Health Implications of Perchlorate Ingestion (2005) / Chapter Skim
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From page 3... ...
to assess independently the adverse health effects of perchlorate ingestion from clinical, toxicologic, and public-health perspectives. They also asked the NRC to evaluate the relevant scientific literature and key findings underlying EPA's 2002 draft risk assessment, Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization.
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The committee was asked to assess the current state of the science regarding potential adverse effects of disruption of thyroid function by perchlorate in humans and laboratory animals at various stages of life. It was asked to evaluate the animal studies with particular attention to key end points,including changesinbrainmorphometry,behavior,thyroid hormone levels, and thyroid histopathology.
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by the pituitary gland, and increases in serum thyroid hormone concentrations lead to decreases in TSH secretion. TSH stimulates virtually every step of thyroid hormone production and secretion, and such tight control of TSH secretion maintains thyroid hormone production and secretion within normal or nearly normal limits and thereby protects against both hypothyroidism (deficiency of thyroid hormone production)
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Because the body maintains the serum concentrations of thyroid hormones within narrow limits through feedback control mechanisms, there is remarkable compensation for iodide deficiency. Generally, thyroid hormone production is normal even when iodide intake is quite low.
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In those studies, perchlorate doses ranged from 0.007 to 9.2 mg per
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On the basis of the studies of long-term treatment of hyperthyroidism in which patients continued to be given perchlorate after their hyperthyroidism resolved and the clinical studies of healthy adults, the perchlorate dose required to cause hypothyroidism in adults would probably be more than 0.40 mg/kg per day, assuming a 70-kg body weight. However, in pregnant women, infants, children, and people with low iodide intake or pre-existing thyroid dysfunction, the dose required to cause hypothyroidism may be lower.
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From page 9... ...
· Changes in thyroid function in newborns. The available epidemiologic evidence is not consistent with a causal association between exposure during gestation to perchlorate in the drinking water at up to 120 ppb and changes in thyroid hormone and TSH production in normal-birthweight, full-term newborns.
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From page 10... ...
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. In occupational studies, perchlorate doses as high as 0.5 mg/kg per day have not been associated with adverse effects on thyroid function in workers.
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From page 11... ...
Linear measurements of several brain regions of the male and female pups at several postnatal ages were compared with control values. The most consistent change observed was a statistically significant increase in the width of the corpus callosum; however, the dose at which that change was observed was not consistent between studies.
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The committee agreed that the two male offspring did have benign thyroid tumors and noted that the observations are expected in rats given high concentrations of goitrogenic chemicals known to interfere with thyroid hormone homeostasis. The committee concludes that the thyroid tumors in the offspring were most likely treatment-related but that thyroid cancer in humans resulting from perchlorate exposure is unlikely because of the hormonally mediated mode of action and species differences in thyroid function.
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From page 13... ...
Ultimately, EPA's model shows birth defects in children and tumors in adults as possible effects of inhibition of thyroid iodide uptake. 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.
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From page 14... ...
The final step in the RfD process is the application of uncertainty factors to the NOAEL, LOAEL, or BMD to extrapolate from the study population to the general human population, which includes sensitive groups. For the perchlorate risk assessment, EPA based its point of departure on reported changes in brain morphometry, thyroid histopathology, and serum thyroid hormone concentrations after oral administration of perchlorate to rats.
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Furthermore, those studies typically focused on changes in serum thyroid hormone and TSH concentrations or clinical manifestations of the changes, not on inhibition of iodide uptake by the thyroid. Therefore, the committee is not recommending using the available epidemiologic studies to derive the point of departure for the risk assessment.
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From page 16... ...
No additional factors are needed for duration or database uncertainties.4 First, if inhibition of iodide uptake by the thyroid is used, chronic exposure will have no greater effect than that resulting from short-term exposure. In fact, it may well have less effect because of the capacity of the pituitary-thyroid system to compensate for iodide deficiency by increasing iodide uptake.
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From page 17... ...
Especially critical issues in perchlorate risk assessment have been the effect of perchlorate on placental and breast iodide transport and the influence of iodide status on the effects of perchlorate. The committee recommends a series of in vitro studies using human tissues and animal studies to determine the role of NIS in placental iodide transport, the susceptibility of 5For comparison, EPA's draft RfD in its 2002 draft risk assessment was 0.00003 mg/kg per day.
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From page 18... ...
Studies of NIS in those tissues, and possible effects of perchlorate on them, might be done but at a much lower priority than studies of the placenta and mammary gland. 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)
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