Genotoxicity bioassays

Malhi PK, Grover IS. 1987. Genotoxic effects of some organophosphoms pesticides 11. In vivo chromosomal aberration bioassay in bone marrow cells in rat. Mutat Res 188 45-51. 

Fernandez P, M Grifoll, AM Solanas, JM Bayiona, J Albalges (1992) Bioassay-directed chemical analysis of genotoxic compounds in coastal sediments. Environ Sci Technol 26 817-829. 

Vidic T, Lah B, Berden-Zrimec M, Marinsek-Logar R (2008) Bioassays for evaluating the water-extractable genotoxic and toxic potential of soils polluted by metal smelters. Environ Toxicol 24 472 183... 

As performance data has become available on these strains, ICH (1997) has incorporated their use into pharmaceutical testing guidelines in lieu of the second rodent species tests (that is, to replace the long-term mouse bioassay when the traditional rat study has been performed). FDA has stated that they would accept such studies when performed in a validated model. In fact, CBER has accepted such studies as a sole carcinogenicity bioassay in some cases where there was negative traditional genotoxicity data and strong evidence of a lack of a mechanistic basis for concern. 

Grifoll M, Solanas AM, Bayona JM. 1992. Bioassay directed chemieal eharaeterization of genotoxic agents in the dissolved and particulate water phases of the Besos and Llobregat rivers (Barcelona, Spain). Arch Environ Contam Toxicol 23(1) 19-25. 

Mononuclear Cell Leukemia (MNCL) is unique to the rat, and is only common in the F-344 (common name Fischer rat) inbred rat strain, which is the strain used by the U.S. National Toxicology Program (NTP). Elevated incidences of MNCL have been observed in a number of chronic bioassays in the F-344 rat. The frequency differs between males and females, with an incidence in males around 50%, and an incidence in females around 30%, with a large variation from study to study. It has been shown for some genotoxic carcinogens that exposure does not lead to an increase in MNCL in the F-344 rat, while a number of substances, which are believed to be noncarcinogens,... 

One especially successful method of testing complex mixtures is bioassay-directed fractionation followed by chemical identification of active compounds. Until now this method has mainly been used for the testing and identification of genotoxic compounds in environmental mixtures such as extracts of air particulates, exhaust condensates, and cooked foods. In this approach, each fraction is bioassayed untd the major class of specihc chemical(s) responsible for the activity can be isolated and chemically characterized, which make a risk assessment of the mixture possible. 

Cycloheximide is genotoxic in Escherichia coli with metabolic activation and in the mouse sperm morphology assay. Carcinogenicity bioassays in the mouse and rat are inconclusive. ... 

Genotoxic studies have shown primarily negative results. Carcinogenicity bioassays are not available for hydrogen cyanide. ... 

Limited carcinogenicity data for chlorine dioxide and chlorite do not indicate a particular cancer concern, but adequate animal cancer bioassays have not been performed. Genotoxicity testing has produced mixed results. Chlorine dioxide and chlorite do not appear to be reproductive toxicants. 

Fortunately, a number of in situ, short-term bioassays to detect genotoxic and related effects have become available. These include a variety of measured endpoints such as aneuploids, chromosal aberrations, DNA damage, dominant lethal mutation, gene mutation, inhibition of intercellular communication, micronuclei, mitotic recombination and gene conversions, and sister chromatid exchange and cell transformation (IARC, 1989). A detailed discussion of these tests is beyond the scope of this book. However, such tests are important from our perspective as atmospheric chemists because, as we shall see, they can be used to detect biologically active compounds in very complex mixtures, and hence serve to focus chemical analysis efforts (IARC, 1989, p. 20). We emphasize in advance the... 

TABLE 10.25 Mass Concentrations of Individual Genotoxic PAHs and PACs in the Whole Sample and in Subfractionated Extracts,1 Their Absolute Mutagenic Potencies and Potencies Relative to Benzotalpyrene = 1.00, and Contributions of Each to the Overall Total Potency of a Composite Mixture of Ambient Aerosols Collected at Four Urban Sites in Southern California for One Year (1993) and Subjected to Bioassay-Directed Chemical Analysis Using the hlAlv2... 

HERP value is the lifetime daily exposure rate experienced by humans (in milligrams per kilogram of body weight) that lowers, by one-half, the percent of tumor-free animals in a bioassay experiment over a standard lifetime of the animal. Asterisks imply that the substance acts as a promoter of cancer and is not genotoxic itself. 

Unfortunately, there has been an uncritical acceptance of the notion that a positive result in a rodent bioassay automatically implies a carcinogenic risk for humans. While this may well be the case for genotoxic agents, for nongenotoxic substances there will be exceptions, especially if the proliferative response occurs only at high doses" (Cohen and Ellwein 1991, 903). 

Selection of representative bioassays is crucial for successful application of the pT-scale. Sub-cellular tests such as enzyme assays may not be sufficiently relevant in their indicative power of environmental hazard instead of tests using cells or whole organisms. Future refinements to the pT-scale might be the incorporation of additional genotoxicity or immunotoxicity tests to a test battery to augment its diagnostic power in terms of hazard assessment. 

Seven bioassays a) acute bacterial test (Vibrio fischeri) b) algal test (Pseudokirchneriella subcapitata) c) acute crustacean test (Daphnia magna) d) acute fish test (Pimephales promelas) e) SOS chromotest (Escherichia coli PQ 3 7) f) genotoxicity Mutatox test (Vibrio fischeri mutant) g) fluctuation AMES test (Salmonella typhimurium his- TA 98, 100, 1535, 1537) Tire cmmbs 1) Unspecifiedfiltration of water extracts for the first four tests 2) Soxhlet extraction for the three last tests... 

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