Subchronic/chronic toxicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) in rats. Part II. Biochemical effects.
Groups of 20 male and 20 female rats were given five different oral doses of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) or one dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) divided into four daily loading doses and six biweekly maintenance doses. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest assigned to an off-dose period of another 13 weeks. At the end of the dosing period, liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependently increased starting at the lowest dose (7- to 10-fold) with maximum induction (50- to 100-fold) at the middle or second highest dose. There was a slight reversibility of this effect in HpCDD-treated rats, particularly at lower doses, and a pronounced reversibility in TCDD-dosed rats, both in accordance with respective toxicokinetics. The activity of phosphoenolpyruvate carboxykinase in liver was dose-dependently decreased (up to 60%) at the two or three highest doses of HpCDD and also in the TCDD dosage group. Liver tryptophan 2,3-dioxygenase activity was decreased at the two highest doses of HpCDD (up to 41%), particularly in females. Serum tryptophan concentrations were elevated in rats found moribund due to wasting. There was a dose-dependent decrease in serum glucose concentrations (up to 30%) at the end of the dosing period. Serum thyroxin (T4) concentrations showed a dose-dependent decrease (78% at the highest dose) beginning in the middle dose for HpCDD and in the TCDD dosage group. Serum triiodothyronine (T3) concentrations were only slightly affected, except that they were somewhat decreased in moribund animals. The results demonstrate that similar biochemical changes occur in rats after single as after multiple dosing with HpCDD and TCDD. Based on these endpoints, the relative potency of HpCDD after subchronic exposure is in agreement with the international toxic equivalency factor (I-TEF) of 0.01 and, more specifically, with a TEF of 0.007 based on LD50 values in the same strain of rats.
Viluksela
M
M
Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7417, USA.
Stahl
B U
BU
Birnbaum
L S
LS
Rozman
K K
KK
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D019363:Cytochrome P-450 CYP1A1 / Q000032:analysis / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000032:analysis / Q000096:biosynthesis*; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013974:Thyroxine / Q000097:blood; D018675:Toxicity Tests; D014284:Triiodothyronine / Q000097:blood; D014364:Tryptophan / Q000097:blood; D014366:Tryptophan Oxygenase / Q000032:analysis / Q000096:biosynthesis*
D001786:Blood Glucose; D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D014284:Triiodothyronine; D014364:Tryptophan; D003577:Cytochrome P-450 Enzyme System; D014366:Tryptophan Oxygenase; D019363:Cytochrome P-450 CYP1A1; D019764:Phosphoenolpyruvate Carboxykinase (ATP); C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin; D013974:Thyroxine