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Risk Assessment Considerations

Current risk assessment procedures are typically based on overall daily exposure levels, and tend to emphasize effects resulting from continuous exposures over a lifetime. This basis is widely recognized to be an oversimplification. There has been an increasing realization that exposures are more likely to be experienced as episodes (i.e., bursts or spikes, or intermittent exposures) of varying levels. As scientists delve further into the subject, they are discovering that Haber's Law (i.e., concentration multiplied by duration) does not properly explain the relationship between exposure/dose and an effect.

The complexities of exposure effects on toxic responses require consideration of the entire exposure profile, including the timing, duration, and intermittent nature of exposures reflecting realistic scenarios encountered in practical settings. The proper metric for exposure may be highly dependent on the pharmacokinetic properties of the chemical or exposure in question. The toxic effects considered in models must be carefully chosen to reflect the sensitive endpoints based on the exposure characteristics.

Models have been developed over the last decade which begin to address the effect of duration of exposure in addition to exposure levels; however, most of these models do not incorporate mechanistic information. In addition, only limited work has been done on developing efficient designs for studying dose-rate effects, and these designs tend to be simplistic.

Under the sponsorship of EPA and others, at an August 1998 workshop in DC, participants discussed how exposure-duration and toxicity relationships are or can be incorporated into the risk assessment process for less-than-lifetime exposures. Dr. Lefohn, A.S.L. & Associates, was invited to participate in the workshop and provide one of the short presentations. The workshop participants discussed

    • the current understanding of dose-duration relationships and their underlying mechanistic basis;
    • which approaches can be used in modeling these relationships;
    • how to include these methods in risk assessment; and
    • future directions in this area.

During the meeting, several presentations were made to provide specific examples of the various issues. The remainder of the meeting was organized around breakout sessions that discussed where current risk assessment approaches could be improved.

Much of the current risk assessment methodology is based on Haber's Law (i.e., C x T). A very important conclusion reached by one of the working groups was:

If C x T, pure and simple, does not work (it is not appropriate), then resulting risk assessments become more problematic. Current default methods often assume a simple C x T relationship. The inappropriateness of this assumption can result in both overestimates and underestimates of risk, with the latter being more likely when extrapolation is toward periods of shorter duration....

As a result of the workshop, the EPA published the report "Summary of the U.S. EPA Workshop on the Relationship between Exposure Duration and Toxicity" in September 1998, which summarizes the recommendations of the panel. Copies of the report can be obtained by writing:

U.S. Environmental Protection Agency
Risk Assessment Forum
401 M Street SW
Washington, DC 20460

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