Health Implications of Perchlorate Ingestion (2005)Board on Environmental Science and Toxicology
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Perchlorate-a powerful oxidant used in solid rocket fuels by the military and aerospace industry-has been detected in public drinking water supplies of over 11 million people at concentrations of at least 4 parts per billion (ppb). High doses of perchlorate can decrease thyroid hormone production by inhibiting the uptake of iodide by the thyroid. Thyroid hormones are critical for normal growth and development of the central nervous system of fetuses and infants. This report evaluates the potential health effects of perchlorate and the scientific underpinnings of the 2002 draft risk assessment issued by the U.S. Environmental Protection Agency (EPA). The report finds that the body can compensate for iodide deficiency, and that iodide uptake would likely have to be reduced by at least 75 per cent for months or longer for adverse health effects, such as hypothryroidism, to occur. The report recommends using clinical studies of iodide uptake in humans as the basis for determining a reference dose rather than using studies of adverse health effects in rats that serve as EPA's basis. The report suggests that daily ingestion of 0.0007 milligrams of perchlorate per kilograms 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.
- A more realistic representation of effects of changes in serum thyroid hormone and TSH concentrations would be hypertrophy or hyperplasia of the thyroid, which might lead eventually to hypothyroidism. If perchlorate exposure did result in hypothyroidism, possible outcomes would be metabolic sequelae at any age and abnormal growth and development in fetuses or children.
- Although the committee found that available data are sufficient to derive an RfD for perchlorate, new research could provide a more complete understanding of the array of effects of perchlorate, especially regarding the effects of chronic exposure and the effects on sensitive populations.
- Changes in thyroid function in newborns. No data are available on the association of perchlorate exposure with thyroid dysfunction in the groups of greatest concern, low-birthweight or preterm newborns, offspring of mothers who had iodide deficiency during gestation, or offspring of hypothyroid mothers.
- Congenital hypothyroidism. The available epidemiologic evidence is not consistent with a causal association between perchlorate exposure and congenital hypothyroidism as defined by the authors of the studies reviewed by the committee. All studies of that association were negative.
- Development of thyroid tumors, as an ultimate result of perchlorate-caused inhibition of thyroid iodide uptake, is unlikely in humans.
- Effects downstream of inhibition of iodide uptake by the thyroid have not been clearly demonstrated in any human population exposed to perchlorate, even at doses as high as 0.5 mg/kg per day.
- Exposure to perchlorate can increase the incidence of thyroid tumors in rats when the doses are high enough to decrease thyroid hormone production and increase TSH secretion.
- Hypothyroidism and other thyroid disorders in adults. The evidence from chronic, occupational-exposure studies and ecologic investigations in adults is not consistent with a causal association between perchlorate exposure at the doses investigated and hypothyroidism or other thyroid disorders in adults.
- It is not possible to extrapolate data quantitatively from rodents to humans for purposes of human health risk assessment. Most experimental studies in animals designed to characterize the effects of perchlorate exposure have been done in rats. However, rats are much more sensitive to agents that disturb thyroid function than are humans, so the relevance of rat studies in quantitative terms to humans is limited.
- Neurodevelopmental outcomes. Although the committee considers the inclusion of ADHD plausible, it questions the appropriateness of autism as an end point given that autism has not been observed in the spectrum of clinical outcomes in children who had congenital hypothyroidism and were evaluated prospectively.
- No studies have investigated the relationship between perchlorate exposure and adverse outcomes among especially vulnerable groups, such as low-birthweight or preterm infants.
- Perchlorate has an antithyroid effect on rats at high doses (30 mg/kg of ammonium perchlorate per day). That effect is characterized by decreases in serum thyroid hormone and increases in serum TSH with morphologic changes in the thyroid gland.
- The available studies did not assess the possibility of adverse outcomes in the offspring of mothers who were exposed to perchlorate and had a low dietary iodide intake.
- The committee finds that EPA's mode-of-action model adequately represents the possible early sequence of events after perchlorate exposure, but it does not think that the model is an accurate representation of possible outcomes after changes in thyroid hormone and TSH production.
- The committee finds that there is no evidence for a causative relationship between perchlorate ingestion and any biologically meaningful stimulatory or inhibitory effect on the immune system in rodents, and concludes that the side effects in humans were probably toxic effects of the very high doses of perchlorate given to those patients.
- The committee found that the animal studies of potential adverse effects of perchlorate provided qualitative information, but the usefulness of the studies for quantitatively estimating the risk of adverse effects in humans is small.
- The committee reviewed the human and animal data and found that the human data provided a more reliable point of departure for the risk assessment than the animal data.
- The data are inadequate to determine whether or not a causal relationship exists between perchlorate exposure of pregnant rats and neurodevelopmental abnormalities in their pups, given the flaws in experimental design and methods in the studies conducted to evaluate that end point.
- The data are inadequate to determine whether or not perchlorate exposure during gestation and lactation in rats has effects on behavior, given the lack of sensitivity of the tests conducted to evaluate that end point.
- The data favor rejection of a causal relationship between perchlorate exposure and immunotoxicity.
- The first adverse health effect that could result from perchlorate exposure in the proposed continuum of effects would be hypothyroidism. However, hypothyroidism should not be used as the basis of the risk assessment.
- The primary sources of uncertainty in estimating an RfD for perchlorate in drinking water arise from the absence of data on possible effects of exposure among populations at greatest risk of adverse effects of iodide deficiency (pregnant women and their fetuses and newborns).
- There are no data to suggest that perchlorate has effects that are not mediated through inhibition of iodide transport in the thyroid gland.
- Thyroid cancer in adults. The epidemiologic evidence is insufficient to determine whether or not there is a causal association between exposure to perchlorate and thyroid cancer. However, the committee questions the biologic plausibility of thyroid cancer as a likely outcome of perchlorate exposure.