Toxicology for the Health and Pharmaceutical Sciences

Antonio Peña-Fernández, Mark D. Evans, Marcus S. Cooke, Antonio Peña-Fernández, Mark D. Evans, Marcus S. Cooke

• Publisher: CRC Press
• Year: 2021
• Print ISBN: 9781138303362
• eBook ISBN: 9781351398008
• Topic: Medicine
• Subtopic: Pharmacology

There is an increasing need for knowledge of toxicology to safeguard the use of chemicals in industry and in the public and private sectors. The study of toxicology is becoming increasingly relevant in human health sciences, as future health and clinical professionals will be pivotal in addressing and managing emerging chemical threats and hazards related to modern anthropogenic activities and technological development.

Comprising a series of chapters from leading toxicology, pharmacy and public health academics and experts across Europe, the United States and beyond, Toxicology for the Health and Pharmaceutical Sciences provides a concise yet comprehensive volume that can be used as a relevant textbook on toxicology for the clinical, healthcare, educational and professional sectors.

Key Features:

• Includes cutting edge information regarding the very lastest environmental threats to public health
• Provides a detailed case study based on a real-world scenario that allows the reader to practice human health risk assessment
• Describes innovative guidance and tools to respond to chemical incidents and attacks, which enables the reader to tailor an effective protection and remediation response

This book covers the fundamentals and recent developments in toxicology, to respond to local and global chemical, pharmaceutical and environmental threats. Thus, this volume has chapters specifically designed to support the understanding of the most current toxicology-related subjects for any undergraduate/postgraduate health programs as well as aid the delivery of continuing professional development training on up-to-date topics in toxicology for current practicing health professionals wishing to improve their background knowledge in toxicology. The book is also vital reading and reference for policy makers and others that influence and set regulations that have an impact on the environment and human health.

1

Introduction to Toxicology

Mª Teresa Hernández, Mª del Carmen Berrocal, Domingo Ly-Pen and Mª Victorina Aguilar

DOI: 10.1201/9780203730584-1

CONTENTS

1.1 The Concept of Toxicology and Areas of Action

1.2 Concept of What Is Toxic

1.3 Determining Factors of Toxicity

1.3.1 Biological System

1.3.2 Routes of Exposure

1.3.3 Toxicokinetic Processes

1.4 Intoxication and Types

1.4.1 Duration of Chemical Exposure Needed to Produce Toxicity

1.4.2 Etiology of Toxic Agent

1.4.3 Characteristics of the Appearance or Location of the Toxic Effect

1.4.4 Dose Effect or Dose Response

1.5 Dose-Response Relationships to Mixtures of Chemical Substances

1.6 Modern Toxicology Research

Bibliography

1.1 THE CONCEPT OF TOXICOLOGY AND AREAS OF ACTION

From the etymological point of view, the word “toxicology” is derived from two Greek words: toxikon (poison) and logos (treatise), which means “the science of poisons”. According to Paracelsus (1493–1541), often called the Grandfather of Modern Toxicology, “all substances are poisons; there is none which is not poison. The right dose differentiates a poison from a remedy”.

Orfila (1787–1853), the founder of the science of toxicology, in his famous Treatise of Toxicology (1813), defined a poison as “any substance, taken or applied in any way in small doses in a living organism, which destroys health or ends life entirely”. According to this definition, substances would be classified as poisons and nonpoisons, the dose being crucial to establish their difference, and thus making the distinction between poisoning by overdose and poisoning itself.

With the advances of toxicology, this definition is now incomplete and the word “poison” is misleading. Since Paracelsus, it is well known that it is the dose that makes the poison; a chemical that is perfectly safe at one dose may be lethal at another. For example, at very high doses even table salt or drinking water can be harmful, especially if you consider the influence of other factors, such as stage of life, age, diet, diseases and concomitant exposures to various agents. Therefore, one of the most accepted definitions of toxicology today is “the study of the adverse effects of chemicals or physical agents on living organisms” (Gilbert 2012).

The change of paradigm in toxicology implies a transition from an in vivo science (in which the use of animals in experimental laboratory conditions were required to study parameters, such as the lethal dose for half of the population of animals) to a science in which the following are studied (even virtually): routes of exposure, mechanisms of action, events and key processes of the target molecule, cellular responses, and even the macroscopic and organographic effects on human health and the environment (Meek et al. 2014).

From a historical point of view, toxicology was consolidated as a scientific discipline, independent of medicine but related through forensic toxicology. For the development of this branch and of other more recent ones, a prerequisite was the development of increasingly sensitive and specific analysis techniques capable of analyzing toxic agents in biological samples, mainly blood and urine, of exposed subjects to confirm the presence of the toxin responsible (analytical toxicology). Analytical toxicology, with the advances in pharmacological toxicology and with the support of appropriate regulatory legislation, contributed to the current successes of forensic toxicology and clinical toxicology, which aims to diagnose and treat intoxications like any other disease that has a pathological character; that is, it can manifest in an acute and chronic way, before the death of the subject (Bello 2001).

New lifestyles, exposure to new substances and so forth have given rise to the development of different subdisciplines of toxicology. These subdisciplines are often closely related to each other, and their knowledge and application serves to protect public health.

The development of the chemical industry has contributed to these advances in toxicology in the twentieth century, and interest has grown in increasing toxicological knowledge in relation to health in the workplace. The grouping of national toxicological societies by continental blocks has also been of crucial importance, represented by SOT in North America, EUROTOX in Europe, ASIATOX in Asia, ALATOX in Latin America and toxicological societies in Africa, such as those in South Africa and Cameroon. From the international cooperation of the different societies, the International Union of Toxicology (IUTOX) was created in 1980. It has played an important role in the applied knowledge of toxicology (Repetto and Repetto 2009).

The different subdisciplines of modern toxicology are outlined in Figure 1.1 and are established according to the way of addressing a toxic event in three areas that correspond to the type of work performed (Jaramillo et al. 2006):

1. General: the general basis of toxic actions. This includes mechanisms of action and ways of counteracting their effects.
2. Descriptive: the science of toxicity testing to provide information about safety evaluation and regulatory requirements. The different aspects and toxicological studies are grouped on toxic agents such as metal toxicology, toxicology of organic solvents, toxicology of pesticides and so forth.
3. Mechanistic: studies, identifies and attempts to understand the mechanisms by which toxic agents exert toxic effects on living beings, in order to produce safer substances and develop a rational treatment of intoxication.
4. Regulatory: integrates the information obtained from the mechanistic and descriptive areas to determine the level of risk to health and to the handling of exposure to chemical substances.

Figure 1.1 Subdisciplines of toxicology. The field of toxicology can divided into various subdisciplines, derived from the vertical and horizontal integration of toxicology with other sciences. Modern toxicology is a conglomerate of subdisciplines that cooperate to promote knowledge of physicochemical toxicity.

To further investigate the fundamental mechanisms and processes involved in toxic phenomena, it is necessary to integrate toxicological investigations with the knowledge of other basic sciences (Figure 1.1). This integration can be achieved by two methods (Bello 2001):

1. Vertical integration gives rise to the appearance of diverse subdisciplines: genetic, molecular toxicology, inmunotoxicology, neurotoxicology and so forth.
2. Horizontal integration is oriented towards practical applications with repercussions that affect the environment and human health. In this way, two areas appear:
   1. Retrospective toxicology: typical of the forensic branch oriented to the investigation of a toxin in corporal organs and its medicolegal aspects.
   2. Predictive toxicology: oriented towards the prediction of possible toxic effects in specific situations, including drug use, drug interactions and presence of contaminants or additives not allowed in food.

This horizontal integration of toxicology with other sciences gives rise to the appearance of different applied branches, among which we must highlight:

• Clinical toxicology, based on physiology, clinical chemistry and pharmacology, which studies the pathological changes caused by toxic agents, establishes treatments for intoxicated patients and analyzes new techniques to treat intoxications.
• Occupational or professional toxicology, based on occupational medicine and occupational hygiene. Occurrence of occupational diseases is related to toxic substances present in work environments. Therefore, toxicology investigates the harmful effects produced by substances for occupational use and determines safe exposure limits.
• Environmental toxicology, which relies on ecology and environmental chemistry to analyze the impact of pollutants present in the environment of living organisms. It is the subdiscipline responsible for evaluating the vast environmental impact produced by exposures to chemical products present in the environment, with special attention to living species other than humans in air, soil or water. A complex environment requires paying attention to the persistence of pollutants in soil, water and air, and knowing the capacity they have to join the food chain.

The joint work between ecologists and environmental toxicologists is increasing our knowledge about the impact of agrochemicals on native species. Monitoring changes of speciation, due to the effect of nearby mines or chemical plants, has led to development of the field of ecotoxicology. This is a branch of environmental toxicology, which studies the particular way(s) in which toxins impact the population dynamics of an ecosystem (Newman 2010).

• Food toxicology is a multidisciplinary approach, studying adverse effects of exposure by living organisms to chemical substances present in food. This area is supported by chemical analysis, food science and nutrition.
  It is important to know what products are safe to eat, and in what amounts; this discipline investigates the safety of the components that are added to food, deliberately or accidentally, as natural and synthetic additives or contaminants. Accidental contaminants are generally synthetic or natural environmental contaminants, such as polychlorinated biphenyls (PCBs) and methylmercury, which are found in fish; microbial toxins such as those produced by Escherichia coli in contaminated food; and fungal toxins, such as aflatoxins, which can contaminate grains. Recently, scientists have investigated and debated about the safety of genetically modified organisms (GMOs) as food products and the influence of new conservation technologies on food safety.
• Pharmacological toxicology studies the safety of pharmaceutical products. Toxicity testing helps ensure that pharmaceutical products are safe for humans. Advances in pharmacology and toxicological research help to ensure that the beneficial effects of therapeutic agents are not outweighed by undesired side effects.
• Forensic toxicology establishes the causes of death caused by toxins in humans and animals, their circumstances, and their medicolegal implications.

1.2 CONCEPT OF WHAT IS TOXIC

As with other fields of knowledge, toxicology has its own distinctive vocabulary: toxin, toxicant, poison and xenobiotic are often used interchangeably in the literature; however, there are subtle differences between them. The term “toxin” is best reserved for harmful substances made by living organisms (e.g. poisonous marine organisms, infectious pathogens or venomous spiders). The word “poison” is widely used for this purpose during everyday life, but it may convey a misleading interpretation, because their action depends on the dose, the individual and environmental circumstances, as mentioned previously (Burcham 2014a).

According to toxicologists themselves, the word “toxin” should be used if the foreign material came from a biological source. This means a substance is only poisonous if produced by living cells or organisms.

A “toxicant”, on the other hand, should only be used if the foreign material came from man-made sources; thus it is not produced biologically. The names of toxicants are especially informative when coupled with a prefix that designates the site of toxic action for a given substance; alcohol, for example, is a hepatotoxicant because it causes liver damage at high doses (Burcham 2014b).

The term “xenobiotic” describes chemicals found but not produced in organisms or the environment. This includes numerous substances such as food additives, contaminants, drugs, recreational drugs pesticides, herbicides and industrial reagents.

The term “endobiotic”, in contrast, includes chemical compounds present in the body during normal physiological processes (androgens, neurotransmitters, glucocorticoids, bilirubin, etc.). According to this definition, any substance can damage an organism because all exogenous products (xenobiotics) as the own constituents of the organism (endobiotics) when they are in a certain amount, can produce toxic effects.

This does not mean that external ...

Table of contents

• Cover Page
• Half Title Page
• Title Page
• Copyright Page
• Dedication Page
• Contents Page
• Preface Page
• Acknowledgments Page
• About the Editors Page
• List of Contributors Page
• 1 Introduction to Toxicology
• 2 Toxicokinetics
• 3 Metabolism and Biotransformation of Xenobiotics
• 4 Mechanistic Toxicology
• 5 Genetic Toxicology and Carcinogenesis
• 6 Reproductive and Developmental Toxicology
• 7 Juvenile Toxicology
• 8 In Vitro Toxicity Testing
• 9 In Vivo Toxicity Testing
• 10 Toxicological Applications of Genomic, Proteomic and Metabolomic Technologies
• 11 Toxic Effects of Pharmaceuticals and Cosmetics
• 12 Toxicology of Herbal Medicines
• 13 Toxicology of Industrial Chemicals
• 14 Food Toxicology
• 15 Nanotoxicology
• 16 Human Health Risk Assessment
• 17 Toxicological Modelling
• 18 Human Biomonitoring
• 19 Introduction to Environmental Toxicology
• 20 Exposomics and Environmental Monitoring
• 21 Pesticide Toxicology
• 22 Pharmaceuticals and Cosmetics as Emerging Environmental Contaminants
• 23 Environmental Recovery and Remediation: The role of soil pollution on human health
• 24 Toxicology and Climate Change
• 25 Chemical Warfare and Terrorism
• 26 Toxicology of Drugs of Abuse
• 27 Case Studies in Human Toxicology 1: Human Health Risk Assessments for Arsenic and Beryllium in Urban Soils
• 28 Case Studies in Toxicology 2: Recovering Environments Affected by Chemical Incidents: The Chemical Recovery Navigation Tool
• Index