Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults.

BACKGROUND: Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years. METHODS: We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language. RESULTS: There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (ß per ten-fold increase in DAPs = 3.37; 95% CI: -0.02, 6.77 and ß = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (ß = -3.10; 95% CI: -6.43, 0.22 and ß = -3.67; 95% CI: -7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task. DISCUSSION: We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts.

Prenatal current-use pesticide exposure and children's neurodevelopment at one year of age in the Infants' Environmental Health (ISA) birth cohort, Costa Rica.

BACKGROUND: Pesticide exposure may affect young children's neurodevelopment, but only few cohort studies have addressed possible effects of non-organophosphate pesticides. OBJECTIVE: We evaluated associations between prenatal current-use pesticide exposure and neurodevelopmental outcomes among 1-year-old children from the Infants' Environmental Health (ISA) birth cohort. METHODS: To determine prenatal pesticide exposure, we measured biomarkers of pyrimethanil, chlorpyrifos, synthetic pyrethroids, and 2,4-D in urine samples among 355 women, 1-3 times during pregnancy. One-year post-partum, we evaluated children's neurodevelopment with the Bayley Scales of Infant and Toddler Development 3rd edition (BSID-III). We assessed associations between exposures and neurodevelopmental outcomes (composite and z-scores) using single-chemical linear regression models adjusted for possible confounders (maternal education, parity, sex, gestational age at birth, child age, HOME-score, location of assessment, biomarkers of mancozeb), and studied effect-modification by sex. We evaluated non-linear associations of multiple pesticide exposures with Bayesian kernel machine regression (BKMR). RESULTS: We found higher prenatal urinary 2,4-D concentrations were associated with lower language (ßper ten-fold increase = -2.0, 95 % confidence interval (CI) = -3.5, -0.5) and motor (ßper ten-fold increase = -2.2, 95 %CI = -4.2, -0.1) composite scores among all children. Also, higher chlorpyrifos exposure [measured as urinary 3,5,6-trichloro-2-pyridinol (TCPy)] was associated with lower cognitive composite scores (ßper ten-fold increase = -1.9, 95 %CI = -4.7, 0.8), and lower motor composite scores among boys (ßper ten-fold increase = -3.8, 95 % CI = -7.7, 0.1) but not girls (ßper ten-fold increase = 2.3, 95 %CI = -1.6, 6.3, pINT = 0.11). Finally, higher pyrimethanil was associated with lower language abilities among girls, but not boys. Pyrethroid metabolite concentrations did not explain variability in BSID-III composite scores. Associations were similar for BSID-III z-scores, and we found no evidence for non-linear associations or mixture effects. DISCUSSION: Prenatal exposure to common-use pesticides may affect children's neurodevelopment at 1-year of age, some effects may be sex-specific.

Respiratory and allergic outcomes among 5-year-old children exposed to pesticides.

BACKGROUND: Little is known about the effects of pesticides on children's respiratory and allergic outcomes. We evaluated associations of prenatal and current pesticide exposures with respiratory and allergic outcomes in children from the Infants' Environmental Health Study in Costa Rica. METHODS: Among 5-year-old children (n=303), we measured prenatal and current specific gravity-corrected urinary metabolite concentrations of insecticides (chlorpyrifos, pyrethroids), fungicides (mancozeb, pyrimethanil, thiabendazole) and 2,4-D. We collected information from caregivers on respiratory (ever doctor-diagnosed asthma and lower respiratory tract infections (LRTI), wheeze and cough during last 12 months) and allergic (nasal allergies, itchy rash, ever eczema) outcomes. We fitted separate multivariable logistic regression models for high (≥75th percentile (P75)) vs low (

Infant feeding practices and childhood acute leukemia: Findings from the Childhood Cancer & Leukemia International Consortium.

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81-0.96) or 7 to 12 months (OR 0.85, 0.79-0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71-0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63-0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53-0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B-ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.

Environmental exposures contribute to respiratory and allergic symptoms among women living in the banana growing regions of Costa Rica.

OBJECTIVES: This research evaluates whether environmental exposures (pesticides and smoke) influence respiratory and allergic outcomes in women living in a tropical, agricultural environment. METHODS: We used data from 266 mothers from the Infants' Environmental Health cohort study in Costa Rica. We evaluated environmental exposures in women by measuring seven pesticide and two polycyclic aromatic hydrocarbons metabolites in urine samples. We defined 'high exposure' as having a metabolite value in the top 75th percentile. We collected survey data on respiratory and allergic outcomes in mothers as well as on pesticides and other environmental exposures. Using logistic regression models adjusted for obesity, we assessed the associations of pesticide exposure with multiple outcomes (wheeze, doctor-diagnosed asthma, high (≥2) asthma score based on symptoms, rhinitis, eczema and itchy rash). RESULTS: Current pesticide use in the home was positively associated with diagnosed asthma (OR=1.99 (95% CI=1.05 to 3.87)). High urinary levels of 5-hydroxythiabendazole (thiabendazole metabolite) and living in a neighbourhood with frequent smoke from waste burning were associated with a high asthma score (OR=1.84 (95%CI=1.05 to 3.25) and OR=2.31 (95%CI=1.11 to 5.16), respectively). Women who worked in agriculture had a significantly lower prevalence of rhinitis (0.19 (0.01 to 0.93)), but were more likely to report eczema (OR=2.54 (95%CI=1.33 to 4.89)) and an itchy rash (OR=3.17 (95%CI=1.24 to 7.73)). CONCLUSIONS: While limited by sample size, these findings suggest that environmental exposure to both pesticides and smoke may impact respiratory and skin-related allergic outcomes in women.

Interactions of agricultural pesticide use near home during pregnancy and adverse childhood experiences on adolescent neurobehavioral development in the CHAMACOS study.

BACKGROUND: Studies have documented independent adverse associations between prenatal and early-life exposure to environmental chemicals and social adversity with child neurodevelopment; however, few have considered these exposures jointly. The objective of this analysis is to examine whether associations of pesticide mixtures and adolescent neurobehavioral development are modified by early-life adversity in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort. METHODS: We used linear mixed effects Bayesian Hierarchical Models (BHM) to examine the joint effect of applications of 11 agricultural pesticides within 1 km of maternal homes during pregnancy and youth-reported Adverse Childhood Experiences (ACEs) with maternal and youth-reported internalizing behaviors, hyperactivity, and attention problems assessed via the Behavior Assessment for Children (BASC) (mean = 50, standard deviation = 10) at ages 16 and 18 years (n = 458). RESULTS: The median (25th-75th percentiles) of ACEs was 1 (0-3); 72.3% of participants had low ACEs (0-2 events) and 27.7% had ACEs (3+ events). Overall, there was little evidence of modification of exposure-outcome associations by ACEs. A two-fold increase in malathion use was associated with increased internalizing behaviors among those with high ACEs from both maternal- (ß = 1.9; 95% Credible Interval (CrI): 0.2, 3.7 for high ACEs vs. ß = -0.1; 95% CrI: 1.2, 0.9 for low ACEs) and youth-report (ß = 2.1; 95% CrI: 0.4, 3.8 for high ACEs vs. ß = 0.2; 95% CrI: 0.8, 1.2 for low ACEs). Applications of malathion and dimethoate were also associated with higher youth-reported hyperactivity and/or inattention among those with high ACEs. CONCLUSION: We observed little evidence of effect modification of agricultural pesticide use near the home during pregnancy and adolescent behavioral problems by child ACEs. Future studies should examine critical windows of susceptibility of exposure to chemical and non-chemical stressors and should consider biomarker-based exposure assessment methods.

Exposure to DDT and DDE and functional neuroimaging in adolescents from the CHAMACOS cohort.

BACKGROUND: Epidemiological studies suggest that exposure to p,p'-dichloro-diphenyl-trichloroethane (p,p'-DDT) is associated with poorer cognitive function in children and adolescents, but the neural mechanisms underlying this association remain unclear. OBJECTIVE: We investigated associations of prenatal and childhood exposure to p,p'-DDT and its metabolite p,p'-dichloro-diphenyl-dichloroethylene (p,p'-DDE) with cortical activation in adolescents using functional near-infrared spectroscopy (fNIRS). METHODS: We administered fNIRS to 95 adolescents from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) aged 15-17 years. We assessed cortical activity in the frontal, temporal, and parietal brain regions while participants completed tasks of executive function, language comprehension, and social cognition. We measured serum p,p'-DDT and -DDE concentrations at age 9 years and then estimated exposure-outcome associations using linear regression models adjusted for sociodemographic characteristics. In secondary analyses, we back-extrapolated prenatal concentrations using prediction models and examined their association with cortical activation. RESULTS: Median (P25-P75) p,p'-DDT and -DDE concentrations in childhood were 1.4 (1-2.3) and 141.5 (75.0-281.3) ng/g lipid, respectively. We found that childhood exposure to p,p'-DDT and -DDE was associated with altered patterns of brain activation during tasks of cognition and executive functions. For example, we observed increased activity in the left frontal lobe during a language comprehension task (ß per 10 ng/g lipid increase of serum p,p'-DDE at age 9 years = 3.4; 95% CI: 0.0, 6.9 in the left inferior frontal lobe; and ß = 4.2; 95% CI: 0.9, 7.5 in the left superior frontal lobe). We found no sex differences in the associations of childhood p,p'-DDT and -DDE concentrations with neural activity. Associations between prenatal p,p'-DDT and p,p'-DDE concentrations and brain activity were similar to those observed for child p,p'-DDT and -DDE concentrations. CONCLUSIONS: Childhood p,p'-DDT and -DDE exposure may impact cortical brain activation, which could be an underlying mechanism for its previously reported associations with poorer cognitive function.

Prenatal exposure to organophosphate pesticides and risk-taking behaviors in early adulthood.

INTRODUCTION: Previous studies show evidence for associations of prenatal exposure to organophosphate (OP) pesticides with poorer childhood neurodevelopment. As children grow older, poorer cognition, executive function, and school performance can give rise to risk-taking behaviors, including substance abuse, delinquency, and violent acts. We investigated whether prenatal OP exposure was associated with these risk-taking behaviors in adolescence and young adulthood in a Mexican American cohort. METHODS: We measured urinary dialkyl phosphates (DAPs), non-specific metabolites of OPs, twice (13 and 26 weeks gestation) in pregnant women recruited in 1999-2000 in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a birth cohort set in a primarily Latino agricultural community in the Salinas Valley, California. We followed up children throughout their childhood and adolescence; at the 18-year visit, adolescent youth (n = 315) completed a computer-based questionnaire which included questions about substance use, risky sexual activity, risky driving, and delinquency and police encounters. We used multivariable models to estimate associations of prenatal total DAPs with these risk-taking behaviors. RESULTS: The prevalence of risk-taking behaviors in CHAMACOS youth ranged from 8.9% for smoking or vaping nicotine to 70.2% for committing a delinquent act. Associations of total prenatal DAPs (geometric mean = 132.4 nmol/L) with risk-taking behavior were generally null and imprecise. Isolated findings included a higher risk for smoking or vaping nicotine within the past 30 days (relative risk [RR] per 10-fold increase in prenatal DAPs = 1.89, 95% CI: 1.00, 3.56) and driving without a license (RR = 1.74, 95% CI: 1.25, 2.42). There were no consistent differences by sex or childhood adversity. DISCUSSION: We did not find clear or consistent evidence for associations of prenatal OP exposure with risk-taking behaviors in adolescence/early adulthood in the CHAMACOS population. Our small sample size may have prevented us from detecting potentially subtle associations of early life OP exposure with these risk-taking behaviors.

Prenatal exposure to organophosphate pesticides and functional neuroimaging in adolescents living in proximity to pesticide application.

We have reported consistent associations of prenatal organophosphate pesticide (OP) exposure with poorer cognitive function and behavior problems in our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a birth cohort of Mexican American youth in California's agricultural Salinas Valley. However, there is little evidence on how OPs affect neural dynamics underlying associations. We used functional near-infrared spectroscopy (fNIRS) to measure cortical activation during tasks of executive function, attention, social cognition, and language comprehension in 95 adolescent CHAMACOS participants. We estimated associations of residential proximity to OP use during pregnancy with cortical activation in frontal, temporal, and parietal regions using multiple regression models, adjusting for sociodemographic characteristics. OP exposure was associated with altered brain activation during tasks of executive function. For example, with a 10-fold increase in total OP pesticide use within 1 km of maternal residence during pregnancy, there was a bilateral decrease in brain activation in the prefrontal cortex during a cognitive flexibility task (ß = -4.74; 95% CI: -8.18, -1.31 and ß = -4.40; 95% CI: -7.96, -0.84 for the left and right hemispheres, respectively). We also found that prenatal OP exposure was associated with sex differences in brain activation during a language comprehension task. This first functional neuroimaging study of prenatal OP exposure suggests that pesticides may impact cortical brain activation, which could underlie previously reported OP-related associations with cognitive and behavioral function. Use of fNIRS in environmental epidemiology offers a practical alternative to neuroimaging technologies and enhances our efforts to assess the impact of chemical exposures on neurodevelopment.

Prevalence and Clinical Profile of Severe Acute Respiratory Syndrome Coronavirus 2 Infection among Farmworkers, California, USA, June-November 2020.

During the ongoing coronavirus disease (COVID-19) pandemic, farmworkers in the United States are considered essential personnel and continue in-person work. We conducted prospective surveillance for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and antibody prevalence among farmworkers in Salinas Valley, California, during June 15-November 30, 2020. We observed 22.1% (1,514/6,864) positivity for SARS-CoV-2 infection among farmworkers compared with 17.2% (1,255/7,305) among other adults from the same communities (risk ratio 1.29, 95% CI 1.20-1.37). In a nested study enrolling 1,115 farmworkers, prevalence of current infection was 27.7% among farmworkers reporting >1 COVID-19 symptom and 7.2% among farmworkers without symptoms (adjusted odds ratio 4.16, 95% CI 2.85-6.06). Prevalence of SARS-CoV-2 antibodies increased from 10.5% (95% CI 6.0%-18.4%) during July 16-August 31 to 21.2% (95% CI 16.6%-27.4%) during November 1-30. High SARS-CoV-2 infection prevalence among farmworkers underscores the need for vaccination and other preventive interventions.

Environmental Health Threats to Latino Migrant Farmworkers.

Approximately 75% of farmworkers in the United States are Latino migrants, and about 50% of hired farmworkers do not have authorization to work in the United States. Farmworkers face numerous chemical, physical, and biological threats to their health. The adverse effects of these hazards may be amplified among Latino migrant farmworkers, who are concurrently exposed to various psychosocial stressors. Factors such as documentation status, potential lack of authorization to work in the United States, and language and cultural barriers may also prevent Latino migrants from accessing federal aid, legal assistance, and health programs. These environmental, occupational, and social hazards may further exacerbate existing health disparities among US Latinos. This population is also likely to be disproportionately impacted by emerging threats, including climate change and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Latino migrant farmworkers are essential to agriculture in the United States, and actions are needed to protect this vulnerable population.

Variability and predictors of weekly pesticide exposure in applicators from organic, sustainable and conventional smallholder farms in Costa Rica.

OBJECTIVE: Estimates of pesticide exposure among applicators from low- and middle-income countries (LMICs) are scarce, and exposure assessment methods are sometimes costly or logistically unfeasible. We examined the variability in weeklong pesticide exposure among applicators in Costa Rica and its predictors. METHODS: We conducted a cross-sectional survey among 221 pesticide applicators from organic, sustainable and conventional farms in 2016. We administered structured questionnaires to assess pesticide application practices at two time points (4-6 weeks apart). We adapted an existing algorithm to fit the context of smallholders and derive weekly pesticide exposure scores. We used linear mixed-effect models to examine within-worker and between-worker score variability. We then identified sociodemographic and occupational predictors of weekly pesticide exposure scores. RESULTS: We observed high within-worker and between-worker variability in weekly pesticide exposures (eg, up to 180-fold and 70-fold differences in average weekly exposures within and between workers, respectively; intraclass correlation coefficient=0.4). Applicators working on conventional and sustainable farms had exposure scores twofold and 1.5-fold higher than those working in organic farms, respectively. Farm workers who received training on pesticide use had weekly pesticide exposure scores of 33% (95% CI 1% to 55%) lower than those who did not receive any training. CONCLUSIONS: In this study of applicators from smallholder farms in Costa Rica, we determined the importance of collecting questionnaire data on self-reported pesticide use repeatedly due to its high variability within workers and absence of application records. Our questionnaire-based exposure algorithm could allow the calculation of semiquantitative estimates of average pesticide exposure for applicators from other LMICs.

Early immune stimulation and childhood acute lymphoblastic leukemia in Costa Rica: A comparison of statistical approaches.

BACKGROUND: Although epidemiologic studies suggest that early immune stimulation is protective against childhood leukemia, evidence for this relationship is equivocal for Hispanic children, who are disproportionately affected by this disease. The complex biological processes underlying immune stimulation and leukemogenesis may benefit from novel statistical approaches that account for mixed exposures and their nonlinear interactions. In this study, we utilized targeted machine learning and traditional statistical methods to investigate the association of multiple measures of early immune stimulation with acute lymphoblastic leukemia (ALL) in Costa Rican children. MATERIALS AND METHODS: We used data from a population-based case-control study conducted in Costa Rica (2001-2003). Cases of ALL (n = 240) were diagnosed in 1995-2000 (age >1 year and <15 years at diagnosis) and were identified through the National Cancer Registry and National Children's Hospital. Population controls (n = 578) were frequency-matched to cases by birth year and drawn from the National Birth Registry. Data on surrogate measures of early immune stimulation were collected through in-home interviews. We fitted multivariable models, utilizing targeted causal inference (varimpact), unconditional logistic regression, and latent class analysis (LCA). RESULTS: In varimpact analysis, contact with any pet [risk difference (RD) = -0.17, 95% CI: -0.25, -0.10)] or any farm animal (RD = -0.07, 95% CI: -0.13, 0.00) and allergies (RD = -0.08, 95% CI: -0.17, 0.01) were associated with a reduced risk of ALL, whereas experiencing a fever longer than one week was associated with an increased risk (RD = 0.23, 95% CI: 0.12, 0.33). In unconditional logistic regression models, contact with any pet or farm animal and a complete vaccination scheme were inversely associated with odds of ALL (OR = 0.44, 95% CI: 0.31, 0.62; OR = 0.66, 95% CI: 0.49, 0.90; OR = 0.45, 95% CI: 0.24, 0.83; respectively), whereas experiencing a fever longer than one week was positively associated with ALL (OR = 2.44, 95% CI: 1.61, 3.70). Two-class and three-class LCA revealed a group with elevated risk for ALL whose exposure profile was mainly characterized by reduced exposure to pets and farm animals. CONCLUSIONS: Using distinct statistical approaches, we observed that exposure to pets and farm animals was inversely associated with ALL risk, whereas having a fever longer than one week (a putative proxy of severe infection) was associated with an increased risk. For multifactorial diseases such as childhood leukemia, we recommend estimating the joint effects of multiple exposures by applying diverse statistical methods and interpreting their results together. Overall, we found support for the hypothesis that early immune stimulation offers protection against childhood ALL.

Parental tobacco smoking and risk of childhood leukemia in Costa Rica: A population-based case-control study.

INTRODUCTION: The role of environmental and behavioral exposures on childhood leukemia etiology is poorly understood. We examined the association of maternal and paternal tobacco smoking at different time points with the risk of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in Costa Rican children. MATERIALS AND METHODS: We conducted a population-based case-control study on childhood leukemia in Costa Rica. Cases (n ALL = 252; n AML = 40) were diagnosed between 1995 and 2000 (aged <15 years at diagnosis) and identified from the Costa Rican Cancer Registry and the National Children's Hospital. A total of 578 frequency-matched population controls were sampled from the National Birth Registry. Parental tobacco smoking was assessed via face-to-face interviews. We used logistic regression models to examine the association of paternal and maternal tobacco smoking before conception, during pregnancy, and after birth with childhood ALL and AML risk, adjusted for child sex, birth year, maternal/paternal age, and parental education. RESULTS: Paternal smoking before conception, during pregnancy, and after birth was associated with an increased risk of childhood AML (Odds Ratio (OR): 2.51, 95% CI: 1.21-5.17; OR: 3.21, 95% CI: 1.56-6.60; and OR: 2.83, 95% CI: 1.36-5.90, respectively). Maternal smoking during pregnancy was also associated with a modest, but imprecise increase in AML risk. We observed null associations of maternal and paternal smoking with ALL in the offspring. CONCLUSION: Our results suggest an association between parental smoking and risk of AML, but not ALL, in Costa Rican children. These findings add to the established evidence of numerous health risks associated with smoking and highlight the potential harm of smoking during sensitive windows of the development of fetus and child.

Manganese exposure and working memory-related brain activity in smallholder farmworkers in Costa Rica: Results from a pilot study.

Main sources of manganese (Mn) in the general population are diet and drinking water. Mn is also found in ethylene bisdithiocarbamate (EBDC) fungicides used in agriculture or emitted into the air by ferromanganese plants and welding fumes, which can be additional environmental and occupational sources of exposure. High occupational Mn exposure has been linked with motor, behavioral, and cognitive impairment, but its effects on neural function remain poorly understood. We conducted a functional neuroimaging study in a sample of 48 farmworkers in Zarcero County, Costa Rica, an agricultural region where EBDC fungicides are sprayed. We measured Mn concentrations in farmworkers' toenails (n = 40 farmworkers) and hair (n = 33 farmworkers), and recorded brain activity in the dorsolateral prefrontal cortex during a letter-retrieval working memory task using functional near-infrared spectroscopy (fNIRS). We estimated exposure-outcome associations using multivariable linear regression models adjusted for age and education level. Geometric mean (geometric standard deviation) toenail and hair Mn concentrations were 0.40 µg/g (3.52) and 0.24 µg/g (3.54), respectively. We did not find strong evidence that Mn concentrations were associated with working memory-related brain activity in this sample of farmworkers; we also found null associations between working memory task accuracy and brain activity. However, our small sample size may have limited our ability to detect small effect sizes with statistical precision. Our study demonstrates that fNIRS can be a useful and feasible tool in environmental epidemiology for examining the effects of toxicants, like Mn, on neural function. This may prove to be important for elucidating neuropathological pathways that underlie previously reported associations of elevated Mn exposure with neurotoxic effects.

Maternal residential pesticide use and risk of childhood leukemia in Costa Rica.

Evidence suggests that early-life exposure to pesticides inside the home may be associated with childhood leukemia, however data from Latin American countries are limited. We examined whether self-reported maternal residential pesticide use and nearby pesticide applications-before and after child's birth-were associated with acute lymphoblastic leukemia (ALL) in the Costa Rican Childhood Leukemia Study (CRCLS), a population-based case-control study (2001-2003). Cases (n = 251 ALL) were diagnosed between 1995 and 2000 (age <15 years at diagnosis) and were identified through the Costa Rican Cancer Registry and National Children's Hospital. Population controls (n = 577) were drawn from the National Birth Registry. We fitted unconditional logistic regression models adjusted for child sex, birth year, and socioeconomic status to estimate the exposure-outcome associations and also stratified by child sex. We observed that self-reported maternal insecticide use inside the home in the year before pregnancy, during pregnancy, and while breastfeeding was associated with increased odds of ALL among boys [adjusted Odds Ratio (aOR) = 1.63 (95% confidence interval [95% CI]: 1.05-2.53), 1.75 (1.13-2.73), and 1.75 (1.12-2.73), respectively. We also found evidence of exposure-response relationships between more frequent maternal insecticide use inside the home and increased odds of ALL among boys and girls combined. Maternal report of pesticide applications on farms or companies near the home during pregnancy and at any time period were also associated with ALL. Our study in Costa Rica highlights the need for education to minimize pesticide exposures inside and around the home, particularly during pregnancy and breastfeeding.

Maternal blood and hair manganese concentrations, fetal growth, and length of gestation in the ISA cohort in Costa Rica.

BACKGROUND: Animal studies have shown that both deficiency and excess manganese (Mn) may result in decreased fetal size and weight, but human studies have reported inconsistent results. METHODS: We examined the association of blood and hair Mn concentrations measured at different times during pregnancy with fetal growth among term births and length of gestation in a cohort of 380 mother-infant pairs living near banana plantations aerially sprayed with Mn-containing fungicides in Costa Rica. We used linear regression and generalized additive models to test for linear and nonlinear associations RESULTS: Mean (± SD) blood Mn concentration was 24.4 ± 6.6 µg/L and geometric mean (geometric SD) hair Mn concentration was 1.8 (3.2) µg/g. Hair Mn concentrations during the second and third trimesters of gestation were positively related to infant chest circumference (ß for 10-fold increase = 0.62 cm; 95% CI: 0.16, 1.08; and ß = 0.55 cm; 95% CI: -0.16, 1.26, respectively). Similarly, average maternal hair Mn concentrations during pregnancy were associated with increased chest circumference (ß for 10-fold increase = 1.19 cm; 95% CI: 0.43, 1.95) in infants whose mothers did not have gestational anemia, but not in infants of mothers who had gestational anemia (ß = 0.39 cm; 95% CI: -0.32, 1.10; pINT=0.14). All these associations were linear. Blood Mn concentrations did not show consistent linear nor nonlinear relationships with any of the birth outcomes CONCLUSIONS: Mn plays an important role in fetal development, but the extent to which environmental exposures may cause adverse health effects to the developing fetus is not well understood. Among women living near banana plantations in Costa Rica, we did not observe linear or nonlinear associations of Mn concentrations with lowered birth weight or head circumference, as reported in previous studies. However, we did find positive linear associations between maternal hair Mn concentrations during pregnancy and infant chest circumference.

Blood and hair manganese concentrations in pregnant women from the infants' environmental health study (ISA) in Costa Rica.

Manganese (Mn), an essential nutrient, is a neurotoxicant at high concentrations. We measured Mn concentrations in repeated blood and hair samples collected from 449 pregnant women living near banana plantations with extensive aerial spraying of Mn-containing fungicide mancozeb in Costa Rica, and examined environmental and lifestyle factors associated with these biomarkers. Mean blood Mn and geometric mean hair Mn concentrations were 24.4 µg/L (8.9-56.3) and 1.8 µg/g (0.05-53.3), respectively. Blood Mn concentrations were positively associated with gestational age at sampling (ß = 0.2; 95% CI: 0.1 to 0.2), number of household members (ß = 0.4; 95% CI: 0.1 to 0.6), and living in a house made of permeable and difficult-to-clean materials (ß = 2.6; 95% CI: 1.3 to 4.0); and inversely related to smoking (ß = -3.1; 95% CI: -5.8 to -0.3). Hair Mn concentrations were inversely associated with gestational age at sampling (% change = 0.8; 95% CI: -1.6 to 0.0); and positively associated with living within 50 m of a plantation (% change = 42.1; 95% CI: 14.2 to 76.9) and Mn concentrations in drinking water (% change = 17.5; 95% CI: 12.2 to 22.8). Our findings suggest that pregnant women living near banana plantations aerially sprayed with mancozeb may be environmentally exposed to Mn.

Pesticide exposure, birth size, and gestational age in the ISA birth cohort, Costa Rica.

Purpose: To examine associations of prenatal biomarkers of pesticide exposure with birth size measures and length of gestation among newborns from the Infants' Environmental Health (ISA) birth cohort, Costa Rica. Methods: We included 386 singleton liveborn newborns with data on birth size measures, length of gestation, and maternal urinary biomarkers of chlorpyrifos, synthetic pyrethroids, mancozeb, pyrimethanil, and 2, 4-D during pregnancy. We associated biomarkers of exposure with birth outcomes using multivariate linear regression and generalized additive models. Results: Concentrations were highest for ethylene thiourea (ETU, metabolite of mancozeb), median = 3.40; p10-90 = 1.90-6.79 µg/L, followed by 3,5,6-trichloro-2-pyridinol (TCP, metabolite of chlorpyrifos) p50 = 1.76 p10-90 = 0.97-4.36 µg/L, and lowest for 2,4-D (p50 = 0.33 p10-90 = 0.18-1.07 µg/L). Among term newborns (≥37 weeks), higher prenatal TCP was associated with lower birth weight and smaller head circumference (e.g., ß per 10-fold-increase) during the second half of pregnancy = -129.6 (95% confidence interval [CI] = -255.8, -3.5) grams, and -0.61 (95% CI = -1.05, -0.17) centimeters, respectively. Also, among term newborns, prenatal 2,4-D was associated with lower birth weight (ß per 10-fold-increase = -125.1; 95% CI = -228.8, -21.5), smaller head circumference (ß = -0.41; 95% CI = -0.78, -0.03), and, during the second half of pregnancy, with shorter body length (ß = -0.58; 95% CI = -1.09, -0.07). Furthermore, ETU was nonlinearly associated with head circumference during the second half of pregnancy. Biomarkers of pyrethroids and pyrimethanil were not associated with birth size, and none of the biomarkers explained the length of gestation. Conclusions: Prenatal exposure to chlorpyrifos and 2,4-D, and, possibly, mancozeb/ETU, may impair fetal growth.