Subchronic dose-response study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats

Toxicol Appl Pharmacol. 1995 May;132(1):1-13. doi: 10.1006/taap.1995.1080.

Abstract

Toxic and biochemical potencies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in a 13-week feeding study in female Sprague-Dawley rats. The diets were supplemented with 0, 0.2, 0.4, 0.7, 5, or 20 micrograms TCDD/kg diet. The estimated daily intakes were calculated to be 0, 14, 26, 47, 320, or 1024 ng TCDD/kg body wt/day. At the end of the study, TCDD concentrations were measured in liver and adipose tissue. The lowest estimated daily intake that caused an increase in liver weight was 320 ng TCDD/kg/day, while an intake of 47 ng TCDD/kg/day resulted in a decrease in plasma thyroid hormone concentrations and a decrease in body weight gain. Decreases in relative thymus weights, loss of hepatic retinoids, and induction of CYP1A1 and CYP1A2 activities were already found at 14 ng/kg/day, the lowest dose used. Therefore, 95% confidence limits for the no-effect levels (CNELs) were calculated from the corresponding dose-response relationships by using sigmoidal curve fittings (Hill, Weibull, and a Logistic model) and a probability level of p < 0.05. For increases in CYP1A1 and CYP1A2 activities, the right critical values for the CNELs ranged from 0.7 to 4 ng TCDD/kg/day (Hill and Weibull). Based on hepatic TCDD residue levels, these right critical values for the CNELs ranged from 0.06 to 0.4 ng TCDD/g liver (wet weight) (Hill and Weibull). The CNELs in this study agree very well with the no-observed-adverse-effects levels as reported before in chronic, carcinogenicity, and reproductive studies with rats and TCDD, i.e., 1 ng/kg/day.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Food Contamination
  • Organ Size / drug effects
  • Polychlorinated Dibenzodioxins / administration & dosage*
  • Polychlorinated Dibenzodioxins / pharmacokinetics
  • Polychlorinated Dibenzodioxins / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Thyroid Hormones / blood
  • Tissue Distribution
  • Vitamin A / blood

Substances

  • Polychlorinated Dibenzodioxins
  • Thyroid Hormones
  • Vitamin A
  • Cytochrome P-450 Enzyme System