Issues in biochemical applications to risk assessment: can in vitro studies assist us in species extrapolation?

Abstract

Then take the sites where the compound X induced tumors and use tissues or isolated cells from those tissues in a short-term assay to determine whether compound X induces mutations, DNAdamage, DNArepair, or any of a number of other end points for short-term assays, such as induction of aneuploidy. One can take all of the short-term tests that can be done to assess genotoxicity, take the tissues from the rodents or any other laboratory animal, explant those tissues, and see what one can learn from the in vitro estimates of genotoxicity to make an extrapolation based on actual data from the in vitro studies back to the in vivo studies, knowing full well that compound X did induce tumors in the animal. To find out whether compound X could induce tumors in the human, the protocol is very simple. One would take the tissues of interest from human donors and do exactly the same types of short-term assays as one can do with the rodent tissues to investigate DNA damage, DNA repair, mutagenesis, or other short-term assays. The types of tissues which are available for genotoxicity research in short-term assays include most of the epithelial tissues from the human, the tissues which are the sites in the body where most cancer occurs. Therefore, taking epithelial tissues and explanting those tissues or isolating cells from those tissues for use in a variety of short-term tests is useful. In Curt Harris' review of this topic, he discussed the techniques for explanting the epithelial tissues and indicated that cells isolated from many of these tissues could grow in primary culture in a clonal manner. One obvious exception to that generality is the liver. I don't think that there really is any cell culture methodology for clonal growth of rat or human liver currently available. But the point is that one can make risk assessment from the short-term assays if one can scientifically and logically extrapolate in vitro studies back to the in vivo situation. The suggestion I will use as a springboard into the discussion for the entire group is that I believe that human cells will be useful for risk assessment purposes if certain criteria are met. Extrapolation of genetic toxicology data from in vitro Introduction