is determined by use of the equation:

RfD = NOAEL/(UF x MF),

where the NOAEL (no-observed-adverse-effect level) is the highest dose at which there is no statistically significant adverse effect in the test animals beyond that exhibited by a control group, and the UF accommodates uncertainties in the extrapolation of dose-threshold data to humans. The MF is applied when scientific uncertainties in the study are not accommodated by the UF. When the data do not demonstrate a NOAEL, a LOAEL (lowest-observed-adverse-effect level) may be used. This is the lowest dose at which a statistically significant adverse effect is observed.

The NOAEL and the LOAEL depend on the design of the study, particularly on the selection of the experimental dose groups. If the dose groups are far apart, then the LOAEL may be significantly higher than the true concentration at which adverse effects occur and the NOAEL may be much lower than the minimum concentration producing an adverse effect. In the present context, the term adverse effect is defined as any effect that results in a functional impairment or pathological lesion that may affect the performance of the whole organism, or that reduces the ability of the organism to respond to additional challenges (Dourson, 1986).

By definition, a UF is a number that reflects the degree of uncertainty that must be considered when experimental data are extrapolated to humans (Dourson and Stara, 1983; Barnes and Dourson, 1988). When the critical study (the one with the best available dose-response data) is selected for calculation of the reference dose, five factors may contribute to the composite uncertainty factor:

  • the need to extrapolate from animal data to humans when human exposure data are unavailable or inadequate;

  • the need to accommodate human response variability to include sensitive subgroups;

  • the nature, severity, and chronicity of the effect;

  • the need to accommodate the necessity of using LOAEL rather than NOAEL data; and

  • the need to extrapolate from a data base that is inadequate or incomplete.

The overall UF may vary from 1 to 10,000, depending on the combination of these individual factors, but usually does not exceed 100. An MF between 1 and 10 may be used to account for scientific uncertainties, either in the study or in the data base, that are not explicitly taken into consideration in any of the five factors listed above (Barnes and Dourson,

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