IncludedACGIH Region Regions RegionRegion

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Nose, nasopharynx

Head airways (HAR)

Extrathoracic (E) Nasopharynx (NP)

Mouth, oropharynx, laryngopharynx

Trachea, bronchi, and conductive bronchioles (to terminal bronchioles)

Respiratory bronchioles, alveolar ducts, alveolar sacs, alveoli

Anterior nasal passages (ETj)

All other extrathoracic (Et2)

Tracheobronchial Tracheobronchial Tracheobronchial Trachea and

Gas exchange (GER)

Alveolar (A) Pulmonary (P)

large bronchi

Bronchioles (bb)

Alveolar-interstitial (Al)

4.3 Extrathoracic Airways

As shown in Figure 2.4, the extrathoracic airways were partitioned by ICRP (6) into two distinct clearance and dosimetric regions: the anterior nasal passages (ET,) and all other extrathoracic airways (ET2), i.e., the posterior nasal passages, the naso- and oropharynx, and the larynx. Particles deposited on the surface of the skin that lines the anterior nasal passages (ETj) are assumed to be subject only to removal by extrinsic means (nose blowing, wiping, etc.). The bulk of material deposited in the naso-oropharynx or larynx (ET2) is subject to fast clearance in the layer of fluid that covers these airways. The 1994 ICRP model recognizes that diffusional deposition of ultrafine particles in the extrathoracic airways can be substantial, whereas earlier ICRP models did not (7-9).

4.4 Thoracic Airways

Radioactive material deposited in the thorax is generally divided between the tracheobronchial (TB) region, where deposited particles are subject to relatively fast mucociliary clearance (duration in hours to 1 or 2 days), and the alveolar-interstitial (AI) region, where macrophage-mediated particle clearance is much slower (duration up to several weeks), and dissolution rates for insoluble particles not cleared by macrophages can have half-times measured in months or years.

For purposes of dosimetry, the ICRP (6) divided the deposition of inhaled material in the TB region between the trachea and bronchi (BB) and in the more distal, small conductive airways, known as bronchioles (bb). However, the subsequent efficiency with which mucociliary transport in either type of airway can clear deposited particles is controversial. To be certain that doses to bronchial and bronchiolar epithelia would not be underestimated, the ICRP Task Group assumed that as much as half the number of particles deposited in these airways is subject to relatively "slow" mucociliary clearance that lasts up to about 1 week. The likelihood that an insoluble particle is cleared relatively slowly by the mucociliary system depends on its size.

4.5 Gas-Exchange Airways and Alveoli

The ICRP (6) model also assumed that material deposited in the AI region is subdivided among three compartments (AI1, AI2, and AI3) each of which is cleared more slowly than TB deposition, and the subregions clear at different characteristic rates.

4.6 Regional Deposition Estimates

Figure 2.7 depicts the predictions of the ICRP (6) Task Group Model in terms of the fractional deposition in each region as a function of the size of the inhaled particles. It reflects the minimal lung deposition between 0.1 and 1 mm, where deposition is determined largely by the exchange in the deep lung between tidal and residual lung air. Deposition increases below 0.1 mm as diffusion becomes more efficient with decreasing particle size. Deposition increases with increasing particle size above 1 mm as sedimentation and impaction become increasingly effective.

Figure 2.7. Fractional deposition in each region of the respiratory tract for a reference light worker (normal nose breather) in the 1994 ICRP model.

Although aerodynamic diameter is an excellent index of particle behavior for relatively compact particles that differ greatly in shape and density, it is inadequate for fibers that deposit by interception, as well as by inertia, gravitational displacement, or diffusion. The aerodynamic diameter of mineral or vitreous fibers whose aspect ratio (length/width) is greater than 10 is about three times their physical diameter. Fibers whose diameters are less than 3 mm can penetrate into bronchioles whose diameters are less than 500 mm. For thin fibers longer than 10 or 20 mm, interception, whereby an end of the fiber touches a surface and is collected, accounts for a significant enhancement of deposition (10).

Less complex models for size-selective regional particle deposition have been adopted by occupational health and community air pollution professionals and agencies, and these have been used to develop inhalation exposure limits within specific particle size ranges. Distinctions are made between: (7) those particles that are not aspirated into the nose or mouth and therefore represent no inhalation hazard; (2) the inhalable (aka inspirable) particulate mass (IPM), i.e., those that are inhaled and are hazardous when deposited anywhere within the respiratory tract; (3) the thoracic particulate mass (TPM), i.e., those that penetrate the larynx and are hazardous when deposited anywhere within the thorax; and (4) the respirable particulate mass (RPM), i.e., those particles that penetrate through the terminal bronchioles and are hazardous when deposited within the gasexchange region of the lungs. These criteria are described in more detail later in this chapter in the sections devoted to exposure assessment. 4.7 Translocation and Retention

Particles that do not dissolve at deposition sites can be translocated to remote retention sites by passive and active clearance processes. Passive transport depends on movement on or in surface fluids that line the airways. There is a continual proximal flow of surfactant to and onto the mucociliary escalator, which begins at the terminal bronchioles, where it mixes with secretions from Clara and goblet cells. Within midsized and larger airways are additional secretions from goblet cells and mucus glands that produce a thicker mucous layer that has a serous subphase and an overlying more viscous gel layer. The gel layer that lies above the tips of the synchronously beating cilia is found in discrete plaques in smaller airways and becomes more of a continuous layer in the larger airways. The mucus that reaches the larynx and the particles carried by it are swallowed and enter the GI tract.

The total transit time for particles cleared during the relatively rapid mucociliary clearance phase varies from ~2 to 24 hours in healthy humans (11). Macrophage-mediated particle clearance via the bronchial tree takes place during a period of several weeks. Compact particles that deposit in alveolar zone airways are ingested by alveolar macrophages within about 6 hours, but the movement of the particle-laden macrophages depends on the several weeks that it takes for the normal turnover of the resident macrophage population. At the end of several weeks, the particles not cleared to the bronchial tree via macrophages have been incorporated into epithelial and interstitial cells, from which they are slowly cleared by dissolution and/or as particles via lymphatic drainage pathways, passing through pleural and eventually hilar and tracheal lymph nodes. Clearance times for these later phases depend strongly on the chemical nature of the particles and their sizes, and half-times range from about 30 to 1,000 days or more.

All of the characteristic clearance times cited refer to inert, nontoxic particles in healthy lungs. Toxicants can drastically alter clearance times. Inhaled materials that affect mucociliary clearance rates include cigarette smoke (12, 13), sulfuric acid (14, 15), ozone (16, 17), sulfur dioxide (17a), and formaldehyde (18). Macrophage-mediated alveolar clearance is affected by sulfur dioxide (19), nitrogen dioxide and sulfuric acid (20), ozone (16, 20), silica dust (21), and long mineral and vitreous fibers (22, 23). Cigarette smoke affects the later phases of alveolar zone clearance in a dose-dependent manner (24). Clearance pathways and rates that affect the distribution of retained particles and their dosimetry can be altered by these toxicants.

Long mineral and manufactured vitreous fibers cannot be fully ingested by macrophages or epithelial cells and can clear only by dissolution. Most glass and slag wool fibers dissolve relatively rapidly within the lung and/or break up into shorter length segments. Chrysotile asbestos is more biopersistent than most vitreous fibers and can subdivide longitudinally, creating a larger number of long fibers. The amphibole asbestos varieties (e.g., amosite, crocidolite, and tremolite) dissolve much more slowly than chrysotile. The close association between the biopersistence of inhaled long fibers and their carcinogenicity and fibrogenicity has been described by Eastes and Hadly (25), and additional data on the influence of fiber length on the biopersistence of vitreous fibers following inhalation was described by Bernstein et al. (26).

4.8 Ingestion Exposures and Gastrointestinal (GI) Tract Exposures

Chemical contaminants in drinking water or food reach human tissues via the GI tract. Ingestion may also contribute to the uptake of chemicals that were initially inhaled, because material deposited on or dissolved in the bronchial mucous blanket is eventually swallowed.

The GI tract may be considered a tube running through the body, whose contents are actually external to the body. Unless the ingested material affects the tract itself, any systemic response depends on absorption through the mucosal cells that line the lumen. Although absorption may occur anywhere along the length of the GI tract, the main region for effective translocation is the small intestine. The enormous absorptive capacity of this organ results from the presence in the intestinal mucosa of projections, termed villi, each of which contains a network of capillaries; the villi have a large effective total surface area for absorption.

Although passive diffusion is the main absorptive process, active transport systems also allow essential lipid-insoluble nutrients and inorganic ions to cross the intestinal epithelium and are responsible for the uptake of some contaminants. For example, lead may be absorbed via the system that normally transports calcium ions (27). Small quantities of particulate material and certain large macromolecules such as intact proteins may be absorbed directly by the intestinal epithelium.

Materials absorbed from the GI tract enter either the lymphatic system or the portal blood circulation; the latter carries material to the liver, from which it may be actively excreted into the bile or diffuse into the bile from the blood. The bile is subsequently secreted into the intestines. Thus, a cycle of translocation of a chemical from the intestine to the liver to bile and back to the intestines, known as the enterohepatic circulation, may be established. Enterohepatic circulation usually involves contaminants that undergo metabolic degradation in the liver. For example, DDT undergoes enterohepatic circulation; a product of its metabolism in the liver is excreted into the bile, at least in experimental animals (28).

Various factors modify absorption from the GI tract and enhance or depress its barrier function. A decrease in gastrointestinal mobility generally favors increased absorption. Specific stomach contents and secretions may react with the contaminant and possibly change it to a form with different physicochemical properties (e.g., solubility), or they may absorb it, alter the available chemical, and change the translocation rates. The size of ingested particulates also affects absorption. Because the rate of dissolution is inversely proportional to particle size, large particles are absorbed to a lesser degree, especially if they are fairly insoluble in the first place. Certain chemicals, e.g., chelating agents such as EDTA, also cause a nonspecific increase in the absorption of many materials.

As a defense, spastic contractions in the stomach and intestine may eliminate noxious agents via vomiting or by accelerating the transit of feces through the GI tract.

4.9 Skin Exposure and Dermal Absorption

The skin is generally an effective barrier against the entry of environmental chemicals. To be absorbed via this route (percutaneous absorption), an agent must traverse a number of cellular layers before gaining access to the general circulation (Fig. 2.8) (29). The skin consists of two structural regions, the epidermis and the dermis, which rest on connective tissue. The epidermis consists of a number of layers of cells and varies in thickness depending on the region of the body; the outermost layer is composed of keratinized cells. The dermis contains blood vessels, hair follicles, sebaceous and sweat glands, and nerve endings. The epidermis represents the primary barrier to percutaneous absorption, the dermis is freely permeable to many materials. Passage through the epidermis occurs by passive diffusion.

PigmenL cells (P

Keratin (ayer (K

Mild itnii, Hirer wi i-ttffl skirt. AlUlil <itr$ip(rt[i, »lirtfiif,

•A-hipr rn^mifn!^ lepwibiiir rhemlrjih rr.iainu unri

Idealized

PigmenL cells (P

Keratin (ayer (K

Idealized

Surface laye* (S)

/Satsceous (ail) gland

/Hair follicle

Epidermal cells Basal cells

Surface laye* (S)

/Satsceous (ail) gland

/Hair follicle

Epidermal cells Basal cells

Mild itnii, Hirer wi i-ttffl skirt. AlUlil <itr$ip(rt[i, »lirtfiif,

•A-hipr rn^mifn!^ lepwibiiir rhemlrjih rr.iainu unri

Figure 2.8. Idealized section of skin. The horny layer is also known as the stratum corneum. From Birmingham (29).

The main factors that affect percutaneous absorption are the degree of lipid solubility of the chemicals, the site on the body, the local blood flow, and the skin temperature. Some environmental chemicals that are readily absorbed through the skin are phenol, carbon tetrachloride, tetraethyl lead, and organophosphate pesticides. Certain chemicals, e.g., dimethyl sulfoxide (DMSO) and formic acid, alter the integrity of skin and facilitate penetration of other materials by increasing the permeability of the stratum corneum. Moderate changes in permeability may also result following topical applications of acetone, methyl alcohol, and ethyl alcohol. In addition, cutaneous injury may enhance percutaneous absorption.

Interspecies differences in percutaneous absorption are responsible for the selective toxicity of many insecticides. For example, DDT is about equally hazardous to insects and mammals if ingested but is much less hazardous to mammals when applied to the skin. This results from its poor absorption through mammalian skin compared to its ready passage through the insect exoskeleton. Although the main route of percutaneous absorption is through the epidermal cells, some chemicals may follow an appendageal route, i.e., entering through hair follicles, sweat glands, or sebaceous glands. Cuts and abrasions of the skin can provide additional pathways for penetration. 4.10 Absorption Through Membranes and Systemic Circulation

Depending upon its specific nature, a chemical contaminant may exert its toxic action at various sites in the body. At a portal of entry—the respiratory tract, GI tract, or skin—the chemical may have a topical effect. However, for actions at sites other than the portal, the agent must be absorbed through one or more body membranes and enter the general circulation, from which it may become available to affect internal tissues (including the blood itself). Therefore, the ultimate distribution of any chemical contaminant in the body is highly dependent on its ability to traverse biological membranes. There are two main types of processes by which this occurs: passive transport and active transport.

Passive transport is absorption according to purely physical processes, such as osmosis; the cell has no active role in transfer across the membrane. Because biological membranes contain lipids, they are highly permeable to lipid-soluble, nonpolar, or nonionized agents and less so to lipid-insoluble, polar, or ionized materials. Many chemicals may exist in both lipid-soluble and lipid-insoluble forms; the former is the prime determinant of the passive permeability properties of the specific agent.

Active transport involves specialized mechanisms, and cells actively participate in transfer across membranes. These mechanisms include carrier systems within the membrane and active processes of cellular ingestion, phagocytosis and pinocytosis. Phagocytosis is the ingestion of solid particles, whereas pinocytosis refers to the ingestion of fluid containing no visible solid material. Lipid-insoluble materials are often taken up by active-transport processes. Although some of these mechanisms are highly specific, if the chemical structure of a contaminant is similar to that of an endogeneous substrate, the former may also be transported.

In addition to its lipid-solubility, the distribution of a chemical contaminant also depends on its affinity for specific tissues or tissue components. Internal distribution may vary with time after exposure. For example, immediately following absorption into the blood, inorganic lead localizes in the liver, the kidney, and in red blood cells. Two hours later, about 50% is in the liver. A month later, approximately 90% of the remaining lead is localized in bone (30).

Once in the general circulation, a contaminant may be translocated throughout the body. In this process it may (1) become bound to macromolecules, (2) undergo metabolic transformation (biotransformation), (3) be deposited for storage in depots that may or may not be the sites of its toxic action, or (4) be excreted. Toxic effects may occur at any of several sites.

The biological action of a contaminant may be terminated by storage, metabolic transformation, or excretion; the latter is the most permanent form of removal. 4.11 Accumulation in Target Tissues and Dosimetric Models

Some chemicals concentrate in specific tissues because of physicochemial properties such as selective solubility or selective absorption on or combined with macromolecules such as proteins. Storage of a chemical often occurs when the rate of exposure is greater than the rate of metabolism and/or excretion. Storage or binding sites may not be the sites of toxic action. For example, carbon monoxide produces its effects by binding with hemoglobin in red blood cells; on the other hand, inorganic lead is stored primarily in bone but exerts its toxic effects mainly on the soft tissues of the body.

If the storage site is not the site of toxic action, selective sequestration may be a protective mechanism because only the freely circulating form of the contaminant produces harmful effects. Until the storage sites are saturated, a buildup of free chemical may be prevented. On the other hand, selective storage limits the amount of contaminant that is excreted. Because bound or stored toxicants are in equilibrium with their free form, as the contaminant is excreted or metabolized, it is released from the storage site. Contaminants that are stored (e.g., DDT in lipids and lead in bone) may remain in the body for years without effect. However, upon weight loss and mobilization of body reserves, the stored chemicals can enter the circulation and produce toxic effects. For example, pregnant women who had prior excessive exposure to lead can increase their own blood lead levels and also create high and possibly damaging levels of lead exposures to their fetus. Accumulating chemicals may also produce illnesses that develop slowly, as occurs in chronic cadmium poisoning.

A number of descriptive and mathematical models have been developed to permit estimation of toxic effects from knowledge of exposure and one or more of the following factors: translocation, metabolism, and effects at the site of toxic action.

More complex models that require data on translocation and metabolism have been developed for inhaled and ingested radionuclides by the International Commission on Radiological Protection (69).

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