Hematotoxic interactions: occurrence, mechanisms and predictability

The available data on the binary chemical interactions involving hematotoxicants, particularly organic chemicals causing a reduction in either the number of white/red blood cells or the capacity of hemoglobin to transport oxygen, are limited. These observations are limited to investigations in rodents of the enhancement or attenuation of the hematotoxicity of benzene, dichloromethane and dimethylanilines following prior administration of inducers of CYP 2E1 or co-administration of substrates for this isoenzyme. The relevance of these data on interactions for humans exposed at low concentrations can be assessed only when the mechanism of interaction is understood at a quantitative level, and incorporated within a physiological modeling framework. The present study exemplifies the predictability of the magnitude of binary chemical interactions in humans exposed to low concentrations, by developing a physiological model of the modulation by toluene of dichloromethane-induced carboxyhemoglobinemia. Consistent with the basic biochemical principles, this modeling exercise suggests that, with competitive metabolic inhibition mechanism, the threshold for binary chemical interactions will follow a downward trend with increasing number of substrates or structurally-similar substances in a mixture. The use of this kind of mechanistic models, along with data from descriptive chemical interaction studies, will form the very basis of mechanistic risk assessment methods for complex chemical mixtures.