Tissue distribution and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats after intravenous injection

Abstract

Male Sprague-Dawley rats (240-290 g) received intravenously a nonlethal (9.25 micrograms/kg) or a lethal (72.7 micrograms/kg) dose of 14C-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administered as an emulsion. Animals were euthanized between 5 min and 16 days (lethal dose) or 32 days (nonlethal dose) after treatment. Tissue distribution was considered complete after 24 hr, as by this time radioactivity levels in white adipose tissue had reached a maximum. The highest levels of radioactivity were found in liver (5% of dose/g tissue), followed by white fat (1% of dose/g tissue); serum was lowest at 0.01% of dose/ml serum. Relatively high levels of radioactivity were also detected in most known target organs of TCDD toxicity, e.g., brown fat, adrenals, and thyroid. The pattern of organ distribution of TCDD was essentially the same after the lethal and the nonlethal dose, but did not follow a simple lipophilicity relationship, as levels in liver were higher than those in white fat, and those in brain were extremely low. A pool of TCDD in liposomes initially trapped in lung and spleen was redistributed within 24 hr mainly to liver and adipose tissue. Affinity of TCDD to storage fat seemed to play a more important role as a driving force for redistribution than did induction of cytochrome P450 1A2. The terminal slope of elimination of TCDD from tissues indicated a half-life of 16 days after the nonlethal dose. After the lethal dose radioactivity declined in all tissues for 2 to 8 days and then increased again, reflecting shrinking tissue volumes as well as remobilization of TCDD caused by the process of body mass wasting. Distribution data for 17 tissues and serum were subjected to regression analysis and resulted in up to two uptake phases and up to three elimination phases for a given tissue. After the nonlethal dose TCDD was mainly excreted via feces; combined urinary and fecal excretions occurred with a biological half-life of 16.3 +/- 3.0 days. Much longer half-lives were detected in white fat and skin. After the lethal dose, the fecal excretion of TCDD-derived radioactivity decreased after 8 days, and urinary excretion increased starting 12 days after dosing. Radioactivity in liver and white fat and the extractable portion in feces was mainly unchanged TCDD, as determined by thin-layer chromatography. Radioactivity in urine indicated the presence of a metabolite(s) of TCDD only.