TY - JOUR
T1 - 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
AU - Viluksela, Matti
AU - Stahl, Bernhard U.
AU - Birnbaum, Linda S.
AU - Schramm, Karl Werner
AU - Kettrup, Antonius
AU - Rozman, Karl K.
N1 - Funding Information:
We appreciate the skillful technical assistance of Margitta Lebofsky, Cindy Palmer, Janice Hood, and Sandra Markham (Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center) and Richard Smith, Clement Dowdell, and Reginald Pierce (Laboratory Animal Resources, University of Kansas Medical Center). We thank Professor Jouko Tuomisto, Dr. Michael J. DeVito, and Dr. Angelique P. J. M. Van Birgelen for helpful comments on the manuscript. Although the research described in this article has been funded in part by the United States Environmental Protection Agency under Assistance Agreement C R 820241-01-0 to K.K.R., it has not been subjected to the Agency’s peer and administrative review and, therefore, may not necessarily reflect the views of the Agency, and no official endorsement should be inferred. Support was also obtained from GSF-Forschungszentrum für Umwelt und Gesundheit, Germany, and the Academy of Finland, Research Council for Environmental Sciences (Grant 5410/4011/89). Bernhard Stahl was supported by a fellowship of the Deutsche Forschungsgemeinschaft (Sta 300/3-1).
PY - 1997/10
Y1 - 1997/10
N2 - 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 μg/kg) were divided into four daily lending doses and six biweekly maintenance doses. Positive controls were administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, total dose 70/41.9 μg/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 soup. 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.
AB - 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 μg/kg) were divided into four daily lending doses and six biweekly maintenance doses. Positive controls were administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, total dose 70/41.9 μg/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 soup. 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.
UR - https://www.scopus.com/pages/publications/0030728162
U2 - 10.1006/taap.1997.8239
DO - 10.1006/taap.1997.8239
M3 - Article
C2 - 9344888
AN - SCOPUS:0030728162
SN - 0041-008X
VL - 146
SP - 207
EP - 216
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 2
ER -