Exposure to Manganese in Drinking Water during Childhood and Association with Attention-Deficit Hyperactivity Disorder: A Nationwide Cohort Study

Abstract

Background: Manganese (Mn) in drinking water may increase the risk of several neurodevelopmental outcomes, including attention-deficit hyperactivity disorder (ADHD). Earlier epidemiological studies on associations between Mn exposure and ADHD-related outcomes had small sample sizes, lacked spatiotemporal exposure assessment, and relied on questionnaire data (not diagnoses)-shortcomings that we address here.

Objective: Our objective was to assess the association between exposure to Mn in drinking water during childhood and later development of ADHD.

Methods: In a nationwide population-based registry study in Denmark, we followed a cohort of 643,401 children born 1992-2007 for clinical diagnoses of ADHD. In subanalyses, we classified cases into ADHD-Inattentive and ADHD-Combined subtypes based on hierarchical categorization of International Classification of Diseases (ICD)-10 codes. We obtained Mn measurements from 82,574 drinking water samples to estimate longitudinal exposure during the first 5 y of life with high spatiotemporal resolution. We modeled exposure as both peak concentration and time-weighted average. We estimated sex-specific hazard ratios (HRs) in Cox proportional hazards models adjusted for age, birth year, socioeconomic status (SES), and urbanicity.

Results: We found that exposure to increasing levels of Mn in drinking water was associated with an increased risk of ADHD-Inattentive subtype, but not ADHD-Combined subtype. After adjusting for age, birth year, and SES, females exposed to high levels of Mn (i.e., $>100\mu g/L$) at least once during their first 5 y of life had an HR for ADHD-Inattentive subtype of 1.51 [95% confidence interval (CI): 1.18, 1.93] and males of 1.20 (95% CI: 1.01, 1.42) when compared with same-sex individuals exposed to $<5\mu g/L$. When modeling exposure as a time-weighted average, sex differences were no longer present.

Discussion: Mn in drinking water was associated with ADHD, specifically the ADHD-Inattentive subtype. Our results support earlier studies suggesting a need for a formal health-based drinking water guideline value for Mn. Future Mn-studies should examine ADHD subtype-specific associations and utilize direct subtype measurements rather than relying on ICD-10 codes alone. https://doi.org/10.1289/EHP6391.

Figure 1.

Geographical distribution of manganese concentrations in public drinking water across Denmark. Each dot represents one of the 3,509 waterworks. Most recent sample at each waterworks by end of exposure period (December 2012). The island of Bornholm is shown in the top left inset. For temporal changes refer to Video S1.

Figure 2.

Hazard ratios (HRs) for the association between highest exposure to manganese in drinking water during the first 5 y of life and ADHD by subtype for (A) females and (B) males. Smoothed HRs with 95% CIs. Cox proportional hazards model with age as underlying time scale and additionally adjusted for birth year and SES (maternal highest attained education and paternal income). Values below detection limit ($5\mathrm{\mu }\mathrm{g}/\mathrm{L}$) were imputed using robust regression on order statistics. Given that exposure is skewed to the right and CIs increase along with fewer study population members in the high end of exposure, only exposures until $750\mathrm{\mu }\mathrm{g}/\mathrm{L}$ (99% percentile of the study population) are shown in this figure for better visualization. Note: ADHD, attention-deficit hyperactivity disorder; CI, confidence interval; SES, socioeconomic status.