Dosage scaling of alcohol in binge exposure models in mice: An empirical assessment of the relationship between dose, alcohol exposure, and peak blood concentrations in humans and mice.

Binge drinking is a remarkably prevalent behavior. In 2015, 27% of U.S. residents 18 years old or older reported at least one episode of binge drinking in the previous month. Rodent models for binge drinking are widely used to study the mechanisms by which alcohol causes a variety of adverse health effects in humans. Concerns have been raised that many binge-drinking studies in rodents involve alcohol doses that would be unrealistically high in humans. Allometric dosage scaling can be used to estimate the dose of a drug or chemical in mice that would be necessary to achieve similar biological effects at a realistic dose in humans. However, it has become apparent that no single allometric conversion factor is applicable for all drugs and chemicals, so it is necessary to evaluate each compound empirically. In the present study, we compared the area under the blood alcohol concentration vs. time curve (AUC) and the peak blood alcohol concentration following oral alcohol administration at various doses in mice and humans, using data from previously published studies. The results demonstrated that the oral dose of alcohol must be larger in mice (on a g of alcohol to kg of body weight basis) than in humans to achieve similar alcohol AUC values or to achieve similar peak concentrations in the blood. The dose required in mice was about 2-fold greater than the dose required in humans to achieve similar alcohol AUC and peak concentrations. The results shown here were substantially different from the average 5-12-fold difference between mice and humans calculated in previous studies using agents other than alcohol. Results shown here demonstrate that an empirical approach using data from several independent experiments provides information needed to determine the alcohol dose in mice that produces a similar level of exposure (AUC and peak concentration) as in humans. The results indicate that a single alcohol dose in the range of 5-6 g/kg, a range often used in mouse models for binge drinking, is not excessive when modeling human binge drinking. Results presented here illustrate that in mice both alcohol AUC and peak alcohol concentration correlate well with an important biological effect - activation of the hypothalamic-pituitary-adrenal axis - as indicated by increased corticosterone AUC values.