Application of mass balance models and the chemical activity concept to facilitate the use of in vitro toxicity data for risk assessment.

Practical, financial, and ethical considerations related to conducting extensive animal testing have resulted in various initiatives to promote and expand the use of in vitro testing data for chemical evaluations. Nominal concentrations in the aqueous phase corresponding to an effect (or biological activity) are commonly reported and used to characterize toxicity (or biological response). However, the true concentration in the aqueous phase can be substantially different from the nominal. To support in vitro test design and aid the interpretation of in vitro toxicity data, we developed a mass balance model that can be parametrized and applied to represent typical in vitro test systems. The model calculates the mass distribution, freely dissolved concentrations, and cell/tissue concentrations corresponding to the initial nominal concentration and experimental conditions specified by the user. Chemical activity, a metric which can be used to assess the potential for baseline toxicity to occur, is also calculated. The model is first applied to a set of hypothetical chemicals to illustrate the degree to which test conditions (e.g., presence or absence of serum) influence the distribution of the chemical in the test system. The model is then applied to set of 1194 real substances (predominantly from the ToxCast chemical database) to calculate the potential range of concentrations and chemical activities under assumed test conditions. The model demonstrates how both concentrations and chemical activities can vary by orders of magnitude for the same nominal concentration.