(including susceptible subpopulations) that is likely to have no appreciable risk of deleterious health effects during a lifetime. The reference dose characterizes exposure conditions that are unlikely to cause noncancer health effects, which are typically assumed to have a threshold dose above which adverse health effects would be expected to occur.

Traditionally, reference doses are determined by identifying the most sensitive health effects that are relevant to the human, selecting a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL), and dividing the NOAEL or LOAEL by one or more uncertainty factors to provide a margin of safety. Uncertainty factors are applied to address uncertainties with using experimental animal data for human effects (interspecies differences) to account for variable susceptibilities in the human population (intraspecies differences), to adjust for differences between the LOAEL and NOAEL when a LOAEL is used instead of a NOAEL (LOAEL-to-NOAEL extrapolation), to account for uncertainties with predicting chronic exposure effects on the basis of subchronic exposure studies (subchronic to chronic extrapolation), and to address uncertainties when the database on the chemical is inadequate. Sometimes a modifying factor is used to account for additional uncertainty not addressed by the standard uncertainty factors.

Typically, uncertainty factors are assigned values ranging from 1 to 10. If information about a factor is sparse and uncertainty is high, a default value of 10 is generally used. If information is available, the uncertainty factor might be reduced to 1. For an uncertainty factor that falls between 1 and 10, a factor of 3 is typically assigned, because 3 is the approximate logarithmic mean of 1 and 10, and it is assumed that the uncertainty factor is distributed lognormally (EPA 1994). To calculate a reference dose, the NOAEL or LOAEL is divided by the product of the uncertainty factors. EPA typically uses a maximum of 3,000 for the product of four uncertainty factors that individually are greater than 1 and a maximum of 10,000 with five uncertainty factors (Dourson 1994).

More recently, the benchmark dose is being used as the starting point for calculating reference doses. The benchmark dose is a dose with a specified low level of excess health risk, generally in the range of 1% to 10%, which can be estimated from data with little or no extrapolation outside the experimental dose range. Specifically, the benchmark dose is derived by modeling the data in the observed experimental range, selecting an incidence level within or near the observed range (e.g., the effective dose producing a 10% increased incidence of response), and determining the upper confidence limit on the model. To account for experimental variation, a lower confidence limit or uncertainty factors on the benchmark dose are used to ensure that the specified excess risk is not likely to be exceeded.

To derive an MCLG, the reference dose is multiplied by a typical adult