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PubMed2002

Protection by beverages, fruits, vegetables, herbs, and flavonoids against genotoxicity of 2-acetylaminofluorene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in metabolically competent V79 cells.

Chinese hamster lung fibroblasts, genetically engineered for the expression of rat cytochrome P450 dependent monooxygenase 1A2 and rat sulfotransferase 1C1 (V79-rCYP1A2-rSULT1C1 cells), were utilized to check for possible protective effects of beverages of plant origin, fruits, vegetables, and spices against genotoxicity induced by 2-acetylaminofluorene (AAF) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Antigenotoxic activities of juices from spinach and red beets against AAF could be monitored with similar effectivity by the HPRT-mutagenicity test (IC(50)=0.64%; 2.57%) and alkaline single cell gel electrophoresis (comet assay; IC(50)=0.12%; 0.89%) which detects DNA strand breaks and abasic sites. Applying the comet assay, genotoxicity of PhIP could, however, be demonstrated only in the presence of hydroxyurea and 1-[beta-D-arabinofuranosyl]cytosine, known inhibitors of DNA repair synthesis. As expected, AAF and PhIP were unable to induce any genotoxic effects in the parent V79 cells. Genotoxic activity of PhIP was strongly reduced in a dose-related manner by green tea and red wine, by blueberries, blackberries, red grapes, kiwi, watermelon, parsley, and spinach, while two brands of beer, coffee, black tea, rooibos tea, morellos, black-currants, plums, red beets, broccoli (raw and cooked), and chives were somewhat less active. One brand of beer was only moderately active while white wine, bananas, white grapes, and strawberries were inactive. Similarly, genotoxicity of AAF was strongly reduced by green, black, and rooibos tea, red wine, morellos, black-currants, kiwi, watermelon, and spinach while plums, red beets, and broccoli (raw) were less potent. Broccoli cooked exerted only moderate and white wine weak antigenotoxic activity. With respect to the possible mechanism(s) of inhibition of genotoxicity, benzo[a]pyrene-7,8-dihydrodiol (BaP-7,8-OH) and N-OH-PhIP were applied as substrates for the CYP1A family and for rSULT 1C1, respectively. Morellos, black-currants, and black tea strongly reduced the genotoxicity of BaP-7,8-OH, onions, rooibos tea, and red wine were less potent while red beets and spinach were inactive. On the other hand, red beets and spinach strongly inhibited the genotoxicity of N-OH-PhIP, rooibos tea was weakly active while all other items were inactive. These results are suggestive for enzyme inhibition as mechanism of protection by complex mixtures of plant origin. Taken together, our results demonstrate that protection by beverages, fruits, and vegetables against genotoxicity of heterocyclic aromatic amines may take place within metabolically competent mammalian cells as well as under the conditions of the Salmonella/reversion assay.

2-Acetylaminofluorene↗

PubMed1999

Impact of dimethyl sulfoxide and examples of combined genotoxicity in the SOS chromotest.

The bacterial SOS chromotest with Escherichia coli PQ37 was used for the assessment of genotoxicity of combined xenobiotic treatments. The modulation of test compound genotoxicity by dimethyl sulfoxide (DMSO), a common solvent for test compounds, was assessed as well. It was shown that DMSO modulated SOS chromotest genotoxicity of several xenobiotics: in comparison to test compound dissolution in water, the commonly used addition of 3.2% (v/v) DMSO as solvent lead to a significant increase in the genotoxicity of K(2)RhCl(5) and beta-propiolactone (BPL). However, the effects of cisplatin decreased significantly when DMSO was added. Thus, albeit DMSO is not genotoxic in this test itself, it can interfere with SOS chromotest responses. Further experiments were performed in the absence of DMSO. BPL and cisplatin in combination showed an over-additive synergism in SOS genotoxicity as well as K(2)RhCl(5) and cisplatin did. Addition of Pd(NH(3))(4)Cl(2) and NaAsO(2), which are non-genotoxic in the SOS chromotest, did not enhance the K(2)RhCl(5)- or BPL-mediated SOS sfiA induction. Nevertheless, at the highest subcytotoxic dose of NaAsO(2) tested (200 microM), a slight yet significant suppression of BPL-mediated SOS genotoxicity was observed. These results confirm that the SOS chromotest is a useful tool for the rapid evaluation of the combined genotoxicity of compound mixtures. However, the use of DMSO as test solvent has to be taken with caution.

Cisplatin↗

PubMed1998

The genotoxic hazards of domestic wastes in surface waters.

Despite the noteworthy genotoxic potency of many industrial wastewaters, the genotoxic hazard posed to the downstream ecosystem and its associated biota will be determined by genotoxic loading. Municipal wastewaters, although ranking low in potency, can achieve loading values that are several orders of magnitude greater than those of most industries. Although these wastewaters are generally mixtures of wastes from several different sources, the volumetric proportion of the daily discharge that is of industrial origin rarely exceeds 30%. Genotoxicity calculations for the Montreal Urban Community (MUC) municipal wastewater treatment facility indicate that over 90% of the genotoxic loading (31.1 kg benzo(a)pyrene equivalents per day) is nonindustrial in origin. Moreover, a mass balance of surface water genotoxicity for St. Lawrence river at Montreal indicates that over 85% of the total contributions from the Montreal region are nonindustrial in origin. Additional calculations for the Great Lakes, and other rivers throughout the world, provide further support of a strong relationship between surface water genotoxicity and population. Despite some information about physical/chemical properties, the identity of the putative genotoxins in municipal wastewaters and surface waters remains a mystery. Likely candidates include potent genotoxins, such as N-nitroso compounds and aromatic amines, known to be present in human sanitary wastes, as well as genotoxic PAHs known to be present in many municipal wastewaters. Calculations based on literature data indicate that human sanitary wastes may be able to account for a substantial fraction (4-70%) of the nonindustrial loading from municipal wastewaters. Similar calculations suggest that pyrogenic PAHs that enter municipal wastewaters via surface runoff can only account for a small fraction (<5%) of the genotoxic loading values discussed.

Fresh Water↗

PubMed2000

Genotoxic hazards of azo pigments and other colorants related to 1-phenylazo-2-hydroxynaphthalene.

Azo pigments are used extensively as coloring agents in inks, paints and cosmetics. We have surveyed the literature for genotoxic and cancer data on nine colorants, which are structurally related to 1-phenylazo-2-hydroxynaphthalene (C.I. Solvent yellow 14). C.I. Solvent yellow 14 is metabolized by oxidative and peroxidative enzymes. Metabolically activated C.I. Solvent yellow 14 forms both RNA and DNA adducts. It induces liver nodules in rats upon oral administration. Although there is a mixture of negative and positive findings in short-term tests and in animal cancer studies, C.I. Solvent yellow 14 should be considered genotoxic. C.I. Pigment red 3 should be considered carcinogenic but is only weakly genotoxic. C.I. Solvent yellow 7, C.I. Pigment orange 5, C.I. Pigment red 4, and C.I. Pigment red 23 should be considered genotoxic. C.I. Pigment red 53:1 is not genotoxic, and observations of spleen tumors in male rats but not in female rats or mice seem to be related to toxic effects of high doses of C.I. Pigment red 53:1 in this organ. The data in the literature indicate that Pigment red 57:1 is not genotoxic or carcinogenic. We did not find sufficient data for a relevant evaluation of C.I. Pigment red 2 and C.I. Pigment red 64:1. Some of the colorants have in common the 2-amino-1-naphthol structure. This compound is not genotoxic. On the other hand, reductive cleavage of the azo bonds or hydrolysis of anilido bonds would produce aromatic amines, most of which have been under suspicion for genotoxicity or carcinogenicity. For C.I. Pigment red 53:1 and 57:1, sulphonated aromatic amines would be formed that are not genotoxic.

Animals↗

PubMed2004

A 2.5-year genotoxicity profile for a partially restored polluted river.

This study evaluates water genotoxicity of the Kishon River, the most polluted river in Israel that is under restoration. Water samples were collected every other month (January 2001-May 2003) from five sites, and genotoxicity was assayed by the alkaline comet assay using a fish hepatoma cell line (RTH-149). Genotoxicity in the Kishon River was reduced during 2002 as compared to the previous year. The results further revealed fluctuations in genotoxicity levels at all sites throughout the studied period with variations for the same month during consecutive years and seasonality. In general, summer samples were more genotoxic than winter samples. In the vast majority of the 75 water samples, all four parameters for genotoxicity that were employed revealed significant higher genotoxic levels than the controls. Comet percentage values in Kishon River samples were, on average, 1.8-2.4 times higher than controls. Damage score, comet tail length, and cumulative tail length values were 2.2-3.1, 2.4-3.7, and 2.4-3.7 times higher than controls, respectively. The Histadrut Bridge and Haifa fishing harbor (3.0 m depth) emerged as the most polluted sites, whereas Kiryat Haroshet was the least contaminated. Results call for a long-term genotoxicity follow-up plan at the Kishon River in order to assess the possibly evolving chronic genotoxicity state.

Animals↗

PubMed2002

Appropriate in vitro test conditions for genotoxicity testing of fibers.

With the exception of asbestos fibers, little information is available on genotoxicity testing of fibers (i.e., respirable-sized, fiber-shaped particulates, RFP). In contrast to standard genotoxicity testing of soluble substances, fibers bring about specific problems. Test results can be influenced by fiber dimensions, surface properties, and biopersistence. The mechanisms of fiber-induced genotoxicity are not yet clear, but direct interaction with the genetic material and indirect effects via production of reactive oxygen species (ROS) have been proposed. Asbestos did not significantly induce gene mutations in bacterial and mammalian systems but led to a clear induction of structural and numerical chromosome aberrations in cultured mammalian cells. It is the purpose of this article to critically review positive in vitro genotoxicity data obtained for asbestos in the comet assay, the chromosome aberration test, and the micronucleus test and to identify the test conditions that are specifically required for the detection of asbestos-induced genotoxicity. It is concluded that appropriate cell systems are available for testing fiber-induced genotoxicity. Fiber samples have to be well characterized and phagocytosis and cytotoxic effects have to be determined for the correct interpretation of genotoxicity test results. A combination of the micronucleus test and the comet assay using continuous treatment (without exogenous metabolic activation) seems to be well suited to detect genotoxic activity of asbestos fibers with high accuracy. Further investigations are needed to shown whether this approach can be recommended for genotoxicity testing of fibers in general.

Asbestos↗

PubMed2004

Assessment of the sensitivity of the computational programs DEREK, TOPKAT, and MCASE in the prediction of the genotoxicity of pharmaceutical molecules.

Computational models are currently being used by regulatory agencies and within the pharmaceutical industry to predict the mutagenic potential of new chemical entities. These models rely heavily, although not exclusively, on bacterial mutagenicity data of nonpharmaceutical-type molecules as the primary knowledge base. To what extent, if any, this has limited the ability of these programs to predict genotoxicity of pharmaceuticals is not clear. In order to address this question, a panel of 394 marketed pharmaceuticals with Ames Salmonella reversion assay and other genetic toxicology findings was extracted from the 2000-2002 Physicians' Desk Reference and evaluated using MCASE, TOPKAT, and DEREK, the three most commonly used computational databases. These evaluations indicate a generally poor sensitivity of all systems for predicting Ames positivity (43.4-51.9% sensitivity) and even poorer sensitivity in prediction of other genotoxicities (e.g., in vitro cytogenetics positive; 21.3-31.9%). As might be expected, all three programs were more highly predictive for molecules containing carcinogenicity structural alerts (i.e., the so-called Ashby alerts; 61% +/- 14% sensitivity) than for those without such alerts (12% +/- 6% sensitivity). Taking all genotoxicity assay findings into consideration, there were 84 instances in which positive genotoxicity results could not be explained in terms of structural alerts, suggesting the possibility of alternative mechanisms of genotoxicity not relating to covalent drug-DNA interaction. These observations suggest that the current computational systems when applied in a traditional global sense do not provide sufficient predictivity of bacterial mutagenicity (and are even less accurate at predicting genotoxicity in tests other than the Salmonella reversion assay) to be of significant value in routine drug safety applications. This relative inability of all three programs to predict the genotoxicity of drugs not carrying obvious DNA-reactive moieties is discussed with respect to the nature of the drugs whose positive responses were not predicted and to expectations of improving the predictivity of these programs. Limitations are primarily a consequence of incomplete understanding of the fundamental genotoxic mechanisms of nonstructurally alerting drugs rather than inherent deficiencies in the computational programs. Irrespective of their predictive power, however, these programs are valuable repositories of structure-activity relationship mutagenicity data that can be useful in directing chemical synthesis in early drug discovery.

Computer Simulation↗

PubMed1991

Determination of the genotoxic status of a chemical.

Before a non-genotoxic mechanism of action is proposed for a rodent carcinogen, or predicted for an untested chemical, adequate knowledge of the genotoxic status of the chemical must exist. The current absence of absolute agreement on the set of assays to use when evaluating genotoxicity suggests that a practical approach should be adopted, as outlined, for example, by Arni et al. (1988). In that approach, the chemical is evaluated for gene mutagenicity to Salmonella, for its ability to induce chromosomal aberrations in cultured mammalian cells, and if appropriate, gene mutations in cultured mammalian cells. Consideration of the chemical structure and the expected metabolism of the test chemical also contribute to the classification of an agent as a putative non-genotoxin. Judgement is required when interpreting isolated positive test responses generated in peripheral short-term tests. When attempting to study the mode of action of an established rodent carcinogen that is thought to operate by a non-genotoxic mechanism of action, genotoxicity data generated in vivo, if possible in the target tissue, are of great value. Compounds defined as non-genotoxic by these methods then become candidates for the study of those non-genotoxic toxicities that may predict or explain non-genotoxic rodent carcinogenesis.

Animals↗

PubMed2006

Evidence of genotoxicity related to high PAH content of sediments in the upper part of the Seine estuary (Normandy, France).

In order to characterize the genotoxicity in the Seine estuary and Seine bay, chemical and toxicological analyses were performed on 17 sediments collected in June 2001 and June 2003. Many potent mutagenic and/or carcinogenic compounds - including polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and metals - were detected. Those compounds were found to be at relatively high concentrations in the upper part of the Seine estuary but were barely detectable at sites outside the plume from the Seine. The levels of pollution did not vary significantly between the two sampling periods, except that PAH concentrations in sediments collected at Oissel and Le Havre showed a marked increase in June 2003. The toxicity of organic extracts from sediments was evaluated by both embryotoxicity and in vitro genotoxicity (SOS Chromotest) assays. Organic extracts from sediments taken from the Seine estuary appeared significantly more embryotoxic than those from the Seine bay. In addition, the sediment extracts from the upper part of the Seine estuary exhibited higher genotoxicity than those from the lower part, and no genotoxicity was reported for sediments from the Seine bay. The genotoxic activity was detected only after adding an S9 microsomal fraction, suggesting the preponderant involvement of pro-genotoxic organic compounds. In addition, SOS Chromotest responses obtained with purified organic fractions revealed that PAH and, to a lesser extent, unknown polar organic compounds were probably responsible for this genotoxicity. Altogether, these results suggest that sediments from the upper Seine estuary are genotoxic and embryotoxic, and therefore, could be potentially hazardous for species living or feeding in the area.

Animals↗

PubMed2005

Evaluation of industrial, hospital and domestic wastewater genotoxicity with the Salmonella fluctuation test and the SOS chromotest.

An evaluation of the genotoxic potential of different wastewaters collected in the Rouen area was performed with the SOS chromotest (on Escherichia coli PQ37) and the Salmonella fluctuation test on Salmonella typhimurium strains TA98, TA100 and TA102 with or without metabolic activation. The samples were taken during two 1-week periods, one in January and one in April 2003. Six sites were selected for wastewater sampling in order to allow a comparative study between an area of mixed discharge (industrial, hospital and domestic) and an area of primarily domestic discharge. Out of a total of 71 daytime samples tested, 46 (65%) were positive in at least one assay: 22 samples out of 33 in January (67%), and 24 samples out of 38 in April (63%). The two genotoxicity tests have different sensitivities. Indeed, the Salmonella fluctuation test allowed the detection of 56% of the samples as genotoxic in January (18 out of 33), and 63% in April (24 out of 38) while the SOS chromotest allowed the detection of 18% of the samples as genotoxic, whatever the sampling period. The samples collected in domestic wastewater are at least as genotoxic as the samples collected in mixed wastewater. The possible source of the detected genotoxicity (industrial, hospital or domestic) is discussed. The results of this study show that the different types of wastewaters present a genotoxic risk. Additional studies should be undertaken in the analytical field in order to try to identify and quantify the compounds responsible for the genotoxicity. This difficult task will be necessary in order to identify the sources of toxicants and thus to take preventive and/or curative measures to limit the toxicity of the wastewater.

France↗

PubMed2006

Strategy for genotoxicity testing--metabolic considerations.

The report from the 2002 International Workshop on Genotoxicity Tests (IWGT) Strategy Expert Group emphasized metabolic considerations as an important area to address in developing a common strategy for genotoxicity testing. A working group convened at the 2005 4th IWGT to discuss this area further and propose practical strategy recommendations. To propose a strategy, the working group reviewed: (1) the current status and deficiencies, including examples of carcinogens "missed" in genotoxicity testing, established shortcomings of the standard in vitro induced S9 activation system and drug metabolite case examples; (2) the current status of possible remedies, including alternative S9 sources, other external metabolism systems or genetically engineered test systems; (3) any existing positions or guidance. The working group established consensus principles to guide strategy development. Thus, a human metabolite of interest should be represented in genotoxicity and carcinogenicity testing, including evaluation of alternative genotoxicity in vitro metabolic activation or test systems, and the selection of a carcinogenicity test species showing appropriate biotransformation. Appropriate action triggers need to be defined based on the extent of human exposure, considering any structural knowledge of the metabolite, and when genotoxicity is observed upon in vitro testing in the presence of metabolic activation. These triggers also need to be considered in defining the timing of human pharmaceutical ADME assessments. The working group proposed two strategies to consider; a more proactive approach, which emphasizes early metabolism predictions to drive appropriate hazard assessment; and a retroactive approach to manage safety risks of a unique or "major" metabolite once identified and quantitated from human clinical ADME studies. In both strategies, the assessment of the genotoxic potential of a metabolite could include the use of an alternative or optimized in vitro metabolic activation system, or direct testing of an isolated or synthesized metabolite. The working group also identified specific areas where more data or experiences need to be gained to reach consensus. These included defining a discrete exposure action trigger for safety assessment and when direct testing of a metabolite of interest is warranted versus the use of an alternative in vitro activation system, a universal recommendation for the timing of human ADME studies for drug candidates and the positioning of metabolite structural knowledge (through in silico systems, literature, expert analysis) in supporting metabolite safety qualification. Lastly, the working group outlined future considerations for refining the initially proposed strategies. These included the need for further evaluation of the current in vitro genotoxicity testing protocols that can potentially perturb or reduce the level of metabolic activity (potential alterations in metabolism associated with both the use of some solvents to solubilize test chemicals and testing to the guidance limit dose), and proposing broader evaluations of alternative metabolic activation sources or engineered test systems to further challenge the suitability of (or replace) the current induced liver S9 activation source.

2-Acetylaminofluorene↗

PubMed2000

Genotoxic effects of allyl isothiocyanate (AITC) and phenethyl isothiocyanate (PEITC).

Two isothiocyanates (ITCs) commonly found in human diet, allyl isothiocyanate (AITC) and phenethyl isothiocyanate (PEITC), were tested for genotoxic effects in a battery of assays: Salmonella/microsome assay with TA 98 and TA 100, differential DNA repair assay with E. coli and micronucleus (MN) induction assay with human derived Hep G2 cells. Albeit to a different degree, both ITCs induced genotoxic effects in all test systems. AITC was more genotoxic in bacterial test systems than in Hep G2 cells; in contrast, the effect of PEITC was stronger in Hep G2 cells. In in vivo assays with E. coli indicators in which mice were exposed to relatively high doses of the compounds (90 and 270 mg/kg), AITC induced moderate but significant effects; PEITC failed to induce significant effects in any of the organs. To find out the reason for the weak genotoxicity of AITC and PEITC under in vivo test conditions, we exposed E. coli indicator cells to the test substances in the absence or presence of rat liver homogenate (with and without cofactors), bovine serum albumin (BSA) and human saliva. All of them markedly attenuated the genotoxicity of AITC and PEITC, implying that the test substances are detoxified by direct non-enzymatic binding to proteins. Additional experiments carried out on the mechanistic aspects of AITC and PEITC-induced genotoxicity showed that the compounds induce the formation of thiobarbituric acid reactive substances (TBARS) in Hep G2 cells. Furthermore, in in vitro assays with E. coli, radical scavengers reduced the differential DNA damage induced by AITC and PEITC. The latter two findings give a clue that reactive oxygen species might be involved in the genotoxic effect of the ITCs. Although ITCs have been repeatedly advocated as very promising anticancer agents, the data presented here indicate that the compounds are genotoxic, and probably carcinogenic, in their own right.

Adult↗

PubMed2002

The cytotoxic and genotoxic potential of surface water and wastewater effluents as determined by bioluminescence, umu-assays and selected biomarkers.

Two bacterial tests employing Photobacterieum phosphoreum (Microtox bioluminescence test) and Salmonella typhimurium TA 1535 pSK1002 (umu-assay) were evaluated to estimate the cytotoxic and genotoxic potential of water samples from the selected rivers in Germany as well as the primary and secondary effluents of some sewage treatment plants. Rainbow trout (Onchorynchus mykiss) were exposed to different concentrations (20-40%) of secondary effluent in the model online aquatic monitoring plant WaBoLu-Aquatox. The toxic potential of water samples from the exposure tanks was determined in two prokaryotic test systems and the biomarkers acethylcholinesterase (AChE) activity in muscle tissue and DNA unwinding assay in liver tissue of fish. Samples from the tested rivers showed no inhibition of the bioluminescence of P. phosphoreum or growth of umu-bacteria. Only primary effluent samples from the treatment plants at the Saale River inhibited the light emission or the growth of test bacteria by more than 20%. The induction ratio of umu-bacteria was in most of the river samples less than the threshold for genotoxicity (IR < 1.5). Only some samples from the Saale River, especially at sites downstream of secondary effluents caused genotoxic responses in the umu-assay. Samples of primary effluents contained the greatest genotoxic potential up to GEUI = 6 which was not detectable in samples of secondary effluents. A concentration range 20-40% secondary effluent inhibited AChE activity in muscle tissue and significantly increased DNA fragmentation in liver tissue of rainbow trout. In contrast, no cytotoxic or genotoxic responses in the umu-assay were caused by water samples. Both bacterial methods can be successfully used to analyse the cytotoxic and genotoxic response of industrial and domestic wastewater and to estimate the effectiveness of sewage treatment units. However, because of their low sensitivity and high susceptibility, they are not reliable as a single test for the detection of cytotoxicity and genotoxicity in surface water. The application of prokaryotic tests systems with biomarkers such as AChE activity and DNA fragmentation in different tissues of test organisms seems to be a useful combination for the assessment of cytotoxic and genotoxic potential in surface water and secondary effluent.

Acetylcholinesterase↗

PubMed1996

Evaluation of the genotoxicity potential (by Mutatox test) of ten pesticides found as water pollutants in Cyprus.

Ten pesticides: aldicarb, aldicard sulfone, aldicarb oxide, carbofuran, propoxur, methomyl, diuron, linuron, alachlor and parathion-methyl, found as water pollutants in Cyprus, were evaluated for their genotoxicity potential with the Mutatox test, both directly and after exogenous activation with S9 hepatic enzymes. A dark variant (M 169) of the Photobacterium phosphoreum was used as the test organism. Trials were undertaken in triplicate using ground-water spiked with pesticides solutions at testing concentration theoretically corresponding to acute effects of 0.004%, up to a maximum of 2%. All tested pesticides were found to be 'suspect genotoxic' directly and after S-9 activation, except for Alachlor which after S-9 activation was found to be 'genotoxic' at 30 micrograms/l. Among the ten pesticides Linuron was found to be 'suspect genotoxic' after S-9 activation at the lowest concentration, i.e. 2 micrograms/l. Genotoxicity after activation with S-9 was demonstrated at a concentration 1-3 orders of magnitude lower than the respective concentration for direct genotoxic effects. Moreover, genotoxicity after S-9 was developed at levels where the acute toxic effects (Microtox) were 'non measurable' to 'negligible'. The investigation of possible genotoxic effects provides essential information on the impacts of pesticides on the Ecosystem and can contribute to the selection of pesticides with the least possible effects.

Animals↗

PubMed1996

Detection of genotoxic activity in native hospital waste water by the umuC test.

The genotoxic potential of the waste water of a hospital was evaluated by the umuC test. Within 2 years over 800 native waste water samples were analysed. Genotoxic activity was found in 13% of the samples. The highest genotoxic activity occurred in the morning hours, but genotoxic samples were detected also during the day and at night. 96% of the genotoxic waste water samples revealed a genotoxic potential without growth inhibition of test bacteria monitored as OD600, in the same way as antineoplastic drugs like mitomycin C or cisplatin. 4% of the genotoxic waste water samples showed combined cytotoxic and genotoxic activities as seen in control experiments using glutaraldehyde containing disinfectants and certain antibiotics.

Bacterial Proteins↗

PubMed2001

Investigation of the role of the 2',3'-epoxidation pathway in the bioactivation and genotoxicity of dietary allylbenzene analogs.

The genotoxic potential of naturally occurring allylbenzene analogs, including safrole, eugenol, estragole, and others, has been examined in many studies over the past 30 years. It has been established that these compounds are subject to biotransformation in the liver, which can lead to the formation of reactive electrophilic intermediates. The major route of bioactivation is via hydroxylation of the 1' carbon atom of the allylic side chain. We have synthesized 2',3'- (allylic) epoxide derivatives of allylbenzene, estragole eugenol and safrole, and have used them to characterize the genotoxic potential of epoxidation at the allylic double bond for allylbenzene and its naturally occurring analogs. In order to assert that this pathway has the potential for genotoxicity, it is necessary to demonstrate (1) that epoxide metabolites of these compounds are capable of forming covalent adducts with DNA bases; and (2) that these epoxide metabolites are actually formed in vivo. We have demonstrated that allylic epoxides derived from allylbenzene and estragole are capable of forming covalent adducts with all four deoxyribonucleotides in vitro and, in the case of deoxyguanosine, form at least four different adducts. We also deduce, from evidence obtained using the isolated perfused rat liver, that formation of potentially genotoxic 2',3' epoxide metabolites occurs readily in vivo, but that these metabolites are rapidly further metabolized to less toxic dihydrodiol or glutathione conjugates. We conclude that 2',3' epoxide metabolites of allylbenzene analogs are formed in vivo and that these epoxides are sufficiently reactive to facilely form covalent bonds with DNA bases. Epoxide formation at the allylic double bond represents, therefore, a potentially genotoxic bioactivation pathway for allylbenzene analogs. However, comparison of the relative kinetics of epoxide metabolism and epoxide formation suggests that a wide margin of protection from DNA covalent adduct formation exists in the rat liver, thus preventing genotoxicity resulting from this pathway to any significant degree. In this regard, we have also observed that the general rate of epoxide hydrolysis is much greater in human liver than in rat liver. We therefore suggest that while the epoxidation pathway poses a potential genotoxic threat to humans, no actual genotoxicity occurs as a result of this metabolic pathway.

Animals↗

PubMed2002

Genotoxicity risk assessment: a proposed classification strategy.

Recent advances in genetic toxicity (mutagenicity) testing methods and in approaches to performing risk assessment are prompting a renewed effort to harmonize genotoxicity risk assessment across the world. The US Environmental Protection Agency (EPA) first published Guidelines for Mutagenicity Risk Assessment in 1986 that focused mainly on transmissible germ cell genetic risk. Somatic cell genetic risk has also been a risk consideration, usually in support of carcinogenicity assessments. EPA and other international regulatory bodies have published mutagenicity testing requirements for agents (pesticides, pharmaceuticals, etc.) to generate data for use in genotoxicity risk assessments. The scheme that follows provides a proposed harmonization approach in which genotoxicity assessments are fully developed within the risk assessment paradigm used by EPA, and sets out a process that integrates newer thinking in testing battery design with the risk assessment process. A classification strategy for agents based on inherent genotoxicity, dose-responses observed in the data, and an exposure analysis is proposed. The classification leads to an initial level of concern for genotoxic risk to humans. A total risk characterization is performed using all relevant toxicity data and a comprehensive exposure evaluation in association with the genotoxicity data. The result of this characterization is ultimately used to generate a final level of concern for genotoxic risk to humans. The final level of concern and characterized genotoxicity risk assessment are communicated to decision makers for possible regulatory action(s) and to the public.

Animals↗

PubMed1997

Genotoxicity induced in human lymphoblasts by atmospheric reaction products of naphthalene and phenanthrene.

The genotoxic risks from exposure to polycyclic aromatic hydrocarbons (PAH) have long been recognized. Less well understood are the potential genotoxic risks of the atmospheric reaction products of this class of compounds. In this investigation, we have utilized several human cell genotoxicity assays to evaluate naphthalene, phenanthrene, and their atmospheric reaction products 1-nitronaphthalene, 2-nitronaphthalene, 1-hydroxy-2-nitronaphthalene, 2-hydroxy-1-nitronaphthalene, 1,4-naphthoquinone and 2-nitrodibenzopyranone. In addition, reaction products of naphthalene were generated in a 6700-1 Teflon environmental chamber, collected on a solid adsorbent, extracted and fractionated by normal-phase HPLC. Individual fractions were then analyzed using GC-MS, and tested for genotoxicity. Genotoxicity was determined using the human B-lymphoblastoid cell line, MCL-5, which expresses several transfected P450 and epoxide hydrolase genes. Mutagenicity was evaluated at both the heterozygous tk locus and the hemizygous hprt locus, permitting detection of both intragenic and chromosomal scale mutational events. Test compounds were also screened using the CREST modified micronucleus assay. Genotoxicity results indicate that 2-nitronaphthalene and 2-nitrodibenzopyranone possess greater mutagenic potency than their parent compounds, and interestingly, both compounds induced significant increases in mutation frequency at tk but not hprt. These results suggest a mechanistic difference in human cell response as compared to bacteria, where both compounds were previously shown to induce point mutations in the Salmonella reversion assay. The genotoxicity of 2-nitronaphthalene and 2-nitrodibenzopyranone in human cells, together with their high concentrations in ambient air relative to nitro-PAH directly emitted from combustion sources, emphasizes the need to consider atmospheric reaction products of PAH in genotoxicity assessments.

Air Pollutants↗