Critical effective methods to detect genotoxic carcinogens and neoplasm-promoting agents.

Abstract

Neoplasia in fish can result from contamination of waters with carcinogens and promoters. Cancer in fish, therefore, is a possible indicator of cancer risk to man and serves as a guide to the need for preventive approaches involving improved means of waste disposal and environmental hygiene. Moreover, cancer in fish indicates that this important food source may be contaminated. Detection of genotoxic carcinogens to which fish are exposed can be achieved quickly and efficiently by carefully selected batteries of complementary in vitro and in vivo bioassays. One such battery consists of the Ames test, a reverse mutation assay in prokaryotic Salmonella typhimurium, and the Williams test, involving DNA repair in freshly explanted metabolically highly competent liver cells from diverse species, including humans. Determination of DNA-carcinogen adducts by varied techniques, including 32P-postlabeling, as well as DNA breakage, mammalian cell mutagenicity, chromosome aberrations, sister chromatid exchange, or cell transformation represent additional approaches, each with its own advantages and disadvantages. More research is needed on systems to apprehend neoplasm promoters, but tests to determine interruption of intercellular communications through gap junctions appear promising. Other approaches rely on measurement of enzymes such as ornithine decarboxylase and protein kinase C. Approaches to the definition of risk to fish or humans require characterization of the genotoxic or nongenotoxic properties of a chemical, relative potency data obtained in select, limited rodent bioassays, and knowledge of prevailing environmental concentrations of specific carcinogens.

Predicting rodent carcinogenicity of halogenated hydrocarbons by in vivo biochemical parameters

“…Weisburger and Williams have classified some inorganic carcinogens and DNAreactive carcinogens as genotoxic [7]. As nongenotoxic carcinogens they list promoters, hormones, cytotoxic chemicals, peroxisome proliferators, immunosuppressors, solid state carcinogens, and a final miscellaneous category.…”

“…When Weisburger and Williams proposed that there are both nongenotoxic and genotoxic carcinogens [6], little subsequent effort was put into the difficult area of predicting nongenotoxic carcinogenesis. One subset of chemicals often found to be carcinogenic to rodents, the halogenated hydrocarbons, is notoriously difficult to predict with mutagenic predictors [l-5, 7-91 or to mechanistically explain via the somatic mutation theory of carcinogenesis [6,7,10].…”

Evaluation of the genotoxicity of environmental contaminants in sediments to rainbow trout hepatocytes

“…Evaluation of genotoxic potential using fish cell systems is therefore relevant for screening the potential danger of complex mixtures. Genotoxic activity may be assayed at the molecular level using the DNA adducts assay (Masfaraud et al, 1992), unscheduled DNA synthesis (Weisburger and Williams, 1991), and the alkaline DNA unwinding assay ; and at a higher level of organization, the micronucleus, chromosome aberration, and sister chromatid exchange assays (Al-Sabti and Hardig, 1990;Means et al, 1988;Lobillo et al, 1991).…”

Complementarity of genotoxic and nongenotoxic predictors of rodent carcinogenicity

“…Since there is evidence that there are multiple causes of chemical carcinogenesis [1][2][3][4], it is reasonable that multiple predictors would provide the most wholistic, comprehensive prediction of rodent carcinogens. The many short-term tests for predicting the potential carcinogenicity of chemicals to rodents and/or humans usually depend on mutagenicity or genotoxicity in some form [5-91. To date, almost all attempts to construct useful batteries of predictive tests have included only mutagenic or genotoxic parameters.…”