Commentary on “Evaluation of Possible Carcinogenic Risk to Humans Based on Liver Tumors in Rodent Assays

Abstract

Dr. Cohen’s commentary provides an excellent review of human risk evaluation for rodent liver carcinogens, based on the mode of action (MOA) framework. This approach identifies key steps in the pathogenesis of neoplasia and then determines whether these key steps are likely to occur in humans exposed to the test article. While this provides an excellent basis for assessment of human risk for rodent carcinogens, it does not provide a compelling argument for application in the opposite direction, that is, that all relevant modes of action for all rodent carcinogens have been identified or could be identified in shorter term (e.g., thirteen-week) studies. The two-year rodent bioassay (carcinogenicity study) has recently been criticized as being imprecise and too costly. The costs involve time and animal use as well as monetary costs for laboratory activities and professional evaluation. The bioassay is also criticized as being overly sensitive, lacking specificity, and not necessarily defining human risk. One has to agree that the two-year rodent bioassay is not a perfect model, if one defines a perfect model as having 100% sensitivity and 100% specificity for the target outcome. By that standard, there are no perfect models. Even well-controlled tests in humans are not perfect for outcomes in all humans because of variability in genetic makeup and environment that may not be evident as being relevant a priori. This is more likely to occur when dealing with new molecular targets in pharmaceutical development. The rodent bioassay is a hazard identification tool and does not necessarily provide all information needed for risk assessment. Dr. Cohen reviews the evolution of the MOA framework as applied to rodent carcinogenicity studies and applies this to rodent liver carcinogens. The MOA framework has been applied previously in determining the relative human risk for rodent liver tumors (Holsapple et al. 2006). The application of the MOA framework depends on the identification of key events necessary for development of neoplasms in the rodent model. Note that this is not necessarily the mechanism of action, the actual molecular events associated with primary or secondary alterations in DNA, but key events in the progression of tumor development. Dr. Cohen points out that carcinogenicity is due to two basic processes, direct genotoxicity and nongenotoxic (epigenetic) effects, which result in increased cell replications that lead to an increased chance of spontaneous genetic defects. Potential relevant epigenetic effects also include changes in cell cycle control, genetic repair mechanisms, or signals for cellular differentiation that allow cells with genetic alterations to survive. These effects may not be associated directly with increased cell replications. A basic premise of Dr. Cohen’s argument is that all key events associated with development of liver neoplasms in rodents can be detected in shorter term (thirteen-week) studies (Allen et al. 2004). This is likely correct, at least for all key events identified to date. Since the liver is a common site of carcinogenicity in the rodent, carcinogenic effects in the liver have been extensively studied, and the key events associated with most rodent carcinogens have been identified. It should be noted that the reference Dr. Cohen cites (Allen et al. 2004) involves chemicals in tests in the National Toxicology Program. Most effects of these chemicals are likely associated with chemical toxicity or nonspecific epigenetic events (e.g., enzyme induction) and do not represent novel pharmacologic target mediated events. Dr. Cohen also points out that detection of these changes has high sensitivity but low specificity, which would then be considered to be hazard identification rather than risk assessment. His approach then applies the MOA process to assess potential human cancer risk of these identified key events and may involve additional mechanistic studies. Dr. Cohen’s proposal is in line with the current direction of proposals for improvements in toxicology testing recently proposed by the National Research Council (2007; reviewed by Krewski et al. 2009). This vision of testing is to eventually move to toxicology testing in vitro that tests critical pathways of human toxicity. The envisioned outcome of this exercise Address correspondence to: Gerald G. Long, Experimental Pathology Laboratories Inc, P.O. Box 169, Sterling, VA 20167; e-mail: glong@epl-inc.com. Abbreviations: FDA, Food and Drug Administration; GLP-1, glucagonlike peptide 1; MOA, mode of action; PPAR, peroxisome proliferatoractivated receptor.