Introduction of the concept of “safe” genotoxin exposure levels and how this benefitted patients and the pharmaceutical industry
Swansea-led work on “genotoxic thresholds” provided peace of mind to 25,000 patients who took anti-viral tablets (Viracept) contaminated with the genotoxin ethyl methanesulphonate (EMS). This work concurrently under-pined changes to regulatory guidelines for drug assessment with respect to low dose exposures to genotoxins. Genotoxins are the term for chemicals (and physical agents like radiation) that damage DNA, DNA damage leads to cancer and so genotoxin exposures are in general not a good thing.
Previously (before 2008), genotoxicity was assumed to be linear with respect to drug dose and genotoxic drugs were discarded. This was based on the precautionary principle as no one really understood low dose effects. Our research on low dose exposures to carcinogenic genotoxins validated genotoxic thresholds - low level genotoxic exposures do not pose significant risks to DNA. This is now incorporated into worldwide regulatory guidelines. The Viracept incident (where a Roche drug was found to be contaminated with very low levels of a potent genotoxic carcinogen) tested this threshold approach. The European Medicines Agency (July 2008) accepted that there was no long term risk to patients who received contaminated tablets, thus providing peace of mind to the affected patients and producing a paradigm shift in relation to genotoxin exposures.
Dose-response relationships for DNA damage/mutation (y-axis) and dose (x-axis). The solid line represents the linear dose-response that has been widely accepted to exist, although it has been extrapolated from high doses without any low dose data. The dotted line represents the threshold dose response that we have proven to exist for some DNA damaging agents, by specifically looking at the low dose region.
Contamination of Roche’s drug Viracept causes worldwide concern: http://www.irinnews.org/report/72816/zambia-aids-drug-recall-creates-panic)
EM(E)A document with conclusions of Viracept incident with numbers of patients affected:http://www.emea.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/11/WC500015048.pdf
European Food standards Agency (EFSA) report on genotoxicity and the fact that thresholds exist, citing role of Swansea in genotoxic threshold story: http://www.efsa.europa.eu/en/efsajournal/pub/2379.htm
General overview of Viracept case: http://www.aidsrestherapy.com/content/6/1/18
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