Broberg et al. Discussion This is to our knowledge the first study investigating the potential health impact of long-term lithium exposure from drinking water and other environmental sources on the thyroid. We found an association between lithium exposure, as assessed by lithium con- centrations in urine, and markers of thyroid function. The positive associations between lithium and TSH and the inverse association between lithium and T4 are consistent with reports of hypothyroidism as a side effect of chronic use of lithium medication (Grandjean and Aubry 2009b; Lazarus 2009). Lithium treatment is also associated with weight gain (Grandjean and Aubry 2009b); however, we noted only a small, nonsignificant association between urinary lithium concentration and BMI in our study population. The positive association with T4 and inverse association with TSH suggest that selenium may have had a beneficial effect on thyroid function in this population, but, contrary to expectations, we did not observe similar associations with iodine. Cesium was not associated with T4 or TSH, despite accumulation of cesium in the thyroid (Bandazhevsky 2003). The main strength of our study is the use of a biomarker of lithium exposure in urine combined with analysis of biomarkers for sele- nium, iodine, and cesium—all elements that may influence thyroid function—as well as sensitive markers in plasma of effect on the thyroid. However, the study has a few weak- nesses. First, several elements were highly correlated in both drinking water and urine (Concha et al. 2010); thus, it is not possible to account for potential confounding by other elements, particularly boron. Nevertheless, whereas lithium was associated with both T4 and TSH, boron was associated with T4 only. To our knowledge, there are no data that show that boron is toxic to the thyroid; because little is known about the toxicology of boron, the possibility that boron may influence T4 cannot be excluded. In contrast, arsenic and cesium were not associated with TSH or T4. A second limitation is that we were not able to enroll a random sample of women, although we tried to recruit a representative population of the women living in this area. Finally, the cross- sectional nature of the study limits our ability to determine temporal relations between lith- ium exposures and the outcomes assessed. We believe that exposure levels would have been relatively stable over time, and that they would have begun very early in life. In support of this notion, the levels of lithium in drinking water, which contributes to a substantial fraction of the lithium in urine, have been stable during the period measured (2004–2008; Concha et al. 2010), and most of the women had lived in the area > 2 years. Apart from our study, there are very few reports on the health effects of chronic lithium exposure besides the side effects of medication. In a recent study of suicide risk in relation to lithium concentrations in tap water in 18 municipalities of Oita prefecture in Japan, Ohgami et al. (2009) reported that the standardized mortality ratio for suicide was inversely associated with water lithium concentrations. In that study, water concen- trations ranged from 0.7 to 59 gμ/L, in con - trast with a range from 8 to 1,005 μg/L in our study population (Concha et al. 2010). The Oita study has also been criticized for not considering lithium intake via food, which may reach > 100 μg/day (Desai and Chaturvedi 2009). In the present study, we estimated associations with urinary lithium concentrations, a biomarker of total exposure. T4 was negatively correlated, and TSH weakly positively correlated with BMI. These associations may have been due to an effect of lithium on the thyroid, but we could not prove it statistically. In contrast with lithium, selenium was inversely associated with TSH and positively associated with T4. The pos- sibility of an effect of selenium on thyroid function is consistently correlated with thy- roid markers, which is in accordance with the proposed role of selenoenzymes, includ- ing deiodinase activities (Lu and Holmgren 2009). However, because the deiodinases regulate the conversion of T4 to the thyroid hormone triiodothyronine (T3), we would expect selenium to be inversely associated with T4. Selenium is also present in seleno- proteins such as glutathione peroxidase and the thioredoxin reductase family, which are important for protection of the thyroid gland from excess hydrogen peroxide and reactive oxygen species produced by the follicles for biosynthesis of thyroid hormones (Kohrle and Gartner 2009; Lu and Holmgren 2009; Prummel et al. 2004). We found no asso- ciation between urinary iodine and the thy- roid markers among the women in our study population, most of whom had adequate iodine status (WHO et al. 2007), with 62% having urinary concentrations > 100 μg/L. This suggests that the observed associations of lithium with markers of thyroid function were not due to confounding by low iodine con- centrations. Because the iodine concentrations in this population were relatively high, we could not analyze the combined effect of high lithium and low iodine concentrations on thyroid function. Further studies on geographic distribution of elevated lithium concentrations in drinking water, as well as studies of the effects of expo- sure to lithium via drinking water and other environmental sources in women, men, and children, are highly warranted. 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