1
GENERAL PRINCIPLES OF TOXICOLOGY

ROBERT C. JAMES, STEPHEN M. ROBERTS, AND PHILLIP L. WILLIAMS

This chapter provides a concise description of the basic principles of toxicology and illustrates how these principles are used to make reasonable judgments concerning the potential health hazards and/or risks associated with chemical exposures. This chapter will explain:

• Some basic definitions and terminology used in toxicology and the area of risk assessment
• The general areas of study within toxicology, the scientific disciplines toxicologists draw upon, and specialized areas of interest within toxicology
• How whole animal studies and in vitro techniques provide the primary basis for hazard identification
• The importance of dose and the generation of dose-response relationships will be explained, and then, how dose-response data are used to predict the outcome of a particular chemical exposure
• Factors that may alter a chemical's toxicity or the dose-response relationship
• The basic methods and considerations used to develop exposure guidelines protective of public health

1.1 BASIC DEFINITIONS AND TERMINOLOGY

The literal meaning of the term toxicology is "the study of poisons." The root word toxic entered the English language around 1655 from the Late Latin word toxicus (which meant poisonous), which itself was derived from the earlier ancient Greek term for the poisons into which arrows were dipped, toxikón. The early history of toxicology focused on understanding the uses of different poisons, but today toxicology has evolved into a modern science whose interest has been expanded to encompass all adverse health effects produced by any chemical substance. The following definitions are provided to help the reader understand several basic terms that may be used in this and other chapters:

• Toxic. Having the characteristic of being able to produce an undesirable or adverse health effect at some dose.
• Toxicity. Any adverse effect that a chemical or physical agent might produce within a living organism.
• Toxicology. The science that deals with the study of the adverse effects (toxicities) that chemicals or physical agents may produce in living organisms under specific conditions of exposure. It is a science that attempts to qualitatively identify all the hazards (i.e., organ toxicities) associated with a substance, as well as to quantitatively determine the exposure conditions under which those hazards/toxicities are induced. Toxicology is the science that experimentally investigates the occurrence, nature, incidence, mechanism, and risk factors for the adverse effects of toxic substances.

As these definitions indicate, the toxicities of interest span a broad biologic and physiologic spectrum. The adverse effects of interest may range from something relatively minor like irritation or tearing, to a more serious response like acute but reversible liver or kidney damage, to an even more serious and permanent disability like cirrhosis of the liver or cancer in a specific tissue. Given this broad range of potentially adverse effects to consider, it is useful for those unfamiliar with toxicology to define additional terms that will be discussed in subsequent chapters of this book.

• Exposure. A measure of the opportunity to have contact with a chemical present in one's environment. The presence of a chemical in an environmental medium of contact (e.g., in the air we breathe, the water we drink, on surfaces we touch, in foods we might eat). Exposure levels are typically expressed as the concentration of the chemical in the contact medium (e.g., as the ppm concentration in air, or in mg/l of water).
• Dose. A dose is the total amount of a toxicant an organism receives as the result of some exposure. The most common use of the term dose refers to the applied dose, i.e., the amount of chemical present at the site of contact. But different definitions and terms arise for the concept of dose as we move from the site of contact on the body to the actual amount absorbed by the body and then the amount absorbed by various tissues within the body. So, more specific definitions for the term dose include the following:
  • Applied Dose. Represents the total amount of the chemical that is directly applied to, or has direct contact with, body surfaces that are the portal(s) of entry (via absorption) into the body. The applied dose may be higher than the absorbed dose because not all of the chemical may get across the cell membranes at the site of contact.
  • Internal/Absorbed dose. The quantity of a toxicant that is ultimately absorbed into the organism and distributed systemically throughout the body. The ratio of the absorbed dose/applied dose is referred to as the chemical's bioavailability.
  • Delivered/Effective/Target Organ Dose. The amount of toxicant reaching the target organ (i.e., the specific organ adversely affected by the toxicant).
  • Exposure Concentration Response Curves (As a Surrogate Measure of Dose). In many ecological toxicity studies, the effects of a chemical on the test organism is measured as a function of the exposure concentration (i.e., the toxicant is usually added to an aquatic or soil medium and the response is measured as a function of the concentration in that medium. In these situations, exposure-response curves are generated instead of traditional dose-response plots because the applied dose is not known, and the response is a function of the organism's activity with the test medium.
• Acute Exposure. Exposure that occurs only for a brief period of time (generally less than 24 h). Frequently, this term is applied to a single exposure (or dose), but it also may be an applicable term for repeated exposures that occur within a relatively short time period.
• Subacute Exposure. Resembles acute exposure except that the exposure duration is greater, e.g., from several days to 1 month in animal studies.
• Subchronic Exposure. Exposures repeated or spread over an intermediate time range. For animal testing, this time range is generally considered to be 1-3 months.
• Chronic Exposure. Exposures (either repeated or continuous) over a long period of time. In animal testing, chronic exposures are those ranging between 90 days and the animal's lifetime. But it generally represents exposures that occur for a majority of that species' lifetime. For human exposures, it is defined as a long-term exposure measured in years.
• Acute Toxicity. An adverse or undesirable effect that is manifested within a relatively short time interval ranging from almost immediately to within several days following exposure (or dosing). An example would be chemical asphyxiation from exposure to a high concentration of carbon monoxide (CO). Acute toxicities that are not fatal may be reversible.
• Chronic Toxicity. A permanent or lasting adverse effect that is manifested after exposure to a toxicant. Examples would be the development of silicosis following a long-term exposure to silica in workplaces such as foundries or liver cirrhosis following chronic alcohol consumption.
• Local Toxicity. An adverse or undesirable effect that is manifested at the toxicant's site of contact with the organism. Examples include an acid's ability to cause severe irritation, blistering or scarring of the eyes, upper respiratory tract, or skin.
• Systemic Toxicity. An adverse or undesirable effect that can be seen anywhere within the organism. It typically involves an organ in the body with selective tissue vulnerability to a toxicity induced by the chemical. Systemic toxicities require the toxicant first be absorbed and distributed to the target organ and the organ adversely affected may be distant from the site at which absorption occurs. Examples include the adverse effects on the kidney or central nervous system (CNS) resulting from the acute or chronic ingestion or inhalation of mercury.
• Reversible Toxicity. Any adverse effect that can be reversed once exposure is stopped. The reversibility of toxic effect depends on a number of factors, including the duration and magnitude of the exposure, and the ability of the affected tissue to repair or regenerate once exposure ceases. Examples include liver regeneration following an acute overdose of acetaminophen, or the generation of new skin after an excessive exposure to sun has led to a sunburn, blistering, and the sloughing of dead skin.
• Delayed or Latent Toxicity. An adverse or undesirable effect that appears long after the initiation and/or cessation of exposure to the toxicant. One example is the cervical cancer occurring during adulthood produced by an in utero exposure to diethylstilbestrol (DES). Almost all chemical-induced cancers are examples of a latent toxicity.
• Allergic Reaction. A reaction to a toxicant caused by an altered state of the normal immune response. The outcome of the exposure can be immediate (anaphylaxis) or delayed (cell-mediated).
• Idiosyncratic Reaction. A response that occurs rarely and unpredictably. They typically cannot be explained by the known mechanism of toxicity of the causative agent.
• Mechanism of Toxicity. Those...