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Early-life exposure to organophosphate pesticides and pediatric respiratory symptoms in the CHAMACOS cohort.

Introduction

Asthma is the most prevalent pediatric chronic disease [Pijnenburg 2012; World Health Organization (WHO) 2007], and is a leading cause of hospitalization in children (Mellon and Parasuraman 2004) and school absenteeism due to chronic disease (Mellon and Parasuraman 2004). It is estimated that by 2025, > 350 million people globally, mostly children, will have asthma (Pawankar et al. 2011; WHO 2007). Early-life exposures to maternal smoking, secondhand tobacco smoke, and various ambient air pollutants have been linked to respiratory symptoms and disease in childhood (Pawankar et al. 2011; Selgrade et al. 2013; WHO 2007) and adulthood (Stocks and Sonnappa 2013; WHO 2007). The impact of early-life exposures on later respiratory health is biologically plausible: During the first half of gestation, bronchi are developing and airways are branching; during the second half of gestation, alveoli begin to develop; and for several years after birth, the lungs continue to mature with rapid increase in number, size, and complexity of the alveoli (De Luca et al. 2010).

Organophosphate pesticides (OPs) are one of the most commonly used classes of insecticides worldwide. The U.S. Environmental Protection Agency (EPA) phased out most residential use of OP pesticides by the mid-2000s. However, in 2007, 15 million kg of OPs--36% of total insecticide use--were applied in agriculture in the United States (Grube et al. 2011; Guha et al. 2013; U.S. EPA 2013). Widespread OP exposure in the general U.S. population is supported by the frequent detection of diakyl phosphates (DAPs), urinary metabolites of OP pesticides, in the U.S. National Health and Nutrition Examination Survey (NHANES) (Bradman et al. 2005; CDC 2004, 2014).

OPs depress acetylcholinesterase (AChE), allowing acetylcholine to build up in neuronal junctions, including those of the parasympathetic nervous system, which helps modulate control of the airways (Barnes 1986). In animal studies, the OPs--chlorpyrifos, parathion, and diazinon--induced airway hyperreactivity at doses below those causing AChE inhibition (Fryer et al. 2004; Lein and Fryer 2005; Ndlovu et al. 2011; Proskocil et al. 2013). OP exposure has been associated with respiratory symptoms in adults in occupational settings (Hoppin et al. 2006; Kwak et al. 2009; Ndlovu et al. 2011) and in case studies of children following pesticide poisonings (Cavari et al. 2013); however, there have been few investigations of respiratory symptoms following low-level exposure. One nested case-control study (Salam et al. 2004) reported an association between maternal report of exposure to pesticides and herbicides in the first year of life and asthma before 5 years of age. A cross-sectional study of Lebanese children 5-16 years of age (Salameh et al. 2003) reported an association between parental report of para-occupational and residential exposure to pesticides and respiratory symptoms. As noted by others (Kwak et al. 2009; Ndlovu et al. 2011), these studies were based on reported exposure to pesticides, and no studies of children's respiratory health have included biological measures of exposure.

Here we investigate associations between maternally reported respiratory symptoms consistent with possible asthma and pre- and postnatal exposure to OPs, as measured by DAP metabolite concentrations in urine samples collected from pregnant women and their children from an agricultural community in California. We previously reported an association between maternal work in agriculture and increased levels of Th2 (T helper cell) cytokines in these children at age 2 years, which likely play a key role in the pathophysiology of allergic diseases, including childhood asthma (Duramad et al. 2006).

Methods

Study setting and design. The Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study is a longitudinal birth cohort investigating the effects of in utero and postnatal environmental exposures on growth, neurodevelopment, and respiratory disease in residents of the Salinas Valley, California (Eskenazi et al. 2007). Approximately 235,000 kg of OP pesticides were applied in this agricultural valley during the years of enrollment [California Department of Pesticide Regulation (CDPR) 2001]. Detailed methods have been described elsewhere (Eskenazi et al. 2007). In brief, pregnant women were screened for eligibility between October 1999 and 2000 at community clinics primarily serving farmworker families. Women were eligible for enrollment if they were [greater than or equal to] 18 years old, < 20 weeks gestation, Spanish- or English-speaking, eligible for low-income health insurance, receiving prenatal care, and planning to deliver at the local county hospital. Research protocols were approved by the University of California, Berkeley, Committee for the Protection of Human Subjects. Written informed consent was obtained from the mothers and verbal assent was obtained from the children at age 7 years.

A total of 601 pregnant women were enrolled in the CHAMACOS cohort. Of these, 526 delivered live-born surviving singletons. We assessed respiratory symptomatology for 344 of these children at 5 years of age and 347 at 7 years, with 327 assessed at both time points and 364 children assessed at least once. A total of 359 mothers of the 364 children had a urinary DAP measurement during their pregnancy.

Maternal interviews and respiratory symptom assessment. Information on respiratory symptoms and relevant covariates was obtained by maternal interviews and home visits. Mothers were interviewed twice during pregnancy (mean[+ or -]SD = 13.5 [+ or -] 4.8 and 26.4 [+ or -] 2.4 weeks gestation), after delivery, and when children were 0.5, 1, 2, 3.5, 5, and 7 years old. Urine samples were collected at each prenatal visit and at each child visit, except at 7 years, and stored at -80[degrees]C. Homes were inspected by trained personnel when the children were 6 and 12 months old. Additional data from prenatal and delivery records were abstracted by a registered nurse.

For the present study, we used maternal report of the child's respiratory symptoms when the child was 5 and 7 years of age. Mothers were asked questions based on the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire (Asher et al. 1995; Holguin et al. 2007; Kraai et al. 2013; Stellman et al. 2013). Additionally, mothers were asked whether the child had been prescribed any medication for asthma or wheezing/whistling, or tightness in the chest. We defined respiratory symptoms as a binary outcome based on a positive response to any of the following during the previous 12 months: a) wheezing or whistling in the chest; b) wheezing, whistling, or shortness of breath so severe that the child could not finish saying a sentence; c) trouble going to sleep or being awakened from sleep because of wheezing, whistling, shortness of breath, or coughing that was not associated with a cold; or d) having to stop running or playing active games because of wheezing, whistling, shortness of breath, or coughing that was not associated with a cold. In addition, a child was included as having respiratory symptoms if the mother reported use of asthma controller or rescue medications, even in the absence of the above symptoms. We also analyzed separately the binary outcome of maternal report of the child having to stop running or playing active games due to coughing that was not associated with a cold in the previous 12 months (i.e., exercise-induced coughing). Exercise-induced coughing was included under the respiratory symptoms variable--all children with exercise-induced coughing were also classified as having respiratory symptoms. Children who were not categorized as positive for exercise-induced coughing but had other respiratory symptoms were classified as noncases for these analyses and were not excluded from the analyses. Exercise-induced coughing was analyzed separately without including coughing that was associated with sleep (either trouble going to sleep or being awakened from sleep) because coughing associated with sleep issues may be related to health conditions other than asthma. We did not analyze wheezing separately because of the relatively small percentage of mothers who reported on wheezing.

OP pesticide exposure: DAP metabolites. Six nonspecific DAP metabolites--three dimethyl phosphate (DM) and three diethyl phosphate (DE) metabolites--were measured in urine samples collected from mothers twice during pregnancy and from children at 0.5, 1, 2, 3.5, and 5 years of age. Analyses were conducted by the Division of Laboratory Science at the Centers for Disease Control and Prevention (CDC) using gas chromatography-tandem mass spectrometry and quantified using isotope dilution calibration (Bravo et al. 2002). Detailed methods of urine sample collection and analysis are described elsewhere (Bradman et al. 2005). To account for urine dilution, we measured specific gravity using a hand-held refractometer (National Instrument Company Inc., Baltimore, MD) and measured creatinine concentration using a commercially available diagnostic assay (Vitros CREA slides; Ortho Clinical Diagnostics, Raritan, NJ). The individual DAP metabolites were summed on a molar basis to yield total DAPs, as well as total DE and DM metabolites (Bradman et al. 2005). These metabolites are biomarkers for about 80% of OP pesticides used in the Salinas Valley (CDC 2009). In 2001, the most commonly used OPs in the Salinas Valley that metabolized to DEs were diazinon (60,571 kg) and chlorpyrifos (24,923 kg) and to DMs were malathion (43,781 kg) and oxydemeton methyl (26,244 kg) (CDPR 2001).

Data analysis. We examined the relationship of DEs, DMs, and total DAP concentrations (nanomoles per liter) from maternal urine collected during the first and second halves of pregnancy (0-20, 21-40 weeks gestation), and the average of the two pregnancy samples. For childhood metabolite concentrations, we used the area under the curve (AUC) from the five measurements made during childhood to summarize DAP concentrations over time during childhood. We calculated the time-weighted average concentration for each time interval by multiplying the time between measurements in years by the average of the two measured concentrations. The AUC was calculated by summing the time-weighted averages from each time interval using the trapezoidal method. We excluded from the AUC calculation 86 children who were missing DAP measurements at either 6 months or 5 years or missing more than one measurement from the other three time points. For children with a single missing DAP measurement at 1, 2, or 3.5 years of age (n = 65), we derived the time-weighted average for the interval defined by time points with available data by calculating the mean of the two closest measures. A total of 270 children had a childhood AUC calculation and data on the relevant covariates. We also performed a sensitivity analysis of the association between respiratory symptoms during the previous year reported at 5 or 7 years of age and a summary of childhood OP exposures based on measured values through 3.5 years of age only. In this analysis we excluded the concurrent 5-year value to ensure that the DAP measurements preceded the respiratory symptoms and exercise-induced coughing outcomes. DAP concentrations in maternal samples were corrected for urinary dilution using urine specific gravity, and child DAP samples were corrected for urinary dilution by dividing by urinary creatinine concentration. The variables for total concentrations of DEs, DMs, and total DAPs were [log.sub.10]-transformed.

We used generalized estimating equation (GEE) models (Hubbard et al. 2010; Zeger and Liang 1986) to estimate the longitudinal associations of prenatal and early childhood DAPs on respiratory symptoms in children at 5 and 7 years of age, while accounting for within-subject correlation of repeated measures of respiratory symptoms that were assessed at 5 and 7 years of age (Hubbard et al. 2010; Zeger and Liang 1986). The repeated measures of respiratory symptoms were assessed at 5 and 7 years of age and were defined as positive if they were categorized as such at age 5 or 7 years or both. The same definition was done for exercise-induced coughing.

Covariates were selected based on directed acyclic graphs (DAGs) and included in models if associated with respiratory symptoms in bivariate analysis (p < 0.25). Final adjusted models controlled for child's sex, maternal smoking during pregnancy (yes/no), exposure to secondhand tobacco smoke in the first year of life (yes/no), season of birth (wet/pollen/dry/mold), mean daily particulate matter concentrations with aerodynamic diameter [less than or equal to] 2.5 [micro]m ([PM.sub.2.5]) during first 3 months of life, breastfeeding duration (months), signs of moderate or extensive mold noted at either home visit (6 and 12 months), home located [less than or equal to] 150 m from a highway in first year of life (based on geographic information system), and signs of cockroaches noted at home visit (6 and 12 months). We also controlled for the child's age in months. Season of birth corresponds generally, but not exactly, to mold = fall, wet = winter, pollen = spring, dry = summer. Discrete seasons of high spore and pollen concentrations were determined by ambient aeroallergen concentrations that were measured throughout the birth periods of the participants. Detailed methods for the differentiation of the four seasons have been described elsewhere (Harley et al. 2009). Average [PM.sub.2.5] concentration in the first 3 months of life was calculated using data from the Monterey Unified Air Pollution Control District (MBAPCD) air monitoring station, which uses high-volume Sierra-Andersen gravimetric samplers for 24 hr every sixth day (Thermo Scientific, Waltham, MA). We conducted sensitivity analyses to verify the robustness and consistency of our findings. Models were re-run without adjusting for specific gravity (maternal DAPs) or urine creatinine (child DAPs). Additional models were run controlling for both prenatal DAP levels (we analyzed average and first and second halves of pregnancy measurements separately) and DAP concentrations measured during childhood (calculated by the AUC) in the same model. Potential selection bias due to exclusion from final models of children with missing outcome data or missing covariates was addressed by comparing our results to GEE models that included stabilized inverse probability weights (Hernan et al. 2004). Weights were determined using multiple logistic regression with independent demographic variables selected based on a "Super Learner" algorithm using V-fold cross-validation (van der Laan et al. 2007). Estimates for both weighted and unweighted regression models yielded similar results (data not shown), suggesting that selection bias did not substantially modify our results.

We analyzed the data using SPSS (version 20.0; IBM Corp., Somers, NY) for bivariate analyses, Stata (version IC11.2; StataCorp, College Station, TX) for GEE models, and R (v.2.14.2; R Foundation for Statistical Computing, Vienna, Austria) for Super Learner models. We set statistical significance at p < 0.05 for all analyses.

Results

Characteristics of the CHAMACOS cohort are shown in Table 1. The cohort subjects were primarily born of mothers who were from Mexico, had less than a high school education, and lived in families with income at or below the federal poverty level. A total of 78% of pregnant mothers and about 70% of 5- and 7-year-olds lived in a household with at least one farm worker. The geometric mean (GM) of total DAP, DE, and DM specific gravity-adjusted concentrations during pregnancy were 147, 24, and 106 nmol/L, respectively (Table 2). Child creatinine-adjusted total DAP concentrations decreased with age, averaging 205, 233, 216, 152, and 131 nmol/g-creatinine at 0.5, 1, 2, 3.5, and 5 years of age, respectively (Table 2). The geometric mean (GM) of total DAP, DE, and DM creatinine-adjusted concentrations during childhood as measured by the AUC were 1,655, 259, and 1,281 nmol/ year/g-creatinine (Table 2). Maternal DAP metabolites were not correlated with childhood measurements (total DAPs: r = -0.01 to 0.01, p = 0.84 to 0.95; DEs: r = -0.07 to -0.01, p = 0.25 to 0.93; DMs: r = 0.00 to 0.02, p = 0.7 to 0.97). A total of 25.9% and 16.1% of 5- and 7-year-olds, respectively, were reported to have respiratory symptoms or to be taking controller or rescue medication during the previous 12 months (see Supplemental Material, Table S1). A total of 11.1% and 3.8% of 5- and 7-year-olds, respectively, were reported to have had to stop running or playing active games because of coughing that was not associated with a cold during the previous 12 months (i.e., exercise-induced coughing) (see Supplemental Material, Table S1).

Total average DAPs and DM urinary concentrations during pregnancy were not significantly associated with reported respiratory symptoms assessed at 5 and 7 years (Table 3). However, higher prenatal DE concentrations were nonsignificantly associated with increased odds of respiratory symptoms [adjusted odds ratio (aOR) for a 10-fold increase in concentration = 1.44; 95% confidence interval (CI): 0.98, 2.12, p = 0.07]. Prenatal total DAPs, DE, and DM concentrations were not significantly associated with exercise-induced coughing. Examining timing of exposure, we found no associations with DAP concentrations in the first half of pregnancy, but significantly increased odds of respiratory symptoms in the children with total DAPs and DE metabolites from the second half of pregnancy (aOR for a 10-fold increase in concentration = 1.77; 95% CI: 1.06, 2.95, p = 0.03; aOR = 1.61; 95% CI: 1.08, 2.39, p = 0.02, respectively) (Table 3). DM metabolites from the second half of pregnancy were not significantly associated with respiratory symptoms.

The concentrations of total DAPs, DEs, and DMs measured in child urine collected between the ages of 6 months and 5 years (AUC) were significantly associated with both reported respiratory symptoms and exercise-induced coughing at 5 and 7 years of age (total DAPs, aOR for a 10-fold increase in concentration = 2.53; 95% CI: 1.32, 4.86, p = 0.005 for symptoms; aOR = 5.40; 95% CI: 2.10, 13.91, p < 0.001, for coughing) (Table 4). Similar results were obtained when the AUC-based estimate of childhood exposure was derived for metabolite concentrations through 3.5 years of age only (see Supplemental Material, Table S2).

Similar results were obtained when we did not adjust maternal DAP concentrations for specific gravity or child AUC levels for creatinine and when the models included both prenatal and child AUC measures in the same model (data not shown).

Discussion

To our knowledge, the present study is the first prospective investigation of the relationship of prenatal and postnatal OP exposure and respiratory symptoms in children and the first study to investigate this relationship using a biomarker of exposure. Our results are consistent with findings from cross-sectional studies of associations between maternal report of early-life exposure to pesticides and asthma (Salam et al. 2004; Salameh et al. 2003). Our finding that prenatal exposure to OP pesticides as assessed by DAP metabolites in the second half of pregnancy, and particularly those that devolve to DE metabolites (e.g., chlorpyrifos, diazinon), is associated with increased odds of reported respiratory symptoms 5 to 7 years later is biologically plausible. OP pesticides can readily pass through the placenta (Rauh et al. 2006; Whyatt et al. 2009), and DAP metabolites can be found in amniotic fluid (Bradman et al. 2003). Furthermore, during the second half of pregnancy the alveoli are forming and surfactant is being synthesized; lung surfactant dysfunction is known to be related to the pathophysiology of asthma (Hameed et al. 2013; Wright et al. 2000).

We also found that postnatal exposure to OPs over the course of childhood was associated with higher odds of reported respiratory symptoms assessed at 5 and 7 years of age. These findings are consistent with previous results from our cohort, which showed that maternal work in agriculture during the child's first year of life was associated with increased levels at age 2 years of Th2 cytokines, which are thought to play an important role in the development of asthma (Duramad et al. 2006).

Use of DAP metabolites as a marker of OP exposure is both a strength and a limitation of our study. Assessing exposure to specific individual OP pesticides is challenging because there are sensitive and specific assays for only a few parent compounds in blood or pesticide-specific metabolites in urine (e.g., TCPy for chlorpyrifos). DAPs are nonspecific metabolites commonly used as biomarkers in epidemiological studies; they represent an integrated measure of exposure to many OPs, reflecting the usual scenario in agricultural communities (Chen et al. 2012; Sudakin and Stone 2011). However, because OP pesticides can break down into DAPs in the environment, urinary DAP concentrations may reflect exposure both to the parent pesticide compounds and to preformed DAPs in food or dust (Lu et al. 2005).

In addition, because exposure to OP pesticides is highly variable, DAP metabolite levels may fluctuate considerably from day to day. These sources for exposure misclassification are nondifferential, and we assume that exposure misclassification resulting in bias toward the null may have potentially occurred in this study. Bias toward the null has been also previously suggested for associations between DAP measurements and health effects in children (Bradman et al. 2013). However, we assessed exposure to OP pesticides by measuring DAPs in urines collected twice during pregnancy and five times throughout early childhood, providing a better estimate of early-life exposure than single measurements.

This study has other strengths, particularly its longitudinal design and relatively large sample size. Furthermore, we used the well-established validated ISAAC questionnaire to interview the mothers about their children's respiratory symptoms, and we adjusted for many covariates including exposure to other environmental agents and socioeconomic factors in the first year of life. Additionally, our study population was relatively homogeneous with regard to cultural and socioeconomic background, reducing the potential for uncontrolled confounding.

Our study was conducted within an agricultural community, and, as expected, the prenatal concentrations of urinary DAP metabolites in women from our study were higher than those in a representative U.S. sample of women of reproductive age (i.e., NHANES) (Bradman et al. 2005). In the current CHAMACOS study sample, the median of total maternal DAP concentrations among pregnant women was 127.5 nmol/L. NHANES median DAP levels, also measured between 1999 and 2000, were 72 nmol/L among pregnant women and 90 nmol/L among nonpregnant women of childbearing age (Bradman et al. 2005). Still, more than a quarter of the NHANES sample had DAP levels above the median levels measured in our current study, suggesting that the findings of this study have relevance for nonagricultural populations.

Conclusions

Prevention and control of pediatric chronic respiratory diseases is a global health priority (Samolinski et al. 2012; WHO 2007), and it has been suggested that prevention should begin before childbirth (Samolinski et al. 2012). Although indoor use of most OPs was phased out by the U.S. EPA during the early to mid-2000s, these pesticides are still widely used in agriculture (Grube et al. 2011; U.S. EPA 2013). Our findings suggest that early-life exposure to OP pesticides is associated with respiratory symptoms consistent with a possible diagnosis of asthma among a population of children of primarily Mexican origin and living in an agricultural community in California. More research is needed to determine whether our findings are generalizable to other study populations as well as to further assess the possibility of susceptible period(s) and the mechanisms by which OP exposure may affect respiratory system development. Future studies on potential early-life exposure to pesticides should consider more objective measures of respiratory health such as spirometry.

Received: 5 February 2014; Accepted: 3 November 2014; Advance Publication: 4 November 2014; Final Publication: 1 February 2015.

REFERENCES

Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. 1995. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 8(3):483-491; doi:10.1183/09031936.95.08030483.

Barnes PJ. 1986. Neural control of human airways in health and disease. Am Rev Respir Dis 134(6):1289-1314.

Bradman A, Barr DB, Claus Henn BG, Drumheller T, Curry C, Eskenazi B. 2003. Measurement of pesticides and other toxicants in amniotic fluid as a potential biomarker of prenatal exposure: a validation study. Environ Health Perspect 111:1779-1782; doi:10.1289/ehp.6259.

Bradman A, Eskenazi B, Barr DB, Bravo R, Castorina R, Chevrier J, et al. 2005. Organophosphate urinary metabolite levels during pregnancy and after delivery in women living in an agricultural community. Environ Health Perspect 113:1802-1807; doi:10.1289/ehp.7894.

Bradman A, Kogut K, Eisen EA, Jewell NP, Quiros-Alcala L, Castorina R, et al. 2013. Variability of Organophosphorous Pesticide metabolite levels in spot and 24-hr urine samples collected from young children during 1 week. Environ Health Perspect 121:118-124; doi:10.1289/ehp.1104808.

Bravo R, Driskell WJ, Whitehead RD Jr, Needham LL, Barr DB. 2002. Quantitation of dialkyl phosphate metabolites of organophosphate pesticides in human urine using GC-MS-MS with isotopic internal standards. J Anal Toxicol 26:245-252; doi:10.1093/jat/26.5.245.

Cavari Y, Lifshitz M, Leibson T, Shorer Z, Rubinstein M, Sofer S. 2013. Severe and uncommon complications of anticholinesterase intoxication in children [in Hebrew]. Harefuah 152(7):391-394.

CDC (Centers for Disease Control and Prevention). 2004. 2001-2002 National Health and Nutrition Examination Survey (NHANES). Atlanta, GA:Centers for Disease Control and Prevention, National Center for Health Statistics. Available: http://www.cdc.gov/nchs/about/major/nhanes/ datalink.htm [accessed 4 February 2014].

CDC (Centers for Disease Control and Prevention). 2009. Organophosphorus insecticides: dialkyl phosphate metabolites. In: Fourth National Report on Human Exposure to Environmental Chemicals. Atlanta, GA:Centers for Disease Control and Prevention, National Center for Health, Division of Laboratory Sciences, 117-133. Available: http:// www.cdc.gov/exposurereport/pdf/fourthreport.pdf [accessed 4 February 2014].

CDC (Centers for Disease Control and Prevention). 2014. Fourth National Report on Human Exposure to Environmental Chemicals, Updated Tables, August, 2014. Atlanta, GA:Centers for Disease Control and Prevention. Available: http://www.cdc.gov/ exposurereport/pdf/fourthreport_updatedtables_ aug2014.pdf [accessed 18 September 2014].

CDPR (California Department of Pesticide Regulation). 2001. Summary of Pesticide Use Report Data for 2001. Available: http://calpip.cdpr.ca.gov/year.cfm [accessed 4 February 2014].

Chen L, Zhao T, Pan C, Ross JH, Krieger RI. 2012. Preformed biomarkers including dialkylphosphates (DAPs) in produce may confound biomonitoring in pesticide exposure and risk assessment. J Agric Food Chem 60(36):9342-9351; doi:10.1021/jf303116p.

De Luca G, Olivieri F, Melotti G, Aiello G, Lubrano L, Boner AL. 2010. Fetal and early postnatal life roots of asthma. J Matern Fetal Neonatal Med 23(suppl 3):80-83; doi:10.3109/14767058.2010.509931.

Duramad P, Harley K, Lipsett M, Bradman A, Eskenazi B, Holland N, et al. 2006. Early environmental exposures and intracellular Th1/ Th2 cytokine profiles in 24-month-old children living in an agricultural area. Environ Health Perspect 114:1916-1922; doi:10.1289/ehp.9306.

Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C, et al. 2007. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect 115:792-798; doi:10.1289/ehp.9828.

Fryer AD, Lein PJ, Howard AS, Yost BL, Beckles RA, Jett DA. 2004. Mechanisms of organophosphate insecticide-induced airway hyperreactivity. Am J Physiol Lung Cell Mol Physiol 286:L963-L969; doi:10.1152/ajplung.00343.2003.

Grube A, Donaldson D, Kiely T, Wu L. 2011. Pesticides Industry Sales and Usage: 2006 and 2007 Market Estimates. Washington, DC: U.S. Environmental Protection Agency, Office of Chemical Safety and Pollution Prevention. Available: http://www.epa. gov/opp00001/pestsales/07pestsales/market_ estimates2007.pdf [accessed 4 February 2014].

Guha N, Ward MH, Gunier R, Colt JS, Lea CS, Buffler PA, et al. 2013. Characterization of residential pesticide use and chemical formulations through self-report and household inventory: the Northern California Childhood Leukemia Study. Environ Health Perspect 121:276-282; doi:10.1289/ ehp.1204926.

Hameed A, Sherkheli MA, Hussain A, Ul-haq R. 2013. Molecular and physiological determinants of pulmonary developmental biology: a review. Am J Biomed Res 1(1):13-24; doi:10.12691/ajbr-1-1-3.

Harley KG, Macher JM, Lipsett M, Duramad P, Holland NT, Prager SS, et al. 2009. Fungi and pollen exposure in the first months of life and risk of early childhood wheezing. Thorax 64(4):353-358; doi:10.1136/thx.2007.090241.

Hernan MA, Hernandez-Diaz S, Robins JM. 2004. A structural approach to selection bias. Epidemiology 15(5):615-625; doi:10.1097/01.ede.0000135174.63482.43.

Holguin F, Flores S, Ross Z, Cortez M, Molina M, Molina L. 2007. Traffic-related exposures, airway function, inflammation, and respiratory symptoms in children. Am J Respir Crit Care Med 176(12):1236-1242; doi:10.1164/rccm.200611-1616OC.

Hoppin JA, Umbach DM, London SJ, Lynch CF, Alavanja MCR, Sandler DP. 2006. Pesticides associated with wheeze among commercial pesticide applicators in the Agricultural Health Study. Am J Epidemiol 163:1129-1137; doi:10.1093/aje/kwj138.

Hubbard AE, Ahern J, Fleischer NL, Van der Laan M, Lippman SA, Jewell N, et al. 2010. To GEE or not to GEE: comparing population average and mixed models for estimating the associations between neighborhood risk factors and health. Epidemiology 21(4):467-474; doi:10.1097/EDE.0b013e3181caeb90.

Kraai S, Verhagen LM, Valladares E, Goecke J, Rasquin L, Colmenares P. 2013. High prevalence of asthma symptoms in Warao Amerindian children in Venezuela is significantly associated with open-fire cooking: a cross-sectional observational study. Respir Res 14(1):76; doi:10.1186/1465-9921-14-76.

Kwak ES, Just A, Whyatt R, Miller RL. 2009. Phthalates, pesticides, and bisphenol-A exposure and the development of nonoccupational asthma and allergies: how valid are the links? Open Allergy J 2:45-50; doi:10.2174/1874838400902010045.

Lein PJ, Fryer AD. 2005. Organophosphorus insecticides induce airway hyperreactivity by decreasing neuronal M2 muscarinic receptor function independent of acetylcholinesterase inhibition. Toxicol Sci 83:166-176; doi:10.1093/toxsci/kfi001.

Lu C, Bravo R, Caltabiano LM, Irish RM, Weerasekera G, Barr DB. 2005. The presence of dialkylphosphates in fresh fruit juices: implication for organophosphorus pesticide exposure and risk assessments. J Toxicol Environ Health A 68(3):209-227; doi:10.1080/15287390590890554.

Mellon M, Parasuraman B. 2004. Pediatric asthma: improving management to reduce cost of care. J Manag Care Pharm 10(2):130-141.

Ndlovu V, Dalvie MA, Jeebhay MF. 2011. Pesticides and the airways--a review of the literature. Curr Allergy Clin Immunol 24(4):212-217.

Pawankar R, Canonica GW, Holgate ST, Lockey RF, eds. 2011. WAO White Book on Allergy. Milwaukee, WI:World Allergy Organization, 1-216. Available: http://www.worldallergy.org/UserFiles/file/ WAO-White-Book-on-Allergy_web.pdf [accessed 4 February 2014].

Pijnenburg MW. 2012. Pediatric asthma: where to go? Eur Respir Rev 21 (1 25): 1 73-174; doi:10.1183/09059180.00004012.

Proskocil BJ, Bruun DA, Jacoby DB, van Rooijen N, Lein PJ, Fryer AD. 2013. Macrophage TNF[alpha] mediates parathion-induced airway hyperreactivity in guinea pigs. Am J Physiol Lung Cell Mol Physiol 304(8):519-529; doi:10.1152/ajplung.00381.2012.

Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB, et al. 2006. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics 118:e1845-e1859; doi:10.1542/peds.2006-0338.

Salam MT, Li YF, Langholz B, Gilliland FD, Children's Health Study. 2004. Early-life environmental risk factors for asthma: findings from the Children's Health Study. Environ Health Perspect 112:760-765; doi:10.1289/ehp.6662.

Salameh P, Baldi I, Brochard P, Raherison C, Abi Saleh B, Salamon R. 2003. Respiratory symptoms in children and exposure to pesticides. Eur Respir J 22:507-512; doi:10.1183/09031936.03.00107403a.

Samolinski B, Fronczak A, Wtodarczyk A, Bousquet J. 2012. Council of the European Union conclusions on chronic respiratory diseases in children. Lancet 379(9822):e45-e46; doi:10.1016/S0140-6736(12)60514-5.

Selgrade MK, Blain RB, Fedak KM, Cawley, MA. 2013. Potential risk of asthma associated with in utero exposure to xenobiotics. Birth Defects Res C Embryo Today 99(1):1-13; doi:10.1002/bdrc.21028.

Stellman SD, Thomas PA, Osahan S, Brackbill RM, Farfel MR. 2013. Respiratory health of 985 children exposed to the World Trade Center disaster: report on World Trade Center Health Registry wave 2 follow-up, 2007-2008. J Asthma 50(4):354-363; doi:10.3109/02770903.2013.776073.

Stocks J, Sonnappa S. 2013. Early life influences on the development of chronic obstructive pulmonary disease. Ther Adv Respir Dis 7(3):161-173; doi:10.1177/1753465813479428.

Sudakin DL, Stone DL. 2011. Dialkyl phosphates as biomarkers of organophosphates: the current divide between epidemiology and clinical toxicology. Clin Toxicol (Phila) 49(9):771-781; doi:10.3109/15563650. 2011.624101.

U.S. EPA (U.S. Environmental Protection Agency). 2013. Pesticide Registration Status for Organophosphates. Available: http://www.epa.gov/pesticides/ reregistration/status.htm [accessed 4 February 2014].

van der Laan MJ, Polley EC, Hubbard AE. 2007. Super Learner. U.C. Berkeley Division of Biostatistics Working Paper Series, 2007: Working Paper 222. Available: http://biostats.bepress.com/ucbbiostat/ paper222 [accessed 4 February 2014].

WHO (World Health Organization). 2007. Global Surveillance, Prevention and Control of Chronic Respiratory Diseases: A Comprehensive Approach (Bousquet J, Khaltaev NG, eds). Available: http:// www.who.int/gard/publications/GARD_Manual/ en/ [accessed 4 February 2014].

Whyatt RM, Garfinkel R, Hoepner LA, Andrews H, Holmes D, Williams MK, et al. 2009. A biomarker validation study of prenatal chlorpyrifos exposure within an inner-city cohort during pregnancy. Environ Health Perspect 117:559-567; doi:10.1289/ ehp.0800041.

Wright SM, Hockey PM, Enhorning G, Strong P, Reid KB, Holgate ST, et al. 2000. Altered airway surfactant phospholipid composition and reduced lung function in asthma. J Appl Physiol (1985) 89(4):1283-1292.

Zeger SL, Liang KY. 1986. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42:121-130.

Rachel Raanan, (1) Kim G. Harley, (1) John R. Balmes, (2,3) Asa Bradman, (1) Michael Lipsett, (4) and Brenda Eskenazi (1)

(1) Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California, Berkeley, California, USA; (2) Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, California, USA; (3) Divison of Occupational and Environmental Medicine, University of California, San Francisco, San Francisco, California, USA; (4) California Department of Public Health, Richmond, California, USA

Address correspondence to R. Raanan, Center for Environmental Research and Children's Health (CERCH), UC Berkeley School of Public Health, 1995 University Ave., Suite 265, Berkeley, CA 94704 USA. Telephone: (510) 642-9431. E-mail: rachelraananrr@gmail.com

Supplemental Material is available online (http:// dx.doi.org/10.1289/ehp.1408235).

We thank the CHAMACOS staff, students, community partners, and participants and families, without whom this study would not be possible. We especially thank M. Vedar, R. Gunier, the CHAMACOS field office staff as well as N. Holland and the staff of the UC Berkeley School of Public Health Biorepository for their assistance in specimen management and D. Barr and her staff at the CDC for the measurements of urinary dialkyl phosphate metabolites.

This work was supported by the grants 2P01ES009605 from the National Institute of Environmental Health Sciences and RD-82670901, RD-83171001, and RD-83451301 from the U.S. EPA (B.E.), and by a post-doctoral fellowship from the Environment and Health Fund, Jerusalem, Israel

(R.R.).

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the funders.

A.B. has served as a consultant on cases unrelated to the issues covered in this paper and has participated as a member of the Science Advisory Board for The Organic Center, a nonprofit organization that provides information for scientific research about organic food and farming. J.R.B. is the physician member of the California Air Resources Board, a paid position. The other authors declare they have no actual or potential competing financial interests.
Table 1. Sociodemographic and household characteristics, CHAMACOS
cohort, California (n = 364).

Characteristic                                  n (%)

Child's sex
  Boys                                        174 (47.8)
  Girls                                       190 (52.2)
Season of birth
  Mold                                        131 (36.0)
  Wet                                          68 (18.7)
  Pollen                                       80 (22.0)
  Dry                                          85 (23.3)
Breastfeeding duration
  Never breastfed                              17 (4.7)
  [less than or equal to] 6 months            174 (47.8)
  > 6 months                                  173 (47.5)
Mother's country of birth
  Mexico                                      314 (86.2)
  United States                                45 (12.4)
  Other                                         5 (1.4)
Maternal education
  [less than or equal to] 6th grade           166 (45.6)
  7-12th grade                                125 (34.3)
  Completed high school                        73 (20.1)
Maternal history of asthma
  Yes                                          17 (4.7)
  No                                          346 (95.3)
Mother smoked during pregnancy
  Yes                                          15 (4.1)
  No                                          349 (95.9)
Agricultural workers in the household
    during pregnancy
  Yes                                         283 (77.8)
  No                                           81 (22.3)
Family income at 5 and 7 years
  < Poverty level                             294 (80.8)
  [greater than or equal to]                   70 (19.2)
    Poverty level
Infant around smokers (0-12 months)
  Yes                                          29 (8.1)
  No                                          329 (91.9)
Home < 150 m from highway (6 or 12 months)
  Yes                                          17 (5.1)
  No                                          319 (94.9)
Mean daily PM2 5 near home (0-3 months)
  < 8 [micro]g/[m.sup.3]                      175 (48.1)
  8-12 [micro]g/[m.sup.3]                     149 (40.9)
  [greater than or equal to]                   40 (11.0)
    12 [micro]g/[m.sup.3]
Signs of rodents at home visit
    (6 or 12 months)
  Yes                                         141 (42.0)
  No                                          195 (58.0)
Signs of cockroaches at home visit
    (6 or 12 months)
  Yes                                         224 (66.7)
  No                                          112 (33.3)
Signs of moderate/extensive mold at
    home visit (6 or 12 months)
  Yes                                         220 (65.5)
  No                                          116 (34.5)
Gas stove in home (6 or 12 months)
  Yes                                         298 (83.2)
  No                                           60 (16.8)
Agricultural workers in the
    household at 5 years
  Yes                                         241 (70.1)
  No                                          103 (29.9)
Agricultural workers in the
    household at 7 years
  Yes                                         235 (67.7)
  No                                          112 (32.3)

A total of 344 and 347 children were assessed at 5 and 7 years,
respectively. A total of 327 children were assessed for
respiratory symptoms at both time points (at 5 and 7 years of
age), and 364 children were assessed at least once. Information
was missing for the following covariates: maternal history of
asthma (n = 1), infant around smokers (n = 6), distance of home
from highway (n = 28), signs of rodents, cockroaches, and mold (6
or 12 months; n = 28), and gas stove at home (n = 6).

Table 2. DAP metabolite concentrations, measured in maternal
urine during pregnancy (nmol/L) and in children's urine at
follow/up visits (nmol/g-creatinine) between 0.5 and 5 years of
age, CHAMACOS.

Measurements of            n      DF (%)     GM (95% CI)
pregnancy (nmol/L)

First half of pregnancy
 Total DAPs                262     90.1        111 (93, 133)
  DE                       262     76.7         16 (13, 19)
  DM                       262     84.0         74 (61, 90)
Second half of pregnancy
  Total DAPs               338     99.4        126 (113, 141)
  DE                       338     98.2         21 (18, 24)
  DM                       339     99.4         86 (76, 97)
Pregnancy average
  Total DAPs               359      100        147 (132, 163)
  DE                       359      100         24 (21, 27)
  DM                       360      100        106 (94, 119)
At 6 months
  Total DAPs               320     99.1        205 (172, 243)
  DE                       320     89.7         38 (31, 47)
  DM                       320     88.8         97 (79, 119)
At 1 year
  Total DAPs               331     95.8        233 (197, 275)
  DE                       331     93.1         61 (53, 70)
  DM                       331     79.5        112 (91, 139)
At 2 years
  Total DAPs               325     96.3        216 (183, 254)
  DE                       325     71.4         23 (18, 30)
  DM                       325     96.0        148 (125, 176)
At 3.5 years
  Total DAPs               262     94.3        152 (126, 184)
  DE                       262     60.3          5 (4, 7)
  DM                       262     92.8        125 (103, 152)
At 5 years
  Total DAPs               313     91.4        131 (110, 156)
  DE                       313     52.4          3 (2, 4)
  DM                       313     88.5        102 (85, 123)
AUC (0.5-5 years;
    nmol/year/g-crt)
  Total DAPs               278   91.0-98.9   1,655 (1,482, 1,849)
  DE                       278   52.5-92.3     259 (229, 292)
  DM                       278   78.0-96.7   1,281 (1,139, 1,440)

Measurements of            Minimum   25th      50th    75th
pregnancy (nmol/L)

First half of pregnancy
 Total DAPs                  4        40         107     312
  DE                         0.2       6          13      39
  DM                         2        21          75     234
Second half of pregnancy
  Total DAPs                 6        68         123     235
  DE                         0.7       8          22      51
  DM                         2        40          88     175
Pregnancy average
  Total DAPs                10        75         141     301
  DE                         0.4      11          25      51
  DM                         5        51          97     231
At 6 months
  Total DAPs                 2        76         184     608
  DE                         0.1      13          56     132
  DM                         0.7      29          84     338
At 1 year
  Total DAPs                 4        80         222     655
  DE                         0.8      31          69     140
  DM                         0.8      28         118     484
At 2 years
  Total DAPs                 3        93         223     592
  DE                         0.0       3          47     120
  DM                         2        53         158     435
At 3.5 years
  Total DAPs                 2        53         174     448
  DE                         0.0       0.6        11      52
  DM                         2        43         141     348
At 5 years
  Total DAPs                 0.9      47         148     346
  DE                         0.0       0.3         6      42
  DM                         0.8      40         113     288
AUC (0.5-5 years;
    nmol/year/g-crt)
  Total DAPs               118       836       1,636   3,048
  DE                        14       136         251     529
  DM                        79       605       1,244   2,510

Measurements of            90th    Maximum
pregnancy (nmol/L)

First half of pregnancy
 Total DAPs                  826    5,026
  DE                          95    2,436
  DM                         622    5,019
Second half of pregnancy
  Total DAPs                 499    2,366
  DE                         124      630
  DM                         388    3,175
Pregnancy average
  Total DAPs                 577    2,555
  DE                          99    1,245
  DM                         504    3,175
At 6 months
  Total DAPs               1,702   78,235
  DE                         292   78,010
  DM                       1,511   10,073
At 1 year
  Total DAPs               1,752   10,552
  DE                         254    1,972
  DM                       1,223   10,298
At 2 years
  Total DAPs               1,389    5,943
  DE                         324    3,926
  DM                       1,009    5,843
At 3.5 years
  Total DAPs                 933    9,240
  DE                         146      546
  DM                         867    8,694
At 5 years
  Total DAPs                 840   10,085
  DE                         113      634
  DM                         772   10,052
AUC (0.5-5 years;
    nmol/year/g-crt)
  Total DAPs               6,335   18,927
  DE                         966   16,580
  DM                       5,636   15,460

Abbreviations: crt, creatinine; DF, detection frequency. 25th,
50th, 75th, and 90th are percentiles. Limits of detection for all
DE analytes ranged from 0.05 to 0.2 [micro]g/L, and for all DM
analytes, 0.08 to 0.58 [micro]g/L. Pregnancy measurements were
specific gravity adjusted, and childhood measurements were
creatinine adjusted.

Table 3. Associations [aOR (95% CI)] (a,b) of repeated measures
of respiratory outcomes at 5 and 7 years of age with maternal
urinary DAP metabolites (nmol/L) collected at pregnancy. (c,d)

Timing of           n      Respiratory       p-Value
measurement                  symptoms

First half
    of pregnancy
  Total DAPs       241   1.11 (0.72, 1.72)   0.63
  DEs              241   1.03 (0.64, 1.65)   0.91
  DMs              241   1.08 (0.74, 1.58)   0.69
Second half
    of pregnancy
  Total DAPs       313   1.77 (1.06, 2.95)   0.03
  DEs              313   1.61 (1.08, 2.39)   0.02
  DMs              313   1.45 (0.90, 2.33)   0.12
Pregnancy
    average (4)
  Total DAPs       331   1.28 (0.77, 2.13)   0.34
  DEs              331   1.44 (0.98, 2.12)   0.07
  DMs              331   1.17 (0.74, 1.85)   0.5

Timing of          Exercise-induced    p-Value
measurement          coughing (e)

First half
    of pregnancy
  Total DAPs       1.24 (0.58, 2.66)    0.59
  DEs              0.86 (0.46, 1.60)    0.64
  DMs              1.19 (0.60, 2.37)    0.62
Second half
    of pregnancy
  Total DAPs       1.25 (0.50, 3.11)    0.64
  DEs              1.20 (0.70, 2.04)    0.50
  DMs              1.28 (0.56, 2.94)    0.56
Pregnancy
    average (4)
  Total DAPs       1.14 (0.47, 2.74)    0.77
  DEs              0.94 (0.57, 1.57)    0.82
  DMs              1.24 (0.57, 2.71)    0.58

(a) Adjusted for child's sex and exact age, maternal smoking
during pregnancy, infant (0-12 months) being around smokers,
season of birth (mold-wet-pollen-dry), mean daily [PM.sub.2.5]
during first 3 months of life, breastfeeding duration, signs of
moderate-extensive mold at home visit (6 or 12 months), distance
(< 150 m) from highway (6 or 12 months), and signs of cockroaches
at home visit (6 or 12 months). (b) Adjusted odds ratios reflect
change per 10-fold increase in metabolite concentrations (the
metabolites were modeled as [log.sub.10]-transformed variables).
(c) Urinary measurements were adjusted for specific gravity.
After excluding mothers with missing covariate data, specific
gravity-adjusted DAP concentrations were available for 241
mothers during the first half of pregnancy and for 313 mothers
during the second half of pregnancy. (d) Pregnancy average is
derived from the average of the two measurements taken during
pregnancy; for mothers who did not have both measurements, the
average reflects the single measurement available. (e) Any report
on respiratory symptoms including exercise-induced coughing was
also included under the respiratory symptoms variable; i.e., all
children classified as positive for exercise-induced coughing
were also classified as having respiratory symptoms.

Table 4. Repeated measures of respiratory outcomes at ages 5 and
7 associated with the AUC of urinary DAP metabolites (nmol/
g-creatinine) measured between 0.5 and 5 years of age [aOR (95%
CI)]. (a,b)

Childhood    n        Respiratory      p-Value
AUC                    symptoms

Total DAPs   270   2.53 (1.32, 4.86)   0.005
DEs          270   2.35 (1.27, 4.34)   0.006
DMs          270   2.17 (1.19, 3.98)   0.01

Childhood     Exercise-induced    p-Value
AUC             coughing (a)

Total DAPs   5.40 (2.10, 13.91)   < 0.001
DEs          3.62 (1.38, 9.55)      0.009
DMs          4.46 (1.81, 10.98)     0.001

(a) Adjusted for child's sex and exact age, maternal smoking
during pregnancy, infant (0-12 months) being around smokers,
season of birth (mold-wet-pollen-dry), mean daily [PM.sub.2.5]
during first 3 months of life, breastfeeding duration, signs of
moderate-extensive mold at home visit (6 or 12 months), distance
([less than or equal to] 150 m) from highway (6 or 12 months),
and signs of cockroaches at home visit (6 or 12 months). (b)
Adjusted odds ratios reflect change per 10-fold increase in
metab-olite concentrations (nmol-year-g creatinine) between 0.5
and 5 years of age as assessed by the AUC to summarize DAP
concentrations over time during childhood (the metabolites were
modeled as [log.sub.10]-transformed variables). For the AUC
analysis (n = 270), we excluded children who did not have an AUC
calculation (due to missing DAP measurements) and children with
missing covariate data. (c) Any report on respiratory symptoms
including exercise-induced coughing was also included under the
respiratory symptoms variable; i.e., all children classified as
positive for exercise-induced coughing were also classified as
having respiratory symptoms.
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Title Annotation:Research: Children's Health
Author:Raanan, Rachel; Harley, Kim G.; Balmes, John R.; Bradman, Asa; Lipsett, Michael; Eskenazi, Brenda
Publication:Environmental Health Perspectives
Article Type:Report
Geographic Code:7ISRA
Date:Feb 1, 2015
Words:7705
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