Abstract
A multigeneration study on the reproductive toxicity of TCDD in rats was conducted. In this paper, the results of extensive pharmacokinetic evaluations are presented. The time course of tissue concentrations within the framework of a multigeneration study was investigated, using radioactive labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a substance with a long elimination half-life. So far, long term exposure to TCDD has generally been conducted by administering the same daily doses via the feed. Since the half-life of TCDD in rats is several weeks, the concentration of the test substance can be predicted to change continuously during such a study. Therefore we intended to expose the animals to a constant tissue concentration by using a loading dose/maintenance dose approach. To achieve this, the animals were treated with initial loading doses of 50, 120 or 250 ng TCDD/kg body wt. Based on the elimination half-life of 3 weeks and a planned dosing interval of 7 days, the weekly maintenance doses were calculated to be 20% of the loading dose. During the postnatal phase of rapid growth, this dosing schedule was insufficient to keep the tissue concentration of TCDD constant. It was necessary to administer a second loading dose and to increase the weekly maintenance dose to 40% of the loading dose. While it was possible to control the tissue concentrations in the F0 generation, a considerably larger variation was observed during the different developmental stages of the F1 generation. The fluctuations could be reduced by using a complex dosing schedule, but even with that it was impossible to achieve completely steady levels in liver and adipose tissue. This was mainly due to the fact that levels in liver and adipose tissue did not change together. In the case of a lipophilic substance with a long elimination half-life, attempts at a risk assessment on the basis of a multigeneration test cannot rest on the assumption of defined tissue levels during the study while pharmacokinetic variables are difficult to control in such a study.
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Koch, E., Thiel, E., Chahoud, E. et al. Four generation reproductive toxicity study with 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD) in rats. Arch Toxicol 69, 271–279 (1995). https://doi.org/10.1007/s002040050170
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DOI: https://doi.org/10.1007/s002040050170