PARADOXICAL DOSE-RESPONSE EFFECTS OF FLUORIDE In dealing with concentration or dose-response effects in biological sys-

In dealing with concentration or dose-response effects in biological systems, one usually expects to find fairly regular monotonic changes, especially at low concentrations of a promoting or an inhibiting reagent. Oftentimes, however, competing reactions and/or interfering species produce anomalous “paradoxical” effects. These occur when the rate of a reaction or a response at first increases with increasing concentration of a reagent and then shows a decrease followed again by an increase at still higher concentrations. Alternatively, the effect may at first decrease and then increase with increasing concentrations and then again decrease with further increases in concentration. A stimulatory or beneficial effect of a subinhibitory concentration of a toxic substance is also known as hormesis. In many cases a paradoxical effect may go unnoticed or be too small to be statistically significant, even though it is reproducible. In other cases it is statistically significant but not readily explained. In still other cases, in view of what is known about the system, plausible explanations or mechanisms can be proposed and investigated. As far back as 1964 special attention was drawn to paradoxical concentration and dose-response effects in biological systems in a first-ever survey1 and also in a review of examples involving fluoride.2 Later research on the phenomenon, focusing mainly on hormesis aspects, does not appear to have attracted much interest. No doubt this neglect reflects the general lack of treatment of the topic in standard textbooks of biochemistry and toxicology, thereby creating the impression among teachers and students that paradoxical effects may not be important or may not even exist. In fact, the latter became the focus of a dispute a few years ago in Fluoride.3 Nevertheless, as discussed below, research reports in this issue and in other recent issues of Fluoride indicate that both in vitro and in vivo paradoxical dose-response effects of fluoride are not uncommon.