Caloric requirement approach

The reasons for using these three measures and the advantages and disadvantages of their use have been described by Davidson et al. (1986) and Vocci and Farber (1988). In these papers, it is also explained why the body weight can be used in aU three cases. However, the body weight should be taken to the power of 1, 0.67, and 0.75 for the body weight approach, the body surface area approach, and the caloric requirement approach, respectively. These figures indicate that the approach used to correct for differences in body size will clearly affect the value of the NOAEL adjusted to the body size of humans. 

S.3.2.3 Adjustment for Differences in Body Size Caloric Requirement Approach... 

Eor the purpose of assessing the remaining interspecies uncertainty, Vermeire et al. (1999) collected and analyzed data for 184 chemicals tested in different species and via different exposure routes. NOAELs were selected from studies with mice, rats, and dogs exposed to the same chemical via the same exposure route and with the same duration of exposure. Two categories of exposure duration were defined, subacute and (sub)chronic, in order to increase the comparability of the different studies. The definition of these exposure categories is species specific, partly depending on their maximum lifetime. Subacute exposure was defined as 21-50 days for the mouse and rat, and as 28-90 days for the dog (sub)chronic exposure was defined as 90-730 days for the mouse and rat, and as 365-730 days for the dog. The oral NOAELs were adjusted to account for differences in metabolic size, i.e., by the caloric requirement approach (Section 5.3.2.3). 

Feron et al. (1990) concluded that the sensitivity of humans to chemicals is probably not very different from that of other mammals, and that a systematic error is made by carrying out extrapolation by using the body weight approach. For metabolizable compounds, the authors strongly recommended a procedure that takes the metabolic rate into account (1F° ) for scaling across species, i.e., dose correction for differences in body size between experimental animals and humans by the caloric requirement approach (Section 5.3.2.3). This approach was also considered to provide a contribution to reducing the size of the traditional safety factor in a justifiable way. 

ECETOC (2003) recommended that in the absence of any substance- or species-specific mechanism or PBPK modeling (Section 4.3.6), allometric seating based on metabolic rate (W° ) (caloric requirement approach. Section 5.3.2.3) is considered to provide an appropriate default for an assessment factor for interspecies differences with respect to systemic effects. Allometric scaling was stated as being a tool for estimating interspecies differences of internal exposure or body burden and to provide indirectly information on differences in sensitivity between species. Typical scaling factors for interspecies adjustment were noted as 7 for mouse, 4 for rat, and 2 for dog however. 

In conclusion, if no substance-specific data are available, it is recommended as a default to correct for differences in metabolic size (differences in body size between humans and experimental animals) by using allometric scaling based on the caloric requirement approach (see Table 5.4). The assessment factor accounting for remaining interspecies differences should preferentially be described probabilistically as suggested by Vermeire et al. (1999, 2001) and KEMI (2003), or a deterministic default factor of 2.5 could be used for extrapolation of data from rat studies to the human situation. 

For oral exposures, administered doses should be scaled from animals to humans on the basis of the caloric requirement approach (Section 5.3.2.3), i.e., body weight normalized by the 3/4 power. It is noted that the 3/4 power is consistent with current science, including empirical data that allow comparison of potencies in humans and animals, and it is also supported by analysis of the allometric variation of key physiological parameters across mammalian species. It is also noted that it is generally more appropriate at low doses, where sources of nonlinearity such as samration of enzyme activity are less likely to occur. 

The caloric requirement, or metabolic rate approach, has also been proposed as an alternative to correction for differences in body size based on body weight. 

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