ABSTRACT"Intrinsic" and "idiosyncratic" drug-induced liver injury reactions are commonly thought to arise by different modes of action. Intrinsic toxicity is reproducible in animals and occurs dose-dependently at sublethal doses. Environmental and genetic sensitivity factors can influence the toxicity of intrinsic hepatotoxicants. Among these is inflammatory stress. For example, exposure of mice to inflammatory bacterial lipopolysaccharide (LPS) causes a leftward shift in the dose-response relationship for acetaminophen hepatotoxicity; that is, acetaminophen toxicity is enhanced by LPS-induced inflammatory stress. Idiosyncratic reactions present themselves very differently than intrinsic ones; they happen in a minority of patients, with variable time of onset and no obvious relationship to drug dose, and they are not reproducible in usual animal tests. Although these characteristics seem to distinguish them from intrinsic reactions, consideration of fundamental principles of dose response can explain the differences. For a drug that causes idiosyncratic hepatotoxicity, the liver may not be a typical target for toxicity because the dose-response curve for hepatotoxicity lies to the right of the lethal dose. However, a sporadically occurring sensitivity factor, such as an inflammatory episode, could shift the dose-response curve for hepatotoxicity to the left, thereby bringing hepatotoxic doses into the therapeutic range. This hypothesis can account for the bizarre characteristics of idiosyncratic reactions and is supported by recent results showing that several drugs associated with human idiosyncratic reactions can be rendered hepatotoxic to rodents upon interaction with an inflammatory stimulus. In light of this view, intrinsic and idiosyncratic reactions may not be that different after all.Once upon a time, there were two toxicities, "intrinsic" and "idiosyncratic," recognized widely to be very different villains. Although both are unsavory characters, intrinsic toxicity behaves predictably, and for the most part, his presence can be avoided with appropriate precaution. He is gentlemanly, obeying the dictates of classic toxicologic protocol by acting in a dose-dependent manner and with remarkable consistency within and across species (Table 1). When the great-great-great grandfather of toxicology, Paracelsus, declared that "all things are toxic, it is only the dose that distinguishes a remedy from a poison," he was, of course, referring to this intrinsic toxicity fellow.Idiosyncratic toxicity is the more diabolical of the two characters. Enveloped in a dark cloak that hides his menacing countenance, he seems to sneer at the laws of dose response. Even when illuminated under the lamppost of conventional wisdom, he remains all but invisible to the eyes of preclinical safety testing. This menace lurks in the shadows of drug efficacy, pouncing unpredictably to attack unsuspecting vic-