Allometric modeling

It seems highly improbable that either in vitro model systems or computer simulations will be introduced in the near future that would give researchers the confidence to administer drugs to humans without prior testing in other animal species. Most likely animal models will continue to be used as predictors for pharmacokinetics and toxicity of drugs in humans. Improvements in allometric models, or the correlation of pharmacokinetics among different species, is to be encouraged. Also, hair has been identified... 

Allometric Modeling of Mammalian Cyanogen Chloride Inhalation Lethality... 

In IH toxicology, the dose received by an animal is directly related to the amount of air inhaled. " Minute volume (F ) is a commonly used respiratory measurement, and Bide et al. (2000) have reviewed the existing mammalian Fm data (as well as species body mass) for the purpose of supporting IH toxicology research. Table 9.1 provides F and M values from Bide et al for several mammalian species (non-anesthetized) that were used for allometric modelling in this chapter. An empirical relationship (for both anesthetized and nonanesthetized animals) of F, as a function of M has also been developed. Based on allometric scaling law, F should scale to the 0.75 power, but Bide et al found that F, scales to the 0.809 power [with standard error (SE) of 0.01 for this value] based on the available experimental data for nonanesthetized, adult mammals ... 

Toxicity is a function of many factors, and some of these i.e. metabolic, circulatory, etc.) may also scale allometrically in their effect. Allometric modeling can be used to empirically account for the cumulative effect of these factors and scale the nominal LD50 (mg) as a function of species body mass, as shown in eqn (9.4). A human estimate can be obtained from mammalian data by extrapolating to a 70 kg human. ... 

Table 9.9 Linear regression results for allometric modeling of CK mammalian median lethal concentrations. ...

McNamara (1976) did not investigate the use of an allometric model for AC lethality. However, he does provide the following breakdown of the relative sensitivity to AC IH toxicity by species with respect to the animal LCtjo values that he reports ... 

With the exception of the guinea pig, all of the resistant species are medium to larger mammals, and with the exception of the dog, the sensitive species are smaller mammals. This suggests that the allometric modelling of AC lethality may be possible, with the LCjo increasing as a function of M (opposite to that observed for CK). 

A common problem in the allometric modeling of IH toxicity has been how to best statistically treat non-independent parameters (see Section 9.2.1). Often, both regressor and predictor terms are dependent on the species body mass (M). A solution has been developed [eqn (9.6)] that is both faithful to the definition of a nominal IH dose [eqn (9.5)] and eliminates non-independent parameters. 

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