Toxicology is the study of poisons, or, more comprehensively, the identification and quantification of adverse outcomes associated with exposures to physical agents, chemical substances and other conditions. As such, toxicology draws upon most of the basic biological sciences, medical disciplines, epidemiology and some areas of chemistry and physics for information, research designs and methods. Toxicology ranges from basic research investigations on the mechanism of action of toxic agents through the development and interpretation of standard tests characterizing the toxic properties of agents. Toxicology provides important information for both medicine and epidemiology in understanding aetiology and in providing information as to the plausibility of observed associations between exposures, including occupations, and disease. Toxicology can be divided into standard disciplines, such as clinical, forensic, investigative and regulatory toxicology; toxicology can be considered by target organ system or process, such as immunotoxicology or genetic toxicology; toxicology can be presented in functional terms, such as research, testing and risk assessment.
It is a challenge to propose a comprehensive presentation of toxicology in this Encyclopaedia. This chapter does not present a compendium of information on toxicology or adverse effects of specific agents. This latter information is better obtained from databases that are continually updated, as described in the last section of this chapter. Moreover, the chapter does not attempt to set toxicology within specific subdisciplines, such as forensic toxicology. It is the premise of the chapter that the information provided is relevant to all types of toxicological endeavours and to the use of toxicology in various medical specialities and fields. In this chapter, topics are based primarily upon a practical orientation and integration with the intent and purpose of the Encyclopaedia as a whole. Topics are also selected for ease of cross-reference within the Encyclopaedia.
In modern society, toxicology has become an important element in environmental and occupational health. This is because many organizations, governmental and non-governmental, utilize information from toxicology to evaluate and regulate hazards in the workplace and nonoccupational environment. As part of prevention strategies, toxicology is invaluable, since it is the source of information on potential hazards in the absence of widespread human exposures. Toxicological methods are also widely used by industry in product development, to provide information useful in the design of specific molecules or product formulations.
The chapter begins with five articles on general principles of toxicology, which are important to the consideration of most topics in the field. The first general principles relate to understanding relationships between external exposure and internal dose. In modern terminology, “exposure” refers to the concentrations or amount of a substance presented to individuals or populations—amounts found in specific volumes of air or water, or in masses of soil. “Dose” refers to the concentration or amount of a substance inside an exposed person or organism. In occupational health, standards and guidelines are often set in terms of exposure, or allowable limits on concentrations in specific situations, such as in air in the workplace. These exposure limits are predicated upon assumptions or information on the relationships between exposure and dose; however, often information on internal dose is unavailable. Thus, in many studies of occupational health, associations can be drawn only between exposure and response or effect. In a few instances, standards have been set based on dose (e.g., permissible levels of lead in blood or mercury in urine). While these measures are more directly correlated with toxicity, it is still necessary to back-calculate exposure levels associated with these levels for purposes of controlling risks.
The next article concerns the factors and events that determine the relationships between exposure, dose and response. The first factors relate to uptake, absorption and distribution—the processes that determine the actual transport of substances into the body from the external environment across portals of entry such as skin, lung and gut. These processes are at the interface between humans and their environments. The second factors, of metabolism, relate to understanding how the body handles absorbed substances. Some substances are transformed by cellular processes of metabolism, which can either increase or decrease their biological activity.
The concepts of target organ and critical effect have been developed to aid in the interpretation of toxicological data. Depending upon dose, duration and route of exposure, as well as host factors such as age, many toxic agents can induce a number of effects within organs and organisms. An important role of toxicology is to identify the important effect or sets of effects in order to prevent irreversible or debilitating disease. One important part of this task is the identification of the organ first or most affected by a toxic agent; this organ is defined as the “target organ”. Within the target organ, it is important to identify the important event or events that signals intoxication, or damage, in order to ascertain that the organ has been affected beyond the range of normal variation. This is known as the “critical effect”; it may represent the first event in a progression of pathophysiological stages (such as the excretion of small-molecular-weight proteins as a critical effect in nephrotoxicity), or it may represent the first and potentially irreversible effect in a disease process (such as formation of a DNA adduct in carcinogenesis). These concepts are important in occupational health because they define the types of toxicity and clinical disease associated with specific exposures, and in most cases reduction of exposure has as a goal the prevention of critical effects in target organs, rather than every effect in every or any organ.
The next two articles concern important host factors that affect many types of responses to many types of toxic agents. These are: genetic determinants, or inherited susceptibility/resistance factors; and age, sex and other factors such as diet or co-existence of infectious disease. These factors can also affect exposure and dose, through modifying uptake, absorption, distribution and metabolism. Because working populations around the world vary with respect to many of these factors, it is critical for occupational health specialists and policy-makers to understand the way in which these factors may contribute to variabilities in response among populations and individuals within populations. In societies with heterogeneous populations, these considerations are particularly important. The variability of human populations must be considered in evaluating the risks of occupational exposures and in reaching rational conclusions from the study of nonhuman organisms in toxicological research or testing.
The section then provides two general overviews on toxicology at the mechanistic level. Mechanistically, modern toxicologists consider that all toxic effects manifest their first actions at the cellular level; thus, cellular responses represent the earliest indications of the body’s encounters with a toxic agent. It is further assumed that these responses represent a spectrum of events, from injury through death. Cell injury refers to specific processes utilized by cells, the smallest unit of biological organization within organs, to respond to challenge. These responses involve changes in the function of processes within the cell, including the membrane and its ability to take up, release or exclude substances; the directed synthesis of proteins from amino acids; and the turnover of cell components. These responses may be common to all injured cells, or they may be specific to certain types of cells within certain organ systems. Cell death is the destruction of cells within an organ system, as a consequence of irreversible or uncompensated cell injury. Toxic agents may cause cell death acutely because of certain actions such as poisoning oxygen transfer, or cell death may be the consequence of chronic intoxication. Cell death can be followed by replacement in some but not all organ systems, but in some conditions cell proliferation induced by cell death may be considered a toxic response. Even in the absence of cell death, repeated cell injury may induce stress within organs that compromises their function and affects their progeny.
The chapter is then divided into more specific topics, which are grouped into the following categories: mechanism, test methods, regulation and risk assessment. The mechanism articles mostly focus on target systems rather than organs. This reflects the practice of modern toxicology and medicine, which studies organ systems rather than isolated organs. Thus, for example, the discussion of genetic toxicology is not focused upon the toxic effects of agents within a specific organ but rather on genetic material as a target for toxic action. Likewise, the article on immunotoxicology discusses the various organs and cells of the immune system as targets for toxic agents. The methods articles are designed to be highly operational; they describe current methods in use in many countries for hazard identification, that is, the development of information related to biological properties of agents.
The chapter continues with five articles on the application of toxicology in regulation and policy-making, from hazard identification to risk assessment. The current practice in several countries, as well as IARC, is presented. These articles should enable the reader to understand how information derived from toxicology tests is integrated with basic and mechanistic inferences to derive quantitative information used in setting exposure levels and other approaches to controlling hazards in the workplace and general environment.
A summary of available toxicology databases, to which the readers of this encyclopaedia can refer for detailed information on specific toxic agents and exposures, can be found in Volume III (see “Toxicology databases” in the chapter Safe handling of chemicals, which provides information on many of these databases, their information sources, methods of evaluation and interpretation, and means of access). These databases, together with the Encyclopaedia, provide the occupational health specialist, the worker and the employer with the ability to obtain and use up-to-date in- formation on toxicology and the evaluation of toxic agents by national and international bodies.
This chapter focuses upon those aspects of toxicology relevant to occupational safety and health. For that reason, clinical toxic-ology and forensic toxicology are not specifically addressed as subdisciplines of the field. Many of the same principles and approaches described here are used in these subdisciplines as well as in environmental health. They are also applicable to evaluating the impacts of toxic agents on nonhuman populations, a major concern of environmental policies in many countries. A committed attempt has been made to enlist the perspectives and experiences of experts and practitioners from all sectors and from many countries; however, the reader may note a certain bias towards academic scientists in the developed world. Although the editor and contributors believe that the principles and practice of toxic-ology are international, the problems of cultural bias and narrowness of experience may well be evident in this chapter. The chapter editor hopes that readers of this Encyclopaedia will assist in ensuring the broadest perspective possible as this important reference continues to be updated and expanded.