Mixtures and their risk assessment in toxicology.

For communities generally and for persons living in the vicinity of waste sites specifically, potential exposures to chemical mixtures are genuine concerns. Such concerns often arise from perceptions of a site's higher than anticipated toxicity due to synergistic interactions among chemicals. This chapter outlines some historical approaches to mixtures risk assessment. It also outlines ATSDR's current approach to toxicity risk assessment. The ATSDR's joint toxicity assessment guidance for chemical mixtures addresses interactions among components of chemical mixtures. The guidance recommends a series of steps that include simple calculations for a systematic analysis of data leading to conclusions regarding any hazards chemical mixtures might pose. These conclusions can, in turn, lead to recommendations such as targeted research to fill data gaps, development of new methods using current science, and health education to raise awareness of residents and health care providers. The chapter also provides examples of future trends in chemical mixtures assessment.

Binary weight-of-evidence evaluations of chemical interactions--15 years of experience.

The paper reflects on the last 15years of experience in the field of mixtures risk assessment. It summarizes results found in various documents developed by the Agency for Toxic Substances and Disease Registry (ATSDR) of the weight-of-evidence (WOE) approach applied to 380 binary combinations of chemicals. Of these evaluations, 156 assessments indicated possible additivity of effects [=], 76 indicated synergism (greater-than-additive effects [>]), and 57 indicated antagonism (less-than-additive effects [<]). However, 91 combinations lacked the minimum information needed for making any assessments and, hence, were undetermined. The paper provides examples of the rationale behind some of the WOE decisions and discusses the importance of expert judgments in risk assessment evaluations. Examples are given regarding the importance of human variability in mixtures' ability to affect human health and regarding the dose versus effect relationships.

Computational toxicology methods in public health practice.

ABSTRACT Hazard identification and health risk assessment traditionally rely on results of experimental testing in laboratory animals. It is a lengthy and expensive process, which at the end still involves large uncertainty because the sensitivity of animals is unequal to the sensitivity of humans. The Agency for Toxic Substances and Disease Registry (ATSDR) Computational Toxicology and Method Development Laboratory develops and applies advanced computational models that augment the traditional toxicological approach with multilevel cross-extrapolation techniques. On the one hand, these techniques help to reduce the uncertainty associated with experimental testing, and on the other, they encompass yet untested chemicals, which otherwise would be left out of public health assessment. Computational models also improve understanding of the mode of action of toxic agents, and fundamental mechanisms by which they may cause injury to the people. The improved knowledge is incorporated in scientific health guidance documents of the Agency, including the Toxicological Profiles, which are used as the basis for scientifically defensible public health assessments.

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.