Measuring the impact of manganese exposure on children's neurodevelopment: advances and research gaps in biomarker-based approaches

Background: Children's exposure to manganese (Mn) is a public health concern and consistent policy guidelines for safe levels of Mn exposure is lacking. The complexity of establishing exposure thresholds for Mn partially relates to its dual role as an essential micronutrient with low levels required for good health, but also as a neurotoxin at high levels. Questions exist about the age-related susceptibility to excess Mn, particularly for children, and how best to measure chronic exposures. To address this concern we conducted a systematic review of studies examining children's exposure to Mn and neurodevelopmental outcomes focused on selection of biomarker-based and environmental measurements of Mn exposure to identify the scientific advances and research gaps. Methods: PubMed and EMBASE databases were searched through March 2016 for studies that were published in English, used a biomarker-based or environmental measurement of Mn exposure, and measured at least one neurological outcome for children aged 0-18 years. Ultimately, thirty-six papers from 13 countries were selected. Study designs were cross-sectional (24), prospective cohorts (9), and case control (3). Neurodevelopmental outcomes were first assessed for Mn exposure in infants (6 papers), toddlers or preschoolers (3 papers) and school-age children (27 papers). Results: Studies of school-aged children most frequently measured Intelligence Quotient (IQ) scores using Mn biomarkers of hair or blood. Higher hair concentrations of Mn were consistently associated with lower IQ scores while studies of blood biomarkers and IQ scores had inconsistent findings. Studies of infants and toddlers most frequently measured mental and psychomotor development; findings were inconsistent across biomarkers of Mn (hair, cord blood, tooth enamel, maternal or child blood and dentin). Although few studies measured environmental sources of Mn, hair biomarkers were associated with Mn in drinking water and infant formula. Only one paper quantified the associations between environmental sources of Mn and blood concentrations. Conclusion: Hair-Mn was the more consistent and valid biomarker of Mn exposure in school-aged children. Accurate measurement of children's exposure to Mn is crucial for addressing these knowledge gaps in future studies. However, research on biomarkers feasible for fetuses and infants is urgently needed given their unique vulnerability to excessive Mn.