Genetoxic Thresholds

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 methanesuphonate (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 piece of mind to the affected patients and producing a paradigm shift in relation to genotoxin exposures.‌

375 x 187‌‌‌

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. 

Links:

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

References:

  1. Parry JM, Fielder RJ, McDonald A (1994). Guidelines for testing of chemicals: Thresholds for aneuploidy-inducing chemicals. Mutagenesis 9: 503-504.
  2. Parry JM, Jenkins GJS, Haddad F, Bourner R, Parry EM. (2000). In vitro and in vivo extrapolations of genotoxin exposures: consideration of factors which influence dose-response thresholds. Mutation research - genetic toxicology and environmental mutagenesis. 464:53-63.
  3. Jenkins GJS, Doak SH, Johnson GE, Quick E, Waters EM, Parry JM (2005). Do dose response thresholds exist for genotoxic alkylating agents? Mutagenesis 20:389-398. 
  4. Doak SH, Jenkins GJS, Johnson GE, Quick E, Parry EM, Parry JM (2007). Mechanistic influences for mutation induction curves following exposure to DNA-reactive carcinogens. Cancer Research 67:3904-3911. 
  5. Johnson GE, Doak SH, Griffiths SM, Quick EL, Skibinski DO, Zoulikha M Zaïr ZM, Jenkins GJ (2009). Non-linear dose–response of DNA-reactive genotoxins: Recommendations for data analysis. Mutation Research 678:95-100.
  6. Zair M, Jenkins GJ, Doak SH, Singh R, Brown K, and Johnson GE (2011).  N-Methylpurine DNA Glycosylase Plays a Pivotal Role in the Threshold Response of Ethyl Methanesulfonate-Induced Chromosome Damage. Toxicological Sciences 119: 346–358.