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  • How serious is the adverse effect that might be predicted? Mutagenicity in many assays, DNA damage in human cells, cell transformation, and production of DNA adducts in vitro are evidence of higher levels of concern, especially for potential carcinogenesis. Evidence of enzyme induction without DNA damage or mutagenesis is of lesser concern.

  • Does the evidence provide mechanistic or mode of action information which lends biological plausibility to effects observed in humans or animals?

  • Is the mechanism or mode of action consistent with the type of effect, caused by similar substances, such as plants in the same family?

  • Is there information suggesting that the concentrations used in vitro are relevant or irrelevant? Concern should increase if the active ingredient and/or metabolite of concern reach relevant concentrations in blood or tissue (see Chapter 3).

  • Is there consistency in more than one assay?

The answers to these questions determine the appropriate level of concern, as described in Table 7-1. Information such as that in the right column warrants higher levels of concern about public safety and risk of consumption. In vitro information such as that described in the left column warrants lower levels of concern, while information described in the middle column warrants concern, but additional information may be required to warrant conclusion that a risk exists.

ANNEX 7-1 USE OF GENETIC TOXICOLOGY INFORMATION

Genetic toxicology is the study of the ability of substances to cause selective damage to the DNA of living organisms (or RNA in the case of RNA viruses). In addition to providing the raw materials for evolution, genetic alterations are associated with a large proportion of human diseases, including cancer. Chromosomal aberrations, such as deletions, inversions, and translocations, have been associated with leukemia, lymphoma, and some solid tumors.

The term genotoxic is applied to substances (or physical agents like ultraviolet light or X-rays) that have an intrinsic ability to damage DNA (not simply due to gross toxicity that may secondarily result in damage to DNA). Different genotoxicants interact with DNA in different ways, cause different types of DNA alterations, and can be detected using different assay systems (Preston and Hoffmann, 2001).

For example, substances that cause heritable changes in DNA sequence are called mutagens. A mutation may result from an alteration in a single DNA base or addition or deletion of one or more DNA bases (point muta-



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