Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. II. Biochemical effects.
Groups of 20 male and 20 female rats were given five different oral doses 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-heptaCDD (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 necropsied and the rest provided with an off-dose period of another 13 weeks. Liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependently increased in rats dosed with the mixture starting at the lowest dose (13- to 16-fold increase), with the effect reaching maximum at the middle dosage (74- to 112-fold increase), as well as in the positive control groups. There was some indication of reversibility at the lower doses and in positive controls during the off-dose period. The activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver was dose-dependently decreased (maximally by 51%). This effect was more distinct in males than in females. Liver tryptophan 2,3-dioxygenase (TdO) activity decreased maximally by 53% at the two highest doses. This effect was more distinct in females than in males. Serum tryptophan concentrations were increased in rats moribund due to wasting. Some reversibility was apparent by the end of the off-dose period regarding all three biochemical markers of CDD toxicity. Serum glucose concentrations were decreased at the three highest doses of the mixture and in positive controls, maximally by 30%, with some reversibility during the off-dose period. There was a dose-dependent decrease of serum thyroxine (T4) concentrations in rats given the mixture and in the PCDD and HxCDD dosage groups (maximally by 69%), with some reversibility in males during the off-dose period. Serum triiodothyronine (T3) levels were not much affected, except that they tended to be decreased in rats moribund with hemorrhage or anemia. The results demonstrate that comparable biochemical changes 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 compounds or as a mixture. This study supports the validity of the toxic equivalency factor (TEF) method and the notion of additive toxicity for CDDs as currently used in the risk assessment of these compounds.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, 66160-7417, USA.
M
M
Viluksela
B U
BU
Stahl
L S
LS
Birnbaum
K K
KK
Rozman
D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose; D002423:Cause of Death; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006403:Hematologic Tests; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012989:Soil Pollutants / Q000633:toxicity*; D013963:Thyroid Hormones / Q000097:blood; D014364:Tryptophan / Q000097:blood; D014366:Tryptophan Oxygenase / Q000378:metabolism
D015415:Biomarkers; D001786:Blood Glucose; D000072317:Polychlorinated Dibenzodioxins; D012989:Soil Pollutants; D013963:Thyroid Hormones; D014364:Tryptophan; C046838:1,2,3,6,7,8-hexachlorodibenzodioxin; D014366:Tryptophan Oxygenase; C048647:peptide-tryptophan 2,3-dioxygenase; D019363:Cytochrome P-450 CYP1A1; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D019764:Phosphoenolpyruvate Carboxykinase (ATP); C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin