This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schröter, C. Articles by Schulte-Hermann, R. Search for Related Content PubMed PubMed Citation Articles by Schröter, C. Articles by Schulte-Hermann, R.

Dose-Response Studies on the Effects of -, ß-, and -Hexachlorocyclohexane on Putative Preneoplastic Foci, Monooxygenases, and Growth in Rat Liver¹

Institut für Toxikologie und Pharmakologie der Universität Marburg, Pilgrimstein 2, D-3550 Marburg, Federal Republic of Germany

-, ß-, and -hexachlorocyclohexane (-, ß-, -HCH) isomers are widespread environmental pollutants; -HCH can cause liver tumors in rats and mice. In the present study we have checked first the tumor-initiating activity of HCH using the appearance of phenotypically altered foci in female rat liver as an end point. Foci were identified by means of the -glutamyltransferase (GGT) reaction and by morphological alterations. No evidence of initiating activity was found. Secondly, we have attempted to determine quantitatively the ability of HCH isomers to promote tumor development. For this purpose growth and phenotypic changes of foci were used as an end point. Rats received a single dose of N-nitrosomorpholine. Then five different doses of each HCH isomer or phenobarbital (PB) (as a positive control) were administered continuously via the diet for 4, 15, and 20 weeks. Both number and size of altered foci were enhanced by doses of 2 to 3 mg/kg or more of the three isomers; in addition, foci phenotypes showed a pronounced shift towards strong expression of GGT and sharp demarcation from the surrounding liver. Based on daily doses the three HCH isomers were approximately equipotent; based on concentrations in liver or adipose tissue, -HCH was severalfold more effective than - and ß-HCH. Thirdly, size and DNA and monooxygenase activities of the liver were determined. All three parameters were enhanced by HCH isomers and PB. However, no strict correlations were found. Rather, at the highest doses tested PB was the most effective inducer of monooxygenases, -HCH was the most potent inducer of liver growth, and all three HCHs were more potent than PB as inducers of focal expansion. Thus, induction of liver growth appears to be associated with foci expansion (tumor promotion); however, neither liver growth nor monooxygenase induction can be used for quantitative predictions of foci expansion by chemical compounds. Finally, no-observed-effect levels were estimated for the parameters studied and are discussed in relation to human exposure.

¹ Dedicated to Professor Dr. W. Koransky on the occasion of his 65th birthday. This study was supported by GSF, Munich, Federal Republic of Germany, and by Deutsche Forschungsgemeinschaft.

² Present address: Institut für Tumorbiologie-Krebsforschung der Universität Wien, Borschkegasse 8a, A-1090 Wien, Austria.

³ To whom requests for reprints should be addressed.

Received 5/ 8/86. Revised 8/27/86. Accepted 9/10/86.

This article has been cited by other articles:

				O. Moennikes, A. Buchmann, A. Romualdi, T. Ott, J. Werringloer, K. Willecke, and M. Schwarz Lack of Phenobarbital-mediated Promotion of Hepatocarcinogenesis in Connexin32-Null Mice Cancer Res., September 1, 2000; 60(18): 5087 - 5091. [Abstract] [Full Text]

				B. Grasl-Kraupp, G. Luebeck, A. Wagner, A. Low-Baselli, M. de Gunst, T. Waldhor, S. Moolgavkar, and R. Schulte-Hermann Quantitative analysis of tumor initiation in rat liver: role of cell replication and cell death (apoptosis) Carcinogenesis, July 1, 2000; 21(7): 1411 - 1421. [Abstract] [Full Text] [PDF]

				B. Kroll, S. Kunz, T. Klein, and L. R. Schwarz Effect of lindane and phenobarbital on cyclooxygenase-2 expression and prostanoid synthesis by Kupffer cells Carcinogenesis, August 1, 1999; 20(8): 1411 - 1416. [Abstract] [Full Text] [PDF]

				C. Q. Zhao, M. R. Young, B. A. Diwan, T. P. Coogan, and M. P. Waalkes Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression PNAS, September 30, 1997; 94(20): 10907 - 10912. [Abstract] [Full Text] [PDF]