Edition Principles of TOXICOLOGY 3rd (Third Edition) Karen E. Stine & Thomas M. Brown pdf free download

Principles of Toxicology has evolved (through three editions now) from a course originally developed and taught by us at Clemson University beginning in the spring of 1987. In searching for a textbook to accompany this new introductory course on the basic principles and concepts of toxicology, we discovered that, unfortunately, many of the available books were more appropriate as reference materials for more advanced students, while others were too narrowly focused on a single topic (such as biochemical toxicology or ecological toxicology) for our purposes.

Edition Principles of TOXICOLOGY 3rd (Third Edition) Karen E. Stine & Thomas M. Brown pdf free download

Thus, we developed this book. The purpose of the book is to serve as a compre-hensive, yet readable, textbook for a first course in toxicology at the undergraduate or beginning graduate level. We have chosen to cover the broad and interdisciplinary field of toxicology through a “levels of organization” approach, with initial chapters focusing on molecular and cellular toxicology, the middle of the book emphasiz-ing physiological toxicology, and a later chapter introducing ecological toxicology. Additional chapters cover a few of the many applied areas within the field.

Each of these chapters combines background material in the appropriate disci-pline (to help students review and remember basics) with new information on toxi-cology in a manner that stresses key principles and concepts. We have also included a selection of case studies in which these principles and concepts are applied to specific real-world issues, and an extensive cross-referencing system to help students tie it all together.

We would like to thank all of our colleagues (and students) who have contributed suggestions, comments, and support to this project over the years, as well as the editors and staff at CRC Press/Taylor & Francis Group who have helped make this book a reality.

Measuring Toxicity and Assessing Risk

Toxicology is the science of poisons and has as its focus the study of the adverse effects of chemicals on living organisms. Although almost any substance in suf-ficient quantities (even water) can be a poison, toxicology focuses primarily on substances that can cause these adverse effects after exposure to relatively small quantities. Knowledge of the relative toxicity of substances is fundamental to all applications of toxicology, from development of a new drug to the modeling of the effects of an environmental pollutant. This chapter describes approaches used by toxicologists to determine the toxicity of a substance. We consider principles of the dose versus response relationship, methods used to evaluate toxicity in laboratory animals, and subsequent statistical analyses for quantitation of toxicity. We also discuss the use of toxicity data in assessing the risks of exposure to potentially hazardous substances.

Toxicokinetics

Interactions of a poison with an organism can be considered in three phases: exposure, toxicokinetics, and toxicodynamics. During the exposure phase, contact is established between the poison and the body via one or more routes, for example, a volatile air pol-lutant is inhaled into the body. Then, during the toxicokinetic phase, the poison under-goes movement (Greek: kinesis) within the body. This movement includes absorption into the circulatory system, distribution among tissues (including those that will serve as sites of action), and then elimination from the body. The toxicodynamic phase is the exertion of power (Greek: dynamos) of the poison through its actions on affected target molecules and tissues. These phases can be overlapping, so that once exposure occurs, all phases of action can be in effect simultaneously in the body.

Biotransformation

The previous chapter began a discussion of the toxicokinetic phase. This phase con-sists of movement (Greek: kinesis) of a poison in the body, including absorption into the circulatory system, distribution among tissues including sites of action, and elimination from the body. This chapter focuses in more detail on the aspect of elimination that involves the loss of the parent drug from the body due to biotrans-formation of the parent drug to metabolites. This biotransformation generally aids in the excretion of the parent drug in the urine or feces.

Metabolites are the products of enzyme-catalyzed chemical changes in a drug or toxicant. These products may vary in toxicity or therapeutic effect from the par-ent drug or the toxicant. When biotransformation results in a less toxic product, the process is generally known as detoxification. Some reactions, however, lead to the formation of products that are more toxic than the parent. These reactions are then known as intoxication or bioactivation reactions. In cases in which the parent drug or toxicant is reversibly bound to a protein, or otherwise temporarily sequestered, only to be released later into the blood, the metabolite may, in fact, be the parent compound itself.

Cellular Sites of Action

Many toxic substances are known to cause poisoning through a chain of events that begins with action at a very specific target. Often, this target is a biological molecule with which the toxicant binds or reacts, such as one or more of the various types of proteins, lipids, and nucleic acids within the cell. Symptoms resulting from exposure to a toxicant may relate directly to this molecular event, or may be complicated by secondary effects, just as symptoms of a disease may be due to physiological imbalances that are secondary to the initial infection. Therefore, identification of the primary site of action requires careful collection and interpretation of biochemi-cal and physiological evidence. For some toxicants, this initial event in poisoning, or molecular lesion, has been characterized. For many other toxicants, the precise interaction of the toxicant with one or more specific biological molecules has yet to be demonstrated. With the increasingly powerful experimental techniques available, however, it is likely that precise molecular sites of action will be described for many more toxicants in the near future.

The nature of the interaction between the toxicant and the binding site is also important. Toxicants may bind covalently to cellular macromolecules, leading typi-cally to long-lived or virtually permanent changes within the cell. This is a typi-cal pattern for toxicants which are electrophilic, behaving as electron acceptors and interacting readily with nucleophilic electron donors (including nucleophilic sulfurs, nitrogens, and oxygens in proteins and nucleic acids). Noncovalent binding (such as formation of ionic bonds or hydrogen bonds) tends to be much more easily revers-ible. In some cases, the toxicant may even affect a target molecule indirectly, through alteration of the cellular environment in which the target molecule resides and func-tions. One straightforward example of this would be effects mediated through tox-icant-induced alterations in pH; another might be the disruption of the membrane structure produced by some lipophilic compounds, which may indirectly impact membrane-associated proteins.

Genomics and New Genetics in Toxicology

The study of genomics is based upon information first gathered in an organized way in an undertaking known as the Human Genome Project. This project was executed by an international consortium and resulted in a data bank of the linear sequence of DNA over not only all human chromosomes, but also those of a number of model species. These data (GenBank) are freely available to international science through the National Center for Biotechnology Information (NCBI) of the National Library of Medicine, U.S. Building on this foundation, the information in this data bank accumulates as the genomes of additional species are analyzed. The availability of these linear sequence data has led to the growing disciplines of genomics, compara-tive genomics, bioinformatics, systems biology, and toxicogenomics.

Carcinogenesis

Cancer is not a single disease, but rather a general term referring to many kinds of malignant growths that invade adjoining tissues and sometimes spread to distant tis-sues. Carcinomas are cancers of epithelial tissue, whereas sarcomas are cancers of supporting tissues (such as connective or muscle tissues).

The presenting symptom of cancer is often a cellular mass or tumor. Tumors are often characterized as falling along a continuum between benign and malig-nant, based on the characteristics of their cells. Benign tumors are encapsulated, slowly growing, noninvasive, and can be controlled by excision; malignant tumors are nonencapsulated, rapidly growing, invasive, disseminating, and recalcitrant to treatment. Most tumors appear to have originated from a single cell of origin, yet are heterogeneous in nature due to accumulation of different mutations in different cells during subsequent rounds of cellular division.

Staging is a method for describing the status of a cancer for diagnosis and man-agement. The general classification of each case into stages I–IV is based on a scor-ing system known as TNM: development of the tumor (T), involvement of lymph nodes (N) in the region of the tumor, and degree of metastases (M). For example, the tumor is categorized from T0 (no evidence of a tumor) to T4 (a massive lesion with extensive invasion into adjacent tissues). A combination of clinical, radiographic, surgical, and pathological techniques is used to determine TNM scores. Staging is performed in diagnosis and periodically throughout treatment to evaluate manage-ment and remediation of the disease.

Reproductive Toxicology and Teratology

The functions of reproduction and development are complex and involve many rela-tively unique cellular-level processes. As such, the effects of toxicants on the process of reproduction and on developing organisms may be quite different from those of the same toxicant on other systems in the adult organism. This chapter first reviews a few basic concepts in reproduction and development and then considers the effects of toxicants on reproductive function (the production of eggs in the female and sperm in the male). It concludes with an examination of the effects of toxicants on develop-ing organisms.

Respiratory Toxicology

The primary functions of the respiratory system are to deliver oxygen to the blood-stream where it can be routed throughout the body to every cell, and to remove the waste product of metabolism—carbon dioxide. Mitochondria within cells require oxygen to carry out oxidative phosphorylation, the series of reactions whereby energy contained in chemical bonds in food is repackaged into the bonds in the molecule ATP (a form of energy the cell can directly use). Although some cells in the body can function without oxygen for a short time, many cells (such as heart or brain cells) are absolutely dependent on an adequate supply of oxygen in order to survive. The respiratory system also plays a role in the process of speech, the defense of the body, and the regulation of body pH. It is also a rapid route by which volatile xenobiotics can reach the brain.

Cardiovascular Toxicology

The basic function of the cardiovascular system is transport. This is the system that is responsible for carrying gases, nutrients, waste products, cells, hormones, and other substances from one part of the body to another. As such, it plays a major part in homeostasis through its role in regulating the composition of both intracellular and extracellular fluids. The system is also critical in temperature regulation. Finally, it is the circulatory system that carries defensive elements (cells and molecules of the immune system) to areas of the body that require them. Physically, the system con-sists of a pump (the heart), a network of tubes (the vascular system), and a transport fluid (the blood). All three components can be affected by toxicants, and we will consider each of them in turn.

Neurotoxicology

In general, the nervous system has three functions. First of all, specialized cells detect sensory information from the environment and then relay that information to other parts of the nervous system (such as the brain, for example). A second segment of the system directs the motor functions of the body, often in direct response to sensory input. Finally, part of the nervous system is involved in processing of information. These integrative functions include such processes as thought, consciousness, learning, and memory. All of these functions are potentially vulnerable to the actions of toxicants.



    


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