Toxicokinetics of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in Two Substrains of Male Long-Evans Rats after Intravenous Injection

Toxicokinetics of a nontoxic intravenous dose of ¹⁴C-labeledTCDD were studied in two substrains of Long-Evans (L-E) ratswith a fivefold difference in sensitivity in terms of TCDD-inducedmortality. The Turku/AB Long-Evans rat (T L-E) is the most sensitiverat strain with an oral LD50 of 17.7 µg/kg, whereas theCharles River Long-Evans rat (CR L-E) is a more resistant strain(oral LD50 95.2 µg/kg). Samples of 18 tissues were collected1, 2, 4, 8, 16, and 32 days after dosing and analyzed for radioactivity.Body weight and fecal and urinary excretion of radioactivitywere monitored daily during the 32-day study period. CR L-Erats grew significantly faster than T L-E rats, increasing theirbody weight by 60% in 32 days compared with only 16% in T L-Erats. This difference was not caused by toxicity, because theweight gain was identical in control and TCDD-treated rats ofboth substrains. Tissue concentrations of [¹⁴C]TCDD-associatedradioactivity and area under the curve (AUC) values were lowerin CR L-E than in T L-E rats. The most pronounced differenceswere found in thymus, white adipose tissue, brown adipose tissue,and adrenals. The decrease of TCDD concentration in tissueswas faster in CR L-E than in T L-E rats, whereas fecal and urinaryexcretion was faster in T L-E than in C L-E rats. Eliminationhalf-life was 20.0 days in T L-E rats and 28.9 days in CR L-Erats. Differential toxicokinetics of TCDD in the two L-E substrainsprovide a likely explanation for the greater sensitivity ofthe T L-E strain, since observed differences in tissue concentrationsand AUC values are in good agreement with the difference insusceptibility. In addition to the more efficient tissue uptakeof TCDD in T L-E rats than in CR L-E rats, the major contributingfactor to differences in toxicokinetics seems to be a differentialgrowth rate (dilution by growth), which in turn appears to providean explanation for the difference in susceptibility. More rapidexcretion of TCDD in T L-E rats than in CR L-E rats is clearlya result of higher tissue concentrations in T L-E rats. However,this faster excretion rate is not sufficient to counterbalancethe much slower dilution by growth in T L-E rats than in CRL-E rats. Thus, dilution by growth can be a more important factorin determining the toxicokinetics and toxicity of TCDD in rodentsthan is excretion.