A Procedure for Developing Risk-Based Reference Doses

Reference doses (RfDs) for toxic substances based on a no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL) are established to restrict human exposures to only nontoxic or minimally toxic levels. In order to calculate a risk-based RfD, for the point of departure it is necessary to replace a NOAEL or LOAEL by a benchmark dose (BMD) estimated to be associated with a specified level of estimable risk in or near the low end of an experimental dose range. Then the RfD is calculated by dividing the BMD by a series of uncertainty factors. Among these uncertainty factors is one for interindividual sensitivity, typically assigned a value of 10. If information is available on interindividual sensitivity, this default factor can be replaced with a factor expected to provide protection for a specified proportion of a population. Examination of published databases suggests interindividual effects often to be approximately log-normal. For example, in order to illustrate the procedure for establishing a risk-based RfD, a standard deviation of the logarithm (base e) of individual sensitivity of 1.7 was selected, i.e., a factor of 5.5. This value is near the upper range of values reported in the literature (D. Hattis et al., 1999, in Characterizing Human Variability in the Risk Assessment Process, ILSI Press, Washington, DC). Using this information in combination with an RfD based on a benchmark dose associated with a specified level of risk, the risk at the RfD can be estimated. For example, a benchmark dose associated with a risk of 10% divided by 60, to account for interindividual variation, is expected to limit risk at the RfD to about 1 in 10,000. If the standard deviation of the logarithm (base e) of individual sensitivity is 1.2, a more typical value, the divisor is approximately 20. These would replace an RfD having an unknown risk based on the LOAEL divided by 100. Or, an RfD with a specified level of risk could be estimated. The estimate of risk can be improved for a specific case by replacing an overall estimate of the standard deviation for interindividual variability by an estimate of the standard deviation for a particular class of chemicals and/or biological endpoint, if available. Risks can be substantially lower for smaller values of interindividual variability. Determination of an RfD still would require an additional uncertainty factor for animal to human extrapolation.