Toxic Effects, Factors, and Interactions [Toxic Effects] [Factors Influencing Toxicity] [Chemical Interactions]
Materials excerpted January 2004 from Toxicology Tutorials, Developed through the National Library of Medicine
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
Some xenobiotics may also act indirectly by:
modification of an essential biochemical function
interference with nutrition
alteration of a physiological mechanism
Systemic Toxic Effects
Toxic effects are generally categorized according to the site of the toxic effect. In some cases, the effect may occur at only one site. This site is referred to as the specific target organ. In other cases, toxic effects may occur at multiple sites. This is referred as systemic toxicity. Following are types of systemic toxicity:
Genetic Toxicity (somatic cells)
Acute toxicity occurs almost immediately (hours/days)
after an exposure. An acute exposure is usually
a single dose or a series of doses received within a 24 hour period.
Death is a major concern in cases of acute exposures. Examples
In 1989, 5,000 people died and 30,000 were permanently disabled due to exposure to methyl isocyanate from an industrial accident in India.
Many people die each year from inhaling carbon monoxide from faulty heaters.
Non-lethal acute effects may also occur, e.g., convulsions and respiratory irritation.
Subchronic toxicity results
from repeated exposure for several weeks or months. This
is a common human exposure pattern for some pharmaceuticals and
environmental agents. Examples are:
Ingestion of coumadin tablets (blood thinners) for several weeks as a treatment for venous thrombosis can cause internal bleeding.
Workplace exposure to lead over a period of several weeks can result in anemia.
Chronic toxicity represents cumulative damage to specific organ systems and takes many months or years to become a recognizable clinical disease. Damage due to subclinical individual exposures may go unnoticed. With repeated exposures or long-term continual exposure, the damage from these subclinical exposures slowly builds-up (cumulative damage) until the damage exceeds the threshold for chronic toxicity. Ultimately, the damage becomes so severe that the organ can no longer function normally and a variety of chronic toxic effects may result.
Examples of chronic toxic affects are:
cirrhosis in alcoholics who have ingested ethanol for several years
chronic kidney disease in workmen with several years exposure to lead
chronic bronchitis in long-term cigarette smokers
pulmonary fibrosis in coal miners (black lung disease)
Carcinogenicity is a complex multistage process of abnormal cell growth and differentiation which can lead to cancer. At least two stages are recognized. They are initiation in which a normal cell undergoes irreversible changes and promotion in which initiated cells are stimulated to progress to cancer. Chemicals can act as initiators or promoters.
The initial neoplastic transformation results from the mutation of the cellular genes that control normal cell functions. The mutation may lead to abnormal cell growth. It may involve loss of suppresser genes that usually restrict abnormal cell growth. Many other factors are involved (e.g., growth factors, immune suppression, and hormones).
A tumor (neoplasm) is simply an uncontrolled growth of cells. Benign tumors grow at the site of origin; do not invade adjacent tissues or metastasize; and generally are treatable. Malignant tumors (cancer) invade adjacent tissues or migrate to distant sites (metastasis). They are more difficult to treat and often cause death.
Developmental Toxicity pertains to adverse toxic effects to the developing embryo or fetus. This can result from toxicant exposure to either parent before conception or to the mother and her developing embryo-fetus. The three basic types of developmental toxicity are:
Chemicals cause developmental toxicity by two methods. They can act directly on cells of the embryo causing cell death or cell damage, leading to abnormal organ development. A chemical might also induce a mutation in a parent's germ cell which is transmitted to the fertilized ovum. Some mutated fertilized ova develop into abnormal embryos.
Genetic Toxicity results from damage to DNA and altered genetic expression. This process is known as mutagenesis. The genetic change is referred to as a mutation and the agent causing the change as a mutagen. There are three types of genetic change:
If the mutation occurs in a germ cell the effect is heritable. There is no effect on the exposed person; rather the effect is passed on to future generations. If the mutation occurs in a somatic cell, it can cause altered cell growth (e.g. cancer) or cell death (e.g. teratogenesis) in the exposed person.
Factors Influencing Toxicity
The toxicity of a substance depends on the following:
form and innate chemical activity
dosage, especially dose-time relationship
ability to be absorbed
distribution within the body
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.
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
The dosage is the most important and critical factor in determining if a substance will be an acute or a chronic toxicant. Virtually all chemicals can be acute toxicants if sufficiently large doses are administered. Often the toxic mechanisms and target organs are different for acute and chronic toxicity. Examples are:
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. For example, 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. For example:
alcohol may enhance the effect of many antihistamines and sedatives
antidotes function by antagonizing the toxicity of a poison (atropine counteracts poisoning by organophosphate insecticides)
Humans are normally exposed to several chemicals
at one time rather than to an individual chemical. Medical treatment
and environment exposure generally consists of multiple exposures.
hospital patients on the average receive 6 drugs daily
home influenza treatment consists of aspirin, antihistamines, and cough syrup taken simultaneously
drinking water may contain small amounts of pesticides, heavy metals, solvents, and other organic chemicals
air often contains mixtures of hundreds of chemicals such as automobile exhaust and cigarette smoke
gasoline vapor at service stations is a mixture of 40-50 chemicals
Normally, the toxicity of a specific chemical is determined by the study of animals exposed to only one chemical. Toxicity testing of mixtures is rarely conducted since it is usually impossible to predict the possible combinations of chemicals that will be present in multiple-chemical exposures.
Xenobiotics administered or received simultaneously
may act independently of each other. However, in many cases, the
presence of one chemical may drastically affect the response to
another chemical. The toxicity of a combination of chemicals may
be less or it may be more than would be predicted from the known
effects of each individual chemical. The effect that one chemical
has on the toxic effect of another chemical is known as an interaction.
Types of Interactions
There are four basic types of interactions. Each is based on the expected effects caused by the individual chemicals.The types of interactions are:
This table quantitatively illustrates the percent of the population affected by individual exposure to chemical A and chemical B as well as exposure to the combination of chemical A and chemical B. It also gives the specific type of interaction:
The interactions described can be categorized
by their chemical or biological mechanisms as follows:
chemical reactions between chemicals
modifications in absorption, metabolism, or excretion
reactions at binding sites and receptors
Additivity is the most common type of drug interaction. Examples of chemical or drug additivity reactions are:
Two central nervous system (CNS) depressants taken at the same time, a tranquilizer and alcohol, often cause depression equal to the sum of that caused by each drug.
Organophosphate insecticides interfere with nerve conduction. The toxicity of the combination of two organophosphate insecticides is equal to the sum of the toxicity of each.
Chlorinated insecticides and halogenated solvents both produce liver toxicity. The hepatotoxicity of an insecticide formulation containing both is equivalent to the sum of the hepatotoxicity of each.
Antagonism is often a desirable effect in toxicology and is the basis for most antidotes. Examples include:
Potentiation occurs when a chemical that does not have a specific toxic effect makes another chemical more toxic. Examples are:
The hepatotoxicity of carbon tetrachloride is greatly enhanced by the presence of isopropanol. Such exposure may occur in the workplace.
Normally, warfarin (a widely used anticoagulant in cardiac disease) is bound to plasma albumin so that only 2% of the warfarin is active. Drugs which compete for binding sites on albumin increase the level of free warfarin to 4% causing fatal hemorrhage.
Synergism can have serious health effects. With synergism, exposure to a chemical may drastically increase the effect of another chemical. Examples are:
Exposure to both cigarette smoke and radon results in a significantly greater risk for lung cancer than the sum of the risks of each.
The combination of exposure to asbestos and cigarette smoke results in a significantly greater risk for lung cancer than the sum of the risks of each.
The hepatotoxicity of a combination of ethanol and carbon tetrachloride is much greater than the sum of the hepatotoxicity of each.
Different types of interactions can occur at different target sites for the same combination of two chemicals. For example, chlorinated insecticides and halogenated solvents (which are often used together in insecticide formulations) can produce liver toxicity with the interaction being additive.
The same combination of chemicals produces
a different type of interaction on the central nervous system.
Chlorinated insecticides stimulate the central nervous system
whereas halogenated solvents cause depression of the nervous system.
The effect of simultaneous exposure is an antagonistic interaction.