Optimal dose–response analysis relies on target site dosimetry, by mathematically describing the four major processes of pharmacokinetics: bioavailability, distribution, metabolism, and elimination. In other words, uncertainty factors for animal to human extrapolation and even human interindividual extrapolation are replaced with efforts to directly compare the dose of chemical in the target tissue under both the experimental conditions and the human exposure conditions of interest. This comparison is then used to assess the likelihood of health effects in humans from the observed responses of the experimental animals. In contrast to the use of uncertainty or “safety” factors, this approach tries to provide a direct estimate of risk, rather than a conservative upper bound.