Toxicology and Bioterrorism: Introduction
Toxicology is the study of the adverse effects produced in living organisms by chemical agents under varying conditions of exposure. It is an evolving discipline, historically supported by associated disciplines such as pharmacology and pathology, and increasingly informed by molecular biochemistry, epidemiology, and statistical and information sciences. Toxicology is a critical pathophysiologic cornerstone on which any understanding of the health effects of chemical and nuclear agents is built. The medical and public health consequences of BCN terrorism operates at the nexus of three major scientific domains: clinical medicine, public health, and toxicology. With the probable exception of intensivists, emergency room physicians, occupational medicine physicians, and medical toxicologists, practicing clinicians’ comfort level with applied toxicology is usually limited to medical therapeutics. One of the purposes of this book is to enable clinicians and front-line public health practitioners to understand some of the fundamental principles intrinsic to BCN terrorism, many of which are usefully generalizable to other public health and clinical issues.
Basic knowledge of the principles of toxicology is important for a deeper understanding of the pathophysiology from BCN agents. Understanding toxicologic principles is important when considering the health effects of BCN terrorism for several reasons. First, knowing these principles will facilitate an understanding of how cells and cellular structures, tissues, organs, and ultimately, individuals respond to these agents. This short overview of toxicology summarizes physicochemical properties common to many of the chemical agents covered in this book.
Toxicology: The Study of Poisons
The study of poisons, as toxicology is rightly viewed, stretches back into antiquity. The scientist and alchemist Paracelsus conducted extensive experimentation on metals from which basic concepts, such as dose and dose response, were placed on more scientific rigorous ground. Indeed, it was Paracelsus (Fig. 8–1) who observed that all chemicals may be injurious given the right circumstances, an aphorism widely quoted but infrequently sourced. Careful clinical observations by the Italian physician Ramazzini (1710–1767), the English surgeon Sir Percival Pott (1780–1843), and many others established the connection between trades and a wide variety of disease processes. Propelled by Newtonian scientific principles, the Industrial Revolution of the 17th and 18th centuries vastly expanded the number, utility, and adverse health and environmental consequences of a wide range of hazardous materials and led directly to the creation of entire industries, including the chemical and pharmaceutical industries from which many of the chemical agents discussed in The Bioterrorism Sourcebook emerged.
In time, the health hazards brought about as a result of this remarkable economic transformation were recognized and led to the creation of the discipline of industrial toxicology in the 1930s. Indeed, some of the earliest pioneers in this area were physicians, such as Harvard’s Alice Hamilton, whose work integrated field investigation, clinical assessment, and laboratory-based toxicologic evaluations. The social, economic, and public health consequences of the Industrial Revolution led not only to the recognition of new diseases, but also to substantial changes in the prevalence of many known diseases. Advances in mathematics and physics led in time to the discovery of radiation, and a host of medical and public health consequences have followed over time. The commercial, industrial, and medical applications of atomic physics generated a host of previously unknown medical diseases. For example, in the early 1900s, case reports of a progressively destructive mandibular cancer (“phossy jaw”) were described in women painting radioactive phosphorus on the watch hands of time pieces. Twentieth-century developments in atomic and quantum physics led to the creation of thermonuclear bombs and the nuclear energy industry (see Section IV). Radiation burns, radiation sickness, and hematopoietic and thyroid cancers are a few of the medical conditions that resulted from the new technologies arising from these scientific discoveries. Diseases such as asbestosis or silicosis that were known in ancient times occurred in increasing numbers as technology transformed many processes such as mining, foundry work, or shipbuilding from ones involving relatively few skilled tradesmen to huge industries where exposure levels and the number of exposed individuals were increased dramatically.
More often than not, the adverse human and environmental consequences of chemicals and processes occur only after a delay that can be of considerable length. This biological fact has considerable implications in terms of prevention and regulation of industry. Further, the human body’s innate ability to deal with a wide number of toxicants interjects substantial variability in the clinical manifestations of toxicity, a fact that complicates the study of toxicologically mediated disease. Even at present, detailed knowledge of adverse effects is confined largely to toxicants with which our experience has been longest. Mechanisms of injury, distribution, metabolism, excretion, and chronic sequelae are far better understood with metals such as lead, arsenic, and mercury, for example. One need only point out that of the four million chemicals now known—of which approximately 50,000 are in regular use—only a tiny fraction of them have been evaluated according to best modern toxicologic practices.
This chapter confines itself to basic principles of toxicology with the aim of informing subsequent chapters on chemical and nuclear agents, their acute and chronic health effects, and medical and public health control strategies. Each of these aspects, in part, is based on toxicologic properties and our body’s response to toxicants.
Principles of Toxicology
Understanding of the toxic effects of chemicals is predicated on an understanding of the physical state of compounds, how they enter the body and are transported to sites where they exert their effects, how they are broken down or metabolized, and finally how they are ultimately eliminated from the body. The composite description of these actions—absorption, distribution, metabolism, and excretion—is termed toxicokinetics.
The physical form in which a substance exists under ambient environmental conditions plays a significant role in determining what, if any, toxic effect it might have. Changes in these environmental variables may alter the physical state and therefore the potential toxicity of any given substance. The three most basic physical states are solids, liquids, and gases, but these in turn may be modified under the right environmental conditions into fumes, mists, or vapors.
Solids present minimal risk when undisturbed, but they may create airborne dust or fibers if subject to disruption or mechanical attrition by crushing, grinding, or detonation. Due to the progressively narrow branching structure of the lung, dust particles or fibers ranging from three to seven micrometers find their way to the distal airways and alveoli of the lung where they have their characteristic health effects. Asbestos fibers, for example, are typically 5 microns in size and when inhaled settle into terminal bronchioles and alveoli and initiate an inflammatory process that may culminate in the pneumoconiosis that bears the name of this mineral.
Liquids are free-flowing incompressible fluids that may be pure, or come in the form of mixtures (if a solid is dissolved in it) or solutions (if another liquid is dissolved in it). To some degree, all liquids are in equilibrium with the atmosphere. This equilibrium is affected by the intrinsic volatility of the liquid and by ambient conditions of temperature and pressure. For example, gasoline is a volatile liquid that evaporates more readily as temperature or pressure increases. Partially evaporated liquids at the interface between the liquid itself and the air are vapors. Consequently, vapors are potentially hazardous through dermal and respiratory routes of exposure. Vapors may also be generated from solids through a process known as sublimation. Vapors are diffusible in air, with essentially gaseous properties, and may reform (or condense) under suitable conditions.
Gases are compressible fluids that expand freely and uniformly to occupy the space available under ambient environmental conditions. The principal health risk from gases arises via inhalation. Gases and vapors may be denser than air, a fact that has direct health consequences. Gases and vapors that are denser than air will preferentially seek the lower ground and will collect in pits and other confined spaces. “Ideal” chemical warfare agents, including VX and mustard gas, are designed with this property in mind and cause greater injury to those exposed as a result.
Another aspect of this property is that the encroaching gas or vapor may displace oxygen and thereby cause asphyxiation. Asphyxiation is an important clinical syndrome from both an occupational and BCN perspective. There are two types of asphyxiation: hypoxic asphyxiation and histotoxic asphyxiation. The former occurs when a gas or vapor simply displaces oxygen from the environment and the oxygen-poor atmosphere lowers the partial pressure of oxygen in the blood. Hypoxic asphyxiation can occur with both inorganic gases (e.g., sulfur dioxide) and volatile organic solvents. Simple asphyxiants displace oxygen from respirable air such that the higher the concentration of a simple asphyxiant, the lower the concentration of oxygen. At some level, the resulting oxygen deprivation begins to have adverse clinical consequences (Table 8–1
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