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Title: A mode of action for induction of liver tumors by Pyrethrins in the rat

Abstract

High doses of Pyrethrins produce liver tumors in female rats. To elucidate the mode of action for tumor formation, the hepatic effects of Pyrethrins have been investigated. Male Sprague-Dawley CD rats were fed diets containing 0 (control) and 8000 ppm Pyrethrins and female rats' diets containing 0, 100, 3000 and 8000 ppm Pyrethrins for periods of 7, 14 and 42 days and 42 days followed by 42 days of reversal. As a positive control, rats were also fed diets containing 1200-1558 ppm sodium Phenobarbital (NaPB) for 7 and 14 days. The treatment of male rats with 8000 ppm Pyrethrins, female rats with 3000 and 8000 ppm Pyrethrins and both sexes with NaPB resulted in increased liver weights, which were associated with hepatocyte hypertrophy. Hepatocyte replicative DNA synthesis was also increased by treatment with Pyrethrins and NaPB. The treatment of male and female rats with Pyrethrins and NaPB produced significant increases in hepatic microsomal cytochrome P450 (CYP) content and a marked induction of CYP2B-dependent 7-pentoxyresorufin O-depentylase and testosterone 16{beta}-hydroxylase activities. Significant increases were also observed in CYP3A-dependent testosterone 6{beta}-hydroxylase activity. The hepatic effects of Pyrethrins were dose-dependent in female rats with 100 ppm being a no effect level and on cessationmore » of treatment were reversible in both sexes. This study demonstrates that Pyrethrins are mitogenic CYP2B form inducers in rat liver. The mode of action for Pyrethrins-induced rat liver tumor formation appears to be similar to that of NaPB and some other non-genotoxic CYP2B inducers of hepatic xenobiotic metabolism.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [1]
  1. BIBRA International Ltd, Woodmansterne Road, Carshalton, Surrey, SM5 4DS (United Kingdom) and Centre for Toxicology, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH (United Kingdom)
  2. BIBRA International Ltd, Woodmansterne Road, Carshalton, Surrey, SM5 4DS, England and Centre for Toxicology, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH (United Kingdom)
  3. Inveresk Research, Tranent, EH33 2NE, Scotland (United Kingdom)
  4. ConTox Ltd, Fort Washington, PA 19034-0368 (United States)
  5. Ohio State University, Columbus, OH 43082 (United States)
  6. Science Strategies LLC, Charlottesville, VA 22902 (United States). E-mail: tom@sciencestrategies.com
Publication Date:
OSTI Identifier:
20976852
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 218; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2006.11.004; PII: S0041-008X(06)00416-9; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOSYNTHESIS; CARCINOGENS; DIET; DNA; ENZYME INDUCTION; HYDROXYLASES; HYPERTROPHY; LIVER; METABOLISM; NEOPLASMS; PHENOBARBITAL; RATS; SEX; SODIUM; TESTOSTERONE

Citation Formats

Price, Roger J., Walters, David G., Finch, John M., Gabriel, Karl L., Capen, Charles C., Osimitz, Thomas G., and Lake, Brian G. A mode of action for induction of liver tumors by Pyrethrins in the rat. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.11.004.
Price, Roger J., Walters, David G., Finch, John M., Gabriel, Karl L., Capen, Charles C., Osimitz, Thomas G., & Lake, Brian G. A mode of action for induction of liver tumors by Pyrethrins in the rat. United States. doi:10.1016/j.taap.2006.11.004.
Price, Roger J., Walters, David G., Finch, John M., Gabriel, Karl L., Capen, Charles C., Osimitz, Thomas G., and Lake, Brian G. Mon . "A mode of action for induction of liver tumors by Pyrethrins in the rat". United States. doi:10.1016/j.taap.2006.11.004.
@article{osti_20976852,
title = {A mode of action for induction of liver tumors by Pyrethrins in the rat},
author = {Price, Roger J. and Walters, David G. and Finch, John M. and Gabriel, Karl L. and Capen, Charles C. and Osimitz, Thomas G. and Lake, Brian G.},
abstractNote = {High doses of Pyrethrins produce liver tumors in female rats. To elucidate the mode of action for tumor formation, the hepatic effects of Pyrethrins have been investigated. Male Sprague-Dawley CD rats were fed diets containing 0 (control) and 8000 ppm Pyrethrins and female rats' diets containing 0, 100, 3000 and 8000 ppm Pyrethrins for periods of 7, 14 and 42 days and 42 days followed by 42 days of reversal. As a positive control, rats were also fed diets containing 1200-1558 ppm sodium Phenobarbital (NaPB) for 7 and 14 days. The treatment of male rats with 8000 ppm Pyrethrins, female rats with 3000 and 8000 ppm Pyrethrins and both sexes with NaPB resulted in increased liver weights, which were associated with hepatocyte hypertrophy. Hepatocyte replicative DNA synthesis was also increased by treatment with Pyrethrins and NaPB. The treatment of male and female rats with Pyrethrins and NaPB produced significant increases in hepatic microsomal cytochrome P450 (CYP) content and a marked induction of CYP2B-dependent 7-pentoxyresorufin O-depentylase and testosterone 16{beta}-hydroxylase activities. Significant increases were also observed in CYP3A-dependent testosterone 6{beta}-hydroxylase activity. The hepatic effects of Pyrethrins were dose-dependent in female rats with 100 ppm being a no effect level and on cessation of treatment were reversible in both sexes. This study demonstrates that Pyrethrins are mitogenic CYP2B form inducers in rat liver. The mode of action for Pyrethrins-induced rat liver tumor formation appears to be similar to that of NaPB and some other non-genotoxic CYP2B inducers of hepatic xenobiotic metabolism.},
doi = {10.1016/j.taap.2006.11.004},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 218,
place = {United States},
year = {Mon Jan 15 00:00:00 EST 2007},
month = {Mon Jan 15 00:00:00 EST 2007}
}
  • Prolonged treatment with high doses of Pyrethrins results in thyroid gland tumors in the rat. To elucidate the mode of action for tumor formation, the effect of Pyrethrins on rat thyroid gland, thyroid hormone levels and hepatic thyroxine UDPglucuronosyltransferase activity was investigated. Male Sprague-Dawley CD rats were fed diets containing 0 (control) and 8000 ppm Pyrethrins and female rats diets containing 0, 100, 3000 and 8000 ppm Pyrethrins for periods of 7, 14 and 42 days and for 42 days followed by 42 days of reversal. As a positive control, rats were also fed diets containing 1200-1558 ppm sodium Phenobarbitalmore » (NaPB) for 7 and 14 days. The treatment of male rats with 8000 ppm Pyrethrins, female rats with 3000 and 8000 ppm Pyrethrins and both sexes with NaPB resulted in increased thyroid gland weights, which were associated with follicular cell hypertrophy. Thyroid follicular cell replicative DNA synthesis was increased by treatment with Pyrethrins and NaPB for 7 and/or 14 days. Treatment with Pyrethrins and NaPB increased hepatic microsomal thyroxine UDPglucuronosyltransferase activity and serum thyroid stimulating hormone levels (TSH), but reduced serum levels of either thyroxine (T{sub 4}) and/or triiodothyronine (T{sub 3}). The effects of Pyrethrins in female rats were dose-dependent, with 100 ppm being a no-effect level, and on cessation of treatment were essentially reversible in both sexes. The concordance between the effects of Pyrethrins and NaPB suggests that the mode of action for Pyrethrins-induced rat thyroid gland tumors is similar to that of some other non-genotoxic inducers of hepatic xenobiotic metabolism.« less
  • No abstract prepared.
  • The influence of radiation dose distribution on the frequency of /sup 239/Pu-induced liver tumors was evaluated in the Chinese hamster. Different concentrations of /sup 239/Pu citrate or /sup 239/PuO/sub 2/ particles of known sizes were injected intravenously via the jugular vein. About 60% of the injected /sup 23/Pu citrate was deposited in the liver and 40% in the bone. The /sup 239/Pu citrate was rather uniformly distributed throughout the liver parenchyma. Injected plutonium oxide particles were taken up by the reticuloendothelial system with 90% of the body burden deposited in the liver. The /sup 239/PuO/sub 2/ particles were localized inmore » the Kupffer cells and produced nonuniform dose distributions that were dependent on particle size. There was an activity- and dose-dependent increase in the incidence of total liver parenchymal cell tumors following injection with either plutonium particles or citrate. Plutonium citrate also produced hemangiosarcomas of the liver and tumors in bone and bone marrow. The latent period for liver tumor appearance in animals exposed to /sup 239/Pu citrate or /sup 239/PuO/sub 2/ particles increased as the injected activity decreased. These data indicate that, in Chinese hamster liver, local radiation dose distribution is less important in altering tumor incidence than injected activity or average dose. However, the more uniform irradiation from /sup 239/Pu citrate administration was more effective in cancer production than the nonuniform irradiation from /sup 239/PuO/sub 2/ particle.« less