An understanding of pharmacokinetic factors can assist greatly in both dose-setting after toxicity studies and in the interpretation of the results. Selected chemicals on-test by the NTP are nominated for disposition studies. The absorption, both oral and dermal, distribution, metabolism, and excretion of these chemicals are studied in rats and other species as needed. The effect of dose on disposition is determined, as is the route of exposure. These studies help to predict the results upon chronic exposure. Xenobiotics to be studied are radiolabeled with 14C or 3H by custom syntheses. Distribution and excretion are compared after iv, oral, and/or dermal exposures at several doses, the highest being 1/10th of the LD 50. Disposition after an iv dose is examined at multiple time points after treatment. The excreta, expired air, and volatiles are analyzed for radioactivity which is resolved into parent compound and metabolites by organic solvent extraction and chromatography. Metabolites are then characterized by chemical and/or enzymatic means. Current focus has been on citral, """"""""oil of lemon."""""""" This chemical is a common flavoring and fragrance. Previous work demonstrated that citral is rapidly metabolized and eliminated, primarily in the urine. Some of the citral is oxidatively decarboxylated and eliminated as 14 CO2. Glucuronide and sulfate conjugates were also identified. Identification and characterization of some of these metabolites is in progress.
