The NAS perchlorate review: is the RfD acceptable?

Risk assessors should always carefully evaluate whether a given reference dose (RfD) is the most appropriate choice for assessing risk. In the case of perchlorate, Ginsberg and Rice (2005) suggested that the RfD proposed by the National Research Council (NRC) is inappropriate because the NRC did not thoroughly evaluate the underlying science. However, we suggest that the NRC RfD is inappropriate because of the NRC's "unconventional" approach.

In contrast to Ginsberg and Rice (2005), we applaud the insightful and conclusive discussion of the science of perchlorate and the thyroid by the NRC (2005). The NRC concluded that human studies are the most relevant for risk assessment, and that the thyroid has a remarkable ability to compensate for iodine deficiency, so that hypothyroidism would be the first observed adverse effect. By definition, this is perchlorate's critical effect (Faustman and Omenn 2001), although U.S. Environmental Protection Agency (EPA) methods allow for the use of a known and immediate precursor (the choice of immediate precursor is based on practice of using the highest no observed adverse effect level (NOAEL) of the critical effect and is codified in several places (e.g., Barnes and Dourson 1988, p. 473). The NRC also concluded that in healthy adults the perchlorate dose required to cause hypothyroidism would be > 0.4 mg/kg-day.

In risk assessment parlance, this dose would be a NOAEL of the critical effect. The practice of risk assessment allows us to draw conclusions about public health in the absence of observable data and in the presence of scientific uncertainty. The traditional practice of developing RfD, a dose-response part of risk assessment (Barnes and Dourson 1988), would suggest two possible approaches to developing an RfD from the perchlorate data. The first would be to use the NOAEL of the critical effect from an adult population and apply uncertainty factors to account for sensitive populations and for lack of precision in defining a NOAEL. The second approach would be to use the NOAEL of an immediate precursor effect in a sensitive population and apply appropriate uncertainty factors.

Using the first approach with the NRC NOAEL, the RfD would lie in the range of 0.04-0.004 mg/kg-day depending on the choice of uncertainty factor. Using the second approach, a NOAEL of 0.005 mg/kg-day (Gibbs et al. 2004) can be identified from thyroid hormone and goiter data in a sensitive population. The RfD based on this approach would lie near the value of 0.002 mg/kg-day proposed by Strawson et al. (2004).

In contrast, the approach the NRC actually used was a nonstandard approach for developing an RfD based on the inhibition of iodine uptake, a distant precursor to the critical effect. This nonstandard approach yields a safe dose, but it is not an RfD, by definition, because, according to the NRC's own scheme, it is not based on the critical effect or its known and immediate precursor.

We continue to advocate that the best risk assessment approach for perchlorate is to use data collected from sensitive populations such as children and, in particular, the published and ongoing work in Chile. This is consistent with the NRC's conclusion that the data from Chile could be considered in the evaluation of the U.S. experience with perchlorate in drinking water (NRC 2005). Specifically, the Chilean experience (Crump et al. 2000; Tellez et al. 2005) can be used to help frame the public debate in the United States, which suggests perchlorate water standards as low as 1 ppb. In Chile, perchlorate water concentrations of 100-120 ppb do not result in an exposure that would inhibit iodine uptake inhibition in adults. In fact, these concentrations have not caused any adverse effects in pregnant women, neonates, or older children exposed chronically. Following traditional RfD methods and using data from a sensitive human population results in an RfD that can be used with high confidence in the United States.

Toxicology Excellence for Risk Assessment (TERA) is a nonprofit organization dedicated to the best use of toxicity dam for risk values.

The authors have collectively studied the toxicity of perchlorate since 1991 on behalf of U.S. EPA and the nonprofit corporation Toxicology Excellence for Risk Assessment at the request of the Perchlorate Study Group. Opinions expressed in this commentary, however, reflect solely those of the authors and not of any organization or other individual. Resources to support this technical commentary were provided by the developmental reserve fund of TERA.

REFERENCES

Barnes DG, Dourson ML. 1988. Reference dose (RfD): description and use in health risk assessments. Regul Toxicol Pharmacol 8:471-486.

Crump C, Michaud P, Tellez R, Reyes C, Gonzalez G, Montgomery EL, et al. nction in newborns or school-age children? J Occup Environ Med 42: 603-612.

Faustman EM, Omenn GS. 2001. Risk Assessment. In: Casarett and Doull's Toxicology: The Basic Science of Poisons (Klaassen CD, ed.). 6th ed. New York: McGraw-Hill, 92.

Gibbs JP, Narayanan L, Mattie DR. 2004. Crump et al. study among school children in Chile: subsequent urine and serum perchlorate levels are consistent with perchlorate in water in Taltal. J Occup Environ Med 46(6):516-517.

Ginsberg G, Rice D. 2005. The NAS perchlorate review: questions remain about the perchlorate RfD. Environ Health Perspect Environ Health Perspect 113:1117-1119; doi:10.1289/ehp.8254 [Online 25 May 2005].

NRC (National Research Council). 2005. Health Implications of Perchlorate Ingestion. Washington, DC:National Academies Press.

Strawson J, Zhao Q, Dourson M. 2004. Reference dose for perchlerate based on thyroid hormone change in pregnant women as the critical effect. Regul Toxicol Pharmacol 39:44-65.

Tellez RT, Michaud P, Reyes C, Blount BC, Van Landingham CB, Crump KS, et al. 2005. Long-term environmental exposure to perchlorate through drinking water and thyroid function during pregnancy and the neonatal period. Thyroid 15(9):963-975.

Joan Strawson

Michael L. Dourson

Qiyu (Jay) Zhao

Toxicology Excellence for Risk Assessment

Cincinnati, Ohio

E-mail: [e-mail]