A STRAW MAN PROPOSAL FOR A QUANTITATIVE DEFINITION OF THE RfD

ABSTRACT

This paper discusses the merits and disadvantages of a specific proposal for a numerical calculation of the reference dose (RfD) with explicit recognition of both uncertainty and variability. It is suggested that the RfD be the lower (more restrictive) value of:

• The daily dose rate that is expected (with 95% confidence) to produce less than 1/100,000 incidence over background of a minimally adverse response in a standard general population of mixed ages and genders, or

• The daily dose rate that is expected (with 95% confidence) to produce less than a 1/1000 incidence over background of a minimally adverse response in a definable sensitive subpopulation.

Developing appropriate procedures to make such estimates poses challenges. To be a viable replacement for current RfDs, a numerical definition needs to be

• A plausible representation of the risk management values that both lay people and “experts” believe are intended to be achieved by current RfDs, (while better representing the “truth” that current RfDs cannot be expected to achieve zero risk with absolute confidence for a mixed population with widely varying sensitivities),

• Estimable with no greater amount of chemical specific information than is traditionally collected to estimate current RfD values,

• Subjected to a series of comparisons with existing RfDs to evaluate overall implications for current regulatory values,

• A more flexible value in the sense of facilitating the development of procedures to allow the incorporation of more advanced technical information—e.g., defined data on human distributions of sensitivity; information on comparative pharmacokinetic and/or pharmacodynamics in humans vs. test species, etc.

The discussion evaluates the straw man proposal in the light of each of these points, and assesses the risks and uncertainties inherent in present RfDs by applying existing distributional information on various uncertainty factors to 18 of 20 randomly-selected entries from IRIS. The analysis here suggests that current RfDs seem to meet the 1/100,000 risk criterion with only somewhat better than 50% confidence. However, the current RfDs appear to generally fall short of the goal of meeting this risk criterion with 95% confidence, typically by an order of magnitude in dose or somewhat more. The single most important uncertainty is the extent of human interindividual variability in the doses of specific chemicals that cause adverse responses. Our major conclusion is that with some important assumptions, it is currently feasible to both specify quantitative probabilistic performance objectives for RfDs and to make tentative assessments about whether specific current RfDs for real chemicals seem to meet those objectives. Similarly it is also possible to make preliminary estimates of how much risk is posed by exposures in the neighborhood of current RfDs, and what the uncertainties are in such estimates. It is therefore possible to harmonize cancer and noncancer risk assessments by making quantitative noncancer risk estimates comparable to those traditionally made for carcinogenic risks. The benefits from this change will be an increase in the candor of public discussion of the possible effects of exposures to chemicals posing non-cancer risks, and encouragement for the collection of better scientific information related to toxic risks in people—particularly the extent and distributional form of interindividual differences among people in susceptibility.

Key Words: :

• Uncertainty factors
• Probabilistic analysis
• Quantitative risk assessment
• Noncancer
• Interspecies
• Population distributions
• Thresholds