Reference Dose - Determination

Determination

RfDs are usually derived from animal studies. Animals (typically rats) are dosed with varying amounts of the substance in question, and the largest dose at which no effects are observed is identified. This dose level is called the "No observable effect level," or NOEL. To account for the fact that humans may be more or less sensitive than the test animal, a 10-fold uncertainty factor is usually applied to the NOEL. This uncertainty factor is called the "interspecies uncertainty factor" or Uf_inter. An additional 10-fold uncertainty factor, the "intraspecies uncertainty factor" or Uf_intra, is usually applied to account for the fact that some humans may be substantially more sensitive to the effects of substances than others. Additional uncertainty factors may also be applied. In general:

Frequently, a "No observed adverse effect level" or NOAEL is used in place of a NOEL. If adverse effects are observed at all dose levels tested, then the smallest dose tested, the "Lowest observed adverse effect level" or LOAEL, is used to calculate the RfD. An additional uncertainty factor usually applied in these cases, since the NOAEL, by definition, would be lower than the LOAEL had it been observed. If studies using human subjects are used to determine a RfD, then the interspecies uncertainty factor can be reduced to 1, but generally the 10-fold intraspecies uncertainty factor is retained. Such studies are rare.