Joint and Independent Neurotoxic Effects of Early Life Exposures to a Chemical Mixture: A Multi-pollutant Approach Combining Ensemble Learning and G-computation

Background: Exposure to mercury (Hg) is associated with adverse developmental effects. However, Hg occurs with a multitude of chemicals. We assessed the associations of developmental exposure to multiple pollutants with children's neurodevelopment using a novel approach.

Methods: Hg, polychlorinated biphenyls (PCBs), and perfluoroalkyl substances were measured in maternal and children's blood at 5-years (n=449 and 419). At 7-years, children were administered Boston Naming Test (BNT) and the Strengths and Difficulties Questionnaire (SDQ). We used the G-formula combined with SuperLearner to estimate independent and joint effects of chemicals at both ages. We constructed flexible exposure-response relationships and assessed interactions.

Results: Most chemicals showed negative relationships with BNT scores. An inter-quartile range (IQR) increase in maternal Hg and perfluorooctanoic acid (PFOA) was associated with 0.15 standard deviation [SD] (95% Confidence Interval [CI]: -0.29,-0.03) and 0.14 SD (95%CI: -0.26,-0.05) lower scores in BNT, whereas a joint IQR increase in the mixture of chemicals was associated with 0.48 SD (95%CI: -0.69,-0.25) lower scores in BNT. An IQR increase in PFOA was associated with 0.11 SD (95%CI: 0.02,0.26) higher total SDQ difficulties scores. Maternal ∑PCBs concentrations were associated with lower SDQ scores (β=-0.09 SD; 95%CI: -0.19,0), whereas 5-years ∑PCBs showed a negative association (β=-0.09 SD; 95%CI: -0.21,0). Finally, a joint IQR increase in the mixture was associated with 0.22 SD (95%CI: 0.04,0.4) higher SDQ scores.

Conclusions: Using a novel statistical approach, we confirmed associations between prenatal mercury exposure and lower cognitive function. The potential developmental effects of PFASs need additional attention.