Introduction to the concept of signal toxicity.

Silent Spring by Rachel Carson (1962) established a role for environmental chemicals in cancer and Our Stolen Future by Theo Colbone, Dianne Dumanoski and John Peterson Myers (1996) coined the concept of "Endocrine Disrupting Chemicals (EDCs)" with its mechanistic plausibility for all the living organisms. For basic biologists, seeing a non-monotonic dose-response curve was a matter of course. In contrast, for the toxicologists at that time, the dose-response curves should be monotonic. It took some time for toxicologists to accept the plausibility that animals and humans are subject to the effects of EDCs act in a way that is explained by the new paradigm of receptor-mediated toxicity or in other words "signal toxicity." In classical toxicology, a toxic substance reaches a cellular target and induces malfunction. The target molecules are proteins including enzymes, lipid membranes, DNA, and other components of the cell which are damaged by the toxic substances. On the other hand, in the case of signal toxicity, a chemical binds to a specific receptor - after that, the chemical itself is not important. The signal from the receptor initiates a cascade of molecular events that leads to various changes in the cells and organs. When the signal is abnormal for a cell or an organ in terms of quality, intensity and timing, then the signal will induce adverse effects to the target. An extreme example of signal toxicity is the 1981 Nobel Prize in Physiology or Medicine work by Drs. Hubel and Wiesel. They blocked the signal of sharp images from the retina to the brain and found that the visual cortex needed this signal at the correct time for its proper development. In humans, such signal disruption is well known to induce "form-deprivation amblyopia" in infants. The concept of signal toxicity widens the range of systems vulnerable to EDCs and facilitates the understanding of their biological characteristics. For example, compared with intrinsic ligands, xenobiotic chemicals usually act as weak agonists and/or weak antagonists of receptor systems; the dose-response characteristics and the dose range will depend on the signaling system of concern. If the signal is used for organogenesis and functional maturation, there would be a critical period in the development during which the disturbance of such signals may cause irreversible changes. Since recepter-based signaling mechanisms are usually an amplification systems, it is hard to set a threshold in its dose response, and the outcome of signal toxicity is often stochastic at low doses. This review attempts to explain the benefits of incorporating the concept of signal toxicology for widening the range of toxicology for the better protection of human and environmental health in modern civilized life, where chemicals are designed to be less toxic in terms of traditional toxicity but not yet in "signal toxicity."