An understanding of pharmacokinetic factors can assist greatly in both dosesetting for 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 effect of the route of exposure. These studies help to predict the results upon chronic exposure. Xenobiotics to be studied are radiolabeled with 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 LD50. 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 work has focused on the disposition of citral (""""""""oil of lemon""""""""), a common flavoring and fragrance. We have characterized its absorption after both oral and dermal exposures. Because of its volatility, much of a dermal dose becomes unavailable for absorption. Some of the citral is oxidatively decarboxylated and metabolized to carbon dioxide. Most of the citral is eliminated in the urine. However, some of the citral is metabolized and enters the anabolic pathways of the organism. No citral can be detected in the blood within 5 minutes of an iv treatment. There are many metabolites of which the mono- and di- carboxylic acids of the two isomers which make up citral, geranial and neral, and their glucuronide and sulfate conjugates appear to be especially important.
