Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. 
Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. What was reviewed?
This systematic review critically evaluated and synthesized the global literature on the associations between early-life exposure to toxic heavy metals and neurodevelopmental outcomes in children. The review included 68 observational studies (48 longitudinal, 20 cross-sectional), published between 2006 and 2025, and extracted data from diverse regions and populations. The heavy metals of interest were lead (Pb), mercury (Hg), cadmium (Cd), arsenic (As), and, to a lesser extent, manganese (Mn) and other trace metals. The review focused on studies that measured heavy metal concentrations in biological samples (maternal blood, urine, hair, milk, or umbilical cord blood; child blood, urine, hair, nails) and assessed neurodevelopment using validated, standardized instruments. Its goal was to provide an updated, comprehensive synthesis of how prenatal and early childhood exposure to these metals affects cognitive, motor, behavioral, and social developmental domains.
Who was reviewed?
The systematic review encompassed a total sample of 215,195 individuals, with study populations drawn from 23 countries, including Japan, China, Spain, Norway, South Korea, Saudi Arabia, Mexico, Brazil, the USA, India, Taiwan, Italy, Canada, Seychelles, Greece, Bangladesh, Tanzania, Poland, Nepal, Bolivia, Malaysia, and the Democratic Republic of Congo. The reviewed studies largely concentrated on children in early life stages, particularly infancy (0–2 years), preschool (2–6 years), and, to a lesser extent, middle childhood and preadolescence. Both male and female children were included, with most studies reporting a male predominance. The review included studies with and without formal diagnoses of neurodevelopmental disorders, provided that neurodevelopmental assessments were conducted using validated tools. Most samples came from population-based cohorts, and exposure was typically determined via biomonitoring of heavy metals in relevant maternal or child specimens.
Most important findings
| Key Findings | Relevance to HTMC Certification and Regulation |
|---|---|
| Lead (Pb) exposure demonstrated the most consistent and robust association with cognitive, motor, and behavioral impairments, especially when exposure occurred prenatally. | Highlights the need for stringent Pb limits in consumer products, food, and environments, especially for pregnant women and children. |
| Mercury (Hg) and methylmercury (MeHg) exposures were frequently linked to cognitive and motor delays, behavioral issues, and global neurodevelopmental deficits, though some studies noted positive effects likely due to confounding from fish-derived nutrients. | Emphasizes the importance of considering both sources and forms of Hg in certification, and the necessity to distinguish between toxic effects and nutritional confounding. |
| Cadmium (Cd), arsenic (As), and manganese (Mn) exposures were also associated with increased risks of neurodevelopmental disorders, including ADHD and ASD, as well as impairments in cognition, motor skills, and social behavior. | Justifies the inclusion of these metals in HTMC testing panels and the need for low permissible exposure thresholds. |
| Most adverse associations were seen with prenatal exposures, particularly during the first trimester, identifying critical windows of vulnerability for the developing brain. | Underlines the significance of exposure prevention strategies targeted at pregnant women and infants within HTMC protocols. |
| Most effect sizes were small, but moderate and large effects were reported, especially for Pb, Cd, and Hg. The clinical and public health impact is magnified by the ubiquity and cumulative nature of exposure. | Even small effect sizes justify low regulatory limits due to large population-level consequences. |
| Biological sample type, metal measurement method, and developmental assessment instrument varied widely, contributing to heterogeneity in results. | Points to the need for standardization in testing and reporting requirements for certification programs. |
| Some studies observed positive or null associations, particularly with Hg in populations with high fish consumption, suggesting that nutritional context can modulate toxic effects. | HTMC should account for dietary sources and potential confounding in exposure-risk assessments. |
Key implications
The review confirms that early-life exposure to heavy metals, especially lead, mercury, cadmium, and arsenic, is reliably associated with adverse neurodevelopmental outcomes, most strongly when exposure occurs prenatally. HTMC certification programs should prioritize stringent, low thresholds for these metals in products intended for pregnant women and young children. Because small effect sizes can yield major population impacts, even trace exposures warrant regulation. Standardized testing methods and validated assessment tools should be mandated to ensure the reliability of certification and facilitate international harmonization. Certification criteria should also consider the cumulative and interactive effects of multiple metals, as well as population-specific dietary and environmental factors that may influence risk. Ultimately, certification programs grounded in the evidence base provided by this review will be better positioned to protect vulnerable populations and support regulatory alignment globally.
Citation
da Silva, A.S., Santos, R.M.S., De Marco, P.G., Rezende, V.H.M., Martins, T.C., Silva, J.R., Romano-Silva, M.A., & Miranda, D.M.d. (2025). Neurodevelopmental Outcomes Associated with Early-Life Exposure to Heavy Metals: A Systematic Review. International Journal of Environmental Research and Public Health, 22, 1308. https://doi.org/10.3390/ijerph22081308
Heavy metals are high-density elements that accumulate in the body and environment, disrupting biological processes. Lead, cadmium, arsenic, mercury, nickel, tin, aluminum, and chromium are of greatest concern due to persistence, bioaccumulation, and health risks, making them central to the HMTC program’s safety standards.
Lead is a neurotoxic heavy metal with no safe exposure level. It contaminates food, consumer goods and drinking water, causing cognitive deficits, birth defects and cardiovascular disease. HMTC’s rigorous lead testing applies ALARA principles to protect infants and consumers and to prepare brands for tightening regulations.
Cadmium is a persistent heavy metal that accumulates in kidneys and bones. Dietary sources include cereals, cocoa, shellfish and vegetables, while smokers and industrial workers receive higher exposures. Studies link cadmium to kidney dysfunction, bone fractures and cancer.
