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Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment
four general steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization (NRC 1983, 1994).
Step 1: Hazard identification entails identifying the contaminants that are suspected to pose health hazards, quantifying the concentrations at which they are present in the environment, describing the specific forms of toxicity (neurotoxicity, carcinogenicity, etc.) that the contaminants of concern can cause, and evaluating the conditions under which these forms of toxicity might be expressed in exposed humans.
Step 2: Dose-response assessment entails further evaluating the conditions under which the toxic properties of a chemical might be manifested in exposed people, with particular emphasis on the quantitative relation between the dose and the toxic response. The development of this relationship may involve the use of mathematical models. This step may include an assessment of variations in response—for example, differences in susceptibility between young and old people.
Step 3: Exposure assessment involves specifying the population that might be exposed to the agent of concern, identifying the routes through which exposure can occur, and estimating the magnitude, duration, and timing of the doses that people might receive as a result of their exposure.
Step 4: Risk characterization involves integrating information from the first three steps to develop a qualitative or quantitative estimate of the likelihood that any of the hazards associated with the agent of concern will be realized in exposed people. This is the step in which risk-assessment results are expressed. Risk characterization should also include a full discussion of the uncertainties associated with the estimates of risk (Adapted from NRC 1994).
Toxicogenomic information has a potential role in all aspects of the risk-assessment process. For example, in hazard identification, toxicogenomic data could inform the types of hazard a chemical presents (for example, whether it poses cancer or noncancer risks) and the modes and mechanisms of toxic action1
The EPA (EPA 2005) provides the following definitions: “The term ‘mode of action’ is defined as a sequence of key events and processes, starting with interaction of an agent with a cell, proceeding through operational and anatomical changes, and resulting in cancer formation. A ‘key event’ is an empirically observable precursor step that is itself a necessary element of the mode of action or is a biologically based marker for such an element. Mode of action is contrasted with ‘mechanism of action,’ which implies a more detailed understanding and description of events, often at the molecular level, than is meant by mode of action. The toxicokinetic processes that lead to formation or distribution of the active agent to the target tissue are considered in estimating dose but are not part of the mode of action as the term is used here. There are many examples of possible