Toxicity is complex with many influencing factors; dosage is the most important. Xenobiotics, or chemicals foreign to the body, cause many types of toxicity by a variety of mechanisms. Some chemicals are themselves toxic and are sometimes referred to as "parent" compounds. 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
- 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 (Cr). 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 central nervous system (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.
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)
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:
- Acute Toxicity
- Subchronic Toxicity
- Chronic Toxicity
- Developmental 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 are:
- In 1989, 5,000 people died and 30,000 were permanently disabled due to exposure to methyl isocyanate from an industrial accident in Bhopal, 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; 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 of tumors.
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.
Organ Specific Toxic Effects
Blood and Cardiovascular Toxicity
Blood and Cardiovascular Toxicity results from xenobiotics acting directly on cells in circulating blood, bone marrow, and heart. Examples of blood and cardiovascular toxicity are:
- hypoxia due to carbon monoxide binding of hemoglobin preventing transport of oxygen
- decrease in circulating leukocytes due to chloramphenicol damage to bone marrow cells
- leukemia due to benzene damage of bone marrow cells
- arteriosclerosis due to cholesterol accumulation in arteries and veins
Dermal Toxicity may result from direct contact or internal distribution to the skin. Effects range from mild irritation to severe changes, such as corrosivity, hypersensitivity, and skin cancer. Examples of dermal toxicity are:
- dermal irritation due to skin exposure to gasoline
- dermal corrosion due to skin exposure to sodium hydroxide (lye)
- dermal hypersensitivity due to skin exposure to poison ivy
- skin cancer due to ingestion of arsenic or skin exposure to UV light
Eye Toxicity results from direct contact or internal distribution to the eye. The cornea and conjunctiva are directly exposed to toxicants. Thus, conjunctivitis and corneal erosion may be observed following occupational exposure to chemicals. Many household items can cause conjunctivitis. Chemicals in the circulatory system can distribute to the eye and cause corneal opacity, cataracts, retinal and optic nerve damage. For example:
- acids and strong alkalis may cause severe corneal corrosion
- corticosteroids may cause cataracts
- methanol (wood alcohol) may damage the optic nerve
Hepatotoxicity is toxicity to the liver, bile duct, and gall bladder. The liver is particularly susceptible to xenobiotics due to a large blood supply and its role in metabolism. Thus it is exposed to high doses of the toxicant or its toxic metabolites. The primary forms of hepatotoxicity are:
Immunotoxicity is toxicity of the immune system. It can take several forms: hypersensitivity (allergy and autoimmunity), immunodeficiency, and uncontrolled proliferation (leukemia and lymphoma). The normal function of the immune system is to recognize and defend against foreign invaders. This is accomplished by production of cells that engulf and destroy the invaders or by antibodies that inactivate foreign material. Examples are:
- contact dermatitis due to exposure to poison ivy
- systemic lupus erythematosus in workers exposed to hydrazine
- immunosuppression by cocaine
- leukemia induced by benzene
The kidney is highly susceptible to toxicants for two reasons. A high volume of blood flows through it and it filtrates large amounts of toxins which can concentrate in the kidney tubules. Nephrotoxicity is toxicity to the kidneys. It can result in systemic toxicity causing:
- decreased ability to excrete body wastes
- inability to maintain body fluid and electrolyte balance
- decreased synthesis of essential hormones (e.g., erythropoietin)
Neurotoxicity represents toxicant damage to cells of the central nervous system (brain and spinal cord) and the peripheral nervous system (nerves outside the CNS). The primary types of neurotoxicity are:
- neuronopathies (neuron injury)
- axonopathies (axon injury)
- demyelination (loss of axon insulation)
- interference with neurotransmission
Reproductive Toxicity involves toxicant damage to either the male or female reproductive system. Toxic effects may cause:
- decreased libido and impotence
- interrupted pregnancy (abortion, fetal death, or premature delivery)
- infant death or childhood morbidity
- altered sex ratio and multiple births
- chromosome abnormalities and birth defects
- childhood cancer
- delayed puberty
Respiratory Toxicity relates to effects on the upper respiratory system (nose, pharynx, larynx, and trachea) and the lower respiratory system (bronchi, bronchioles, and lung alveoli). The primary types of respiratory toxicity are:
- pulmonary irritation
- reactive airway disease
- allergic alveolitis
- fibrotic lung disease
- lung cancer
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