Dosimetric Adjustment Factor

It is also noted that there is overlap in the individual UFs and that the application of five UFs of ten for the chronic reference value (yielding a total UF of 100,000) is inappropriate. In fact, in cases where maximum uncertainty exists in all five areas, it is unlikely that the database is sufficient to derive a reference value. Uncertainty in four areas may also indicate that the database is insufficient to derive a reference value. In the case of the RfC, the maximum UF would be 3,000, whereas the maximum would be 10,000 for the RfD. This is because the derivation of RfCs and RfDs has evolved somewhat differently. The RfC methodology (US-EPA 1994) recommends dividing the interspecies UF in half, one-half (10° ) each for toxicokinetic and toxicodynamic considerations, and it includes a Dosimetric Adjustment Factor (D AF, represents a multiplicative factor used to adjust an observed exposure concentration in a particular laboratory species to an exposure concentration for humans that would be associated with the same delivered dose) to account for toxicokinetic differences in calculating the Human Equivalent Concentration (HEC), thus reducing the interspecies UF to 3 for toxicodynamic issues. RfDs, however, do not incorporate a DAF for deriving a Human Equivalent Dose (HED), and the interspecies UF of 10 is typically applied, see also Section 5.3.4. It is recommended to limit the total UF applied for any particular chemical to no more than 3000, for both RfDs and RfCs, and avoiding the derivation of a reference value that involves application of the full 10-fold UF in four or more areas of extrapolation. 

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. 

Collectively, these studies adequately identify a LOAEL for respiratory effects associated with intermediate-duration inhalation exposure to chlorine dioxide. The intermediate-duration inhalation MRL for chlorine dioxide was based on the LOAEL of 1 ppm identified in the Paulet and Desbrousses (1972) study, which was adjusted to 0.15 ppm (LOAELadj) to compensate for intermittent exposure, converted to the human equivalent concentration (LOAELjjgc) of 0.3 ppm, and then divided by an uncertainty factor of 300 (3 for interspecies extrapolation using dosimetric adjustments, 10 for the use of a LOAEL, and 10 to account for sensitive populations). 

EPA (IRIS 2002) has derived an RPC of 2x10 " mg/m for chlorine dioxide based on a LOAEL of 2.76 mg/m (1 ppm) for respiratory effects (peribronchiolar edema and vascular congestion in the lungs) in rats exposed to chlorine dioxide vapors 5 hours/day, 5 days/week for 2 months (Paulet and Desbrousses 1972). The LOAEL was converted to a LOAEL hec of 0.64 mg/m and divided by an uncertainty factor of 3,000 (10 for extrapolation of a chronic RPC from a subchronic study, 3 for interspecies extrapolation using dosimetric adjustments, 10 for intrahuman variability, and 10 to account for extrapolation from a LOAEL for mild effects and for the lack of inhalation developmental and reproductive toxicity studies). 

Human equivalent concentration (HEC). The HEC is used to describe the dose of an agent to which humans are exposed through inhalation. The HEC is the estimated concentration that is equivalent to that used in an experimental animal species. The HEC is estimated using adjustment factors that account for such species-dosimetric differences as ventilatory parameters and lung surface areas, as well as factors related to the gas, aerosol, or particulate nature of the agent. 

The existing methods available for scientifically defensible risk characterization are not yet ideal since each step has an associated uncertainty resulting from data limitation and incomplete knowledge on exact mechanism of action of the toxic chemical on the human body. For noncancer end points, safety factors or uncertainty factors are applied since these effects are assumed to have a threshold below which no adverse effect is expected to be observed. US EPA has used the concept of a reference concentration (RfC) to estimate acceptable daily human exposure from HAPs. The RfC was adapted for inhalation studies based on a reference dose (RfD) method previously used for oral exposure assessment. The derivation of the RfC differs from that for the RfD in the use of dosimetric adjustment to extrapolate the exposure concentration for animals to a human equivalent concentration. Both are estimates, with uncertainty spaiming perhaps an order of magnitude, of a daily exposure to the human population, including sensitive subgroups, which would be without appreciable risk of deleterious effects over a lifetime. 

ATSDR (1995c) derived an intermediate-duration inhalation MRL of 9 mg/m3 for JP-4 based on a LOAEL of 500 mg/m3 for hepatic fatty degeneration in mice exposed continuously to the vapor for 90 days. The MRL was derived from this LOAEL by dosimetrically adjusting to a human equivalent concentration and applying an uncertainty factor of 300 (10 for the use of a LOAEL, 3 for interspecies... 

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