PRINCIPLES OF TOXICOLOGY - Biology East Borneo

260 MUTAGENESIS AND GENETIC TOXICOLOGY• Extrapolation of test results in order to make a quantitative evaluation of the hazard ofexposures for humans• Prioritization of human hazards caused by specific compounds• Institution of remedial procedures that should be undertaken to minimize the human hazardOne of the most difficult areas of analysis is the correct application of mutagenicity tests to arriveat a quantifiable human hazard from exposure to a given substance. There is frequently goodcorrelation between the mutagenicity and carcinogenicity of a substance in animal tests (Table12.4). However, this may be misleading because models for carcinogenicity determination areoften characterized by chronic procedures utilizing very high doses in nonprimate species. Thesemay bear little resemblance to aspects of exposure in the human model, such as magnitude androute of exposure, metabolic patterns, and environment (which are qualitative factors), andexposure dose (which is quantitative).As noted previously, the time and expense that are involved with lifetime carcinogenicity assayshave strongly influenced the use of test batteries as predictive measures of carcinogenic potential.Among many others, Ashby and Tennant (1994), Anderson et al. (1994), Benigni and Giuliani (1987),and Blake et al. (1990), have addressed the question of applicability of multiple test systems to theclassification of a substance as genotoxic or not, and carcinogenic or not. It is important in these effortsto distinguish among “sensitivity” (ability to identify a known carcinogen), “specificity” (ability toidentify a noncarcinogen), and “accuracy” (correct results of either type). Parodi et al. (1990) reportedon qualitative correlations associated with studies of up to 300 substances conducted during the period1976 through 1988. Initial measures of sensitivity, specificity, and accuracy were approximately 90percent, if the decision is based solely on Salmonella assays. As more substances have been tested,this estimate has ranged from 45 to 91 percent. Best results typically are reported for sensitivity, whereaccuracy generally is on the order of 65 to 75 percent. Consideration of the quantitative correlationbetween short-term genotoxicity tests and carcinogenic potency has yielded extremely variableestimates, ranging from approximately 30 to over 90 percent. The overwhelming conclusion was thata battery of test systems that addresses differing endpoints is required if the goal is to develop aconfident conclusion regarding predictivity.As is the case with many areas of toxicology, one may choose between in vivo and in vitro testsystems, each with their attendant advantages and disadvantages. The testing of chemicals in experimentalanimals has all the advantages of any intact in vivo system; that is, it has all of the biochemicaland physiological requirements to make anthropomorphization more reliable. However, in vivomutagenicity testing may require an investment of many thousands of dollars and a long period oftime. These disadvantages often force the tester to use a less expensive, well-established short-termTABLE 12.4 Comparative Mutagenicity of Various CompoundsCompoundEstablishedhumancarcinogen Bacteria Yeast DrosophilaMammaliancellsEpichlorohydrin N N O Y Y YEthyleneimine N O Y Y Y YTrimethyl phosphate O Y O Y Y YTris N Y O Y Y YEthylene dibromide N Y Y Y Y NVinyl chloride Y Y Y Y Y YChloroprene Y Y O O O YUrethane N Y Y Y Y ON = no; Y = yes; O = not tested.Humancells