Early indicators of response in biologically based risk assessment for nongenotoxic carcinogens

The proposed existence of dose-response thresholds for nongenotoxic carcinogens has led to a major controversy in the risk extrapolation process. To resolve this debate, there has been a significant investment in mechanism-based risk assessment research. The ability to utilize this mechanistic research for risk assessment procedures is still limited and may not warrant the expense. Alternatively, an approach can be used to identify dose-response thresholds through the utilization of sensitive indicators of biological response. This approach does not rely upon a mechanistic framework for the development of pathology, is solely dependent on already existing technology, and takes into account the possibility of background levels of pathway activation. For this approach, sensitive biochemical responses need to be identified and linked to the introduction of the toxicant through dose response, by time of response, and, when possible, through a proposed biochemical mechanism. The weakness of this approach is that more sensitive unidentified responses may exist requiring that a safety factor of 10 be used to define a NOEL. For dioxin-like compounds, using a surrogate marker of response CYP1A1 induction, this approach yields an estimate of the acceptable daily intake of 5-50 fg/kg/day. This limit is remarkably similar to the results of the original EPA linear extrapolation (6 fg/kg/day). A similar approach can be used for other nongenotoxic carcinogens and the analysis can be completed within 1 year.