except when there is adequate evidence to support mechanistic modeling (there has been no such case).

Another refinement in dose-response assessment has been the derivation of the RfD or low-dose cancer risk from a POD that is calculated using BMD methodology (EPA 2000a). In noncancer risk assessment, this approach has the advantage of making better use of the dose-response evidence available from bioassays than do calculations based on NOAELs. It also provides additional quantitative insight into the risk presented in the bioassay at the POD because for quantal end points the POD is defined in terms of a given risk for the animals in the study.

EPA’s treatment of noncancer and low-dose nonlinear cancer end points is a major step by the agency in an overall strategy to harmonize cancer and noncancer approaches to dose-response assessment. Other aspects of this harmonization for the different end points include consideration of the same cross-species factors (EPA 2006b), and the same pharmacokinetic adjustments. EPA staff have also explored for noncancer end points dose-response modeling that results in probabilistic descriptions (for example, for acrolein, Woodruff et al. 2007) and that could be readily integrated into benefits evaluation (for thyroid-disrupting chemicals, Axelrad et al. 2005). But these approaches have not found their way into agency practice.

Scientific, Technical, and Operational Problems with the Current Approach

The committee recognizes EPA’s efforts to examine and refine dose-response assessment methodology and practice and the agency’s work to clarify its approaches and practices in guidelines and other documents (for example, EPA 2000a, 2002b, 2004, 2005b). A number of improvements over the last decade can be noted, such as the movement toward using MOA determinations and the application of BMD methods. However, the current framework has important structural problems, some of which have been exacerbated by recent decisions. Figure 5-1 presents an outline of the current framework for dose-response assessment and risk characterization in EPA and some major limitations in the framework, which are discussed below.

Potential Low-Dose Linearity for Noncancer and “Nonlinear” Cancer End Points

Thresholds are assumed for noncarcinogens and for carcinogens believed to operate through an MOA considered nonlinear at low doses. The rationale is that at levels below the threshold dose, clearance pathways, cellular defenses, and repair processes have been thought to minimize damage so that disease does not result. However, as illustrated in Figure 5-2, threshold determinations should not be made in isolation, inasmuch as other chemical exposures and biologic factors that influence the same adverse effect can modify the dose-response relationship at low doses and should therefore be considered.

Nonlinear Cancer End Points

The current determination of “nonlinearity” based on MOA assessment is a reasonable approach to introduce scientific evidence on MOA into cancer dose-response assessment. However, some omissions in this overall approach for low-dose nonlinear carcinogens could yield inaccurate and misleading assessments. For example, the current EPA practice of determining “nonlinear” MOAs does not account for mechanistic factors that can create linearity at low dose. The dose-response relationship can be linear at a low dose when an exposure contributes to an existing disease process (Crump et al. 1976, Lutz 1990). Effects



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