Carcinogenesis, Bioassays, and the Regulatory Modus Operandi

Abstract

The major provocative conjecture of Dr. Cohen’s article is contained in the subtitle: ‘‘The Two-Year Bioassay Is No Longer Necessary.’’ I truly wish that I could board this train; I cannot. Neither, however, do I wish to lay on the tracks to derail an attempt to shift from a tired toxicological paradigm: the two-year rodent carcinogen bioassay. The difficulty appears to be the need to accept Cohen’s specific mechanistic views of carcinogenesis for the alternative he suggests to be viable. Everyone would appreciate having at their disposal bioassays that could predict carcinogenesis, mechanisms included, using less time, labor, and treasure than expended by the currently employed two-year rodent models and their kin. Cohen’s proposal here for hepatocellular carcinogens is an approach that might go some distance in reaching that goal after some rethinking. Yet one disturbing exigency comes to mind that might present an impasse: how would quantitative risk assessment or potency ranking be gleaned from short-term studies? The biological unit of time for carcinogenesis is not celestial, but physiologic, best correlated with species life span. The rationale of the two-year rodent studies is that they employ the majority of life span without significant compromise of study viability, which can be thwarted for many reasons. Early nonneoplastic lesions are often considered to be indicators of the eclipse of the viable chronic dose. Moreover, carcinogenesis, per se, will not be adequately realized, either qualitatively or quantitatively, by studies employing only a small fraction of rodent lifetime. I am skeptical that employing early nonneoplastic lesions will give a valid quantitative measure of potency, which should be the primary regulatory parameter. There may also be other technical concerns with Cohen’s approach. They are likely to be with the experimental details and, most importantly, over reaching a consensus on utility. Balanced regulation, guided by risk assessment, is best based on the use of scientific models that have a reasonable level of consensus. To do other than this results in a degree of bickering not compatible with public confidence in science-based regulation. Moreover, one has only to view the history of the Interagency Coordinating Committee on the Validation of Alternative Methods and its international counterparts, European Centre for the Validation of Alternative Methods and the Japanese Center for the Validation of Alternative Methods, to know that it is not just an ephemeral premonition to worry that consensus about alternative models, such as the Cohen proposal, will be elusory. I have more general concerns with Cohen’s approach that I would like to air.