Authors' Response To the Editor: We appreciate the interest Dr Kimbrough has taken on this topic, but the data he presents provides little reason to alter our conclusions. First, Dr Kimbrough suggests that nitrate levels of 31 mg/L caused the effects we identified for perchlorate. However, this level is below the US Environmental Protection Agency's (EPA) Maximum Contaminant Level, California EPA's Public Health Goal, and the World Health Organization's guideline value,1–3 and we have not found any human evidence linking drinking water nitrate concentrations this low to changes in thyroid hormones. In fact, in an experimental human dosing study by Hunault et al,4 oral doses of sodium nitrate in water of about 1000 mg/day (many times higher than the levels cited by Dr Kimbrough) were not associated with changes in thyroid hormone levels. Second, Dr Kimbrough discusses the potency of perchlorate relative to nitrate, citing data from a study in Chinese hamster ovary cells, transfected with human sodium-iodide symporter (NIS), placed in a laboratory plate, and exposed to single acute doses of perchlorate or nitrate5 (the primary mechanism of perchlorate and nitrate thyroid toxicity is competitive inhibition of the NIS). However, the relevance of these data to humans is not known because these experimental conditions are much different than what actually occurs in living human beings, where chronic exposures, exposures to multiple agents, lifestyle factors, demographics, illnesses, age, and complex physiologic and biochemical processes can make toxic mechanisms much more complicated. We do not believe that public health should rely on effects in hamster ovary cells on a laboratory plate, especially when human data are available. Third, Dr Kimbrough states that perchlorate intake from food is greater than that from drinking water, but cites a study where drinking water exposure was based solely on whether or not a person lived in a county where any single water sample tested positive for perchlorate.6 This probably led to major errors because many counties have many different water sources and perchlorate concentrations can vary dramatically from source to source and over time. In fact, 88.7% of all water samples collected from the “exposed” counties in this study had perchlorate concentrations below detection, highlighting the substantial misclassification that likely occurred. It should be noted that at a drinking water concentration of 7.9 μg/L (the median estimated perchlorate concentration in the exposed communities of our study),7 the perchlorate dose from water in a 66 kg pregnant women drinking 2 liters per day would be 0.24 μg/kg-day. This is 4 times the median perchlorate intake estimated to be from food (0.06 μg/kg-day).6 Fourth, the database Dr Kimbrough used to calculate nitrate-perchlorate correlations is likely biased. In California, water sources with high concentrations of nitrate or perchlorate are tested more often than water sources with low concentrations of these agents.8 Given this, it seems very likely that each time a source with a known high level of nitrate is tested for nitrate, it would also be more likely to be tested for perchlorate if a previous perchlorate measurement from the source had been high, and less likely to be also tested for perchlorate if a previous perchlorate measurement had been low. Similarly, each time a source with a known high level of perchlorate is tested, it is probably more likely to be tested for nitrate if a previous nitrate measurement had been high. Because the Kimbrough analysis excluded sources in which only nitrate or only perchlorate were tested, this nonrandom selection of sources probably caused the number of high nitrate-high perchlorate sources to be overrepresented, and the number of high nitrate-low perchlorate or high perchlorate-low nitrate sources to be underrepresented. This would cause both the reported perchlorate-nitrate correlation coefficient and the mean nitrate level in the perchlorate exposed areas to be artificially high. In summary, we thank Dr Kimbrough for reraising several important issues: the critical importance of thyroid hormone in neurodevelopment, and the fact that people are exposed to multiple agents that potentially affect thyroid hormone, including perchlorate. We discussed the possibility that nitrate was a confounder in our paper, but have found no evidence for this. We believe it is also important to note that nitrate could interact with perchlorate. That is, some people might be particularly susceptible to perchlorate because they are coexposed to other thyroid inhibiting factors like nitrate, low iodine, thiocyanate, autoimmune thyroid disease, polychlorinated biphenyls, or other factors.9–11 To fully address the effects of perchlorate, the possibility that these coexposures could make perchlorate toxicity worse needs to be considered. Craig Steinmaus, MD School of Public Health, University of California, Berkeley Mark D. Miller, MD Pediatric Environmental Health Specialty Unit, University of California, San Francisco Allan H. Smith, PhD School of Public Health, University of California Berkeley
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Nov 3, 2022
Henrik Albert Kolstad + 12
