Table 1.

Continuum of effects associated with any exposure to xenobiotics reflecting a sequence of effects of differing severity (ARA, 2012).

Adaptive effects: This continuum starts at low dose with upstream indicators of change, or adaptive effects, where the organism’s ability to withstand a challenge is enhanced. Doses associated with such effects are often referred to as No Observed Adverse Effect Levels (NOAELs). The concepts of homeostasis and hormesis are relevant here

Compensatory effects: As dose increases, compensatory effects occur, which enable the organism to maintain overall function without further enhancement or significant cost. Doses associated with such effects are also often NOAELs. Some of these effects might be judged to be the critical effect

Critical effect: As dose further increases, the critical effect is reached. This is the first adverse effect, or its known precursor, that occurs to the most [relevant or] sensitive species as the dose rate of an agent increases.a Doses associated with such effects are Lowest Observed Adverse Effect Levels (LOAELs). The highest NOAEL below this LOAEL is generally used in the dose response, and the focus is on determining this NOAEL in a sensitive population

Adverse effects: As dose further increases, the critical effect is exceeded, and adverse effects are manifested as biochemical changes, functional impairments, or pathologic lesions. These progressively more severe effects impair the performance of the organism, and/or reduce its ability to respond to additional challenges. At some point these adverse effects become manifestly overt and irreversible, and frank effects or clinical disease ensues

^aNote that the bracketed phrase “relevant or” is important since the most relevant specie is always preferred over the most sensitive species (e.g. if data shows that the rat is more sensitive than the human, the human data are still preferred), but when such information is not available, data from the most sensitive species are chosen. Also the term “precursor” in this definition is singular, meaning the immediate precursor, not just any prior effect. This restriction is important both because it ties the concept of critical effect into common medical practice of focusing on important endpoints, and because the resulting dose response—such as an RfD—is more meaningful, since without the restriction multiple and different RfDs can be estimated.