Tissue concentrations and induction of a hepatic monooxygenase in male Wistar rats after repeated doses of defined polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDDs and PCDFs) mixtures

Abstract

Two groups of male Wistar rats were treated 16 times (every 3rd day) subcutaneously with a defined mixture of polychlorinated dibenzo-p-dioxins (PCDDs) or of polychlorinated dibenzofurans (PCDFs). These mixtures contained no measurable amount of 2,3,7,8-TCDD. Each single dose was calculated to contain either 57 ng I-TEq (international 2,3,7,8-T4CDD toxicity equivalencies)/kg body weight of the PCDD mixture or 39 ng I-TEq/kg body weight of the PCDF mixture. Both mixtures contained a large excess of non-2,3,7,8-substituted congeners. The activities of ethoxyresorufin O-deethylase (EROD) in liver microsomes were correlated with the corresponding concentrations of PCDDs or PCDFs in hepatic tissue. Data were compared with results obtained after single injections of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-T4CDD). As expected, a complex kinetic situation resulted, because of the different tissue distributions and elimination half-lives of the various congeners: (1) 2,3,7,8-substituted PCDDs: the time course of the concentrations in liver and adipose tissue was similar for all congeners, the levels increased during the treatment period and decreased after treatment. Tissue concentrations of all 2,3,7,8-substituted PCDDs were considerably higher in liver than in adipose tissue. The liver/adipose tissue concentration ratios increased with the degree of chlorination. The ratio of 1,2,3,7,8-P5CDD was much lower than those of all other 2,3,7,8-substituted congeners. (2) 2,3,7,8-substituted PCDFs: 1,2,3,7,8-P5CDF was rapidly eliminated from liver and adipose tissue while 2,3,4,7,8-P5CDF largely persisted after the treatment period in both tissues. 2,3,7,8-T4CDF was eliminated even more rapidly than 1,2,3,7,8-P5CDF and could not be detected after treatment in both tissues. Time courses of the concentrations of 2,3,4,7,8-P5CDF, H6CDFs, H7CDFs and OCDF in liver and adipose tissue were similar: the levels of all congeners increased during the treatment period but no clear-cut decrease was observed within 34 days after the last treatment. Tissue concentrations of all 2,3,7,8-substituted PCDFs were higher in liver than in adipose tissue. The liver/adipose tissue concentration ratios increased with the degree of chlorination. The ratios of 2,3,7,8-T4CDF and 1,2,3,7,8-P5CDF were much lower than those of all other 2,3,7,8-substituted congeners. (3) non-2,3,7,8-substituted PCDDs and PCDFs: a number of non-2,3,7,8-substituted PCDD and PCDF congeners were found in both tissues in concentrations below 1 ng/g. In adipose tissue nearly all congeners were found during the treatment period showing a decrease after the treatment. In liver samples, many higher chlorinated PCDF congeners (with >4 chlorine atoms) could be detected. Most of those substituted in three of the four 2, 3, 7 and 8-positions persisted after treatment. In contrast, only one 1,4,6,9-substituted isomer of each PCDD homologue group was found during treatment with high recoveries after the third injection, but a rapid decline occurred already during the treatment period....

Polychlorinated dibenzo-p-dioxins and the human immune system: 4. Studies on two Spanish families with increased body burdens of highly chlorinated PCDDs

“…This has been shown for PCDDs in animal studies (Korner et al, 2002), and can be assumed for the Spanish families, unless all components of the mixture were eliminated from the adipose tissue at an extremely slow rate. A change in the composition of the body burdens is shown by the ratios between various components (Table 3).…”

Risks and Management of Dioxins and Dioxin-like Compounds in Baltic Sea Fish: An Integrated Assessment

“…On the other hand, Nagao et al (1993) showed that the TEF of 0.5 for 4-PeCDF, proposed already by NATO/CCMS (1988a) and retained for mammals and fish by WHO in 1998, overestimated the cleft palate inducing potency of 4-PeCDF in mice about 2.5-fold, suggesting 0.2 as a TEF; the potencies of the PCDF mixtures studied were also clearly overestimated, unlike those of the PCDD mixtures that better conformed with WHO TEFs. Korner et al (2002) concluded that I-TEFs overestimated the potency for EROD induction of the mixtures including 4-PeCDF in the concentration range tested in rats. It thus is possible that the risks associated with 4-PeDCF differ from those indicated by the present TEFs.…”

“…There is less information on the pharmacokinetics of other DLCs than TCDD, including PCBs, and on mixtures of DLCs especially in chronic exposures , Krowke et al 1990, Darnerud et al 1996b, Kodavanti et al 1998, van der Plas et al 1998, Korner et al 2002. The total effect of congener-specific kinetics is thus difficult to elucidate.…”

“…The TEF concept may be particularly poorly applicable to complex mixtures of DLCs. However, even among PCDD/Fs the effects of mixtures have been over-predicted by the relative (Korner et al 2002).…”

Uncertainties related to the assignment of a toxic equivalency factor for 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin

“…In this study, weaker PCB congeners displayed response curves that were displaced to the right of the TCDD response curve to a much greater extent than would be predicted by current TEF estimates. For example, the ratio of EROD (Korner et al, 2002). In this study, animals were repeatedly treated with a I-TEq-(international 2,3,7,8-TCDD toxicity equivalencies) defined mixture of PCDDs in a comparison to TCDD.…”