Questions and Answers
What the NAS Committee Report Says about Perchlorate And Where it Fits into the Regulatory Process
In February 2005, the U.S. Environmental Protection Agency (EPA) established its official reference dose of perchlorate at 0.0007 milligrams per kilogram per day, and translated that number to a Drinking Water Equivalent Level (DWEL) of 24.5 parts per billion (ppb). This level is consistent with the recommended reference dose included in the National Academy of Sciences' ("NAS" or "NAS Committee") January 2005 report on the health implications of perchlorate.
Federal regulators will now need to determine whether to proceed with a national drinking water standard for perchlorate. California is already engaged in the process of developing its own enforceable drinking water standard, also known as a maximum contaminant level (MCL). The MCL is required under California law to be set as close as is economically and technologically feasible to the final PHG. U.S. EPA would follow a similar process if it determines an MCL is necessary.
The Perchlorate Study Group submitted an executive summary and position paper to California's Office of Environmental Health Hazards Assessment analyzing the findings of the NAS report. These documents can be found at http://www.councilonwaterquality.org/media/20050211.html.
Translating the Best Available Science into the Best Possible Regulation
Q: What are the next steps in EPA's regulatory process for perchlorate?
A: EPA's 24.5 ppb DWEL may be used by officials throughout the agency to make site-specific cleanup or interim drinking water standard decisions involving perchlorate. States and private parties also may look to EPA's RfD and DWEL as they make similar decisions.
At this juncture, EPA is contemplating two regulatory decisions:
First, EPA may revise its 2003 Interim Guidance on perchlorate. That guidance recommended that EPA Regions use a range of 4 ppb to18 ppb for site-specific cleanup decisions or interim drinking water standards. Since EPA's guidance values of 4 ppb to18 ppb were based on older scientific studies and analyses, the agency might choose to change the guidance to reflect its new DWEL.
Second, EPA must decide whether to promulgate a Federal drinking water standard (MCL) for perchlorate. EPA will only proceed with a standard if it determines that perchlorate adversely affects human health, is known or likely to substantially occur in public water systems at frequencies and levels that would cause adverse health effects, and that setting a Federal standard for perchlorate presents a meaningful opportunity to reduce the risk from perchlorate exposure.
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Q: The EPA and the NAS Committee recommended a reference dose. What is a reference dose?
A: A reference dose (RfD) is defined by EPA 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 risk of deleterious effects during a lifetime." (http://www.epa.gov/iris/gloss8.htm)
The definition is based on the assumption that exposure could occur throughout the lifetime and takes into account all stages of life. Also, the definition takes into account "sensitive subgroups," such as pregnant women, infants and children, and fetuses.
It is sometimes misunderstood to mean that doses above the RfD are unsafe. This is not correct. Because the RfD incorporates a number of safety factors to ensure that the value is health-protective, when a dose exceeds an RfD value, it does not mean that an adverse effect will occur. (http://www.epa.gov/safewater/uic/classv/pdfs/appd.pdf)
The RfD is not a regulatory standard - it is one of the building blocks assembled into a regulatory standard, and should not be misinterpreted as serving the purposes of a regulatory standard.
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Q: What level is safe for pregnant women? What level is safe for children? Why not be extra protective?
A: To derive their recommended reference dose, the NAS Committee selected as its starting point the NOEL dose of 0.007 milligrams per kilogram per day. This level is the lowest dose used in a clinical study of adults by Greer et al. (2002). At this dose, there was no difference in the amount of iodide uptake inhibition by the thyroid between people exposed to perchlorate and those not exposed to perchlorate. The Committee indicated that this effect, inhibition of iodide uptake by the thyroid, is the first effect that must occur before any other effects of exposure can occur. However, the Committee is clear that iodide uptake inhibition is not an adverse effect. They state that this dose has no measurable effect at all on the human body. (See page 113) Using standard default EPA conversion practices, this is equivalent to 245 ppb in drinking water.
The Committee then divided this dose by a safety factor of 10 to account for sensitive populations. They identified the most sensitive population to be fetuses; particularly those of pregnant women who have hypothyroidism or iodide deficiency (see Page 115). The Committee's resulting recommended reference dose (0.0007 milligrams per kilogram of body weight per day) would be equivalent to 24.5 ppb in drinking water.
The NAS Committee acknowledges that they used an unconventional approach to develop their reference dose and used as its starting point a dose that causes no effects at all. This dose is already 57-fold lower than the dose that the NAS Committee identified as the minimum dose before any adverse effects of perchlorate exposure could occur. Any level of exposure below the Committee's reference dose of 245 ppb is clearly safe, since no adverse effect can occur to anybody, including pregnant women, their fetuses, infants, and children, at levels of exposure that are below the highest dose at which no effects at all occur. No public health benefit is gained by reducing exposures any further below this level.
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Q: How does EPA derive an RfD, and how did the NAS Committee derive one in the case of perchlorate?
A: Typically, EPA derives an RfD by starting with the highest dose at which no adverse effects can be observed (the No Observed Adverse Effect Level, or NOAEL). (http://www.epa.gov/iris/rfd.htm) It is unprecedented to use the level at which no effect at all, even a mundane, biochemical effect, is observed (the No Observed Effect Level, or NOEL); however, this is the starting point that the NAS Committee used in the case of perchlorate. The Committee defined a NOEL as "the highest dose at which there are no statistically or biologically significant increases in the frequency or severity of any effect between the exposed populations and its appropriate control." (See page 112)
Where a NOAEL is used, uncertainty factors are then customarily applied to this starting dose to account for scientific uncertainty and to ensure that the RfD protects public health. For example, to account for sensitive populations such as pregnant women, children, infants and fetuses, the EPA typically divides the NOAEL by an uncertainty factor of 3 or 10.
The NOEL dose that the Committee selected as its starting point was 0.007 milligrams per kilogram per day. The Committee states this dose has no measurable effect at all on the human body. (See page 113) The Committee then divided this dose by a safety factor of 10 to account for sensitive populations. Given their departure from standard practice in their selection of a NOEL as the starting point for their reference dose, it is puzzling that the NAS felt they needed to apply an additional ten-fold safety factor. As the Committee itself states, below the level that has no effect, "all other proposed effects of perchlorate exposure would be avoided." (See page 119) There is no apparent precedent for this level of conservatism.
The Committee identified the NOAEL for perchlorate as 0.4 milligrams per kilogram body weight per day, stating that, in adults, "sustained exposure" (i.e., several months or longer) to more than 0.4 milligrams per kilogram of perchlorate per day is likely required before any harm could occur.
If, alternatively, an uncertainty factor of 3 or 10 for sensitive populations was applied to the NOAEL identified by the NAS Committee, the resulting dose would be 0.04 to 0.13 milligrams per kilogram per day. Applying standard default EPA exposure assumptions about how much a typical person weighs and how much water they drink makes this dose equivalent to 1,400 to 4,655 ppb in drinking water.
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Q: What is a NOEL?
A: The NAS Committee defines a NOEL as "the highest dose at which there are no statistically or biologically significant increases in the frequency or severity of any effect between the exposed populations and its appropriate control." (See page 112)
The Committee states that a dose of 0.007 milligrams per kilogram of body weight per day is the NOEL. (See page 113) Using standard default EPA conversion practices (http://www.epa.gov/OGWDW/standard/setting.html), this is equivalent to 245 ppb in drinking water.
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Q: What are "uncertainty" or "safety" factors?
A: As with most issues in life, health and safety decisions must be made absent absolute certainty. "Uncertainty" or "safety" factors are incorporated into the process to account for a lack of scientific data or to address possible variability in population sensitivity when deriving a safe dose level. EPA's definition of uncertainty factors can be found at .
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Q: Is it appropriate to apply a safety factor to a NOEL? Is there a precedent for this? Are there scientific arguments against it?
A: Applying a safety factor to a NOEL is unusual and no precedent has been identified wherein EPA has applied safety factors to an analogous endpoint to derive an RfD.
The NAS Committee acknowledges that its recommendation "differs from the traditional approach." (See page 9) Moreover, the Committee does not provide any supporting precedent to justify applying a safety factor to this kind of dose.
In this instance, the Committee recommends a reference dose that is more than 570 times lower than the dose it concludes does not cause adverse effects in humans. No additional health protection is gained by setting a reference dose below the threshold dose.
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Q: What is the ppb level in drinking water that equates to the NOEL as defined by the NAS Committee?
A: EPA uses standard default conversion factors for body weight (70 kilograms) and tap water consumption (2 liters per day) to translate RfDs to drinking water equivalents in ppb. For most people in a population, these assumptions are conservative since most people do not drink this much water each day (i.e., 2 liters per day is the 84th percentile of the adult drinking water rate, meaning 84 percent of the population drinks less than this amount each day). The following ppb equivalents correspond to various perchlorate doses:
PPB-EQUIVALENTS FOR VARIOUS DOSES
|No Observed Adverse Effect Level (NOAEL) [0.4 mg/kg per day]
|No Observed Effect Level (NOEL) [0.007 mg/kg per day]
|NAS Committee recommended reference dose [0.0007 mg/kg per day]
The Committee based its reference dose on the NOEL instead of the NOAEL, and applied an additional 10-fold safety factor to account for sensitive populations.
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Q: Are all the sources of perchlorate additive in the body?
A: The effect of perchlorate in the body at doses above 0.007 milligrams per kilogram per day (equivalent to 245 ppb in drinking water using EPA default assumptions) will be the same, regardless of whether its source is from drinking water or food. Perchlorate is not absorbed through the skin.
To calculate the total dose from all sources, however, it is not correct to simply add the concentrations found in water, milk and various other foods. This is because when calculating a total dose, the amounts of water, milk and other foods that a person ingests also must be considered. (http://www.cfsan.fda.gov/~dms/clo4data.html)
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Q: What body weight should be used to calculate a safe drinking water concentration using the NAS Committee's recommended reference dose?
A: By definition, a reference dose assumes exposure over a lifetime and takes into account the special considerations of sensitive populations such as pregnant women, children, infants and the developing fetus. (http://www.epa.gov/iris/RFD_FINAL.pdf) The NAS Committee calculated a reference dose by starting with a NOEL and applying a 10-fold safety factor to ensure protection of potentially sensitive populations. If this value was used to calculate a safe drinking water concentration, any additional adjustment to account for sensitive populations, such as using body weights and drinking water consumption rates for the sensitive population, would be unnecessary and in essence "double counting."
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Q: Who decides whether and how the additional studies should be conducted?
A: The NAS Committee made several recommendations for future research, although noting that sufficient data now exist to move forward with the regulatory process.
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Q: The NAS Committee says perchlorate is "unlikely" to cause cancer. What studies did the Committee review in order to reach this conclusion?
A: The NAS Committee stated "it is unlikely that perchlorate poses a risk of cancer in humans." (see page 95)
"There are no reports of the appearance of a new thyroid disorder, thyroid nodules, or thyroid carcinoma in any patient treated with potassium perchlorate for hyperthyroidism. Iodide deficiency in the thyroid gland, a possible consequence of perchlorate administration or exposure, is not associated with an increase in thyroid cancer ... In hyperthyroid patients treated with antithyroid drugs, there was no increase in thyroid cancer mortality" (see page 40)
"The committee notes, however, that on the basis of its understanding of the biology of human and rodent thyroid tumors, it is unlikely that perchlorate poses a risk of thyroid cancer in humans." (see page 7)
"In addition, EPA's science policy document on the assessment of thyroid follicular-cell tumors notes that although there may be some qualitative similarities, there is evidence that "humans may not be as sensitive quantitatively to thyroid cancer development of thyroid-pituitary disruption as are rodents" . The increased sensitivity may be due to marked species differences in the physiology of the thyroid gland . The EPA and IARC documents provide guidance for the evaluation of thyroid follicular-cell tumors based on mode of action (for example, tumors secondary to hormone imbalance)." (see page 95)
One of the animal studies of perchlorate looked at two-generations of rats that were exposed to perchlorate in drinking water. A certain type of thyroid tumor known as a follicular cell tumor was identified in two of the rats given perchlorate. On page 95 of the report, the NAS Committee indicates that these types of tumors are not unexpected in rats when they are exposed to agents that affect the thyroid because "spontaneous thyroid follicular-cell adenomas can occasionally be observed in control rats of this strain and age." In other words, thyroid tumors occur often in rats (especially Sprague Dawley rats as were studied here) even when they are not exposed to anything. The Committee also notes that, in this regard, rats are much different than humans, stating "humans may not be as sensitive quantitatively to thyroid cancer development of thyroid-pituitary disruption as are rodents...The increased sensitivity may be due to marked species differences in the physiology of the thyroid gland."
Rats are known to respond much more rapidly and to a greater extent to agents that affect their thyroid than do humans because of many physiological differences. When a rat is exposed to an agent that affects the thyroid, more thyroid stimulating hormone (TSH) is produced than in a human at a comparable dose, which causes a much more rapid production of thyroid cells. When cells multiply rapidly, the likelihood that cellular mutations will occur increases, which can lead to tumors. Since TSH levels are not affected in humans at equivalent doses, stimulation of the thyroid to produce more cells does not occur. The NAS states that these agents "can be assumed not to be carcinogenic in humans in concentrations that do not lead to alterations in thyroid hormone homeostasis." (see page 95)
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Q: What is a simple definition of "point of departure?"
A: In risk assessment, the "point of departure" is the dose selected as the starting point to which uncertainty or safety factors are applied to derive a "safe" dose. () Historically, this starting point is either the NOAEL or the LOAEL. The use of a NOEL is a dramatic departure from current policy and constitutes a much more conservative starting point than has been used for any other regulated chemical.
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