H. Poiger

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.

Half-lives of tetra-, penta-, hexa-, hepta-, and octachlorodibenzo-p-dioxin in rats, monkeys, and humans--a critical review

The elimination half-lives (t1/2) in Sprague-Dawley rats for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2, 3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HxCDD), 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) and 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD) were estimated in long-term studies by Schlatter, Poiger and others. Furthermore, there are some published half-lives of TCDD in adult humans. The average half-life of TCDD in adult humans is approximately 2840 days, while in Sprague-Dawley rats the average t1/2 of TCDD is 19 days. The t1/2 of TCDD in humans is about 150 times that of rats. This factor was used to calculate the t1/2 values of the other polychlorinated dibenzo-p-dioxins (PCDDs) in humans from the rat data. Furthermore, the terminal t1/2 values of PCDDs in adult humans were calculated from the regression equation: logt1/2H = 1.34 logt1/2R + 1.25 which was recently established for 50 xenobiotics (t1/2H = terminal half-lives in days for humans, t1/2R = terminal half-lives in days for rats). The following terminal half-lives in adult humans were obtained: 12.6 years for 1,2,3,7,8-PeCDD, 26-45 years for 1,2,3,4,7,8-HxCDD, 80-102 years for 1,2,3,4,6,7,8-HpCDD and ca. 112-132 years for OCDD. These half-lives of PCDDs are critically compared with measured t1/2 values of PCDDs and other persistent organic pollutants in rats, monkeys and humans.

Fluorimetric determination of tetracyclines in biological materials

A method for the fluorimetric determination of tetracyclines in biological materials based on solvent extraction of mixed tetracycline-calcium trichloroacetate ion pairs from aqueous solutions is described. The extraction of tetracycline (TC) and chlorotetracycline (CTC) is almost quantitative, whereas only very poor extraction occurs with oxytetracycline (OTC). However, saturation of the aqueous phase with sodium chloride results in complete extraction of OTC into the organic phase. This effect enables OTC to be determined in the presence of TC and CTC. Ethyl acetate was found to be the most suitable extractant. The fluorescence of the organic phase is measured after addition of magnesium ions and a base.The excitation maxima of all three tetracycline derivatives are at about 400 nm and emission maxima are at 500 nm. They differ only very slightly and cannot be used for differentiation between the derivatives. The following detection limits for CTC in biological materials were found: serum, 0.05 µg ml–1; muscle tissue, 0.125 µg g–1; kidney, 0.15 µg g–1; liver, 0.3 µg g–1; and milk powder with high fat content, 2 µg g–1. Recoveries were between 30 and 45%.

Influence of phenobarbital and TCDD on the hepatic metabolism of TCDD in the dog

The influence of phenobarbital and TCDD pretreatment on the formation and biliary excretion of TCDD-metabolites following single doses of3H-TCDD was investigated. Without pretreatment, 24.5% of the absorbed3H-TCDD dose was excreted in the bile within 110 h. Phenobarbital did not influence this rate, whereas a single dose of 10 μg of unlabeled TCDD/kg b.wt nine days earlier resulted in a doubling of the amount of radioactive material eliminated in the bile (47.4%).