Testing chemicals used in the pharmaceutical, agrochemical, and consumer products industries for their potential to cause cancer (carcinogenicity testing) uses large numbers of animals. This can involve up to 800 rodents for each substance, with approximately 12,500 animals used annually in Great Britain. The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) has awarded two grants, totalling almost £900,000, to Professor Robert Newbold from Brunel University and Professor Gareth Jenkins from Swansea University to develop new testing methods based on human cells which will substantially reduce the numbers of animals used in coming years.
The need to find alternative methods for assessing cancer risk that are faster, more efficient and have reduced reliance on animals is urgent. The current carcinogenicity studies are time consuming and expensive and are of limited practicality for use for large scale chemical evaluation programmes such as REACH, the European Union regulation concerning the Registration, Evaluation, Authorisation and restriction of Chemicals. Moreover, the latest amendment to the EU Cosmetics Directive prescribes a ban on animal testing of all cosmetic ingredients.
Rodent cell-based in vitro assays for detecting a chemical’s potential to damage DNA and/or cause mutations (genotoxicity assays) are already used in regulatory carcinogenicity testing strategies, but they have limitations as stand alone tests. They have a high rate of misleading positives (where chemicals that do not damage DNA in vivo are wrongly classified as potental carcinogens), requiring animal experiments for clarification. These tests also do not detect chemicals that cause cancer in other (non-DNA damage related) ways. Cell transformation assays based on rodent cells have been proposed for identifying genotoxic and non-genotoxic carcinogens, but because the mechanisms by which chemicals transform cells in these assays are poorly understood, they are not currently accepted for regulatory purposes.
Professor Newbold will work with collaborators from Queen Mary University of London, AstraZeneca and the Lawrence Berkeley National Laboratory, University of California USA, to develop new tests for carcinogenic chemicals based on human cells. The tests will monitor the effects of these chemicals on the two key biochemical processes that cause cells to bypass critical barriers that would normally cause them to age and die. This cell aging process, known as senescence, is considered to be a major safeguard in our cells that protects us against cancer.
Professor Jenkins plans to study how chemicals interrupt the mechanisms by which cells communicate with each other, and to combine this information with data from currently used in vitro genotoxicity assays to provide a better prediction of which chemicals are potential carcinogens. The study, which is being conducted in collaboration with Roche and GE Healthcare, will also consider how harmful chemical doses that cause effects in vitro can be extrapolated to doses likely to cause effects in vivo in man.
Dr Vicky Robinson, Chief Executive of the NC3Rs said: “Each year the NC3Rs strategic grants programme focuses on an area of biological research where there is a real need to advance one or more of the 3Rs (Replacement, Reduction and Refinement of animal use). Carcinogenicity testing uses large numbers of animals and currently relies on inefficient and expensive testing methodologies; our grants to Professors Newbold and Jenkins will deliver tests that will benefit both animals and the industries in which they are used.”
Dr Elmar Gocke, Group Head Genotoxicology, Non-clinical Safety, from F Hoffmann-La Roche, who is collaborating with Gareth Jenkins’ work said: “In the pharmaceutical industry, genetic toxicity testing plays an important role in screening out chemical structures that might damage the genetic material. Test results are crucial in determining the relevance to human exposure. However, the accumulation of confusing in vitro or in vivo test results can hamper, rather than aid, progress in devising new treatments. Our work with Professor Jenkins will contribute to a better understanding of the carcinogenetic processes leading to more cogent risk assessments.”
Notes for Editors:
For more information contact the NC3Rs media office.
- The NC3Rs is a scientific organisation which leads the discovery, development and promotion of new ways to replace, reduce and refine the use of animals in research and testing (the 3Rs). It is primarily supported by Government, but also receives funding from the charitable and industrial sectors. The centre has an annual budget of approximately £5.5 million and is the UK’s major funder of 3Rs research. Further information about the NC3Rs can be found at www.nc3rs.org.uk