EPA Cancer Risk Assessment and Low-Dose Extrapolation

The present EPA approach is to use linear extrapolation from high doses to low doses under two distinct scenarios (1) when a mutagenic compound is known to directly interact with DNA and (2) when the MOA of a carcinogen is not well-defined. The Cancer Guidelines (US EPA 2005b) stated  

When the weight of evidence evaluation of all available data are insufficient to establish the mode of action for a tumor site and when scientifically plausible based on the available data, linear extrapolation is used as a default approach, because linear extrapolation generally is considered to be a health-protective approach. Nonlinear approaches generally should not be used in cases where the mode of action has not been ascertained. Where alternative approaches with significant biological support are available for the same tumor response and no scientific consensus favors a single approach, an assessment may present results based on more than one approach. 

the EPA has recognized the nonlinearity of indirect genotoxins, but does not depart from the assnmption of linearity withont a well-defined nnderstanding of 

The EPA does not list MO As with probable low-dose nonlinearity. While several MOAs have some acceptance as being nonlinear or having a threshold (e.g., cytotoxicity followed by regeneration, and receptor-mediated processes), the establishment of nonlinear dose-responses for specific carcinogenic MOAs is still controversial (Andersen et al. 2003). More discussion on implementation of nonlinear extrapolation by regulatory agencies for nonlinear carcinogens is presented later in this chapter. 

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