Note to File
Date
June 15, 2020
From
Samuel Hernandez P.E., Perchlorate Team Leader, U.S. Environmental Protection Agency
Subject
Recent Perchlorate Study

The EPA has reviewed the research study Allosteric Regulation of Mammalian Na+/I−Symporter Activity by Perchlorate published in May 2020 by Llorente-Esteban et al., in which the authors find that in vitro electrophysiological experiments have shown that the transport mechanism of iodide by the NIS protein is prevented when perchlorate competes for the binding of sodium by further reducing the stoichiometry of available iodide transport sites. The results of this new mechanistic study appears to be consistent with the EPA's analysis of the impacts of perchlorate on the thyroid and the Agency's derivation of the proposed Maximum Contaminant Level Goal (MCLG) for perchlorate.
While Llorente-Esteban et al.(2020), provide some new information about the mechanism of perchlorate's iodide uptake inhibition (IUI), the EPA does not believe that this new information would lead the Agency to a different MCLG from the one proposed by the Agency in 2019. The EPA utilized a Biologically Based Dose Response (BBDR) model to predict IUI and subsequent changes in thyroid hormone production (USEPA 2018). 
In addition, the BBDR model's estimates of IUI were verified against results from a human in vivo study that measured IUI attributable to perchlorate exposure (Greer et al., 2002) and were found to be consistent. Furthermore, because Greer et al. (2002) was conducted using human test subjects, the mechanism described by Llorente-Esteban et al. (2020) is assumed to be operational and thus represented in the Greer et al. (2002) results. Therefore, the Agency does not believe that refinements in modeling based on the new in vitro study are needed.
The EPA developed the BBDR model in response to recommendations from the Science Advisory Board (SAB, 2013). The EPA conducted two independent peer reviews of the BBDR model and methodology to derive a perchlorate MCLG in 2017 and 2018. The peer review panel determined the models were "fit for purpose" to inform an MCLG for perchlorate (External Peer Reviewers for U.S. EPA. 2017, 2018).

References:
External Peer Reviewers for U.S. EPA. (2017). External Peer Review of EPA's Draft Biologically Based Dose-Response Model and Draft BBDR Model Report for Perchlorate in Drinking Water.
External Peer Reviewers for U.S. EPA. (2018). External Peer Review for U.S. EPA's Proposed Approaches to Inform the Derivation of a Maximum Contaminant Level Goal for Perchlorate in Drinking Water.
Greer, M.A., Goodman, G., Pleus, R.C., Greer, S.E. (2002). Health effects assessment for environmental perchlorate contamination: The dose response for inhibition of thyroidal radioiodine uptake in humans. Environmental Health Perspectives. 110 (9), 927-937.
Llorente-Esteban, A., Manville, R.W., Reyna-Neyra, A., Abbott, G.W., Amsel, L.M., Carrasco, N. (2020) Allosteric regulation of mammalian Na+/I− symporter activity by perchlorate. Nat Struct Mol Biol. https://doi.org/10.1038/s41594-020-0417-5.
SAB for the U.S. EPA. (2013). SAB Advice on Approaches to Derive a Maximum Contaminant Level Goal for Perchlorate. EPA-SAB-13-004.
USEPA. (2018). Proposed Approaches to Inform the Derivation of a Maximum Contaminant Level Goal for Perchlorate in Drinking Water. EPA 816-R-19-008.
