Overview
Health Implications of Perchlorate Ingestion is the most comprehensive and authoritative source of scientific information on human health issues relating to perchlorate. This landmark report was published by the National Academy of Sciences (NAS) National Research Council (NRC) in 2005.
The NRC select panel on perchlorate comprised 15 world-renowned experts in toxicology, thyroid endocrinology, pediatric endocrinology, epidemiology and other areas of science directly related to perchlorate. The panel was engaged by U.S. EPA to review perchlorate science in response to significant questioning and criticism of the scientific basis for EPA’s 2002 draft risk assessment for perchlorate. In 2005, EPA adopted the NRC-derived Reference Dose (RfD), which remains in effect today.
The NRC panel focused on the perchlorate dose-response relationship. The panel’s review concluded that below a threshold equal to 245 ppb in water, no measurable effects were reported. The NRC estimated that a dose 50 times greater than this threshold must be ingested on a daily basis for several months or years for an adverse effect to occur (such as hypothyroidism). NRC further concluded that a perchlorate exposure 10-fold less than this threshold dose —equivalent to 24.5 parts per billion (ppb) — would be safe for even the most sensitive population, identified as the pregnant woman and her fetus (all others being less sensitive).
It is important to underscore NRC’s scientific logic in providing a level of safety far exceeding customary regulatory practice. NRC chose to base its RfD on a No Observed Effect Level (NOEL) of a non-adverse effect, rather than the no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL), which EPA has traditionally used as the point of departure. The NOEL is the dose at which no effect occurs, adverse or otherwise, and results in a substantially more conservative RfD than the traditional and also conservative approach using the NOAEL or LOAEL.
Equally important, no new scientific information has been published in the peer-reviewed literature since the NRC report refuting the NAS panel’s conclusions relating to the fundamental knowledge of perchlorate and its effects on human health.
This study is a review of newer studies on perchlorate that focus on foundational toxicology and pharmacology. It was conducted based on the concern that perchlorate in drinking water may be a cause of neurodevelopmental changes in infants. The review concludes that there are no studies demonstrating perchlorate has adverse effects on infants
60 years of perchlorate research led to the National Academy of Sciences’ (NAS) landmark report. Now, 10 years later, new science still overwhelmingly supports the NAS conclusions.
A comprehensive analysis of where the U.S. EPA’s science is either incomplete or out of date in its determination to set a regulatory standard for perchlorate.
This review, prepared by Intertox at the request of the Perchlorate Study Group, examined all the studies on perchlorate since the 2005 NAS report and found that none of the foundational science on perchlorate has changed: low levels do not pose a public health concern.
This review examined all studies investigating possible adverse effects of perchlorate exposure in adults, pregnant women and newborns and concluded that there is no credible or consistent evidence that environmental exposure to perchlorate has any adverse effect on thyroid function.
The U.S. EPA’s Office of the Inspector General concluded that EPA’s perchlorate reference dose (RfD) is conservative and protective of human health, and further reducing the perchlorate exposure below the RfD does not effectively lower risk.
Agency for Toxic Substances and Disease Registry profile on perchlorate, including clarification that perchlorate has no cancer effect.
This report concluded, among other findings, that levels of perchlorate below the equivalent of 245 parts per billion in water do not have a measureable effect on human health.
This study looked at urinary measures of perchlorate, nitrate and thiocyanate in the U.S. population between 2005 and 2014. Among the findings, Corey et al. reported that total exposure of perchlorate from food and water sources has decreased since 2005, and confirmed that perchlorate contributes to less than 1 percent of Iodine Uptake Inhibition.
This study by Taylor et al. about the effect of perchlorate on the human body contains several design shortcomings that do not scientifically support the study’s conclusions and are contrary to the results of other human and animal studies on perchlorate. New studies warrant a thorough scientific evaluation of design and methods to determine reliability as well as the weight of the scientific database. In this case, there are a number of other well-designed and peer-reviewed animal and human studies that reached contrary results to the Taylor et al. study regarding perchlorate’s effect on the developing nervous system. The study also does not demonstrate that perchlorate causes an adverse effect—it merely generates a hypothesis that the authors suggest should be further explored. Scientifc consensus remains that environmental levels of perchlorate are unlikely to have an impact on human health.
In their review, Tarone et al. (2010) state: “…analyses of TSH in the first day after birth, even if tightly controlled statistically for hours since birth, would be of questionable validity for making inferences about adverse effects of perchlorate or any other potential goitrogen on thyroid function. Results of analyses of TSH values during the first 24 hours after birth cannot be interpreted as evidence of thyroid disease, and thus there is no biologic rationale or scientific justification for evaluating these very early TSH measurements in studies of potential harm from perchlorate exposure.” These conclusions cast further doubt on the conclusions of Steinmaus et al 2010.
The Steinmaus study used data collected within the first 24 hours of birth in an attempt to show that in some cases of perchlorate exposure some infants had greater odds of increased levels of Thyroid Stimulating hormone or TSH. While this in itself is actually harmless, it is also a well-documented scientific fact that the first 24 hours after birth is a period of natural “TSH surge.” This makes the Steinmaus conclusions highly suspect. See Tarone et. al 2010 and the American Academy of Pediatrics (2006).
Based on the same data set as Blount et al. (NHANES 2001-2002), this study reported the same results. This manuscript also evaluated the influence of thiocyanate (an iodide inhibitor, obtained from cigarette smoking in this case) which strengthened the predictive power reported in Blount et al. (2006). The mean urine concentration of perchlorate was 2.52 ± 0.55 ppb for current smokers and 3.15 ± .88 ppb for nonsmokers.
Based on NHANES 2001-2002 data, Blount et al. reported that in women (but not men) with spot urinary iodine measurements of less than 100 µg/l, perchlorate exposure was a negative predictor of total T4 and a positive predictor of serum TSH. However, exposures to perchlorate were not associated with serum total T4 or serum TSH levels outside of normal ranges. The mean urine concentration of perchlorate was 2.84 ppb and the range was 2.54-3.18 ppb.
This group studied the effects of prolonged exposure — six months — to perchlorate at different levels (250 ppb and 1500 ppb) on 13 healthy volunteers. The study found that even at the highest dose, perchlorate had no effect on thyroid function, again supporting the NAS 2005 conclusions.
This study evaluated whether newborns had higher rates of primary congenital hypothyroidism (PCH) or elevated concentrations of thyroid-stimulating hormone in a community where perchlorate was detected in groundwater wells. The findings, according to the Journal of Occupational and Environmental Medicine, suggest that residence in a community with potential perchlorate exposure has not impacted PCH rates or newborn thyroid function.
Healthy adult volunteers, including both men and women, consumed perchlorate in drinking water at various dose levels for 14 days. At the low dose, equivalent to 180-220 ppb, there was no detectable inhibition of iodide uptake by the thyroid (the thyroid uses iodine to produce hormones essential to growth and metabolism). There was no adverse change in thyroid hormone levels associated with any dose level.
The study compared the prevalence of thyroid disease in Medicaid-eligible residents of Clark County, Nevada, which had perchlorate in drinking water up to 24 ppb, to Medicaid-eligible residents in other Nevada counties where perchlorate is not present in drinking water. It found no evidence of a higher rate of any thyroid disease in Clark County.
This study, similar to the one above, examined the thyroid function of more than 540 newborns in Las Vegas and Reno. Scientists looked for changes in thyroid stimulating hormone (TSH) as evidence that the Las Vegas newborns were compensating for decreased levels of thyroid hormones. There was no difference in TSH levels in newborns in the two cities.
Healthy male volunteers consumed perchlorate equivalent to either 1,500 or 5,000 ppb in drinking water for 14 days. There was approximately 10 percent and 38 percent inhibition of iodide uptake at the lower and upper levels, respectively. No adverse changes in thyroid hormone levels were observed at either level.
The actual number of cases of congenital hypothyroidism was compared to the expected number in seven counties in Nevada and California where perchlorate was detected in water at levels of 4-16 ppb. The study determined that perchlorate in drinking water at these low levels has no measurable effect on thyroid development of newborns.
These studies examined employees who worked with perchlorate-based chemicals and were exposed to it in the air for several years. Breathing perchlorate is the same as drinking perchlorate in terms of its health effects. Workers in the highest exposure category absorbed doses of perchlorate equal to drinking two liters of water per day containing an average of 17,000 ppb of perchlorate. No differences in blood chemistry or thyroid hormones were found in the workers, nor was evidence of thyroid abnormalities observed in any group. The Lamm data showed that the lowest dose of perchlorate that could possibly cause an adverse effect to thyroid hormone levels, if ingested regularly for years, was 20,000 ppb.
Reference Dose
Studies show that the perchlorate Reference Dose recommended by the National Academy of Sciences is conservative and health protective, and that exposure to perchlorate is unlikely to be above this level.
This is another PBPK model, but it uses data from a range of human and animal studies to set the model’s parameters. The modeling predicts that for women of reproductive age, the 95th percentile (meaning that most of the population will have lower exposures) of the population’s perchlorate dose from food and water is 0.15 µg /kg-d which is 21 percent of the RfD set by the EPA.
Testing different types of food from around the U.S., this study reported the amount of iodine and perchlorate in these foods. From this data, and estimating what might be consumed, the authors developed a model. The paper reported that the greatest dietary exposure (highest upper bound) to perchlorate was in children age 2 (0.39 µg /kg-day). This dose was 56 percent of the U.S. EPA RfD of 0.7 mg /kg-day.
Based on the NHANES 2001-2002 data set, Blount et al. estimated that the mean dose of perchlorate based on urinary output was 0.066 µg/kg-d and the 95th percentile was 0.234 µg/kg-d. These values were 9 percent and 33 percent, respectively, below the RfD of 0.7 µg /kg-d. This manuscript also reported that all samples analyzed for perchlorate detected low levels of perchlorate.
Pregnant Women & Infants
No study has shown that perchlorate causes adverse effects to infants, pregnant women or fetuses.
This study found that neonatal thyroid hormone levels, maternal thyroid hormone levels or maternal diet of food sufficient in iodine were not associated with cognitive outcomes in children with the average age of 7.7 years (based on a population having an iodine-sufficient diet). This study did not evaluate perchlorate exposures, but levels of perchlorate estimated to cause changes in thyroid hormones is greater than levels found in the environment. Given that the US population has also been repeatedly determined to be iodine sufficient, this study’s findings suggest that the low levels of perchlorate found in the environment will not negatively impact IQ in children.
This study, “Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy” used a battery of neurodevelopment tests (e.g., IQ tests) on children up to five years old to conclude that treatment of hypothyroxinemia does not affect IQ. If IQ deficits were caused by maternal hypothyroxinemia, treatment of the disease should affect the outcome. In this finding, Casey et al. supports conclusions of an earlier study by Lazarus et al. in 2012 (CATS Study), and several other studies which show no association between hypothyroxinemia and IQ or treatment of hypothyroxinemia and IQ.
The Casey results are important as U.S. EPA evaluates what kind of action to take on perchlorate regulation. U.S EPA previously stated that children exposed gestationally to maternal hypothyroxinemia showed reduced cognitive abilities; however that conclusion has been challenged by an EPA peer review, and is based on older studies with weaker study design.
This study examined a small cohort of 13 infants and mothers and found evidence that breast-fed babies can metabolize perchlorate, decreasing potential risks from exposure (although doses measured were below any levels known to have an effect).
This study examined 134 pregnant women from Athens, Greece, and came to the same conclusions of Pearce et al (2010 – 2011) and Pearce (2010) which analyzed women in Wales, Italy, Argentina and California, and found that while low-level perchlorate exposure is ubiquitous in the population, it is not associated with alterations in thyroid function during the critical first trimester of pregnancy.
This study examined hundreds of pregnant women from Los Angeles, CA and Cordoba, Argentina and came to the same conclusion as Pearce (2010): low-level perchlorate exposure is ubiquitous in the population, however it is not associated with alterations in thyroid function during the critical first trimester of pregnancy.
This study showed low-level perchlorate exposure does not affect thyroid function in pregnant women based on an examination of thousands of women in Cardiff, Wales and Turin, Italy.
This study reported that perchlorate was detected in powdered infant formula (PIF). Iodine was also measured. It estimated mean and maximum doses from formula in 1 or 6 month-old infants. It stated “Infants consuming certain bovine milk-based PIFs with lactose may be at risk for exceeding the RfD…” but that “…clinical relevance of exceeding the perchlorate RfD in both an iodide-sufficient and iodide-deficient state are unclear.” The median bovine milk PIF perchlorate concentration was 1.37 ppb and the range was 0.68-5.05 ppb.
In a study of newborn infants, there was no association found between cord blood levels of perchlorate, nitrate, and thiocyanate and body weight, length and head circumference. No doses were measured or estimated.
In a study of women in the northeast U.S., no association was found between the amount of iodine, perchlorate, and cotinine (biomarker of tobacco smoke exposure) in colostrum (the first breast milk following birth) or urine. The median colostrum perchlorate concentration was 2.5 ppb and the range was <0.05-188.9 ppb.
Using measurements of perchlorate, thiocyanate, and iodine in breast milk and urine, the researchers estimated the doses of each to newborn breastfed infants using a mathematical calculation based on average infant body weights and intake levels (not actual values). The median breast milk perchlorate concentration was 7.3 ppb and the range was 0.01-48 ppb. The manuscript reported that nine of the 13 infants in the study may have ingested perchlorate at greater than the RfD.
In a study of women in the northeast U.S., this paper reports that neither breast milk nor urinary perchlorate levels were statistically correlated to the amount of iodine in these fluids. The study noted that iodine is needed by the thyroid gland to make thyroid hormones. The median breast milk perchlorate concentration was 9.1 ppb and the range was 1.3-411 ppb.
This study was conducted in Israel and looked at the effect among newborns whose mothers lived in areas where perchlorate levels in drinking water were as low as 3 ppb and as high as 340 ppb. The study found no differences in key hormone levels among any of the newborns, providing evidence that the NAS reference dose is conservative and health protective to the most sensitive individuals in the population.
This study found no impacts from perchlorate on pregnant women during the critical period between the late first and early second trimesters, and no effect on fetal development or thyroid levels in newborns. The study examined pregnant women and babies from three cities in Chile, where perchlorate levels range from non-detect to 110 ppb, and daily intake of dietary iodide is equivalent with the U.S.
This study of newborns and school-age children in three cities in northern Chile, where perchlorate occurs naturally in drinking water in varying concentrations up to 110 ppb, showed no adverse health effects even at the highest levels.
The effect of perchlorate in drinking water on neonatal blood thyroid-stimulating hormone (thyrotopin; TSH0) levels was examined for Las Vegas and Reno, Nevada. This study of neonatal TSH levels in the first month of life found no effect from living in the areas with environmental perchlorate exposures of =15 µg/L (P= 0.97).
This study, similar to the one above, examined the thyroid function of more than 540 newborns in Las Vegas and Reno, Nevada. Scientists looked for changes in thyroid stimulating hormone (TSH) as possible evidence that the Las Vegas newborns were compensating for decreased levels of thyroid hormones. There was no difference in TSH levels in newborns in the two cities.