Expanding the reference dose concept to incorporate and optimize beneficial effects while preventing toxic responses from nonessential toxicants.

Increasing evidence that low-level exposure to toxic agents induces beneficial effects indicates the need to examine if and how the current EPA Reference Dose (RfD) derivation process could take this phenomenon into account. This paper examines conditions that affect how the RfD process could incorporate chemically induced beneficial effects while preventing toxic responses. Incorporation of beneficial responses in the RfD process will be affected by: (1) Size of the dosage range over which the beneficial effects are observed; (2) Proximity of the optimal beneficial response dosage to the NOAEL; (3) Size of the intraspecies UF. Based on data estimating the distance of the median dosage of the optimal beneficial response from the NOAEL and the recently described lack of independence of the inter- and intraspecies uncertainty factors (UFs), noncarcinogenic toxic substances whose RfDs are based on animal model data are predicted to have their toxic effects prevented and possible beneficial effects optimized in the general population by use of an intraspecies UF of 5. In contrast, current EPA practices of employing a 10-fold UF for intraspecies variation in animal-model-based RfD derivation while protecting against harmful effects also lead to the general population missing estimated beneficial effects. Such a conclusion has important policy implications since no debate has been directed toward the distribution of population-based pollution-related benefits, but only toward the prevention of their harmful effects.