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PubMed1989

Genotoxicity of aniline derivatives in various short-term tests.

Various substituted aniline derivatives were tested for genotoxicity in several short-term tests in order to examine the hypothesis that a substitution at both ortho positions (2,6-disubstitution) could prevent genotoxicity due to steric hindrance of an enzymatic activation to electrophilic intermediates. In the Salmonella/microsome assay, 2,6-dialkylsubstituted anilines and 2,4,6-trimethylaniline (2,4,6-TMA) were weakly mutagenic in strain TA100 when 20% S9 mix was used, although effects were small compared to those of 2,4-dimethylaniline and 2,4,5-trimethylaniline (2,4,5-TMA). In Drosophila melanogaster, however, 2,4,6-TMA and 2,4,6-trichloroaniline (TCA) were mutagenic in the wing spot test at 2-3 times lower doses than 2,4,5-TMA. In the 6-thioguanine resistance test in cultured fibroblasts, 2,4,6-TMA was again mutagenic at lower doses than 2,4,5-TMA. Two methylene-bis-aniline derivatives were also tested with the above methods: 4,4'-methylene-bis-(2-chloroaniline) (MOCA) was moderately genotoxic in all 3 test systems whereas 4,4'-methylene-bis-(2-ethyl-6-methylaniline) (MMEA) showed no genotoxicity at all. DNA binding studies in rats, however, revealed that both MOCA and MMEA produced DNA adducts in the liver at levels typically found for moderately strong genotoxic carcinogens. These results indicate that the predictive value of the in vitro test systems and particularly the Salmonella/microsome assay is inadequate to detect genotoxicity in aromatic amines. Genotoxicity seems to be a general property of aniline derivatives and does not seem to be greatly influenced by substitution at both ortho positions.

Aniline Compounds↗

PubMed1993

Genotoxic effects of selected peroxisome proliferators.

Peroxisome proliferators, a class of structurally dissimilar chemicals including hypolipidemic drugs and industrial plasticizers, have been shown to be associated with hepatocarcinogenesis although an initiating effect could not yet be demonstrated in the cell systems utilized. For this reason the genotoxic potential of the peroxisome proliferators nafenopin, ciprofibrate and di(2-ethylhexyl)adipate (DEHA) was determined in primary cultures of adult rat hepatocytes. To further test if these compounds are genotoxic per se or the genotoxic effect is due to peroxisome proliferation, the cultures were exposed for 3 and 51 h. Treatment for 3 h with the hypolipidemic drugs nafenopin and ciprofibrate induced statistically significant increases of SCE at concentrations > or = 30 and 100 microM respectively. At higher concentrations statistically significant increases of chromosomal aberrations (nafenopin: 100 microM; ciprofibrate: > or = 100 microM) and micronuclei (ciprofibrate: > or = 250 microM) were also found. The presence of peroxisome proliferators in the media until harvesting (51 h) did not significantly alter the dose response of SCE, micronuclei and chromosomal aberration induction by ciprofibrate, while long-term exposure to nafenopin resulted in statistically significant increases of chromosomal aberrations and micronuclei at concentrations > or = 30 microM. The differences were statistically significant at 30 and 100 microM for micronuclei, and at 30 microM for chromosomal aberrations. Neither short- nor long-term exposure to DEHA produced a significant genotoxic effect up to 200 microM. The peroxisome proliferators tested were not cytotoxic at any concentration, as determined by mitotic index. These results clearly demonstrate that the peroxisome proliferators nafenopin and ciprofibrate can cause genotoxic effects in primary cultures of adult rat hepatocytes. The comparison of short- and long-term exposure does not suggest a strong correlation between the induction of peroxisome proliferation and genotoxicity, since long-term exposure did not significantly alter the dose response and--except for nafenopin--the extent of the genotoxic effects.

Adipates↗

PubMed1994

The structural basis of the genotoxicity of nitroarenofurans and related compounds.

The CASE (Computer-Automated Structure Evaluation) methodology has been applied to an investigation of the basis of the genotoxicity (sfiA induction) of 79 nitroarenofurans and related molecules examined with the E. coli PQ37 genotoxicity assay (SOS chromotest). CASE identified 9 major activating structural fragments (biophores) responsible for the probability of genotoxicity (SAR). With respect to quantitative features, CASE identified 8 major molecular subunits related to the genotoxic potency (QSAR). Both the SAR as well as the QSAR analysis indicate that a nitro group on position 2 of the furan ring is important for activity provided one or more aromatic rings are attached to the furan ring, i.e. 2-nitrobenzofuran, 2-nitronaphthofuran, 2-nitroanthrafuran and 8-nitropyrenofuran. Additionally, a small substituent at position 3 of the furan ring, i.e. the methyl group of R7371, the ethyl group of R7427 and the butyl group of R7429, enhance the activity of 2-nitronaphtho[2,1-b]furan (R6597), whereas longer aliphatic chains decrease activity. Moreover, the activity of the nitro group at position 2 of the furan ring was increased by substitution of a methoxy group at position 7 of the R6597 structure. Additionally the n-octanol/water partition coefficient (log P) was found to be an important descriptor for the genotoxic potency in E. coli PQ37. Using the identified descriptors CASE correctly predicted the probability of genotoxicity of all of the genotoxicants and non-genotoxicants in the data base. The calculated genotoxic potency was equally good: 94% of all predicted results were within plus/minus one order of magnitude of the experimental result. Using CASE in the predictive mode, the program correctly predicted the probability of sfiA induction in E. coli of 95.8% of 24 "unknown" nitroarenofurans which were not part of the learning set (QSAR with r = 0.88-0.97).

Benzofurans↗

PubMed1996

Series: current issues in mutagenesis and carcinogenesis, No. 65. The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view.

The publication of several studies reporting genotoxic effects of paracetamol, one of the world's most popular over-the-counter drugs, has raised the question of regulatory action. Paracetamol does not cause gene mutations, either in bacteria or in mammalian cells. There are, however, published data giving clear evidence that paracetamol causes chromosomal damage in vitro in mammalian cells at high concentrations and indicating that similar effects occur in vivo at high dosages. Available data point to three possible mechanisms of paracetamol-induced genotoxicity: (1) inhibition of ribonucleotide reductase; (2) increase in cytosolic and intranuclear Ca2+ levels; (3) DNA damage caused by NAPQI after glutathione depletion. All mechanisms involve dose thresholds. Studies of the relationship between genotoxicity and toxic effects in the rat (induction of micronuclei in rat bone marrow including dose-response relationship, biotransformation of paracetamol at different dosages, concomitant toxicity and biochemical markers) have recently been completed. These studies, which employed doses ranging from the dose resulting in human therapeutic peak plasma levels to highly toxic doses, give convincing evidence that genotoxic effects of paracetamol appear only at dosages inducing pronounced liver and bone marrow toxicity and that the threshold level for genotoxicity is not reached at therapeutic dosage. Reliable studies on the ability of paracetamol to affect germ cell DNA are not available. However, based on the amount of drug likely to reach germ cells and the evidence of thresholds, paracetamol is not expected to cause heritable damage in man. Various old and poorly designed long-term studies of paracetamol in the mouse and rat have given equivocal results. A few of these studies showed increased incidence of liver and bladder tumours at hepatotoxic doses. National Toxicology Program (U.S.A.) feeding studies have shown that paracetamol is non-carcinogenic when given at non-hepatotoxic doses up to 300 mg/kg/d to the rat and up to 1000 mg/kg/d to the mouse. Taking into account the knowledge of the hepatotoxicity and metabolism of paracetamol and the existence of thresholds for its genotoxicity, the animal studies do not indicate a carcinogenic potential at non-hepatotoxic dose levels. Based on this updated assessment of the genotoxicity and carcinogenicity of paracetamol, it is concluded that there is no need for regulatory action.

Acetaminophen↗

PubMed1988

Assessment of the potential germ cell mutagenicity of industrial and plant protection chemicals as part of an integrated study of genotoxicity in vitro and in vivo.

An approach is described that enables the germ cell mutagenicity of chemicals to be assessed as part of an integrated assessment of genotoxic potential. It is recommended, first, that the genotoxicity of a chemical be defined by appropriate studies in vitro. This should involve use of the Salmonella mutation assay and an assay for the induction of chromosomal aberrations, but supplementary assays may be indicated in specific instances. If negative results are obtained from these 2 tests there is no need for the conduct of additional tests. Agents considered to be genotoxic in vitro should then be assessed for genotoxicity to rodents. This will usually involve the conduct of a bone marrow cytogenetic assay, and in the case of negative results, a genotoxicity test in an independent tissue. Agents found to be non-genotoxic in vivo are regarded as having no potential for germ cell mutagenicity. Agents found to be genotoxic in vivo may either be assumed to have potential as germ cell mutagens, or their status in this respect may be defined by appropriate germ cell mutagenicity studies. The basis of the approach, which is supported by the available experimental data, is that germ cell mutagens will be evident as somatic cell genotoxins in vivo, and that these will be detected as genotoxins in vitro given appropriate experimentation. The conduct of appropriate and adequate studies is suggested to be of more value than the conduct of a rigid set of prescribed tests.

Animals↗

PubMed1989

Investigations on the use of EDTA-permeabilized E. coli cells in liquid suspension and animal-mediated genotoxicity assays.

The potential use of EDTA-permeabilized E. coli cells for the investigation of genotoxic effects of compounds with a large molecular configuration in vitro and in animal-mediated differential DNA-repair assays was studied. The indicator for the induction of (repairable) DNA damage was a pair of E. coli K-12 strains (343/765 and 343/753) differing vastly in DNA-repair capacity (uvr+/rec+ vs. uvrB/recA). Investigations on the influence of EDTA treatment on the viability of these strains show that during short-term exposure (3 min), the EDTA level should not exceed 0.5 mmole/l in the pretreatment mix, since at higher concentrations a marginal titer reduction of the repair-deficient strain occurs, thus indicating a weak genotoxic activity of this chelating agent. Comparisons of the results gained in vitro with permeabilized and untreated cells demonstrate that EDTA exposure leads to a substantial enhancement of the sensitivity of the indicator bacteria towards DNA damage induced by B(a)P and N-Ac-2AAF which is essential for the detection of genotoxic activities of these polycyclic aromatic compounds. Experiments to elucidate the possibility of employing EDTA-treated cells in vivo show that following intravenous and oral administration the recovery rates of permeabilized indicator strains from various mouse organs are substantially lower than those found under identical conditions (exposure time 150 min) with untreated strains. Nevertheless enough viable cells can be recovered from liver, spleen, kidneys, lungs and stomach to allow the investigation of organ-specific genotoxicity. It is furthermore noteworthy that exposure of permeabilized indicator cells in control animals (for 150 min) resulted in a marginal reduction of the relative survival of the repair-deficient strain in all organs investigated, whereas with non-treated strains such effects are only detectable after extended exposure periods. The observation of a slightly elevated genotoxic background under in vivo conditions does not prevent the assessment of the organ distribution of genotoxic effects induced by mutagens and/or carcinogens: in the case of B(a)P, intraperitoneal administration to mice in the dose range of 10-50 mg/kg body weight resulted in a pronounced dose-dependent inactivation of the uvrB/recA cells in the liver. Also in the lungs differential killing effects occurred at the highest dose tested, whereas no genotoxic activities were detectable in stomach, kidneys and spleen of the host animals.

Acetoxyacetylaminofluorene↗

PubMed1995

The genetic toxicology of ethylenethiourea: a case study concerning the evaluation of a chemical's genotoxic potential.

Ethylenethiourea (ETU) is a metabolite, environmental degradation product and minor technical impurity of the ethylenebisdithiocarbamate (EBDC) class of fungicides. The genetic toxicology of ETU is important given that ETU causes thyroid tumors in rodents and liver tumors in mice. Although it is clear that ETU induces thyroid tumors via a non-genotoxic, threshold mechanism, the role ETU plays in inducing mouse liver tumors remains to be fully elucidated. Recently, Dearfield (Mutation Res., 317, 111-132, 1994) reviewed the genetic toxicology of ETU, and concluded that, although ETU is not a potent genotoxic agent, it is weakly genotoxic. This view stands in contrast to reports from several independent authorities that have generally concurred that ETU is not a mammalian genotoxin (IARC, 1987; MAFF, 1990; NTP, 1992; FAO/WHO, 1994). These conflicting reports highlight a generic problem in genotoxicity safety assessment: although individual test results typically yield either a positive or negative response, the overall evaluation of an extensive battery of tests for a particular chemical rarely yields an unambiguous conclusion. Recently, Mendelsohn et al. (Mutation Res., 266, 43-60, 1992) showed that the response of a chemical to a battery of genotoxicity tests is not a dichotomous (i.e., either positive or negative) property, but rather, appears to be a continuous property that ranges from strongly negative to strongly positive. We have used these data, together with a four-step weight of the evidence procedure, to evaluate ETU. Our analysis indicates that ETU is not genotoxic in mammalian systems and suggests that ETU likely induces mouse liver tumors by a non-genotoxic mechanism.

Animals↗

PubMed1989

Inhibition of in vivo genotoxicity by coffee.

The possible role of coffee in modulating the in vivo genotoxicity of the well established genotoxic chemicals, mitomycin C, cyclophosphamide, procarbazine and adriamycin, was evaluated. Coffee was administered orally to mice that received the genotoxic chemicals ip. Genotoxicity was assessed in the bone-marrow micronucleus test. Doses of coffee in the range 225 to 1125 mg (dry weight)/kg body weight caused significant reductions in the in vivo genotoxicity of mitomycin C, cyclophosphamide and procarbazine but not adriamycin. The inhibitory effect was significant when the coffee was given about 2 hr before the genotoxin; there was a lesser effect when coffee was given together with the genotoxin but there was no inhibition when coffee was given 2-4 hr after the genotoxin. An experiment with mitomycin C demonstrated that the reduction in genotoxicity was dependent on the coffee dose. The inhibition of genotoxicity by coffee was observed in bone-marrow cells sampled 24, 48 or 68 hr after injecting cyclophosphamide. Freshly brewed coffee extract, standard instant coffee, decaffeinated instant coffee and freeze-dried home-brew coffee all exerted inhibitory effects.

Analysis of Variance↗

PubMed1994

Genotoxicity of the alkenylbenzenes alpha- and beta-asarone, myristicin and elimicin as determined by the UDS assay in cultured rat hepatocytes.

While the alkenylbenzenes alpha- and beta-asarone are hepatocarcinogenic in rodents, myristicin and elimicin, two other alkenylbenzenes, are not. The present study investigated the mechanism of genotoxicity of the asarones to elucidate the role of cytochrome P-450 and obtain further information about the relationships between the structure, metabolism and genotoxicity of the alkenylbenzenes. The data on the ability of these compounds to induce unscheduled DNA synthesis (UDS) in hepatocytes derived from male Fischer 344 rats are presented in this paper. Cytotoxicity was assessed by lactate dehydrogenase leakage. Elimicin and alpha- and beta-asarone are genotoxic in the UDS assay but myristicin is not. The genotoxicity of the asarones is inhibited by the cytochrome P-450 inhibitor cimetidine but the sulfotransferase inhibitor pentachlorophenol (PCP) is without effect. The major metabolite of the asarones in hepatocytes was identified by liquid chromatography-mass spectrometry as 2,4,5-trimethoxycinnamic acid but this was not genotoxic when tested separately. Simple allylbenzenes such as safrole, estragole and methyleugenol are activated by sequential 1-hydroxylation and sulfation, and this is the likely mechanism of the genotoxicity of elimicin. The propenyl analogues isosafrole, anethole and methylisoeugenol, which cannot undergo 1-hydroxylation, are not genotoxic. The positive results obtained with the asarones suggest the occurrence of a novel activation 'option' for alkenylbenzenes which features a 2-methoxy group in the aromatic ring.

Alkylation↗

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↗

PubMed2004

Application of simplified in vitro screening tests to detect genotoxicity of aristolochic acid.

Aristolochic acid (AA), the active compound found in Aristolochia extracts, has been used as a traditional medicine. However, products containing AA were withdrawn from the market in the early 1980s because AA was found to be a potent carcinogen. Some genotoxicity studies of AA were conducted after the carcinogenicity of AA was reported. The purpose of this study was to check the ability of simplified, screening tests for genotoxicity to indicate the genotoxic activities of AA. Four commonly used in vitro genotoxicity endpoints were examined. In a bacterial mutation screening test, AA was mutagenic to tester strains TA98 and TA100 with and without rat liver S9. In the L5178Y mouse lymphoma cell gene mutation test, mutagenic activity was observed at > or = 25 microg/ml with or without S9. A concentration-dependent increase in structural chromosome aberrations was observed in CHO cells, with significant increases at 50 microg/ml without S9 and at 25 microg/ml with S9. Significant increases in micronucleated binucleated cells were observed in CHO cells treated with AA at > or = 25 microg/ml with or without S9. These results demonstrated that the genotoxicity of AA would have been easily detected if simple screening versions of in vitro genotoxicity assays had been used during early product development. It is suggested that simplified screening tests such as those used in this study would be a rapid and economical way of obtaining the preliminary genotoxicity profiles of new substances or products as an aid to decision-making for further development.

Animals↗

PubMed2006

Genotoxic potential of medroxyprogesterone acetate in cultured human peripheral blood lymphocytes.

Medroxyprogesterone acetate was studied at three different concentrations (1, 5 and 10 microM), for its genotoxic effects in human peripheral blood lymphocyte culture using chromosomal aberrations and sister chromatid exchanges as parameters. Duplicate peripheral blood cultures were treated with three different concentrations (1, 5 and 10 microM) of medroxyprogesterone acetate. The study was carried out both in the absence as well as in the presence of metabolic activation (S9 mix) with and without NADP. Medroxyprogesterone acetate was found genotoxic at 5 and 10 microM in the presence of S9 mix with NADP. To study the possible mechanism of the genotoxicity of medroxyprogesterone acetate, superoxide dismutase and catalase at different doses were used separately and in combination with 10 microM of medroxyprogesterone at different doses in the presence of S9 mix with NADP. Superoxide dismutase treatment results in an increase of the genotoxic damage but catalase treatment reduce the genotoxic damage of medroxyprogesterone acetate. Catalase treatment in combination with superoxide dismutase also results in the further reduction of the genotoxic damage. The results of the present study reveal that medroxyprogesterone acetate is genotoxic only in the presence of metabolic activation (S9 mix) with NADP. Treatments with superoxide dismutase and catalase suggests the possible generation of reactive oxygen species by redox cycling of various forms of quinones, similar to estrogens, that are the results of aromatic hydroxylation by cytochrome P450s.

Antioxidants↗

PubMed2004

Differentiation of DNA reactive and non-reactive genotoxic mechanisms using gene expression profile analysis.

Genotoxic stress triggers a variety of biological responses including the transcriptional activation of genes regulating DNA repair, cell survival and cell death. Here, we investigated whether gene expression profiles can differentiate between DNA reactive and DNA non-reactive mechanisms of genotoxicity. We analyzed gene expression profiles and micronucleus levels in L5178Y cells treated with cisplatin and sodium chloride. The assessment of cisplatin genotoxicity (up to six-fold increase in the number of micronuclei) and gene expression profile (increased expression of genotoxic stress-associated genes) was in agreement with cisplatin mode of action as a DNA adduct-forming agent. The gene expression profile analysis of cisplatin-treated cells identified a number of genes with robust up regulation of mRNA expression including genes associated with DNA damage (i.e. members of GADD45 family), early response (i.e. cFOS), and heat shock protein (i.e. HSP40 homologue). The gene expression changes correlated well with DNA damage as measured by DNA-protein crosslinks and platinum-DNA binding. To differentiate the genotoxic stress-associated expression profile of cisplatin from a general toxic stress, we have compared the gene expression profile of cisplatin-treated cells to cells treated with sodium chloride, which causes osmotic shock and cell lysis. Although the sodium chloride treatment caused a two-fold induction of micronuclei, the gene expression profile at equitoxic concentrations was remarkably distinct from the profile observed with cisplatin. The profile of sodium chloride featured a complete lack of expression changes in genes associated with DNA damage and repair. In summary, the gene expression profiles clearly distinguished between DNA reactive and non-reactive genotoxic mechanisms of cisplatin and sodium chloride. Our results suggest the potential utility of gene expression profile analysis for elucidating mechanism of action of genotoxic agents.

Animals↗

PubMed2005

Genotoxicity of heat-processed foods.

Gene-environment interactions include exposure to genotoxic compounds from our diet and it is no doubt, that humans are regularly exposed to e.g. food toxicants, not least from cooked foods. This paper reviews briefly four classes of cooked food toxicants, e.g. acrylamide, heterocyclic amines, nitrosamines and polyaromatic hydrocarbons. Many of these compounds have been recognised for decades also as environmental pollutants. In addition cigarette smokers and some occupational workers are exposed to them. Their occurrence, formation, metabolic activation, genotoxicity and human cancer risk are briefly presented along with figures on estimated exposure. Several lines of evidence indicate that cooking conditions and dietary habits can contribute to human cancer risk through the ingestion of genotoxic compounds from heat-processed foods. Such compounds cause different types of DNA damage: nucleotide alterations and gross chromosomal aberrations. Most genotoxic compounds begin their action at the DNA level by forming carcinogen-DNA adducts, which result from the covalent binding of a carcinogen or part of a carcinogen to a nucleotide. The genotoxic and carcinogenic potential of these cooked food toxicants have been evaluated regularly by the International Agency for Research on Cancer (IARC), which has come to the conclusion that several of these food-borne toxicants present in cooked foods are possibly (2A) or probably (2B) carcinogenic to humans, based on both high-dose, long-term animal studies and in vitro and in vivo genotoxicity tests. Yet, there is insufficient scientific evidence that these genotoxic compounds really cause human cancer, and no limits have been set for their presence in cooked foods. However, the competent authorities in most Western countries recommend minimising their occurrence, therefore this aspect is also included in this review.

Acrylamide↗

PubMed2005

Genotoxicity test system based on p53R2 gene expression in human cells: examination with 80 chemicals.

p53R2, which encodes a subunit of ribonucleotide reductase, is activated by DNA damage induced by gamma-ray and ultraviolet irradiation, and also by genotoxic chemicals such as adriamycin. For the purpose of constructing an easy-operating genotoxicity test system using human cell lines, we developed a p53R2-dependent luciferase reporter gene assay, and demonstrated dose-dependent luminescence caused by adriamycin in two human cell lines that express wild-type p53, MCF-7 and HepG2. The performance of this assay system was evaluated with 80 chemicals including those known in the Ames test as genotoxic or non-genotoxic. When the luciferase activity of cells treated with the test sample was over 200% to that of control cells in a dose-dependent increasing manner, the sample was judged positive as a genotoxic chemical. Forty of 43 Ames-positive chemicals induced luciferase activity in this assay system. Eight Ames-negative chemicals also induced luciferase activity. These eight chemicals are genotoxic in other in vitro test systems using mammalian cells. It is suggested that this assay system can be applied to rapid screening of chemicals for potential human genotoxicity.

Dose-Response Relationship, Drug↗

PubMed2006

Report of the IWGT working group on strategies and interpretation of regulatory in vivo tests I. Increases in micronucleated bone marrow cells in rodents that do not indicate genotoxic hazards.

In vivo genotoxicity tests play a pivotal role in genotoxicity testing batteries. They are used both to determine if potential genotoxicity observed in vitro is realised in vivo and to detect any genotoxic carcinogens that are poorly detected in vitro. It is recognised that individual in vivo genotoxicity tests have limited sensitivity but good specificity. Thus, a positive result from the established in vivo assays is taken as strong evidence for genotoxic carcinogenicity of the compound tested. However, there is a growing body of evidence that compound-related disturbances in the physiology of the rodents used in these assays can result in increases in micronucleated cells in the bone marrow that are not related to the intrinsic genotoxicity of the compound under test. For rodent bone marrow or peripheral blood micronucleus tests, these disturbances include changes in core body temperature (hypothermia and hyperthermia) and increases in erythropoiesis following prior toxicity to erythroblasts or by direct stimulation of cell division in these cells. This paper reviews relevant data from the literature and also previously unpublished data obtained from a questionnaire devised by the IWGT working group. Regulatory implications of these findings are discussed and flow diagrams have been provided to aid in interpretation and decision-making when such changes in physiology are suspected.

Aniline Compounds↗

PubMed2006

Follow-up testing of rodent carcinogens not positive in the standard genotoxicity testing battery: IWGT workgroup report.

At the Plymouth Third International Workshop on Genotoxicity Testing in June 2002, a new expert group started a working process to provide guidance on a common strategy for genotoxicity testing beyond the current standard battery. The group identified amongst others "Follow-up testing of tumorigenic agents not positive in the standard genotoxicity test battery" as one subject for further consideration [L. Müller, D. Blakey, K.L. Dearfield, S. Galloway, P. Guzzie, M. Hayashi, P. Kasper, D. Kirkland, J.T. MacGregor, J.M. Parry, L. Schechtman, A. Smith, N. Tanaka, D. Tweats, H. Yamasaki, Strategy for genotoxicity testing and stratification of genotoxicity test results-report on initial activities of the IWGT Expert Group, Mutat. Res. 540 (2003) 177-181]. A workgroup devoted to this topic was formed and met on September 9-10, 2005, in San Francisco. This workgroup was devoted to the discussion of when it would be appropriate to conduct additional genetic toxicology studies, as well as what type of studies, if the initial standard battery of tests was negative, but tumor formation was observed in the rodent carcinogenicity assessment. The important role of the standard genetic toxicology testing to determine the mode of action (MOA) for carcinogenesis (genotoxic versus non-genotoxic) was discussed, but the limitations of the standard testing were also reviewed. The workgroup also acknowledged that the entire toxicological profile (e.g. structure-activity relationships, the nature of the tumor finding and metabolic profiles) of a compound needed to be taken into consideration before the conduct of any additional testing. As part of the meeting, case studies were discussed to understand the practical application of additional testing as well as to form a decision tree. Finally, suitable additional genetic toxicology assays to help determine the carcinogenic MOA or establish a weight of evidence (WOE) argument were discussed and formulated into a decision tree.

Acetamides↗

PubMed2005

Biomonitoring of the genotoxic potential of aqueous extracts of soils and bottom ash resulting from municipal solid waste incineration, using the comet and micronucleus tests on amphibian (Xenopus laevis) larvae and bacterial assays (Mutatox and Ames tests).

The management of contaminated soils and wastes is a matter of considerable human concern. The present study evaluates the genotoxic potential of aqueous extracts of two soils (leachates) and of bottom ash resulting from municipal solid waste incineration (MSWIBA percolate), using amphibian larvae (Xenopus laevis). Soil A was contaminated by residues of solvents and metals and Soil B by polycyclic aromatic hydrocarbons and metals. MSWIBA was predominantly contaminated by metals. Two genotoxic endpoints were analysed in circulating erythrocytes taken from larvae: clastogenic and/or aneugenic effects (micronucleus induction) after 12 days of exposure and DNA-strand-breaking potency (comet assay) after 1 and 12 days of exposure. In addition, in vitro bacterial assays (Mutatox and Ames tests) were carried out and the results were compared with those of the amphibian test. Physicochemical analyses were also taken into account. Results obtained with the amphibians established the genotoxicity of the aqueous extracts and the comet assay revealed that they were genotoxic from the first day of exposure. The latter test could thus be considered as a genotoxicity-screening tool. Although genotoxicity persisted after 12 days' exposure, DNA damage decreased overall between days 1 and 12 in the MSWIBA percolate, in contrast to the soil leachates. Bacterial tests detected genotoxicity only for the leachate of soil A (Mutatox). The results confirm the ecotoxicological relevance of the amphibian model and underscore the importance of bioassays, as a complement to physico-chemical data, for risk evaluation.

Aliivibrio fischeri↗