The effect of environmental factors on the pharmacokinetic behaviour of organic solvent vapours

Abstract

A review of the literature concerning environmental factors affecting toxicokinetic behaviour of organic solvents revealed that alcohol consumption and exposure to other organic solvents are of great importance among such factors. An insight into how environmental factors affect the toxicokinetic behaviour of organic solvents is discussed by modelling (a) the effect of alcohol consumption on the toxicokinetics of trichloroethylene (TRI), and (b) the effect of the metabolic interaction between benzene and toluene. In general, hepatic metabolism of an organic solvent (substrate) is assumed to follow the Michaelis-Menten equation, v = Vmax.S/(Km + S), where v is the rate of substrate metabolism, Vmax and Km the maximum velocity and Michaelis constant for the metabolism, respectively, and S the substrate concentration in the liver. On the assumption of competitive inhibition, inhibition of the substrate metabolism by the simultaneous presence of ethanol or other organic solvents (inhibitors) can be expressed as follows: v = Vmax.S/[Km + (Km/Ki)I + S] where I is the inhibitor concentration in the liver and Ki the inhibitor constant toward the substrate metabolism. An increase in Vmax without a change in Km can represent enzyme induction due to alcohol consumption or previous repetitive exposure to other solvents. A simulation study on the effect of alcohol consumption on the metabolism of TRI revealed that the lower the exposure concentration, the larger the inhibitory effect of ethanol. In contrast, the effect of enzyme induction following alcohol consumption makes its full appearance only when the exposure concentration is high. Another simulation study on the mutual metabolic interaction between benzene and toluene suggested that at low exposure concentrations of both benzene and toluene where enzymes are supposed to have in reserve some capacity to catalyse the metabolism of both solvents, each solvent inhibits only slightly the metabolism of the other. On the other hand, at high exposure concentrations where enzymes have little or no capacity in reserve, the simultaneous presence of benzene and toluene notably suppresses the metabolism of each other.