TOXICOLOGY

Toxicology is the science of poisons. Understanding the potential for toxicity of agents found in nature has been a necessity for human survival. Learning to use natural toxins for purposes such as hunting and warfare was as much a part of human adaptation of the environment as was the taming of fire. One of the first known examples of the unwanted toxicity of a manufactured product was the lead poisoning that occurred in Roman times as a result of lead plumbing and lead dishware. Today, the emphasis of toxicology is on detecting and preventing the unwanted effects of chemical and physical agents, although concerns about the intentional misuse of chemicals, including chemical warfare, will persist for the foreseeable future.

As a science, toxicology is at the interface between chemistry and biology. There are three "laws" of toxicology. The oldest, that "the dose makes the poison," is attributed to Paracelsus, a fifteenth-century German physician. The concept that all chemical agents are toxic at some dose is central to a respect for the inherent hazard of all chemicals. The second "law" of toxicology, that the biologic actions of chemicals are specific to each chemical, has been attributed to Ambroise Paré, a sixteenth-century French surgeon who recognized that toxic agents have different effects dependent upon their inherent nature. Understanding the specific action of chemicals, known as hazard identification, depends upon recognizing the structural determinants of the activity of chemicals, and the biological niches in which chemicals interact. Very subtle changes in chemical structure can make an enormous difference in biological effects. The third "law" is that humans are animals. Protection against the toxicity of chemicals today would be impossible without the ability to study the effects of toxic agents in laboratory animals. As a corollary, animal rights activists advocating a ban on all animal research present a major threat to environmental protection and public health.

Toxicologists generally consider two types of dose-response relationships. One has a threshold below which no effect is expected. For example, one drop of fuming sulfuric acid will burn a hole in skin, yet this same drop in a bathtub full of water dilutes the sulfuric acid to a level at which no effects will occur. This theoretical threshold (experimentally known as a "no-observed-effect level") is presumed to exist for all agents, except for those that produce their effects through mutation, most notably many cancer-causing agents. A mutation can theoretically occur through a single chemical molecule producing a specific change in the chemical structure of a DNA molecule, thereby altering the genetic code from that of a normal cell to that of a mutated cell. As a further simplification, two molecules have twice as much chance as causing this effect. This can be described as a linear one-hit relationship between the dose of a mutational agent and the likelihood that the mutation will occur. The theoretical risk for any one molecule causing a mutation is infinitely small—there are about 1 trillion molecules of benzene, a known cause of leukemia, in every breath taken in an average American city, yet very few people develop leukemia. There are also many defense mechanisms within cells, as well as DNA repair mechanisms, that can impact on the likelihood of chemical exposures causing cancer.

Extrapolation of data from laboratory animals to humans, and from high to low doses, is central to modern toxicology. In addition to understanding dose-response relationships, knowledge about differences among species in the uptake, metabolism, and disposition of chemicals is also of importance. There is a strong similarity among mammalian species. Where differences do exist, attention to the kinetics of the processes that determine how an external exposure level is translated to the dose of a chemical at a target organ provides information of value to cross-species extrapolation.

A major challenge in modern toxicology is to prevent unwanted effects of otherwise valuable chemicals, including therapeutic agents. Understanding chemical mutagenesis and carcinogenesis has permitted the development of bacterial mutagenesis assays, such as the Ames test. These and other short-term assays for toxic effects are routinely used during the development phase of new chemicals to screen out potential toxic agents. Before marketing, additional testing is often required, depending in part on the use of the chemical. For new pharmaceutical agents, extensive toxicity and efficacy data are required, including studies in humans. Such agents are expected, at anticipated human dose levels, to have a biological effect of benefit to the consumer. In contrast, the developers of consumer chemicals, such as a new paint, hope that no biological effects will occur at usual doses to humans.

There are intermediate agents, such as insecticides and herbicides, for which a biological effect is intended at usual doses—for these agents, protection of humans depends, in large part, on our different biology. Accordingly, premarket testing is usually less rigorous for consumer chemicals than for therapeutic agents, and there is more dependence on structure-activity relationships (SAR). SAR, in essence, is a comparative analysis of aspects of chemical structure in relation to the existing toxicological database—a useful, but not completely effective, approach. In the United States, the Toxic Substances Control Act requires premanufacturing notification of new chemicals to the U.S. Environmental Protection Agency, which has the option of asking for additional testing. Such tests might include a battery of shorter-term and longer-term tests for acute and chronic diseases, including cancer. The recognition of the dangers inherent in compounds that bioaccumulate or otherwise persist in the environment has led to tests to identify and exclude such compounds from commerce.

Long-term animal assays, usually two-year studies in male and female rats and mice, are the mainstay of thorough safety assessment of chemicals, particularly those for which there is a concern about cancer or other chronic effects. The basic approach is to first perform a multiple-dose ninety-day study to choose the maximum tolerated dose (MTD). This dose is then used for a two-year study. Sole reliance on standard safety-assessment approaches carries a small but finite risk of missing a potentially toxic agent, a risk which is lessened if studies assessing the mechanism of toxicity of the chemical are also performed. A major goal of toxicological research is a better understanding of the processes by which chemical agents produce adverse biological effects, which will lead to the development of better safety-assessment tests.

The pathways of chemicals into and through the body are usually considered under the headings of absorption, distribution, metabolism, and excretion. Absorption, the process by which an external dose is converted to an internal dose, occurs by ingestion, inhalation, or through the skin. Distribution of a chemical depends in part on the pathway of entry and on specific chemical and biological factors; for example, only certain types of chemicals are able to penetrate the blood-brain barrier and enter the central nervous system.

Much emphasis has been placed on understanding chemical metabolism, as this is central both to the impact and to the detoxification of chemicals. The activity of many of the metabolic enzymes can vary greatly among individuals due to genetic and environmental factors, including types of food. Further, metabolic rates may vary within a given individual at different times due to induction of metabolic enzymes by these same environmental factors. Studies of resistance to cancer chemotherapeutic agents have led to an understanding of mechanisms by which toxic agents can be rapidly transported out of an otherwise susceptible cell, including specific transporter proteins, which can also be induced in response to environmental factors.

The major metabolic organ is the liver, but all organs have some level of metabolic enzymes. Certain chemicals, such as benzene, are harmless until they are metabolized by the body to form toxic chemical intermediates. Further, not all chemicals are metabolized; some pass through the body unchanged, while others react directly with biological targets.

Major excretory pathways are through urination, defecation, and exhalation. Lactation is also a means of excretion, particularly of fat-soluble chemicals, to the potential detriment of the infant.

Differential sensitivity to chemicals is an important subject to toxicologists for which modern molecular biology is providing new insights, particularly through the understanding of the human genome. For most human disease, genetics will determine what is necessary, but the environment, defined broadly, will determine what is sufficient. A reasonable estimate is that over two-thirds of human disease is environmentally determined. Many of the genetic and environmental factors responsible for disease operate at the level of modifying the absorption, distribution, metabolism, or excretion of exogenous chemicals, including food constituents.

Susceptibility to toxic agents is also conferred by factors such as age, gender, and concomitant conditions. Children, the elderly, and those with preexisting disease tend to be more susceptible to environmental toxins than are healthy adults. For example, the greater respiratory ventilation per unit of body mass in children accounts for the tragic finding of death due to carbon monoxide poisoning in the children, but not the adults, in a snowbound car.

So-called safety factors have traditionally been used in establishing public health and regulatory guidelines and standards based on toxicological data. These are based on no-observed-effect levels in animals, which are then reduced by a factor of ten to provide assurance that the animal data is protective of humans. In general, a tenfold factor is used to account for the possibility that humans are more sensitive than the animal species from which the data are obtained. Another tenfold factor is based on the greater diversity in susceptibility factors among humans than in inbred laboratory animals. The resultant hundredfold safety level has been used on a relatively routine basis for establishing acceptable daily intake (ADI) levels by the Food and Drug Administration, as well as for other regulatory standards. Additional factors of ten can be added based upon the toxic endpoint involved, or in order to protect children. Conversely, when there is a sufficiently robust database on humans, such as for certain air pollutants, routine factors of ten are not used, and scientific judgment contributes to the determination of an appropriate margin of safety.

The effect of toxic agents on ecosystems has become increasingly recognized as being important to human health. Traditionally, ecotoxicology (in relation to human health) has focused on contamination of the food chain, including the biomagnification and bioaccumulation of toxic agents within foods. The recognition of the role of ecosystems in overall planetary health, including feedback loops affecting climate, desertification, and crop yield, as well as the importance of the natural world and its animal and plant components to human well-being, has led to additional emphasis on understanding the toxicity of chemical and physical agents to components of nature.

Bernard D. Goldstein

(see also: Ames Test; Benzene; Carcinogenesis; Ecosystems; Environmental Determinants of Health; Environmental Protection Agency; Ethics of Public Health; Genes; Genetics and Health; Lead; Maximum Tolerated Dose; One-Hit Model; Risk Assessment, Risk Management; Safety Assessment; Safety Factors; Threshold )

Bibliography

Goldstein, B. D., and Henifin, M. S. (2000). "Reference Guide on Toxicology." In Reference Manual on Scientific Evidence, 2nd edition. Washington, DC: Federal Judicial Center.

Klaassen, C. D., ed. (1996). Casarett and Doull's Toxicology: The Basic Science of Poisons, 5th edition. New York: McGraw-Hill.

Lippman, M., ed. (1999). Environmental Toxicants: Human Exposures and Their Health Effects, 2nd edition. New York: John Wiley.

Toxicology

Toxicology is the science of poisons, which are sometimes referred to as toxins or toxicants. The former term applies to all natural poisons produced by organisms, such as the botulinum toxin produced by the bacteria Clostridium botulinum. The latter more generic term includes both natural and anthropogenic (human-made) toxicants like dichlorodiphenyl trichloroethane (DDT), which is perhaps the most commonly recognized toxicant.

Even though the botulinum toxin is extremely toxic to humans, and DDT is relatively toxic to insects, it is important to recognize that virtually any element or compound will become toxic at some concentration. For example, iron, which is an essential component of hemoglobin , can cause vomiting, liver damage, and even death if it is ingested in excess. This concept of toxicity was recognized five centuries ago by the Swiss alchemist and physician Paracelsus (1493–1541), who stated that, "The right dose differentiates a poison from a remedy." How much of the toxicant an organism receives depends on both the exposure and dose. Exposure is a measure of the amount of a toxicant that comes into contact with the organism through air, water, soil, and/or food. Dose is a measure of the amount of toxicant that comes into contact with the target organ or tissue, within the organism, where it exerts a toxic effect. The dose is largely determined by how effectively the toxicant is absorbed, distributed, metabolized , and eliminated by the body.

As a consequence, basic toxicological studies include measurements of the effects of increasing doses of a toxicant on an organism or some component of that organism (e.g., tissue, cell, subcellular structure, or compound). The measurements are commonly plotted as dose–response curves. A dose–response curve typically ranges from relatively low concentrations that do not elicit a toxic effect to higher concentrations that are increasingly toxic.

One of the great challenges to the science of toxicology is the prediction and discovery of chronic, sublethal responses. For example, in the 1920s, excessive exposure of workers to tetraethyl lead (the lead in leaded gasoline) in several United States gasoline production facilities caused approximately fifteen deaths, and over three hundred cases of psychosis. Despite this discovery of the apparent hazard of lead in gasoline, and the concerns of many at the time, rigorous scientific studies were required to demonstrate the subtle, sublethal dangers of chronic lead exposure, including adverse neurological effects in children, which eventually led to the ban of lead additives in gasoline in the United States.

Characterizing Toxicity

One measure of response is acute toxicity, which is the amount of a toxicant that will cause an adverse effect within a relatively short period of time (e.g., from instantaneous to within a few days). Another measure of response is chronic toxicity, which is the long-term response to a toxicant. Although the same types of dose–response curves are used to measure the chronic toxicity
of toxicants, those measurements are more difficult to quantify because the responses are often less absolute and more complex. For example, chronic benzene toxicity causes lung cancer, but it may be years before that benzene-induced cancer appears, and many other factors may retard the development of that cancer (antagonistic effect), contribute to its development (synergistic effect), or independently cause lung cancer (e.g., smoking cigarettes).

Forms of toxicity can also be characterized by the type of adverse response they create. Carcinogens cause cancer, either by the initiation or promotion of an uncontrolled growth of cells. Mutagens cause mutations by altering the DNA sequences of chromosomes. Teratogens cause mutations in the DNA structure of developing fetuses that can result in developmental abnormalities. The latter form of toxicity includes the infamous teratogen thalidomide, which was prescribed as a sedative for pregnant women before it was found to cause severe birth defects in their children.

Differences in Sensitivities

Resolving the adverse effects of a toxicant are further complicated by the variations in those effects in different species. Some species are more sensitive to certain toxicants than others, and the effects of toxicants on different tissues often vary between species. Because such variations occur between humans and rodents, in spite of the similarity (95%) in their DNA, extrapolations of laboratory studies on the effects of toxicants on rats and mice to human health must always take this into account. Moreover, the toxic effects of a pollutant on the gall bladder of humans cannot be determined in studies involving rats because rats do not have gall bladders.

There are also relatively large differences in the sensitivities and effects of toxicants between individuals of the same species. Fetuses, neonates , and infants are more sensitive to the neurotoxic effects of lead than older individuals, because lead interferes with the development of the central nervous system, which is formed during the first few years of life. Finally, healthy individuals are generally less sensitive to pollutants than individuals with weakened immune systems who are less capable of responding to additional threats to their health.

Genetics also plays a major role in the sensitivities of individuals. Although some differences have been observed in humans, the most commonly recognized genetic differences in toxic responses have been observed in other species. These include the acquired genetic resistance of some mosquitoes to DDT and some bacteria to antibiotics. However, the development of molecular techniques to genotype humans has now made it possible to identify individual sensitivities to different toxicants.

Risk Assessment

Another important aspect of toxicology is risk assessment, which is a characterization of the potential adverse effects resulting from exposure to a toxicant. Risk is the probability of an adverse outcome. The basic steps involved in risk assessment are the identification of the magnitude of the hazard, which is the potential for harm of a toxicant, and the resultant characterization of risk, which is the probability of realizing that harm. The results of risk assessments are routinely used by regulators to establish acceptable concentrations of toxicants in the environment.

Environmental Toxicology

Environmental toxicology is a relatively recent field that examines the occurrence of, exposure to, and form of toxicants in the environment, and the comparative effects of these toxicants on different organisms. DDT, for example, is a pesticide that has been used to control mosquitoes responsible for spreading malaria. Although this pesticide is effective in combating the spread of malaria, DDT and its chemical products have also been found to affect reproduction in birds by causing egg shell thinning, and in other organisms (e.g., alligators) by altering their estrogen balance. Consequently, studies of toxicology now extend well beyond dose–response assays of toxicants on specific target organisms to analyses of their impact on entire ecosystems.

In addition to anthropogenic toxicants like pesticides, environmental toxicologists also study naturally occurring toxicants, such as metals and metalloids. Selenium, for example, is a naturally occurring element that is essential at low concentrations in the diet of many animals. Excessive intake of selenium, however, can be toxic to organisms. In the 1980s scientists working at Kesterson Slough in the San Joaquin Valley, California, observed a large number of deformed and dying waterfowl. The slough was part of a water project designed to receive and evaporate excess irrigation water and remove pesticides from the highly productive agriculture regions in the San Joaquin Valley. The observed effects on the waterfowl were eventually linked to an excess of selenium in the water. The selenium accumulated in the slough because the soils and runoff from the valley were naturally rich in selenium, and because evaporation in the slough further increased its concentration in the water. In this example, it was discovered that a rare, but naturally occurring and essential element was unwittingly concentrated to toxic levels in the environment by human activity.

see also Cancer; DDT (Dichlorodiphenyl trichloroethane); Hazardous Waste; Health, Human; Lead; Risk.

Bibliography

Crosby, Donald G. (1998). Environmental Toxicology and Chemistry. New York: Oxford University Press.

Needleman, H.L. (1998). "Clair Patterson and Robert Kehoe: Two Views of Lead Toxicity." Environmental Research 78(2):79–85.

Ohlendorf, H.M.; Hoffman, D.J.; Daiki, M.K.; and Aldrich, T.W. (1986). "Embryonic Mortality and Abnormalities of Aquatic Birds—Apprent Impacts of Selenium from Irrigation Drainwater." Science of the Total Environment 52(44).

Williams, P.L.; James, R.C.; and Roberts, S.M., eds. (2000). Principles of Toxicology: Environmental and Industrial Applications, 2nd edition. New York: John Wiley & Sons.

internet resource

Society of Toxicology. Available from http://www.toxicology.org.

A. Russell Flegal and Christopher H. Conaway

TOX TOWN

A user friendly website, Tox Town http://toxtown.nlm.nih.gov/main.html has been developed by the National Institutes of Health to provide information on toxic substances likely to be encountered in everyday situations and the health risks associated with them. The site can be searched by clicking on an individual toxic such as mercury, toluene or asbestos to see where it might occur, or by clicking on a location, such as a school building, or drinking water to see what toxics could be encountered. Links to sites describing the health and environmental effects of each toxic substance are easily accessed.

Toxicology

Definition

Toxicology is the scientific study of poisons or toxins. The National Library of Medicine describes toxicology as "the study of the adverse effects of chemicals or physical agents on living organisms." How these toxins affect humans is based in understanding these basic relationships.

Description

The Swiss physician and alchemist Philippus Aureolus, also known as Paracelsus (1493–1541) and said to be the father of the modern science of toxicology, wrote, "All things are poison, and nothing is without poison, the dose alone makes a thing not a poison." In other words, if poisoning is to be caused, an exposure to a potentially toxic chemical must result in a dose that exceeds a physiologically determined threshold of tolerance. Smaller exposures do not cause poisoning.

The dose of toxin is a crucial factor to consider when evaluating effects of a toxin. Small quantities of a substance like strychnine taken daily over an extended period of time might have little to no effect, while one large dose in one day could be fatal. In addition, some toxins may only affect a particular species of organism, such as pesticides and antibiotics killing insects and microorganisms with significantly less harmful effects to humans.

Organisms vary greatly in their tolerance of exposure to chemicals. Even within populations of the same species great variations in sensitivity can exist. In rare cases, some individuals may be extremely sensitive to particular chemicals or groups of similar chemicals, a phenomenon known as hypersensitivity. Organisms are often exposed to a wide variety of potentially toxic chemicals through medicine, food, water, and the atmosphere.

The study of the disruption of biochemical pathways by poisons is a key aspect of toxicology. Poisons affect normal physiology in many ways; but some of the more common mechanisms involve the disabling of enzyme systems, induction of cancers, interference with the regulation of blood chemistry, and disruption of genetic processes.

Toxic agents may be physical (for example, radiation), biological (for example, poisonous snake bite), or chemical (for example, arsenic) in nature. In addition, biological organisms may cause disease by invading the body and releasing toxins. An example of this is tetanus, in which the bacterium Clostridium tetanus releases a powerful toxin that travels to the nervous system.

Toxic agents may also cause systemic or organspecific reactions in the body. Cyanide affects the entire body by interfering with the body's capacity for utilizing oxygen. Lead has three specific target organs: the central nervous system, the kidneys, and the hemopoietic (blood-cell generating) system. The target organ is affected by the dose and route of the toxin. For example, the initial effects of a chemical may affect the nervous system; repeated exposure over time might cause chronic damage to the liver.

Function

The toxicologist employs the tools and methods of science to understand more completely the consequences of exposure to toxic chemicals. Toxicologists typically assess the relationship between toxic chemicals and environmental health by evaluating such factors as:

• Risk—To assess the risk associated with exposure to a toxic substance, toxicologists first measure the exposure characteristics and then compute the doses that enter the human body. Then they compare these numbers to derive an estimate of risk, sometimes based on animal studies. In cases where human data exist for a toxic substance, such as benzene, more straightforward correlations with human risk of illness or death are possible.
• Precautionary strategies—Given recommendations from toxicologists, government agencies sometimes decide to regulate a chemical based on limited evidence from animal and human epidemiological studies that the chemical is toxic.
• Clinical data—Some toxicologists devise new techniques and develop new applications of existing methods to monitor changes in the health of individuals exposed to toxic substances. For example, one academic research group in the United States has spent many years developing new methods for monitoring the effects of exposure to oxidants (for example, free radicals) in healthy and diseased humans.
• Epidemiological evidence—Another way to understand the environmental factors contributing to human illness is to study large populations that have been exposed to substances suspected of being toxic. Scientists then attempt to tie these observations to clinical data. Ecological studies seek to correlate exposure patterns with a specific outcome. Case-control studies compare groups of persons with a particular illness with similar healthy groups, and seek to identify the degree of exposure required to bring about the illness. Other studies may refine the scope of environmental factor studies; or, examine a small group of individuals in which there is a high incidence of a rare disease and a history of exposure to a particular chemical.
• Evidence of bioaccumulation—When a chemical is nonbiodegradable, it may accumulate in biosystems, resulting in very high concentrations accumulating in animals at the top of food chains. Chlorinated pesticides such as dieldrin and DDT, for example, have been found in fish in much greater concentrations than in the seawater where they swim.

Role in human health

Humans are exposed to complex mixtures of chemicals, many of which are synthetic and have been either deliberately or accidentally released into the environment. In some cases, people actively expose themselves to chemicals that are known to be toxic, such as smoking cigarettes, drinking alcohol, or taking recreational drugs. Voluntary exposure to chemicals also occurs when people take medicines to deal with illness, or when they choose to work in an occupation that involves routinely dealing with dangerous chemicals. Most exposures to potentially toxic chemicals are inadvertent, and involve living in an environment that is contaminated with small concentrations of pollutants, such as those associated with pesticide residues in food, lead from gasoline combustion, or sulfur dioxide and ozone in the urban atmosphere.

Drugs given to improve health can lead to toxicity even when given in appropriate doses. Conditions such as dehydration and other forms of physiological compromise can make the patient more vulnerable to toxicity. Drugs like digoxin, lidocaine, and lithium are common examples of drugs with potentially toxic effects. Interactions of substances in the body may also produce toxic effects. For example, if two central nervous system depressants are taken at once, as in the case of combining alcohol and a tranquilizer, the effects are additive and could lead to extreme depression of the central nervous system functions.

The health care system's role related to toxicology includes education and prevention as well as treatment of both acute and chronic effects of toxins. Agencies such as the Food and Drug Administration (FDA) and the Occupational Safety and Health Administration (OSHA) work with health care and industry to offer guidelines and restrictions on the manufacture and use of pharmaceuticals, foods, and other substances.

Health care workers are involved by being aware of these regulations, and staying informed. They also provide education, such as, teaching new parents about the dangers of lead paint consumption by children, and help prevent exposure to toxins, such as, tetanus vaccination, or monitoring for signs of lithium toxicity. The Poison Control Center uses nurses and other allied health workers to inform the public of immediate actions to take in the event of a poisoning emergency. Emergency interventions at the hospital include blood and urine tests, gastric lavage with administration of absorbent activated charcoal, and administration of antidotes when available.

Common diseases and disorders

Toxicologists have ranked the most commonly encountered toxic chemicals in the United States. In descending order of frequency of encounter, they are as follows:

• Arsenic—Toxic exposure occurs mainly in the workplace, near hazardous waste sites, or in areas with high natural levels. A powerful poison, arsenic can, at high levels of exposure, cause death or illness.
• Lead—Toxic exposure usually results from breathing workplace air or dust, or from eating contaminated foods. Children may be exposed to lead from eating lead-based paint chips or playing in contaminated soil. Lead damages the nervous system, kidneys, and the immune systems.
• Mercury—Toxic exposure results from breathing contaminated air, ingesting contaminated water and food, and possibly having dental and medical treatments. At high levels, mercury damages the brain, kidneys, and developing fetuses.
• Vinyl chloride—Toxic exposure occurs mainly in the workplace. Breathing high levels of vinyl chloride for short periods can produce dizziness, sleepiness, unconsciousness, and, at very high levels, death. Breathing vinyl chloride for long periods of time can give rise to permanent liver damage, immune reactions, nerve damage, and liver cancer.
• Benzene—Benzene is formed in both natural processes and human activities. Breathing benzene can produce drowsiness, dizziness, and unconsciousness. Long-term exposure affects the bone marrow and can produce anemia and leukemia.
• Polychlorinated biphenyls (PCBs)—PCBs are mixtures of chemicals. They are no longer produced in the United States, but remain in the environment. They can irritate the nose and throat, and cause acne and rashes. They have been shown to cause cancer in animal studies.
• Cadmium—Toxic exposure to cadmium occurs mainly in workplaces where cadmium products are made. Other sources of exposure include cigarette smoke and cadmium-contaminated foods. Cadmium can damage the lungs, cause kidney disease, and irritate the digestive tract.

KEY TERMS

Antidote— A substance that combats the effects of a poison or toxin.

Gastric lavage— The act of emptying out the stomach via orogastric or nasogastric tube.

Resources

BOOKS

Klaassen, Curtis D. Casarett & Doull's Toxicology: The Basic Science of Poisons. New York: McGraw Hill, 2001.

ORGANIZATIONS

American Association of Poison Control Centers (AAPCC). 〈http://www.aapcc.org〉.

OTHER

National Library of Medicine Toxicology Tutor Web site. 〈http://sis.nlm.nih.gov/ToxTutor;〉 and, TOXNET, 〈http://www.nlm.nih.gov/toxnet〉.

Toxicology

Toxicology is the scientific study of poisons (or toxins). Major topics in toxicology include the detection and chemical analysis of poisons, the study of the metabolic effects of these substances on organisms, and the investigation of methods for treatment of poisoning.

The Swiss physician and alchemist Philippus Aureolus, also known as Paracelsus (1493-1541) and said to be the father of the modern science of toxicology, wrote "All things are poison, and nothing is without poison, the dose alone makes a thing not a poison." In other words, if poisoning is to be caused, an exposure to a potentially toxic chemical must result in a dose that exceeds a physiologically determined threshold of tolerance. Smaller exposures do not cause poisoning.

Physiology is the study how organisms function, and the disruption of biochemical pathways by poisons is a key aspect of toxicology. Poisons affect normal physiology in many ways, but some of the more common mechanisms involve the disabling of enzyme systems, induction of cancers, interference with the regulation of blood chemistry, and disruption of genetic processes.

Organisms vary greatly in their tolerance of exposure to chemicals, and even within populations of the same species there can be great variations in sensitivity. In rare cases, some individuals may be extremely sensitive to particular chemicals or groups of similar chemicals, a phenomenon known as hypersensitivity.

Organisms are often exposed to a wide variety of potentially toxic chemicals through medicine, food, water , and the atmosphere. Humans are exposed to complex mixtures of chemicals, many of which are synthetic and have been either deliberately or accidentally released into the environment.

In some cases, people actively expose themselves to chemicals that are known to be toxic, such as when smoking cigarettes, drinking alcohol , or taking recreational drugs. Voluntary exposure to chemicals also occurs when people take medicines to deal with illness, or when they choose to work in an occupation that involves routinely dealing with dangerous chemicals. However, most exposures to potentially toxic chemicals are inadvertent, and involve living in an environment that is contaminated with small concentrations of pollutants, for example, those associated with pesticide residues in food, lead from gasoline combustion , or sulfur dioxide and ozone in the urban atmosphere.

Traditionally, the discipline of toxicology has only dealt with the direct effects of poisonous chemicals on organisms, and particularly on humans. Recently, however, ecologists have broadened the scope of toxicological investigations to include the indirect effects of chemicals in the environment, a field known as ecotoxicology. Ecotoxicology could be defined as the study of the ecological effects of toxic chemicals, including the direct effects, but also the indirect consequences caused by changes in the structure of habitats, or in the abundance of food. A herbicide used in forestry may not cause direct, toxic effects to animals at the doses given during the pesticide application, but the pesticide may change the vegetation, and thereby change the ecological conditions upon which animals depend.

Toxicology in practice

The toxicologist employs the tools and methods of science to better understand the consequences of exposure to toxic chemicals. Toxicologists typically assess the relationship between toxic chemicals and environmental health by evaluating such factors as:

• Risk. To assess the risk associated with exposure to a toxic substance, the toxicologist first measures the exposure characteristics and then computes the doses that enter the human body. He or she then compares these numbers to derive an estimate of risk, sometimes based on animal studies. In cases where human data exist for a toxic substance, such as benzene , more straightforward correlations with the humans risk of illness or death are possible.
• Precautionary strategies. Given recommendations from toxicologists, government agencies sometimes decide to regulate a chemical based on limited evidence from animal and human epidemiological studies that the chemical is toxic. Such decisions may have both ethical and political ramifications; to fail to issue warnings about a "suspect" chemical could leave vulnerable members of the population at risk of contracting an avoidable illness; on the other hand, any restrictions placed on the use of the chemical could place burdensome cleanup costs on private industry.
• Clinical data. Some toxicologists devise new techniques and develop new applications of existing methods to monitor changes in the health of individuals exposed to toxic substances. For example, one academic research group in the United States has spent many years developing new methods for monitoring the effects of exposure to oxidants (e.g., free radicals) in healthy and diseased humans.
• Epidemiological evidence. Another way to understand the environmental factors contributing to human illness is to study large populations that have been exposed to substances suspected of being toxic. Scientists then attempt to tie these observations to clinical data. Ecologic studies seek to correlate exposure patterns with a specific outcome. Case-control studies compare groups of persons with a particular illness with similar healthy groups, and seek to identify the degree of exposure required to bring about the illness. Other studies may refine the scope of environmental factor studies, or examine a small group of individuals in which there is a high incidence of a rare disease and a history of exposure to a particular chemical.
• Evidence of bio-accumulation. When a chemical is nonbiodegradable, it may accumulate in biosystems, with the result that very high concentrations may accumulate in animals at the top of food chains. Chlorinated pesticides such as dieldrin and DDT, for example, have been found in fish in much greater concentrations than in the seawater where they swim.

Common toxic materials

Toxicologists have ranked the most commonly encountered toxic chemicals in the United States. In descending order of frequency of encounter, they are as follows:

• Arsenic. Toxic exposure occurs mainly in the workplace, near hazardous waste sites, or in areas with high natural levels. A powerful poison, arsenic can, at high levels of exposure, cause death or illness.
• Lead. Toxic exposure usually results from breathing workplace air or dust, or from eating contaminated foods. Children may be exposed to lead from eating lead-based paint chips, or playing in contaminated soil . Lead damages the nervous system , kidneys, and the immune systems.
• Mercury. Toxic exposure results from breathing contaminated air, ingesting contaminated water and food, and possibly having dental and medical treatments. At high levels, mercury damages the brain , kidneys, and developing fetuses.
• Vinyl chloride. Toxic exposure occurs mainly in the workplace. Breathing high levels of vinyl chloride for short periods can produce dizziness, sleepiness, unconsciousness, and, at very high levels, death. Breathing vinyl chloride for long periods of time can give rise to permanent liver damage, immune reactions, nerve damage, and liver cancer .
• Benzene. Benzene is formed in both natural processes and human activities. Breathing benzene can produce drowsiness, dizziness, and unconsciousness. Long-term exposure affects the bone marrow and can produce anemia and leukemia.
• Polychlorinated biphenyls (PCBs). PCBs are mixtures of chemicals. They are no longer produced in the United States, but remain in the environment. They can irritate the nose and throat, and cause acne and rashes. They have been shown to cause cancer in animal studies.
• Cadmium. Toxic exposure to cadmium occurs mainly in workplaces where cadmium products are made. Other sources of exposure include cigarette smoke and cadmium-contaminated foods. Cadmium can damage the lungs, cause kidney disease, and irritate the digestive tract.

Toxicology and the private citizen

Whenever a group of citizens becomes concerned about the toxicity of a chemical substance, they typically want immediate answers to the following questions:

• Is this chemical harmful?
• At what level of exposure is this chemical harmful?
• What are the symptoms of exposure to this chemical?

Unfortunately, from the point of view of the toxicologist, the answers to these questions are seldom simple. This problem is compounded by the fact that most chemicals of unknown toxicity did not exist until at most a few decades ago, so data for long-term exposure may not exist.

Even when the question is as apparently straightforward, such as "Is such-and-such a chemical harmful?", the answer will seldom be as simple as, "Yes, in amounts exceeding 16 parts per million." This is because a complete scientific answer must take into account other factors such as the age of the individual exposed, the duration of exposure, and whether other environmental pollutants are present that could interact with and magnify the substance's toxicity. In the same way, workplace guidelines for adults who spend an eight-hour day in a factory may be difficult to apply to a residential setting where children and homemakers spend most of their time.

Because modern science and technology developed many of the chemicals scientists are now evaluating for toxicity, it is perhaps not surprising that many laypersons have grown skeptical about the ability of scientists to identify toxic materials. Because toxicologists report their findings in the form of statistics and probabilities, separate government agencies have been known to issue conflicting regulations governing exposure to substances based on different interpretations of the same data.

See also Contamination; Poisons and toxins.

Bill Freedman
Randall Frost

toxicology is essentially the science of poisons. It was recognized long ago that the toxicity of any substance is related to dose. The sixteenth-century iconoclast Paracelsus is credited with the statement: ‘All substances are poisons, there is none which is not a poison. The right dose differentiates a poison from a remedy.’ Toxicology had its origins in medicine and therapeutics, and to this day one of the key steps in the development of new drugs is the evaluation of the ‘therapeutic window’. This window corresponds to the range of doses where a beneficial effect is obtained but below the dose which causes unacceptable side-effects.

Throughout history the substances that have been used for medicine — as well as the poisons used to eliminate political rivals, as practised from classical times through to the Renaissance — have been almost exclusively derived from natural sources. Despite a recent emphasis on the toxicity of synthetic chemicals, arising in part from the influential writings of Rachel Carson, it is interesting to note that Nature has been endlessly inventive in its production of toxic agents. Such natural toxic substances are sometimes used as part of defence mechanisms as, for example, in the case of snake venoms. However, sometimes the toxic substances are by-products of normal metabolism by many different species. Several varieties of the mould Aspergillus produce a group of carcinogens called aflatoxins, which cause liver injury and cancer. A proper understanding of the occurrence and actions of natural toxins is vital to the maintenance of a healthy lifestyle. In a number of countries cassava is a major source of carbohydrate, but if it is not properly treated ingestion of the naturally occurring cyanogenic (cyanide-forming) glycosides can be fatal.

From the mid nineteenth century onwards the increasing use of pure chemicals as drugs paved the way for the development of toxicology as a more exact science which aimed to unravel the mechanisms of action of toxic substances. Very few drugs or toxic agents are active without some sort of metabolic activation; a chemical or physical change brought about in the body. Usually the effect of these changes is to render the substance more water soluble so that it may be excreted as rapidly as possible. In some instances metabolism results in the formation of a reactive chemical species, which binds to cellular macromolecules such as DNA or proteins. Such modifications can then lead to biological consequences, which are manifested as a frank toxic effect. However, there are protective mechanisms for dealing with such reactive species within cells; many are converted into substances that are ultimately excreted in urine.

In some cases unfortunate toxicological incidents can have beneficial consequences in the long term. For example, it was noted that soldiers returning from World War I who had been exposed to sulphur mustard had very depressed white blood cell counts. Ultimately, this observation led to the development of nitrogen mustards which, soon after World War II, began to be widely used in the treatment of cancers such as leukaemia. A rather different story relates to the discovery of a class of potent carcinogens, the nitrosamines. Several poisoning incidents in the textile industry, starting in the late 1930s, were associated with the use of dimethylnitrosamine (DMN) as a solvent for rayon. It was shown in animal models that acute administration of DMN produced a characteristic type of liver damage similar to that seen in workers. However, chronic administration of low doses of DMN produced liver tumours. It was subsequently found that many other nitrosocompounds produced tumours in different organs in many species of animals. Paradoxically, some nitrosocompounds were found to have antitumour activity and, like the nitrogen mustards described above, probably act by damaging the DNA in tumours in such a way that the cells cannot repair the damage and die.

There are sometimes great differences between species and between individuals with regard to the toxicity of a particular substance. A famous example is penicillin, which was tested for toxicity in rats before being given to humans. As rats tolerated large doses of penicillin with no ill effect, the drug was considered safe enough to be administered to humans, and the age of antibiotics was born. It was subsequently found that guinea pigs are very susceptible to toxicity from penicillin — history might have been very different if guinea pigs had been the test animal of choice. For many drugs which require metabolism to be active, or, in some cases, for toxicity to be apparent, polymorphism (occurrence in more than one form) of key metabolic enzymes can lead to spectacular differences in individual susceptibility. Debrisoquine, a drug used in the treatment of high blood pressure, was found to be very slowly metabolized by 1 in 10 Caucasian people, due to a genetic polymorphism for a particular enzyme. In affected individuals, administration of the drug caused a dramatic fall in blood pressure due to the persistence of the active drug in the circulation.

Despite much current public concern about health effects from environmental chemicals, there is little or no evidence of large numbers of cases of any disease being due to exposure to such agents. It is not that chemicals are any more or less toxic than those to which earlier generations were exposed — it is rather that contemporary exposure levels have been progressively reduced to such an extent that effects are almost undetectable. As our understanding of the mechanisms of toxicity of chemicals has improved, it is less likely that highly dangerous industrial chemicals will be present in the environment. However, as indicated above, our exposure to natural toxic agents remains a major source of concern.

Over much of its history the study of toxicology has relied upon the manifestation of some adverse health effect, in either humans or experimental animals, as an indication of the toxic effects of any particular substance. As the Human Genome Project attains one of its first goals of obtaining the complete sequence of the human genome (and as the complete sequences of the genomes of many other species have either already been, or will shortly be, completed), it is likely that approaches to toxicological questions will be quite different in the near future. Many pharmaceutical companies have led the way in the exploitation of this technology for rapid and comprehensive screening of adverse side effects of the increasing numbers of novel substances that are being examined for beneficial effects.

David Shuker

Bibliography

Klassen, C. D. (1996). Casarett and Doull's Toxicology: the basic science of poisons. McGraw Hill, New York.
Timbrell, J. A. (1991). Principles of biochemical toxicology, (2nd edn). Taylor and Francis, London.