In a general sense, the longer the duration of exposure, that is, the longer the body (or tissues in the body) is in contact with a chemical, the greater the opportunity for toxic effects to occur. Frequency of exposure also has an important influence on the nature and extent of toxicity. The total amount of a chemical required to produce a toxic effect is generally less for a single exposure than for intermittent or repeated exposures. More total chemical is required to produce toxicity for intermittent or chronic exposure because many chemicals can be eliminated from the body, because tissue injuries can often be repaired, and because adaptation of tissues can occur over time. Some toxic effects occur only after chronic exposure; this is because sufficient amounts of chemical cannot be attained in the tissue by a single exposure. Sometimes a chemical has to be present in a tissue for a considerable time to produce injury. For example, the neurotoxic and carcinogenic effects from exposure to heavy metals usually require long-term repeated exposure.

The time between exposure to a chemical and onset of toxic effects varies depending on the chemical and the exposure. For example, the toxic effects of carbon monoxide, sodium cyanide, and carbon disulfide are evident within minutes. For many chemicals, the toxic effect is most severe between one and a few days after exposure. However, some chemicals produce "delayed" toxicity; in fact, the neurotoxicity produced by some chemicals is not observed until a few weeks after exposure. The most delayed toxic effect produced by chemicals is cancer: in humans, it usually takes 10 to 30 years between exposure to a known human carcinogen and the detection of a tumor.

3.C.1.3 Routes of Exposure

Exposure to chemicals in the laboratory can occur by several different routes: (1) inhalation, (2) contact with skin or eyes, (3) ingestion, and (4) injection. Important features of these different pathways are detailed below.

3.C.1.3.1
Inhalation

Toxic materials that can enter the body via inhalation include gases, the vapors of volatile liquids, mists and sprays of both volatile and nonvolatile liquid substances, and solid chemicals in the form of particles, fibers, and dusts. Inhalation of toxic gases and vapors can produce poisoning by absorption through the mucous membranes of the mouth, throat, and lungs and can also damage these tissues seriously by local action. Inhaled gases and vapors can pass into the capillaries of the lungs and be carried into the circulatory system. This absorption can be extremely rapid. Because of the large surface area of the lungs in humans (about 75 square meters (m2)), this is the main site for absorption of many toxic materials.

The factors governing the absorption of gases and vapors from the respiratory tract differ significantly from those that govern the absorption of particulate substances. Factors controlling the absorption of inhaled gases and vapors include the solubility of the gas in body fluids and the reactivity of the gas with tissues and the fluid lining the respiratory tract. Gases or vapors that are highly water-soluble, such as methanol, acetone, hydrogen chloride, and ammonia, dissolve predominantly in the lining of the nose and windpipe (trachea) and therefore tend to be absorbed from those regions. These sites of absorption are also potential sites of toxicity. Formaldehyde is an example of a reactive, highly water-soluble vapor for which the nose is a major site of deposition. In contrast to water-soluble gases, reactive gases with low water-solubility, such as ozone, phosgene, and nitrogen dioxide, penetrate farther into the respiratory tract and thus come into contact with the smaller tubes of the airways. Gases and vapors that are not water-soluble but are more fat-soluble, such as benzene, methylene chloride, and trichloroethylene, are not completely removed by interaction with the surfaces of the nose, trachea, and small airways. As a result, these gases penetrate the airways down into the deep lung, where they can diffuse across the thin lung tissue into the blood. The more soluble a gas is in the blood, the more of it will be dissolved and transported to other organs.

In the case of inhaled solid chemicals, an important factor in determining if and where a particle will be deposited in the respiratory tract is its size. One generalization is that the largest particles (³5 microns (µm)) are deposited primarily in the nose, smaller particles (1 to 5 µm) in the trachea and small airways, and the smallest particles in the lungs. Thus, depending on the size of an inhaled particle, it will be deposited in different sections of the respiratory tract, and the location can affect the local toxicity and the absorption of the material. In general, particles that are water-soluble will dissolve within minutes or days, and chemicals that are not water-soluble but have a moderate degree of fat-solubility will also clear rapidly into the blood. Those that are not water-soluble or highly fat-soluble will not dissolve and will be retained in the lungs for long periods of time. Metal oxides, asbestos, and silica are examples of water-insoluble inorganic particles that might be retained in the lungs for years.

A number of factors can affect the airborne concentrations of chemicals. Vapor pressure (the tendency of



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