TOXICOKINETICS OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN 2 SUBSTRAINS OF MALE LONG-EVANS RATS AFTER INTRAVENOUS-INJECTION

Toxicokinetics of a nontoxic intravenous dose of C-14-labeled TCDD wer e studied in two substrains of Long-Evans (L-E) rats with a fivefold d ifference in sensitivity in terms of TCDD-induced mortality. The Turku /AB Long-Evans rat (T L-E) is the most sensitive rat strain with an or al LD50 of 17.7 mu g/kg, whereas the Charles River Long-Evans rat (CR L-E) is a more resistant strain (oral LD50 95.2 mu g/kg). Samples of 1 8 tissues were collected 1, 2, 4, 8, 16, and 32 days after dosing and analyzed for radioactivity. Body weight and fecal and urinary excretio n of radioactivity were monitored daily during the 32-day study period . CR L-E rats grew significantly faster than T L-E Fats, increasing th eir body weight by 60% in 32 days compared with only 16% in T L-E rats . This difference was not caused by toxicity, because the weight gain was identical in control and TCDD-treated rats of both substrains. Tis sue concentrations of [C-14]TCDD-associated radioactivity and area und er the curve (AUC) values were lower in CR L-E than in T L-E rats. The nest pronounced differences were found in thymus, white adipose tissu e, brown adipose tissue, and adrenals. The decrease of TCDD concentrat ion in tissues was faster in CR L-E than in T L-E rats, whereas fecal and urinary excretion was faster in T L-E than in C L-E rats. Eliminat ion half-life was 20.0 days in T L-E rats and 28.9 days in CR L-E rats . Differential toxicokinetics of TCDD in the two L-E substrains provid e a likely explanation for the greater sensitivity of the T L-E strain , since observed differences in tissue concentrations and AUC values a re in good agreement with the difference in susceptibility. Ln additio n to the more efficient tissue uptake of TCDD in T L-E rats than in CR L-E rats, the major contributing factor to differences in toxicokinet ics seems to be a differential growth rate (dilution by growth), which in rum appears to provide an explanation for the difference in suscep tibility. More rapid excretion of TCDD in T L-E rats than in CR L-E ra ts is clearly a result of higher tissue concentrations in T L-E rats. However, this faster excretion rate is not sufficient to counterbalanc e the much slower dilution by growth in T L-E rats than in CR L-E rats . Thus, dilution by growth can be a more important factor in determini ng the toxicokinetics and toxicity of TCDD in rodents than is excretio n. (C) 1996 Society of Toxicology