Chapter 4

### INTRODUCTION

Pharmacology deals with drugs and their chemical properties or characteristics, their mode of action, the physiological response to drugs, and the clinical uses of drugs. Pharmacology intersects with toxicology when the physiological response to a drug is an adverse effect. Toxicology is often regarded as the science of poisons or poisoning, but developing a strict definition for poison is problematic. A poison is any substance, including any drug, that has the capacity to harm a living organism. The Renaissance physician Paracelsus (1493-1541) is famously credited with offering the philosophical definition of poisons: "What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison." However, poisoning inherently implies that damaging physiological effects result from exposure to pharmaceuticals, illicit drugs, or chemicals. So each drug in the pharmacopeia is a potential poison, and individual dose-, situation-, environment-, and gene-related factors contribute to a drug's ability to achieve its adverse potential.

Some chemicals may inherently be poisons, such as lead, which has no known necessary physiological role in the human body, and which is known to cause neuronal injury even at very low exposure levels. Most pharmaceuticals are threshold poisons; at therapeutic dosing the drug is used to confer a health advantage, but at higher doses the drug may produce a toxic effect. For instance, iron is a nutrient essential for heme synthesis and numerous physiological enzyme functions, but overdose of ferrous sulfate can lead to life-threatening multi-organ dysfunction.

### DOSE-RESPONSE

Evaluation of the dose-response or the dose-effect relationship is crucially important to toxicologists. There is a graded dose-response relationship in an individual and a quantal dose-response relationship in the population (see Chapters 2 and 3). Graded doses of a drug given to an individual usually result in a greater magnitude of response as the dose is increased. In a quantal dose-response relationship, the percentage of the population affected increases as the dose is raised; the relationship is quantal in that the effect is specified to be either present or absent in a given individual (Figure 4–1). This quantal dose-response phenomenon is extremely important in toxicology and is used to determine the median lethal dose (LD50) of drugs and other chemicals.

###### Figure 4–1.

Dose-response relationships. A. The toxic response to a chemical is evaluated at several doses in the toxic or lethal range. The midpoint of the curve representing percent of population responding (response here is death) versus dose (log scale) represents the LD50, or the concentration of drug that is lethal in 50% of the population. B. A linear transformation of the data in panel A, obtained by plotting the log of the dose administered versus the percent of the population killed, in probit units.

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