Genotoxic compound

Although trichloroethylene itself may not be genotoxic, several of its metabolites are reactive and potentially genotoxic compounds (Miller and Guengerich 1982). Several isomers of 1,2-dichlorovinyl-cysteine, a product of trichloroethylene metabolism in the kidney, are mutagenic in the in vitro Ames assay... 

Fernandez P, M Grifoll, AM Solanas, JM Bayiona, J Albalges (1992) Bioassay-directed chemical analysis of genotoxic compounds in coastal sediments. Environ Sci Technol 26 817-829. 

One especially successful method of testing complex mixtures is bioassay-directed fractionation followed by chemical identification of active compounds. Until now this method has mainly been used for the testing and identification of genotoxic compounds in environmental mixtures such as extracts of air particulates, exhaust condensates, and cooked foods. In this approach, each fraction is bioassayed untd the major class of specihc chemical(s) responsible for the activity can be isolated and chemically characterized, which make a risk assessment of the mixture possible. 

However, concern would remain if a genotoxic compound induces tumours only at doses above 25-fold exposure over human exposure. 

Fibrillar structures (presence) Fibr Possible genotoxic parameter Genotoxic compounds Liver tissue 16-32... 

With the carcinogenic and mutagenic properties of certain key airborne PAHs and PACs as background, let us now examine the contributions of these genotoxic compounds to the bacterial and human cell mutagenicities of ambient air. 

Genotoxic compounds are those which are capable of causing genetic damage by interaction with DNA. Examples of genotoxic endpoints are chromosome aberrations (CA), sister chromatid ex-... 

Unequivocally genotoxic compounds, in the absence of other data, that are presumed to be transspecies carcinogens, implying a hazard to humans (chronic toxicity of up to 1 year may be needed if drug is intended to be used chronically to detect early tumorigenic effects)... 

Detects spectrum of weakly to strongly genotoxic compounds ... 

Unequivocally genotoxic compounds need not to be subjected to longterm carcinogenicity studies. However, if such a drug is intended to be administered chronically to humans a chronic toxicity study (up to one year) may be necessary to detect early tumorigenic effects. In practice, this option has not been used since 1997. Main concern of industry is the lack of historical comparison data. The tumor evaluation was always based on 2 year data. 

The effects of genotoxic compounds are considered non-threshold. Thus, risk assessment for a given exposure is usually performed by a linear or sub-linear extrapolation from the high dose effects observed in animals to the lower human exposure. Since the outcome of the extrapolation depends on the model applied and extrapolation over different orders of magnitude is error prone, the European Food and Safety Authority (EFSA 2005) recommended to avoid this extrapolation and proposed the MOE approach. This approach uses the benchmark dose, or the T25 calculated from a carcinogenicity study and compares this with human exposure. A MOE of 10,000 and more is considered to be of minor concern. The advantage is that neither a debatable extrapolation from high to low doses needs to be performed nor are hypothetical cancer cases calculated. For details of the different approaches see, SCHER, SCCP, SCENIHR (2008). 

Apoptosis is induced by a variety of stimuli, such as genotoxic compounds, tumor necrosis factor, Eas ligand, and various environmental stresses. Despite the diversity of apoptosis-inducing agents, numerous experiments indicate that signals leading to the activation of members of the intracellular cysteine protease family, for instance, the caspase, may play a pivotal role in the initiation and execution of apoptosis induced by various stimuli. ... 

A number of short-term tests can be used to determine the genotoxic potential of chemicals. These tests use both prokaryotic and eukaryotic cells and measure such end points as gene mutations, chromosomal aberrations, and interactions with critical macromolecules It is widely recognized chat no test can detect all genotoxic compounds, and multiple end points are required to provide a reliable assessment of genotoxiclty. Information from several tests can be combined to reveal two important toxic effects carcinogenesis and mutagenesis. 

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