CLU-IN.ORG | Contaminant Focus: PERCHLORATE, Toxicology

Perchlorate interferes with iodide uptake into the thyroid gland. Because iodide is an essential component of thyroid hormones, perchlorate disrupts how the thyroid functions. In adults, the thyroid helps to regulate the metabolism. In children, the thyroid plays a major role in proper development, in addition to metabolism. Impairment of thyroid function in pregnant mothers may impact the fetus and result in such effects as changes in behavior, delayed development and decreased learning capability. Drinking water contaminated with perchlorate is the most likely way that perchlorate can be ingested.

EPA has established an official reference dose (RfD) of 0.0007 milligrams of perchlorate per kilograms of body weight per day. This level is consistent with the recommended reference dose contained in the National Academy of Science's report of January 2005, Health Implications of Perchlorate Ingestion. A reference dose is a scientific estimate of a daily exposure level that is not expected to cause adverse health effects in humans. A summary for perchlorate and perchlorate salts has been placed on EPA's Integrated Risk Information System (IRIS) that represents the Agency's current thinking on this subject. The RfD, which represents a preliminary estimate of a protective health level but is not a drinking water standard, will be used in EPA's ongoing efforts to determine if regulation of perchlorate in drinking water would represent a meaningful opportunity for reducing risks to human health.

The toxicity of perchlorates has been studied in ecological receptors such as plants, invertebrates, amphibians, fish, and terrestrial birds, reptiles, and mammals. There is experimental evidence that perchlorates are taken up by leafy plants such as lettuce, tobacco plants, and poplar. Also researchers have found perchlorates in fruits and vegetables. However, the studies do not record any toxic effects. Although plants may not be affected by perchlorate toxicity, plant uptake provides a point of entry into the food chain for herbivorous animals.

Perchlorate exerts its effects by competing with iodide at the sodium-iodide symporter (NIS), the transport system that transports iodine into the thyroid gland. Iodine, an essential nutrient, is necessary for the synthesis of the thyroid hormones, triiodothyronine (T3) and thyroxine (T4). If diminished synthesis of T3 and T4 is brought about by perchlorate, health effects similar to those caused by iodine deficiency can be expected. The nature and severity of these effects is dependent on the iodine status of the individual, and the duration and extent of exposure. T3 and T4 play a critical role in the growth and development of fetuses, infants, and young children. Pregnant and lactating women, fetuses, and infants can all be considered sensitive sub-populations. The effects of T3 and T4 disruption in the fetus can be profound, causing mental retardation, reduced bone growth and impaired motor control. Even minor perturbations in fetal T3 and T4 levels are thought to be associated with impaired neurological development.

Laboratory animal studies have been performed on perchlorates in order to determine the mode of action of these salts, specifically, the mechanisms through which they exert their effects. In addition, long term studies have been carried out to determine whether the salts are carcinogenic or can cause adverse reproductive or developmental effects. Many of these are summarized in the Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profile for Perchlorates. However, human experimental (volunteer) studies are available for the perchlorates, unlike most other chemicals. In addition, data on the effects of perchlorates have also been amassed as a consequence of the former therapeutic use in the treatment of hyperthyroid conditions such as Graves disease. Severe hematological effects were seen in some patients receiving therapeutic doses of perchlorates for hyperthyroidism, and these have included fatalities due to aplastic anemia and agranulocytosis. A study of Chilean school-age children exposed to perchlorate-contaminated drinking water did not identify any hematological effects at doses estimated to be 0.004 - 0.008 mg/kg-day. In another study, volunteers exposed to 0.14 mg/kg-day perchlorate for 14 days in a controlled acute exposure study did not show alterations in routine blood chemistry or cell counts. No evidence of hepatotoxicity or renal effects were identified in this study, but a reduction was seen in the uptake of radioactive iodine (RAIU) by the thyroid gland. The effects of this depression were not permanent, and RAIU values were back to baseline 15 days after treatment ceased.

Epidemiological surveys have been performed to determine if there is an increase in hypothyroid conditions in areas where perchlorates are known drinking water contaminants. One such study contrasted the prevalence of thyroid diseases in a Nevada county that had perchlorate-contaminated drinking water with a county whose drinking water was uncontaminated. Statistical analysis of the data showed no significant difference in the prevalence rate of thyroid disease between the two counties.

There are no studies available that describe the reproductive effects of perchlorate in humans. No effects, gross or microscopic, were seen on the uterus, ovaries, testes, or mammary glands of laboratory rats in a 14-day drinking water study. A two-generation perchlorate study in rats found no significant effects on litter size, sex ratios, lactation, number of implantations, or the number of dams delivering litters. The California Environmental Protection Agency's (CalEPA) Office of Environmental Health and Hazard Assessment Committee for Developmental and Reproductive Toxicant Identification (August 2005) found that perchlorate had not been "clearly shown through scientifically valid testing according to generally accepted principles to cause reproductive toxicity."

Perchlorates added to the drinking water of pregnant rats caused changes in the thyroid structure of male offspring at high doses, and increases in TSH. T4 and T3 levels were reduced in rat pups at lower levels than those causing structural changes to the thyroid. In addition to the histopathological changes in the thyroids of these rats, some behavioral changes were noted in pups allowed to survive. However, epidemiological surveys do not show evidence of increased rates of congenital hypothyroidism in Californian newborns in areas of known perchlorate drinking water contamination.

As the toxicity of perchlorates appears to be exerted by action on the thyroid gland, environmental concentrations of perchlorates that do not affect thyroid function can be considered to be without adverse effects. The U.S. EPA Integrated Risk Information System (IRIS) summary gives an RfD of 0.0007 mg/kg/day for perchlorate. As used by the U.S. EPA 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 ATSDR as the chronic minimum risk level (MRL).

Perchlorate is unlikely to pose a risk for thyroid cancer in humans at doses that do not disturb thyroid function. In addition, based on in vitro and in vivo assays to determine genotoxicity, there are no results that indicate that the perchlorates exert mutagenic or clastogenic effects that would result in carcinogenesis.

Adapted from:

1. Evidence on the Reproductive and Developmental Toxicity of Perchlorate. Reproductive and Cancer Hazard Section. Office of Environmental Health Hazard Assessment. California Environmental Protection Agency, September 2005

2. Perchlorate and Perchlorate Salts
U.S. Environmental Protection Agency Integrated Risk Information System, February 2005

3. Public Health Goals for Chemicals in Drinking Water Perchlorate
Office of Environmental Health Hazard Assessment. California Environmental Protection Agency, March 2004

4. Toxicological Profile for Perchlorates September 2005 Draft for Public Comment
Agency for Toxic Substances and Disease Registry (ATSDR)

In response to recommendations made at the February 1999 external peer review of the December 1998 document entitled, Perchlorate Environmental Contamination: Toxicology Review and Risk Characterization, the National Center for Environmental Assessment (NCEA) arranged for a review of the thyroids from all of the studies by independent pathologists using a consistent lesion grading scheme and then convened a pathology working group (PWG). The potential for inconsistency across the studies made use of these data difficult for comparison and development of dose-response analyses; the purpose of the independent peer review and PWG was to decrease variability in response across the studies by providing a common nomenclature for lesions and a consistent pathology review.

Health Implications of Perchlorate Ingestion
National Research Council, Committee to Assess the Health Implications of Perchlorate Ingestion.
National Academies Press, Washington, DC. ISBN: 0309095689, 278 pages, 2005.

At the request of the U.S. EPA, DoD, DOE, and NASA, a National Research Council committee evaluated the potential health effects of perchlorate and the scientific underpinnings of EPA's 2002 draft risk assessment. The committee's report suggests that daily ingestion of 0.0007 milligrams of perchlorate per kilogram of body weight--an amount more than 20 times the reference dose proposed by EPA—should not threaten the health of even the most sensitive populations.

By May of 1997 EPA was engaged in developing a targeted testing strategy to evaluate the potential human health and ecotoxicological effects of potential perchlorate exposures. The National Center for Environmental Assessment first released an external review draft in 1998 and recommendations for additional studies and analyses were made at a 1999 scientific peer review. The external review draft of the revised document, "Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization" responds to those recommendations and incorporates results from extensive laboratory and field studies performed since 1999.

In April of 1997, the existing toxicologic database on perchlorate was determined to be inadequate for quantitative human health risk assessment by an external peer review. A lack of data on the ecotoxicological effects was also noted. The National Center for Environmental Assessment (NCEA) developed this toxicology review document to revise previous provisional oral reference dose (RfD) values for perchlorate with a more comprehensive data base.

A collaboration between the U.S. EPA, the Department of Defense (Air Force), and an inter-industry Perchlorate Study Group is unique in its focus on development of state-of-the art science for accurately determining what constitutes a safe level of perchlorate exposure for humans. The American Council on Science and Health has evaluated the allegations of health risk from perchlorate made by the Environmental Working Group; reviewed the current regulatory process that is ongoing with respect to the establishment of a safe environmental exposure level; and highlighted some of the recent scientific studies that have further characterized the toxicity of perchlorate in both animals and humans.

A review was undertaken to evaluate the available information on developmental and reproductive effects, thyroid iodide receptor kinetics, pharmacological uses of perchlorate outside the treatment of Graves' disease, and absorption, distribution, metabolism and excretion of perchlorate. Summarization of the available information and conclusions make the data more accessible to toxicologists and review panels for consideration in study prioritization and future reference dose development.

Contains the responses to major comments received by California's Office of Environmental Health Hazard Assessment from University of California peer reviewers, U.S. EPA, and others on several drafts of the proposed public health goal technical support document for perchlorate.

The toxicity of perchlorates has been studied in ecological receptors such as plants, invertebrates, amphibians, fish, and terrestrial birds, reptiles, and mammals. There is experimental evidence that perchlorates are taken up by leafy plants such as lettuce, tobacco plants, and poplar. However, the studies do not record any toxic effects. It has been suggested that plant uptake of perchlorates could be used to phytoremediate contaminated sites. Although plants may not be affected by perchlorate toxicity, plant uptake provides a point of entry into the food chain for herbivorous animals.

Earthworms (Eisenia foetida) do not survive if exposed to high concentrations (>700 ppm) of ammonium perchlorate for 14 days. 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 numbers of cocoons produced by earthworms.

A common mechanism probably accounts for the effects of perchlorates in mammals, birds, amphibians, fish, and reptiles. The perchlorate ion competes with and inhibits iodine uptake by the NIS system of the thyroid follicular cells. As T4 levels fall in response to perchlorate, blood levels of thyroid stimulating hormone (TSH) rise. Prolonged exposure to perchlorate can lead to hypertrophy and hyperplasia of the thyroid follicular calls, resulting in an increase in thyroid weight.

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. These minnows, treated with perchlorate at concentrations that have been seen in contaminated surface waters, showed retarded 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. 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 2 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. 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 when 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). The completion of metamorphosis is used as an test of a compound's ability to disrupt thyroid function, metamorphosis being dependent on the synthesis of thyroid hormones. 50-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.

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.

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. 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 to 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.

Adapted from:

Accumulation of perchlorate in tobacco plants: development of a plant kinetic model.
S.E. Sundberg, J.J. Ellington, J.J. Evans, et al.
Journal Environmental Monitoring 2003 5 505-512

Effects of Ammonium Perchlorate on Thyroid Function in Developing Fathead Minnows, Pimephales promelas.
H.M. Crane, D.B. Pickford, T.H. Hutchinson, et al
Environ Health Perspect. 2005 April; 113(4): 396-401.
Published online 2005 January 10. doi: 10.1289/ehp.7333.

Effects of exposure to sodium perchlorate on histology and hormone levels of hatchling and mature male western fence lizards
M. Redick-Harris, L. Talent, and D. Janz.
Society of Environmental Toxicology and Chemistry (SETAC) November 2005
Conference proceedings abstract RED-1117-837256

ER-1223: Ecological Risk Assessment of Ammonium Perchlorate on Fish, Amphibians, and Small Mammals
Strategic Environmental Research and Development Program, 419 pp, Feb 2003

ER-1235: 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, 228 pp, 2006

Phytotransformations of Perchlorate Contaminated Waters
S. Susarla, S.T. Bacchus, G. Harvey, et al
Environmental Technology, Volume 21, Number 9, 1 September 2000 , pp 1055-1065(11)

The Committee commissioned a literature search to identify completed studies of various perchlorate salts (potassium, sodium, ammonium, etc.) to evaluate dose levels that might cause adverse health effects in ecological receptors. Subsequently, data gaps were identified to address the generally weak database on these effects. Scientists conducted an ecological risk assessment following the Superfund paradigm for ecological risk assessments on five test species: two invertebrate species (aquatic and terrestrial), an aquatic vertebrate, and a plant.

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Last updated on Tuesday, August 19, 2008