The overall goal of this project is to evaluate risk-assessment methods traditionally used for noncancer health risks and to compare these methods with newly developed approaches. The report gives a brief economic rationale for preventing noncancer health effects, using figures for years of potential life lost, which reveal that noncancer health effects, such as birth defects, are of the same national economic magnitude as cancer and heart disease. Traditional methods for assessing noncancer risks include identification of no-observed-adverse-effect levels (NOAELs). Reference doses (RfDs) and acceptable daily intakes (ADIs) are derived by dividing NOAELs by uncertainty or modifying factors. Those factors represent a default approach to account for animal-to-human and average-to-sensitive population extrapolation or extrapolation from inadequately designed experiments. If all doses tested produce a response a lowest-observed-adverse-effect level (LOAEL) is used and a safety factor of 10 is applied. Those traditional approaches are compared with benchmark-dose methods in which a curve-fitting procedure is used to find a dose that produces a specific effect. Confidence limits are generated around that dose, which is set at the lower confidence limit to produce a specified percentage change in response. The benchmark dose (BMD) is used to calculate a reference dose.

The method is used for noncancer end points. Although the majority of applications of the BMD approach are related to developmental toxicity, it has also been applied to reproductive toxicity, neurotoxicity, and cancer. The method has been most thoroughly evaluated with reference to developmental toxicity in a series of 4 papers and technical documents by Faustman, Allen, Kavlock, and Kimmel that analyzed over 1825 experimental end points. The BMD method offers an alternative to traditional NOAEL approaches and is in general no more conservative than the use of NOAELs and includes a confidence-limit calculation. A log-logistic model for developmental toxicity has several advantages, and BMD values based on a safety factor of 5 with this model are similar to both continuous and quantal NOAEL values (without confidence limits). Traditional safety-factor approaches used for RfD calculation based on LOAEL values are over-conservative; a factor of 5 is more appropriate than a factor of 10. NOAEL values are not "riskfree" but represent effect levels ranging from below 5% up to 20% effect. That illustrates an important advantage of BMD approaches: a regulatory limit can be consistently set at a given response level rather than being dictated by study design. The BMD method rewards adequately designed experiments by setting higher BMDs, which is in direct contrast to the NOAEL approach. With curve-fitting procedures, the calculation of RfDs is no longer constrained to be one of the experimental doses tested. BMD methods will allow for easy transition to truly biologically based dose-response models when such models are developed.