SUBCHRONIC CHRONIC TOXICITY OF A MIXTURE OF 4 CHLORINATED DIBENZO-P-DIOXINS IN RATS - II - BIOCHEMICAL EFFECTS/

Groups of 20 male and 20 female rats were given five different oral do ses of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3, 7,8-pentaCDD, (PCDD) 1,2,3,4,7,8-hexaCDD (HxCDD), and 1,2,3,4,6,7,8-he ptaCDD (HpCDD) divided into four daily loading doses and six biweekly maintenance doses. PCDD and HxCDD were used as positive controls. The dosing period was 13 weeks, after which half of the rats were necropsi ed and the rest provided with an off-dose period of another 13 weeks. Liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependentl y increased in rats dosed with the mixture starting at the lowest dose (13- to 16-fold increase), with the effect reaching maximum at the mi ddle dosage (74- to 112-fold increase), as well as in the positive con trol groups. There was some indication of reversibility at the lower d oses and in positive controls during the off-dose period. The activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver was dose-depend ently decreased (maximally by 51%). This effect was more distinct in m ales than in females. Liver tryptophan 2,3-dioxygenase (TdO) activity decreased maximally by 53% at the two highest doses. This effect was m ore distinct in females than in males. Serum tryptophan concentrations were increased in rats moribund due to wasting. Some reversibility wa s apparent by the end of the off-dose period regarding all three bioch emical markers of CDD toxicity. Serum glucose concentrations were decr eased at the three highest doses of the mixture and in positive contro ls, maximally by 30%, with some reversibility during the off-dose peri od. There was a dose-dependent decrease of serum thyroxine (T4) concen trations in rats given the mixture and in the PCDD and HxCDD dosage gr oups (maximally by 69%), with some reversibility in males during the o ff-dose period Serum triiodothyronine (T3) levels were not much affect ed, except that they tended to be decreased in rats moribund with hemo rrhage or anemia The results demonstrate that comparable biochemical c hanges occur after multiple as after single dosing with CDDs and that TEFs derived from acute studies can be used to predict the toxicity of mixtures of CDDs regardless whether they are administered as single c ompounds or as a mixture. This study supports the validity of the toxi c equivalency factor (TEF) method and the notion of additive toxicity for CDDs as currently used in the risk assessment of these compounds. (C) 1998 Academic Press.