Poisons and Toxins
Poisons and toxins are molecules that are harmful to living organisms. it is important to note that virtually any substance can be harmful at high enough concentrations--as Paracelsus (1493-1541) said in the sixteenth century, "the dose makes the poison." In common usage, the word poison designates a substance that is harmful in relatively small quantities. There is no absolute limit for this designation, although it generally is reserved for substances that are lethal in adult humans at doses below 100 grams. Toxin is a synonym for poison.
Poisons include both naturally produced compounds and chemicals manufactured by humans. Natural poisons are produced by species of bacteria, fungi, protists, plants, and animals. Modern society produces and uses thousands of chemicals, including more than 65,000 manufactured in the United States. Many of these are poisonous, and their regulation is an important part of the work of the Occupational Safety and Health Agency, or OSHA. Cleanup of toxic wastes and spills is overseen by the Environmental Protection Agency (EPA).
Poisons are toxic because they disrupt metabolic processes or destroy tissue through chemical reactions with cells. While the exact mechanisms of action of poisons are almost as varied as the number of poisons themselves, there are several broad classes of mechanisms.
The brain requires large amounts of oxygen to function, and cannot survive if deprived of it for more than ten minutes. Asphyxiation occurs when the lungs cannot provide enough oxygen for the brain to continue functioning. Because of this, otherwise harmless gases such as nitrogen or carbon dioxide can be poisonous in high concentrations.Carbon monoxide binds to hemoglobin, the molecule that carries oxygen in the blood stream, and in this way leads to asphyxia.
Neural transmission relies on the rapid and precise delivery of chemical signals along neurons and across the spaces between them. Curare, botulinum toxin, and organophosphorus insecticides each interfere with neural transmission.
Curare, a poison derived from a South American shrub, blocks the action of an enzyme vital for intracellular signaling in neurons, the Na+/K+ ATPase. This protein creates the electrochemical gradient whose breakdown carries information from the dendrite to the axon. Death by curare is usually due to paralysis of the respiratory muscles, which cannot contract without neural stimulation, or by fibrillation of the heart, whose cells become desynchronized in their contractions.
Botulinum toxin, from the bacterium Clostridium botulinum, prevents release of the neurotransmitter acetylcholine. Acetylcholine is released by neurons to provoke muscle contraction. Botulinum toxin inactivates a key protein in the axon that allows vesicles of acetylcholine to fuse with the axon membrane, which releases the acetylcholine onto the muscle surface. Death by botulinum toxin is usually due to respiratory paralysis.
Organophosphorus insecticides bind to and inactivate acetylcholinesterase. This enzyme breaks down acetylcholine after its release, to prevent continued muscle contraction in the absence of a new signal. Without this enzyme, muscle continues to contract uncontrollably, leading to tremor, convulsions, and death. Organophosphates are also used in the most common types of chemical weapons.
The heart can be affected by a variety of substances that change its excitability or the force of its contractions. Digitalis, derived from foxglove, is one of the oldest herbal medicines for the heart. In small doses, it is prescribed for congestive heart failure to increase heart output. In slightly larger doses, it is deadly. Digitalis is a type of steroid, called a cardiac glycoside. Other cardiac glycosides are produced by various South American frogs of the genus Bufo. Like curare, this poison isused on arrowtips for hunting.
Cell energy production is dependent on mitochondria, small organelles that transfer the energy from sugar and other foods to create adenosine triphosphate, or ATP. in one step, high-energy electrons are transferred along a chain of proteins called cytochromes. Cyanide binds permanently to these cytochromes, inactivating them. At another step, the energy from these electrons is used to pump H+ ions across the mitochondrial membrane, creating a gradient that is later harnessed to actually produce ATP. Dinitrophenol, a chemical used in dye manufacture, is a membrane- soluble H+ carrier. By shuttling H+ ions back across the mitochondrial membrane, ATP production is prevented. As with many other poisons, neurons and heart muscle cells are most gravely affected.
Chronic exposure to some agents leads to long-term deterioration of health.Lead inhibits production of hemoglobin, causing anemia, as well as interfering with a variety of other biologic pathways. Lead builds up in the tissues, and chronic lead poisoning can cause mental retardation and sterility.
Some chemicals directly affect the cell's DNA (deoxyribonucleic acid). Chemicals that cause changes in DNA sequence, or mutations, are called mutagens. If these sequence changes eliminate the control mechanisms that keep a mature cell from dividing, the cell may become cancerous. Substances that cause cancer are called carcinogens.Asbestos can cause lung cancer when its fibers are inhaled over a long period of time. Chemicals in cigarette smoke are also carcinogens.
The three major routes of exposure for poisons in the human body are the skin, the lungs, and the gastrointestinal tract. Intact skin provides a barrier against many poisons, but because of its large surface area and direct contact with the environment, it is a likely route for accidental exposure through spills, for instance. The lungs provide direct and rapid entry into the bloodstream for most small molecules, although larger particles such as asbestos are trapped in the mucus lining the respiratory passages. Ingestion into the gastrointestinal tract will inactivate many poisons, especially proteins, though digestion. Nonetheless, ingestion is the principal means of entry of botulinum toxin, for instance, which is a protein.
The dose of a poison a person is exposed to is not equivalent to the amount that enters the body, but rather the amount that reaches the target organ. Biochemical transformation in the liver is the principal means by which potential poisons are detoxified. liver cells contain a variety of enzyme systems designed to modify foreign compounds to make them more soluble and less reactive. Excretion through the kidneys is the major means of ridding the body of a toxin.
In some cases, biochemical transformation creates the poison from an otherwise harmless substance. For instance, ethylene glycol, a component of antifreeze, is harmless until it is transformed by the body. Acted on by the enzyme that normally metabolizes ethanol, it is transformed into oxalic acid, which can crystalize in the kidneys, causing kidney failure.
Two poisons can interact synergistically, causing increased toxicity at doses that individually would be lower than the toxic threshold. For instance, asbestos exposure in a smoker increases the risk of lung cancer 40-fold over the risk from wither alone.
One way to measure the toxicity of a compound is by its "LD50" the dose that kills 50% of experimental animals receiving it. However, the LD50 varies among different animals. For instance, in rats, the LD50 for dinitrophenol is 30 milligrams per kilogram of body weight, while in cats it is 75 mg/kg. The over-the-counter analgesic acetaminophen has an LD50 of 338 mg/kg in the mouse, but almost eight times tha--2404 mg/kg--in the rat. In humans, the minimum lethal dose is approximately 10 grams, or 150 mg/kg.
Relatively few poisons have specific antidotes. Instead, the toxic effects are reduced as the compound is metabolized and excreted over time. Administration of ethanol (drinking alcohol) is an antidote for ethylene glycol poisoning, because it occupies the metabolizing enzyme until the ethylene glycol is excreted. An antibody against botulinum toxin is available, which binds to the toxin and inactivates it. However, it must be administered very soon after ingestion, and provokes an anaphylactic immune reaction in approximately 10% of people taking it, which can be as life- threatening as the toxin itself.
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