Use of Toxicological Data in Estimating Reference Values for Risk Assessment

A number of programs within the U.S. Environmental Protection Agency (USEPA) currently set less-than-lifetime exposure limits in addition to the chronic reference dose (RfD) and reference concentration (RfC). A review of procedures within the USEPA for setting reference values suggests that less-thanlifetime reference values should be more routinely developed and captured in the USEPA's online IRIS database where chronic RfDs and RfCs, as well as cancer slope factors, are currently available. A review of standard testing study protocols was conducted to determine what data were available for setting acute, short-term, and longer-term reference values, as well as chronic values. This review was done from the point of view of endpoints assessed for specific organ systems (both structural and functional), life stages covered by exposure and outcome, durations of exposure covered and the outcomes evaluated for each, and evaluation of latency to response and/or reversibility of effects. This review revealed a number of data gaps and research needs, including the need for an acute and/or short-term testing protocol that can be used to set acute and shortterm reference values, a strategy for when to conduct more extensive testing based on initial screening data or other information (e.g., chemical class, pharmacokinetics, mode of action), additonal standard testing guidlines protocols to allow more complete assessment of certain organ systems and life stages, development of pharmacokinetic data for different life stages, toxicity related to aging, and latency to response, particularly long-term latency as a result of developmental exposures. The implications of this review are discussed relative to characterizing hazard data for setting reference values, and the potential effects on uncertainty factors and low-dose extrapolation.