Association Between Heavy Metal Exposure and Autism Spectrum Disorders: Discrepancies, Research Gaps, and Future Priorities of Human Epidemiological Studies

Autism spectrum disorder (ASD) in children is a major public health challenge. The potential epidemiological links between heavy metal exposure and ASD remains a controversial issue. This critical review examines the epidemiological discrepancies, including variations in exposure assessment, study design, and population differences that contribute to the ongoing debate. Key research gaps, such as the need for longitudinal studies and mechanistic insights, are addressed. Finally, we outline future priorities to advance understanding of heavy metals' role in ASD. Lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As) were selected heavy metals. The PubMed and Scopus databases, as well as the Google Scholar search engine, were searched to retrieve original research articles on human epidemiological studies that utilized the selected "exposure keywords" in conjunction with the "outcome keywords." Finally, 36 full-length articles, irrespective of age, sex, regions, and race/ethnicity, were included for the present review. We revealed inconsistent associations between prenatal and childhood urinary, blood, and hair, As and Cd exposure, and ASD outcomes. In contrast, elevated prenatal and early childhood Pb and Hg concentrations in blood and hair samples showed a significant consistent association with both increased ASD risk and symptom severity, even after adjustment for key demographic and environmental confounders. The findings are inconsistent across metals and studies, and should be interpreted with caution due to potential residual confounding and heterogeneity in exposure assessment methods. Large prospective cohort studies are needed to clarify causal relationships. The path analysis of relevant biomarkers is also warranted to establish biological mechanism.