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De Groef
Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects.De Groef B, Decallonne BR, Van der Geyten S, Darras VM, Bouillon R. Eur J Endocrinol. 2006 Jul;155(1):17-25. Review. [abstract only]
"OBJECTIVE: Perchlorate is a known competitive inhibitor of the sodium/iodide symporter (NIS). Possible thyroid-related effects of environmental perchlorate have created great health concerns, especially in the US, resulting in a debated reference dose (RfD) of 0.0007 mg/kg per day in drinking water recommended by the National Academy of Sciences (NAS). However, the impact of other environmental NIS inhibitors and the role of iodine seem to have received little attention in the whole debate.
METHODS: We performed a PubMed search for articles published up to February 2006, using the key terms perchlorate, nitrate, thiocyanate, iodine, NIS, RfD, thyroid (alone or in combinations), with particular attention for human studies. In parallel, we critically analysed the January 2005 NAS' report, entitled 'Health implications of perchlorate ingestion'.
RESULTS: The relative potencies of prevalent environmental NIS inhibitors (nitrate, thiocyanate and perchlorate) to inhibit iodine uptake have been estimated repeatedly with robust results. Our calculations show that nitrate and thiocyanate, acquired through drinking water or food, account for a much larger proportion of iodine uptake inhibition than perchlorate. Furthermore, the iodine uptake inhibitory effects of nitrate and thiocyanate - as defined by their legally accepted maximal contaminant levels in drinking water - exceed the potential effect of the proposed RfD for perchlorate by far.
CONCLUSIONS: Iodine uptake inhibition and any potential downstream effect by perchlorate are highly dependent on the presence of other environmental NIS inhibitors and iodine intake itself. These potential confounders should therefore be considered in future studies and calculations for risk assessment.
"Thiocyanate, having a half-life of approximately 6 days as compared to 8 and 5 h for perchlorate and nitrate respectively, remains in the serum 18-29 times longer than the other anions. Based on these differences in half-lives, the perchlorate equivalency ratios of thiocyanate and nitrate in terms of ingested-weight basis have been recalculated to be 0.5 and 240 respectively."
"The concentration of nitrate allowed in drinking water would cause an I- uptake inhibitory effect that is 12 times greater than that of perchlorate."
"The thyrotoxic potential of perchlorate cannot be seen separately from the effects of other NIS inhibitors such as nitrate and thiocyanate."
"Perchlorate only accounts for a small portion (<10%) of the exposure from drinking water."
"In addition to drinking water, food also contains considerable amounts of nitrate and thiocyanate. Using milk and lettuce as examples, it becomes evident that the contamination of monovalent anions in food expressed as PECs is much higher than what is actually present in the contaminated drinking water sources.... Food contamination is predominantly due to the high levels of nitrate and thiocyanate that would account for 98.83 and 99.98% of the total NIS I- uptake inhibition caused by milk and lettuce respectively. These numbers hardly change when a 50% absorption of thiocyanate in the gut is taken into account: 97.84 and 99.97% for milk and lettuce respectively. Eating just 50 g lettuce would cause an I- uptake inhibition exceeding the effect of the maximum allowed concentration of 24.5 p.p.b. perchlorate in drinking water by 140 times. By drinking just 100 ml milk, an average 70-kg adult has already been exposed to an equivalent of the perchlorate RfD."
"Considering all these data, it is obvious that either the RfD for perchlorate is unrealistically strict, or the MCLs for nitrate and thiocyanate are far too high and should be revised accordingly. The latter is hardly possible, as the natural nitrate content of a crop like lettuce or spinach -- even grown without fertilizer -- would already exceed such an RfD."
"Dietary iodine. An important issue in environmental exposure to NIS inhibitors is the modulation of inhibition by dietary iodine. The model of competitive inhibition developed by Tonacchera et al. predicts that thyroidal I- uptake is approximately proportional to iodide nutrition for any fixed underlying goitrogen load. Unfortunately, little or no data are available on the daily-required dose of dietary I- to withstand inhibition of NIS I- uptake by perchlorate nitrate and thiocyanate present in drinking water and food. The model of Tonacchera et al does not predict the levels of dietary I- and goitrogen load at which effects on thyroid economy will occur.... Iodine supplementation should be given to any person showing iodine deficiency, irrespective of whether there is significant exposure to environmental perchlorate, nitrate, thiocyanate or foods that naturally contain these anti-thyroid compounds or their precursors."
"Other more prevalent NIS competitors such as nitrate and thiocyanate are not acknowledged, while the effect of perchlorate cannot be seen separately from the effects of these anions. Taking into account their individual I- uptake inhibition potential at the level of NIS, which can be considered as robust since several studies agree on the perchlorate equivalence ratios, our calculations show that perchlorate accounts for less than 10% of possible thyroidal effects resulting from the exposure from drinking water; in food, its share is even negligible. The enormous discrepancy between the safe NOEL-based RfD for perchlorate (in the context of iodine uptake inhibition) and the disproportionately high -- legally binding -- LOEL-based RfD for nitrate (in the context of acquired methaemoglobinaemia) is not logical, and measures should be taken accordingly. Due to heterogeneity at several levels (inclusion of prevalent NIS inhibitors, type of exposure, populations exposed and measures of exposure) a meta-analysis of available human data -- if at all possible -- would probably not reveal new conclusions, underlining the need for scientific evidence from carefully designed human clinical studies evaluating the effects of nitrate and thiocyanate (along with dietary iodine) on I- uptake inhibition, in order to determine RfDs for all prevalent NIS inhibitors in drinking water and food. Moreover, further animal studies are needed, investigating not only thyroidal, but also neurodevelopmental endpoints in circumstances of controlled intake of iodine, perchlorate, nitrate and thiocyanate.."
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