SAR/QSAR methods in public health practice.

Methods of (Quantitative) Structure-Activity Relationship ((Q)SAR) modeling play an important and active role in ATSDR programs in support of the Agency mission to protect human populations from exposure to environmental contaminants. They are used for cross-chemical extrapolation to complement the traditional toxicological approach when chemical-specific information is unavailable. SAR and QSAR methods are used to investigate adverse health effects and exposure levels, bioavailability, and pharmacokinetic properties of hazardous chemical compounds. They are applied as a part of an integrated systematic approach in the development of Health Guidance Values (HGVs), such as ATSDR Minimal Risk Levels, which are used to protect populations exposed to toxic chemicals at hazardous waste sites. (Q)SAR analyses are incorporated into ATSDR documents (such as the toxicological profiles and chemical-specific health consultations) to support environmental health assessments, prioritization of environmental chemical hazards, and to improve study design, when filling the priority data needs (PDNs) as mandated by Congress, in instances when experimental information is insufficient. These cases are illustrated by several examples, which explain how ATSDR applies (Q)SAR methods in public health practice.

Chemical-specific health consultation for chromated copper arsenate chemical mixture: port of Djibouti.

The Agency for Toxic Substances and Disease Registry (ATSDR) prepared this health consultation to provide support for assessing the public health implications of hazardous chemical exposure, primarily through drinking water, related to releases of chromated copper arsenate (CCA) in the port of Djibouti. CCA from a shipment, apparently intended for treating electric poles, is leaking into the soil in the port area. CCA is a pesticide used to protect wood against decay-causing organisms. This mixture commonly contains chromium(VI) (hexavalent chromium) as chromic acid, arsenic(V) (pentavalent arsenic) as arsenic pentoxide and copper (II) (divalent copper) as cupric oxide, often in an aqueous solution or concentrate. Experimental studies of the fate of CCA in soil and monitoring studies of wood-preserving sites where CCA was spilled on the soil indicate that the chromium(VI), arsenic and copper components of CCA can leach from soil into groundwater and surface water. In addition, at CCA wood-preserving sites, substantial concentrations of chromium(VI), arsenic and copper remained in the soil and were leachable into water four years after the use of CCA was discontinued, suggesting prolonged persistence in soil, with continued potential for leaching. The degree of leaching depended on soil composition and the extent of soil contamination with CCA. In general, leaching was highest for chromium(VI), intermediate for arsenic and lowest for copper. Thus, the potential for contamination of sources of drinking water exists. Although arsenic that is leached from CCA-contaminated soil into surface water may accumulate in the tissues of fish and shellfish, most of the arsenic in these animals will be in a form (often called fish arsenic) that is less harmful. Copper, which leaches less readily than the other components, can accumulate in tissues of mussels and oysters. Chromium is not likely to accumulate in the tissues of fish and shellfish. Limited studies of air concentrations during cleanup of CCA-contaminated soil at wood- preserving sites showed that air levels of chromium(VI), arsenic and copper were below the occupational standards. Workers directly involved in the repackaging, containment or cleanup of leaking containers of CCA or of soil saturated with CCA, however, may be exposed to high levels of CCA through direct dermal contact, inhalation of aerosols or particulates and inadvertent ingestion. Few studies have been conducted on the health effects of CCA. CCA as a concentrated solution is corrosive to the skin eyes and digestive tract. Studies of workers exposed to CCA in wood-preserving plants have not found adverse health effects in these workers, but the studies involved small numbers of workers and therefore are not definitive. People exposed to very high levels of CCA, from sawing wood that still had liquid CCA in it or from living in a home contaminated with ash containing high levels of chromium(VI), arsenic and copper, experienced serious health effects including nosebleeds, digestive system pain and bleeding, itching skin, darkened urine, nervous system effects such as tingling or numbness of the hands and feet and confusion, and rashes or thickening and peeling of the skin. These health effects of the mixture are at least qualitatively reflective of the health effects of the individual components of CCA (arsenic, chromium(VI) and copper). For a given mixture, the critical effects of the individual components are of particular concern, as are any effects in common that may become significant due to additivity or interactions among the components. Effects of concern for CCA, based on the known effects of the individual components, include cancer (arsenic by the oral route, arsenic and chromium(VI) by the inhalation route), irritant or corrosive effects (all three mixture components), the unique dermal effects of arsenic, neurologic effects (arsenic and chromium(VI), and hematologic, hepatic and renal effects (all three components). Because arsenic, chromium(VI), and copper components affect some of the same target organs, they may have additive toxicity toward those organs. Few studies have investigated the potential toxic interactions among the components (arsenic, chromium(VI) and copper) of CCA. The available interaction studies and also possible mechanisms of interaction were evaluated using a weight-of-evidence approach. The conclusion is that there is no strong evidence that interactions among the components of CCA will result in a marked increase in toxicity. This conclusion reflects a lack of well designed interaction studies as well as uncertainties regarding potential mechanisms of interaction. Confidence in the conclusion is low. Workers exposed to high levels of CCA during cleanup of leaking containers of CCA or soil heavily contaminated with CCA should wear protective clothing and respirators if air concentrations of arsenic are above 10 microg/m3. In addition, they should not eat, drink or use tobacco products during exposure to CCA, and should thoroughly wash after skin contact with CCA and before eating, drinking, using tobacco products or using restrooms. When protective clothing becomes contaminated with CCA, it should be changed, and the contaminated clothing should be disposed off in a manner approved for pesticide disposal. Workers should leave all protective clothing, including work shoes and boots, at the workplace, so that CCA will not be carried into their cars and homes, which would endanger other people. People not involved in the cleanup of the CCA and who are not wearing protective clothing should be prevented from entering contaminated areas. Leaking containers of CCA must be repackaged and contained to prevent direct exposure of on-site personnel; and contaminated soil needs to be removed to prevent the CCA from leaching into surface water and groundwater, thereby contaminating sources of drinking water.

Considerations and procedures in the derivation of ATSDR minimal risk levels.

Minimal risk levels (MRLs) are health-based guidance values derived for individual substances by conducting a thorough review of the literature, identifying appropriate target organs of response, and identifying a dose level where a no adverse effect or the lowest adverse effect level is seen. This level is then evaluated for uncertainty in the data base and for other extenuating factors and subsequently adjusted with uncertainty or modifying factors. The resulting calculation yields the MRL that is defined as an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. Typically, MRLs are derived for different durations of exposure (acute, intermediate, chronic) and for different routes of exposure (oral, inhalation). The MRLs serve as useful reference values in evaluating human health from exposure to substances found at hazardous waste sites. Because of numerous requests of various programs, recent work has focused on expanding the applicability of MRLs to other situations and routes of exposure (dermal, food supply, intramuscular) beyond the traditional oral and inhalation exposure routes at waste sites. Results of work, in conjunction with the Agency for Toxic Substances and Disease Registry's computational toxicology laboratory, shows that the use of computational methods, such as physiologically based pharmacokinetic modeling, may allow the MRL process to be adapted to unique durations and routes of exposure such as intramuscular injections.