Toxicokinetics of a nontoxic intravenous dose of 14C-labeled TCDD were studied in two substrains of Long-Evans (L-E) rats with a fivefold difference 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 oral LD50 of 17.7 microgram/kg, whereas the Charles River Long-Evans rat (CR-L-E) is a more resistant strain (oral LD50 95.2 microgram/kg). Samples of 18 tissues were collected 1, 2, 4, 8, 16, and 32 days after dosing and analyzed for radioactivity. Body weight and fecal and urinary excretion of radioactivity were monitored daily during the 32-day study period. CR L-E rats grew significantly faster than T L-E rats, increasing their 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. Tissue concentrations of [14CC]TCDD-associated radioactivity and area under the curve (AUC) values were lower in CR L-E than in T L-E rats. The most pronounced differences were found in thymus, white adipose tissue, brown adipose tissue, and adrenals. The decrease of TCDD concentration 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. Elimination half-life was 20.2 days in T L-E rats and 28.9 days CR L-E rats. Differential toxicokinetics of TCDD in the two L-E substrains provide a likely explanation for the greater sensitivity of the T L-E strain, since observed differences in tissue concentrations and AUC values are in good agreement with the difference in susceptibility. In addition 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 toxicokinetics seems to be a differential growth rate (dilution by growth), which in turn appears to provide an explanation for the difference in susceptibility. More rapid excretion of TCDD in T L-E rats than in CR L-E rats is clearly a result of higher tissue concentrations in T L-E rats. However, this faster excretion rate is not sufficient to counterbalance 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 determining the toxicokinetics and toxicity of TCDD in rodents than is excretion.