Dioxins tissue distribution

Gasiewicz TA, Neal RA. 1979. 2,3,7,8-Tetrachlorodibenzo-p-dioxin tissue distribution, excretion, and effects on clinical parameters in guinea pigs. Toxicol Appl Pharmacol 51 329-339. 

Table III. Tissue Distribution in Dams Following a Single Oral Dose of 200 /Ag/kg of C -2,3,7,8-Tetrachlorodibenzo- >-Dioxin on Gestation Day 16, 17, or 18 (/ g/gram of tissue)...

Hektoen, H., K. Ingebrigtsen, E.M. Brevik, and M. Oehme. 1992. Interspecies differences in tissue distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin between cod (Gadus morhua) and rainbow trout (Oncorhynchus mykiss), Chemosphere 24 581-587. 

Olson, J.R., T.A. Gasiewicz, and R.A. Neal. 1980b. Tissue distribution, excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the golden Syrian hamster. Toxicol. Appl. Pharmacol. 56 78-85. 

Abraham, K., R. Krowke, and D. Neubert. 1988. Pharmacokinetics and biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1. Dose-dependent tissue distribution and induction of hepatic ethoxyresorufin O-deethylase in rats following a single injection. Arch. Toxicol. 62(5) 359-368. 

Hektoen, H., Berge, J.A., Ingebrigtsen, K., Rnutzen, I, Oehme, M. (1994) Elimination of polychlorinated dibenzofurans and dibenzo-p-dioxins from blue mussel, (Mytilus edulis) and tissue distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). Chemosphere 29, 1491-1499. 

Norback, D.H., Engblom, J.F., Allen, J.R. (1975) Tissue distribution and excretion of octachlorodibenzo-p-dioxin in rat. Toxicol. Appl. Pharmacol. 32, 330-338. 

Abraham K, Wiesmuller T, Brunner H, et al. 1989b. Absorption and tissue distribution of various polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) in the rat. Arch Toxicol 63 193-202. 

Allen JR, Van Miller JP, Norback DH. 1975. Tissue distribution, excretion and biological effects of [14C]tetrachlorodibenzo-p-dioxin in rats. Food Cosmet Toxicol 13 501-505. 

Curtis LR, Kerkvliet NI, Baecher-Steppan L, et al. 1990. 2,3,7,8-Tetrachlorodibenzo-p-dioxin pretreatment of female mice altered tissue distribution but not hepatic metabolism of a subsequent dose. Fundam Appl Toxicol 14 523-531. 

Diliberto JJ, Akubue PI, Luebke RW, et al. 1995. Dose-response relationships of tissue distribution and induction of CYP1A1 and CYP1A2 enzymatic activities following acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Toxicol Appl Pharmacol 130 197-208. 

Kedderis LB, Andersen ME, Bimbaum LS. 1993b. Effect of dose, time and pretreatment on the biliary excretion and tissue distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. Fundam Appl Toxicol 21(4) 405-411. 

Nolan RJ, Smith FA, Heftier JG. 1979. Elimination and tissue distribution of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) in female guinea pigs following a single oral dose. Toxicol Appl Pharmacol... 

Norback DH, Engblom JF, Allen JR. 1975. Tissue distribution and extraction of octachlorodibenzo-para-dioxin in the rat. Toxicol Appl Pharmacol 32 330-338. 

Ryan JJ, Schecter A, Lizotte R, et al. 1985c. Tissue distributions of dioxins and fiirans in humans from the general population. Chemosphere 14 929-932. 

Van Miller JR, Marlar RJ, Allen JR. 1976. Tissue distribution and excretion of tritiated tetrachlorodibenzo-p-dioxin in non-human primates and rats. Food Cosmet Toxicol 14 31-34. 

Kedderis, L.B., Mills, J.J., Andersen, M.E., and Bimbaum, L.S., 1993, A physiologically based pharmacokinetic model for 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) in the rat tissue distribution and CYPIA induction, Toxicol. Appl. Pharmacol, 121, 87-98. 

Pathological changes observed in animals treated with chlorodibenzo-dioxins were inconsistent from animal to animal and species to species. Hepatic lesions were observed consistently, but the nature, degree, and distribution of the lesions were variable. Changes in organs other than the liver were sporadic and unpredictable. Gross and microscopic examination of tissues after chlorodibenzodioxin treatment did not reveal the cause of death. An in-depth evaluation of the toxicity associated with chronic exposure to the chlorodibenzodioxins is needed. 

PK modeling can take the form of relatively simple models that treat the body as one or two compartments. The compartments have no precise physiologic meaning but provide sites into which a chemical can be distributed and from which a chemical can be excreted. Transport rates into (absorption and redistribution) and out of (excretion) these compartments can simulate the buildup of chemical concentration, achievement of a steady state (uptake and elimination rates are balanced), and washout of a chemical from tissues. The one- and two-compartment models typically use first-order linear rate constants for chemical disposition. That means that such processes as absorption, hepatic metabolism, and renal excretion are assumed to be directly related to chemical concentration without the possibility of saturation. Such models constitute the classical approach to PK analysis of therapeutic drugs (Dvorchik and Vesell 1976) and have also been used in selected cases for environmental chemicals (such as hydrazine, dioxins and methyl mercury) (Stem 1997 Lorber and Phillips 2002). As described below, these models can be used to relate biomonitoring results to exposure dose under some circumstances. 

Carrier, G., R.C. Brunet, and J. Brodeur. 1995. Modeling of the toxicokinetics of polychlorinated dibenzo-p-dioxins and dibenzofurans in mammalians, including humans. I. Nonlinear distribution of PCDD/PCDF body burden between liver and adipose tissues. Toxicol. Appl. Pharmacol. 131(2) 253-266. 

LEUNG, H.W., WENDLING, J.M., ORTH, R., HILEMAN, F. and PAUSTENBACH, D.J. (1990). Relative distribution of 2,3,7,8-tetrachlorodi-benzo-p-dioxin in human hepatic and adipose tissues, Toxicol. Lett. 50, 275-282. 

PBPK models for 2,3,7,8-TCDD are discussed below. The pharmacokinetic behavior of 2,3,7,8-TCDD, especially distribution, has been shown to be dose-dependent and involves protein binding and enzyme induction in hepatic tissue. Thus, terms describing these interactions have been included in the animal models described below. Furthermore, since induction of these dioxin-binding proteins is a process mediated by the interaction of a dioxin-receptor (the Ah receptor) complex with specific binding sites on DNA additional terms were included in the models. For a detailed explanation regarding the Ah receptor and its involvement in the mechanism of action of 2,3,7,8-TCDD and structurally related halogenated aromatic hydrocarbons, see Section 2.4.2. 

TCDD and related chemicals, as well as the pharmacokinetics of dioxins in experimental animals. For CDDs, toxicity and toxicokinetics cannot be dealt with separately. Based on results from research in these fields, it has become apparent that the comparison of responses from animals to humans (or even between animal species) should be done on the basis of body-burden or target-tissue dose, rather than on the basis of administered dose. By doing so, species-specific toxicokinetic considerations such as dose-dependent distribution, the existence of tissue-specific sequestering chemical entities (i.e., CYP1A2), and body composition (i.e., percent fat) can be taken into account. A discussion of relationships between administered dose, body burden, and biological responses is presented below. 

Abbott BD, Bimbaum LS, Dilberto JJ. 1996. Rapid distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to embryonic tissues in C57BL/6N mice and correlation with palatal uptake in vitro. Toxicol Appl Pharmacol 141 256-263. 

Engblom JF, Norback DH. 1973. Chlorinated dibenzo-p-dioxin distribution with rat tissues and subtractions of the liver. Fed Proc Fed Amer Soc Exp Biol 32 236. 

Ryan JJ, Schecter A, Sun WF, et al. 1986. Distribution of chlorinated dibenzo-p-dioxins and chlorinated dibenzofiirans in human tissues from the general population. In Rappe C, Choudhary G, Keith LH, eds. Chlorinated dioxins and dibenzofiirans in perspective. Chelsea, MI Lewis Publishers, Inc., 3-16. 

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