As these definitions indicate, the toxic responses that form the study of toxicology span a broad biological and physiological spectrum. Effects of interest may range from something relatively minor such as irritation or tearing to a more serious response like acute and reversible liver or kidney damage, to an even more serious and permanent disability such as cirrhosis of the liver or liver cancer. Given this broad range of potentially adverse effects to consider, it is perhaps useful for those unfamiliar with toxicology to define some additional terms, listed in order of relevance to topics that will be discussed in Chapters 2–24 of this book.

• Exposure—a measure of the opportunity for contact with a chemical in one’s environment. The presence of a chemical in an environmental media 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 water).
  
• Dose—describes the total amount of a toxicant an organism receives as the result of some exposure. The definition of dose typically refers to the applied dose, but different definitions and terms arise for the concept of dose as we move from the site of contact on the body to that amount absorbed and then distributed to the various tissues of the body. For example:
  
• Applied dose—this is the total amount of the chemical that is directly applied to or has direct contact with those body surfaces that represent a portal of entry (via absorption) into the body. The applied dose can be higher than the absorbed dose because all of the chemical does not necessarily get across the membranes or surfaces at the site of contact.
  
• Internal/absorbed dose—the actual quantity of a toxicant that is ultimately absorbed into the organism and distributed systemically throughout the body.
  
• Delivered/effective/target organ dose—the amount of toxicant reaching the organ (known as the target organ) that is adversely affected by the toxicant.
  
• Acute exposure—exposure that occurs only for a brief period of time (generally <24 h). Often it is considered to be a single exposure (or dose) but may consist of repeated exposures within a short time period.
  
• Subacute exposure—resembles acute exposure except that the exposure duration is greater, for example, 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 this exposure ranges between 90 days to a lifetime. It is generally any exposure that occurs for the majority of that species’ lifetime. In occupational settings it is generally considered to be for a number of years or more and may include either a working lifetime or an entire lifetime of an individual.
  
• 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).
  
• Chronic toxicity—a permanent or lasting adverse effect that is manifested after exposure to a toxicant. An example would be the development of silicosis following a long-term exposure to silica in workplaces such as foundries.
  
• 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 burning of the eyes, upper respiratory tract irritation, and skin burns.
  
• 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 the toxic effect of the chemical distant from the point of entry of the toxicant (i.e., toxicant requires absorption and distribution within the organism to produce a systemic effect). Examples would include the adverse effects on the kidney or central nervous system (CNS) resulting from the acute or chronic ingestion of mercury.
  
• Reversible toxicity—an adverse or undesirable effect that can be reversed once exposure is stopped. Reversibility of toxicity depends on a number of factors, including the extent of exposure (time and amount of toxicant) and the ability of the affected tissue to repair or regenerate. An example includes hepatic toxicity from acute acetaminophen exposure and liver regeneration.
  
• Delayed or latent toxicity—an adverse or undesirable effect appearing long after the initiation and/or cessation of exposure to the toxicant. An example is cervical cancer during adulthood resulting from in utero exposure to diethylstilbestrol (DES).
  
• 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 to a toxicant occurring at exposure levels much lower than those generally required to cause the same effect in most individuals within the population. This response is genetically determined, and a good example would be sensitivity to nitrates due to deficiency in NADH (reduced-form nicotinamide adenine dinucleotide phosphate)–methemoglobin reductase.
  
• Mechanism of toxicity—the necessary biological interactions by which a toxicant exerts its toxic effect on an organism. A simple example is CO asphyxiation due to the binding of CO to hemoglobin, thus preventing the transport of oxygen within the blood.
  
• Toxicant—any substance that causes a harmful (or adverse) effect when in contact with a living organism at a sufficiently high concentration.
  
• Toxin—any toxicant produced by an organism (floral or faunal, including bacteria), that is, naturally produced toxicants. An example would be the pyrethrins, which are natural pesticides produced by pyrethrum flowers (i.e., certain chrysanthemums) that serve as the model for the man-made insecticide class pyrethroids.
  
• Potency—a measure of the ability of a chemical to express its toxicity per unit of dose or dosage. The more potent a chemical, the less dosage needed to induce the toxicity it produces. In general terms, the less potent a chemical is, the safer it is because the probability of achieving a dose sufficient to induce toxicity via a particular route of exposure is lessened. Similarly, more potent chemicals tend to be more dangerous because it takes a smaller dose from an exposure to be able to induced toxicity.
  
• Hazard—the qualitative nature of the adverse or undesirable effect (i.e., the type of adverse effect or toxicity the chemical produces) resulting from exposure to a particular toxicant or physical agent. For example, asphyxiation is the hazard from acute exposures to CO. Cancer, liver toxicity, and immunotoxicity are other hazards (types of toxicities) a chemical exposure might potentially represent. A hazard typically refers to the kind(s) of toxic effect(s) the chemical can produce if the exposure/dose is sufficient.
  
• Safety—the measure or mathematical probability that a specific exposure situation or dose will not produce a toxic effect.
  
• Risk—as generally used in toxicology, the measure or probability that a specific exposure situation or dose will produce a toxic effect.
  
• Risk assessment—the process by which the potential (or probability of) adverse health effects of exposure are characterized. In risk assessment, a safe exposure concentration is extrapolated from the dose–response curve for an adverse effect produced by the chemical that is used to derive a safe exposure concentration. Alternatively, a risk assessment might determine the probability and/or acceptability of a toxicity occurring at a known or measured exposure level.

1.2 TOXICOLOGY: A DIVERSE SCIENCE WITH TWO BASIC GOALS

Toxicology has become a science that builds on and uses knowledge developed in many related medical sciences, such as physiology, biochemistry, pathology, pharmacology, medicine, and epidemiology, to name only a few. Toxicology has evolved from the study of poisons to the study of all adverse effects induced by all chemicals or substances. Although toxicology is a science where a number of areas of specialization have evolved, all toxicologists fall into three principal areas of endeavor: descriptive toxicology, research/mechanistic toxicology, and applied toxicology.

Descriptive toxicologists are scientists whose work focuses on the toxicity testing of chemicals. This work is done primarily at commercial and governmental toxicity testing laboratories, and the studies performed at these facilities are designed to generate basic toxicity information that identifies the various organ toxicities (hazards) the test agent is capable of inducing over those exposure conditions necessary to induce each effect. A thorough description of a chemical’s toxicology would identify all possible acute and chronic toxicities, including the genotoxic, reproductive, teratogenic (developmental), and carcinogenic potential of the test agent. It would identify important metabolites of the chemical that are generated as the body attempts to break down and eliminate the chemical, as well as understand how the chemical is absorbed into the body and distributed to tissues throughout the body, identify tissue accumulation or elimination, and ultimately determine how it is excreted from the body. Hopefully, appropriate dose–response test data are generated for those toxicities of greatest concern and that toxicity produced at the lowest dose during the completion of the descriptive studies so that the relative safety of any given exposure or dose level that humans might typically encounter can be predicted.

Basic research or mechanistic toxicologists are scientists who study the chemical or agent in depth for the purpose of gaining an understanding of how the chemical or agent initiates those biochemical or physiological changes within the cell or tissue that result in the toxicity (adverse effect). The goal of mechanistic studies is to understand the specific biological reactions (i.e., the adverse chain of events) within the affected organism that ultimately result in the toxic effect being studied. Mechanistic experiments are performed at the molecular, biochemical, cellular, and tissue level of the affected organism. So, mechanistic assessments may incorporate and apply the knowledge of a number of many other related scientific disciplines within the biological and medical sciences (e.g., physiology, biochemistry, genetics, molecular biology, pathology). Because animal species are generally used to identify chemical-induced hazards, and because there may be significant species-specific responses to a chemical, mechanistic studies help provide the information on those key changes required to induce toxicity, and help reduce the uncertainty of the animal-to-human extrapolation we need to make to develop a safe exposure guideline.

Applied toxicologists are scientists concerned with the use of chemicals in a “real world” or nonlaboratory setting. The primary goal of applied toxicologists is the control of chemical exposures in all work and nonwork environments by setting safe exposure guidelines for each exposure pathway (e.g., air, skin, ingestion exposure to the chemical) in that environment. Toxicologists who work in this area of toxicology use descriptive and mechanistic toxicity studies to limit the dose received by each or all exposure pathways to a total dose of the chemical that is believed to be safe. The process whereby this safe dose or level of exposure is derived is generally referred to as the area of risk assessment. Within applied toxicology a number of subspecialties occur. Forensic toxicology is that unique combination of analytical chemistry, pharmacology, and toxicology concerned with the medical and legal aspects of drugs and poisons; it is concerned with the determination of which chemicals are present and responsible in exposure situations of abuse, overdose, poisoning, and death that become of interest to the police, medical examiners, and coroners. Clinical toxicology specializes in ways to treat poisoned individuals and focuses on determining and understanding the toxic effects of medicines, simple over-the-counter (nonprescription) drugs, and other household products. Environmental toxicology is the subdiscipline concerned with those chemical exposure situations found in our general living environment. These exposures may stem from the agricultural application of chemicals, the release of chemicals during modern-day living (e.g., chemicals released by household products), regulated and unintentional industrial discharges into air or waterways, and various nonpoint emission sources (e.g., the combustion by-products of cars). Within this area there may be even further subspecialization (e.g., ecotoxicology, aquatic toxicology, mammalian toxicology, avian toxicology). Occupational toxicology is the subdiscipline concerned with the chemical exposures and diseases found in the workplace, the identification of the hazards or injuries that overexposure to an occupationally used chemical might represent, and the prevention of these exposures or the treatment of the injuries they might produce.

Regardless of the specialization within toxicology, or the types of toxicities of major interest to the toxicologist, essentially every toxicologist performs one or both of the two basic functions of toxicology, which are to (1) examine the nature of the adverse effects produced by a chemical or physical agent (hazard/toxicity identification function) and (2) assess the probability of these toxicities occurring under specific conditions of exposure (dose–response and risk assessment function). Ultimately, the goal and basic purpose of toxicology is to understand the toxic properties of a chemical so that these adverse effects can be prevented by the development of appropriate handling or exposure guidelines.

1.3 HAZARD IDENTIFICATION FUNCTION

The hazard identification or the discovery of the toxicities a chemical produces requires the testing of chemicals at doses high enough to induce the full spectrum of toxicities a chemical can induce. Typically, the hazard identification process involves traditional animal testing to uncover the spectrum of adverse effects (hazards) the chemical is capable of producing at some dose. One way of characterizing and identifying the hazard is by examining toxicities as a function of exposure duration, as previously described for acute, subacute, subchronic, and chronic exposures.

Because each chemical induces a different spectrum of toxic effects and one does not know beforehand which set of toxicity tests to perform to adequately capture and identify the possible hazards posed by the chemical, the chemical is examined using as wide a range of test systems as possible to ensure that all potential hazards for that chemical have been identified. For a complete toxicological evaluation the typical hazard assessment would follow a scheme similar to that illustrated in Figure 1.1. Typically, one would perform these tests using a tiered approach that starts with short exposure interval testing such as acute and subacute exposure periods (tier 1) and subsequently moves through subchronic tests (tier 2) and then chronic tests (tier 3). At each tier, specialized tests are performed in addition to those assessing target organ toxicities by route of exposure. For example, during the acute testing phase, dermal and reparatory tract irritation may be necessary as well as tests for the development of sensitization by the chemical. During subchronic and chronic testing, target organ testing is augmented by reproductive and developmental studies, testing for immunotoxicity, genotoxicity and mutagenicity, and a chronic bioassay for possible carcinogenic responses.

A tiered approach such as this allows the dose ranges to be set and as the duration of exposure increases, the dose needed to induce the effect is usually lowered (see Table 1.1). The shorter the duration of exposure the lower the cost of the test and the more time-efficient the study. So, trying to identify the end points of interest and toxic dose range is done more time and cost efficiently by seeking the toxicities a chemical induces by testing the chemical short-term tests first. However, both the types of hazards seen and the doses inducing these effects can change with the duration of exposure; and the hazards seen at shorter exposure durations cannot be assumed to be those that will be found after longer durations of exposure. For example, cancer is a latent disease that may require a lifetime of exposure to detect. The route of exposure may also impact the hazard because as the site of absorption is altered it may impact the occurrence of localized effects (like irritation or cellular necrosis at the site of contact) and it can change the tissue distribution as well as the target organ concentration per unit of absorbed dose. Either change may produce a different pattern of target organs affected with different routes of exposure. For example, after testing trichloroethylene (TCE) for carcinogenicity using the mouse as the test organism, it was observed that inhalation exposure induced lung tumors but not liver tumors while oral administration induced liver tumors but not lung tumors. This kind of route-specific toxicity occurs frequently enough that regulatory agencies like the EPA no longer rely upon data gathered by one route of exposure to predict hazards or risk for another route of exposure, that is, there can be considerable uncertainty associated with route-to-route extrapolations without a mechanistic basis for doing so.

1.4 DOSE–RESPONSE/RISK ASSESSMENT FUNCTION

It is probably safe to say that among lay individuals there exists considerable confusion about the term toxic. If asked, most lay individuals would probably define a toxic substance using either a definition that one would apply to highly poisonous or very potently toxic chemicals or something that implies that only some chemicals produce adverse effects in humans and so can be described as toxic chemicals or those substances that we should all avoid. To help illustrate this point, and to begin to emphasize the fact that the toxicity is a function of dose, the reader is invited to take the following pop quiz. First, cross-match the doses shown in column A that produce lethality in 50% of the animals (lethal dose [LD₅₀]) with the chemicals listed in column B. These chemicals are a collection of food additives, medicines, drugs of abuse, poisons, pesticides, and hazardous substances for which the correct LD₅₀ is listed somewhere in column A. To perform this cross-matching, first photocopy Table 1.3 and simply mark the ranking of the dose (i.e., the number corresponding next to the dose in column A) you believe correctly corresponds to the chemical it has been measured for in column B. (Note: The doses are listed in descending order, and the chemicals have been listed alphabetically. So, the three chemicals you believe to be the safest should have the three largest doses [you should rank them as 1, 2, and 3], and the more unsafe or dangerous you perceive the chemical to be, the higher the numerical ranking you should give it. After testing yourself with the chemicals listed in Tables 1.3, review the correct answers in tables found at the end of this chapter.)

Now, take the allowable workplace chronic exposure levels for the following chemicals—aspirin, gasoline, iodine, several different organic solvents, and vegetable oil mists—and again rank these substances going from the highest to lowest allowable workplace air concentration (listed in Table 1.4). Remember that the lower (numerically) the allowable air concentration, the more potently toxic the substance is per unit of exposure. Review the correct answers for tables recreated at the end of this chapter.