Toxicokinetic Variability

In general, an intraspecies factor of 10 should be sufficient to reflect the toxicokinetic variability between healthy adults however, it is not sufficient with regard to toxicodynamic variability and possibly only considers risk groups to a limited extent. 

In their analyses, statistics on the relevant extrapolation factor from animals to humans, as reported in the literature, were considered synoptically, and distinctions were made between (1) publications which focused on allometrically justifiable differences (2) publications which examined the toxicodynamic or toxicokinetic variability and (3) pubhcations which considered the total (gross) interspecies factor. In addition, consideration of PBPK models was discussed as a possible alternative. 

Dome, J.L. and A.G. Renwick. 2005. The refinement of uncertainty/safety factors in risk assessment by the incorporation of data on toxicokinetic variability in humans. Toxicol. Sci. 86 20-26. 

Three analyses have been carried out to characterize the interindividual toxicokinetic variability in the estimates of the MeHg-ingested dose corresponding to a given concentration of Hg in a biomarker (Stem 1997 Swartout and Rice 2000 (see also EPA 1997) Clewell et al. 1999). Each... 

Failure to consider interindividual toxicokinetic variability can result in... 

Interindividual toxicokinetic variability can be addressed in the derivation of the RfD by application of an uncertainly factor to a central- tendency estimate of the ingested dose. 

It is uncertain which values are most appropriate for the model parameters used to derive the central-tendency estimates. The basis for each choice should be carefully considered with reference to discussions already presented in the published analyses of toxicokinetic variability. 

The starting point for addressing interindividual toxicokinetic variability should be a central-tendency estimate of the ingested dose corresponding to a critical biomarker concentration (e.g., a benchmark hair concentration). 

For an RfD based on maternal-hair Hg coneentration, an uncertainty-faetor adjnstment of 2 shonld be applied to the central-tendency estimate of dose to be inclnsive of 95% of the toxicokinetic variability in the popnlation. An uncertainty-factor adjnstment of 2-3 should be applied to be inclusive of 99% of the toxicokinetic variability. 

The BMDL of 12 ppm is nearly identical to the BMDL currently used by EPA (11 ppm). Given the toxicokinetic variability and uncertainties in the data, an uncertainty factor of at least 10 is supported by the committee. Therefore, on the basis of its analysis of the available data, the committee finds that the value of EPA s current RfD for MeHg (0.1 pg/kg per day) is scientifically justifiable for the protection of public health. 

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