A Textbook of Modern Toxicology

Ernest Hodgson, Ernest Hodgson

• Publisher: Wiley
• Year: 2011
• ISBN:
  9781118211298
• Edition: 4
• Topic: Physical Sciences
• Subtopic: Industrial & Technical Chemistry

A Textbook of Modern Toxicology is a unique resource that provides both students and practitioners with a wide-ranging, accessible overview of the discipline. Suitable for courses in environmental, pharmacological, medical, and veterinary toxicology, this essential text features chapters written by experts who address a range of key topics.

The Fourth Edition includes additional chapters on new approaches to toxicology - molecular methods (-omics: toxicogenomics, proteomics, and metabolomics), bioinformatics, and systems biology – and continues the legacy of its predecessors to provide up-to-date insights into acute toxicity and chemical carcinogenesis, organ toxicity, in vitro and in vivo toxicity testing, ecological risk assessment, and many other areas of toxicology that help foster a solid comprehension of the field.

Also featured in the Fourth Edition are end-of-chapter questions and a Solutions Manual available separately for academic adopters.

PART I

INTRODUCTION

CHAPTER 1

Introduction to Toxicology

ERNEST HODGSON

Since the publication of the 3rd edition of this textbook (2004) major changes have been initiated in toxicology as the tools of molecular biology, genomics, proteomics, metabolomics, bioinformatics, and systems biology are increasingly brought to bear on the critical areas of mode of action, toxicity testing, and risk analysis. Chapter 2 provides information on new methodology and Part VIII—New Approaches in Toxicology is composed of two chapters of commentary on the current and expected impact of these new methods. While the traditional aspects and subdisciplines of toxicology, as outlined below, are still active and viable, during the next few years all are likely to be impacted and their development accelerated by these new approaches.

1.1 DEFINITION AND SCOPE

Toxicology can be defined as that branch of science that deals with poisons, and a poison can be defined as any substance that causes a harmful effect when administered, either by accident or by design, to a living organism. By convention, toxicology also includes the study of harmful effects caused by physical phenomena, such as radiation of various kinds, noise, and so on. In practice, however, many complications exist beyond these simple definitions, both in bringing more precise definition to the meaning of poison and to the measurement of toxic effects. Broader definitions of toxicology, such as “the study of the detection, occurrence, properties, effects, and regulation of toxic substances,” although more descriptive, do not resolve the difficulties. Toxicity itself can rarely, if ever, be defined as a single molecular event, but is, rather, a cascade of events starting with exposure, proceeding through distribution and metabolism, and ending with interaction with cellular macromolecules (usually DNA or protein) and the expression of a toxic end point (Figure 1.1). This sequence may be mitigated by excretion and repair. It is to the complications, and to the science behind them and their resolution, that this textbook is dedicated, particular to the how and why certain substances cause disruptions in biologic systems that result in toxic effects. Taken together, these difficulties and their resolution circumscribe the perimeter of the science of toxicology.

Figure 1.1 Fate and effect of toxicants in the body.

The study of toxicology serves society in many ways, not only to protect humans and the environment from the deleterious effects of toxicants, but also to facilitate the development of more selective toxicants such as anticancer and other clinical drugs, pesticides, and so forth.

Poison is a quantitative concept, almost any substance being harmful at some doses but, at the same time, being without harmful effect at some lower dose. Between these two limits, there is a range of possible effects, from subtle long-term chronic toxicity to immediate lethality. Vinyl chloride may be taken as an example. It is a potent hepatotoxicant at high doses, a carcinogen with a long latent period at lower doses, and apparently without effect at very low doses. Clinical drugs are even more poignant examples because, although therapeutic and highly beneficial at some doses, they are not without deleterious side effects and may be lethal at higher doses. Aspirin (acetylsalicylic acid), for example, is a relatively safe drug at recommended doses and is taken by millions of people worldwide. At the same time, chronic use can cause deleterious effects on the gastric mucosa, and it is fatal at a dose of about 0.2–0.5 g/kg. Approximately 15% of reported accidental deaths from poisoning in children result from ingestion of salicylates, particularly aspirin.

The importance of dose is well illustrated by metals that are essential in the diet but are toxic at higher doses. Thus, iron, copper, magnesium, cobalt, manganese, and zinc can be present in the diet at too low a level (deficiency), at an appropriate level (maintenance), or at too high a level (toxic). The question of dose—response relationships is fundamental to toxicology (see Section 1.4).

The definition of a poison, or toxicant, also involves a qualitative biological aspect because a compound, toxic to one species or genetic strain, may be relatively harmless to another. For example, carbon tetrachloride, a potent hepatotoxicant in many species, is relatively harmless to the chicken. Certain strains of rabbit can eat Belladonna with impunity while others cannot. Compounds may be toxic under some circumstances but not others or, perhaps, toxic in combination with another compound but nontoxic alone. The methylenedioxyphenyl insecticide synergists, such as piperonyl butoxide, are of low toxicity to both insects and mammals when administered alone, but are, by virtue of their ability to inhibit xenobioticmetabolizing enzymes, capable of causing dramatic increases in the toxicity of other compounds.

The measurement of toxicity is also complex. Toxicity may be acute or chronic, and may vary from one organ to another as well as with age, genetics, gender, diet, physiological condition, or the health status of the organism. As opposed to experimental animals, which are highly inbred, genetic variation is a most important factor in human toxicity since the human population is highly outbred and shows extensive genetic variation. Even the simplest measure of toxicity, the LD₅₀ (lethal dose; the dose required to kill 50% of a population under stated conditions) is highly dependent on the extent to which the above variables are controlled. LD₅₀ values, as a result, vary markedly from one laboratory to another.

Exposure of humans and other organisms to toxicants may result from many activities: intentional ingestion, occupational exposure, environmental exposure, as well as accidental and intentional (suicidal or homicidal) poisoning. The toxicity of a particular compound may vary with the portal of entry into the body, whether through the alimentary canal, the lungs, or the skin. Experimental methods of administration such as injection may also give highly variable results; thus, the toxicity from intravenous (IV), intraperitoneal (IP), intramuscular (IM), or subcutaneous (SC) injection of a given compound may be quite different. Thus, toxicity may vary as much as 10-fold with the route of administration. Following exposure, there are multiple possible routes of metabolism, both detoxifying and activating, and multiple possible toxic end points (Figure 1.1).

Attempts to define the scope of toxicology, including that which follows, must take into account that the various subdisciplines are not mutually exclusive and are frequently interdependent. Due to overlapping of mechanisms as well as use and chemical classes of toxicants, clear division into subjects of equal extent or importance is not possible.

Many specialized terms are used in the various subdisciplines of toxicology as illustrated in the Dictionary of Toxicology, 2nd edition (Hodgson et al., 1998). However, some terms are of particular importance to toxicology in general; these and some more recent terms are defined in the glossary to be found at the end of this volume.

Although B through F (following) include subdivisions that encompass essentially all of the many aspects of toxicology, there are two new approaches (A, following) that serve to integrate the discipline as a whole.

A. Integrative Approaches

1. Bioinformatics. In the narrow and original meaning, bioinformatics was the application of information technology to molecular biology. While this is still the most important aspect of bioinformatics, it is increasingly applied to other fields of biology, including molecular and other aspects of toxicology. It is characterized by computationally intensive methodology and includes the design of large databases and the development of techniques for their manipulation, including data mining.

2. Systems Biology. Although systems biology has been defined in a number of ways, some involving quite simple approaches to limited problems, in the currently most commonly accepted sense, it is an integrative approach to biological structure and function that will be of increasing importance to biology in general and toxicology in particular. In large part, biology has been reductionist throughout its history, studying organs as components of organisms, cells as components of organs, enzymes, nucleic acids, and so on, as components of cells, with the goal of describing function at the molecular level. Systems biology, on the other hand, is holistic and has the objective of discerning interactions between components of biological systems and describing these interactions in rigorous mathematical models. Furthermore, the proponents of systems biology aim to integrate these models at higher and higher levels or organization in order to develop an integrated model of the entire organism.

Clearly, systems biology is in its infancy; however, the ultimate value of having an integrative model that could clarify all of the effects, from the most proximate to the ultimate, of a toxicant on a living organism, will provide enormous benefits not only for fundamental studies but in such applied areas as human health risk assessment.

B. Modes of Toxic Action. This includes the consideration, at the fundamental level of organ, cell, and molecular function, of all events leading to toxicity in vivo: uptake, distribution, metabolism, mode of action, and excretion. The term mechanism of toxic action is now more generally used to describe an important molecular event in the cascade of events leading from exposure to toxicity, such as the inhibition of acetylcholinesterase in the toxicity of organophosphorus and carbamate insecticides. Important aspects include the following:

1. Biochemical and molecular toxicology consider events at the biochemical and molecular levels, including enzymes that metabolize xenobiotics, generation of reactive intermediates, interaction of xenobiotics or their metabolites with macromolecules, gene expression in metabolism and modes of action, signaling pathways in toxic action, and so on.

2. Behavioral toxicology deals with the effects of toxicants on animal and human behavior, which is the final integrated expression of nervous function in the intact animal. This involves both the peripheral and central nervous systems, as well as effects mediated by other organ systems, such as the endocrine glands.

3. Nutritional toxicology deals with the effects of diet on the expression of toxicity and with the mechanisms of these effects.

4. Carcinogenesis includes the chemical, biochemical, and molecular events that lead to the large number of effects on cell growth collectively known as cancer.

5. Teratogenesis includes the chemical, biochemical, and molecular events that lead to deleterious effects on development.

6. Mutagenesis is concerned with toxic effects on the genetic material and the inheritance of these effects.

7. Organ toxicity considers effects at the level of organ function (e.g., neurotoxicity, hepatotoxicity, and nephrotoxicity).

C. Measurement of Toxicants and Toxicity. These import...

Table of contents

• COVER
• TITLE PAGE
• COPYRIGHT
• PREFACE TO THE FOURTH EDITION
• CONTRIBUTORS
• PART I: INTRODUCTION
• PART II: CLASSES OF TOXICANTS
• PART III: TOXICANT PROCESSING IN VIVO
• PART IV: TOXIC ACTION
• PART V: ORGAN TOXICITY
• PART VI: APPLIED TOXICOLOGY
• PART VII: ENVIRONMENTAL TOXICOLOGY
• PART VIII: NEW APPROACHES IN TOXICOLOGY
• GLOSSARY
• INDEX