Investigations into the biological relevance of in vitro clastogenic and aneugenic activity.
In the current study we present a view of events leading to chemically induced DNA damage in vitro from both a cytogenetic and molecular aspect, focusing on threshold mediated responses and the biological relevance of DNA damaging events that occur at low and high cellular toxicity levels. Current regulatory mechanisms do not take into account chemicals that cause significant DNA damage only at high toxicity. Our results demonstrate a defined threshold for micronucleus induction after insult with the alkylating agent MMS. Other results define a significant change in gene expression following treatment with chemicals that give rise to structural DNA damage only at high toxicity. Pairs of chemicals with a similar mode of action but differing toxicity levels were chosen, the chemicals that demonstrated structural DNA damage only at high levels of toxicity showed an increase in heat shock protein gene expression whereas the chemicals causing DNA damage events at all levels of toxicity did not induce changes in heat shock gene expression at identical toxicity levels. The data presented indicates that there are a number of situations where the linear dose response model is not appropriate for risk estimation. However, deviation from linear risk models should be dependent upon the availability of appropriate experimental data such as that shown here.
Parry
J M
JM
Centre for Molecular Genetics and Toxicology, School of Biological Sciences, University of Wales Swansea, Singleton Park, Swansea, UK. jmp@swansea.ac.uk
Fowler
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Quick
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Parry
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D000477:Alkylating Agents / Q000494:pharmacology / Q000633:toxicity; D000677:Amsacrine / Q000494:pharmacology / Q000633:toxicity; D000782:Aneuploidy; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000187:drug effects / Q000648:ultrastructure; D003571:Cytochalasin B / Q000494:pharmacology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000633:toxicity; D005047:Etoposide / Q000494:pharmacology / Q000633:toxicity; D020869:Gene Expression Profiling; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000648:ultrastructure; D008741:Methyl Methanesulfonate / Q000494:pharmacology / Q000633:toxicity; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D015125:Oxyquinoline / Q000494:pharmacology / Q000633:toxicity; D012306:Risk; D059005:Topoisomerase II Inhibitors
D000477:Alkylating Agents; D004791:Enzyme Inhibitors; D009153:Mutagens; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D003571:Cytochalasin B; D015125:Oxyquinoline; D006147:Guanine; C008450:7-methylguanine; D005047:Etoposide; D008741:Methyl Methanesulfonate