A. Wallace Hayes

CHAPTER 12 – Principles of Biological Tests for Toxicity

Toxicologic tests are the tests that define the conditions that must be present when a biological cell is affected by a given chemical entity, and the nature of the effect which is produced. The principles of toxicologic methodology are based on the premise that all effects of chemicals on living tissues are the result of a reaction with, or an interaction between any given chemical entity and some component of the living biological system. The study of toxicologic methods is centered on the detection and evaluation of the nature of the chemical-induced changes in function and structure, and the significance of these effects on living cells. As a result of the development of this toxicologic methodology, certain general principles have become apparent: In order for a chemical to produce a biological effect, it must come into immediate contact with the biological cells (or receptors) under consideration; For each chemical there exists a quantity below which it produces no detectable effect on all biological systems, and a quantity at which it produces a significant effect on all biological systems; Cells having similar functions and similar metabolic pathways in various species will generally be affected similarly by a given chemical entity; Small changes in the structure of a chemical agent may greatly influence the biological action of that agent.

CHAPTER 2 – Numbers in Toxicology

No chemical agent is entirely safe and likewise no chemical agent should be considered as being entirely harmful. The single most important factor that determines the potential harmfulness or safeness of a compound is the relationship between the concentration of the chemical and the effect that is produced upon the biological mechanism. If one considers that the ultimate effect is manifested as an all-or-none response such as death of the biological mechanism, and that a minimal concentration produces no effect, then there must be a range of concentrations of the chemical that would give a graded effect somewhere between the two extremes. The experimental determination of this range of doses is the basis of the dose–response relationship. Experience has shown that the biological variation in response to chemicals within members of a species is generally small as compared to the biological variation among species. The data obtained from such an experiment may be plotted in the form of a distribution or frequency–response curve. In toxicology, frequency–response curves are not commonly used. Rather, it is conventional to plot the data in the form of a curve relating the dose of the chemical to the cumulative percentage of animals showing the response (such as death). Such curves are commonly known as dose–response curves.

CHAPTER 3 – Biologic Factors That Influence Toxicity

Whenever a chemical is applied or administered to a complex system such as the human, unless the receptor is located at the site of application, the chemical must be translocated within the human to a receptor site if it is eventually going to produce an effect. Simultaneously while the processes of translocation are taking place, the chemical will be reaching incidental sites where it may be “chemically bound” (or “adsorbed”) or “biotransformed” to new chemical entities. Furthermore, the initial chemical and its products will reach sites that serve to “eliminate” or “excrete” them from the body. The processes of absorption from some site of administration, translocation, and elimination occur simultaneously and regulate the presence and concentration of each chemical in the various compartments of the body. The kinetics involved in the translocation and elimination of a chemical agent supply the details of a fundamental concept in toxicology, which states that whenever a chemical is administered on multiple occasions over a period of time so that its rate of administration exceeds the rate of elimination, the agent will accumulate in the animal, thereby influencing the degree of toxicity that is produced. The biological factors, such as accumulation and storage of chemical in organism, reserve functional capacity of organs, absorption and translocation of chemicals, and tolerance to chemicals that influence the processes of translocation, elimination, and accumulation of chemicals in the body, are considered in this chapter.

CHAPTER 1 – Introduction, Scope, and Principles

This chapter introduces toxicology and discusses its history, principles, and scopes. Toxicology is approached as the study of the effects of chemicals on biological systems, with emphasis on the mechanisms of harmful effects of chemicals and the conditions under which harmful effects occur. Modern toxicology is a multidisciplinary science and as such had to await the development of many of the natural sciences before it could become a quantitative field. The father of modern toxicology was M J B Orfila, who was the author of the first book devoted entirely to studies of the harmful effects of chemicals. Toxicology borrows freely from the principles of chemistry, and more particularly biochemistry. It is dependent upon a knowledge and understanding of physiology. Familiarity with statistics and public health is fundamental to the study of toxicology. The subject can be divided into sections, such as environmental, medical, and economic on the basis of the disciplines involved. There are at least four basic principles that are generally applicable to all chemical-induced biological effects of toxicologic interest. First, the chemical must get to the effector site in a biological system to produce a biological effect. Second, not all chemical-induced biological effects are harmful. Third, the occurrence and intensity of chemical-induced biological effects are dose related, and fourth, effects of chemicals on animals, if properly qualified, are applicable to humans.

CHAPTER 8 – Normal Toxic Effects of Chemicals

This chapter discusses the normal toxic effects of chemical that are not intended for introduction to biological systems and those that are intended for introduction to biological systems. Many chemicals that are not intended for introduction into biological systems have been produced for use by humans. Undue exposure of humans to such chemicals is usually incidental or accidental in nature, but may be intentional when such agents are used with suicidal intent, or for recreation. Such exposures may cause toxicity due to caustic or corrosive nature of the chemical, carcinogenic nature, or teratogenic nature of the chemical. Pathologic sequelae are those permanent malfunctions or malformations of tissue that remain after exposure to the chemical agent has been discontinued but which were initially caused by the chemical.

CHAPTER 14 – Clinical Toxicology

This chapter deals with clinical toxicology, which is primarily concerned with two areas in toxicology applicable to clinical medicine. The first involves the documentation, diagnosis, and treatment of harmful effects of chemicals on humans. The second involves the acquisition and interpretation of epidemiologic data and the estimation of risk associated with exposures of human populations to chemicals of all types. Documentation of causation in deaths as well as less severe toxicities when chemicals are believed to be involved is the element of toxicology commonly referred to as Forensic Toxicology. It utilizes the data obtained from pathologic facilities and analytical chemical laboratories. In the case of illness, such data help define the nature of therapy that would be used. In the case of death, such data are the main reliable documentation for statistics on chemical-induced deaths. The diagnosis of illness associated with exposure to chemicals follows the same procedures used for the diagnosis of any illness except that it requires that the clinician familiarize himself with the effects of the suspected chemical(s) on humans. The treatment of chemical-induced illness depends upon whether the illness is due to an acute overdose or accumulation of the chemical that is present in the patient at the time the diagnosis is made. Under these conditions, treatment is directed toward decreasing the body load of the causative agent while maintaining adequate vital functions (respiration and cardiac function). Risk assessment in toxicology refers to the estimation of the probability of occurrence of a harmful effect(s) resulting from exposure to a chemical agent.

CHAPTER 15 – Information Sources in Toxicology

The ultimate sources of information in toxicology are the same as they are in any science. They are the scientific data created throughout the world under laboratory or field conditions that are interpreted and reported by the original investigators in printed form in scientific journals. These reports constitute the primary journal literature. It is important to recognize that all other printed sources of toxicologic information such as textbooks, special reports, monographs, and handbooks, as well as the electronic databases, do not create scientific information. Rather, they are mechanisms for locating, referencing, organizing, systematizing, condensing, abstracting, or reviewing the primary journal literature. Although toxicology has its own specific literature sources, it borrows freely from a host of other sciences, which are the origins of data and concepts relevant to toxicology. This chapter recommends reference texts that may be considered as additional reading in the general field of toxicology, followed by a list and brief description of the most common computer database systems.

CHAPTER 4 – Chemical Factors That Influence Toxicity

The chemical factors that influence the processes of translocation, elimination, and accumulation of chemicals in the body are considered in this chapter. The degree of ionization of a chemical in a solution is a determinant of the ability of compounds to traverse membranes. Likewise, the solubility of the compounds in the lipid material is an important factor with respect to transfer of chemicals across membranes. The chemical structure of a compound determines the ability of the compound to have a biological action, and around this fact is built the science of structure–activity relationship. The chemical factors that influence toxicity fall into two categories. The first category is composed of those chemical and physicochemical properties of compounds that individually and collectively determine the ability of the compounds to pass across biological membranes. Such properties are important because they regulate the translocation of the chemical throughout the biological tissue. The second category comprises the chemical structure of compounds that enables them to produce specific actions on the tissues and to be susceptible to transformation by the mechanisms present in the biological specimen. Such biotransformation mechanisms are important because they may result in the formation of products possessing less toxicity than the parent compound or in the production within the organism of products possessing greater toxicity than the parent compound.

CHAPTER 10 – The Basis of Selective Toxicity

Selective toxicity refers to the variability in toxicologic response of cells to xenobiotic agents. This chapter is concerned with the variation among biological cells, tissues, and organisms when they are exposed to foreign chemicals. Biological variation among cells is frequently observed as a variation among whole animals, and much of this text has been directed toward a description of some mechanisms that account for variation among animals in response to chemicals. Most chemicals that serve a useful purpose for man do so by influencing the function of only a very limited number or type of cells or systems. The mechanisms involved in selective toxicity are those that influence the concentration (i.e., translocation systems) and chemical properties of the agent and its products (i.e., biotransformation systems), and the existence of specific receptor systems in cells.

CHAPTER 9 – Abnormal Response to Chemicals

A hypersensitive response may be defined as a normal pharmacologic or toxicologic response of greater intensity than that which occurs in the majority of the population following a given dose of the chemical agent. In contrast to this, a sensitization reaction to a chemical is the response involving the immune mechanism. It is an abnormal effect of the chemical in the sense that it is different from the pharmacologic effect associated with ordinary doses or the toxicologic effect resulting from excessive doses of the chemical. The immunogenic mechanisms play a significant role in all branches of human health. These mechanisms are of particular importance in toxicology because so many simple chemicals have varying degrees of haptenic activity. Many simple chemicals have haptenic qualities, and all degrees of such activity are found. For example, phenol is rarely antigenic, even under laboratory experimental conditions, whereas the sedative drug phethenylate (phenylethylhydantoin) induces allergic symptoms in virtually every human who receives the drug on multiple occasions. In clinical medicine four types of immunologic responses are recognized: type 1 (immediate responses), type 2 (cytotoxic responses), type 3 (immune complex sensitization responses), and type 4 (delayed sensitization responses).