Interactions in Toxicokinetics

As regards absorption through the skin, it is well known that surface-active compounds and skin irritants can enhance the absorption of other chemicals. 

Chemicals are distributed throughout the body via the bloodstream (or the lymph in special cases). Lipophilic compounds are to a large extent bound to proteins in the blood instead of just dissolved in water. A more lipophilic compound may remove a less lipophUic substance from the binding site and thus severely increase the concentration of unbound compound available for toxicological effect. This situation is well known for medical dmgs administered simultaneously (Feron et al. 1995c). 

The majority of compounds that enter the organism require metabolism in order to be excreted. If the parent compound is responsible for the toxicity and its metabolites are less toxic, an increased biotransformation rate will reduce the toxicity, and conversely. However, if the chemical s toxicity is mainly due to its metabolite, stimulating the biotransformation will enhance the toxicity. 

A review of the literature (Krishnan and Brodeur 1991) demonstrated that the majority of toxicokinetic interaction results from metabohc induction or inhibition caused by some components of the mixture. These interactions may alter tissue dosimetry and thereby the toxicity of components in the mixture. The tissue doses of chemicals in mixture can be predicted with PBTK models when the binary interactions between aU of the components in the mixture are known (Haddad et al. 1999a,b, 2000a,b). However, the quantitative characteristics of each of these binary interactions have to be determined by experimentation. Given the complexity of the mixtures, to which humans are exposed, this would obviously require an unreahstic large number of experiments in order to characterize the quahtative and quantitative nature of the possible interactions. 

In a second experiment rats were pre-exposed to the mixture of all 10 chemicals (50 ppm each) 4 h a day for 3 consecutive days. On day four the rats were once more exposed and the kinetics of the compounds followed in blood. There seemed to be a systematic decrease (although not statistically significant) in blood concentrations indicative of greater metabolism due to enzyme induction. 

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