PRINCIPLES OF TOXICOLOGY - Biology East Borneo

1.3 THE IMPORTANCE OF DOSE AND THE DOSE–RESPONSE RELATIONSHIP 15mean). Typically, a frequency–response curve for each dose of interest is not used to illustrate thedose–response relationship; instead, cumulative dose–response curves are generally used because theydepict the summation of several frequency–response curves over a range of different dosages.Graphically, the separate results for each dose are depicted as a point (the average response) with barsextending above and below it to exhibit one standard deviation greater and less than this averageresponse (see Figure 1.1b). A further refinement is then made by plotting the cumulative response inrelation to the logarithm of the dose, to yield plots that are typically linear for most responses between0 and 100 percent, and it is from this curve that several basic features of the dose–response relationshipcan be most readily identified (see Figures 1.1c,d).In Figure 1.2, a cumulative dose–response curve is featured with a dotted line falling through thehighest dose that produces no response in the test animals. Because this dose, and all doses lower thanit, fail to produce a toxic response, each of these doses might be referred to as no-observable-effectlevels (NOELs), which are useful to identify because they represent safe doses of the chemical. Thehighest of these NOELs is commonly referred to as the “threshold” dose, which may be simply definedas the dose below which no toxicity is observed (or occurs). For all doses that are larger than thethreshold dose, the response increases with an increase in the dose until the dose is high enough toproduce a 100 percent response rate (i.e., all subjects respond). All doses larger than the lowest doseproducing a 100 percent response will also produce a 100 percent response and so the curve becomesflat as increasing dose no longer changes the response rate. For therapeutic effects, this region of thedose–response curve is typically the region physicians seek when they prescribe medicines. Becausephysicians are seeking a beneficial (therapeutic) effect, typically they would select a dose in this region(c)(d)Figure 1.1 Continued