Prenatal Organophosphorus Pesticide Exposure and Child Neurodevelopment at 24 Months: An Analysis of Four Birth Cohorts

Stephanie M Engel, Asa Bradman, Mary S Wolff, Virginia A Rauh, Kim G Harley, Jenny H Yang, Lori A Hoepner, Dana Boyd Barr, Kimberly Yolton, Michelle G Vedar, Yingying Xu, Richard W Hornung, James G Wetmur, Jia Chen, Nina T Holland, Frederica P Perera, Robin M Whyatt, Bruce P Lanphear, Brenda Eskenazi, Stephanie M Engel, Asa Bradman, Mary S Wolff, Virginia A Rauh, Kim G Harley, Jenny H Yang, Lori A Hoepner, Dana Boyd Barr, Kimberly Yolton, Michelle G Vedar, Yingying Xu, Richard W Hornung, James G Wetmur, Jia Chen, Nina T Holland, Frederica P Perera, Robin M Whyatt, Bruce P Lanphear, Brenda Eskenazi

Abstract

Background: Organophosphorus pesticides (OPs) are used in agriculture worldwide. Residential use was common in the United States before 2001.

Objectives: We conducted a pooled analysis of four birth cohorts (children's centers; n = 936) to evaluate associations of prenatal exposure to OPs with child development at 24 months.

Methods: Using general linear models, we computed site-specific and pooled estimates of the association of total dialkyl (ΣDAP), diethyl (ΣDEP), and dimethylphosphate (ΣDMP) metabolite concentrations in maternal prenatal urine with mental and psychomotor development indices (MDI/PDI) and evaluated heterogeneity by children's center, race/ethnicity, and PON1 genotype.

Results: There was significant heterogeneity in the center-specific estimates of association for ΣDAP and ΣDMP and the MDI (p = 0.09, and p = 0.05, respectively), as well as heterogeneity in the race/ethnicity-specific estimates for ΣDAP (p = 0.06) and ΣDMP (p = 0.02) and the MDI. Strong MDI associations in the CHAMACOS population per 10-fold increase in ΣDAP (β = -4.17; 95% CI: -7.00, -1.33) and ΣDMP (β = -3.64; 95% CI: -5.97, -1.32) were influential, as were associations among Hispanics (β per 10-fold increase in ΣDAP = -2.91; 95% CI: -4.71, -1.12). We generally found stronger negative associations of ΣDAP and ΣDEP with the 24-month MDI for carriers of the 192Q PON1 allele, particularly among blacks and Hispanics.

Conclusions: Data pooling was complicated by center-related differences in subject characteristics, eligibility, and changes in regulations governing residential use of OPs during the study periods. Pooled summary estimates of prenatal exposure to OPs and neurodevelopment should be interpreted with caution because of significant heterogeneity in associations by center, race/ethnicity, and PON1 genotype. Subgroups with unique exposure profiles or susceptibilities may be at higher risk for adverse neurodevelopment following prenatal exposure.

Citation: Engel SM, Bradman A, Wolff MS, Rauh VA, Harley KG, Yang JH, Hoepner LA, Barr DB, Yolton K, Vedar MG, Xu Y, Hornung RW, Wetmur JG, Chen J, Holland NT, Perera FP, Whyatt RM, Lanphear BP, Eskenazi B. 2016. Prenatal organophosphorus pesticide exposure and child neurodevelopment at 24 months: an analysis of four birth cohorts. Environ Health Perspect 124:822-830; http://dx.doi.org/10.1289/ehp.1409474.

Conflict of interest statement

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 Board for The Organic Center, a nonprofit organization that provides information for scientific research about organic food and farming. The other authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
Distributions of dialkylphosphate metabolite sums in individual cohorts. The 25th, 50th, and 75th percentiles by center are represented by the lower, middle, and upper bars in the central boxes. The arithmetic mean by center is marked by the open diamond. Outliers at the upper and lower end of the exposure distribution are indicated by circles. Whiskers indicate 95% CIs.
Figure 2
Figure 2
Restricted cubic splines for log10 ∑DAP association with the 24-month MDI in the (A) CHAMACOS cohort, (B) HOME cohort, (C) Columbia cohort, (D) Mount Sinai cohort, and (E) pooled population. Splines demonstrate a roughly linearly declining relationship in the individual cohorts and the overall pooled population below approximately 2 nmol/g creatinine, which attenuates at higher concentrations. Although the HOME (B) and Columbia (C) cohorts appear to show a U-shape curve, the 95% CIs (dashed lines) demonstrate substantial imprecision around these estimates.

References

    1. Barr DB, Allen R, Olsson AO, Bravo R, Caltabiano LM, Montesano A, et al. Concentrations of selective metabolites of organophosphorus pesticides in the United States population. Environ Res. 2005;99(3):314–326.
    1. Barr DB, Wong LY, Bravo R, Weerasekera G, Odetokun M, Restrepo P, et al. Urinary concentrations of dialkylphosphate metabolites of organophosphorus pesticides: National Health and Nutrition Examination Survey 1999–2004. Int J Environ Res Public Health. 2011;8(8):3063–3098.
    1. Bayley N. San Antonio, TX: Harcourt Brace & Company; 1993. Bayley Scales of Infant Development. 2nd ed.
    1. Berkowitz GS, Obel J, Deych E, Lapinski R, Godbold J, Liu Z, et al. 2003. Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort. Environ Health Perspect 111 79 84, doi:10.1289/ehp.5619
    1. Berkowitz GS, Wetmur JG, Birman-Deych E, Obel J, Lapinski RH, Godbold JH, et al. 2004. In utero pesticide exposure, maternal paraoxonase activity, and head circumference. Environ Health Perspect 112 388 391, doi:10.1289/ehp.6414
    1. Bravo R, Caltabiano LM, Weerasekera G, Whitehead RD, Fernandez C, Needham LL, et al. Measurement of dialkyl phosphate metabolites of organophosphorus pesticides in human urine using lyophilization with gas chromatography-tandem mass spectrometry and isotope dilution quantification. J Expo Anal Environ Epidemiol. 2004;14(3):249–259.
    1. Caldwell BM, Bradley RH. Little Rock, AR: University of Arkansas at Little Rock; 1984. Administration Manual: Home Observation For Measurement of the Environment. Revised ed.
    1. Chen A, Yolton K, Rauch SA, Webster GM, Hornung R, Sjödin A, et al. 2014. Prenatal polybrominated diphenyl ether exposures and neurodevelopment in U.S. children through 5 years of age: the HOME Study. Environ Health Perspect 122 856 862, doi:10.1289/ehp.1307562
    1. Chen J, Chan W, Wallenstein S, Berkowitz G, Wetmur JG. Haplotype-phenotype relationships of paraoxonase-1. Cancer Epidemiol Biomarkers Prev. 2005;14(3):731–734.
    1. Chen J, Kumar M, Chan W, Berkowitz G, Wetmur JG. 2003. Increased influence of genetic variation on PON1 activity in neonates. Environ Health Perspect 111 1403 1409, doi:10.1289/ehp.6105
    1. Chen L, Zhao T, Pan C, Ross JH, Krieger RI. Preformed biomarkers including dialkylphosphates (DAPs) in produce may confound biomonitoring in pesticide exposure and risk assessment. J Agric Food Chem. 2012;60(36):9342–9351.
    1. Cole SR, Hernán MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol. 2008;168(6):656–664.
    1. Costa LG, Richter RJ, Li WF, Cole T, Guizzetti M, Furlong CE. Paraoxonase (PON 1) as a biomarker of susceptibility for organophosphate toxicity. Biomarkers. 2003;8(1):1–12.
    1. Curl CL, Fenske RA, Kissel JC, Shirai JH, Moate TF, Griffith W, et al. Evaluation of take-home organophosphorus pesticide exposure among agricultural workers and their children. Environ Health Perspect. 2002;110:A787–A792.
    1. Desquilbet L, Mariotti F. Dose-response analyses using restricted cubic spline functions in public health research. Stat Med. 2010;29(9):1037–1057.
    1. Deziel NC, Friesen MC, Hoppin JA, Hines CJ, Thomas K, Freeman LE. 2015. A review of nonoccupational pathways for pesticide exposure in women living in agricultural areas. Environ Health Perspect 123 515 524, doi:10.1289/ehp.1408273
    1. Engel SM, Berkowitz GS, Barr DB, Teitelbaum SL, Siskind J, Meisel SJ, et al. Prenatal organophosphate metabolite and organochlorine levels and performance on the Brazelton Neonatal Behavioral Assessment Scale in a multiethnic pregnancy cohort. Am J Epidemiol. 2007;165(12):1397–1404.
    1. Engel SM, Wetmur J, Chen J, Zhu C, Barr DB, Canfield RL, et al. 2011. Prenatal exposure to organophosphates, paraoxonase 1, and cognitive development in childhood. Environ Health Perspect 119 1182 1188, doi:10.1289/ehp.1003183
    1. Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell NP, Barr DB, et al. 2004. Association of in utero organophosphate pesticide exposure and fetal growth and length of gestation in an agricultural population. Environ Health Perspect 112 1116 1124, doi:10.1289/ehp.6789
    1. 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
    1. Fukuto TR. Mechanism of action of organophosphorus and carbamate insecticides. Environ Health Perspect. 1990;87:245–254.
    1. Grube A, Donaldson D, Kiely T, Wu L. Washington, DC: U.S. Environmental Protection Agency; 2011. Pesticides Industry Sales and Usage: 2006 and 2007 Market Estimates. EPA 733-R-11-001.
    1. Holland N, Furlong C, Bastaki M, Richter R, Bradman A, Huen K, et al. 2006. Paraoxonase polymorphisms, haplotypes, and enzyme activity in Latino mothers and newborns. Environ Health Perspect 114 985 991, doi:10.1289/ehp.8540
    1. Icenogle LM, Christopher NC, Blackwelder WP, Caldwell DP, Qiao D, Seidler FJ, et al. Behavioral alterations in adolescent and adult rats caused by a brief subtoxic exposure to chlorpyrifos during neurulation. Neurotoxicol Teratol. 2004;26(1):95–101.
    1. Levin ED, Addy N, Baruah A, Elias A, Christopher NC, Seidler FJ, et al. Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations. Neurotoxicol Teratol. 2002;24(6):733–741.
    1. Lu C, Bravo R, Caltabiano LM, Irish RM, Weerasekera G, Barr DB. The presence of dialkylphosphates in fresh fruit juices: implication for organophosphorus pesticide exposure and risk assessments. J Toxicol Environ Health A. 2005;68(3):209–227.
    1. Martin JA, Hamilton BE, Osterman MJK, Curtin SC, Mathews TJ. Births: Final Data for 2013. Natl Vital Stat Rep. 2015;64(1):1–65.
    1. Quirós-Alcalá L, Bradman A, Smith K, Weerasekera G, Odetokun M, Barr DB, et al. Organophosphorous pesticide breakdown products in house dust and children’s urine. J Expo Sci Environ Epidemiol. 2012;22(6):559–568.
    1. Rauch SA, Braun JM, Barr DB, Calafat AM, Khoury J, Montesano AM, et al. 2012. Associations of prenatal exposure to organophosphate pesticide metabolites with gestational age and birth weight. Environ Health Perspect 120 1055 1060, doi:10.1289/ehp.1104615
    1. Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB, et al. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics. 2006;118(6):e1845–e1859.
    1. Ray DE, Richards PG. The potential for toxic effects of chronic, low-dose exposure to organophosphates. Toxicol Lett. 2001;120(1–3):343–351.
    1. Ricceri L, Markina N, Valanzano A, Fortuna S, Cometa MF, Meneguz A, et al. Developmental exposure to chlorpyrifos alters reactivity to environmental and social cues in adolescent mice. Toxicol Appl Pharmacol. 2003;191(3):189–201.
    1. Spaan S, Pronk A, Koch HM, Jusko TA, Jaddoe VW, Shaw PA, et al. Reliability of concentrations of organophosphate pesticide metabolites in serial urine specimens from pregnancy in the Generation R Study. J Expo Sci Environ Epidemiol. 2015;25(3):286–294.
    1. Timofeeva OA, Roegge CS, Seidler FJ, Slotkin TA, Levin ED. Persistent cognitive alterations in rats after early postnatal exposure to low doses of the organophosphate pesticide, diazinon. Neurotoxicol Teratol. 2008;30(1):38–45.
    1. U.S. EPA (U.S. Environmental Protection Agency) Washington, DC: U.S. EPA, Office of Pesticide Programs; 2000. Chlorpyrifos. Revised Risk Assessment and Agreement with Registrants.
    1. U.S. EPA. Washington DC: U.S. EPA, Office of Pesticide Programs; 2001. Diazinon Revised Risk Assessment and Agreement with Registrants.
    1. Vatanparast J, Naseh M, Baniasadi M, Haghdoost-Yazdi H. Developmental exposure to chlorpyrifos and diazinon differentially affect passive avoidance performance and nitric oxide synthase-containing neurons in the basolateral complex of the amygdala. Brain Res. 2013;1494:17–27.
    1. Westreich D, Cole SR. Invited commentary: positivity in practice. Am J Epidemiol. 2010;171(6):674–677.
    1. Wetmur JG, Kumar M, Zhang L, Palomeque C, Wallenstein S, Chen J. Molecular haplotyping by linking emulsion PCR: analysis of paraoxonase 1 haplotypes and phenotypes. Nucleic Acids Res. 2005;33(8):2615–2619.
    1. Whyatt RM, Camann D, Perera FP, Rauh VA, Tang D, Kinney PL, et al. Biomarkers in assessing residential insecticide exposures during pregnancy and effects on fetal growth. Toxicol Appl Pharmacol. 2005;206(2):246–254.
    1. Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, et al. 2004. Prenatal insecticide exposures and birth weight and length among an urban minority cohort. Environ Health Perspect 112 1125 1132, doi:10.1289/ehp.6641
    1. Yolton K, Xu Y, Sucharew H, Succop P, Altaye M, Popelar A, et al. 2013. Impact of low-level gestational exposure to organophosphate pesticides on neurobehavior in early infancy: a prospective study. Environ Health 12 1 79, doi:10.1186/1476-069X-12-79
    1. Zhang X, Driver JH, Li Y, Ross JH, Krieger RI. Dialkylphosphates (DAPs) in fruits and vegetables may confound biomonitoring in organophosphorus insecticide exposure and risk assessment. J Agric Food Chem. 2008;56(22):10638–10645.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit