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PubMed1992

Interaction and distinction of genotoxic and non-genotoxic events in carcinogenesis.

Multistage carcinogenesis involves genotoxic as well as non-genotoxic mechanisms. The importance of genotoxic events in human carcinogenesis is apparent from the analysis of tumours: for example, five to six genetic alterations can be found in most malignant colorectal tumours. While such measurable "footprints" (e.g. ras, p53 mutations) can be left in tumours by genotoxic events, non-genotoxic events cannot directly generate them. Thus, the lack of specific indicators of non-genotoxic events in carcinogenesis makes the identification of non-genotoxic carcinogens difficult. It is also important to emphasize that apparent "genotoxic" endpoints (mutations, chromosome aberrations) could be induced by "non-genotoxic" agents through indirect mechanisms (e.g. induced cell proliferation and/or genomic instability, oxidative damage, deamination of 5-methyl cytosine). This emphasizes the need for differentiating "events" from the actual "activities" of chemicals and the difficulty of classification of carcinogens into genotoxic and non-genotoxic. One of the best models for the study of interaction of genotoxic and non-genotoxic mechanisms during carcinogenesis is a two-stage carcinogenesis system using mouse skin, rat liver or cultured cells. Molecular analysis of tumours produced on mouse skin by the classical initiation-promotion protocol indicates that the mutation spectra of oncogenes, e.g. Ha-ras, are determined by initiating (genotoxic) and not by promoting (non-genotoxic) agents. However, since usually no tumours appear without the application of tumour-promoting agents, the manifestation of genotoxic events (Ha-ras mutation) is dependent on the action of non-genotoxic agents. Using a BALB c 3T3 two-stage cell transformation system, we have now succeeded in confirming this and have quantitated the initiation and promotion events. These studies may help us not only in understanding mechanisms of carcinogenesis but also in developing molecular quantitative risk assessment in terms of multistage carcinogenesis.

3T3 Cells↗
PubMed1992

Overview of genotoxic carcinogens and non-genotoxic carcinogens.

It is known that carcinogens designated on the basis of longterm animal test results are extremely diverse in character, both in terms of potencies and the mechanism of action, which leads to complexity in their assessment for cancer risk to humans. The classification of carcin0ogens into two categories, namely, genotoxic and non-genotoxic varieties has been proposed to give a longical foundation on which cancer risk assessment can be reasonably based. The term "genotoxic carcinogen" indicates a chemical capable of producing cancer by directly altering the genetic material of target cells, while "non-genotoxic carcinogen" represents a chemical capable of producing cancer by some secondary mechanism not related to direct gene damage. This classification has contributed to the exclusion of various rodent-specific carcinogens from the group of chemicals with potential cancer risk to humans. However, the term, "nongenotoxic carcinogen" tends to give the mistaken impression that carcinogens shown to be negative for mutagenicity in a series of test systems might be harmless to humans. It should be realized that clear-cut criteria for this classification have not been established because of insufficiencies in the available information concerning mechanisms of action of non-genotoxic carcinogens. Future scientific advances leading to elucidation of the subcellular mechanisms of carcinogenesis are necessary for establishment of the unified, more realistic and mechanism-based approach to cancer risk estimation form exposure to chemicals.

Animals↗
PubMed1992

The in vivo and in vitro genotoxicity of aromatic amines in relationship to the genotoxicity of benzidine.

Benzidine and 12 related aromatic amines have been studied for the effects of substituent groups and pi orbital conjugation on their genotoxicity as measured by their mutagenicity in vitro with Salmonella and by chromosomal aberrations (CA) in vivo in the bone-marrow cells of mice. The in vitro studies indicated increases in mutagenicity with increases in the electron withdrawing ability of para' substituents. Mutagenicity also increases with increased conjugation as shown by the degree of planarity of the biphenyl compounds and by comparing the mutagenicities of biphenyl amines to stilbenes as well as to ethylene bridged diphenyl compounds. The relative in vitro mutagenicity results were not predictive of relative in vivo CA results. The 3 most genotoxic compounds in vivo were the conjugated amines without substituents in the para' position. The CA values for 4-aminostilbene were exceptionally high. These in vivo results indicate increased genotoxicity for benzidine analogs without substitution in the para' position.

Aminobiphenyl Compounds↗
PubMed1992

D and C Red No. 9: genotoxic or non-genotoxic carcinogen?

The azo-compound, D and C Red No. 9 was assayed for genotoxicity in vivo using the rat micronucleus test and the rat ex vivo liver UDS assay. Uniformly negative results were obtained in both assays, even though large oral doses were used (2 g/kg). These results suggest that the tumorigenic effects of this compound in rats are mediated through non-genotoxic rather than a genotoxic mechanism. Further experiments using additional end-points such as 32P-post-labelling would further substantiate this conclusion.

Administration, Oral↗
PubMed1992

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

A physico-chemical carcinogen-screening test was used to measure the rate constants of electron attachment, kes, of 105 chemicals that had been screened in long-term rodent bioassays and short-term in vitro tests by the NCI/NTP. In the ke test, a pulse-conductivity technique is used to generate and monitor the decay of excess electrons that serve as nucleophilic surrogates for the target tissue of rodents. Of the 61 chemicals that had been found to be rodent carcinogens as well as Salmonella mutagens, 36 yield kes that are equal to or greater than the diffusion-controlled ke of carbon tetrachloride and are considered to be positive ke test responses. In contrast, 29 of the remaining 44 chemicals that are putative non-carcinogens and non-mutagens yield kes that are negative ke test responses. These results are combined with the ke responses of 46 non-mutagenic carcinogens and 20 mutagenic non-carcinogens that were reported earlier and are evaluated to determine the degree to which the measure of electron-accepting capacity that ke provides complements or overlaps the electrophilicity or DNA reactivity of chemicals that is indicated by positive mutagenicity responses in the Ames Salmonella tester strains or by positive structural alerts, S/As, of the chemicals. The combined ke test results indicate that the overall predictivity of the ke test is comparable to and complements the Ames Salmonella test and S/As in identifying rodent carcinogens. Moreover, the electrons serve as non-discriminate nucleophilic targets for both genotoxic and non-genotoxic electron-accepting molecules and appear to attach with equal efficiency to carcinogens that are active in various tissues of rodents. This property of excess electrons suggests that the predictivity of the ke test could be enhanced by combining the measured ke with an appropriate lipophilicity or pharmacokinetic parameter. A pre-chemical electron-transfer step that had been proposed to precede chemical interactions between the carcinogen and target tissue is discussed in light of recent developments in electron-donor/-acceptor chemistry and in the application of structure--activity relationships to identify carcinogens.

Animals↗
PubMed1992

Structure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster.

Sixteen pyrrolizidine alkaloids (PAs) were examined for their genotoxic potency in the wing spot test of Drosophila melanogaster following oral application. This in vivo assay tests for the induction of somatic mutation and mitotic recombination in cells of the developing wing primordia. All PAs tested except the C9-monoester supinine were clearly genotoxic. Depending on their chemical structure, however, genotoxicity of the PAs varied widely in a range encompassing about three orders of magnitude. In general, macrocyclic diester-type PAs were the most and 7-hydroxy C9-monoester types the least genotoxic representatives studied, while open diesters were intermediate in this respect. Stereoisomeric PAs mostly showed similar, but sometimes also clearly unequal genotoxicity. An increasing number of hydroxy groups in the PA molecule seemed to reduce its genotoxic potency. With respect to the structure/activity relationships, there appears to be a good correlation between hepatotoxicity of PAs in experimental rodents and genotoxicity in the wing spot test of Drosophila. This suggests that PAs are bioactivated along similar pathways in the mammalian liver and in the somatic cells of Drosophila. The genotoxic potential of PAs in the Drosophila wing spot test and their carcinogenic potential in mammals also seem correlated, although the information in the literature on carcinogenicity of the non-macrocyclic PAs with moderate to low genotoxic potency is concededly limited. Comparisons with other genotoxicity tests suggest that the wing spot test is particularly suitable for genotoxins like PAs, on the one hand because of the versatile metabolic bioactivation system of Drosophila and on the other hand also because of its excellent sensitivity to the crosslinking agents among the genotoxins.

Animals↗
PubMed1992

Non-genotoxic factors in the carcinogenetic process: problems of detection and hazard evaluation.

In the classical two-stage models of carcinogenesis, initiation has been usually related to a DNA-damage/gene-mutation event, while promotion has been related to the non-genotoxic effects of clonal expansion of preneoplastic cells and/or modulation of cell differentiation. It is now clear that the process of carcinogenesis is linked to more than one irreversible alteration in the genome. Likewise, we can envisage that non-genotoxic events can take place after perhaps 0, 1, 2 or more irreversible alterations in the genome. Initiating and promoting activities of a chemical can be considered clearly separated in theory, but in practice, the chemicals we work with only rarely will be purely of the genotoxic or non-genotoxic type. We will discuss an empirical approach to classify genotoxic or prevalently non-genotoxic chemical carcinogens. For prevalently non-genotoxic carcinogens we will analyze what fraction of them can be detected as promoters of in vivo rat liver carcinogenesis. We will analyze carcinogenic potency of genotoxic and non-genotoxic carcinogens.

Animals↗
PubMed1992

Prediction of non-genotoxic carcinogenesis.

The distinction between genotoxic and non-genotoxic mechanisms of chemical carcinogenesis is now generally accepted. This acceptance implies a revised approach to the definition and measurement of genotoxicity. It is proposed that genotoxicity should be assessed as part of the overall evaluation of the toxicity of chemicals, not as a separate and isolated activity. The level and duration of dosing plays a critical role in the observation of genotoxic phenomena, and such parameters should assume greater importance in the interpretation of genotoxicity data. Toxic events associated empirically with the non-genotoxic aspects of chemical carcinogenicity are discussed.

Animals↗
PubMed1992

Rational approach to the quantification of genotoxicity.

The question of how many and which short-term tests (STT) are necessary for a satisfactory characterization of the genotoxic properties of chemicals is still open. The answer is important for both basic mutagenicity research and risk assessment. This paper, aimed at giving a rational answer to the problem, analyzes with multivariate statistical methods the data generated by the International Program for the Evaluation of Short-Term Tests for Carcinogens (IPESTTC). Although it has been found that this data base has a limited reliability for assessing the ability of STTs to predict carcinogenicity, the IPESTTC results are an important source of information on the relationships among different assays, and their ability to identify genotoxic chemicals. A scale of genotoxicity of the chemicals was established by studying with factor analysis their results in 20 IPESTTC tests. The next step of the analysis consisted in the identification of the STT batteries which are the most able to reproduce the genotoxicity scale based on the entire set of STTs. Different batteries were ranked according to their ability to quantify genotoxicity. As a general conclusion, this study indicated that an articulated range of STTs is necessary, and it is not possible to use only one assay (e.g., Salmonella) as an exhaustive indicator of genotoxicity.

Carcinogenicity Tests↗
PubMed1992

The genotoxicity of industrial wastes and effluents.

A review of the literature published on the genotoxicity of industrial wastes and effluents using short-term genetic bioassays is presented in this document. The importance of this task arises from the ubiquity of genotoxic compounds in the environment and the need to identify the sources of contamination so that efforts aimed at control and minimization can be implemented. Of even greater significance is the immediate concern for the welfare of human health and the environment. Subheadings of this document include a description of the genetic bioassays that have been used to test industrial wastes, a compendium of methods commonly used to prepare crude waste samples for bioassay, and a review of the genetic toxicity of wastes and effluents. Wastes and effluents have been grouped according to industrial source. Major categories include chemical and allied products, pulp and paper manufacturing, defense and munitions, petroleum refining, primary metal industries, and miscellaneous industrial manufacturers. Within each industrial category, a synopsis of individual genetic toxicity studies is presented, followed by an interpretation of results on a comprehensive, industry-wide basis. In this evaluation, a discussion of the types and extent of genotoxic damage caused by a particular set of wastes is presented, and potential sources of genotoxic activity are identified. Concluding the document is a commentary, which discloses potential shortcomings in the way in which current legislation protects human heath and the environment from the release of genotoxic substances via industrial wastes and effluents. It also provides an assessment of the genotoxic burden that industrial wastes place on the environment.

Industrial Waste↗
PubMed1992

Evaluation of genotoxicity of tert.-butylhydroquinone in an hepatocyte-mediated assay with V79 Chinese hamster lung cells and in strain D7 of Saccharomyces cerevisiae.

tert.-Butylhydroquinone (TBHQ) has been reported to be genotoxic in some short-term assays but non-genotoxic in others. We have examined cytotoxicity and genotoxicity of TBHQ, a principal metabolite of the phenolic antioxidant 2(3)-tert.-butyl-4-hydroxyanisole (BHA), in an hepatocyte-mediated assay with V79 Chinese hamster lung cells including both sister-chromatid exchange (SCE) and thioguanine-resistance (TGR) endpoints. The ability of BHA and of TBHQ to elicit a genotoxic response in Saccharomyces cerevisiae strain D7 was also investigated. In V79 cytotoxicity tests, TBHQ without hepatocytes produced a 50% reduction in colony formation at 4.2 micrograms/ml and was lethal to 100% of the cells at concentrations above 5 micrograms/ml. At partially cytotoxic dose levels, (0.17-3.4 micrograms/ml of medium), TBHQ sometimes increased significantly the frequency of SCE. TBHQ also produced sporadic statistically significant increases in the mutation frequency at the HGPRTase (TGR) gene locus when tested alone or with activation by rat or hamster hepatocytes. Mitotic gene conversion and reverse mutation were not induced in strain D7 of Saccharomyces cerevisiae by exposure to BHA or to TBHQ for 4 h at concentrations as high as 200 micrograms/ml for BHA or 500 micrograms/ml for TBHQ, either alone or with activation by rat-liver S9. Incubation of the yeast cells with BHA or TBHQ for 24 h in growth medium without activation also did not induce genotoxic activity. The slight and sporadic response to TBHQ in the V79 test system may indicate weak genotoxicity which is sensitive to slight differences in test conditions. The classification and test strategies adopted for compounds such as TBHQ could have important implications for regulatory decisions and for the validation of short-term tests.

Animals↗
PubMed1992

In vivo detection of genotoxicity in waste water from a wheat and rye straw paper pulp factory.

The genotoxicity of waste water from a wheat and rye straw paper pulp mill was investigated by in vivo genotoxicity tests using micronuclei and sister chromatid exchange as endpoints. Micronuclei were studied in mussels (Mytilus edulis) and sister chromatid exchange in fish (Nothobranchius rachowi). The paper mill uses chlorine dioxide for bleaching, and the bleaching effluent as well as the combined effluent, i.e. the mixture of all waste water streams, were both tested. Both effluents induced micronuclei and sister chromatid exchanges, although the presence of toxic substances could mask the expression of genotoxicity in some cases for both test systems. The study revealed that genotoxins are produced in the chlorine dioxide bleaching process as well as in the pulping process, indicating also genotoxic activity of non-chlorinated compounds. In contrast to previous studies in which mutagenicity was determined with bacterial assays, genotoxins were only associated with chlorinated organics from bleaching with chlorine and failed in detecting genotoxins in chlorine dioxide bleaching effluents. Aquatic in vivo genotoxicity tests are sensitive and efficient systems and seem to be a promising tool in effluent testing.

Animals↗
PubMed1992

Species differences in the genotoxicity of cyclophosphamide and styrene in three in vivo assays.

Species differences in dispositional factors such as distribution, metabolism and excretion may often account for species differences in the toxic responses to foreign chemicals. In this study we compared the genotoxic responses of cyclophosphamide (CP) and styrene (ST) between Porton rats and LACA Swiss mice in three in vivo assays (bone marrow micronucleus (MN), sperm morphology (SM) and sister-chromatid exchange (SCE) assays). The sensitivities of the three assays were compared by the doses of the compounds required to elicit a significant genotoxic response. The baseline levels for the MN, SCE and SM assays were 1.1-1.4 and 1.2-1.3 MNPCEs/1000 PCEs, 0.23-0.24 and 0.20-0.21 SCEs/chromosome, 3.5-5.7% and 1.6-1.9% abnormal sperm in mice and rats, respectively. CP was a potent genotoxin in the MN and SCE assays but weakly genotoxic in the SM assay. At comparable doses, the rat was approximately 3-, 2.5- and 1.8-fold more sensitive to CP than mice in the MN, SM and SCE assays, respectively. ST produced weak genotoxic responses in all assays in mice and only in the SM and SCE assays in rats. The mice were more sensitive to ST in the MN and SM assays, while it was difficult to compare the species in the SCE assay. For both compounds the sensitivity of the three assays, in decreasing order, were SCE greater than MN much greater than SM. For CP the relative responses in the Porton rats and LACA Swiss mice were qualitatively similar to previous reports. Although the use of different strains may explain differences between the studies in the magnitude of the responses observed. The results for ST in the rat shows that the choice of genotoxic endpoint can determine whether a response is detectable. Moreover, the discrepancies between the results for ST in this study and others, suggest that as well as using a battery of in vivo tests, it may be prudent to select more that one strain or species to fully assess a compound's ability to produce DNA damage.

Animals↗
PubMed1992

Use of batch and fed-batch fermentation for studies on the variation of glutathione content and its influence on the genotoxicity of methyl-nitro-nitrosoguanidine in yeast.

We have applied fermenter techniques to analyse the variations of glutathione (GSH) content in cultures of the diploid strain D7 of Saccharomyces cerevisiae. Choosing various experimental conditions of controlled batch and fed-batch fermentation we give evidence that the GSH levels of the yeast cultures depend on growth phase, the carbon source supply and the carbon source metabolism in an unexpectedly complex manner. Additionally, we analysed yeast cells with low GSH levels which were obtained either by depleting GSH with chloroacetophenone (CN) chemically or by using a GSH-deficient diploid strain (gsh1/gsh1). In order to study the relevance of the factors influencing the GSH concentration for genotoxicity testing in yeast we have used N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) which is activated by GSH. We show that in cells which are GSH proficient the extent of genotoxicity of MNNG correlates well with the GSH levels in the cells. Conditions of high GSH content (stationary phase of growth) corresponds with high genotoxic activity of MNNG, whereas conditions of low GSH content as logarithmic growth, glucose repression, GSH deficiency caused by the gsh1 mutation and GSH depletion by CN treatment correspond with a very moderate genotoxic effect of MNNG. These findings emphasize the necessity to use metabolically highly standardized cells for genotoxicity testing, since the carbon source catabolism, the concentration of glucose, growth rate and possibly other parameters influence the metabolization of xenobiotic agents in yeast.

Fermentation↗
PubMed1992

Organ-specific distribution of genotoxic effects in mice exposed to cooked food mutagens.

The induction of organ-specific genotoxic effects of five cooked food mutagens in Swiss albino mice was investigated in microbial animal-mediated assays. The indicator of the induction of DNA damage was a pair of Escherichia coli K12 strains, differing vastly in repair capacity (uvrB/recA versus uvr+/rec+). All compounds gave positive results in the tested dose range between 2.5 and 40 mg/kg body weight (i.p. administration, exposure time 120 min). 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) were slightly more genotoxic than 2-amino-3,8-dimethylimidazo[4,5-f]quinoline (MeIQx), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) which caused similar effects. When the compounds were administered orally, higher doses were required to induce repairable DNA damage. The pattern of organ-specific effects was essentially similar for all compounds; genotoxicity was most pronounced in livers and lungs, whereas in kidneys, spleen and testes comparatively lower effects were measured. The activity of PhIP, MeIQ and IQ in the blood was similar to that observed in the liver. The results obtained in vivo were compared with data gained in vitro with subcellular organ fractions. Our findings indicate the following. (i) The concentrations required to induce repairable DNA damage in microbial animal-mediated assays are substantially higher than might be expected on the basis of the liquid suspension tests. (ii) The ranking order of the genotoxicity of the various compounds in vitro is similar to that measured in vivo, but the differences in genotoxic potencies are less pronounced in the living animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Genotoxic effectivity--comparison of 36 nitrated furan and arenofuran derivatives on a quantitative scale. Statistical comparison of T7 and other short-term tests.

Thirty-six nitrated furan and arenofuran derivatives were measured and quantitatively characterized by the T7 inactivation test. A wide range of substances previously studied allowed us to compare the collected quantitative data with those obtained by other workers using different short-term tests. Based on comparative statistical evaluation of these data a borderline was determined for the genotoxic effect: compounds having in our short-term test mutagenicity index (MI) values smaller than 8.0 are positive while the higher values represent negative genotoxicity. Classification of 36 nitrofuran/nitroarenofuran derivatives is given both on the basis of the quantitative genotoxicity scale and in terms of +/- on the qualitative scale. All but one compound were found to be genotoxic and the genotoxic activities of these compounds were compared with the results of other carcinogenicity or mutagenicity tests.

Carcinogenicity Tests↗
PubMed1992

Genotoxicity of chryseno[4,5-bcd]thiophene and its sulfone derivative.

Our recent syntheses of chryseno[4,5-bcd]thiophene together with its potential sulfone metabolite, chryseno[4,5-bcd]thiophene-4,4-dioxide, have made these compounds available for genotoxicity testing. Such toxicity testing is of interest as this thiophene is an isoster of the established carcinogen benzo[a]pyrene and is one of the thiaarenes which are potential environmental contaminants found in fossil fuels. Although the thiophene was less mutagenic than benzo[a]pyrene in Salmonella strains TA98 and TA100 after S9 activation, it exhibited in vivo chromosomal aberration activity equal to that of benzo[a]pyrene in the bone-marrow cells of mice. A reduced activity with Salmonella as well as in the bone-marrow cell assay for the sulfone does not support its role as the key active metabolic intermediate for the genotoxicity of the thiophene. Our molecular orbital calculations would be consistent with the concept of activation through a diol-epoxide mechanism and offers an explanation for the reduced genotoxicity of the sulfone via this mechanism. These genotoxicity studies support the concern that sulfur isosters of established carcinogenic polycyclic aromatic hydrocarbons could themselves be toxic.

Animals↗