THE IMPORTANCE OF DOSE AND THE DOSE–RESPONSE RELATIONSHIP

It is probably safe to say that among lay individuals there exists considerable confusion between the terms poisonous and toxic. If asked, most lay individuals would probably define a toxic substance using the same definition that one would apply to highly poisonous chemicals, that is, chemicals capable of producing a serious injury or death quickly and at very low doses. However, this is not a particularly useful definition because all chemicals may induce some type of adverse effect at some dose, so all chemicals may be described as toxic. As we have defined toxicants (toxic chemicals) as agents capable of producing an adverse effect in a biological system, a reasonable question for one to ask becomes “Which group of chemicals do we consider to be toxic?” or “Which chemicals do we consider safe?” The short answer to both questions, of course, is all chemicals; for even relatively safe chemicals can become toxic if the dose is high enough, and even potent, highly toxic chemicals may be used safely if exposure is kept low enough. As toxicology evolved from the study of just those substances or practices that were poisonous, dangerous, or unsafe, and instead became a more general study of the adverse effects of all chemicals, the conditions under which chemicals express toxicity became as important as, if not more important than, the kind of adverse effect produced. The importance of understanding the dose at which a chemical becomes toxic (harmful) was recognized centuries ago by Paracelsus (1493–1541), who essentially stated this concept as “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” In a sense this statement serves to emphasize the second function of toxicology, or risk assessment, as it indicates that concern for a substance’s toxicity is a function of one’s exposure to it. Thus, the evaluation of those circumstances and conditions under which an adverse effect can be produced is key to considering whether the exposure is safe or hazardous. All chemicals are toxic at some dose and may produce harm if the exposure is sufficient, but all chemicals produce their harm (toxicities) under prescribed conditions of dose or usage. Consequently, another way of viewing all chemicals is that provided by Emil Mrak, who said “There are no harmless substances, only harmless ways of using substances.” These two statements serve to remind us that describing a chemical exposure as being either harmless or hazardous is a function of the magnitude of the exposure (dose), not the types of toxicities that a chemical might be capable of producing at some dose. For example, vitamins, which we consciously take to improve our health and well-being, continue to rank as a major cause of accidental poisoning among children, and essentially all the types of toxicities that we associate with the term “hazardous chemicals” may be produced by many of the prescription medicines in use today. Because all chemicals are toxic at some dose, what judgments determine their use? To answer this, one must first understand the use of the dose–response relationship because this provides the basis for estimating the safe exposure level for a chemical. A dose–response relationship is said to exist when changes in dose produce consistent, nonrandom changes in effect, either in the magnitude of effect or in the percent of individuals responding at a particular level of effect. For example, the number of animals dying increases as the dose of strychnine is increased, or with therapeutic agents the number of patients recovering from an infection increases as the dosage is increased. In other instances, the severity of the response seen in each animal increases with an increase in dose once the threshold for toxicity has been exceeded.