The aging process can result in altered sensitivity to chemical toxicity. This can relate to either pharmacodynamic or pharmacokinetic factors. Current work examines the alterations that occur with advancing age in the processes of absorption, distribution, metabolism, and excretion of toxicants. Absorption through the GI tract does not change with age for compounds which are passively absorbed. Likewise, we have not observed changes with age (from 3 through 30 months) in the dermal absorption of either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2,3,4,7,8- pentachlorodibenzofuran, two highly toxic environmental contaminants. Studies are in progress to determine whether the percutaneous absorption of a more readily metabolized isomer, 2,3,7,8-tetrachlorodibenzofuran (TCDF), will be affected with age. While previous studies from this group have examined glucuronidation and glutathione conjugation changes with age, current efforts are focusing on glycine conjugation as an important detoxification route. Benzyl acetate, a model substrate, is hydrolyzed to benzyl alcohol, oxidized to benzoic acid, and then conjugated to form hippuric acid. There are no changes in this major route of metabolism, although there appears to be an increase with age in the levels of glutathione conjugation which occurs as a minor pathway. However, the rate of hydrolysis to benzyl alcohol appears to decline with age. The conjugation of salicylic acid, another substrate for the glycine transferase, has been reported to decline with age. In light of the lack of change in conjugation of benzoic acid, we are re-examining the disposition of salicylate in old rodents. It is possible that there is more than one enzyme involved in glycine conjugation.
