The proposed existence of dose-response thresholds for nongenotoxic carcino
gens has led to a major controversy in the risk extrapolation process. To r
esolve this debate, there has been a significant investment in mechanism-ba
sed risk assessment research. The ability to utilize this mechanistic resea
rch 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 re
sponse. This approach does not rely upon a mechanistic framework for the de
velopment of pathology, is solely dependent on already existing technology,
and takes into account the possibility of background levels of pathway act
ivation. For this approach, sensitive biochemical responses need to be iden
tified and linked to the introduction of the toxicant through dose response
, by time of response, and, when possible, through a proposed biochemical m
echanism. 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 CY
P1A1 induction, this approach yields an estimate of the acceptable daily in
take of 550 fg/kg/day. This limit is remarkably similar to the results of t
he original EPA linear extrapolation (6 fg/kg/day). A similar approach can
be used for other nongenotoxic carcinogens and the analysis can be complete
d within 1 year.