Genotoxicity Assessment Methods

It is tempting to classify all in vivo techniques as risk-assessment methods. For example, host-mediated-type studies have been incorrectly assumed to be more applicable to risk assessment than related in vitro studies. This is not necessarily true, since the genotoxic end points are still measured by in vitro test systems coupled with the animal host, and therefore the data are still valid only to detect potential. Attributing greater relevance to such tests may result in erroneous conclusions regarding safety or risk. Actually, there are very few practical risk-assessment assays available to evaluate genotoxicity, and our ability to extrapolate results from these to humans is uncertain, since evidence demonstrating mutation induction in humans is technically not possible. 

For some substances, a wealth of genotoxicity data may be available from studies conducted in vitro and/or in vivo. In addition to studies conducted according to test guidehne methods, there may be nonstandard studies available in which first site of contact tissues, i.e., skin, epithelium of the respiratory or gastrointestinal tract, have been examined. In addition, data from plant, fungal, or insect Drosophila) systems may be available. Occasionally, studies of genotoxic effects in humans may also be available. The vahdity and usefulness of each of the data sets to the overall assessment... 

Gronlund (1992) has investigated methods used for quantitative risk assessment of non-genotoxic substances, with special regard to the selection of assessment factors. Gronlund found that humans, in most cases, seem to be more sensitive to the toxic effects of chemicals than experimental animals, and that the traditional 10-fold factor for interspecies differences apparently is too small in order to cover the real variation. It was also noted that a general interspecies factor to cover all types of chemicals and all types of experimental animals cannot be expected. It was concluded that a 10-fold factor for interspecies variability probably protects a majority, but not all of the population, provided that the dose correction for differences in body size between experimental animals and humans is performed by the body surface area approach (Section 5.3.2.2). If the dose correction is based on the body weight approach (Section 5.3.2.1), the 10-fold factor was considered to be too small in most cases. 

Gronlund (1992) has investigated methods used for quantitative risk assessment of non-genotoxic substances, with special regard to the selection of assessment factors. Gronlund found that the 10-fold factor suggested for interindividual variability probably protects a majority but not all of the population. 

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. 

Fernandez, M., L Haridon, J., Gauthier, L. Zoll-Moreux, C. (1993) Amphibian mieronueleus test(s) a simple and reliable method for evaluating in vivo genotoxic effects of freshwater pollutants and radiations. Initial assessment. Mutat. Res., 292, 83-99... 

The outputs from risk assessment will normally include information about the relationship between dose and risk and estimates of levels of doses and thus risks in the population. For contaminants that have a toxicological threshold the Provisional Tolerable Weekly Intake (PTWI) might be defined and the number of consumers who have the potential to exceed this level of intake quantified. If a PTWI cannot be established (such as for genotoxic carcinogens) then it may be possible to quantify the proportion of a population exposed to a given level of risk by using QRA methods. If QRA methods cannot be applied then a qualitative assessment can be made such as to reduce intake levels to as low as is reasonably practicable. In either case it is the function of risk management to identify an optimal course of action to minimise the risk to consumers. 

Snyder RD, Pearl GS, Mandakas G, Choy WN, Goodsaid F, Rosenblum IY (2004) Assessment of the sensitivity of the computational programs DEREK, TOPKAT and MCASE in the prediction of the genotoxicity of pharmaceutical molecules. Environ Mol Mutagen 43 143-158 Todeschini R, Consonni V (2000) Handbook of Molecular Descriptors. In the series of Methods and Principles in Medicinal Chemistry, Vol. 11. Wiley VCH Weinheim... 

Numerous test methods are available for assessing the genotoxic potential of substances. There are essentially three main categories of genotoxic damage that can be caused by a substance ... 

Novel methods to detect effects at population level. Ecogenotoxicology has been described as an approach that applies the principles and techniques of genetic toxicology to assess the potential of environmental pollution, in the form of genotoxic agents, on the health of the ecosystem (Shugart and Theodorakis,... 

In this context, this chapter is meant to review the existing in vitro testing methods and update on the emerging in vitro approaches for the assessment of genotoxicity and carcinogenicity. 

The aim of this chapter is to review the existing in vitro tests for the assessment of genotoxic and carcinogenic hazard and novel methods and approaches currently under development. 

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