What is Toxicology?

The traditional definition of toxicology is "the science of poisons."  As our understanding of how various agents can cause harm to humans and other organisms, a more descriptive definition of toxicology is  "the study of the adverse effects of chemicals or physical agents on living organisms".

These adverse effects may occur in many forms, ranging from immediate death to subtle changes not realized until months or years later. They may occur at various levels within the body, such as an organ, a type of cell, or a specific biochemical. Knowledge of how toxic agents damage the body has progressed along with medical knowledge. It is now known that various observable changes in anatomy or body functions actually result from previously unrecognized changes in specific biochemicals in the body.

The historical development of toxicology began with early cave dwellers who recognized poisonous plants and animals and used their extracts for hunting or in warfare. By 1500 BC, written recordings indicated that hemlock, opium, arrow poisons, and certain metals were used to poison enemies or for state executions.

With time, poisons became widely used and with great sophistication. Notable poisoning victims include Socrates, Cleopatra, and Claudius. By the time of the Renaissance and Age of Enlightenment, certain concepts fundamental to toxicology began to take shape. Noteworthy in this regard were the studies of Paracelsus (1500AD) and Orfila (1800 AD).

Paracelsus determined that specific chemicals were actually responsible for the toxicity of a plant or animal poison. He also documented that the body's response to those chemicals depended on the dose received. His studies revealed that small doses of a substance might be harmless or beneficial whereas larger doses could be toxic. This is now known as the dose-response relationship, a major concept of toxicology. Paracelsus is often quoted for his statement: "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."

Orfila, a Spanish physician, is often referred to as the founder of toxicology. It was Orfila who first prepared a systematic correlation between the chemical and biological properties of poisons of the time. He demonstrated effects of poisons on specific organs by analyzing autopsy materials for poisons and their associated tissue damage.

The 20th century is marked by an advanced level of understanding of toxicology. DNA (the molecule of life) and various biochemicals that maintain body functions were discovered. Our level of knowledge of toxic effects on organs and cells is now being revealed at the molecular level. It is recognized that virtually all toxic effects are caused by changes in specific cellular molecules and biochemicals.

Xenobiotic is the general term that is used for a foreign substance taken into the body. It is derived from the Greek term xeno which means "foreigner." Xenobiotics may produce beneficial effects (such as a pharmaceuticals) or they may be toxic (such as lead).

As Paracelsus proposed centuries ago, dose differentiates whether a substance will be a remedy or a poison. A xenobiotic in small amounts may be non-toxic and even beneficial but when the dose is increased, toxic and lethal effects may result.

The development of Toxicology Tutor was based on the concepts presented in the University of Maryland's introductory course on toxicology, Essentials of Toxicology. These basic principles of toxicology are similar to those taught in other major university programs and are well described in the literature. The volume of literature and textbooks pertaining to toxicology is quite extensive and a listing of all the excellent textbooks is beyond the scope of this tutorial.

While other references were selectively used, the textbooks listed below have served as the primary resources for this tutorial. They are quite comprehensive and among those texts widely used in basic toxicology training courses.

 

Basic Toxicology Terminology

Toxicology is an evolving medical science and so is toxicology terminology. Most terms are quite specific and will be defined as they appear in the tutorial. However, some terms are more general and used throughout the various sections. Those most commonly used are discussed in the following frames.

Toxicology is the study of the adverse effects of chemicals or physical agents on living organisms. A toxicologist is a scientist that determines the harmful effects of agents and the cellular, biochemical, and molecular mechanisms responsible for the effects.

Terminology and definitions for materials that cause toxic effects are not always consistently used in the literature. The most common terms are toxicant, toxin, poison, toxic agent, toxic substance, and toxic chemical.

Toxicant, toxin, and poison are often used interchangeably in the literature; however, there are subtle differences as indicated below:

A toxic agent is anything that can produce an adverse biological effect. It may be chemical, physical, or biological in form. For example, toxic agents may be chemical (such as cyanide), physical (such as radiation) and biological (such as snake venom).

A distinction is made for diseases due to biological organisms. Those organisms that invade and multiply within the organism and produce their effects by biological activity are not classified as toxic agents. An example of this is a virus that damages cell membranes resulting in cell death.

If the invading organisms excrete chemicals which is the basis for toxicity, the excreted substances are known as biological toxins. The organisms in this case are referred to as toxic organisms. An example is tetanus. Tetanus is caused by a bacterium, Clostridium tetani. The bacteria C. tetani itself does not cause disease by invading and destroying cells. Rather, it is a toxin that is excreted by the bacteria that travels to the nervous system (a neurotoxin) that produces the disease.

A toxic substance is simply a material which has toxic properties. It may be a discrete toxic chemical or a mixture of toxic chemicals. For example, lead chromate, asbestos, and gasoline are all toxic substances. Lead chromate is a discrete toxic chemical. Asbestos is a toxic material that does not consist of an exact chemical composition but a variety of fibers and minerals. Gasoline is also a toxic substance rather than a toxic chemical in that it contains a mixture of many chemicals. Toxic substances may not always have a constant composition. For example, the composition of gasoline varies with octane level, manufacturer, time of season, etc.

Toxic substances may be organic or inorganic in composition

Toxic substances may be systemic toxins or organ toxins.

A systemic toxin is one that affects the entire body or many organs rather than a specific site. For example, potassium cyanide is a systemic toxicant in that it affects virtually every cell and organ in the body by interfering with the cell's ability to utilize oxygen.

Toxicants may also affect only specific tissues or organs while not producing damage to the body as a whole. These specific sites are known as the target organs or target tissues.

Benzene is a specific organ toxin in that it is primarily toxic to the blood-forming tissues.

Lead is also a specific organ toxin; however, it has three target organs (central nervous system, kidney, and hematopoietic system).

A toxicant may affect a specific type of tissue (such as connective tissue) that is present in several organs. The toxic site is then referred to as the target tissue.

There are many types of body cells and they can be classified in several ways.

basic structure (e.g., cuboidal cells)

tissue type (e.g., hepatocytes of the liver)

germinal cells (e.g., ova and sperm)

somatic cells (e.g., non-reproductive cells of the body)

Germ cells are those cells that are involved in the reproductive process and can give rise to a new organism. They have only a single set of chromosomes peculiar to a specific sex. Male germ cells give rise to sperm and female germ cells develop into ova. Toxicity to germ cells can cause effects on the developing fetus (such as birth defects, abortions).

Somatic cells are all body cells except the reproductive germ cells. They have two sets (or pairs) of chromosomes. Toxicity to somatic cells causes a variety of toxic effects to the exposed individual (such as dermatitis, death, and cancer).

Toxic Effects

Toxicity is complex with many influencing factors; dosage is the most important. Xenobiotics cause many types of toxicity by a variety of mechanisms. Some chemicals are themselves toxic. Others must be metabolized (chemically changed within the body) before they cause toxicity.

Many xenobiotics distribute in the body and often affect only specific target organs. Others, however, can damage any cell or tissue that they contact. The target organs that are affected may vary depending on dosage and route of exposure. For example, the target for a chemical after acute exposure may be the nervous system, but after chronic exposure the liver.

Toxicity can result from adverse cellular, biochemical, or macromolecular changes.

Examples are: cell replacement, such as fibrosis

damage to an enzyme system

disruption of protein synthesis

production of reactive chemicals in cells

DNA damage

Some xenobiotics may also act indirectly by:

modification of an essential biochemical function

interference with nutrition

alteration of a physiological mechanism

Factors Influencing Toxicity

The toxicity of a substance depends on the following:

form and innate chemical activity

dosage, especially dose-time relationship

exposure route

species

age

sex

ability to be absorbed

metabolism

distribution within the body

excretion

presence of other chemicals

The form of a substance may have a profound impact on its toxicity especially for metallic elements. For example, the toxicity of mercury vapor differs greatly from methyl mercury. Another example is chromium. Cr3+ is relatively nontoxic whereas Cr6+ causes skin or nasal corrosion and lung cancer.

The innate chemical activity of substances also varies greatly. Some can quickly damage cells causing immediate cell death. Others slowly interfere only with a cell's function.

For example: hydrogen cyanide binds to cytochrome oxidase resulting in cellular hypoxia and rapid death

nicotine binds to cholinergic receptors in the CNS altering nerve conduction and inducing gradual onset of paralysis

Exposure route is important in determining toxicity. Some chemicals may be highly toxic by one route but not by others. Two major reasons are differences in absorption and distribution within the body.

For example: ingested chemicals, when absorbed from the intestine, distribute first to the liver and may be immediately detoxified

inhaled toxicants immediately enter the general blood circulation and can distribute throughout the body prior to being detoxified by the liver

Frequently there are different target organs for different routes of exposure.

Toxic responses can vary substantially depending on the species. Most species differences are attributable to differences in metabolism. Others may be due to anatomical or physiological differences. For example, rats cannot vomit and expel toxicants before they are absorbed or cause severe irritation, whereas humans and dogs are capable of vomiting.

Selective toxicity refers to species differences in toxicity between two species simultaneously exposed. This is the basis for the effectiveness of pesticides and drugs.

Examples are: an insecticide is lethal to insects but relatively nontoxic to animals

antibiotics are selectively toxic to microorganisms while virtually nontoxic to humans

Age may be important in determining the response to toxicants. Some chemicals are more toxic to infants or the elderly than to young adults.

For example: parathion is more toxic to young animals

nitrosamines are more carcinogenic to newborn or young animals

Although uncommon, toxic responses can vary depending on sex.

Examples are: male rats are 10 times more sensitive than females to liver damage from DDT

female rats are twice as sensitive to parathion as male rats

The ability to be absorbed is essential for systemic toxicity to occur. Some chemicals are readily absorbed and others poorly absorbed.

Nearly all alcohols are readily absorbed when ingested, whereas there is virtually no absorption for most polymers. The rates and extent of absorption may vary greatly depending on the form of the chemical and the route of exposure.

For example: ethanol is readily absorbed from the gastrointestinal tract but poorly absorbed through the skin

organic mercury is readily absorbed from the gastrointestinal tract; inorganic lead sulfate is not

Metabolism, also known as biotransformation, is a major factor in determining toxicity. The products of metabolism are known as metabolites. There are two types of metabolism - detoxification and bioactivation. Detoxification is the process by which a xenobiotic is converted to a less toxic form. This is a natural defense mechanism of the organism. Generally the detoxification process converts lipid-soluble compounds to polar compounds. Bioactivation is the process by which a xenobiotic may be converted to more reactive or toxic forms.

The distribution of toxicants and toxic metabolites throughout the body ultimately determines the sites where toxicity occurs. A major determinant of whether or not a toxicant will damage cells is its lipid solubility. If a toxicant is lipid-soluble it readily penetrates cell membranes. Many toxicants are stored in the body. Fat tissue, liver, kidney, and bone are the most common storage depots. Blood serves as the main avenue for distribution. Lymph also distributes some materials.

The site and rate of excretion is another major factor affecting the toxicity of a xenobiotic. The kidney is the primary excretory organ, followed by the gastrointestinal tract, and the lungs (for gases). Xenobiotics may also be excreted in sweat, tears, and milk.

A large volume of blood serum is filtered through the kidney. Lipid-soluble toxicants are reabsorbed and concentrated in kidney cells. Impaired kidney function causes slower elimination of toxicants and increases their toxic potential.

The presence of other chemicals may decrease toxicity (antagonism), add to toxicity (additivity), or increase toxicity (synergism or potentiation) of some xenobiotics.