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., $>100\mathrm{\mu }\mathrm{g}/\mathrm{L}$) 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 $<5\mathrm{\mu }\mathrm{g}/\mathrm{L}$. 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

中文翻译：

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儿童时期饮用水中锰的暴露及其与注意力缺陷多动障碍的关系：一项全国性队列研究

摘要

背景：

饮用水中的锰可能会增加一些神经发育结局的风险，包括注意力缺陷多动障碍（ADHD）。较早的关于锰暴露与多动症相关结局之间关联的流行病学研究样本规模小，缺乏时空暴露评估，并依赖于问卷数据（非诊断），这是我们在此解决的不足。

目的：

我们的目标是评估儿童时期饮用水中锰的暴露与多动症后期发展之间的关系。

方法：

在丹麦的一项基于全国人口的注册表研究中，我们追踪了1992年至2007年出生的643,401名儿童的临床诊断多动症。在子分析中，我们根据国际疾病分类（ICD）-10代码的分层分类将病例分为注意力不集中和注意力缺陷多动障碍合并子类型。我们从82,574个饮用水样本中获得了Mn值，以较高的时空分辨率估算了生命的前5年中的纵向暴露。我们将暴露建模为峰浓度和时间加权平均值。我们在针对年龄，出生年份，社会经济地位（SES）和城市化程度进行调整的Cox比例风险模型中估计了特定性别的风险比（HRs）。

结果：

我们发现，饮用水中锰含量的升高与注意力不集中多动症亚型风险增加有关，而注意力不集中多动症亚型风险增加。在对年龄，出生年份和SES进行调整后，女性暴露于高水平的Mn（即，$>100\mathrm{\mu }\mathrm{G}/\mathrm{大号}$）在其生命的前5年中至少有一次ADHD注意力不集中亚型的HR为1.51 [95％置信区间（CI）：1.18，1.93]，男性为1.20（95％CI：1.01，1.42）暴露于 $<5\mathrm{\mu }\mathrm{G}/\mathrm{大号}$。当将暴露作为时间加权平均值建模时，性别差异不再存在。

讨论：

饮用水中的锰与多动症有关，特别是注意力不集中的多动症亚型。我们的研究结果支持较早的研究，表明需要正式的基于健康的锰饮用水准则值。未来的锰研究应检查多动症亚型特异性的关联，并利用直接亚型的测量，而不是仅依靠ICD-10代码。https://doi.org/10.1289/EHP6391