Perchlorate
Toxicology
For most human exposures to perchlorate, the primary impact to health is the interference of the hypothalamic-pituitary-thyroid (HPT) axis with normal thyroid function. In vertebrates, perchlorate exposure can potentially disrupt normal thyroid function including thyroid hormone regulation of embryonic development. Perchlorate inhibits iodine uptake by thyroid follicular cells via the sodium-iodine symporter (NIS) protein. Invertebrates lack the HPT axis, but do have NIS homologs; however, mechanisms of perchlorate toxicity to invertebrates are less well-understood. Recent advances in the use of mechanistic frameworks to organize toxicity and exposure data reveal that multiple species share the key molecular initiating event necessary for perchlorate-induced developmental toxicity (i.e., NIS inhibition) (Hines, 2018). The dose required for such initiation spans several orders of magnitude across invertebrate and vertebrate taxonomic groups, including humans, reflecting species-specific sensitivities and the highly conserved nature of the HPT axis across taxa (Hines, 2018).
The following sections explain further the potential impacts of perchlorate to human and ecological receptors:
Human Health
Oral exposure of perchlorate is the most common exposure route for humans. Perchlorate is quickly absorbed through the stomach and intestines and is primarily eliminated via the urine with an elimination half-life of six to eight hours (Brabant, et al., 1992). By competing with iodine at the NIS protein, perchlorate exposure can reduce the availability of iodine in the thyroid gland. Iodine, an essential nutrient, is necessary for the synthesis of the thyroid hormones, triiodothyronine (T3) and thyroxine (T4) (California EPA, 2015). If perchlorate diminishes synthesis of T3 and T4, health effects similar to those caused by iodine deficiency can arise. The nature and severity of these effects depend on the iodine status of the individual and the duration and extent of exposure (California EPA, 2004). T3 and T4 also play a critical role in the growth and development of fetuses, infants, and young children (California EPA, 2005). Therefore, pregnant and lactating women, fetuses, and infants can all be considered sub-populations sensitive to the potential effects of perchlorate. The impact of T3 and T4 disruption in the fetus can be profound, causing intellectual disabilities, reduced bone growth, and impaired motor control (Moog, et al., 2017; Mughal et al., 2018). Even minor perturbations in fetal T3 and T4 levels are thought to be associated with impaired neurological development (California EPA, 2004; Vermiglio, et al., 1990). However, some epidemiological surveys did not show evidence of increased rates of congenital hypothyroidism in Californian newborns in areas of known perchlorate drinking water contamination (Buffler, et al., 2006).
Human data for perchlorate exposures from both experimental studies (as volunteers) and as a consequence of the former therapeutic use of perchlorate in the treatment of hyperthyroid conditions such as Graves' disease are available (Greer, et al. 2002). These studies reported effects ranging from no observed effects in populations, including children, exposed to low levels of perchlorate to severe hematological effects, including fatalities due to aplastic anemia and agranulocytosis observed in patients historically treated with perchlorate at higher doses (ATSDR, 2008).
Laboratory studies with rodents are often used to provide additional evidence related to exposure to chemicals, such as perchlorate, and potential adverse effects in humans. Perchlorates added to the drinking water of pregnant rats changed the thyroid structure of male offspring at high doses, increased thyroid stimulating hormone and reduced T4 and T3 levels in rat pups. These data further support the concern for perchlorate-related impacts on thyroid function.
As of 2005, EPA concluded that perchlorate is unlikely to pose a risk for cancer in humans at doses that do not disturb thyroid function (U.S. EPA, 2005). In addition, based on in vitro and in vivo assays to determine genotoxicity (U.S. EPA, 2002; Ziegler, 1998; ManTech Environmental Technology, 1998; Ziegler, 1999; and Siglin, et al., 2000), California EPA concluded that there are no results that indicate that the perchlorates exert mutagenic or clastogenic effects that would result in carcinogenesis (California EPA, 2004).
Overall, the data support non-cancer effects (primarily impacts on thyroid function) as the primary concern for low-level and longer-term perchlorate exposure.
EPA's Integrated Risk Information System (IRIS) summary provides a reference dose (RfD) of 0.0007 mg/kg/day for perchlorate (U.S. EPA, 2005). As used by the IRIS program, the RfD is defined as an "estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects over a lifetime." This value was calculated by the National Academy of Sciences and was also adopted by the Agency for Toxic Substances and Disease Registry (ATSDR) as the chronic minimum risk level for non-cancer effects (ATSDR, 2008).
References:
Agency for Toxic Substances and Disease Registry (ATSDR), 2008. 
Toxicological Profile for Perchlorates. U.S. Department of Health and Human Services. September.
Brabant G, Bergmann P, Kirsch CM, Kohrle J, Hesch RD, von zur Muhlen A. Early Adaptation of Thyrotropin and Thyroglobulin Secretion to Experimentally Decreased Iodine Supply in Man. Metabolism. 1992;41:1093–1096.
Buffler, P.A., M.A. Kelsh, E.C. Lau, C.H. Edinboro, J.C. Barnard, G.W. Rutherford, J.J. Daaboul, L. Palmer, and F.W. Lorey, 2006. Thyroid Function and Perchlorate in Drinking Water: An Evaluation Among California Newborns, 1998. Environmental Health Perspectives. 114(5): 798-804.
California EPA, Office of Environmental Health Hazard Assessment, 2015, Public Health Goal: Perchlorate in Drinking Water, 212 pp.
California EPA, 2005. Evidence on the Reproductive and Developmental Toxicity of Perchlorate. Reproductive and Cancer Hazard Section. Office of Environmental Health Hazard Assessment. California EPA, 5 pp.
California EPA, 2004. Public Health Goal for Chemicals in Drinking Water.
Office of Environmental Health Hazard Assessment
Greer, M.A., Goodman, G., Pleus, R.C., and S.E. Greer, 2002. Health Effects Assessment for Environmental Perchlorate Contamination: The Dose Response for Inhibition of Thyroidal Radioiodine Uptake in Humans. [published correction appears in Environmental Health Perspectives. 2005 Nov; 113(11):A732] Environmental Health Perspectives. 110(9):927-937. DOI:10.1289/ehp.02110927
Hines, D.E., Edwards, S.W., Conolly, R.B. and Jarabek, A.M., 2018. A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA). Environmental Science & Technology, 52(2): 839-849.
ManTech Environmental Technology, 1998. Genotoxicity Assays for Ammonium Perchlorate. Cellular and Molecular Toxicology Program, Life Sciences and Toxicology Division, ManTech Environmental Technology, Inc. Study No. 6100-001. Final Report.
Moog, Nora K., Sonja Entringer, Christine Heim, Pathik D. Wadhwa, Norbert Kathmann, and Claudia Buss. "Influence of Maternal Thyroid Hormones During Gestation on Fetal Brain Development." Neuroscience 342 (2017): 68-100.
Mughal, Bilal B., Jean-Baptiste Fini, and Barbara A. Demeneix. "Thyroid-disrupting Chemicals and Brain Development: An Update." Endocrine Connections 7, no. 4 (2018): R160-R186.
Siglin, J.C., D.R. Mattie, D.E. Dodd, et al., 2000. A 90-Day Drinking Water Toxicity Study in Rats of the Environmental Contaminant Ammonium Perchlorate. Toxicological Sciences. 57:61-74.
U.S. EPA, 2005. Perchlorate (ClO4-) and Perchlorate Salts. Integrated Risk Information System (IRIS) Summary. February.
U.S. EPA, 2002. Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization (External Review Draft). Archived.
Vermiglio, F., et. al., 1990. Defective Neuromotor and Cognitive Ability in Iodine-Deficient Schoolchildren of an Endemic Goiter Region in Sicily. J Clin Endocrinol Metab 70:79-384.
Ziegler, E, 1998. Salmonella Mutagenicity Testing of Ammonium Perchlorate. A memo from Errol Ziegler of National Institutes of Health, National Institutes of Environmental Health Sciences, to A. Jarabek and V. Dellarco of U.S. Environmental Protection Agency.
Ziegler, E, 1999. Ammonium Perchlorate Micronuclei Summary Test Results. A memo from Errol Ziegler of National Institutes of Health, National Institutes of Environmental Health Sciences, to A. Jarabek of U.S. Environmental Protection Agency.
Ecological Impacts
Perchlorate has been reported in the tissue of plants and animals near contaminated sites (Smith, 2001) but has rarely been detected in higher trophic level organisms (Dean, 2004). Experimental evidence has indicated that perchlorates are taken up by leafy plants such as lettuce, tobacco plants, and poplar trees (Sundberg, 2003). However, the studies do not record any toxic effects to the plants. It has been suggested that plant uptake of perchlorates could be used to phytoremediate contaminated sites (Susarla, 2000). Although plants may not be affected by perchlorate toxicity, plant uptake provides a point of entry into the food chain for herbivorous animals. Biomagnification/bioaccumulation is not considered a major concern for perchlorate, as most calculated bioconcentration factors are less than one (Dean, 2004).
The impact of perchlorate exposure on various ecological receptors, including vertebrates and invertebrates, has been demonstrated in numerous studies. As mentioned previously, the primary mechanism of toxicity is through competitive inhibition of iodide uptake into the thyroid at the NIS on thyroid follicular cells1. This decreases T4 and T3 synthesis and causes a feedback response of increased thyroid-stimulating hormone (TSH) production. These changes in thyroid hormones have wide-ranging impacts on the growth and development of organisms, including neurological development. Although invertebrates lack the HPT axis, they have demonstrated adverse effects following perchlorate exposure, likely through interaction of the chemical and NIS homologs (Sorensen, 2006). The most sensitive effects seen throughout various ecological receptors include reduced fecundity and survival, impaired growth, and developmental/neurological effects, with vertebrates generally being the most sensitive species by approximately an order of magnitude (Hines, 2018).
Earthworms (Eisenia foetida) do not survive if exposed to high concentrations (>700 parts per million [ppm]) of ammonium perchlorate for 14 days (Kendall, 2003). However, this concentration may greatly exceed soil concentrations that could be expected in the environment. High concentrations of perchlorate in an experimentally treated soil also reduced the number of cocoons produced by earthworms.
There is evidence that perchlorates increase the height of thyroid epithelial cells in mosquito fish. Although perchlorates are taken up into mosquito fish tissues, the compounds do not appear to bioaccumulate. Little effect of perchlorate is seen on the growth rate of juvenile mosquito fish, and there is no evidence that the reproductive success of this species has been affected in contaminated surface waters at the Longhorn Army Ammunition Plant (LHAAP). However, a study investigating the effects of ammonium perchlorate on the development of fathead minnows (Pimephales promelas) found that although the hormone T3 was apparently regulated, nonetheless the fish showed poor development (Crane, 2005). These minnows, treated with perchlorate at concentrations that have been detected in contaminated surface waters, showed delayed development, lack of scales, poor pigmentation, and lower wet weight and length than controls.
Several studies have examined the effects of perchlorates on larval and adult amphibians. Perchlorate (ammonium perchlorate, 117 ppm) was taken up by tadpoles of the North American bullfrog (Rana catesbeiana) from water surrounding them (Kendall, 2003). The uptake of perchlorate was directly proportional to exposure time. No effects of perchlorate on the growth or development of tadpoles were noted, and the elimination of the compound was complete two days after exposure ceased. Surface waters at the LHAAP contain perchlorate at concentrations up to 31 ppm, and an investigation was performed to determine the incidence of thyroid disruption consistent with iodide deficiency, altered reproductive activity, and development in larval and adult frogs (Kendall, 2003). Five species of frog were included in the LHAAP study, with 10 adults and 50 larvae per species. Evidence of thyroid disruption was seen in the histopathology of chorus frogs (Pseudacris triserata) from a perchlorate manufacturing plant at LHAAP. When exposed to 10 ppm perchlorate, bullfrog larvae lagged in their development compared to animals from uncontaminated reference locations, but did not show an increase in thyroid size. A 21-day study demonstrated that perchlorate inhibited the completion of metamorphosis in the South African clawed frog (Xenopus laevis) (Kendall, 2003). The completion of metamorphosis is used as a test of a compound's ability to disrupt thyroid function, metamorphosis being dependent on the synthesis of thyroid hormones. Fifty-day median lethal concentration (LC50) studies showed that the ammonium ion, NH4+ contributes to the lethality of ammonium perchlorate, but does not contribute to the inhibitory effects of perchlorates on metamorphosis, as evidenced by a reduction in forelimb emergence and failure in tail reabsorption (Kendall, 2003).
Western fence lizards have been used to investigate the response of reptiles to perchlorates. Newly deposited eggs were incubated on perlite that had been intentionally contaminated with sodium perchlorate. Sodium perchlorate moved through the eggshell membrane and accumulated in the tissues of the developing lizards at concentrations higher than in the incubation medium (perlite). Thyroid hormone levels were reduced in response to perchlorate, and histological examination of the thyroid glands showed changes in the follicular cells and colloid content. However, no significant changes in growth rate, or other effects were observed in male lizards attaining maturity (Redick-Harris., et al., 2005).
A study of the effects of orally administered sodium perchlorate on the hatchlings of the zebra finch identified several dose-dependent deleterious effects on both growth and behavior (Kendall, et al., 2006). The dose levels of perchlorate given in this study were within the expected range of uptake by granivorous birds in a contaminated environment. Overall body mass and tibiotarsal length were both reduced in the two higher dosage groups, but brain and liver mass were increased. No particular deviations from the norm were seen in the thyroid hormones in response to perchlorate. However, the behavior of the finches showed dose-dependent abnormalities. Birds in the high-dose group made fewer attempts to fly, and they were unable to feed themselves or maintain body weight. Changes such as these might be expected to adversely affect the reproductive success of granivorous birds inhabiting a perchlorate-contaminated environment.
An assessment of the effects of perchlorate in raccoons (Procyon lotor) at LHAAP showed no appreciable exposure or effects on thyroid function (Kendall, 2003).
References:
Crane, H.M., D.B. Pickford, T.H. Hutchinson, and J.A. Brown, 2005. Effects of Ammonium Perchlorate on Thyroid Function in Developing Fathead Minnows, Pimephales promelas. Environmental Health Perspective 113(4):396-401.
Dean, K.E., Palachek, R.M., Noel, J.M., Warbritton, R., Aufderheide, J. and Wireman, J., 2004. Development of Freshwater Water-Quality Criteria for Perchlorate. Environmental Toxicology and Chemistry: An International Journal, 23(6), pp.1441-1451.
Hines, D.E., Edwards, S.W., Conolly, R.B. and Jarabek, A.M., 2018. A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA). Environmental Science & Technology, 52(2): 839-849.
Kendall, R., 2003. Ecological Risk Assessment of Ammonium Perchlorate on Fish, Amphibians, and Small Mammals. SERDP Project ER-1223.
Kendall, R., P. Smith, S. McMurry, G. Cobb, T. Anderson, E. Smith, and R. Patina, 2006. Continuation of the Ecological Risk Assessment of Explosive Residues in Rodents, Reptiles, Amphibians, Fish and Invertebrates: An Integrated Laboratory and Field Investigation Related to Live-Fire Ranges in the Department of Defense. Strategic Environmental Research and Development Program (SERDP) Project ER-1235, 228 pp. June.
Redick-Harris, M., L. Talent, and D. Janz. Effects of Exposure to Sodium Perchlorate on Histology and Hormone Levels of Hatchling and Mature Male Western Fence Lizards. SETAC November 2005 Conference proceedings abstract RED-1117-837256.
Smith, P.N., 2001. Preliminary Assessment of Perchlorate in Ecological Receptors at the Longhorn Army Ammunition Plant (LHAAP), Karnack, Texas, 2001. (vol 6, p. 305, 2001). ECOTOXICOLOGY, 27(5): Vol. 6, 305.
Sorensen, M.A., Jensen, P.D., Walton, W.E. and Trumble, J.T., 2006. Acute and Chronic Activity of Perchlorate and Hexavalent Chromium Contamination on the Survival and Development of Culex quinquefasciatus Say (Diptera: Culicidae). Environmental Pollution, 144(3), pp 759-764.
Sundberg, S.E., J.J. Ellington, J.J. Evans, D.A. Keys, and J.W. Fisher, 2003. Accumulation of Perchlorate in Tobacco Plants: Development of a Plant Kinetic Model. Journal Environmental Monitoring 5:505-512.
Susarla, S., S.T. Bacchus, G. Harvey, and S.C. McCutcheon, 2000. Phytotransformations of Perchlorate Contaminated Waters. Environmental Technology 21(9): pp 1055-1065.
Resources
Human Health
The Effects of Ammonium Perchlorate on Thyroids
Mann, P.C. EPA Pathology Working Group, 15 pp, 2020
Perchlorate in Water Supplies: Sources, Exposures, and Health Effects
Steinmaus, C.M.
Current Environmental Health Reports 3(2):136-143(2016)
Public Health Goal for Perchlorate in Drinking Water
California Environmental Protection Agency, Office of Environmental Health Hazard Assessment, 212 pp, 2015
California Human Health Screening Levels for Perchlorate
California Environmental Protection Agency, Office of Environmental Health Hazard Assessment, 9 pp, 2010
Hazard Identification Materials for Perchlorate
California Office of Environmental Health Hazard Assessment website, 2005
Health Implications of Perchlorate Ingestion
National Research Council National Academies Press, Washington, DC. ISBN: 0309095689, 278 pages, 2005
Perchlorates
ATSDR fact sheet, 2 pp, 2005
Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization (External Review Draft)
EPA Office of Research and Development, National Center for Environmental Assessment, 534 pp, 2002
Perchlorate Toxicity Assessment (Human Health)
Jarabek, A., 40 minutes, June 2002
Perchlorate Literature Review and Summary: Developmental Effects, Metabolism, Receptor Kinetics and Pharmacological Uses
Sterner, T.R. and D.R. Mattie. AFRL-HE-WP DTIC: ADA367421, 57 pp, Aug 1998
Ecological Impacts
Wildlife Toxicity Assessment for Perchlorate (Abstract)
Eck , W.S. Chapter 28 of Wildlife Toxicity Assessments for Chemicals of Military Concern, Elsevier, New York. ISBN: 978-0-12-800020-5, 499-553, 2015
The Effects of Ammonium Perchlorate on Reproduction and Development of Amphibians
Dumont, J. SERDP Project ER-1236, 43 pp, 2008
Wildlife Toxicity Assessment for Perchlorate
Salice , C.J., C.A. Arenal, C.L. Tsao, and B.E. Sample. U.S. Army Center for Health Promotion and Preventive Medicine, Document No. 87-MA02T6-05D, 64 pp, 2007
Perchlorate in the Environment – Ecological Considerations (2002)
Smith, P.N., 23 minutes, 2002
Report on the Peer Review of the U.S. Environmental Protection Agency's Draft External Review Document "Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization"
U.S. EPA, Office of Research and Development. EPA/635/R-02/003, 101 pp, 2002
Perchlorate Ecological Risk Studies – A Report on Literature Reviews and Studies Conducted by the Ecological Impact/Transport and Transformation Subcommittee of the Interagency Perchlorate Steering Committee
Long, G.C., R.C. Porter, C. Callahan, and M. Sprenger. Air Force Institute for Environment, Safety, and Occupational Health Risk Analysis, Report Number: IERA-RS-BR-TR-2001-0004, 23 pp, Nov 1998
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