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Factors Influencing Toxicity
The toxicity of a substance depends on the following:
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|  | form and innate chemical activity
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| | dosage, especially dose-time relationship
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| | exposure route
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| | species
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| | age
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| | sex
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| | ability to be absorbed
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| | metabolism
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| | distribution within the body
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| | excretion
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| | presence of other chemicals
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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:
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| | hydrogen cyanide binds to cytochrome oxidase resulting in cellular hypoxia and rapid death
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| | nicotine binds to cholinergic receptors in the CNS altering nerve conduction and inducing gradual onset of paralysis
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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:
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| | ingested chemicals, when absorbed from the intestine, distribute first to the liver and may be immediately detoxified
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| | inhaled toxicants immediately enter the general blood circulation and can distribute throughout the body prior to being detoxified by the liver
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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:
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| | an insecticide is lethal to insects but relatively nontoxic to animals
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| | antibiotics are selectively toxic to microorganisms while virtually nontoxic to humans
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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:
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| | parathion is more toxic to young animals
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| | nitrosamines are more carcinogenic to newborn or young animals
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Although uncommon, toxic responses can vary depending on sex. Examples are:
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| | male rats are 10 times more sensitive than females to liver damage from DDT
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| | female rats are twice as sensitive to parathion as male rats
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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:
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| | ethanol is readily absorbed from the gastrointestinal tract but poorly absorbed through the skin
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| | organic mercury is readily absorbed from the gastrointestinal tract; inorganic lead sulfate is not
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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:
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| | alcohol may enhance the effect of many antihistamines and sedatives
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| | antidotes function by antagonizing the toxicity of a poison (atropine counteracts poisoning by organophosphate insecticides)
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