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Table 5 Systematic Review Study Characteristics

From: Sex difference of pre- and post-natal exposure to six developmental neurotoxicants on intellectual abilities: a systematic review and meta-analysis of human studies

Lead Author, Year

Country (Cohort)

N (%males)

Neuro-toxicant

Compound

Biomarker

Median of Exposure (ppb)

Outcome Measure

Interpretation

Reason Excluded from Meta-Analysis

Baghurst, 1992 [56]

Australia (Port Pirie Cohort Study)

494 (N/A)

Lead

N/A

Lifetime average blood up to 3 years

122.0–282.0*a

FSIQ on WISC-R at 7 years

The negative association between lead exposure and FSIQ was more pronounced in females

No standard error or p-value to calculate effect size

Berghuis, 2018 [51]

Netherlands (DACE Study)

35–40

(~ 54.5)

PCB

PBDE

ΣOH-PCBsc

BDE-47

2nd/3rd trimester serum

2nd/3rd trimester serum

0.4

0.9

FSIQ, PRI, and VCI on WISC-III-NL at 13–15 years

Positive association between ΣOH-PCBs and VCI and FSIQ in females. Negative association between BDE-47 and FSIQ in females

No other combinable study of OH-PCBs or BDE-47 (only data for females)

Castorina, 2017 [58]

USA (CHAMACOS)

248–275 (~ 54.8)

OPP

OPP

OPP

BDCIPP

DPHP

ip-PPP

2nd trimester urine

2nd trimester urine

2nd trimester urine

0.4

0.9

0.3

FSIQ, PRI, VCI on WISC-IV at 7 years

No significant differences between the sexes

No data available

Chen, 2014 [102]

USA (HOME)

190 (44.0)

PBDE

BDE-47

2nd trimester blood

18.9

FSIQ on WPPSI-III at 5 years

No significant differences between the sexes

Not enough combinable date to meta-analyze BDE-47

Choi, 2021 [100]

Norway (MoBA, Preschool ADHD Sub-Study)

310 (56.9)

Phthalate

Phthalate

Phthalate

Phthalate

Phthalate

Phthalate

MBzP,

MiBP,

MnBP,

MEP,

∑DEHPd

∑DiNPe

2nd trimester urine

2nd trimester urine

2nd trimester urine

2nd trimester urine

2nd trimester urine

2nd trimester urine

5.45b

19.64b

21.70b

129.71b

0.30b

0.02b

Verbal and non-verbal WM on SB5 at 3.5 years

The negative association between MiBP, MnBP, and MEP and non-verbal WM was more pronounced in females

Non-combinable outcome measure (i.e., verbal, and nonverbal WM)

Damm, 1993 [59]

Denmark (N/A)

141–162 (45.4–46.9)

Lead

N/A

Shed deciduous teeth at 6 years

Low: < 5,000

High: > 18,700

FSIQ, PIQ, VIQ on the Danish version of the WISC at 8 and 15 years

Females were better at coping with lead-related deficits in PIQ compared to males

No data available

Davidson, 2006 [62]

Republic of Seychelles (SCDS)

711 (N/A)

Mercury

Mercury

Mercury

N/A

Maternal hair at delivery

Hair at 5.5 years

Hair at 5.5 years

6800.0a

6500.0a

6100.0a

GCI on MSCA at 5.5 years and FSIQ on WISC-III at 8.9 years

Positive association between postnatal mercury exposure and global cognition in males

No data available for prenatal exposure. Not enough combinable data to meta-analyze postnatal exposure

Davidson, 2004 [61]

Republic of Seychelles (SCDS)

711 (N/A)

Mercury

N/A

Maternal hair at delivery

5900.0

GCI on MSCA at 5.5 years

No significant differences between the sexes

No data available

Davidson, 1998 [60]

Republic of Seychelles (SCDS)

711 (N/A)

Mercury

Mercury

N/A

Maternal hair at delivery

Hair at 5.5 years

6800.0a

6500.0a

GCI on MSCA at 5.5 years

No significant differences between the sexes

No data available

Ernhart, 1989 [65]

USA (N/A)

146–169 (N/A)

Lead

Lead

N/A

Cord blood

Maternal blood at delivery

58.9a

65.0a

FSIQ, PIQ, and VIQ on WPPSI at 4 years 10 months

No significant differences between the sexes

No data available

Factor-Litvak, 2014 [67]

USA (CCCEH)

328 (47.3)

Phthalate

Phthalate

Phthalate

Phthalate

Phthalate

Phthalate

MnBP

MBzP

MEHHP

MEHP

MEP

MiBP

3rd trimester urine

3rd trimester urine

3rd trimester urine

3rd trimester urine

3rd trimester urine

3rd trimester urine

38.0

14.4

21.8

4.9

141.5

9.2

FSIQ, PRI, and VCI on WISC-IV at 7 years

No significant differences between the sexes

No measure of overall DEHPs

Freire, 2018 [52]

Spain (INMA)

302 (71.5)

Lead

Mercury

N/A

Placenta at birth

Placenta at birth

 < 6.5

0.025

GCI on MSCA at 4–5 years

The negative association between mercury and GCI is more pronounced in males

Same cohort, exposure, and outcome as Llop, 2017

Furlong, 2017 [68]

USA (The Mount Sinai Children’s Environmental Health Center)

141 (51.0)

OPP

OPP

∑DEPf

∑DMPg

2nd/3rd trimester urine

2nd/3rd trimester urine

2.5

4.7

FSIQ, VIQ and PIQ on the WPPSI-III at 6 years and FSIQ, PRI, VCI,on the WISC-IV between 7–9 years

No significant differences between the sexes

No data available

Golding, 2017 [70]

UK (ALSPAC)

1758–1759

(49.9)

Mercury

N/A

1st trimester blood

1.86

FSIQ, PIQ, and VIQ on WISC-III at 8 years

No significant differences between the sexes

Non-linear regression techniques (logistic regression)

Huang, 2015 [72]

Taiwan (TMICS)

73–100 (N/A)

Phthalate

Phthalate

Phthalate

Phthalate

Phthalate

MMP

MEP

MBP

MBzP

ΣMEHPh

3rd trimester urine, urine at 2–3, and urine at 5–6 years

49,840b

66,610b

77,870b

17,430b

58,690b

FSIQ on WPPSI-R at 5 years, WISC-III at 8 years and WISC-IV at 11 years

No significant differences between the sexes

No data available

Huang, 2007 [71]

Republic of Seychelles (SCDS)

643 (N/A)

Mercury

N/A

Maternal hair at delivery

5,990 – 8,790a

FSIQ on WISC-III at 9 years

No significant differences between the sexes

No data available

Ikeno, 2018 [74]

Japan (N/A)

141 (46.8)

PCBs

PCBs

PCBs

Non-Ortho

Mono-Ortho

Coplanar

2nd trimester blood

2nd trimester blood

2nd trimester blood

0.059

8.029

8.101

MPS on the K-ABC at 3.5 years

Strong negative association for total non-ortho PCBs and MPS in males

No other combinable study of PCBs

Jacobson, 2002 [75]

USA (N/A)

124–158 (N/A)

PCBs

PCBs

PCBs

Total PCBs

Total PCBs

Total PCBs

Cord blood

Maternal blood at birth

Maternal milk at 0.5–4.5 months

2.6a

5.7a

829.7a

GCI, VS, and PPS on MSCA at 4 years and FSIQ, VCI, and PRI on WISC-R at 11 years

At 11 years, the negative effects of cord blood PCBs on FSIQ and PRI were more pronounced among males

No standard-error or exact p-value to calculate effect size

Kyriklaki, 2016 [78]

Greece (Rhea Study)

695 (51.6)

PCBs

Total PCBs

1st trimester blood

0.32

GCI on MSCA at 4 years

No significant differences between the sexes

No data available

McBride, 1982 [81]

Australia (N/A)

84–88 (N/A)

Lead

N/A

Blood at 4–5 years

2629.4b

VIQ on the PPVT at 4–5 years

No interpretation made

Non-linear regression technique (mean scores)

McMichael, 1994 [82]

Australia (Port Pirie Cohort Study)

262 (43.3)

Lead

N/A

Incisor teeth at 6 years

8600b

FSIQ, PIQ, and VIQ on WISC-R at 7 years

No significant differences between the sexes

No data available

McMichael, 1988 [84]

Australia (Port Pirie Cohort Study)

474–534 (NA)

Lead

Lead

Lead

Lead

Lead

Lead

Lead

N/A

1st trimester blood

Cord blood

Blood at 6 months

Blood at 15 months

Blood at 2 years

Blood at 3 years

Blood at 4 years

91.00b

95.00b

144.7b

208.9b

213.0b

194.4b

163.3b

GCI and PPS, on MSCA at 4 years

No significant differences between the sexes

No data available

Min, 2009 [85]

USA (N/A)

273–278 (~ 48)

Lead

N/A

Blood at 4 years

61.0

FSIQ, PIQ and VIQ, on WPPSI-R at 4 years and FSIQ, PRI, and VCI, on WISC-IV at 9 and 11 years

No significant differences between the sexes

No data available

Myers, 2003 [86]

Republic of Seychelles (SCDS)

643 (N/A)

Mercury

N/A

Maternal hair at delivery

6900.0a

FSIQ on WISC-III at 9 years

No significant differences between the sexes

No data available

Myers, 1995 [87]

Republic of Seychelles (SCDS)

217 (N/A)

Mercury

N/A

Maternal hair at delivery

7100.0

GCI and PPS on MSCA at 5.5 years

No significant differences between the sexes

No data available

Palumbo, 2000 [89]

Republic of Seychelles (SCDS)

708–711 (N/A)

Mercury

Mercury

N/A

Maternal hair at delivery

Hair at 5.5 years

6800.0a

6500.0a

PPS and VS on MSCA at 5.5 years

No significant differences between the sexes

No data available

Rauh, 2011 [91]

USA (CCCEH)

265 (44.2)

OPP

CPF

Cord blood

0.003a

FSIQ, PRI, VCI, on WISC-IV at 7 years

No significant differences between the sexes

No data available

Ris, 2004 [92]

USA (Cincinnati Lead Study)

195 (53.6)

Lead

N/A

Maternal blood

Blood samples up to 5 years

Range: 50.0–270.0

Learning/IQ factor derived from WRAT-3 and WISC-III at 15–17 years

No significant differences between the sexes

No data available

Schnaas, 2000 [93]

Mexico (Mexico City Prospective Lead Study)

112 (47.3)

Lead

N/A

Blood at 6–18 months

Blood at 24–36 months

Blood at 42–54 months

101b

97b

84b

GCI on MSCA at 3, 3.5, 4, 4.5 and 5 years

No significant differences between the sexes

No data available

Tatsuta, 2014 [94]

Japan (TSCD)

387 (52.2)

PCBs

9CBs

Cord blood

0.22

MPS on K-ABC at 3.5 years

The negative association between the MPS and 9CBs was more pronounced in males

No other combinable study of 9CBs

Vuong, 2017 [98]

USA (HOME)

208 (44.7)

PBDE

∑PBDEsi

Blood at 1 year

Blood at 2 years

Blood at 3 years

Blood at 5 years

118.1b

127.7b

100.5b

64.6b

FSIQ on WISC-IV at 8 years

No significant differences between the sexes

No other combinable study of postnatal PBDEs

Zhu, 2020 [99]

China (MABC)

1865–2128 (~ 52.0)

Phthalate

Phthalate

Phthalate

Phthalate Phthalate

Phthalate

Phthalate

MMP

MBP

MBzP

MEHHP

MEHP

MEOHP

MEP

Mean of three urines

Mean of three urines

Mean of three urines

Mean of three urines

Mean of three urines

Mean of three urines

Mean of three urines

N/A

N/A

N/A

N/A

N/A

N/A

N/A

FSIQ, VCI, and VSI on WPPSI-IV (Chinese version) between 3 to 6 years

Negative association between MBP and VSI and FSIQ in males, whereas in girls’ results were attenuated near zero. Positive association between MEHP and FSIQ in males and MBzP and VCI in males/

No measure of overall DEHPs

  1. *Mean low to mean high quartiles
  2. aArithmetic mean, bgeometric mean
  3. cΣOH-PCBs = 4-OH-PCB-107 + 4-OH-PCB-146 + 4-OH-PCB-187 + 3-OH-PCB-153 + 3′-OH-PCB-138 + 4′-OH-PCB-172; d∑DEHP = MEHHP + MEHP + MEOHP + MECPP + MMCHP; e∑DiNP = cx-MiNP + oxo-MiNP + OH-MiNP; f∑DEP = DEP + DETP + DEDTP; g∑DMP = DMP + DMTP + DMDTP; h ΣMEHP = MEHP + MEHHP + MEOHP; i∑PBDE = BDE-28 + BDE-47 + BDE-99 + BDE-100 + BDE-153;
  4. Abbreviations : ADHD Attention-Deficit/Hyperactivity Disorder, ALSPAC Avon Longitudinal Study of Parents and Children, BDCIPP Bis(1,3-dichloro-2-propyl) Phosphate, BDE Brominated Diphenyl Ethers, BDE-47 Tetrabromodiphenyl Ether, CCCEH Columbia Center for Children's Environmental Health, CHAMACOS Center for the Health Assessment of Mothers and Children of Salinas, CPF Chlorpyrifos, cx-MiNP Mono-4-methyl-7-carboxyheptyl phthalate, DACE Development at Adolescence and Chemical Exposure, DAP Dialkyl Phosphates, DEDTP Diethyl Dithiophosphate, DEHP Bis(2-ethylhexyl) Phthalate, DEP Diethyl phosphate, DETP Diethyl Thiophosphate, DiNP Diisononyl Phthalate, DMDTP Dimethyl Dithiophosphate, DMP Dimethyl Phosphate, DMTP Dimethyl Thiophosphate, DPHP Di(2-propylheptyl) Phthalate, FSIQ Full-Scale IQ, GCI General Cognitive Index, HOME Health outcomes and measures of the environment, INMA INfancia y Medio Ambiente (Environment and Childhood) Project, ip-PPP 2-((isopropyl) phenyl) Phenyl Hydrogen Phosphate, IQ Intelligence Quotient, K-ABC Kaufman Assessment Battery for Children, MBP Monobutyl Phthalate, MBzP Monobenzyl Phthalate, MECPP Mono(2-ethyl-5-carboxypentyl) Phthalate, MEHHP Mono(2-ethyl-5-hydroxyhexyl) Phthalate, MEHP Mono(2-ethylhexyl) Phthalate, MEOHP Mono-(2-ethyl-5-oxohexyl) Phthalate, MEP Mono-ethyl Phthalate, MiBP Mono-isobutyl Phthalate, MMP Mono-methyl Phthalate, MMCHP Mono-2-methylcarboxyhexyl phthalate, MnBP Mono-n-butyl Phthalate, MoBA The Norwegian Mother & Child Cohort Study (den norske Mor & barn-undersøkelsen), MPS Mental Processing Scale, MSCA McCarthy Scales of Children's Abilities, OH-MiNP Mono-4-methyl-7-hydroxyoctyl phthalate, OH-PCB Hydroxylated Polychlorinated Biphenyl, OPP Organophosphate Pesticides, oxo-MiNP Mono-4-methyl-7oxooctyl phthalate, PBDE Polybrominated Diphenyl Ethers, PCB Polychlorinated Biphenyls, PIQ Performance Intelligence, PPS Perceptual Performance Scale, PPVT Peabody Picture Vocabulary Test, PRI Perceptual Reasoning Index, SB5 Standford Binet 5, SCDS Seychelles Child Development Study, SON-R Snijders-Oomen Nonverbal Intelligence Test, TMICS Taiwan Maternal and Infant Cohort Study, TSCD Tohoku Study of Child Development, UK United Kingdom, USA United States of America, VCI Verbal Comprehension Index, VIQ Verbal Intelligence, VS Verbal Scale, VSI Visual Spatial Index, WISC-III Wechsler Intelligence Scale for Children, Third Edition, WISC-IV Wechsler Intelligence Scale for Children, Fourth Edition, WISC-III-NL Wechsler Intelligence Scale for Children, Third Edition, Netherlands Version, WISC-R Wechsler Intelligence Scale for Children, Revised, WPPSI-III Wechsler Preschool & Primary Scale of Intelligence, Third Edition, WPPSI-R Wechsler Preschool & Primary Scale of Intelligence, Revised, WRAT-III Wide Range Achievement Test, Third Edition