in the etiology of childhood leukemia. For example, exposures to solvents, traffic, pesticides, and tobacco smoke have consistently demonstrated positive associations with the risk of developing childhood leukemia. Intake of vitamins and folate supplementation during the preconception period or pregnancy has been demonstrated to have a protective effect. Despite the strength of these findings, the dissemination of this knowledge to clinicians has been limited. Some children may be more vulnerable than others as documented by the high and increasing incidence of childhood leukemia in Hispanics. To protect children's health, it is prudent to establish programs to alter exposure to those factors with well-established associations with leukemia risk rather than to suspend judgment until no uncertainty remains. This is particularly true because other serious health outcomes (both negative and positive) have been associated with the same exposures. Study draws from historical examples to put in perspective the arguments of association versus causation, as well as to discuss benefits versus risks of immediate and long-term preventive actions.
  [Metayer C, Dahl G, Wiemels J, Miller M. 2016. Pediatrics. 138(Suppl 1):S45-S55.]
• Linking Pesticide Exposure with Pediatric Leukemia: Potential Underlying Mechanisms.
  Leukemia is the most common cancer in children, representing 30% of all childhood cancers. The disease arises from recurrent genetic insults that block differentiation of hematopoietic stem and/or progenitor cells (HSPCs) and drives uncontrolled proliferation and survival of the differentiation-blocked clone. Pediatric leukemia is phenotypically and genetically heterogeneous with an obscure etiology. The interaction between genetic factors and environmental agents represents a potential etiological driver. Although information is limited, the principal toxic mechanisms of potential leukemogenic agents (e.g., etoposide, benzene metabolites, bioflavonoids and some pesticides) include topoisomerase II inhibition and/or excessive generation of free radicals, which may induce DNA single- and double-strand breaks (DNA-DSBs) in early HSPCs. Chromosomal rearrangements (duplications, deletions and translocations) may occur if these lesions are not properly repaired. The initiating hit usually occurs in utero and commonly leads to the expression of oncogenic fusion proteins. Subsequent cooperating hits define the disease latency and occur after birth and may be of a genetic, epigenetic or immune nature (i.e., delayed infection-mediated immune deregulation). Here, we review the available experimental and epidemiological evidence linking pesticide exposure to infant and childhood leukemia and provide a mechanistic basis to support the association, focusing on early initiating molecular events.
  [Hernández AF, Menéndez P. 2016. Int J Mol Sci. 17(4):461.]
• Passive exposure to agricultural pesticides and risk of childhood leukemia in an Italian community.
  Exposure to pesticides has been suggested as a risk factor for childhood leukemia, but definitive evidence on this relation and the specific pesticides involved is still not clear.We carried out a population-based case-control study in a Northern Italy community to assess the possible relation between passive exposure to agricultural pesticides and risk of acute childhood leukemia.We assessed passive pesticide exposure of 111 childhood leukemia cases and 444 matched controls by determining density and type of agricultural land use within a 100-m radius buffer around children's homes. We focused on four common crop types, arable, orchard, vineyard and vegetable, characterized by the use of specific pesticides that are potentially involved in childhood induced leukemia. The use of these pesticides was validated within the present study. We computed the odds ratios (OR) of the disease and their 95% confidence intervals (CI) according to type and density of crops around the children's homes, also taking into account traffic pollution and high-voltage power line magnetic field exposure. Childhood leukemia risk did not increase in relation with any of the crop types with the exception of arable crops, characterized by the use of 2.4-D, MCPA, glyphosate, dicamba, triazine and cypermethrin. The very few children (n=11) residing close to arable crops had an OR for childhood leukemia of 2.04 (95% CI 0.50-8.35), and such excess risk was further enhanced among children aged
  [Malagoli C, Costanzini S, Heck JE, Malavolti M, et al. 2016. Int J Hyg Environ Health. 219(8):742-748.]
• Agricultural crop density and risk of childhood cancer in the midwestern United States: an ecologic study.
  This study examined the association of county level agricultural land use and the incidence of specific childhood cancers.Authors linked county-level agricultural census data (2002 and 2007) and cancer incidence data for children ages 0-4 diagnosed between 2004 and 2008 from cancer registries in six Midwestern states. Crop density (percent of county area that was harvested) was estimated for total agricultural land, barley, dry beans, corn, hay, oats, sorghum, soybeans, sugar beets, and wheat. Results found statistically significant exposure-response relationships for dry beans and total leukemias and acute lymphoid leukemias (ALL); oats and acute myeloid leukemias (AML); and sugar beets and total leukemias and ALL. State-level analyses revealed some additional positive associations for total leukemia and CNS tumors and differences among states for several crop density-cancer associations. However, some of these analyses were limited by low crop prevalence and low cancer incidence.The associations observed in this study need to be confirmed by analytic epidemiologic studies using individual level exposure data and accounting for potential confounders that could not be taken into account in this ecologic study.
  [Booth BJ, Ward MH, Turyk ME, Stayner LT. 2015. Environ Health. 14(1):82]
• Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium.
  Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, authors pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39, 1.43 and 1.36, respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49, 1.55 and 1.08, respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants' exposure to multiple pesticides, or recall bias.
  [Bailey HD, Infante-Rivard C, Metayer C, Clavel J, Lightfoot T, et al. 2015. Int J Cancer. 137(11):2644-63.]
• Household pesticide exposure and the risk of childhood acute leukemia in Shanghai, China.
  Childhood acute leukemia (AL) is the most common malignant tumor in children, but its etiology remains largely unknown. Study investigated the relationship between household exposure to pesticides and childhood AL. Between 2009 and 2010 in Shanghai, a total of 248 newly diagnosed cases of AL and 111 gender-, age-, and hospital-matched controls were included. Five nonspecific dialkyl phosphate (DAP) metabolites of organophosphate pesticides (OPPs) [including dimethyl phosphate (DMP), diethyl phosphate (DEP), dimethyl thiophosphate (DMTP), diethyl thiophosphate (DETP), and diethyl dithiophosphate (DEDTP)] in the urine were analyzed by gas chromatography. The results showed that the median DMP, DEP, DMTP, DETP, and DEDEP levels adjusted for creatinine (Cr) in cases were all significantly elevated compared with those in controls. The household use of mosquito repellent was significantly associated with an increased risk of childhood AL. Moreover, higher exposures were significantly associated with an elevated risk of childhood AL for DMs, DEs, and DAPs. Findings support the notion that the household use of pesticides may play a role in the etiology of childhood AL and provide some evidence to warrant further investigation of the link between household pesticide exposures and childhood AL in Shanghai.
  [Zhang Y, Gao Y, Shi R, Chen D, Wang X, et al. 2015. Environ Sci Pollut Res Int. 22(15):11755-63.]
• Relationship between exposure to pesticides and occurrence of acute leukemia in Iran.
  One of the causes of acute leukemia can be exposure to certain chemicals such as pesticides. This study determined the relationship between exposure to pesticides and the occurrence of acute leukemia in Fars province, south of Iran. Between April 2011 and April 2013 in a case-control study conducted in Nemazee Hospital in Shiraz, Southern Iran; 314 subjects diagnosed with acute leukemia (94 pediatric cases and 220 adults) were enrolled to determine any correlation between exposure to pesticides and the occurrence.There was a history of exposure to pesticides among 85% of pediatric cases an d 69% of their controls and 83% of adult cases and 75% of their controls while 87.5% of pediatric cases and 90% of adult cases reported exposure to intermediate and high doses of pesticides and among the controls, the exposure to low doses of pesticides was 70.5% and 65%, respectively. Exposure to indoor pesticides was seen among most of cases and controls. Being a farmer was at a significantly more increased risk of developing acute leukemia in comparison to other jobs, especially for their children. Exposure to pesticides was shown to be one of the most important causes of acute leukemia.
  [Maryam Z, Sajad A, Maral N, Zahra L, et al. 2015. Asian Pac J Cancer Prev. 16(1):239-44.]
• Residential Exposure to Pesticide During Childhood and Childhood Cancers: A Meta-Analysis.
  In this meta-analysis, authors aimed to examine associations between residential childhood pesticide exposures and childhood cancers.The literature search yielded 277 studies that met inclusion criteria.Sixteen studies were included in the meta-analysis, and authors found that childhood exposure to indoor but not outdoor residential insecticides was associated with a significant increase in risk of childhood leukemia (odds ratio [OR] = 1.47; 95% CI, 1.26-1.72; I(2) = 30%) and childhood lymphomas (OR = 1.43; 95% CI, 1.15-1.78; I(2) = 0%). A significant increase in risk of leukemia was also associated with herbicide exposure (OR = 1.26; 95% CI, 1.10-1.44; I(2) = 0%). Results from this meta-analysis indicated that children exposed to indoor insecticides would have a higher risk of childhood hematopoietic cancers. Additional research is needed to confirm the association between residential indoor pesticide exposures and childhood cancers. Meanwhile, preventive measures should be considered to reduce children's exposure to pesticides at home.
  [Chen M, Chang CH, Tao L, Lu C. 2015. Pediatrics. 136(4):719-29.]
• Maternal factors and risk of childhood leukemia.
  The aim of this study was to examine association of childhood leukemia with maternal factors especially during pregnancy, to help in avoiding risk factors.This case-control study included children younger than 18 years diagnosed with leukemia from 2008 to 2012. Statistically significant associations between risk of childhood leukemia with mother's education , occupation and pesticides exposure during pregnancy were found. However, there were no significant links with maternal age, history of fetal loss, history of radiography during pregnancy, history of drug intake and infection during pregnancy.The results showed increased risk of leukemia in children whose mothers were working in agriculture and were exposed to pesticides during pregnancy. The further study needs to be investigated to know association of various maternal risk factors with leukemia which remained unknown in this study.
  [Kumar A, Vashist M, Rathee R. 2014. Asian Pac J Cancer Prev. 15(2):781-4.]
• Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: findings from the childhood leukemia international consortium.
  Maternal occupational pesticide exposure during pregnancy and/or paternal occupational pesticide exposure around conception have been suggested to increase risk of leukemia in the offspring. Authors pooled individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium (CLIC). Using exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls the odds ratio (OR) for maternal exposure during pregnancy and the risk of acute lymphoblastic leukemia (ALL) was 1.01 and for paternal exposure around conception 1.20. For acute myeloid leukemia (AML), the OR for maternal exposure during pregnancy was 1.94 and for paternal exposure around conception 0.91. Finding of a significantly increased risk of AML in the offspring with maternal exposure to pesticides during pregnancy is consistent with previous reports. Study also found a slight increase in risk of ALL with paternal exposure around conception which appeared to be more evident in children diagnosed at the age of 5 years or more and those with T cell ALL which raises interesting questions on possible mechanisms.
  [Bailey HD, Fritschi L, Infante-Rivard C, Glass DC, et al. 2014. Int J Cancer. 135(9):2157-72.]
• Exposure to herbicides in house dust and risk of childhood acute lymphoblastic leukemia.
  Study examines 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. 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, 1.49, and 1.57, respectively. 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.
  [Metayer C, Colt JS, Buffler PA, Reed HD, et al. 2013. J Expo Sci Environ Epidemiol. 23(4):363-70.]
• Pyrethroid pesticide exposure and risk of childhood acute lymphocytic leukemia in Shanghai.
  Significant amounts of pyrethroid pesticides are used throughout China. Previous studies have suggested that exposure to pesticides may increase the risk of childhood cancer; however, few studies have focused on pyrethroid metabolites. This study investigated five nonspecific metabolites of pyrethroid pesticides found in children's urine and examined the correlation with childhood leukemia. A hospital-based case-control study of childhood acute lymphocytic leukemia (ALL) in Shanghai between 2010 and 2011 was carried out and included 176 children aged 0-14 years and 180 controls matched for age and sex. Compared with those in the lowest quartiles of total and individual metabolites, the highest quartiles were associated with an approximate 2-fold increased risk of ALL [total metabolites: odds ratio (OR) = 2.75, 1.43-5.29; cis-DCCA: OR = 2.21; trans-DCCA: OR = 2.33; and 3-PBA: OR = 1.84], and most of the positive trends were significant. Findings suggest that urinary levels of pyrethroid metabolites may be associated with an elevated risk of childhood ALL and represent a previously unreported quantitative exposure assessment for childhood leukemia.
  [Ding G, Shi R, Gao Y, Zhang Y, Kamijima M, et al. 2012. Environ Sci Technol. 46(24):13480-7]
• Risk of childhood acute lymphoblastic leukaemia following parental occupational exposure to pesticides
  Study was performed to ascertain whether there was an association between parental occupational exposure to pesticides and increased risk of acute lymphoblastic leukaemia (ALL) in the offspring. A population-based case-control study of childhood ALL was conducted in Australia. Information about the occupational pesticide exposure of mothers and fathers was collected using job-specific modules. Information on the types and extent of pesticide exposure was collected for mothers and fathers before and around the time of conception, and also for mothers during pregnancy for the index case or control and for 1 year after birth. Paternal occupational exposure to pesticides before or around conception was not related to increased risk of childhood ALL. There was a low prevalence of occupational exposure to pesticides among women that reduced after birth. Paternal occupational exposure to pesticides was not found to be associated with an increased risk of acute lymphoblastic leukaemia in the offspring. The study was underpowered with respect to maternal exposure to pesticides.
  [Glass DC, Reid A, Bailey HD, et al. 2012. Occup Environ Med. 69(11):846-9.]
• Exposure to pesticides and risk of childhood cancer: a meta-analysis of recent epidemiological studies.
  The authors performed a meta-analysis of case-control and cohort studies to clarify the possible relationship between exposure to pesticides and childhood cancers. Two cohort and 38 case-control studies were selected for the first meta-analysis. Meta-analysis of the three cohort studies did not show any positive links between parental pesticide exposure and childhood cancer incidence. However, the meta-analysis of the 40 studies with OR values showed that the risk of lymphoma and leukemia increased significantly in exposed children when their mother was exposed during the prenatal period (OR=1.53; 95% CI 1.22 to 1.91 and OR=1.48; 95% CI 1.26 to 1.75). The risk of brain cancer was correlated with paternal exposure either before or after birth (OR=1.49; 95% CI 1.23 to 1.79 and OR=1.66; 95% CI 1.11 to 2.49). The OR of leukemia and lymphoma was higher when the mother was exposed to pesticides. Despite some limitations in this study, the incidence of childhood cancer does appear to be associated with parental exposure during the prenatal period.
  [Vinson F, Merhi M, Baldi I, Raynal H, Gamet-Payrastre L. 2011. Occup Environ Med. 68(9):694-702.]
• Exposure to professional pest control treatments and the risk of childhood acute lymphoblastic leukemia.
  Previous studies suggest that exposure to pesticides increases the risk of childhood acute lymphoblastic leukemia (ALL). The aim of this analysis was to investigate whether professional pest treatments in or around the home before birth or during childhood increased the risk of childhood ALL. Data from 388 cases and 870 frequency-matched controls were analyzed using unconditional logistic regression, adjusting for study matching variables and potential confounders, to calculate odds ratios (ORs). The ORs for any professional pest control treatments were 1.19 in the year before pregnancy, 1.30 during pregnancy and 1.24 for those done after the child's birth. The ORs for exposure after birth were highest when it occurred between the ages of two and three years. ORs were elevated for termite treatments before birth. ORs were higher for pre-B than T cell ALL and for t(12;21) (ETV6-Runx-1) than other cytogenetic sub-types. Results provide some evidence of a modestly increased risk of ALL for professional pest control treatments done during the index pregnancy and possibly in the child's early years.
  [Bailey HD, Armstrong BK, de Klerk NH, et al. 2011. Int J Cancer. 129(7):1678-88]
• Residential exposures to pesticides and childhood leukemia
  The aim of this study was to conduct a systematic review of published studies on the association between residential/household/domestic exposure to pesticides and childhood leukaemia, and to provide a quantitative estimate of the risk. Publications in English were searched in MEDLINE (1966-31 December 2009) and from the reference list of identified publications. Separate analyses were conducted after stratification for exposure time windows, residential exposure location, biocide category and type of leukaemia. Statistically significant associations with childhood leukaemia were observed when combining all studies. Exposure during and after pregnancy was positively associated with childhood leukaemia, with the strongest risk for exposure during pregnancy. Other stratifications showed the greatest risk estimates for indoor exposure, for exposure to insecticides as well as for acute non-lymphocytic leukaemia (ANLL). Outdoor exposure and exposure of children to herbicides (after pregnancy) were not significantly associated with childhood leukaemia. Findings support the assumption that residential pesticide exposure may be a contributing risk factor for childhood leukaemia but available data were too scarce for causality ascertainment. It may be opportune to consider preventive actions, including educational measures, to decrease the use of pesticides for residential purposes and particularly the use of indoor insecticides during pregnancy.
  [Van Maele-Fabry G, Lantin AC, Hoet P, Lison D. 2011. Environ Int. 37(1):280-91.]
• Residential pesticides and childhood leukemia: a systematic review and meta-analysis.
  Study is a systematic review and meta-analysis of previous observational epidemiologic studies examining the relationship between residential pesticide exposures during critical exposure time windows (preconception, pregnancy, and childhood) and childhood leukemia. Exposures during pregnancy to unspecified residential pesticides insecticides, and herbicides were positively associated with childhood leukemia. Exposures during childhood to unspecified residential pesticides and insecticides were also positively associated with childhood leukemia, but there was no association with herbicides. Positive associations were observed between childhood leukemia and residential pesticide exposures. Further work is needed to confirm previous findings based on self-report, to examine potential exposure-response relationships, and to assess specific pesticides and toxicologically related subgroups of pesticides in more detail.
  [Turner MC, Wigle DT, Krewski D. 2011. Cien Saude Colet. 16(3):1915-31.]
• A systematic review and meta-analysis of childhood leukemia and parental occupational pesticide exposure.
  Authors conducted a systematic review and meta-analysis of childhood leukemia and parental occupational pesticide exposure.They found no overall association between childhood leukemia and any paternal occupational pesticide exposure; there were slightly elevated risks in subgroups of studies with low total-quality scores, ill-defined exposure time windows, and exposure information collected after offspring leukemia diagnosis. Childhood leukemia was associated with prenatal maternal occupational pesticide exposure (OR = 2.09; 95% CI, 1.51-2.88); this association was slightly stronger for studies with high exposure-measurement-quality scores (OR = 2.45; 95% CI, 1.68-3.58), higher confounder control scores (OR = 2.38; 95% CI, 1.56-3.62), and farm-related exposures (OR = 2.44; 95% CI, 1.53-3.89). Childhood leukemia risk was also elevated for prenatal maternal occupational exposure to insecticides (OR = 2.72; 95% CI, 1.47-5.04) and herbicides (OR = 3.62; 95% CI, 1.28-10.3). Childhood leukemia was associated with prenatal maternal occupational pesticide exposure in analyses of all studies combined and in several subgroups.
  [Wigle DT, Turner MC, Krewski D. 2009. Environ Health Perspect. 117(10):1505-13]
• Pediatric acute lymphoblastic leukemia and exposure to pesticides.
  A case-control study of children diagnosed with ALL and their mothers in the Washington DC area finds an association between the development of childhood ALL and common household pesticides, as ALL child-mother pairs have elevated levels for the organophosphate metabolites diethylthiophosphate and diethyldithiophosphate and more case mothers (33%) than controls (14%) reported using insecticides in the home.
  [Soldin, O.P., et al. 2009. Therapeutic Drug Monitoring 31(4):495-501]
• Residential proximity to agricultural pesticide applications and childhood acute lymphoblastic leukemia
  A population based, case control study in California using residential histories and proximity to agricultural pesticide use shows an elevated risk of childhood ALL associated with moderate exposure, but not high exposure, to pesticides classified as organophosphates, chlorophenoxy herbicides, and triazines, and with agricultural pesticides used as insecticides or fumigants.
  [Rull, R.P., et al. 2009. Environ Res 109(7):891-9]
• Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
  An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with agricultural activity finds an elevated risk for AML at high agricultural activity (greater than 60% of county acreage devoted to farming).
  [Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.]
• Association between prenatal pesticide exposures and the generation of leukemia-associated T(8;21)
  A study analyzing umbilical cord blood samples of infants whose meconium sample detected the pesticide propoxur, finds a two-fold increase incidence of t(8;21)(a22;a22), one of the most common cytogenetic abnormalities in childhood acute myeloid leukemia, suggesting that prenatal pesticide exposure is a factor in the generation of leukemia-associated chromosomal translocations.
  [Lafiura, K.M., et al. 2007. Pediatr Blood Cancer 48(5):624-628]
• Household exposure to pesticides and risk of childhood hematopoietic malignancies: The ESCALE study (SFCE)
  We investigated the role of household exposure to pesticides in the etiology of childhood hematopoietic malignancies. The national registry-based case-control study ESCALE (Etude sur les cancers de l'enfant) was carried out in France over the period 2003-2004. Population controls were frequency matched with the cases on age and sex. Maternal household use of pesticides during pregnancy and paternal use during pregnancy or childhood were reported by the mothers in a structured telephone questionnaire. Insecticides (used at home, on pets, or for garden crops), herbicides, and fungicides were distinguished. We estimated odds ratios (ORs) using unconditional regression models closely adjusting for age, sex, degree of urbanization, and type of housing (flat or house). We included a total of 764 cases of acute leukemia (AL), 130 of Hodgkin lymphoma (HL), 166 of non-Hodgkin lymphoma (NHL), and 1,681 controls. Insecticide use during pregnancy was significantly associated with childhood AL [OR = 2.1; 95% confidence interval (CI), 1.7-2.5], both lymphoblastic and myeloblastic, NHL (OR = 1.8; 95% CI, 1.3-2.6), mainly for Burkitt lymphoma (OR = 2.7; 95% CI, 1.6-4.5), and mixed-cell HL (OR = 4.1; 95% CI, 1.4-11.8), but not nodular sclerosis HL (OR = 1.1; 95% CI, 0.6-1.9). Paternal household use of pesticides was also related to AL (OR = 1.5; 95% CI, 1.2-1.8) and NHL (OR = 1.7; 95% CI, 1.2-2.6); but for AL the relationships did not remain after adjustment for maternal pesticide use during pregnancy. The study findings strengthen the hypothesis that domestic use of pesticides may play a role in the etiology of childhood hematopoietic malignancies. The consistency of the findings with those of previous studies on AL raises the question of the advisability of preventing pesticide use by pregnant women.
  [Rudant, J., et al. 2007. Environmental Health Perspectives 115(12):1787-1793]
• Parental occupational exposure to pesticides and the risk of childhood leukemia in Costa Rica.
  In a Costa Rica population-based, case-control study, researchers find parental occupational exposure to pesticides increases the risk of childhood leukemia. Maternal pesticide exposure doubles offspring leukemia risk, whether before conception (OR 2.4), or during the first (OR 22) or second trimesters (OR 4.5) the risk is significant. Paternal pesticide exposure during the second trimester also increases risk (1.5 OR) in offspring. In regards to organophosphates, maternal exposure during the first trimester is three and a half times higher (OR 3.5). Exposure to benzimidazole pesticides during pregnancy also has twice the risk for childhood leukemia (OR 2.2)
  [Monge, P., et al. 2007. Scandinavian Journal of Work, Environment and Health 33(4):293-303]
• 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
  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.
  [Alderton, L.E., et al. 2006. American Journal of Epidemiology 164(3):212-221]
• Household exposure to pesticides and risk of childhood acute leukaemia
  

  The study included 280 incident cases of acute leukemia and 288 controls frequency-matched on gender, age, hospital, and ethnic origin. The data were obtained from standardized face-to-face interviews of the mothers with detailed questions on parental occupational history, home and garden insecticide use, and insecticidal treatment of pediculosis. Odds ratios were estimated using unconditional regression models including the stratification variables parental socioeconomic status and housing characteristics. Acute leukemia was observed to be significantly associated with maternal home insecticide use during pregnancy (OR = 1.8, 95% CI 1.2 to 2.8) and during childhood (OR = 1.7, 95% CI 1.1 to 2.4), with garden insecticide use (OR = 2.4, 95% CI 1.3 to 4.3), and fungicide use (OR = 2.5, 95% CI 1.0 to 6.2) during childhood. Insecticidal shampoo treatment of pediculosis was also associated with childhood acute leukemia (OR = 1.9, 95% CI 1.2 to 3.3). The results reported herein support the hypothesis that various types of insecticide exposure may be a risk factor for childhood acute leukemia. The observed association with insecticidal shampoo treatment of pediculosis, which has never been investigated before, requires further study.

  
  [Menegaux, F., et al. 2006. Occup Environ Med 63(2):131-134]
• Agricultural pesticide use and childhood cancer in California.
  Looking at residential proximity to agricultural pesticides, a population-based case-control study of early childhood cancer, ages 0-4 years, in California finds an elevated risk for leukemia associated with probable and possible carcinogen use and with nearby agricultural applications of organochlorines and organophosphates during pregnancy (metam sodium OR 2.05 and dicofol OR 1.83)
  [Reynolds, P, et al. 2005. Epidemiology 16(1):93-100]
• Childhood cancer and agricultural pesticide use: an ecologic study in California.
  We analyzed population-based childhood cancer incidence rates throughout California in relation to agricultural pesticide use. During 1988-1994, a total of 7,143 cases of invasive cancer were diagnosed among children under 15 years of age in California. Building on the availability of high-quality population-based cancer incidence information from the California Cancer Registry, population data from the U.S. Census, and uniquely comprehensive agricultural pesticide use information from California's Department of Pesticide Regulation, we used a geographic information system to assign summary population, exposure, and outcome attributes at the block group level. We used Poisson regression to estimate rate ratios (RRs) by pesticide use density adjusted for race/ethnicity, age, and sex for all types of childhood cancer combined and separately for the leukemias and central nervous system cancers. We generally found no association between pesticide use density and childhood cancer incidence rates. The RR for all cancers was 0.95 [95% confidence interval (CI), 0.80-1.13] for block groups in the 90th percentile and above for use of pesticides classified as probable carcinogens, compared to the block groups with use of < 1 lb/mi(2). The RRs were similar for leukemia and central nervous system cancers. Childhood leukemia rates were significantly elevated (RR = 1.48; 95% CI, 1.03-2.13) in block groups with the highest use of propargite, although we saw no dose-response trend with increasing exposure categories. Results were unchanged by further adjustment for socioeconomic status and urbanization.
  [Reynolds, P., et al. 2002. Environmental Health Perspectives 110(3):319-324]
• Critical windows of exposure to household pesticides and risk of childhood leukemia.
  The potential etiologic role of household pesticide exposures was examined in the Northern California Childhood Leukemia Study. A total of 162 patients (0-14 years old) with newly diagnosed leukemia were rapidly ascertained during 1995-1999, and 162 matched control subjects were randomly selected from the birth registry. The use of professional pest control services at any time from 1 year before birth to 3 years after was associated with a significantly increased risk of childhood leukemia [odds ratio (OR) = 2.8; 95% confidence interval (CI), 1.4-5.7], and the exposure during year 2 was associated with the highest risk (OR = 3.6; 95% CI, 1.6-8.3). The ORs for exposure to insecticides during the 3 months before pregnancy, pregnancy, and years 1, 2, and 3 were 1.8 (95% CI, 1.1-3.1), 2.1 (95% CI, 1.3-3.5), 1.7 (95% CI, 1.0-2.9), 1.6 (95% CI, 1.0-2.7), and 1.2 (95% CI, 0.7-2.1), respectively. Insecticide exposures early in life appear to be more significant than later exposures, and the highest risk was observed for exposure during pregnancy. Additionally, more frequent exposure to insecticides was associated with a higher risk. In contrast to insecticides, the association between herbicides and leukemia was weak and nonsignificant. Pesticides were also grouped based on where they were applied. Exposure to indoor pesticides was associated with an increased risk, whereas no significant association was observed for exposure to outdoor pesticides. The findings suggest that exposure to household pesticides is associated with an elevated risk of childhood leukemia and further indicate the importance of the timing and location of exposure.
  [Ma, X., et al. 2002. Critical windows of exposure to household pesticides and risk of childhood leukemia. Environmental Health Perspectives 110:955-960]
• Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion
  A small case-control, population-based study finds a significant increase risk for infant acute leukemia for maternal exposure to insecticides (OR 9.68) during pregnancy, including the carbamate propoxur.
  [Alexander, F.E., et al. 2001. Cancer Res 61(6):2542-2546]
• Risk of childhood leukemia associated with exposure to pesticides and with gene polymorphisms.
  A population-based case-control study of childhood ALL finds an increased risk for homeowner use of indoor insecticides and garden and interior plant pesticides, in particular with use during pregnancy and among carriers of the CYP1A1m1 and CYP1a1m2 gene mutations.
  [Infante-Rivard, C., et al. 1999. Epidemiology 10(5):481-487]
• Childhood leukaemia and exposure to pesticides: results of a case-control study in northern Germany
  The association between childhood leukaemia and exposure to pesticides was examined in a population-based case-control study conducted in Lower Saxony, Northern Germany. Between July 1988 and June 1992, 219 newly diagnosed cases were identified, of whom 173 participated in the study. Two sex- and age-matched control groups were recruited: local controls from the same communities as the newly diagnosed cases of leukaemia and state controls from other randomly selected communities in Lower Saxony. An additional study group consisted of 175 cases of solid tumours. When the leukaemia cases were compared with the local controls, positive associations with parental occupational exposure, particularly agriculture-related exposure, were observed, which were statistically non-significant. A significant association was found for pesticide use in gardens (odds ratio = 2.52, 95% confidence interval: 1.0-6.1). No positive associations were seen when the leukaemia cases were compared to the state controls, but this finding could be explained by a higher proportion of state controls living in rural areas. In communities with a significantly elevated standardised incidence ratio of childhood leukaemia over the last decade (1984-1993), the prevalence of pesticide use in the garden was 21%, compared with the 10% in other communities. None of the examined risk factors were more common among cases of solid tumours. Our findings add some evidence to the hypothesis that pesticides are a risk factor for childhood leukaemia, and there are good reasons to consider abundant pesticide use in rural areas as a possible cause for clustering of childhood leukaemia.
  [Meinert, E., et al. 1996. Eur J Cancer32A(11):1943-1948]
• Home pesticide use and childhood cancer: A case-control study
  The association between childhood cancer and home pesticide use was examined in a case-control study of children under 15 years of age. Parents of 252 children diagnosed with cancer in the Denver area between 1976 and 1983 and of 222 control subjects were interviewed regarding use of home pest extermination, yard treatment, and pest strips. The strongest associations were found for yard treatments and soft tissue sarcomas (odds ratios [ORs] around 4.0) and for use of pest strips and leukemias (ORs between 1.7 and 3.0). These results suggest that use of home pesticides may be associated with some types of childhood cancer.
  [Leiss, J., et al. 1995. American Journal of Public Health 85:249-252]
• Case-control study on the association between a cluster of childhood haematopoietic malignancies and local environmental factors in Aalsmeer, The Netherlands.
  In Aalsmeer, a horticultural community near the main international airport in The Netherlands, a more than fourfold increase in the incidence of haematopoietic malignancies in young people was observed between 1980 and 1985. In a population based case-control study, the association with local environmental factors was investigated. For each patient younger than 40 years of age (n = 14) diagnosed between 1975 and 1989, four age and sex-matched controls were selected via local general practitioners. All parents of patients and controls completed a questionnaire on their lifestyle, living conditions, and health, for several years preceding each individual diagnosis. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated, matched, and, if necessary, stratified for neighbourhood. Increased ORs were recorded for intensive use of petroleum products and pesticides by the patients themselves and their fathers: OR petroleum products: 8.0 (95% CI 2.2, 129.9) and 9.0 (1.0, 66.1) respectively; OR pesticides: 6.0 (0.6, 49.3) and 3.2 (1.0, 10.1) respectively. Swimming in a local pond was also significantly associated with the disease: OR = 5.3 (1.3, 17.4). In the 1970s this pond had been polluted by petroleum products and pesticides. The increased incidence of childhood haematopoietic malignancies in Aalsmeer may have been associated with several specific local environmental factors. Interpretation of the results, however, should take into account the fact that confidence intervals were wide because of the limited number of case
  [Mulder, Y.M., et al. 1994. Journal of Epidemiology and Community Health 48:161-165]
• Epidemiological characteristics of childhood acute lymphocytic leukemia. Analysis by immunophenotype. The Childrens Cancer Group.
  While a number of epidemiological studies of childhood acute lymphocytic leukemia (ALL) have been conducted, separate analysis of risk factors for ALL subtypes has generally not been possible. We report the results of an analysis of data obtained from parents of children with ALL (and a control group of children without cancer), linked to a clinical database. Cases were classified into four ALL subtypes, and odds ratios (OR) were determined for each subtype for a broad range of factors. Numerous significant associations were found, some across all subtypes and others that were subtype-specific. Factors with elevated and/or significant ORs included: (i) for common ALL (n = 286): Down syndrome; family history (FH) of bone/joint diseases; postnatal jaundice; birthweight; MMR vaccination; exposure to gases and insecticides; and parental occupational exposure to insecticides. (ii) for pre-B ALL (n = 38): FH of gastrointestinal, hematological or bone/joint diseases, or allergy; cat ownership; exposure to solvents, fumes, petroleum products, cleaning agents and farm animals; and parental exposure to farm animals, fumes and solvents; (iii) for T-cell ALL (n = 158): FH of gastrointestinal disorders, maternal age, male gender, and parental occupational exposure to metals; (iv) for null-cell ALL (n = 65): FH of congenital heart disorders; measles; and parental occupational exposure to fumes, metals or solvents. This analysis should be considered as a hypothesis-generating process for future case-control interview studies.
  [Buckley, J.D., et al. 1994. Leukemia 8(5):856-864]
• Parental occupation and other environmental factors in the etiology of leukemias and non-Hodgkin's lymphomas in childhood: a case-control study
  A hospital-based case-control study in Italy finds a positive association with paternal work as a farmer and childhood ALL
  [Magnani, C., et al. 1990. Tumori 76(5):413-419]
• Occupational Exposures of Parents of Children with Acute Nonlymphocytic Leukemia: A Report from the Childrens Cancer Study Group
  A case-control study finds a consistent pattern of association of AML, also known as acute nonlymphoblastic leukemia (ANLL), risk with paternal exposure to pesticides for jobs held longer than three years, which is substantially increased for children under age 6 at diagnosis. An elevated risk is also found for a child’s direct exposure to pesticides in the home and for maternal exposure to home pesticides at the time of pregnancy.
  [Buckley, J.D., et al. 1989. Cancer Research 49:4030-4037]
• A population-based case-control study of childhood leukemia in Shanghai
  A population based case-control study in China of childhood leukemia cases finds an association between ALL with maternal occupational exposure to pesticides.
  [Shu, X.O., et al. 1988. Cancer 62(3):635-644]
• Environmental factors in childhood leukaemia.
  Various factors have been suspected of influencing childhood leukaemia; this in itself indicates how limited and uncertain is our understanding to date of the epidemiology of the disease. In this case-control study an attempt was made to examine the various hypotheses that have been proposed... The small French case-control study finds paternal occupational exposures to pesticides as a risk factor for leukemia (12 cases versus 3 controls)
  [Laval, G. and Tuyns, A.J. 1988. British Journal of Industrial Medicine 45:843-844]
• Childhood leukemia and parents' occupational and home exposures.
  A case-control study in California finds household pesticide use can more than triple the risk of childhood leukemia and that garden pesticides increase the risk to over six-fold.
  [Lowengart, R., et al. 1987. Journal of the National Cancer Institute 79(1):39-46]