Estimates of exposures to perchlorate from consumption of human milk, dairy milk, and water, and comparison to current reference dose.

To develop an enforceable drinking water standard from a health-based reference dose, sources of exposure and relevant exposure factors across the U.S. population must be considered. Human exposures, expressed as an estimated daily exposure, can be used to evaluate the health protectiveness of a range of potential regulatory values, thus providing a scientific foundation on which decisions can be based. Recent evidence points to detectable levels of perchlorate in milk and other foods. The purpose of this article is to estimate human exposure to perchlorate from ingestion of drinking water, human milk, and dairy milk. Drinking-water exposure was based on a range of possible regulatory values, derived from the recently established reference dose. Exposure to perchlorate from the consumption of milk was based on exploratory Food and Drug Administration dairy milk data, and on additional published perchlorate concentrations in dairy and human milk samples. This effort is exploratory in nature due to the limited data available at this time. However, it is anticipated that these exposure estimates and comparison with the current reference dose will stimulate dialogue and research that will advance the risk assessment for perchlorate.

Genetic factors that might lead to different responses in individuals exposed to perchlorate.

Perchlorate has been detected in groundwater in many parts of the United States, and recent detection in vegetable and dairy food products indicates that contamination by perchlorate is more widespread than previously thought. Perchlorate is a competitive inhibitor of the sodium iodide symporter, the thyroid cell-surface protein responsible for transporting iodide from the plasma into the thyroid. An estimated 4.3% of the U.S. population is subclinically hypothyroid, and 6.9% of pregnant women may have low iodine intake. Congenital hypothyroidism affects 1 in 3,000 to 1 in 4,000 infants, and 15% of these cases have been attributed to genetic defects. Our objective in this review is to identify genetic biomarkers that would help define subpopulations sensitive to environmental perchlorate exposure. We review the literature to identify genetic defects involved in the iodination process of the thyroid hormone synthesis, particularly defects in iodide transport from circulation into the thyroid cell, defects in iodide transport from the thyroid cell to the follicular lumen (Pendred syndrome), and defects of iodide organification. Furthermore, we summarize relevant studies of perchlorate in humans. Because of perchlorate inhibition of iodide uptake, it is biologically plausible that chronic ingestion of perchlorate through contaminated sources may cause some degree of iodine discharge in populations that are genetically susceptible to defects in the iodination process of the thyroid hormone synthesis, thus deteriorating their conditions. We conclude that future studies linking human disease and environmental perchlorate exposure should consider the genetic makeup of the participants, actual perchlorate exposure levels, and individual iodine intake/excretion levels.

Using the ATSDR Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures.

The Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures (Mixtures Guidance Manual) is intended to assist environmental health scientists and toxicologists in determining whether exposure to chemical mixtures at hazardous waste sites may affect public health. The Agency for Toxic Substances and Disease Registry (ATSDR) approach is a semi-quantitative screening process. Step-by-step procedures for assessing noncarcinogenic and carcinogenic effects are outlined in flow charts. Exposure data and toxicological information on the mixture of concern are the preferred basis for an assessment. If suitable whole mixture studies are not available, a components-based approach is undertaken. The hazard index (HI) method is used to screen for noncancer health hazards from potential additivity of the components. Cancer risks for the components are summed to screen for health hazards from potential additivity of carcinogenic effects. A weight-of-evidence (WOE) method is used to evaluate the potential impact of interactions on noncancer and cancer health effects.

Six interaction profiles for simple mixtures.

The Agency for Toxic Substances and Disease Registry (ATSDR) has a program for chemical mixtures that encompasses research on chemical mixtures toxicity, health risk assessment, and development of innovative computational methods. ATSDR prepared a guidance document that instructs users on how to conduct health risk assessment on chemical mixtures (Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures). ATSDR also developed six interaction profiles for chemical mixtures. Two profiles were developed for persistent environmental chemicals that are often found in contaminated fish and also can be detected in human breast milk. The mixture included chlorinated dibenzo-p-dioxins, hexachlorobenzene, dichlorodiphenyl dichloroethane, methyl mercury, and polychlorinated biphenyls. Two profiles each were developed for mixtures of metals and mixtures of volatile organic chemicals (VOCs) that are frequently found at hazardous waste sites. The two metal profiles dealt with (a) lead, manganese, zinc, and copper; and (b) arsenic, cadmium, chromium, and lead; the two VOCs mixtures dealt with (a) 1,1,1-trichloroethane, 1,1-dichloroethane, trichloroethylene, and tetrachloroethylene; and (b) benzene, ethylbenzene, toluene, and xylenes (BTEX). Weight-of-evidence methodology was used to assess the joint toxic action for most of the mixtures. Physiologically based pharmacokinetic modeling was used for BTEX. In most cases, a target-organ toxicity dose modification of the hazard index approach is recommended for conducting exposure-based assessments of noncancer health hazards.