Default Uncertainty and Modifying Factors

Most extrapolations from animal experimental data in the risk assessments require the utilization of uncertainty factors. This is because we are not certain how to extrapolate across species, with species for the most sensitive population, and across duration. To account for variations in the general population and to protect sensitive subpopulations, an uncertainty factor of 10 is used by EPA and ATSDR. The value of 10 is derived from a threefold factor for differences in toxicokinetics and for threefold factor for toxicodynamics. To extrapolate from animals to humans and account for interspecies variability between humans and other mammals, an uncertainty factor of 10 is used by EPA and ATSDR, and as with intraspecies extrapolations, this 10-fold factor is assumed to be associated with in toxicodynamics and toxicokinetics. An uncertainty 

Necrosis, metaplasia, or atrophy Cancer Clinically significant organ impairment 

Alteration in offspring weight Cleft palate, fused ribs 

Altered T-cell activity Necrosis inn immunologic components 

Refinements of the RfC have utilized mechanistic data to modify the interspecies uncertainty factor of 10 (Jarabek, 1995). The reader should appreciate that with the inhalation route of exposure, dosimetric adjustments are necessary and can affect the extrapolations of toxicity data of inhaled agents for human health risk assessment. The EPA has included dosimetry modeling in RfC calculations, and the resulting dosimetric adjustment factor (DAF) used in determining the RfC is dependent on physiochemical properties of the inhaled toxicant as well as type of dosimetry model ranging from rudimentary to optimal model structures. In essence, the use of the DAF can reduce the default uncertainty factor for interspecies extrapolation from 10 to 3.16. 

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