Table 2.

Summary of recent studies including modifiers (sex, co-exposures, exposure timing, genetic polymorphisms) of associations between lead, methyl mercury, arsenic or manganese and non-cognitive behavioral outcomes in children

Reference	Study Design	Sample Size	Study Location	Age	Outcomes	Exposure Metric	Exposure Timing	Exposure Level	Modifier	Key Main Findings
Lead (Pb) and other behavioral outcomes
Horton 2018 [20]	Prospective cohort	133	Mexico	8–11 yrs	Behavior Assessment System for Children (BASC–2)	Tooth dentine	2nd trimester through early childhood	Not reported	Exposure timing, Mn and Zn	Reverse distributed lag models and lagged WQS results: Postnatal Pb, especially 8–12 months, associated with increased behavioral problems [e.g., SD change in BASC score per SD increase in log postnatal Pb, 10-month Pb and overall behavioral problems: β (95% CI) = 0.22 (0.06, 0.38); 10 month Pb and hyperactivity: 0.19 (0.02, 0.37)]. Increased anxiety symptoms at 8–12-month window driven by the metal mixture and dominated by Pb.
Fruh 2019 [35]	Prospective cohort	1006	US	7.8 ± 0.8 yrs (mean age)	Behavior Rating Inventory of Executive Functions (BRIEF); Strengths and Difficulties Questionnaire (SDQ)	Maternal blood	prenatal	Mean (IQR) maternal erythrocyte Pb concentration: 1.2 (0.8–1.5) μg/dL;	Sex	Pb associated with increased emotional problems [per IQR (0.6 μg/dL) increase: β (95% CI) = 0.18 (0.03, 0.33)]. Stronger effects for girls across most subscales; example: Pb and parent-rated total difficulties [0.72 (0.16, 1.27)] vs. boys [0.16 (−0.38, 0.70)]. No Pb-sex interaction.
Barg 2018 [36]	Cross-sectional	206	Uruguay	6.7 ± 0.5 yrs (mean)	Behavior Rating Inventory of Executive Functions (BRIEF); Conners’ Rating Scale (CRS); Teacher Rated	Blood	6.7 ± 0.5 yrs (mean age)	Mean (SD) BPb: 4.2 (2.1) μg/dL	Sex	Pb associated with increased prevalence ratio of BRIEF inhibit subscale [PR (95% CI) = 1.01 (1.00, 1.03)]. Pb not associated with CRS subscales. Sex-specific prevalence ratios for associations between Pb and hyperactivity higher in girls [1.02 (1.00, 1.04)] vs. boys [0.99 (0.97, 1.01); Pb-sex interaction: p < 0.1].
Joo 2018 [37]	Prospective cohort	1751	Korea	5 yrs	Korean Child Behavior Checklist: Korean version of CBCL 1.5–5	Maternal, cord and child blood	Prenatal; maternal blood in early and late pregnancies, cord blood and 2-, 3-, and 5-year-old children’s blood.	GM (SD) μg/dL: early pregnancy: 1.3 (1.5); late pregnancy: 1.2 (1.6); cord blood: 0.9 (1.6); Child blood 2 yrs: 1.6 (1.5); 3 yrs: 1.4 (1.4); 5 yrs: 1.3 (1.4)	Sex, exposure timing	Sex-specific findings for associations of Pb and total behavioral problems differed by exposure timing. Stronger associations of late pregnancy Pb and total behavioral problems in boys [β (95% CI) = 3.0 (0.6, 5.5) vs. girls: 0.4 (−2.1, 2.9); Pb-sex interaction: p=0.1]. Stronger associations of 2-year and 5-year Pb and total behavioral problems in girls [girls: 3.8 (1.3, 6.4) vs. boys: 0.2 (−1.9, 2.3); interaction: p=0.04] and [5.7 (0.4, 11.0) vs. boys: 1.37 (−2.1, 4.8); interaction: p=0.1], respectively.
Rodrigues 2018 [38]	Cross-sectional	165	Brazil	7–12 yrs	Child Behavior Check List (CBCL) by parents: behavior, attention	Blood	7–12 yrs	Mean (Range) BPb: 1.2 (0.2–15.6) μg/dL	Mn	Null associations between Pb and raw total CBCL score [β (95% CI) = −0.74 (−5.3, 3.8)]. Suggestive evidence of synergistic Pb-Mn interaction.
Al-Saleh 2019 [39]	Cross-sectional	206	Saudi Arabia	2–12 mo	Parents’ Evaluation of Developmental Status (PEDS): learning & behavior problems	Maternal blood & urine, infant urine, breastmilk	2–12 mo	Mean (SD) BPb: 2.4 (1.7) μg/dL	MeHg, Mn, DDT + metabolites	Combination of Pb-maternal urine, Mn-breast milk, Mn-blood, and Se-blood correlated with delayed PEDS scores [principal component analysis, RR (95% CI) = 0.42 (0.18, 1.02)].
Arbuckle 2016 [40]	Cross-sectional	1080	Québec	6–11 yrs	Strengths and Difficulties Questionnaire (SDQ) outcomes; emotional symptoms, hyperactivity/inattention, and a total difficulties score with borderline and abnormal scores grouped together and compared with children with normal scores; parent-reported learning disability	Blood	6–11 yrs	GM BPb: 0.9 μg/dL	Maternal smoking	Pb associated with increased odds of hyperactivity/inattention [OR (95% CI) = 2.8 (1.5, 5.2)]. Interaction between prenatal smoking and Pb for total difficulties score [OR (95% CI) = 10.6 (2.8, 39.7) vs. 2.0 (1.4, 2.8) if mother did not smoke during pregnancy].
Ji 2018 [41]	Prospective cohort	1479	US	7.4–12 yrs	ADHD (as determined by the ICD–9 and ICD–10 codes)	Blood	0–4 yrs	Mean (SD) BPb: 2.2 (1.6) μg/dL	Sex	Associations of Pb and odds of any ADHD diagnosis for children with 5–10 μg/dL Pb vs. children with < 5 μg/dL Pb were stronger among boys [(OR (95% CI) = 2.5 (1.5, 4.3)] than girls [0.7 (0.3, 1.7)].
Methyl mercury (meHg) and other behavioral outcomes
Ng, 2015 [65]	Prospective cohort	166	Taiwan	2 yrs	Items on the Child Behavior Checklist (CBCL 1.5/5 Chinese version)	Cord blood	Prenatal	Cord blood THg (μg/L): Median (Range): 12.0 (1.5–47.1)	Genetics, sex	Among APOE ε4 carriers, stronger inverse associations between CBHg (> 12 μg/L) and behavioral outcomes (total problems, total internalizing, emotionally reactive, anxious/depressed). Stronger inverse associations among male APOE ε4 carriers, except between Hg and anxiety, and where associations were strongest among female APOE ε4 carriers.
Patel 2019 [66]	Prospective cohort	389	US	2–8 yrs (BASC) 8 yrs (SCAS)	Behavioral Assessment System for Children (BASC–2) and Spence Children’s Anxiety Scales (SCAS)	Maternal blood, cord blood	prenatal (16, 26 weeks gestations and delivery)	Median: 0.67 μg/L	Exposure timing, sex	Per 1 μg/L increase in mean maternal THg: BASC anxiety: β (95% CI) = 0.71 (−0.12, 1.54); 2-fold increase 16-week THg and BASC anxiety score: 0.83 (0.05, 1.62) points.
Al-Saleh 2019 [39]	Cross-sectional	206	Saudi Arabia	2–12 mo	Parents’ Evaluation of Developmental Status (PEDS): learning & behavior problems	Breastmilk, maternal blood	2–12 mo	Median (Range), breastmilk: 1.4 (1.1–2.1) μg/L; mom blood: 0.5 (0.1–1.0) μg/L	Pb, Mn, DDT + metabolites, Se	No association of MeHg in individual or PCA analyses. No MeHg-Se interaction.
Arsenic (As) and other behavioral outcomes
Rodriguez-Barranco 2016 [73]	Cross-sectional	261	Spain	6–9 yrs	3 tests from the Behavioral Assessment and Research System (BARS): Simple Reaction Time Test (RTT), Continuous Performance Test (CPT) and Selective Attention Test (SAT); AULA Test; Child Behavior Check List (CBCL); Teacher’s Report Form (TRF)	Total As in First-Void Urine (Unadjusted; Urinary Cr included as a covariate in statistical models)	6–9 yrs	Median (IQR): 1.2 (0.5–1.9) μg/L	Sex	SAT latency: β (95% CI) = 3.58 (0.37, 6.79), RTT latency: 12.31(3.51, 21.11), AULA impulsivity omission errors: 0.57 (0.07, 1.07), AULA inattention omission errors: 0.50 (0.03, 0.97). No significant associations for CBCL or TRF. No significant As-sex interactions.
Manganese (Mn) and other behavioral outcomes
Al-Saleh 2019 [39]	Cross-sectional	206	Saudi Arabia	2–12 mo	Parents’ Evaluation of Developmental Status (PEDS): learning & behavior problems	Breastmilk, maternal blood & urine, infant urine	2–12 mo	Median (Range), breastmilk: 16 (7–32) μg/L; mom blood: 14 (5–47) μg/L; mom urine: 2 (0.1–23) μg/L; infant urine: 3 (1–22) μg/L	Pb, meHg, DDT + metabolites	Combination of Mn-breast milk, Mn-blood, Se-blood, and Pb-maternal urine correlated with delayed PEDS scores (principal component analysis, RR (95% CI) = 0.42 (0.18, 1.02).
Horton 2018 [20]	Prospective cohort	133	Mexico	8–11 yrs	Behavior Assessment System for Children (BASC–2): internal & externalizing symptoms	Tooth dentine	2nd trimester through early childhood	Median (IQR), as 55Mn:43Ca across all time points: 1.2E-3 (6.8E-4–2.0E-3)	Zn, Pb, exposure timing	Reverse distributed lag models and lagged WQS results: Prenatal Mn protects against externalizing behavior [SD change in BASC score per SD increase in log Mn at birth, β (95% CI) = −0.15 (−0.24, −0.07)]. Postnatal Mn associated with more anxiety and internalizing behaviors [6-month Mn and anxiety symptoms: 0.18 (0.09, 0.27)]. Joint exposure with Pb, Zn at 12 months associated with more anxiety.
Ode 2015 [91]	Case-control	166 cases, 166 controls	Sweden	5–17 yrs	ADHD diagnosis with DSM criteria	Umbilical cord serum	Birth	Median (Range): 4.1 (1.3–39) μg/L	Se	No association of Mn with ADHD; no interaction with Se.
Rodrigues 2018 [30]	Cross-sectional	165	Brazil	7–12 yrs	Child Behavior Check List (CBCL) by parents: behavior, attention	Hair, toenails, blood	7–12 yrs	Median (Range), hair: 0.7 (0.2–8.8) μg/g, toenails: 0.84 (0.2–13.3) μg/g, blood: 9.0 (1.5–40.4) μg/L	BPb	Toenail Mn associated with more externalizing behavioral problems: β (95% CI) = 10.29 (1.9, 19.6) points per 10-fold Mn increase. Suggestive evidence of synergistic Mn-Pb interaction.
Carvalho 2018 [84]	Cross-sectional	70	Brazil	7–12 yrs	Conners’ Abbreviated Teacher Rating Scale: inattention, hyperactivity	Hair	7–12 yrs	Median (Range): 11.5 (0.5–55.7) μg/g	Sex	Hair Mn associated with worse behavior [β (95% CI) = −6.6 (−12.0, −1.3) points per 10-fold increase; no sex-specific effects.
Menezes-Filho 2014 [90]	Cross-sectional	70	Brazil	7–12 yrs	Child Behavior Check List (CBCL) by parents: behavior, attention	Hair	7–12 yrs	Median (Range): 12 (0.5–55.7) μg/g	Sex	Girls’ total externalizing behavior and inattention associated with Log-MnH: β (95% CI) = 8.85 (2.44, 15.25) and 4.03 (1.50, 6.56); no association in boys.
Oulhote 2014 [87]	Cross-sectional	375	Canada	6–13 yrs	Parent- and teacher-reported Conners’ Rating Scales: hyperactivity	Hair, drinking water	6–13 yrs	Mean (Range), water: 99 (1–2701) μg/L; hair: 1.4 (0.1–20.7) μg/g	Sex	Using SEM with both hair and drinking water Mn, no association with hyperactivity and no sex-specific effects.
Tinkov 2019 [92]	Case-control	90 cases, 90 controls	Russia	4–10 yrs	ADHD diagnosis using ICD–10 criteria	Hair	4–10 yrs	Median (IQR), Cases: 0.21 (0.14–0.32); controls: 0.29 (0.18–0.40) μg/g	Sex, age	Lower hair Mn levels in ADHD Cases, with girls having ~25% lower Mn, and preschool having lower Mn than primary school kids.
Mora 2018 [89]	Prospective cohort	355	Costa Rica	1 year	Bayley Scales of Infant Development (BSID–III): social-emotional scores	Maternal hair, blood, urinary ethylene-thiourea (ETU; mancozeb metabolite)	Prenatal	Median (IQR), hair: 1.7 (0.9–4.1) μg/g; blood: 24.0 (20.3–28.0) μg/L; ETU: 3.3 (2.4–4.9) μg/L	Sex, exposure timing	Among girls, higher ETU associated with lower (worse) social-emotional scores [β (95% CI) per 10-fold increase = −7.4 (−15.2, 0.4) points]. Among boys, higher hair Mn associated with lower social-emotional scores [−4.6 (−8.5, −0.8)]. Association in boys stronger for second half of pregnancy than first; in girls, stronger in first half. Null associations for blood Mn.
Mora 2015 [83]	Prospective cohort	248	United States	7, 9, 10.5 yrs	Behavior Assessment System for Children (BASC–2), Conners’ ADHD/Diagnostic and Statistical Manual Scales (CADS)	Tooth dentine	Prenatal, postnatal	GM (GSD), prenatal: 0.46 (1.48); postnatal: 0.14 (2.47) 55Mn:43Ca AUCx10^4	BPb, sex, exposure timing	Prenatal Mn associated with more parent-reported internalizing problems, fewer teacher-reported inattention at age 7, among those with lower prenatal Pb (<0.8 ug/dl). Postnatal Mn associated with more internalizing, externalizing, and hyperactivity problems in girls and boys.