Pesticide Toxicity and the Developing Brain - Environmental Health ...

© 2008 The AuthorsJournal compilation © 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 228–236Table 1.Summary of literature on organochlorine pesticide exposure and neurodevelopment in children. Average exposure levels are indicated where available.Author, year Population Exposure Outcome ResultsRogan et al. 1986 [8] n = 912 neonates ≤1 month oldBirth cohort from three healthcenters in North CarolinaBrazelton Neonatal BehavioralAssessment Scale (BNBAS)Gladen et al. 1988 [12]Rogan et al. 1991 [13]Gladen et al. 1991 [14]Stewart et al. 2000 [9]Darvill et al. 2000 [15]Ribas-Fitó et al.2003 [16]n = 858 children followedfrom birth to 1 yearBirth cohort from threehealth centers in North Carolinan = 676–18 monthsn = 670–24 monthsBirth cohort from three healthcenters in North Carolinan = 645–3 yearsn = 628–4 yearsn = 636–5 yearsn = 506 (report cards)Birth cohort from three healthcenters in North Carolinan = 141 exposed ≤2 days oldn = 152 unexposed(Oswego birth cohort)Exposure groups based onmaternal report of LakeOntario lifetime fishconsumption ≥40 lbs.Same cohort as in Stewart et al.• 230 at 6 months old• 219 at 12 months oldn = 92 infants 13 months oldBirth cohort living near anelectrochemical factory inSpainDDE – placenta, maternaland cord serum and milk/colostrums combined intoone measure/woman• Median ~2 p.p.m. in milk fatDDE – placenta, maternal andcord serum (prenatal exposure)and milk/colostrums(postnatal exposure)DDE – placenta, maternaland cord serum (prenatalexposure) and milk/colostrums(postnatal exposure)DDE – placenta, maternaland cord serum (prenatalexposure) and milk/colostrums(postnatal exposure)Cord serum levels DDE(median = 0.10 ng/g wet),HCB, MirexCord serum levels DDE, HCB,Mirex; breast milk on a subgroup(the primary exposure was PCB)Cord serum DDE (median =0.85 ng/mL) and HCBBayley Scales of InfantDevelopment (BSID-II):• Mental Development Index (MDI)• Psychomotor DevelopmentIndex (PDI)BSID-II:• MDI• PDI• McCarthy Scales of Children’sAbilities (MSCA): verbal,quantitative, motor, perceptualperformance, memory,general cognitive• School report cardsBNBAS at 12–24 hr and at25–48 hr after birthFagan Test of Infant IntelligenceBSID-II:• MDI• PDIGriffiths Scales ofInfant Development↑Dose-related number ofabnormal reflexes (hyporeflexia)Higher scores on regulation ofstates with borderline significancePrenatal exposure:↑MDI at 6 months = MDI at 12 months=PDI at 6 months = PDI at 12 monthsPostnatal exposure:= MDI/PDI at 6 and 12 monthsPrenatal exposure:=MDI & PDIPostnatal exposure:↑PDI at 24 months not at 18 months=MDIPrenatal exposure:• ↑/↓Diff in quant. score at 3, 4 and5 years with the lowest score at4 years – no dose–response andborderline significance• =for gradesPostnatal exposure:• ↑/↓Diff in motor score at 3, 4 and5 years with the lowest score at 4 yearsand no dose–response• =grades=performance on all clusters• 6 months, no association with DDE• 12 months, inverse correlation,r = –0.14, P = 0.03 (authors report thatthere is no association)p,p′-DDE:↓MDI and PDI-dose-related2X dose of DDE ↓3.5 pointsMDI ↓4.0 points PDI↓Griffiths Scales: locomotor,personal-social, performance andeye-hand coordination(borderline significant)• Associations strongest if shorterperiod of breastfeeding230 BRENDA ESKENAZI ET AL. MiniReview

© 2008 The AuthorsJournal compilation © 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 228–236Continued.Author, year Population Exposure Outcome ResultsEskenazi et al.2006 [11]Ribas-Fitó et al.2006 [17]Torres-Sánchez et al.2007 [18]Fenster et al.2007 [7]Engel et al. 2007 [10]n = 330 at 6 monthsn = 327 at 12 monthsn = 309 at 24 monthsCHAMACOS birth cohortliving in an agriculturalcommunity; mostly Latinofarmworker families inSalinas Valley Californian = 102 4-year-old childrenfrom Ribera d’Ebre cohortn = 405 4-year-old childrenfrom Menorca cohortSpanish childrenn = 225 at 1 monthn = 233 at 3 monthsn = 227 at 6 monthsn = 191 at 12 monthsMexican birth cohort(State of Morelos)n = 419 neonatesCHAMACOS birth cohortliving in an agriculturalcommunity; mostly Latinofarmworker familiesin Salinas Valley Californian = 151 neonatesMt. Sinai birth cohort inNew York City – randomsubset of whole cohort(404 neonates) for this analysisTable 1.Maternal serum DDT and DDEat 26 weeks gestation (±2.9S.D.) for n = 334 or just beforedelivery for n = 26Mean exposures (ng/g lipid):p,p′-DDT = 22.0o,p′-DDT = 1.8p,p′-DDE = 1436.9Cord serum DDT and DDEMedian Ribera d’Ebre, Menorca:DDT: 0.05 ng/ml, 0.08 ng/mlDDE: 0.86 ng/ml, 1.03 ng/mlMaternal serum DDEMean exposures:Prepregnancy 6.8 ng/ml1st trimester 6.4 ng/ml2nd trimester 6.8 ng/ml3rd trimester 7.8 ng/mlMaternal serum DDT andDDE at 26 weeks gestation(±2.9 S.D.) for n = 334 orjust before delivery for n = 26Mean (ng/g lipid):p,p′-DDT = 23.2o,p′-DDT = 1.8p,p′-DDE = 1464.2Maternal serum DDEMedian = 0.6 µg/literBSID-II:• MDI• PDIMCSA:• General cognitive• Memory•VerbalReorganized McCarthy items:•Executive function• Memory span•Verbal memoryBSID-II:• MDI• PDIBNBASBNBAS•p,p′-DDT (1-log 10 increase):↓PDI at 6 (1.73 points) and 12 mo.(2.33 points) not at 24 months↓MDI at 12 (1.71 points) and24 (2.12) months not at 6 months•o,p′-DDT (1-log 10 increase):Borderline significant decrease inMDI at 12 (2.56 points) and 24(3.06 points) months not at 6 months•p,p′-DDE (1-log 10 increase):↓PDI at 6 months (2.14) notat 12 or 24 months=MDICombined cohorts• DDT:↓general cognitive (1.99), memory(3.79 borderline significant), verbal(2.63 borderline significant), executivefunction (2.61), memory span (2.82borderline significant) and verbalmemory (6.1 borderline significant)• DDE:↓memory (1.93) and ‡ in other domainsp,p′-DDE (1st trimester):• ↓PDI at 3 months (10.8),6 months (1.94)12 months (5.72)• =MDINo observed associations betweenmaternal DDT/DDE serum levels andneonatal performance on BNBASAuthors cite that single BNBASmay have limited sensitivityNo association↑↓ signifies a statistically significant effect in the indicated direction (P-value ≤0.05); = signifies no statistically significant effect. DDE, dichlorodiphenyldichloroethylene; DDT, dichlorodiphenyltrichloroethane.MiniReview PESTICIDES AND THE DEVELOPING BRAIN 231

232 BRENDA ESKENAZI ET AL. MiniReviewmeasured by any of the BNBAS clusters [7]. However, wedid observe a non-significant negative association betweenmaternal DDE serum levels and the number of abnormalinfant reflexes [adjusted β = –0.08 abnormal reflexes; 95%confidence interval (CI), –0.25, 0.08; P = 0.31] on theBNBAS [7].The results of the CHAMACOS study for DDE exposureand neonatal neurodevelopment are largely consistent withother studies with the exception of one earlier study ofinfants in North Carolina. One of the earliest studies toinvestigate effects in neonates of in utero exposure to DDEfound that higher levels of DDE in cord serum and breastmilk were associated with hyporeflexia on the BNBAS in abirth cohort of 912 infants in North Carolina [8]. However,these findings were not replicated in a similar analysis of theOswego, New York birth cohort [9]. Although the Oswegocohort study was smaller (n = 293), the BNBAS was administeredtwice during the first 2 days of life and no associationwas observed between exposure to DDE and performanceon the BNBAS. An analysis of a random subset of infantsfrom the Mt. Sinai Medical Center birth cohort (concurrentwith the CHAMACOS cohort) in New York City (n = 151)also found no association between maternal serum DDEand performance on the BNBAS [10]. Thus, the only studythat reported association of in utero DDE exposure andneonatal BNAS performance was the earlier North Carolinastudy conducted in 1986, which may be explained by higheraverage exposure levels. The median DDE exposure level inthe North Carolina birth cohort was 12.06 p.p.b. that washigher than levels in our CHAMACOS cohort at 9.08 p.p.b.However, higher 95th percentile (151.92 p.p.b. versus34.60 p.p.b.) and maximum values (1219.73 p.p.b. versus180.00 p.p.b.) were detected in the CHAMACOS cohortcompared to the North Carolina cohort.The findings for DDE exposure and neurodevelopmentin older infants and children are less consistent than thefindings for neonates. In the CHAMACOS study, we evaluatedinfant neurodevelopment at 6, 12 and 24 months using theBayley Scales of Infant Development (BSID-II) and foundthat in utero exposure to DDE was only significantly associatedwith lower scores on the Psychomotor Development Index(PDI) at 6 months [11]. We also observed that DDE exposurewas associated with lower PDI scores at 12 months andlower Mental Development Index (MDI) scores at 12 and24 months, although the findings were not significant [11].In the North Carolina birth cohort, researches found apositive association between prenatal DDE exposure andthe MDI on the BSID-II at 6 months of age, but not onsubsequent assessments at 12, 18 or 24 months [12,13]. Inthe same cohort, researchers found that DDE exposure waspositively associated with the PDI of the BSID-II at 24months but not at 6, 12 or 18 months [12,13]. At 3, 4 and 5years, slight differences in development were detected inassociation with prenatal and postnatal DDE exposure inthe North Carolina cohort using the McCarthy Scales ofChildren’s Abilities (MCSA) [14]. However, there was noapparent dose–response relationship as the lowest scoreswere observed in the middle exposure category with higherscores in both the low and high exposure categories. Asecond study of the Oswego birth cohort evaluated infantsat 6 and 12 months using the Fagan Test of Infant Intelligence.Similar to the neonatal findings from the Oswego cohort,the authors reported no association between DDE levels incord serum and development at 6 months [15]. However, atthe 12-month evaluation, there was a significant negativecorrelation between DDE exposure and performance on theFagan Test of Infant Intelligence [15]. These results weresimilar to those from a study of 92 children at 13 monthsfrom a birth cohort in Spain. The Spanish children exposedto higher levels of DDE had lower social, mental andpsychomotor development as assessed by the GriffithsScales of Infant Development and the BSID-II [16]. Thesame authors evaluated 4-year-old children in the Riberad’Ebre and Menorca cohorts in Spain using the MCSA, andfound that cord serum DDE levels were only associatedwith a decrease in the memory domain [17]. Finally,research with a Mexican birth cohort found that DDEexposure in utero was associated with a decrease in psychomotordevelopment using the BSID-II at 3, 6 and 12 months,but there was no observed effect on mental development atany age [18]. Thus, results from the Spanish, Mexican andCHAMACOS cohorts suggest a negative effect of DDEon psychomotor development in infants 12 months andyounger while the North Carolina study reported either noassociation or a positive association in infants assessed at 6,12, 18 and 24 months. Mental development was found to bepositively associated with DDE exposure only in the earlyNorth Carolina study at 6 months, and all other studiesfound either no association or a negative association.We also evaluated children’s neurodevelopment at 6, 12and 24 months in the CHAMACOS cohort in relation toDDT exposure. An increase in maternal serum DDT levelon the log scale was associated with a 1.71- and 2.12-pointdecrease on the BSID-II MDI at 12 and 24 months, respectively[11]. There was no significant association of serumDDT with the MDI at the 6-month assessment [11]. We didobserve a significant inverse association between maternalserum DDT and the psychomotor development scores onthe BSID-II at 6 and 12 months but not at 24 months [11].Besides the CHAMACOS study, only one other study hasexamined the association between in utero DDT exposureand children’s development and results were similar. In theSpanish cohorts from Ribera d’Ebre and Menorca, highercord serum DDT levels were significantly associated withpoorer scores in the general cognitive and the executivefunction domains on the MCSA in 4-year-old children [17].Organophosphate pesticidesData are limited on the neurodevelopmental effects resultingfrom exposure to organophosphate pesticides and exposureassessment remains challenging (table 2). Organophosphatepesticide exposure is commonly assessed by measuringorganophosphate dialkylphosphate (DAP) metabolites in© 2008 The AuthorsJournal compilation © 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 228–236

© 2008 The AuthorsJournal compilation © 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 228–236Table 2.Summary of literature on organophosphate pesticide exposure and neurodevelopment in children. Average exposure levels are indicated where available.Author, year Population Exposure Outcome ResultsYoung et al.2005 [19]Rauh et al.2006 [21]Grandjean et al.2006 [23]n = 381 ≤2 month oldsCHAMACOS birth cohortliving in an agriculturalcommunity; mostly Latinofarmworker familiesin Salinas Valley Californian = 254 children 0–3 yearsLongitudinal birth cohortstudy of inner-city mothersin New York Cityn = 72 Ecuadorianchildren 7 years old35 exposed (prenatal) childrenand 37 unexposed childrenMaternal urinary dialkylphosphatemetabolite levels during pregnancy(M = 14 and 26 weeks) and earlypostnatal (M = 7 days)Chlorpyrifos levels in umbilicalcord plasma classified ashigh if >6.17 pg/g plasmaPrenatal exposure assessed byquestionnaire with the motherCurrent exposure assessed byurinary pesticide metabolites(both dimethyl and diethylmetabolites were detectedin 31 children)Brazelton Neonatal BehavioralAssessment Scale (BNBAS)Bayley Scales of InfantDevelopment (BSID-II):• Mental Development Index (MDI)• Psychomotor DevelopmentIndex (PDI)• Child Behaviour Checklist (CBCL)Santa Ana Pegboard, WISC-R,Stanford-Binet copying subtest andfinger tapping, Catsys force plate• ↑Dose-related number ofabnormal reflexes (hyporeflexia)with in utero measure especiallyin infants >3 days at testing• No association with earlypostnatal exposure measures• Linear regression analysis:↓3.327 points on MDI and6.46 on PDI at 36 months=at 12 and 24 months• Logistic regression analysis: Highexposure to chlorpyrifos associatedwith 2.37 (1.08–5.19) ↑odds ofmental delay at 36 months & 4.52(1.61–12.70) ↑odds of psychomotordelay at 36 months• CBCL: ↑in attention problems,attention deficit/hyperactivity disorderand pervasive developmental disorderPrenatal exposure:• ↓scores on the Stanford-Binet copyingtest (2.5 points versus 3.3 points)• =on the Santa Ana, meanreaction time, Digit Span forprenatal exposureCurrent exposure:• ↑in mean reaction time(500 msec. versus 426 msec.)• =on the Santa Ana, DigitSpan Forward or Stanford-Binetfor current exposure• Stunting modified resultsMiniReview PESTICIDES AND THE DEVELOPING BRAIN 233

© 2008 The AuthorsJournal compilation © 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 228–236Continued.Author, year Population Exposure Outcome ResultsEngel et al.2007 [10]Eskenazi et al.2007 [20]n = 404 neonatesMt. Sinai birth cohortin New York City6 months n = 396 children12 months n = 372 children24months n = 372 children356 mothers – CBCL at24 monthsCHAMACOS birth cohortliving in an agriculturalcommunity; mostly Latinofarmworker families inSalinas Valley CaliforniaTable 2.Maternal dialkylphosphatemetabolites (DAPs) andmalathion dicarboxylicacid (MDA) at mean 31.2weeks (S.D. 3.7 weeks)DAPs:Median diethyl metabolites =24.7 nm/literMedian dimethyl metabolites =47.8 nm/literMDA: median below limit of detectionMaternal and child urinarydialkylphosphate metabolites(DAPs) and maternal urinarymetabolite of malathion (MDA)and chlorpyrifos (TCPy)Mean maternal DAP: 114.9 nmol/lMean child DAP:45.5, 59.5 and 70.9 nmol/l at 6,12 and 24 monthsBrazelton Neonatal BehavioralAssessment Scales (BNBAS)Bayley Scales of Infant Development(BSID-II) at 6, 12 and 24 months:• MDI• PDIChild Behaviour Checklist(CBCL) at 24 months:• Attention• Attention deficit/hyperactivity disorder• Pervasive developmental disorder↑↓ signifies a statistically significant effect in the indicated direction (P-value ≤0.05); = signifies no statistically significant effect.DAPs:• total diethyl ↑abnormal reflexesrisk ratio 1.49 (95% CI, 1.12, 1.98)• total dimethyl ↑abnormal reflexes(non-significant but stronger forinfants assessed in first day of life)• total DAPs ↑abnormalreflexes (non-significantMDA: ↑abnormal reflexes risk ratio2.24 (95% CI, 1.55, 3.24) stronger forinfants examined in first 2 daysMaternal DAPs:↓Bayley MDI at 24 months=Bayley PDI at any age↑CBCL at 24 monthsChild DAPs↑Bayley MDI at 24 months=Bayley PDI at any age↑CBCL PDD at 24 monthsMDA and TCPy:=Bayley=CBCL234 BRENDA ESKENAZI ET AL. MiniReview

MiniReview PESTICIDES AND THE DEVELOPING BRAIN 235urine or by measuring the parent compound in blood. Inthe CHAMACOS cohort, we found that DAPs measured inprenatal maternal urine were associated with the number ofabnormal reflexes in neonates as measured by the BNBAS[19]. More than twice the number of neonates born tomothers in the highest exposure group had three abnormalreflexes or more compared to neonates born to mothers inthe lower exposure groups. Similar to the results found forCHAMACOS neonates, Engel et al. reported increasednumbers of abnormal reflexes in infants born to motherswith higher levels of DAPs in urine during pregnancy in abirth cohort study from Mt. Sinai Medical Center in NewYork City [10]. Neither the CHAMACOS nor the Mt. Sinaistudy observed associations between organophosphatepesticide metabolites and other clusters of the BNBAS [6,15].In the CHAMACOS cohort, maternal DAPs were alsoassociated with decreased mental development scores on theBSID-II at 24 months (adjusted β = –3.54; 95% CI, –6.59,0.49; P ≤ 0.05) [20]. However, the observed associationbetween children’s concurrent DAP levels and mental developmentwas in the opposite direction. For every 10-foldincrease in a child’s DAP level, we observed a 2.37 point(95% CI, 0.50, 4.24) increase in the mental developmentscore on the BSID-II at 24 months [20]. Although we haveno clear explanation for this discrepancy, it is possible thatchildren with higher mental development scores are alsomore interactive with their environment and as a resultcome into contact with more pesticide residues. No associationswere observed between maternal or child’s DAP andBSID-II mental performance at 6 or 12 months of age orwith psychomotor performance at any of the three timepoints [20]. In a longitudinal birth cohort study fromColumbia University in New York City, researchers assessedinfants at 12, 24 and 36 months using the BSID-II [21].Chlorpyrifos (a common organophosphate pesticide) levelsin cord plasma were associated with decreases in mental andpsychomotor development at 36 months but not at 12 or 24months. They did not assess the relationship of pesticideexposure during childhood and development.Results from the Child Behaviour Checklist (CBCL) weresimilar for both prenatal and postnatal pesticide exposure inthe CHAMACOS cohort. The CBCL assesses a range ofbehaviour problems that produces scales consistent with theDiagnostic and Statistical Manual of Mental Disordersdiagnoses [22]. Maternal and child DAP levels were associatedwith an odds ratio of 2.25 (95% CI, 0.99–5.16) and 1.71(95% CI, 1.02–2.87), respectively, for maternally reportedpervasive developmental disorder (PDD) at 24 months [20].The PDD scale is made up of items such as ‘avoids eyecontact’, ‘rocks head, body’, and ‘unresponsive to affection’.No association was observed between maternal or child’sDAPS and CBCL-assessed attention problems at 24 months[20]. Researchers from Columbia also found associationswith maternal report of PDD and attention problems withand without hyperactivity at 36 months on the CBCL intheir longitudinal birth cohort, similar to the results fromthe CHAMACOS study [21].One study from Ecuador examined the relationship ofexposure in older children and development. In a study of7-year-old children, Grandjean et al. found that children’sDAP levels were associated with an increase in simple reactiontime while prenatal exposure, which was assessed by amaternal occupational questionnaire, was associated witha decrease on the Stanford-Binet copying test [23]. Nodifferences were reported for the Santa Ana Pegboard testor the Digit Span subtest of the Wechsler IntelligenceScale for Children in relation to either prenatal or postnatalpesticide exposure. Currently, no other studies have beenpublished in older children [23].Conclusions and next stepsPrevious literature and recent work by the Centers forChildren’s Environmental Health Research provide evidenceof pesticide toxicity to the developing human brain. Animportant next step in this research endeavour is to pooldata from studies with similar methods and outcome andexposure measures. We are currently pooling data andcomparing analyses from the Centers for Children’s EnvironmentalHealth Research at University of California,Berkeley, Mt. Sinai School of Medicine and ColumbiaUniversity. Another next step is to identify subpopulationsthat may be more susceptible to pesticide exposure andresulting neurodevelopmental health effects. For example, inthe CHAMACOS cohort, we have found that an individual’ssusceptibility to organophosphate pesticides may vary byage and genotype. Children with a particular variant of theparaoxonase 1 gene had lower levels of the paraoxonaseenzyme that metabolizes organophosphate pesticides, whichmeans they may be at higher risk of health effects fromorganophosphate exposure [24,25]. Future studies shouldexamine the neurodevelopment effects in human beingsassociated with pesticide mixtures and other classes ofpesticides (e.g. carbamates, pyrethroids), and with pesticidemixtures, because there is increasing use of these pesticidesin certain communities that are replacing the organophosphateand organochlorine pesticides.References1 Eskenazi B, Bradman A, Castorina R. Exposures of children toorganophosphate pesticides and their potential adverse healtheffects. Environ Health Perspect 1999;107:409–19.2 Zwiener RJ, Ginsburg CM. Organophosphate and carbamatepoisoning in infants and children. Pediatrics 1988;81:121–6.3 California Department of Pesticide Regulation. Pesticide UseReport (PUR). Available from http://www.cdpr.ca.gov/docs/pur/purmain.htm, 2005.4 Axmon A, Rignell-Hydbom A. Association between biomarkersof exposure to persistent organochlorine compounds (POCs).Chemosphere 2006;64:692–4.5 Lu C, Bravo R, Caltabiano LM, Irish RM, Weerasekera G,Barr DB. The presence of dialkylphosphates in fresh fruitjuices: implication for organophosphorus pesticide exposureand risk assessments. J Toxicol Environ Health A 2005;68:209–27.© 2008 The AuthorsJournal compilation © 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 228–236

236 BRENDA ESKENAZI ET AL. MiniReview6Bradman AS, Schwartz JM, Fenster L, Barr DB, Holland NT,Eskenazi B. Factors predicting organochlorine pesticide levels inpregnant Latina women living in a United States agriculturalarea. J Expo Sci Environ Epidemiol 2006;16:388–99.7Fenster L, Eskenazi B, Anderson M, Bradman A, Hubbard A,Barr DB. In utero exposure to DDT and performance on theBrazelton neonatal behavioral assessment scale. Neurotoxicology2007;3:471–7.8Rogan WJ, Gladen BC, McKinney JD et al. Neonatal effectsof transplacental exposure to PCBs and DDE. J Pediatr1986;109:335–41.9 Stewart P, Reihman J, Lonky E, Darvill T, Pagano J. PrenatalPCB exposure and neonatal behavioral assessment scale(NBAS) performance. Neurotoxicol Teratol 2000;22:21–9.10 Engel SM, Berkowitz GS, Barr DB et al. Prenatal OrganophosphateMetabolite and Organochlorine Levels and Performanceon the Brazelton Neonatal Behavioral Assessment Scale ina Multiethnic Pregnancy Cohort. Am J Epidemiol2007;165:1397–404.11 Eskenazi B, Marks AR, Bradman A et al. In utero exposure todichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene(DDE) and neurodevelopment among youngMexican American children. Pediatrics 2006;118:233–41.12 Gladen BC, Rogan WJ, Hardy P, Thullen J, Tingelstad J, TullyM. Development after exposure to polychlorinated biphenylsand dichlorodiphenyl dichloroethene transplacentally andthrough human milk. J Pediatr 1988;113:991–5.13 Rogan W, Gladen B. PCBs, DDE, and child development at 18and 24 months. Ann Epidemiol 1991;1:407–13.14 Gladen BC, Rogan WJ. Effects of perinatal polychlorinatedbiphenyls and dichlorodiphenyl dichloroethene on later development.J Pediatr 1991;119:58–63.15 Darvill T, Lonky E, Reihman J, Stewart P, Pagano J. Prenatalexposure to PCBs and infant performance on the fagan test ofinfant intelligence. Neurotoxicology 2000;21:1029–38.16 Ribas-Fito N, Cardo E, Sala M et al. Breastfeeding, exposureto organochlorine compounds, and neurodevelopment in infants.Pediatrics 2003;111:e580–5.17 Ribas-Fito N, Torrent M, Carrizo D et al. In utero exposure tobackground concentrations of DDT and cognitive functioningamong preschoolers. Am J Epidemiol 2006;164:955–62.18 Torres-Sanchez L, Rothenerg SJ, Schnaas L et al. In uterop,p′-DDE exposure and infant neurodevelopment: a perinatalcohort in Mexico. Environ Health Perspect 2007;115:435–9.19 Young JG, Eskenazi B, Gladstone EA et al. Association betweenin utero organophosphate pesticide exposure and abnormal reflexesin neonates. Neurotoxicology 2005;26:199–209.20 Eskenazi B, Marks AR, Bradman A et al. Organophosphatepesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect 2007;115:792–8.21 Rauh VA, Garfinkel R, Perera FP et al. Impact of prenatalchlorpyrifos exposure on neurodevelopment in the first 3 yearsof life among inner-city children. Pediatrics 2006;118:e1845–59.22 American Psychiatric Association. Diagnostic and StatisticalManual of Mental Disorders. American Psychiatric Association,Washington, DC, 2000.23 Grandjean P, Harari R, Barr DB, Debes F. Pesticide exposureand stunting as independent predictors of neurobehavioral deficitsin Ecuadorian school children. Pediatrics 2006;117:e546–56.24 Holland N, Furlong C, Bastaki M et al. Paraoxonase polymorphisms,haplotypes, and enzyme activity in Latino mothers andnewborns. Environ Health Perspect 2006;114:985–91.25 Furlong CE, Holland N, Richter RJ, Bradman A, Ho A,Eskenazi B. PON1 status of farmworker mothers and childrenas a predictor of organophosphate sensitivity. PharmacogenetGenomics 2006;16:183–90.© 2008 The AuthorsJournal compilation © 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 228–236