In vitro approaches to develop weight of evidence (WoE) and mode of action (MoA) discussions with positive in vitro genotoxicity results.

A recent analysis by Kirkland et al. [Kirkland, D., Aardema, M., Henderson, L. and Müller, L. (2005) Evaluation of the ability of a battery of 3 in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity. Mutat. Res. 584, 1-256] demonstrated an extremely high false positive rate for in vitro genotoxicity tests when compared with carcinogenicity in rodents. In many industries, decisions have to be made on the safety of new substances, and health risk to humans, without rodent carcinogenicity data being available. In such cases, the usual way to determine whether a positive in vitro genotoxicity result is relevant (i.e. indicates a hazard) for humans is to develop weight of evidence (WoE) or mode of action (MoA) arguments. These are based partly on further in vitro investigations, but usually rely heavily on tests for genotoxicity in one or more in vivo assays. However, for certain product types in the European Union, the use of animals for genotoxicity testing (as well as for other endpoints) will be prohibited within the next few years. Many different examples have been described that indicate DNA damage and genotoxic responses in vitro can arise through non-relevant in vitro events that are a result of the test systems and conditions used. The majority of these non-relevant in vitro events can be grouped under a category of 'overload of normal physiology' that would not be expected to occur in exposed humans. However, obtaining evidence in support of such MoAs is not easy, particularly for those industries prohibited from carrying out in vivo testing. It will become necessary to focus on in vitro studies to provide evidence of non-DNA, threshold or in vitro-specific processes and to discuss the potential for such genotoxic effects to occur in exposed humans. Toward this end, we surveyed the published literature for in vitro approaches that may be followed to determine whether a genotoxic effect observed in vitro will occur in humans. Unfortunately, many of the approaches we found are based on only a few published examples and validated approaches with consensus recommendations often do not exist. This analysis highlights the urgent need for developing consensus approaches that do not rely on animal studies for dealing with in vitro genotoxins.

[1]  P. Finot,et al.  Interactions of histidine-containing test substances and extraction methods with the Ames mutagenicity test. , 1983, Mutation research.

[2]  Ogihara Yukio,et al.  Inhibition of mitochondrial respiration by flavoskyrin, a toxic metabolite of Penicillium islandicum Sopp. , 1986, Toxicology letters.

[3]  F. Beland,et al.  S9-mediated metabolism of 1-nitropyrene to a mutagen in Chinese hamster ovary cells by ring-oxidation under aerobic conditions and by nitroreduction under anaerobic conditions. , 1991, Carcinogenesis.

[4]  W. Lutz,et al.  Discrimination between genotoxicity and cytotoxicity in the induction of DNA double-strand breaks in cells treated with etoposide, melphalan, cisplatin, potassium cyanide, Triton X-100, and gamma-irradiation. , 1998, Mutation research.

[5]  F. Palitti,et al.  Clastogenic effects of two tyrosine kinase inhibitors, tyrphostin 23 and tyrphostin 46, on a transformed (CHO-K1) and on a primary embryonic chinese hamster cell line (CHE). , 2000, Mutagenesis.

[6]  R. C. Moore,et al.  Different effects of 1-beta-D-arabinofuranosylcytosine and aphidicolin in S-phase cells--chromosome aberrations, cell-cycle delay and cytotoxicity. , 1987, Mutation research.

[7]  G. Witz,et al.  The reactivity of selected acrylate esters toward glutathione and deoxyribonucleosides in vitro: structure-activity relationships. , 1994, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[8]  D. Bagchi,et al.  Oxidative mechanisms in the toxicity of metal ions. , 1995, Free radical biology & medicine.

[9]  G. Reifferscheid,et al.  Genotoxicity of dental materials. , 1996, Mutation research.

[10]  V. Jansson,et al.  Inability of chlorophenols to induce 6-thioguanine-resistant mutants in V79 Chinese hamster cells. , 1986, Mutation research.

[11]  Sheila M Galloway,et al.  Population doubling: A simple and more accurate estimation of cell growth suppression in the in vitro assay for chromosomal aberrations that reduces irrelevant positive results , 2004, Environmental and molecular mutagenesis.

[12]  D. Johnston,et al.  Short-term cytogenetic assays of nine cancer chemotherapeutic drugs with metabolic activation. , 1980, Environmental Mutagenesis.

[13]  Ronald D Snyder,et al.  Evaluation of the clastogenic, DNA intercalative, and topoisomerase II‐interactive properties of bioflavonoids in Chinese hamster V79 cells , 2002, Environmental and molecular mutagenesis.

[14]  S Albertini,et al.  Thresholds in genotoxicity responses. , 2000, Mutation research.

[15]  R. Hill,et al.  Chromosome aberrations in Chinese hamster and human cells: a comparison using compounds with various genotoxicity profiles. , 2007, Mutation research.

[16]  H. Stopper,et al.  Evaluation of the in vitro micronucleus test as an alternative to the in vitro chromosomal aberration assay: position of the GUM Working Group on the in vitro micronucleus test. Gesellschaft für Umwelt-Mutations-forschung. , 1998, Mutation research.

[17]  M. Armstrong,et al.  Relationships among cytotoxicity, lysosomal breakdown, chromosome aberrations, and DNA double-strand breaks. , 1987, Mutation research.

[18]  J W Green,et al.  A review of the genotoxicity of marketed pharmaceuticals. , 2001, Mutation research.

[19]  D. Kirkland,et al.  Interpretation of the biological relevance of genotoxicity test results: the importance of thresholds. , 2000, Mutation research.

[20]  S. K. Greenwood,et al.  Chromosome aberrations in vitro related to cytotoxicity of nonmutagenic chemicals and metabolic poisons , 1998, Environmental and molecular mutagenesis.

[21]  Errol Zeiger,et al.  Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: Confirmation of earlier results with 41 additional chemicals , 1990, Environmental and molecular mutagenesis.

[22]  P. Arenaz,et al.  Sodium azide mutagenesis in mammals: inability of mammalian cells to convert azide to a mutagenic intermediate. , 1989, Mutation research.

[23]  T Sofuni,et al.  Primary mutagenicity screening of food additives currently used in Japan. , 1984, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[24]  H. Tsuda.  Enhancing effect of tumor promoter 12-O-tetradecanoylphorbol-13-acetate on 8-azaguanine-resistant mutations induced by N-methyl-N'-nitro-N-nitrosoguanidine in cultured chinese hamster cells. , 1981 .

[25]  C. Nowak.  Studies on the ability of hypotonic solutions to induce chromosomal aberrations in V 79 cells. , 1987, Teratogenesis, carcinogenesis, and mutagenesis.

[26]  R. C. Garner,et al.  Testing of known carcinogens and noncarcinogens for their ability to induce unscheduled DNA synthesis in HeLa cells. , 1978, Cancer research.

[27]  G. Bolcsfoldi,et al.  Mouse lymphoma L5178Y thymidine kinase locus assay of 50 compounds. , 1988, Mutagenesis.

[28]  F. Gonzalez,et al.  A metabolically competent human cell line expressing five cDNAs encoding procarcinogen-activating enzymes: application to mutagenicity testing. , 1991, Chemical research in toxicology.

[29]  B. A. Kunz.  Genetic effects of deoxyribonucleotide pool imbalances. , 1982, Environmental mutagenesis.

[30]  W. Muster,et al.  Genotoxicity of 17 gyrase- and four mammalian topoisomerase II-poisons in prokaryotic and eukaryotic test systems. , 1995, Mutagenesis.

[31]  L. Verschaeve,et al.  The VITOTOX test, an SOS bioluminescence Salmonella typhimurium test to measure genotoxicity kinetics. , 1997, Mutation research.

[32]  D Brusick,et al.  International Commission for Protection Against Environmental Mutagens and Carcinogens. Genotoxicity under extreme culture conditions. A report from ICPEMC Task Group 9. , 1991, Mutation research.

[33]  A. Allison.  Lysosomes and the toxicity of particulate pollutants. , 1971, Archives of internal medicine.

[34]  N. Cozzarelli.  The mechanism of action of inhibitors of DNA synthesis. , 1977, Annual review of biochemistry.

[35]  Sunderman Fw.  Mechanisms of nickel carcinogenesis. , 1989 .

[36]  C. Bacon,et al.  Inhibition of protein synthesis in rat primary hepatocytes by extracts of Fusarium moniliforme-contaminated corn. , 1990, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[37]  W. Muriel,et al.  The mutagenicity of sodium fluoride to L5178Y [wild-type and TK+/- (3.7.2c)] mouse lymphoma cells. , 1986, Mutagenesis.

[38]  J. L. Smith,et al.  2,4-dinitrophenol, lysosomal breakdown and rapid myofilament degradation in vertebrate skeletal muscle , 2004, Naunyn-Schmiedeberg's Archives of Pharmacology.

[39]  P. Howard,et al.  Kinetics and cofactor requirements for the nitroreductive metabolism of 1-nitropyrene and 3-nitrofluoranthene by rabbit liver aldehyde oxidase. , 1991, Carcinogenesis.

[40]  M. Aardema,et al.  Characterization of p53 in Chinese hamster cell lines CHO-K1, CHO-WBL, and CHL: implications for genotoxicity testing. , 1999, Mutation research.

[41]  A. Natarajan,et al.  Potentiation of chromosomal alterations by inhibitors of DNA repair. , 1984, Nucleic acids symposium series.

[42]  W. W. Nichols,et al.  The effect of deoxyadenosine and cytosine arabinoside on the chromosomes of human leukocytes in vitro , 2009 .

[43]  W. G. Levine,et al.  Multiple mechanisms in hepatic microsomal azoreduction. , 1992, Xenobiotica; the fate of foreign compounds in biological systems.

[44]  K. Kawai,et al.  The uncoupling effect of flavoglaucin, a quinol pigment from Aspergillus chevalieri (Mangin), on mitochondrial respiration. , 1983, Toxicology letters.

[45]  M. Mattson,et al.  Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease , 2002, The Journal of Neuroscience.

[46]  D Gatehouse.  Critical features of bacterial mutation assays. , 1987, Mutagenesis.

[47]  J. Ashby.  The genotoxicity of sodium saccharin and sodium chloride in relation to their cancer-promoting properties. , 1985, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[48]  B. A. Kunz.  Mutagenesis and deoxyribonucleotide pool imbalance. , 1988, Mutation research.

[49]  A. Collins,et al.  DNA repair and its inhibition , 1984 .

[50]  S. Ellard,et al.  Micronucleus assays using cytochalasin-blocked MCL-5 cells, a proprietary human cell line expressing five human cytochromes P-450 and microsomal epoxide hydrolase. , 1993, Mutagenesis.

[51]  M. Sorsa.  Butadiene and styrene : assessment of health hazards , 1993 .

[52]  R. Cicchetti,et al.  The role of oxidative stress in the in vitro induction of micronuclei by pesticides in mouse lung fibroblasts. , 2003, Mutagenesis.

[53]  B. Halliwell,et al.  Factors Affecting the Ascorbate- and Phenolic-dependent Generation of Hydrogen Peroxide in Dulbecco's Modified Eagles Medium , 2003, Free radical research.

[54]  Lutz Müller,et al.  Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens I. Sensitivity, specificity and relative predictivity. , 2005, Mutation research.

[55]  H. Glatt,et al.  Genetically engineered V79 Chinese hamster cells metabolically activate the cytostatic drugs cyclophosphamide and ifosfamide. , 1990, Environmental health perspectives.

[56]  G. Pfeifer,et al.  Peroxyl radical mediated oxidative DNA base damage: implications for lipid peroxidation induced mutagenesis. , 2004, Biochemistry.

[57]  T. Kunkel,et al.  International Commission for Protection Against Environmental Mutagens and Carcinogens. Deoxyribonucleoside triphosphate levels: a critical factor in the maintenance of genetic stability. , 1994, Mutation research.

[58]  K. Tempel,et al.  Poly(ADP-ribose)polymerase-activity of chicken embryo cells exposed to nucleotoxic agents. , 1992, Toxicology.

[59]  David Kirkland,et al.  Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens III. Appropriate follow-up testing in vivo. , 2005, Mutation research.

[60]  J. Gielen,et al.  The Salmonella/mammalian microsome mutagenicity test: comparison of human and rat livers as activating systems. , 1985, Mutation research.

[61]  J. Casida,et al.  Phosphine-induced oxidative stress in Hepa 1c1c7 cells. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[62]  Anthony Lynch,et al.  Investigations into the concept of a threshold for topoisomerase inhibitor-induced clastogenicity. , 2003, Mutagenesis.

[63]  C. Harris,et al.  Aflatoxin B1-induced DNA adduct formation and p53 mutations in CYP450-expressing human liver cell lines. , 1997, Carcinogenesis.

[64]  K. Lee,et al.  Vitamins, Phytochemicals, Diets, and Their Implementation in Cancer Chemoprevention , 2004, Critical reviews in food science and nutrition.

[65]  M. Umeda,et al.  Inducibility of chromosomal aberrations by metal compounds in cultured mammalian cells. , 1979, Mutation research.

[66]  W. W. Nichols,et al.  DNA synthesis inhibition as an indirect mechanism of chromosome aberrations: comparison of DNA-reactive and non-DNA-reactive clastogens. , 1998, Mutation research.

[67]  R Scott Obach,et al.  Strategy for genotoxicity testing--metabolic considerations. , 2007, Mutation research.

[68]  B. Merrick,et al.  Chemical reactivity, cytotoxicity, and mutagenicity of chloropropanones. , 1987, Toxicology and applied pharmacology.

[69]  P. Hoffmann,et al.  Genotoxicity assessment of the antiepileptic drug AMP397, an Ames-positive aromatic nitro compound. , 2002, Mutation research.

[70]  A Elhajouji,et al.  Indications for a threshold of chemically‐induced aneuploidy in vitro in human lymphocytes , 1995, Environmental and molecular mutagenesis.

[71]  G. Jenkins,et al.  In vitro and in vivo extrapolations of genotoxin exposures: consideration of factors which influence dose-response thresholds. , 2000, Mutation research.

[72]  A. Zijno,et al.  Analysis of chromosome segregation in cytokinesis-blocked human lymphocytes: non-disjunction is the prevalent damage resulting from low dose exposure to spindle poisons. , 1996, Mutagenesis.

[73]  L. Mi,et al.  The p53 status of Chinese hamster V79 cells frequently used for studies on DNA damage and DNA repair. , 1997, Nucleic acids research.

[74]  L. Levy,et al.  Chromium chloride induces chromosomal aberrations in human lymphocytes via indirect action. , 1987, Mutation research.

[75]  T. Skopek,et al.  Transgenic chinese hamster V79 cell lines which exhibit variable levels of gpt mutagenesis , 1990, Environmental and molecular mutagenesis.

[76]  A. Natarajan,et al.  Chromosomal Aberrations: Basic and Applied Aspects , 2011 .

[77]  T. Sofuni,et al.  Detection of in vitro clastogens and spindle poisons by the mouse lymphoma assay using the microwell method: interim report of an international collaborative study. , 1996, Mutagenesis.

[78]  B. Kihlman.  Experimentally induced chromosome aberrations in plants. I. The production of chromosome aberrations by cyanide and other heavy metal complexing agents. , 1957 .

[79]  P. Kasper,et al.  Human biological relevance and the use of threshold-arguments in regulatory genotoxicity assessment: experience with pharmaceuticals. , 2000, Mutation research.

[80]  D. Tweats,et al.  Further debate of testing strategies. , 1988, Mutagenesis.

[81]  T. Lee,et al.  Induction of chromatid breaks and tetraploidy in Chinese hamster ovary cells by treatment with sodium arsenite during the G2 phase. , 1993, Mutation research.

[82]  N. Yoshimi,et al.  Genotoxicity in the hepatocyte/DNA repair test and toxicity to liver mitochondria of 1-hydroxyanthraquinone and several dihydroxyanthraquinones , 1986, Cell Biology and Toxicology.

[83]  J. S. Mitchell,et al.  Experiments on the Mechanism of Action of Tetra-sodium 2-Methyl-1:4-Naphthohydroquinone Diphosphate as a Mitotic Inhibitor and Radiosensitiser, using the Technique of Tissue Culture: Relation between Cytological Effects and Chemical Constitution , 1952, British Journal of Cancer.

[84]  D. Eunpu.  Editorial introduction , 1993, Journal of Genetic Counseling.

[85]  S. Stohs,et al.  Ricin-induced hepatic lipid peroxidation, glutathione depletion, and DNA single-strand breaks in mice. , 1992, Toxicon : official journal of the International Society on Toxinology.

[86]  A Elhajouji,et al.  Concepts of threshold in mutagenesis and carcinogenesis. , 2000, Mutation research.

[87]  H. Rosenkranz,et al.  SOS induction in Escherichia coli and Salmonella mutagenicity: a comparison using 330 compounds. , 1994, Mutagenesis.

[88]  J. M. Mason,et al.  Aneuploidy in Drosophila, II. Further validation of the FIX and ZESTE genetic test systems employing female Drosophila melanogaster. , 1991, Mutation research.

[89]  D. Kirkland,et al.  Evaluation of thresholds for benomyl- and carbendazim-induced aneuploidy in cultured human lymphocytes using fluorescence in situ hybridization. , 2000, Mutation research.

[90]  M. O. Bradley,et al.  Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of carcinogenic/mutagenic potential. , 1983, Mutation research.

[91]  S. Ellard,et al.  The use of genetically engineered V79 Chinese hamster cultures expressing rat liver CYP1A1, 1A2 and 2B1 cDNAs in micronucleus assays. , 1991, Mutagenesis.

[92]  F. Palitti,et al.  Induction of chromosomal aberrations and SCE by camptothecin, an inhibitor of mammalian topoisomerase I. , 1989, Mutation research.

[93]  J. Chipman,et al.  Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress. , 2003, Toxicology.

[94]  M. Yamada,et al.  Semi-quantitative evaluation of genotoxic activity of chemical substances and evidence for a biological threshold of genotoxic activity. , 2000, Mutation research.

[95]  N. Kruhlak,et al.  An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I. Identification of carcinogens using surrogate endpoints. , 2006, Regulatory toxicology and pharmacology : RTP.

[96]  Christopher J. Rhodes,et al.  Role of oxygen radicals in DNA damage and cancer incidence , 2004, Molecular and Cellular Biochemistry.

[97]  L. Ferguson,et al.  Mutagenicity of anticancer drugs that inhibit topoisomerase enzymes. , 1996, Mutation research.

[98]  L. Ferguson.  Inhibitors of topoisomerase II enzymes: a unique group of environmental mutagens and carcinogens. , 1998, Mutation research.

[99]  R. Bronaugh,et al.  Reduction of azo dyes during in vitro percutaneous absorption. , 1993, Toxicology and applied pharmacology.

[100]  T. Tsutsui,et al.  Induction of unscheduled DNA synthesis in cultured human oral keratinocytes by sodium fluoride. , 1984, Mutation research.

[101]  J. Abraham.  The international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use , 2009 .

[102]  J. Rueff,et al.  Induction of chromosomal aberrations by phenolic compounds: possible role of reactive oxygen species. , 2003, Mutation research.

[103]  K. Turteltaub,et al.  Methods of Dna Adduct Determination and Their Application to Testing Compounds for Genotoxicity , 2022 .

[104]  P. L. Lakshmana Rao,et al.  Cyanide induced DNA fragmentation in mammalian cell cultures. , 1997, Toxicology.

[105]  David Brusick,et al.  Genotoxicity under extreme culture conditions , 1991 .

[106]  J. Ashby,et al.  N-chloropiperidine and calcium hypochlorite: possible examples of toxicity-dependent clastogenicity in vitro. , 1987, Mutation research.

[107]  Diana Anderson,et al.  The effect of the antioxidant catalase on oestrogens, triiodothyronine, and noradrenaline in the Comet assay. , 2003, Teratogenesis, carcinogenesis, and mutagenesis.

[108]  T. R. King.  Simultaneous immunoselection in vitro for H-Y or H-2D antigen-loss variants of a mouse-derived B cell line. , 1996, Mutation research.

[109]  S. Yoshida,et al.  Inhibition of DNA polymerase-α and -β of calf thymus by 1-β-d-arabinofuranosylcytosine-5′-triphosphate , 1977 .

[110]  C. Lam,et al.  Depletion of nasal mucosal glutathione by acrolein and enhancement of formaldehyde-induced DNA-protein cross-linking by simultaneous exposure to acrolein , 1985, Archives of Toxicology.

[111]  W. Benedict,et al.  Induction of morphological transformation in mouse C3H/10T1/2 clone 8 cells and chromosomal damage in hamster A(T1)C1-3 cells by cancer chemotherapeutic agents. , 1977, Cancer research.

[112]  Kihlman Ba,et al.  Potentiation of chromosomal alterations by inhibitors of DNA repair. , 1984 .

[113]  L. Deaven,et al.  Cell-cycle-specific chromosome damage following treatment of cultured Chinese hamster cells with 4'-[(9-acridinyl)-amino]methanesulphon-m-anisidide-HCl. , 1978, Journal of the National Cancer Institute.

[114]  H. Tsuda.  Chromosomal aberrations induced by hydrogen peroxide in cultured mammalian cells , 1981 .

[115]  M Kucerová,et al.  Chromosomal aberrations and SCE in lymphocytes of children revaccinated against smallpox. , 1980, Mutation research.

[116]  N. Suzuki,et al.  Sodium fluoride-induced morphological and neoplastic transformation, chromosome aberrations, sister chromatid exchanges, and unscheduled DNA synthesis in cultured syrian hamster embryo cells. , 1984, Cancer research.

[117]  R. Cicchetti,et al.  Aphidicolin and bleomycin induced chromosome damage as biomarker of mutagen sensitivity: a twin study. , 2004, Mutation research.

[118]  M. Gaulden.  Hypothesis: some mutagens directly alter specific chromosomal proteins (DNA topoisomerase II and peripheral proteins) to produce chromosome stickiness, which causes chromosome aberrations. , 1987, Mutagenesis.

[119]  F. Guengerich,et al.  Purification and characterization of liver microsomal cytochromes p-450: electrophoretic, spectral, catalytic, and immunochemical properties and inducibility of eight isozymes isolated from rats treated with phenobarbital or beta-naphthoflavone. , 1982, Biochemistry.

[120]  D. Chan,et al.  The Protein Kinase CK2 Facilitates Repair of Chromosomal DNA Single-Strand Breaks , 2004, Cell.

[121]  L. Giovannelli,et al.  Oxidative DNA damage in peripheral blood cells in type 2 diabetes mellitus: higher vulnerability of polymorphonuclear leukocytes. , 2003, Mutation research.

[122]  L Müller,et al.  Series: current issues in mutagenesis and carcinogenesis, No. 65. The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view. , 1996, Mutation research.

[123]  Ronald D Snyder,et al.  DNA intercalative potential of marketed drugs testing positive in in vitro cytogenetics assays. , 2006, Mutation research.

[124]  F. W. Sunderman.  Mechanisms of nickel carcinogenesis. , 1989, Scandinavian journal of work, environment & health.

[125]  R. Crebelli,et al.  Threshold-mediated mechanisms in mutagenesis: implications in the classification and regulation of chemical mutagens. , 2000, Mutation research.

[126]  A. Gábelová,et al.  Cytotoxicity and genotoxicity testing of sodium fluoride on Chinese hamster V79 cells and human EUE cells. , 1992, Mutation research.

[127]  L. Kong,et al.  Relationships Between Molecular Structure and Chromosomal Aberrations in In Vitro Human Lymphocytes Induced by Substituted Nitrobenzenes , 1996, Bulletin of environmental contamination and toxicology.

[128]  R. Storer,et al.  The mouse lymphoma L5178Y Tk+/- cell line is heterozygous for a codon 170 mutation in the p53 tumor suppressor gene. , 1997, Mutation research.

[129]  L. Strekowski,,et al.  Enhancement of bleomycin-induced micronucleus formation in V79 cells as a rapid and sensitive screen for non-covalent DNA-binding compounds. , 1999, Mutation research.

[130]  J. Turchi,et al.  Development of a high-throughput screen for inhibitors of replication protein A and its role in nucleotide excision repair. , 2004, Molecular cancer therapeutics.

[131]  T. A. Venkitasubramanian,et al.  Effect of dieldrin on the stability of lysosomes in the rat liver , 1977, Bulletin of environmental contamination and toxicology.

[132]  M. Armstrong,et al.  A quantitative assessment of the cytotoxicity associated with chromosomal aberration detection in Chinese hamster ovary cells. , 1992, Mutation research.

[133]  L. Robertson,et al.  Carcinogenicity of polyhalogenated biphenyls: PCBs and PBBs. , 1990, Critical reviews in toxicology.

[134]  Y. Nozawa,et al.  Cytotoxicity and genotoxicity of xenoclauxin and desacetyl duclauxin fromPenicillium Duclauxii (delacroix) , 2004, Cell Biology and Toxicology.

[135]  S. Loft,et al.  Experimental study of oxidative DNA damage. , 1998, Free radical research.

[136]  T. Kamataki,et al.  Stable expression of human CYP2E1 in Chinese hamster cells: high sensitivity to N,N-dimethylnitrosamine in cytotoxicity testing. , 1996, Mutation research.

[137]  G. Witz,et al.  The Reactivity of Selected Acrylate Esters toward Glutathione and Deoxyribonucleosides in Vitro: Structure-Activity Relationships , 1994 .

[138]  T. Katsumoto,et al.  Cell‐cycle dependent biosynthesis and localization of p53 protein in untransformed human cells , 1995, Biology of the cell.

[139]  D. DeMarini,et al.  Prophage induction by DNA topoisomerase II poisons and reactive-oxygen species: role of DNA breaks. , 1992, Mutation research.

[140]  M. Cooke,et al.  PAH-X: Polynuclear aromatic hydrocarbons: A decade of progress , 1988 .

[141]  W. von der Hude,et al.  Threshold effects in genetic toxicity: perspective of chemicals regulation in Germany. , 2000, Mutation research.

[142]  T. Nicotera,et al.  Induction of superoxide dismutase, chromosomal aberrations and sister-chromatid exchanges by paraquat in Chinese hamster fibroblasts. , 1985, Mutation research.

[143]  M. Sugiyama.  Role of cellular antioxidants in metal-induced damage , 1994, Cell Biology and Toxicology.

[144]  T Satoh,et al.  Advantage of the use of human liver S9 in the Ames test. , 1999, Mutation research.

[145]  K. Voelkerding,et al.  Post-transcriptional regulation of the p53 tumor suppressor gene during growth-induction of human peripheral blood mononuclear cells. , 1995, Oncogene.

[146]  Studies on metabolism and toxicity of styrene: III. The effect of metabolic inactivation by rat-liver S9 on the mutagenicity of phenyloxirane toward Salmonella typhimurium. , 1980, Mutation research.

[147]  R. Ullrich,et al.  The kinase activity of DNA-PK is required to protect mammalian telomeres. , 2004, DNA repair.

[148]  Barry Halliwell,et al.  Oxidative stress in cell culture: an under‐appreciated problem? , 2003, FEBS letters.

[149]  D. Kirkland,et al.  Fluorescence in situ hybridisation with chromosome-specific centromeric probes: a sensitive method to detect aneuploidy. , 1996, Mutation research.

[150]  W. Piegorsch,et al.  Detection of oxidative DNA damage in isolated marine bivalve hemocytes using the comet assay and formamidopyrimidine glycosylase (Fpg). , 2003, Mutation research.

[151]  B. Dash,et al.  Genotoxicity of 'gudakhu', a tobacco preparation. I. In mice in vivo. , 1992, Mutation research.

[152]  E. Horváthová,et al.  Use of single cell gel electrophoresis (comet assay) modifications for analysis of DNA damage. , 1999, General physiology and biophysics.

[153]  B H Margolin,et al.  Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. , 1987, Science.

[154]  D. Kirkland,et al.  Chromosomal aberration tests in vitro: problems with protocol design and interpretation of results. , 1992, Mutagenesis.

[155]  T. Taguchi,et al.  Aphidicolin prevents mitotic cell division by interfering with the activity of DNA polymerase-α , 1978, Nature.

[156]  S. Galloway.  Cytotoxicity and chromosome aberrations in vitro: Experience in industry and the case for an upper limit on toxicity in the aberration assay , 2000, Environmental and molecular mutagenesis.

[157]  Y. Grosse,et al.  Formation of ochratoxin A metabolites and DNA-adducts in monkey kidney cells. , 1995, Chemico-biological interactions.

[158]  T. Yamano.  Dissociation of DDVP-induced DNA strand breaks from oxidative damage in isolated rat hepatocytes. , 1996, Toxicology.

[159]  N. Suzuki,et al.  Cytotoxicity, chromosome aberrations and unscheduled DNA synthesis in cultured human diploid fibroblasts induced by sodium fluoride. , 1984, Mutation research.

[160]  H. Glatt,et al.  Hepatocyte-mediated, but not S9-mediated mutagenicity correlates with the carcinogenicity of methylbenz[a]anthracenes , 1984 .

[161]  M. Aardema,et al.  Sodium fluoride-induced chromosome aberrations in different stages of the cell cycle: a proposed mechanism. , 1989, Mutation research.

[162]  Hook Eb.  International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC meeting report no. 3. Is the incidence of Down syndrome increasing? , 1983, Mutation research.

[163]  A. Gábelová,et al.  The effects of sodium azide on mammalian cells cultivated in vitro. , 1980, Mutation research.

[164]  M. Kirsch‐Volders,et al.  Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors in vitro in human lymphocytes. , 1997, Mutagenesis.