Effects of dose and routes of exposure on the disposition of 2,3,7,8-[3H]tetrabromodibenzo-p-dioxin (TBDD) in the rat.
Polybrominated dibenzo-p-dioxins and dibenzofurans are of major concern because of potential occupational and environmental exposures and their structural similarity to the highly toxic chlorinated analogues. 2,3,7,8-Tetrabromodibenzo-p-dioxin (TBDD) is a closely related analogue in both structure and activity to the most toxic isomer 2,3,7,8-tetrachlorodibenzo-p-dioxin. The objectives of this study were to characterize the effects of dose and routes on absorption, excretion, and terminal tissue distribution of [3H]TBDD in the rat 72 hr after dosing. Rats were treated orally by gavage with 1, 10, 100, or 500 nmol/kg, intratracheally with 1 nmol/kg, or dermally with 1 nmol/kg (200 pmol/1.8 cm2). TBDD exhibited nonlinear oral absorption kinetics with maximum absorption (approximately 80%) occurring at dose < or = 10 nmol/kg, similar to the transpulmonary absorption. In contrast, dermal absorption of TBDD was low (approximately 12%). The major tissue depots of radioactivity were liver, adipose tissue, and skin. Tissue distribution of the oral dose was dose-dependent, with disproportionally greater hepatic concentrations occurring at absorbed doses of > 8 nmol/kg. Liver:adipose tissue (L:F) concentration ratios were 2.9 to 6.6 (lowest to highest oral dose, respectively). The lower L:F ratios observed for the dermal and intratracheal doses at 1 nmol/kg (1.5 and 2, respectively) were likely due to differences in absorbed dose and dose-related tissue distribution. Elimination of radioactivity in feces, the major route of excretion for all dose groups and routes, and urine was also nonlinear with respect to the oral dose. The results of the present study provide important considerations for high- to low-dose and route-to-route extrapolations with TBDD and other dioxins and furans in human risk assessments.
Pharmacokinetics Branch, Environmental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
J J
JJ
Diliberto
L B
LB
Kedderis
J A
JA
Jackson
L S
LS
Birnbaum
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D004147:Dioxins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012869:Skin Absorption; D013723:Teratogens / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014316:Tritium
D004147:Dioxins; D013723:Teratogens; C066841:2,3,7,8-tetrabromodibenzo-4-dioxin; D014316:Tritium