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PubMed1998

Identification of 'genotoxic' and 'non-genotoxic' alerts for cancer in mice: the carcinogenic potency database.

A set of chemicals tested for carcinogenicity in mice that have been analyzed by Gold et al. [L.S. Gold, C.B. Sawyer, R. Magaw, G.M. Backman, M. deVeciana, R. Levinson, N.K. Hooper, W.R. Havender, L. Bernstein, R. Peto, M.C. Pike, B.N. Ames, Environ. Health Perspect. 58 (1984) 9-319; L.S. Gold, M. deVeciana, G.M. Backman, M. Lopipero, M. Smith, R. Blumenthal, R. Levinson, L. Bernstein, B.N. Ames, Environ. Health Perspect. 67 (1986) 161-200; L.S. Gold, T.H. Slone, G.M. Backman, R. Magaw, M. DaCosta, P. Lopipero, M. Blumenthal, B.N. Ames, Environ. Health Perspect. 74 (1987) 237-329; L.S. Gold, T.H. Slone, G.M. Backman, S. Eisenberg, M. DaCosta, M. Wong, N.B. Manley, L. Rohrbach, B.N. Ames, Environ. Health Perspect. 84 (1990) 215-286; L.S. Gold, N.B. Manley, T.H. Slone, T.H. Garfinkle, L. Rohrbach, B.N. Ames, Environ. Health Perspect. 100 (1993) 65-135] in the first five plots of the carcinogenic potency database (CPDB) was subjected to CASE/MULTICASE analyses. Briefly, CASE/MULTICASE is a computer-automated structure evaluation system that is capable of identifying structural features of chemicals associated with a specified biological activity (e.g., carcinogenicity or mutagenicity). These features are then incorporated into a structure-activity relationship (SAR) model for the analyzed database. The mouse CPDB used in this study consists of 627 chemicals, 289 of which are carcinogens, 11 marginal or weak carcinogens (i.e., chemicals requiring high doses to induce cancer) and 327 non-carcinogens. In an internal prediction analysis where the CASE/MULTICASE SAR model was used to predict the carcinogenicity of chemicals used to create the model, a concordance between experimental and predicted results of 96% was obtained. This indicates that the model is able to satisfactorily explain the chemicals in the learning set. In a drop-one cross-validation study where chemicals were removed one at a time and the remaining n - 1 chemicals were used in an iterative method to create a model to predict the removed chemical, CASE/MULTICASE was able to achieve a concordance between experimental and predicted results of 70%. Using a modified validation process designed to investigate the predictivity of a more focused SAR model, the system achieved a 78% concordance between experimental and predicted results. Among the major biophores identified by CASE/MULTICASE associated with cancer causation in mice several are derived from electrophilic or potentially electrophilic compounds (e.g., hydrazines, N-mustards, N-nitrosamines, aromatic amines, reactive halogens, and quinones). Other biophores however are derived from chemicals seemingly devoid of actual or potential DNA-reactivity and as such may represent structural feature of non-genotoxic carcinogens.

Animals↗
PubMed1994

Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro.

To understand the role of betel quid (BQ) in the pathogenesis of oral submucous fibrosis (OSF) and oral cancer, we used DNA damage, cytotoxicity, and cell proliferation assays to study the pathobiological effects of aqueous extracts of three BQ constituents [betel nut (Areca catechu, BN), inflorescence of Piper betle (IPB), and lime], one BN alkaloid (arecoline), and one BN polyphenol [(+)-catechin] on cultured oral mucosal fibroblasts. Extracts of BN and IPB induced DNA strand break formation in a dose-dependent manner. Extracts of BN and IPB, (+)-catechin, and arecoline decreased cell survival and proliferation in a dose-dependent manner. However, aqueous extract of lime (50-800 micrograms/mL) increased cell proliferation by 20-40%. These results indicate that BQ contains not only genotoxic and cytotoxic agents, but also compounds which stimulate cell proliferation. These compounds may act synergistically in the pathogenesis of OSF and oral cancer in BQ chewers. In addition, five anti-oxidants [glutathione (GSH), cysteine, mannitol, catalase, and superoxide dismutase (SOD)] were tested for their protective effects against the cytotoxicity of BQ constituents. GSH (1.95 and 2.6 mmol/L) and cysteine (4 and 8 mmol/L) prevented the arecoline-induced cytotoxicity. In contrast, mannitol, catalase, and SOD did not decrease the arecoline-induced cytotoxicity. These results indicate that thiol depletion, but not the attack of oxygen free radicals, could be the mechanism for arecoline cytotoxicity. GSH could also protect cells from the cytotoxicity of IPB extract. Increasing dietary intake of GSH-rich foods or dietary supplements of GSH may have chemopreventive potential to reduce BQ-associated oral lesions.

Antimutagenic Agents↗
PubMed2000

Report and summary of the major conclusions from statistics in genotoxicity testing working group from the International Workshop on Genotoxicity Test Procedures (IWGTP), March 1999.

A working group of five statisticians experienced in the use of statistical methods in mutagenicity reviewed aspects of the statistical analysis of genotoxicity test procedures. Issues discussed included methods for integrating biological importance and statistical significance, the relationship of the experimental unit to the experimental design, and the impact of new developments in statistics and computing. Three major recommendations were made relating to the need for: (1) the effective use of statistical advice in designing interlaboratory and intralaboratory investigations; (2) the development of appropriate experimental designs for new assays; and (3) education and training in the use of statistical methodology in mutagenicity testing. Environ. Mol. Mutagen. 35:260-263, 2000 Published 2000 Wiley-Liss, Inc.

Guidelines as Topic↗
PubMed1989

Azathioprine, a genotoxic agent to be considered non-genotoxic in man.

Azathioprine, an immunosuppressive drug, has been used for 25 years. Azathioprine is rapidly converted into a number of metabolites after absorption. Maximum blood levels in experimental animals (mice) were 11.3 micrograms/ml after a dosage of 33.3 mg/kg. Generally, levels of less than 1 microgram/ml are found. As azathioprine is ineffective in hypoxanthine guanine phosphoribosyltransferase (HPRT)-deficient patients, it will be clear that for immunosuppressive activity azathioprine must be metabolised. Regarding mutagenic activity, its mutagenicity for bacteria seems irrelevant for man because the nitroimidazole moiety can be reduced by bacteria but not or hardly at all by mammalian tissues. So 6-mercaptopurine (a metabolite of azathioprine) and its metabolites should be regarded as the active compounds. In vitro azathioprine can induce chromosome aberrations and other cytogenetic events at high, non-physiological doses. However, in view of the low blood levels it is unlikely that azathioprine can induce chromosome aberrations in kidney transplant patients. It is more probable that azathioprine inhibits the elimination of such aberrant cells through its immunosuppressive activity. It should be pointed out that in microbial mutagenicity systems also, azathioprine concentrations that are not reached in patients are needed to obtain an increased mutation rate.

Animals↗
PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. Oxidative DNA damage--the effects of certain genotoxic and operationally non-genotoxic carcinogens.

A wide variety of oxidative DNA lesions are commonly present in untreated human and animal DNA. One of these lesions, 8-hydroxydeoxyguanosine, has been shown to lead to base mispairing (mutation) on DNA replication. Other lesions remain to be investigated in this respect. Oxidative DNA lesions on cell replication may, in appropriate circumstances, lead to proto-oncogene activation. Oxidative DNA damage, on fixation, may also lead to cytotoxicity followed by regenerative proliferation. The probable or possible importance of oxidative DNA damage is reviewed for various classes of carcinogens and natural processes, including metal ions, high-energy radiation, miscellaneous chemicals, tumor-promoting agents, polyhydroxyphenols/quinones, lipid metabolism, peroxisome proliferators and thyroid function. It is concluded that although the evidence needs considerable strengthening in many of these examples, the available information indicates the potential importance of oxidative DNA damage in the induction of tumors by these agents. It is also possible that non-cancerous degenerative diseases associated with aging are the result of the accumulation of lesions resulting from unrepaired oxidative DNA damage.

Animals↗
PubMed1991

32P-postlabeling analysis of DNA adducts in rat livers after treatment with genotoxic and non-genotoxic 4-aminoazobenzene derivatives.

Formation of hepatic DNA adducts was studied in rats following intraperitoneal administration of a hepatocarcinogen, 3-methoxy-4-aminoazobenzene (3-MeO-AAB) and a non-hepatocarcinogen, 2-methoxy-4-aminoazobenzene (2-MeO-AAB). The 32P-post-labeling assay revealed 3-MeO-AAB to give more than 20-fold higher amounts of DNA adducts than did 2-MeO-AAB. Furthermore, five adducts, one of which accounted for over 70% of the total modified bases, were found in DNA from 3-MeO-AAB-treated rats, whereas only one adduct was apparent in 2-MeO-AAB-treated DNA. Our data thus suggested that the difference in hepatocarcinogenic activity between 3-MeO-AAB and 2-MeO-AAB might be, at least in part, dependent on quantitative and qualitative differences in their azo dye-DNA adduct formation in the rat liver.

Animals↗
PubMed2001

Genotoxic and non-genotoxic pathways of p53 induction.

Since the initial concept of p53 as a sensor of DNA-damage, the picture of the role of p53 has widened to include the sensing of much more diverse forms of stress, including hypoxia and constitutive activation of growth-promoting cascades. The pathways by which these processes regulate p53 are partially overlapping, but imply different patterns of post-translational modifications. In this review, we summarize current knowledge on post-translational modifications of p53, and we discuss how hypoxia and oncogene activation stresses may induce p53 independently of DNA damage.

Apoptosis↗
PubMed1990

Response of the ke test to NCI/NTP-screened chemicals. I. Non-genotoxic carcinogens and genotoxic non-carcinogens.

The response of a physico-chemical carcinogen-screening test, the k(e) test, to 46 rodent carcinogens and 20 putative non-carcinogens that had been screened in long-term two-species bioassays by the National Cancer Institute/National Toxicology Program are reported. All of the chemicals screened are those that yield mutagenicity responses in the Ames Salmonella/microsome test that are either equivocal or contrary to the rodent carcinogenicity responses. The electron attachment rate constants, k(e)S, of the test chemicals in cyclohexane at 21 degrees C were measured using a pulse-conductivity technique. The k(e)S of 27 of the 46 rodent carcinogens (59%) are equal or greater than the diffusion-controlled k(e) of carbon tetrachloride, which is regarded as the boundary between a positive and negative response; the k(e)S of 8 of the 20 mutagenic non-carcinogens (40%) are less than diffusion-controlled. If the boundary between positive and negative k(e) responses is decreased to half the diffusion-controlled k(e), six additional carcinogens yield a positive ke response which increases the k(e) test sensitivity to 72% while the specificity to non-carcinogens remains at 40%. Comparison of these k(e)S with measures of the chemicals' electrophilicity that had been inferred from chemical structure indicates that k(e) provides a markedly different measure of electrophilicity and one that complements the Ames Salmonella assay. The use of the k(e) test as an analytical tool to indicate the presence of electron-attaching impurities in solvents such as benzene is discussed, as is the sensitivity of the k(e) test to rodent-liver carcinogens.

Animals↗
PubMed1996

SOS chromotest results in a broader context: empirical relationships between genotoxic potency, mutagenic potency, and carcinogenic potency.

Environmental monitoring requires that large numbers of samples be processed in a relatively short period of time. While microbioassays facilitate rapid testing, the results are often difficult to interpret in the broader context of human or animal health. Determining the consequences of exposure to genotoxic substances will ultimately require in situ monitoring of exposed organisms. However, it is immediately possible to construct a broad empirical framework within which available microbioassay results can be interpreted. To do this for SOS Chromotest results, we investigated the empirical relationships between SOS genotoxic potency and mutagenic potency (as measured with the Salmonella/microsome assay), as well as between genotoxic potency and carcinogenic potency (as measured using standard, chronic animal bioassays). Strong relationships were identified between; 1) genotoxic potency and mutagenic potency for 268 direct-acting substances (r2=0.76) and 2) genotoxic potency and mutagenic potency for 126 S9-activated substances (r2=0.65). Ordinary least squares regression analyses of the SOS genotoxicity-Salmonella mutagenicity relationship revealed a significant effect of SOS genotoxicity as well as differences in mutagenic potency that can be attributed to the Salmonella strain used to measure mutagenic potency. Analyses of S9-activated substances revealed a significant interaction between the SOS genotoxic potency (SOSIP) effect and the Salmonella strain effect. Two regression models relating SOS genotoxicity and Salmonella mutagenicity were used to predict the mutagenic potency of several industrial effluent extracts previously analyzed for SOS genotoxicity by White et al. [(1996): Environ Mol Mutagen 27:116-139]. Predictions are consistent with published mutagenic potency values for similar industrial waste materials. A consistent relationship was also identified between genotoxic potency and carcinogenic potency for 51 substances. Linear regression analyses revealed an effect of SOS genotoxic potency as well as differences in carcinogenic potency that may be attributable to experimental animal and route of exposure. The correlation between genotoxicity and carcinogenicity was fairly weak (maximum r value = 0.51). Previous studies revealed similar strength of association between Ames mutagenicity and carcinogenicity. Predicted carcinogenic potencies of previously examined genotoxic, industrial effluent extracts are generally low compared to the pure substances included in the data set.

Animals↗
PubMed1995

Non-genotoxic mechanisms of carcinogenesis: studies of cell transformation and gap junctional intercellular communication.

It is widely accepted that a series of genetic changes accumulate during carcinogenesis. In addition, it is likely that various non-genotoxic mechanisms also operate at different stages of carcinogenesis. It is even possible that non-genotoxic mechanisms indirectly generate genetic changes, e.g., through induction of cell proliferation, active oxygen species or cytosine methylation. This may partially explain why many carcinogens are devoid of activity when tested in the usual genetic toxicology assays. In vitro cell transformation mimics certain stages of in vivo carcinogenesis. It has therefore been proposed that both genotoxic and non-genotoxic aspects of carcinogenesis can be studied in cell transformation systems, with tumor formation by transformed cells in syngenic animals or nude mice as the endpoint. Many genotoxic as well as non-genotoxic carcinogens induce transformation of Syrian hamster embryo, murine Balb/c 3T3 and murine C3H10T1/2 cells; interaction of genotoxic and non-genotoxic mechanisms can be clearly seen in 2-stage cell transformation studies in which a genotoxic initiating agent and a non-genotoxic promoting agent act synergistically to induce transformation of rodent cells. Aberrant control of gap junctional intercellular communication (GJIC) in cell transformation and carcinogenesis is well documented. Possible genotoxic as well as non-genotoxic mechanisms involved in abnormal gap junction communication control in multistage carcinogenesis are discussed.

Animals↗
PubMed1989

Prevalence of genotoxic chemicals among animal and human carcinogens evaluated in the IARC Monograph Series.

To determine whether genotoxic and non-genotoxic carcinogens contribute similarly to the cancer burden in humans, an analysis was performed on agents that were evaluated in Supplements 6 and 7 to the IARC Monographs for their carcinogenic effects in humans and animals and for the activity in short-term genotoxicity tests. The prevalence of genotoxic carcinogens on four groups of agents, consisting of established human carcinogens (group 1, n = 30), probable human carcinogens (group 2A, n = 37), possible human carcinogens (group 2B, n = 113) and on agents with limited evidence of carcinogenicity in animals (a subset of group 3, n = 149) was determined. A high prevalence in the order of 80 to 90% of genotoxic carcinogens was found in each of the groups 1, 2A and 2B, which were also shown to be multi-species/multi-tissues carcinogens. The distribution of carcinogenic potency in rodents did not reveal any specific characteristic of the human carcinogens in group 1 that would differentiate them from agents in groups 2A, 2B and 3. The results of this analysis indicate that (a) an agent with unknown carcinogenic potential showing sufficient evidence of activity in in vitro/in vivo genotoxicity assays (involving as endpoints DNA damage and chromosomal/mutational damage) may represent a hazard to humans; and b) an agent showing lack of activity in this spectrum of genotoxicity assays should undergo evaluation for carcinogenicity by rodent bioassay, in view of the present lack of validated short-term tests for non-genotoxic carcinogens. Overall, this analysis implies that genotoxic carcinogens add more to the cancer burden in man than non-genotoxic carcinogens. Thus, identification of such genotoxic carcinogens and subsequent lowering of exposure will remain the main goal for primary cancer prevention in man.

Animals↗