Subchronic/chronic toxicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) in rats. Part I. Design, general observations, hematology, and liver concentrations.
Groups of 20 male and 20 female adult Sprague-Dawley rats were given five different doses of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD). Total doses for males and females (30.9/18.5, 370/222, 2222/1333, 6667/4000, and 10000/6000 microg/kg) were divided into four daily loading doses and six biweekly maintenance doses. Positive controls were administered 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD, total dose 70/41.9 microg/kg). Liver concentrations, as determined by GC/MS, reflected quite accurately the calculated dose ratios. 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. Body weight gain was dose-dependently reduced throughout the study. Mortality occurred dose-dependently, starting on Day 22 and continuing until the end of the off-dose period. Mortality rates at the end of the off-dose period were 90 and 40% for males and 60 and 10% for females in the two highest dose groups. Clinical signs and necropsy findings suggested that the cause of death was related to wasting (early deaths), gastrointestinal and nasal hemorrhage (between Days 64 and 126), or anemia (late deaths, after Day 111). Prothrombin times were prolonged intermittently, mainly at the highest dose of HpCDD. Platelet counts were dose-dependently decreased at the two highest doses of HpCDD and in the TCDD-treated group. This study demonstrates that the relative potency derived from acute toxicity studies is the same as that observed in this subchronic/chronic toxicity study of HpCDD and TCDD, confirming the validity of 0.007 as the toxic equivalency factor (TEF) for HpCDD, which is in good agreement with the international TEF of 0.01.
Viluksela
M
M
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7417, USA.
Stahl
B U
BU
Birnbaum
L S
LS
Schramm
K W
KW
Kettrup
A
A
Rozman
K K
KK
D000284:Administration, Oral; D000740:Anemia / Q000139:chemically induced / Q000401:mortality; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004844:Epistaxis / Q000139:chemically induced; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000401:mortality; D006400:Hematocrit; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010976:Platelet Count / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D018675:Toxicity Tests; D015430:Weight Gain / Q000187:drug effects
D000072317:Polychlorinated Dibenzodioxins; C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin