Methods for Identifying a Default Cross-Species Scaling Factor

ABSTRACT

The need to identify “toxicologically equivalent” doses across different species is a major issue in toxicology and risk assessment. In this article, we describe an approach for establishing default cross-species extrapolation factors used to scale oral doses across species for non-carcinogenic endpoints. This work represents part of an on-going effort to harmonize the way animal data are evaluated for carcinogenic and non-carcinogenic endpoints. In addition to considering default scaling factors, we also discuss how chemical-specific data (e.g., metabolic or mechanistic data) can be incorporated into the dose extrapolation process. After first examining the required properties of a default scaling methodology, we consider scaling approaches based on empirical relationships observed for particular classes of compounds and also more theoretical approaches based on general physiological principles (i.e, allometry). The available data suggest that the empirical and allometric approaches each provide support for the idea that toxicological risks are approximately equal when daily oral doses are proportional to body weight raised to the 3/4-power. We also discuss specific challenges for dose scaling related to different routes of exposure, acute versus chronic toxicity, and extrapolations related to particular life stages (e.g., childhood).

Key words:

• allometry
• cross-species
• dosimetry
• risk assessment
• dose extrapolation

ACKNOWLEDGMENT

The work presented in this article was funded by the U.S. Environmental Protection Agency (Contract 3W-0477-NASX).

Notes

¹Inhalation exposures are assessed according to methods developed for non-cancer assessment, as described in USEPA (1994) and Jarabek (1995).

²It should be noted that the term “scaling” as used in this document does not specifically address the issue of inter-species uncertainty in risk assessment. In particular, the default scaling factors discussed later will not yield human equivalent doses that exactly describe the relationship in toxicity between humans and experimental species for each and every chemical. Uncertainty will remain on a chemical-specific basis in terms of species differences (and intra-individual differences) in pharmacokinetics and pharmacodynamics. Only by incorporating chemical-specific data into the scaling process can this uncertainty be reduced.

³An exception is work on one chemical, formaldehyde (Monticello and Morgan 1994; Conolly et al. 2000; Schlosser et al. 2003).

⁴Because an MTD is intended to be a dose causing no lethality, whereas an LD₁₀causes 10% lethality, the equivalence of these two end points can be questioned. Antineoplastic drugs typically have very steep dose-response curves, however, and survival near the MTD is maintained by close monitoring and intervention, which the rodent LD₁₀ determinations lack.

⁵If the MTD is considered to be a less severe end point, in such comparisons potencies in the larger species are overestimated vis-à-vis those in rodents; a bias would then be created that would increase the apparent success of surface area scaling compared to scaling by body weight.

⁶Scaling daily doses by the 2/3 power of body weight is called “surface area” scaling because the surface area of similarly shaped objects varies as the 2/3 power of their volume.

⁷Note that for parameters with time in the denominator (e.g., respiration rate, clearance), the value is divided by BW^{− 1/4} whereas for parameters where time is the numerator (e.g., half-life), the value is multiplied by BW^{− 1/4}. Note also that for parameters that contain a volume component (e.g., GFR, cardiac output), the volume itself needs to be scaled to bodyweight.

⁸It should be recognized that the concept of “the child” as used in risk assessment represents a somewhat arbitrary, if necessary, construct and imposes a discrete categorization on a population that is actually characterized by continuously varying and evolving exposure and toxicological variables, some of which become “adult-like” early in life and others that do so only gradually during maturation.