Joost De Jongh

The Toxicokinetics and Metabolism of Polychlorinated Dibenzo-p-Dioxins (PCDDs) and Dibenzofurans (PCDFs) and Their Relevance for Toxicity

This article reviews the present state of the art regarding the toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). The absorption, body distribution, and metabolism can vary greatly between species and also may depend on the congener and dose. In biota, the 2,3,7,8-substituted PCDDs and PCDFs are almost exclusively retained in all tissue types, preferably liver and fat. This selective tissue retention and bioaccumulation are caused by a reduced rate of biotransformation and subsequent elimination of congeners with chlorine substitution at the 2,3,7, and 8 positions. 2,3,7,8-Substituted PCDDs and PCDFs also have the greatest toxic and biological activity and affinity for the cytosolic arylhydrocarbon (Ah)-receptor protein. The parent compound is the causal agent for Ah-receptor-mediated toxic and biological effects, with metabolism and subsequent elimination of 2,3,7,8- substituted congeners representing a detoxification process. Congener-specific affinity of PCDDs and PCDFs for the Ah-receptor, the genetic events following receptor binding, and toxicokinetics are factors that contribute to the relative in vivo potency of an individual PCDD or PCDF in a given species. Limited human data indicate that marked species differences exist in the toxicokinetics of these compounds. Thus, human risk assessment for PCDDs and PCDFs needs to consider species-, congener-, and dose-specific toxicokinetic data. In addition, exposure to complex mixtures, including PCBs, has the potential to alter the toxicokinetics of individual compounds. These alterations in toxicokinetics may be involved in some of the nonadditive toxic or biological effects that are observed after exposure to mixtures of PCDDs or PCDFs with PCBs.

Toxicokinetic interactions between chlorinated aromatic hydrocarbons in the liver of the C57BL/6J mouse: I. Polychlorinated biphenyls (PCBs).

Abstract2,2′,4,4′,5,5′- (PCB 153), 2,3,3′,4,4′,5- (PCB 156) and 3,3′,4,4′,5,5′-hexachlorobiphenyl (PCB 169) were administered orally to three groups of C57BL/6J mice using single doses of 1.5–109.1 mg/kg. Two other groups of mice received binary mixtures of PCB 153 and 156 or PCB 153 and 169. The hepatic deposition, elimination, CYP1a and CYP2b dependent enzyme activities were studied during a 77-day period. Some interactive effects on hepatic deposition and elimination were observed, resulting in increased deposition and faster elimination. These effects were most pronounced for the PCBs 156 and 169. A potentiating effect on hepatic CYP1a dependent 7-ethoxyresorufin-O-deethylation (EROD) activity was observed for the combination of PCB 156 and 153. Based on the results from the present study and earlier studies, it is suggested that the potentiating effect on EROD activity might be caused by a mechanism that is governed by at least two factors. The first is a toxicokinetic modulation of hepatic retention. The second factor is probably an elevation of hepatic Ah receptor levels by PCB 153.

Toxicokinetic mixture interactions between chlorinated aromatic hydrocarbons in the liver of the C57BL/6J mouse: 2. polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs)

Six groups of C57BL/6J mice received single oral doses of 1.5–10.6 nmol/kg 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PnCDD), 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD) or 2,3,4,7,8-pentachlorodibenzofuran (PnCDF) as single compounds or in combination with 300 μmol/kg 2,2′,4,4′,5,5′-hexachlorobiphenyl (HxCB). Two other groups of mice received a mixture of the first three compounds, either with or without HxCB. The hepatic deposition and elimination of the compounds and their CYP1a dependent 7-ethoxyresorufin-O-deethylation (EROD) activity were studied until day 175. Interactive effects on the hepatic deposition of PnCDD were observed in most of the mixed dose groups. For HxCDD and PnCDF interactive effects were either very small or absent. No interactive effects were observed on hepatic elimination rates of PnCDD, HxCDD or PnCDF. No evidence was found for the influence of HxCB cotreatment on the hepatic concentration-response curves of the three compounds or their mixture. Based on the results from the present study it is concluded that PCDDs, PCDFs and PCBs may influence each others, toxicokinetics when administered in mixtures.

Disposition and Elimination of Three Polychlorinated Dibenzofurans in the Liver of the Rat

The disposition and elimination of 1,2,3,6,7,8-HxCDF (HxCDF), 1,2,3,7,8-PnCDF (1-PnCDF), and 2,3,4,7,8-PnCDF (4-PnCDF) were studied in liver of female Sprague-Dawley rats after administration of a single oral dose of 3.5-6.3 micrograms/kg. The disposition of these PCDF congeners was structure and vehicle dependent. Administration in peanut oil caused the highest liver retention, compared with administration through the standard diet. Half-lives in liver for 1-PnCDF, 4-PnCDF, and HxCDF were 3.3, 108, and 73 days, respectively. 4-PnCDF showed very high liver retention: greater than or equal to 70% of the dose in the first days after administration. To study kinetic interaction in the liver, mixtures of 1-PnCDF and 4-PnCDF (Experiment I) and of 4-PnCDF and HxCDF (Experiment II) were administered. The presence of 4-PnCDF in Experiment I did not significantly influence the half-life of 1-PnCDF. In Experiment II the estimated half-life of 4-PnCDF was again 108 days, but for HxCDF an increased half-life was found, 156 days. It is concluded that PCDFs with a chlorine substituent(s) adjacent to the oxygen bridge (4- and 6-positions) are eliminated very slowly with t1/2 much greater than that of TCDD.

The induction and subsequent return to basal activity of liver enzyme activity in male C5/BL/6 mice after a single oral dose of 1,2,3,7,8-PnCDD or 1,2,3,6,7,8-HxCDD

Abstract The reduction of liver enzyme activity after an oral dose of 10 nmol/kg of 1,2,3,7,8-PnCDD (PnCDD) or 1,2,3,6,7,8-HxCDD (HxCDD) was followed in male mice of the C5/BL/6 strain. Two cytochrome P-450 related enzyme activities. EROD and PROD, were used as parameters for the induction of cytochrome P-450. For the PnCDD and HxCDD group, EROD activities were elevated 50 and 10 fold above control level on day 5. These elevations slowly declined, but were still significantly different from control level on day 54 for both groups. PROD activities were not elevated in both groups. Total cytochrome P-450 content of the PnCDD and HxCDD treated groups increased 3 and 2 fold and remained above control level until day 54 and 12 respectively.

Disposition, elimination and enzyme induction of 1,2,3,7,8-PnCDD, 1,2,3,6,7,8-HxCDD and 2,3,4,7,8-PnCDF in the liver of the mouse after a single oral dose☆

Abstract The disposition, elimination and cytochrome P450 related enzyme induction of 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PnCDD), 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD) and 2,3,4,7,8-pentachlorodibenzofuran (PnCDF) were studied in the liver of the male C57BL/6 mouse. Elimination of all compounds from the liver followed first-order kinetics. Half-lives for PnCDD, HxCDD and PnCDF were 15, 52 and 65 days respectively. 7-Ethoxyresorufin-O-deethylation (EROD) activity in the livers of the treated animals showed a good correlation with the liver tissue concentrations but the slopes of these liver concentration-response curves were not equal for all three compounds.