alpha2u-Globulin nephropathy and ravens: do ravens of a different feather flock together?

differentiate significant and trivial chemical hazards and to assess likely risks to humans. This latter justification can be illustrated by the following statement: if all chemicals that are mutagenic in vitro were mutagenic and carcinogenic to humans, and if all rodent carcinogens posed an equal carcinogenic hazard to humans, then there would be no role for mechanistic studies. The fact that these statements are self-evidently untrue therefore provides the main justification for the conduct of mechanistic studies. The value of the results of mechanistic studies aimed at differentiating hazards should be judged solely in terms of the extent to which they either increase or decrease the level of concern over the potential hazard posed to humans by exposure to the substance under study. Within this context , simple experiments, such as confirming that an in vitro mutagen is also mutagenic in vivo or establishing the effect that changing the route of exposure, or the test species, has on the carcinogenicity of a substance, qualify as mechanistic studies. However, the term is usually reserved for investigations that provide a framework within which the rodent toxicity of a substance can be explained and extrapolated to humans. Loose use of the term mechanistic studies can lead to confusion when the derived results offer no guidance on human hazard assessment. For example, it may be interesting to establish that nitrogen mustard is clas-togenic by virtue of its ability to bind cova-lently with DNA, while the similar activity of etoposide is due to its ability to inhibit topoisomerase II enzymes, but such knowledge is of no value for human hazard assessment in the absence of data indicating that one of these mechanisms of clastogenesis is more relevant to human hazard assessment than the other. This single example indicates that when mechanistic data are invoked to qualify the hazard of a rodent carcinogen, there is a need to discuss the context of those data and to make clear how they should alter our perception of the human hazard implied by the initial test data. To date, there are no examples of a mechanism of cancer induction in rodents that is rigorously established and uniformly accepted as being of no relevance to humans. Further, given the potential for occasional high accidental exposures to chemicals and the existence of human poly-morphisms among the enzymes that activate or detoxify chemicals, and among the enzymes and processes that maintain genetic …