The goal of human risk assessment is to decide whether a given exposure level to a particular chemical or substance is acceptable to human health, and to provide risk management measures based on an evaluation and prediction of the effects of that exposure on human health. Within this framework, the current safety paradigm for assessing possible carcinogenic properties of drugs, cosmetics, industrial chemicals and environmental exposures relies mainly on in vitro genotoxicity testing followed by 2-year bioassays in mice and rats. This testing paradigm was developed 40 to 50 years ago with the initial premise that ¿mutagens are also carcinogens¿ and that the carcinogenic risk to humans can be extrapolated from the tumor incidence after lifetime exposure to maximally tolerated doses of chemicals in rodents.
Genotoxicity testing is used as a surrogate for carcinogenicity testing and is required for initiation of clinical trials (Jacobs and Jacobson-Kram 2004) and for most industrial chemicals safety assessment. Although the carcinogenicity-testing paradigm has effectively protected patients and consumers from introduction of harmful carcinogens as drugs and other products, the testing paradigm is clearly not sustainable in the future. The causal link between genetic damage and carcinogenicity is well documented; however, the limitations of genotoxicity/carcinogenicity testing assays, the presence of additional non-genotoxic mechanisms, issues of species-specific effects, and the lack of mechanistic insights provide an enormous scientific challenge.
The 2-year rodent carcinogenicity bioassays are associated with technical complexity, high costs, high animal burden as well as the uncertainty associated with extrapolating from rodents to humans. Additional frustrations exist because of the limited predictability of the 2-year bioassay and, in particular, with regard to the problem of the prediction of false positives. For instance, in the Carcinogenic Potency Project DataBase (CPDB) which includes results from chronic, long-term animal cancer tests with mice, rats, hamsters amounting to a total of 6540 individual experiments with 1547 chemicals, 751 of those chemicals or 51% have positive findings in rodent studies. Similarly, when one considers all chronically used human pharmaceuticals, some 50% induce tumors in rodents. Yet only 20 human pharmaceutical compounds have been identified as carcinogens in epidemiological studies, despite the fact that quite a large number of epidemiological studies have been carried out on these compounds, e.g. NSAID¿s, benzodiazepines, phenobarbital. This high incidence of tumors in bioassays has lead to questions concerning the human relevance of tumors induced in rodents (Knight et al. 2006; Ward 2008).
In summary, dependency on the rodent model as a golden standard of cancer risk assessment is neglecting the high number of false positives and clearly has serious limitations. Consequently, there is a growing appeal for a paradigm change after "50 years of rats and mice". For instance, the current demands for volume of carcinogenic testing together with limitations of animal usage as initially stipulated by REACH (Combes et al. 2006) will require revolutionary change in the testing paradigm.
For the purpose of developing a road map for this needed paradigm change in carcinogenicity testing, a workshop was held in August 2009 in Venice, Italy entitled ¿Genomics in Cancer Risk Assessment.¿ This workshop brought together toxicologists from academia and industry with governmental regulators and risk assessors from the US and the EU, for discussing the state-of-the-art in developing alternative testing strategies for genotoxicity and carcinogenicity, thereby focusing on the contribution from the ¿omics technologies. What follows is a highlight of the major conclusions and suggestions from this workshop as a path forward.
PAULES Richard S.;
AUBRECHT Jiri;
CORVI Raffaella;
GARTHOFF Bernward;
KLENJANS Jos;
2011-06-20
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
JRC58732
0091-6765,
https://publications.jrc.ec.europa.eu/repository/handle/JRC58732,
10.1289/ehp.1002735,
