Loomis's Essentials of Toxicology

By A. Wallace Hayes, Tao Wang, Darlene Dixon and Ted A. Loomis

Loomis's Essentials of Toxicology, Fifth Edition, provides the information on the harmful biologic effects associated with exposures to chemicals of all types. The scope of this book includes a discussion of the major types of chemicals involved, their general properties and detrimental biologic effects, the methods used to demonstrate these effects, the basis for clinical diagnosis, and therapy for the harmful effects of chemicals on humans. Individual examples are used to demonstrate the principle discussed. This reference volume will be an invaluable resource for both toxicologists and graduate and advanced undergraduate students in toxicology and public health.

• Provides a revised and updated edition of one of the "gold" works in the field
• Includes both principles and methods
• Requires minimal background in chemistry and biology
• Expanded Information Sources in Toxicology

• Language: English
• Publisher: Academic Press
• Release date: Oct 24, 2019
• ISBN: 9780128159224

A. Wallace Hayes

A. Wallace Hayes, PhD holds degrees from Auburn University (Ph.D. and MS) and Emory University (AB). He was an NSF predoctoral fellow at Auburn University, an NIH individual postdoctoral fellow at the Vanderbilt University School of Medicine, a NATO Senior Scientist at the Central Veterinary Laboratory in Weybridge, England, and an NIH Research Career Development Awardee. Dr. Hayes has held Professorships at the University of Alabama, the University of Mississippi Medical Center, and Wake Forest University School of Medicine. Dr. Hayes has authored more than 370 peer-reviewed publications, is the editor of Hayes’ Principles and Methods of Toxicology, 7th edition, Human and Experimental Toxicology, Cutaneous and Ocular Toxicology, Toxicology Research and Application, and the co-editor of the Target Organ Toxicity Series of books. Dr. Hayes is the Editor-in-Chief emeritus, of Food and Chemical Toxicology and the co-author of Loomis’ Essential of Toxicology, 5th Edition. Dr. Hayes is past Secretary-General of IUTOX (two terms), past board member of the American Board of Toxicology, past president of the American College of Toxicology, the Toxicology Education Foundation, and the Academy of Toxicological Sciences, the Toxicology Forum, and past member of the council of the Society of Toxicology. Dr. Hayes is a diplomate of the American Board of Toxicology, the Academy of Toxicological Sciences, the American Board of Forensic Medicine, and the American Board of Forensic Examiners. He is a Fellow of the Academy of Toxicological Sciences, the Royal Society of Biology (UK), the Royal Society of Medicine (UK), the American College of Forensic Examiners, and the American College of Nutrition. Dr. Hayes is a registered toxicologist in the European Union (ERT) and a certified nutrition specialist (food safety). Dr. Hayes was honored by the Society of Toxicology in 2006 with its Merit Award, by the Mid-Atlantic Society of Toxicology with its Ambassador Award in 2012, by the American College of Toxicology in 2012 with its Distinguished Scientist Award, and by the International Dose-Response Society in 2013 with its Outstanding Leadership Award, and by The American Academy of Toxicology with its Mildred S. Christian Career Achievement Award in 2021. Dr. Hayes was named a Distinguished Fellow by the American College of Toxicology in 2013 and a fellow of the American Association for the Advancement of Science in 2014.

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Preface

A. Wallace Hayes

Although toxicology is the study of the untoward effects of substances on biological tissues, it is a paradoxical science; it has been used to kill and to cure. Therefore, it requires an understanding of chemical reactions and interactions and of biologic mechanisms. The vastness of the field precludes the possibility that any one mind can absorb much less retain more than a small fraction of the information available to the toxicologist. However, there are certain principles of toxicology that are applicable to large numbers of chemicals, and an understanding of these essentials of toxicology has been maintained in the fifth edition of Loomis’s Essentials of Toxicology.

The first edition of the book was published in 1968 by Professor Loomis in which he laid out some simple but lasting concepts that have evolved over time to become standards in toxicology. Toxicology has a dynamic that reflects the almost daily changes in our understanding of biology, chemistry, and medicine. Information resources were limited in the early years but are now readily available on the internet, thus the expansion of Chapter 15 Information Resources in Toxicology. Toxicologists must have ready access to the best available information, recognizing the need for scientific understanding, including translation of scientific findings into understandable terms that are suitable for decision-making and ensuring consistent prediction of hazards and risks before the actual exposure has occurred and to permit evidence based benefit-risk assessments.

This edition of the book could not have been completed without the strong support of my two coauthors, Darlene Dixon and Tao Wang, and the Academic Press team. We solicit your comments, suggestions, corrections, and criticisms that would make future editions even more accurate and worthwhile.

Chapter 1

Introduction, scope, and principles

Abstract

The harmfulness or safeness of any chemical is related primarily to the amount of that compound in the body. One of the most fundamental observations of any biologic effect of a chemical agent is the relationship between the dose (or concentration) and the response. Thus, research in toxicology focuses on studying the adverse effects of chemicals on biologic cells, tissues, systems, and pathways. The field most closely related to modern toxicology is pharmacology, for a pharmacologist must understand not only the beneficial effects of chemicals but also the harmful effects of those chemicals that may be put to therapeutic use. The environment serves as both a supply source and a dump site for chemicals and their derivatives, and translocates each agent within the environmental pool. Exposure to chemicals in the environment and the public health consequences are continuing sources of concern in toxicology. However, toxicology's central concern lies in the evaluation of potential adverse effects of chemicals on humans. Academia, government agencies, and industry expend considerable effort and money in determining the mode/mechanisms of chemical-biological interactions. Currently, there are more than a million chemical entities to which the human population could be exposed. In spite of the multitude of chemicals that are potentially harmful, only a few have been adequately documented as causative of serious health problems in humans.

Keywords

Chemicals; Toxicology; Compounds; Effects; Environment; Harmful

Early in the days of the development of civilization, man in his quest for food must have attempted to eat a variety of materials of both botanical and animal origin. Through this experience, it is likely that he found that certain substances produced varying degrees of illness or even death. Other materials with a better outcome soon became a desirable form of food. Therefore, it seems reasonable to believe that humans soon recognized that there were harmful and beneficial consequences associated with taking materials into their bodies. All such materials could be placed in two broad classes, one of which was safe and the other harmful. The word poison would be the term used to describe those materials or chemicals that were distinctly harmful to the body, and food would be the term used for those materials that were beneficial and necessary for the body to function. This concept involving the division of chemicals into two categories has persisted to the present day and, as such, serves a useful purpose in society.

With the advancement of society and sciences, people recognize that there are degrees of harmfulness and safeness for any chemical. Even the most innocuous of substances, when taken into the body in sufficient amounts, may lead to undesirable effects. In contrast to this, the most harmful of all chemical agents can be taken into the body in sufficiently small amounts so that there will be no untoward effect from such chemicals. It is apparent that the harmfulness or safeness of a chemical is related primarily to the amount of that compound in the body. The most important factor that determines the effect of a chemical compound is the quantity of the compound that comes in contact with a biologic system. This quantity of the compound is commonly called the dose. (Dose may be expressed using a variety of terminologies and is further discussed in the next chapter.) As the dose is increased from minimal to maximal levels, the response, whether it be beneficial or harmful, is a graded response and is related to progressive changes in the dose over time. One of the most fundamental observations of any biologic effect of a chemical agent is the relationship between the dose (or concentration) and the response. Thus, research in toxicology focuses on studying the adverse effects of chemicals on biologic cells, tissues, systems, and pathways.

The word toxic may be considered synonymous with harmful in regard to the effects of chemicals. Two additional terms related to the words toxic and poison are toxin (naturally occurring toxic materials) and toxicant (all toxic materials whether from nature or man-made). Many chemicals are nonselective in their action to exert harmful effects on all living matter. In contrast to this, a given chemical may selectively produce harm only on specific organisms, cells, or pathways.

When a chemical is said to be toxic, the average person interprets this to mean that it would have a harmful or undesirable effect on humans, regardless of the amount. This may not be true when the toxicologist uses the words toxic or toxicity because what may be harmful to one species may be relatively harmless to another species. In fact, a chemical that is toxic to some organisms may be desirable as far as man is concerned. For example, a mosquito repellent is harmful or even lethal to mosquitoes but relatively harmless to humans and, therefore, indirectly beneficial and desirable to mankind. For this reason, we can make use of chemicals to our advantage. Therefore, if the term toxic or toxicity is used, it is necessary to identify the biologic mechanism on which the harmful effect is produced. Toxicity is a relative property of a chemical and may be directly or indirectly desirable or undesirable as far as man is concerned, but toxicity always refers to a harmful or untoward effect on some biologic mechanism or system.

Toxicity or potency is a relative term often used in comparing one chemical with another. It is common to say that one chemical is more toxic than another chemical. Such a comparison between chemicals is most uninformative unless the statement includes information regarding the biologic mechanism under consideration as well as the conditions under which it is harmful. Therefore, toxicology should be approached as the study of the effects of chemicals on biologic systems, with emphasis on the mechanisms of harmful effects of chemicals and the conditions under which the harmful effects occur.

History

History is filled with toxic events, such as Cleopatra’s voluntary suicide by an asp (a venomous snake) or Socrates’ mandated suicide by hemlock (the poisonous plant, Conium maculatum, a common European herb that was probably the state poison of Ancient Greece). Adding arsenic or hellebore (an herb that is a cardiac poison) to wine was discreet, nearly undetectable and considerably less messy than a gun or a knife. Little has changed in the ensuing years. Poisons, as the solution to delicate political problems, became an art form not unlike painting or sculpture during the Renaissance period. Claims have been made that members of the Russian Politburo allegedly gave Stalin warfarin (a synthetic derivative of coumarin, a chemical found naturally in many plants and used as an anticoagulant medication) and that the US CIA, using botulinum-laced pills, made attempts on the life of Cuban Dictator Fidel Castro. Evidence seems to support the conclusion that Ukrainian President Viktor Yushchenko was poisoned with dioxin (the common name for the group of compounds classified as polychlorinated dibenzodioxins) in an attempt to remove him from office as recently as 2006. Poisoning continue into the 21th century with examples such as the use of nerve gas in subways in Japan, in airports in Malaysia and in homes in the United Kingdom.

Many of the earliest practitioners of toxicology were women. For example, Locusta of Gaul, a notorious poison mixer in Ancient Rome, was hired by Roman nobility to eliminate persons of concern. Lucrezia Borgia, the daughter of Rodrigo Lenzuoli Borgia or Pope Alexander VI, who specialized in faith-based poisoning, was an early Italian who helped develop poisoning into a simple but fine art. It is said that the Borgias selected and laid down rare poisons in their cellars with as much thought as they gave to their vintage wines. Catherine de Medici of Florence and Queen Consort of France tested and carefully studied the effects of various toxic concoctions on the poor and sick, noting the onset of symptoms that occurred. Marquise de Brinvilliers poisoned her father, two brothers, and her sister for their inheritance. Catherine Deshayes or La Voisin sold poisons to wives who wished to get rid of their husbands. One of the most prolific arsenic poisoners was Goeie Mie (‘Good Mary’) of Leiden, the Netherlands, who lived in the 19th century. She poisoned at least 102 friends and relatives (27 died) between 1867 and 1884, distributing arsenic trioxide in hot milk to her victims after opening life insurance policies in their names.

The first biological weapon described in Western literature may have been the poison from a many-headed serpent, the Hydra, to poison Hercules’ arrows. This led to the term toxic (from toxikon, Greek for poison arrow). The Romans used a variety of biological weapons as did Hannibal who had his sailors catapult pots full of venomous snakes onto the decks of opposing fleets. Other biological weapons have included the following: (1) the use of bellows in 4th century BCE China to pump smoke from mustard and other noxious vegetable matter into tunnels dug by besieging armies, (2) smallpox-infected blankets that the British sent to the American Indians during the French and Indian Wars, (3) animal carcasses thrown by Confederate forces into wells during the US Civil War, and (4) sharp bamboo stakes smeared with human feces by the Vietcong during the Vietnam War.

More modern toxic weaponry includes the following: chlorine gas (first lethal chemical used in modern warfare), phosgene, hydrogen cyanide, mustards, tear gas, and zyklon B (crystallized hydrogen cyanide). Chemical agents (mustard, sarin, and tabun) were used in the Iran-Iraq War between 1983 and 1985 during which it was reported that as many as 7000 people were killed by these gases. Sarin gas contained in lunch boxes was released in the Tokyo subway system in 1995 killing 12 people. This attack was followed by the deaths of five people in the United States in 2001 by anthrax-laced letters. And one should not forget the cyanide-laced grape punch that Jim Jones forced his followers to consume killing the entire congregation of 912 people, including 276 children, or the more recent incident in New Sweden, Maine, where one person died from consuming coffee laced with arsenic. Because of its potency and its frequent use among the ruling class, arsenic is often referred to both as The King of Poisons and "The Poisons of Kings.’

Poisons are found naturally in our foods. These natural toxicants include the following: fungal toxins such as aflatoxin, shellfish toxins, bacterial toxins, and algal poisons. Furthermore, the world is full of toxins produced by a variety of plants and animals. Man continues to add to the list arising from his ability to chemically synthesize a large number of useful but potentially harmful materials. Environmental and workplace pollutants, arising from natural and man-made chemicals, are among the many concerns to the toxicologist.

The father of modern toxicology is M. J. B. Orfila, a Spaniard born on the island of Minorca, Spain, who lived from 1787 to 1853. Early in his career, he studied chemistry and mathematics, and subsequently, he studied medicine in Paris. He is said to be the father of modern toxicology because his interests centered on harmful (as well as therapeutic) effects of chemicals and because he introduced quantitative methodology into the study of the actions of chemicals on animals. He was the author of the first book devoted entirely to studies of the harmful effects of chemicals (Orfila, M. J. B.: Traitê des Poisons Tíres des Règnes Minéral, Végétal et Animal, ou, Toxicologie Générale Considérée sous les Rapports de Ia Physiologie, de la Pathologie et de la Médecine Légale. Crochard, Paris, 1814–1815). He also was the first to point out the valuable use of chemical analyses as proof that existing symptomatology was related to the presence of the chemical. His early criticism and demonstration of the inefficiency of many of the antidotes recommended regarding the treatment of poisoning by chemicals remain valid today. He recognized the value of such procedures as artificial respiration, and he understood some of the principals involved in elimination of poison from the body. Like many of his immediate followers, he was concerned with naturally occurring substances whose harmfulness was the focus of considerable folklore.

Although Orfila is considered the father of modern toxicology, Philippus Aureolus Theophrastus Bombastus von Hohenheim, more commonly known Paracelsus, was a significant figure in the history of toxicology. Paracelsus (born in 1492 near Einsiedeln, Switzerland; died in Salzburg on September 24, 1541) formulated many then-revolutionary views that remain part of present-day toxicology. He believed in the value of experimentation, a break with earlier tradition. Paracelsus, however, is best remembered as establishing the dose response when he stated, All substances are poison; there is none that is not a poison. The right dose differentiates a poison and a remedy.

Scope of modern toxicology

Modern toxicology borrows freely from the basic sciences. A knowledge of and an ability to study the interaction between chemicals and biologic mechanisms is predicated on a background in the basic physical, chemical, and biologic subjects. Toxicology borrows freely from the principles of chemistry and more particularly biochemistry. It is dependent upon the knowledge and understanding of physiology. Familiarity with statistics and public health is fundamental to the study of toxicology. Pathology is a major part of toxicology, for a harmful effect from a chemical on a cell, tissue, or organism must necessarily manifest itself in the form of some type of microscopic and/or submicroscopic deviation from the normal. The field most closely related to toxicology is pharmacology, for the pharmacologist must understand not only the beneficial effects of chemicals but also the harmful effects of those chemicals that may be put to therapeutic use.

In the United States in the past half century, the teaching of toxicology has developed from a few incidental lectures given in courses presented in the health sciences and public health fields to programs given in specific areas of the science. Occasionally, one finds general introductory courses that are designed and presented in upper division undergraduate programs. However, toxicology, for the most part, does not often enjoy the status of an independent department within a college or university.

Hence, the student of toxicology continues to study the subject in a fragmented fashion from a variety of sources. In medical schools, the teaching of toxicology is usually allocated to the pharmacology division of the school, where the subject is taught primarily as a description of the harmful effects of therapeutic agents on man. The diagnosis and treatment of chemical intoxication is taught in the clinics, and the clinical chemical methodology is taught in departments of laboratory medicine. These sources of training are usually designed for the medical students and for graduate students of toxicology. Courses in public health and preventive medicine generally include the statistical methodology and problems associated with exposure to chemicals in a working or domestic environment. Veterinary schools have excellent facilities for the study of the harmful effects of chemicals on livestock and pets. These schools instruct in the absorption, distribution, excretion, and metabolism of foreign chemicals and in the treatment of chemical poisoning in animals. Departments of fisheries and oceanography study and instruct in the effects of chemicals on marine forms of biologic tissue. Thus, modern toxicologists are a collection of scientists from multiple disciplines who have a common interest in the harmful biologic effects of chemicals.

There also are engineers and geologists who study the distribution of chemicals in the air, soil, and water. There are the chemists whose interest and ability rest in the detection and quantification of chemicals in biologic tissue and other more environmentally oriented samples. There is the pharmacologist whose interest is in the harmful effects of chemicals used as drugs. There are the industrial health physicians and public health officers who specialize in the control of pollution and the effects of pollutants on populations. There is the pathologist whose studies are concerned with the gross and microscopic effects of foreign chemicals. There are the veterinarians who are concerned with the effects of chemicals and plants, as well as feed additives, on livestock and pets. There are the marine biologists who are concerned with the adverse effects of chemicals on marine life. Immunologists, geneticists, oncologists, and mutagenicists who not only evaluate new agents for activity in their special areas of expertise but also use compounds that produce effects on these systems as tools in their studies.

The multidisciplinary nature of toxicology is one of its greatest strengths, for it combines knowledge and techniques from multiple scientific disciplines into the field of toxicology. It also allows for the practical and logical division of the subject into sections on the basis of the disciplines involved. Fig. 1.1 shows three such divisions: environmental, economic, and medical.

Fig. 1.1

The environmental division includes the roles that engineering, environmental, and chemical specialists play in the identification and quantification of natural and unnatural agents responsible for contamination (pollution) and transfer of chemicals between and within air, soil, and water. The economic division involves the biologists, chemists, and basic medical scientists who identify and quantify the chemicals responsible for toxicologic problems in food, consumer products, medicines, and other products. It also includes the basic laboratory research programs that study the mechanisms responsible for the harmful effects of chemicals on biologic tissue. The medical division utilizes the capabilities of physicians and veterinarians for the diagnosis and therapy of clinical intoxication. As such it involves the forensic aspects of clinical toxicology and the public health consequences of chemically induced adverse effects. As would be expected, there is considerable crossover between these divisions.

Environmental toxicology

The industrial revolution together with population growth continues to produce a complicated array of patterns by which chemicals are transferred from their source into the environment. Some of these patterns are represented in Fig. 1.2. All chemicals eventually become waste and are translocated either as the original agent or as a transformed product of the original agent. Regardless of whether the original agent was man-made, was a product from some biologic sources, or pre-existed in the environment, it will eventually reach the environment. The environment, composed of air, water and soil, serves as both a supply source and a dump site for chemicals and their derivatives and translocates each agent within the environmental pool. The pool serves as an efficient system for diluting agents generally without showing partiality regarding the order of toxicity of various compounds. Hence, dilution by the massive environment is a major mechanism by which chemicals supposedly disappear from existence. Only when the pool is overwhelmed and the patterns of distribution fail, thereby leading to accumulation of agents at sites important to man’s existence, does the system result in adverse chemical-induced effects on man. Some examples are the localized creation of smog over highly industrialized urban areas and the bioaccumulation of industrial waste products (e.g., methyl mercury) in fish consumed by humans.

Fig. 1.2 Waste chemicals and the environmental cycles.

Exposure to chemicals in the environment and the public health consequences are a continuing source of concern in toxicology. Because direct, reliable data regarding what ultimately happens to the large number of chemicals produced and used by humans are fragmented, there is concern about their persistence and possible accumulation in the environment. Some agents accumulate in animals and aquatic species. Others undergo bacterial or biologic transformation to new chemical entities, which also eventually reach the environment. Some agents simply persist because of a high degree of stability. Although it is tempting to believe that the environment is sufficiently massive that it will ultimately dilute agents to concentrations that have no biologic effect, this is clearly not true. Furthermore, the environment is not always a detoxication medium. For example, chlorine, which is added to drinking water, will appear in wastewater, where it can react with organic material to produce chlorinated hydrocarbons, some of which are carcinogens. This is one of many reasons that nationwide monitoring of drinking water supplies has been conducted routinely since the early 1970s. The National Academy of Sciences (Safe Drinking Water Committee) has published volumes on the subject of pollutants in drinking water, covering aspects ranging from the basic principles of water contamination to the potential health effects of contaminated water. Although contamination of air and water presents major problems, contamination of soil by natural and man-made chemicals is considerably more complicated because of the complexity of the chemistry of soils compared with air and water. In addition, all soils contain microorganisms and their nutrients and by-products, as well as air and water. This allows for the transfer of contaminants between these environments. The physical–chemical property of each agent is involved in facilitating or inhibiting the translocation of the agent within the environment. Ascertaining the final depot of waste chemicals and their products is central to understanding and controlling the potential for the occurrence of adverse effects on humans and the environment.

In spite of the large number of chemicals that appear as waste in the environment, the exposures that have occurred, with the exception of certain catastrophes listed in Table 1.1 and some examples of occupationally related tumorigenicity, have not been shown to be responsible for significant acute mortality in humans. There are, however, reports of a positive statistical relationship between water quality and tumorigenicity in humans, but the risks appear to be at the minimum reliable levels of the procedures involved. The sublethal effects associated with exposure of large populations to chemical waste in the environment presents a complicated diagnostic medical problem (see Chapter 14). The uncertainties regarding potential hazards associated with environmental contamination necessitate continued scientific vigilance to safeguard public health and the