Deriving a Data-Based Interspecies Assessment Factor Using the NOAEL and the Benchmark Dose Approach

Abstract

In deriving human health-based exposure limits from animal data, differences in sensitivity to a compound between animals and humans must be taken into account. These interspecies differences can be caused by differences in toxicokinetics and or toxicodynamics. Apart from that, species differ in body size, and this is usually accounted for by scaling doses to body weight (i.e., expressed as mg/kg body weight1.0/day).Adefault assessmentfactor (AF) of 10 is commonly applied to this dose metric to account for potential toxicokinetic and toxicodynamic differences. However, both proportional body weight (BW)scalingand the defaultAFas often applied are not directly based on empirical findings. Attempts have been made to derive data-based assessment factors and allometric scaling powers using various toxicological values such as no-observedadverse-effect-levels (NOAELs). In thisstudy both the NOAEL approach and the benchmark dose (BMD) approach are applied to deriveNOAEL ratios and BMD ratios from mouse and rat studies and, based on that information, toestimate an allometric scaling power and an interspecies AF. To account for interspecies differences in body size, our results confirm earlier findings that allometric body weight scaling with a power of around 0.7 is appropriate. The factor needed to rescale the dose in terms of mg/kgBWto the allometric dose scale ranges from around 1.7 (for dogs) to 10(for mice), similar to other findings. The additional factor required for taking into account interspecies toxicokinetic and toxicodynamic differences, when based on the 95th percentile of the relevant ratio distribution, would be 3.1 for a lower Confidence limit of theBMD (BMDL), and 8.3 for a NOAEL (to be applied to the allometrically scaled dose). These results indicate that the generally used defaultAFof 10 may not cover potential interspecies differences, in particular when applied to results from smaller test species. Therefore, using the default AF of 10 could lead to human exposure limits that are insufficiently protective. Further, our results show that a data-based AF that would be needed for interspecies extrapolation is smaller when the point of departure is aBMDLrather than a NOAEL. In the context of a probabilistic hazard characterization, our results indicate that the (geometric) SD of the interspecies AF distribution should be around 2.0 when the BMDL (or BMD uncertainty distribution) is used, and around 3.4 when the NOAEL is used as a point of departure for further risk assessment.

Key words :

• Adjustment Factor
• Allometric Scaling
• Assessment Factor
• Benchmark Dose
• Critical Effect Dose
• Interspecies Extrapolation
• Probabilistic
• Risk Assessment