Issues in biochemical applications to risk assessment: how do we evaluate individual components of multistage models?

FNational Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709. cess. Both of them will be a carryover of the last two discusslons we've had. The first issue is the so-called first step of transformation, which is the formation of an initiated cell. The formation of an initiated cell is in itself at least a twostep process, and there are many other factors involved. It involves the damage of the DNA either directly or indirectly by the agent. This damage is referred to as promutagenic lesions. In order to obtain an initiated cell, the damage must be fixed by replication. The controversy over the formation of initiated cells is not in the formation of DNA damage but in this fixation step. How can the fixation occur? To bring this into focus with Ray Tennant's discussion (1), when testing mutagenic chemicals with the in vitro test or the Ames test, you obviously do not take the fixation step into account, because the cells of the bacteria are dividing. So if DNA is damaged, mutations are more than likely to occur. However, in the whole animal the fixation step itself could be the limiting step. Jim Swenberg was kind enough to lend me a few slides and I want to illustrate with formaldehyde that you must take this step into account (2). The tumor-response curve obtained with formaldehyde is very nonlinear. I will avoid using the word "threshold," but the slope here is probably approaching zero as the dose decreases. If you look at the promutagenic damage, i.e., the DNA adducts, the DNA adduct levels are fairly linear as you go to lower doses. Assume for purposes of argument that it is linear. Forget that it's formaldehyde. Thus, apparently, the formation of the promutagenic damage alone is not enough. But then, as Jim Swenberg and his co-workers have shown, the induction of cell turnover by formaldehyde is very dose dependent. In fact, the breaks in the tumor curve and in the curve showing the induction of cell turnover are similar. So at lower doses where you saw no tumor response, there was essentially no detectable induction of cell turnover.