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Titre du document / Document title

Interactions in the tumor-promoting activity of carbon tetrachloride, trichloroacetate, and dichloroacetate in the liver of male B6C3F1 mice

Auteur(s) / Author(s)

BULL Richard J. (1) ; SASSER Lyle B. (1) ; LEI Xingye C. (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Molecular Biosciences, Pacific Northwest National Laboratory, Richland, WA 09352, ETATS-UNIS

Résumé / Abstract

Interactions between carcinogens in mixtures found in the environment have been a concern for several decades. In the present study, male B6C3F1 mice were used to study the responses to mixtures of dichloroacetate (DCA), trichloroacetate (TCA), and carbon tetrachloride (CT). TCA produces liver tumors in mice with the phenotypic characteristics common to peroxisome proliferators. DCA increases the growth of liver tumors with a phenotype that is distinct in several respects from those produced by TCA. These chemicals are effective as carcinogens at doses that do not produce cytotoxicity. Thus, they encourage clonal expansion of initiated cells through subtle, selective mechanisms. CT is well known for its ability to promote the growth of liver tumors through cytotoxicity that produces a generalized growth stimulus in the liver that is reflected in a reparative hyperplasia. Thus, CT is relatively non-specific in its promotion of initiated cells within the liver. The objective of this study was to determine how the differing modes of action of these chemicals might interact when given as mixed exposures. The hypothesis was that the effects of two selective promoters would not be more than additive. On the other hand, CT would be selective only to cells not sensitive to its effects as a cytotoxin. Thus, it was hypothesized that neither DCA nor TCA would add significantly to the effects produced by CT. Mice were initiated by vinyl carbamate (VC), and then promoted by DCA, TCA, CT, or the pair-wised combinations of the three compounds. The effect of each treatment or treatment combination on tumor number per animal and mean tumor volume was assessed in each animal. Dose-related increases in mean tumor volume were observed with 20 and 50 mg/kg CT, but each produced equal numbers of tumors at 36 weeks. As the dose of CT was increased to > 100 mg/kg substantial increases in the number of tumors per animal were observed, but the mean tumor size decreased. This finding suggests that initiation occurs as doses of CT increase to ≥ 100 mg/kg, perhaps as a result of the inflammatory response that is known to occur with high doses of CT. When administered alone in the drinking water at 0.1, 0.5 and 2 g/l, DCA increased both tumor number and tumor size in a dose-related manner. With TCA treatment at 2 g/l in drinking water a maximum tumor number was reached by 24 weeks and was maintained until 36 weeks of treatment. DCA treatment did not produce a plateau in tumor number within the experimental period, but the numbers observed at the end of the experimental period were similar to TCA and doses of 50 mg/kg CT. The tumor numbers observed at the end of the experiment are consistent with the assumption that the administered dose of the tumor initiator, vinyl carbamate, was the major determinant of tumor number and that treatments with CT, DCA, and TCA primarily affected tumor size. The results with mixtures of these compounds were consistent with the basic hypotheses that the responses to tumor promoters with differing mechanisms are limited to additivity at low effective doses. More complex, mutually inhibitory activity was more often observed between the three compounds. At 24 weeks, DCA prefaced a decrease in tumor numbers promoted by TCA, but the numbers were not different from TCA alone at 36 weeks.

Revue / Journal Title

Toxicology    ISSN  0300-483X   CODEN TXICDD 

Source / Source

2004, vol. 199, no2-3, pp. 169-183 [15 page(s) (article)] (1 p.1/4)

Langue / Language

Anglais

Editeur / Publisher

Elsevier, Kidlington, ROYAUME-UNI  (1973) (Revue)

Mots-clés anglais / English Keywords

Organic solvent

;

Chlorine Organic compounds

;

Vertebrata

;

Mammalia

;

Rodentia

;

General anesthetic

;

Ethylene(trichloro)

;

Mouse

;

Animal

;

Male

;

Liver

;

Carbon tetrachloride

;

Tumor promotor

;

Carcinogen

;

Trichloroethylene

;

Mots-clés français / French Keywords

Solvant organique

;

Chlore Composé organique

;

Vertebrata

;

Mammalia

;

Rodentia

;

Anesthésique général

;

Ethylène(trichloro)

;

Souris

;

Animal

;

Mâle

;

Foie

;

Méthane(tétrachloro)

;

Promoteur tumeur

;

Carcinogène

;

Trichloroéthylène

;

Mots-clés espagnols / Spanish Keywords

Solvente orgánico

;

Cloro Compuesto orgánico

;

Vertebrata

;

Mammalia

;

Rodentia

;

Anestésico general

;

Etileno(tricloro)

;

Ratón

;

Animal

;

Macho

;

Hígado

;

Metano(tetracloro)

;

Promotor tumor

;

Carcinógeno

;

Tricloroetileno

;

Mots-clés d'auteur / Author Keywords

Trichloroethylene

;

Carbon tetrachloride

;

Dichloroacetate

;

Trichloroacetate

;

Interactions of tumor promoters

;

Localisation / Location

INIST-CNRS, Cote INIST : 15984, 35400011029122.0090

Nº notice refdoc (ud4) : 15748206



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