Prenatal Exposure to DDT and Pyrethroids for Malaria Control and Child Neurodevelopment: The VHEMBE Cohort, South Africa

Background: Although indoor residual spraying (IRS) with dichlorodiphenyltrichloroethane (DDT) and pyrethroids effectively controls malaria, it potentially increases human exposure to these insecticides. Previous studies suggest that prenatal exposure to these insecticides may impact human neurodevelopment. Objectives: We aimed to estimate the effects of maternal insecticide exposure and neurodevelopment of toddlers living in a malaria-endemic region currently using IRS. Methods: The Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) is a birth cohort of 752 mother–child pairs in Limpopo, South Africa. We measured maternal exposure to DDT and its breakdown product, dichlorodiphenyldichloroethylene (DDE), in maternal serum, and measured pyrethroid metabolites in maternal urine. We assessed children’s neurodevelopment at 1 and 2 y of age using the Bayley Scales of Infant Development, third edition (BSID-III), and examined associations with maternal exposure. Results: DDT and DDE were not associated with significantly lower scores for any BSID-III scale. In contrast, each 10-fold increase in cis-DCCA, trans-DCCA, and 3-phenoxybenzoic acid were associated, respectively, with a −0.63 (95% CI: −1.14, −0.12), −0.48 (95% CI: −0.92, −0.05), and −0.58 (−1.11, −0.06) decrement in Social-Emotional scores at 1 y of age. In addition, each 10-fold increase in maternal cis-DBCA levels was associated with significant decrements at 2 y of age in Language Composite scores and Expressive Communication scores [β=−1.74 (95% CI: −3.34, −0.13) and β=−0.40 (95% CI: −0.77, −0.04), respectively, for a 10-fold increase]. Significant differences by sex were estimated for pyrethroid metabolites and motor function scores at 2 y of age, with higher scores for boys and lower scores for girls. Conclusions: Prenatal exposure to pyrethroids may be associated at 1 y of age with poorer social-emotional development. At 2 y of age, poorer language development was observed with higher prenatal pyrethroid levels. Considering the widespread use of pyrethroids, these findings deserve further investigation. https://doi.org/10.1289/EHP2129

. Wet weight (ug/L) and creatinine-adjusted (g/L) maternal urinary concentrations of pyrethroid metabolites, VHEMBE study, Limpopo South Africa. Table S2. Pearson correlation coefficients for maternal serum concentrations of p,p'-DDT and p,p' -DDE (log 10 transformed; lipid-adjusted), and urinary concentrations of pyrethroid metabolites (log 10 transformed; specific-gravity adjusted), VHEMBE study (n=705), Limpopo South Africa. Table S3. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal urinary pyrethroid metabolite concentrations measured before delivery only (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S4. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal p,p'-DDT and p,p'-DDE serum concentrations (log 10 transformed; lipid-adjusted) and children's performance on the Bayley Scales of Infant Assessment (BSID) (3 rd edition) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S5. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S6. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal p,p'-DDT and p,p'-DDE serum concentrations (log 10 transformed; lipid-adjusted) and children's performance on the Bayley Scales of Infant Assessment (BSID) (3 rd edition) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S7. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S8. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal p,p'-DDT and p,p'-DDE serum concentrations (log 10 transformed; lipid-adjusted) and children's performance on the Bayley Scales of Infant Assessment (BSID) (3 rd edition) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S9. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal p,p'-DDT and p,p'-DDE serum concentrations (log 10 transformed; lipid-adjusted) and children's performance on the Bayley Scales of Infant Assessment (BSID) (3 rd edition) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S10. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S11. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S12. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal p,p'-DDT and p,p'-DDE serum concentrations (log 10 transformed; lipid-adjusted) and children's performance on the Bayley Scales of Infant Assessment (BSID) (3 rd edition) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S13. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal p,p'-DDT and p,p'-DDE serum concentrations (log 10 transformed; lipid-adjusted) and children's performance on the Bayley Scales of Infant Assessment (BSID) (3 rd edition) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S14. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Table S15. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa. Figure S1. Directed Acyclic Graph (DAG) of possible confounding in the relationship between DDT/pyrethroid insecticides and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa.                  Table S2. Pearson correlation coefficients for maternal serum concentrations of p,p'-DDT and p,p' -DDE (log 10 transformed; lipid-adjusted), and urinary concentrations of pyrethroid metabolites (log 10 transformed; specific-gravity adjusted), VHEMBE study (n=705), Limpopo South Africa.   Coefficients show the change in scaled BSID score associated with a 10-fold increase in in maternal urinary pyrethroid metabolite concentrations. Models adjusted for maternal education, age, marital status, poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; psychometrician at the time of exam; and urine sample collection before or after delivery. Coefficients show the change in scaled BSID score associated with a 10-fold increase in maternal DDT/E serum concentrations. Models adjusted for maternal education, age, marital status, poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; and psychometrician. a Models include 696 participants. * p<0.05 Table S5. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa.
Sensitivity analysis: Preterm births removed as a covariate in the models.
BSID Measure At 1  Coefficients show the change in scaled BSID score associated with a 10-fold increase in in maternal urinary pyrethroid metabolite concentrations. Models adjusted for maternal education, age, marital status, poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; psychometrician; and time of urine collection (before or after delivery). a Due to 1 missing value, models with 3PBA had 680 participants at 1 year and 670 participants at 2 years. b Social-Emotional outcome models had 688 participants for cis-DBCA, cis-DCCA, and trans-DCCA exposures, and 687 participants for 3PBA. * p<0.05 Coefficients show the change in scaled BSID score associated with a 10-fold increase in maternal DDT/E serum concentrations. Models adjusted for maternal education, age, marital status, HIV status, and poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; and psychometrician. a Models include 646 participants. * p<0.05 Table S7. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa.
Sensitivity analysis: Maternal HIV status included in models.
BSID Measure At 1  Coefficients show the change in scaled BSID score associated with a 10-fold increase in in maternal urinary pyrethroid metabolite concentrations. Models adjusted for maternal education, age, marital status, HIV status, and poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; psychometrician; and time of urine collection (before or after delivery). a Due to 1 missing value, models with 3PBA had 678 participants at 1 year and 668 participants at 2 years. b Social-Emotional outcome models had 688 participants for cis-DBCA, cis-DCCA, and trans-DCCA exposures, and 687 participants for 3PBA. * p<0.05 Table S8. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal p,p'-DDT and p,p'-DDE serum concentrations (log 10 transformed; lipid-adjusted) and children's performance on the Bayley Scales of Infant Assessment (BSID) (3 rd edition) at 1 and 2 years, VHEMBE study, Limpopo, South Africa.
Sensitivity analysis: Restricted to subset of children with blood lead measurements; child blood lead controlled for in models. Coefficients show the change in scaled BSID score associated with a 10-fold increase in maternal DDT/E serum concentrations. Models adjusted for maternal education, age, marital status, poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; child's blood lead at 1 year; and psychometrician. a Models include 497 participants. * p<0.05 Table S9. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal p,p'-DDT and p,p'-DDE serum concentrations (log 10 transformed; lipid-adjusted) and children's performance on the Bayley Scales of Infant Assessment (BSID) (3 rd edition) at 1 and 2 years, VHEMBE study, Limpopo, South Africa.
Sensitivity analysis: Restricted to subset of children with blood lead measurements; child blood lead levels are not controlled for in models.(for comparison with Table S8). Coefficients show the change in scaled BSID score associated with a 10-fold increase in maternal DDT/E serum concentrations. Models adjusted for maternal education, age, marital status, poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; and psychometrician. a Models include 497 participants. * p<0.05 Table S10. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa.
Sensitivity analysis: Restricted to subset of children with lead measurements; child lead level controlled for in models. Coefficients show the change in scaled BSID score associated with a 10-fold increase in in maternal urinary pyrethroid metabolite concentrations. Models adjusted for maternal education, age, marital status, poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; child's blood lead at 1 year; psychometrician; and time of urine collection (before or after delivery). a Due to 1 missing value, models with 3PBA had 490 participants at 1 year and 476 participants at 2 years. b Social-Emotional outcome models had 494 participants for cis-DBCA, cis-DCCA, and trans-DCCA exposures, and 493 participants for 3PBA. * p<0.05  Coefficients show the change in scaled BSID score associated with a 10-fold increase in in maternal urinary pyrethroid metabolite concentrations. Models adjusted for maternal education, age, marital status, poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; psychometrician; and time of urine collection (before or after delivery). a Due to 1 missing value, models with 3PBA had 490 participants at 1 year and 476 participants at 2 years. b Social-Emotional outcome models had 494 participants for cis-DBCA, cis-DCCA, and trans-DCCA exposures, and 493 participants for 3PBA. * p<0.05 Table S12. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal p,p'-DDT and p,p'-DDE serum concentrations (log 10 transformed; lipid-adjusted) and children's performance on the Bayley Scales of Infant Assessment (BSID) (3 rd edition) at 1 and 2 years, VHEMBE study, Limpopo, South Africa.
Sensitivity analysis: Restricted to subset of children with hemoglobin measurements at 1-year; child hemoglobin level controlled for in models. Coefficients show the change in scaled BSID score associated with a 10-fold increase in maternal DDT/E serum concentrations. Models adjusted for maternal education, age, marital status, poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; child hemoglobin at 1 year; and psychometrician. a Models include 573 participants.  Coefficients show the change in scaled BSID score associated with a 10-fold increase in maternal DDT/E serum concentrations. Models adjusted for maternal education, age, marital status, poverty status at delivery, risk for depression (CES-D) and Raven's Coloured Progressive Matrices score (at 1-year visit); food insecurity (USD food security survey); HOME score; preterm delivery; and psychometrician. a Models include 573 participants.   Table S15. Adjusted linear regression β coefficient and 95% confidence interval (CI) for the association between maternal prenatal urinary pyrethroid metabolite concentration (specific gravity-adjusted) and children's performance on the Bayley Scales of Infant Assessment (3 rd edition) (BSID) at 1 and 2 years, VHEMBE study, Limpopo, South Africa.
Sensitivity analysis: Restricted to subset of children with hemoglobin measurements at 1-year; child hemoglobin level not controlled for in models.
(for comparison to Table S14).  Figure S2 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study.  Figure S3 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study.  Figure S4 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study.  Figure S5 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study.  Figure S6 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study.  Figure S7 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study.  Figure S8 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study.  Figure S9 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study. Figure S10 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study. Figure S11 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study. Figure S12 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study. Figure S13 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study. Figure S14 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study. Figure S15 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study. Figure S16 displays graphical output from Bayesian Kernel Machine Regression (BKMR) to indicate whether there is evidence for pair-wise interactions between chemical exposures. Plots show the exposure-response relationships of a specific chemical exposure, when the other member of the paired exposure is held at specified quantiles. For example, the second plot in the first row shows the exposure-response relationships for p,p'-DDE with the Bayley score when p,p'-DDT is held a quantiles of 10%, 25%, 50%, 75%, and 90%. The presence of non-parallel lines in these plots would provide evidence of a bivariate interaction between the paired exposures; however, each pair-wise exposure resulted in parallel lines and therefore suggests no between-chemical interactions in our study.