[Biomechanism-based innovation of toxicology by the fundamental concept of "Signal Toxicity"]

When Rachel Carson wrote the "Silent Spring" in 1962, the toxicology society was influenced in an indirect way mainly on environmental effects of massive use of pesticides. However, at that time, for those who were studying DDT and other pesticides, the biological effect of such chemicals were understood as a result of their long-lasting toxicants with slow elimination rates from the body; bio- persistency and in some case bio- and environmentally accumulative. And the chronic effects became overt including complex endpoints not only liver toxicity but, reproductive, immune, and neuronal. The impact of Silent Spring on toxicology seems to have established the foundations for scientifically accepting the problems widely raised by the Theo Colborn's "Our stolen future", although its main target was reproductive mechanisms including oestrogen and androgen system. For basic receptor biologists, non-monotonic dose-response curve was a matter of course, but for toxicologists at tnat time, all dose-response curves should be monotonic. With further detailed discussion many toxicologists started to understand that there is a good plausibility that such non-monotonic and low dose effect can happen in wild life and may be in humans under certain conditions. Since then, many toxicologists including us have initiated research on the so-called endocrine disrupting chemicals under new paradigm of receptor mediated- or signal-toxicity. To handle this problem, it became clearer that toxicology has to be innovated towards more biologically mechanistic science. This thinking has linked to the trend of toxicogenomics, where classical pathological findings are used to confirm the results of comprehensive mechanistic analysis data. In contrast our idea of toxicogenomics, designated as Percellome Toxicogenomics Project, was to develop comprehensive and quantitative gene expression networks out of transcriptomic data alone. Existing biological knowledge is used to help understand the biological or toxicological meaning of the generated networks. As a whole, the author would like to outline the strategies to cope with the new paradigms and to combine them to construct a more robust toxicological research system under the concept of "signal toxicity". We believe that this activity should contribute to the development of more comprehensive, faster, cheaper (including less animal to use), and reliable system for the identification, and prediction of toxicity for any kind of agents entering our body and environment.