The 2u-globulin mechanism of renal carcinogenesis is among the richest in data and speculation of all proposed nongenotoxic mechanisms of rodent carcinogenesis. It is therefore critical that advantage is taken of the impetus provided by the recent debate and that this hypothesis is reevaluated according to rigorous scientific criteria. Apart from the obvious need to advance our understanding of the potential carcinogenic hazard implicit in this mechanism, there is the subsidiary question of whether an agent such as limonene is formally required to be active in the TgAC and the p53 mouse abbreviated carcinogenicity bioassays. In fact, the suggested need for such abbreviated carcinogenicity bioassays of limonene would probably flow from a full analysis of the 2u-globulin hypothesis, but that, in turn, would imply that these two assays are already confirmed as giving mechanistically diagnostic data, which they are not. Thus, the importance of resolving the 2u-globulin debate.
Science proceeds by way of informed speculation.
However, such speculations should not become personal property to defend at all costs. Rather, they should be vigorously challenged with the aim of either refuting them or transforming them into generally accepted facts. The sooner that happens with the speculations surrounding the 2u-globulin hypothesis, the better. Melnick RL, Kohn MC, Huff J. Weight of evidence versus weight of speculation to evaluate the 2u-globulin hypothesis. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models.