Abstract
The Reference Dose (RfD) and Reference Concentration (RfC) are human health reference values (RfVs) representing exposure concentrations at or below which there is presumed to be little risk of adverse effects in the general human population. The 2009 National Research Council report Science and Decisions recommended redefining RfVs as “a risk-specific dose (for example, the dose associated with a 1 in 100,000 risk of a particular end point).” Distributions representing variability in human response to environmental contaminant exposures are critical for deriving risk-specific doses. Existing distributions estimating the extent of human toxicokinetic and toxicodynamic variability are based largely on controlled human exposure studies of pharmaceuticals. New data and methods have been developed that are designed to improve estimation of the quantitative variability in human response to environmental chemical exposures. Categories of research with potential to provide new data useful for developing updated human variability distributions include controlled human experiments, human epidemiology, animal models of genetic variability, in vitro estimates of toxicodynamic variability, and in vitro-based models of toxicokinetic variability. In vitro approaches, with further development including studies of different cell types and endpoints, and approaches to incorporate non-genetic sources of variability, appear to provide the greatest opportunity for substantial near-term advances.
Acknowledgments
The authors appreciate the valuable input of Weihsueh Chiu and Anna Lowit in developing the plan for this review. Andrea Pfahles-Hutchens contributed to the preparation of this paper. We appreciate the helpful input of numerous USEPA colleagues, including members of USEPA’s Risk Assessment Forum. Development of this review was informed by the presentations and discussion at the National Academy of Sciences Emerging Science for Environmental Health Decisions Workshop, Interindividual Variability: New Ways to Study and Implications for Decision-Making, held on September 30 and October 1, 2015.
Disclosure statement
No potential conflict of interest was reported by the authors.