Major Organ Systems

There are 12 major organ systems in the human body. The digestive and urinary systems process food for energy and eliminate waste products; the respiratory system provides the source of oxygen necessary for oxidative energy production; the cardiovascular, lymphatic, and immune systems circulate oxygen, nutrients, and other compounds within the body and provide a communication network to regulate the function of the various specialized cells and to ward off disease; the nervous and endocrine systems coordinate the actions of the various organ systems; the integumentary, muscular, and skeletal systems provide protection, support, and locomotion for the body; and the reproductive system allows the survival of the species by reproduction. In the discussion that follows we provide an overview of these organ systems, with an emphasis on those of particular significance as either a route of exposure, a target of toxic action, or both. Although the toxic action frequently occurs at the point of entry of the toxin (inhalation, ingestion, dermal exposure), organs in other systems may be affected by migration of the toxin within the body. For example, inhalation of carbon tetrachloride through the respiratory system may have a large impact on the liver, which is part of the digestive system.

All of the organs are composed of variations of four basic tissue types. Epithelial tissues are membrane tissues that often serve as selective barriers, allowing the passage of beneficial compounds and blocking the passage of harmful compounds. Connective tissues provide structure for the network of cells. Nerve tissues are typically specialized for the transmission of information in the form of electrical signals. Muscular tissues are characterized by an ability to expand and contract, imparting the potential for movement to individual tissues and the organism as a whole. Most organs contain all four types of tissues; it is the type and arrangement of these tissues that defines how the organ carries out its particular functions.

10.2.3.1 Digestive and Urinary Systems The digestive and urinary systems process food for energy and eliminate waste products. These two systems are of particular significance for environmental toxicology in their role as portals for the entry and exit of environmental contaminants to and from the body. The digestive system is one of the primary routes by which environmental contaminants are taken into the body and transformed chemically, and it is the main route by which insoluble waste materials are excreted. The urinary system plays a key role in the filtration and elimination of soluble toxic substances and is a primary route by which soluble waste products and excess water are eliminated. A simplified representation of the routes through which environmental contaminants can enter and leave the body through the digestive and urinary systems is provided in Figure 10.2, which is the basis for a mathematical model used for estimating the effects of ingested radioactive materials. Use of this model is discussed in more detail in Example 11.1.

The digestive system consists of the alimentary canal and several accessory glands. Food and water enter the body through the mouth and pass through the esophagus into the stomach. Within the stomach, secreted hydrochloric acid and enzymes combine with muscular contractions to reduce the food to a semiliquid, highly acidic (pH 0.9 to 1.5) mass, which is then expelled into the small intestine. The small intestine is in the form of a coiled tube about 7 m in length. It is lined with a layer of epithelial tissue that allows absorption of the nutrients in solution. This is surrounded by a layer of tissue that is highly penetrated by small blood vessels. A layer of connective and muscular tissues supports these layers and moves the food mass through the tube by peristaltic action. Within the small intestine, the food is further metabolized by enzymatic action and absorbed into the bloodstream or the lymphatic system. Bile, produced by the liver, is an alkaline emulsifying agent that raises the pH and breaks down fat particles to aid in their absorption. After passage through the small intestine, the food enters the large intestine, where the water is reabsorbed and waste products are concentrated into a fecal mass. Waste products comprise both indigestible foodstuffs and excess chemical constituents (calcium, magnesium, iron, phosphates) that must be eliminated to maintain the proper chemical balance of the body. This mass is then expelled through the rectal cavity.

Several accessory glands work in conjunction with the alimentary canal to carry out digestion and metabolism. The salivary glands, the liver, the gallbladder, and

Excretion

Figure 10.2 ICRP model of the digestive system. (From Till and Meyer 1983.)

Excretion

Figure 10.2 ICRP model of the digestive system. (From Till and Meyer 1983.)

the pancreas secrete enzymatic fluids that aid in digestion. Nutrients absorbed from the small intestine are carried by blood to the liver. In the liver, the nutrients are metabolized and released into the circulatory system for delivery to the different parts of the body. The liver serves a variety of functions, the most important of which revolve around its role in digestion and the metabolism of nutrients absorbed from the small intestine. The metabolic action of the liver is a major mechanism for detoxifying substances absorbed along with the nutrients. The liver also plays an important role in the circulatory system through the synthesis of blood proteins, the destruction of old red blood cells, and the storage of iron and vitamins.

Because of the liver's many functions, contaminants can act in a variety of ways to cause liver injury. The principal types of liver damage are necrosis (tissue destruction), cirrhosis (hardening of tissue), and the accumulation of abnormal amounts of fat. A particularly important function of the liver from the standpoint of poisons is the detoxification of compounds by transforming them into a more water-soluble form. Whereas this is an important protection mechanism for some compounds, others that are relatively benign in their administered form can be transformed into more toxic species. This process, known as metabolic activation, is carried out by enzymatic action. For example, the nonmetabolized form of carbon tetrachloride affects primarily the nervous system. However, the critical effect for carbon tetrachloride is typically taken to be liver toxicity, due to metabolites of carbon tetrachloride (ATSDR 2005a). Although the enzymes responsible for metabolic activation are present throughout the body, they are particularly abundant in the liver. Electrophilic intermediate metabolites, produced by metabolic activation of certain compounds, can react with DNA, leading to the initiating step in carcinogenesis.

The kidneys, ureters, urinary bladder, and urethra make up the urinary system, which is the second major route of excretion for waste products. The kidney serves several functions, including the regulation of the water balance and the electrolytic balance of the blood. It carries out this function by the selective filtration of the blood and plasma to remove waste products for elimination from the body. Reabsorption of water, salts, sugar, amino acids, and other essential components such as calcium serves to maintain the water and electrolytic balance of the body. The excess water and waste products are removed from the body through the ureters, bladder, and urethra. The kidney also secretes hormones that regulate red blood cell production, blood pressure, and calcium levels.

Toxic insults to the kidney can result in either decreases in the blood flow, reduction in the removal of wastes, excessive elimination of required chemicals, or an alteration in enzyme production. A variety of contaminants, including metals such as lead, mercury, and uranium; halogenated hydrocarbons such as chloroform, TCE, and PCE; and organic solvents such as ethylene glycol and toluene are known to induce renal (i.e., kidney) dysfunction (Hewitt et al. 1991).

10.2.3.2 Respiratory System The respiratory system is responsible for the intake of oxygen necessary for energy production and the exhalation of waste gases from the body. In the context of toxicology, the respiratory system is of considerable significance because it is the primary route of entry for exposure to airborne contaminants, which may be in a gaseous state or in the form of aerosols (microscopic solid or liquid particles suspended in air). As depicted in Figure 10.3, the respiratory system consists of a series of passages that carry air from the nasal or oral cavities through the trachea into the lungs. Within the lungs, the trachea branch successively into the bronchi, bronchioles, and alveoli. A simplified representation of the routes through which airborne contaminants can enter through the respiratory system and be distributed throughout the body is presented in Figure 10.4. This compartmental model is the basis for a mathematical model used for estimating the effects of inhaled radioactive materials. The use of such models is discussed in more detail in Chapter 11.

The respiratory system is equipped with natural defenses against airborne par-ticulate matter. The nasal cavities are lined with epithelial cells that secrete mucus and support hairs that filter and trap airborne particulates. Particles larger than approximately 10 |im in diameter are generally trapped within the nasal cavity, from where they are either expelled or are swallowed and subsequently eliminated through the alimentary canal. Smaller particles (1 to 10 |im) can be trapped within the tracheobronchial region and subsequently cleared upward into the esophagus, from where they are swallowed and eliminated through the alimentary canal. Respirable particles (less than 1 | m) and gases are inhaled into the alveoli, which

Choledocholithiasis Risk Factors
Figure 10.3 Respiratory tract anatomy. (From Burke 1980; reprinted by permission of John Wiley & Sons, Inc.)

Inhalation

Inhalation

Figure 10.4 ICRP model of the respiratory system. DNP, DTB, and DP refer to deposition in the nasopharangeal, tracheobronchial, and pulmonary regions, respectively. L refers to the lymphatic tissue. Boxes a to h represent subcompartments in each of the 3 respiratory regions, and i and j are subcompartments of lymphatic tissue. (From Till and Meyer 1983.)

Figure 10.4 ICRP model of the respiratory system. DNP, DTB, and DP refer to deposition in the nasopharangeal, tracheobronchial, and pulmonary regions, respectively. L refers to the lymphatic tissue. Boxes a to h represent subcompartments in each of the 3 respiratory regions, and i and j are subcompartments of lymphatic tissue. (From Till and Meyer 1983.)

are small sacs lined by epithelial tissues. Gas exchange in the alveoli results in the intake of oxygen into the blood and the elimination of waste gases such as carbon dioxide in expired air.

Exposure to airborne contaminants can result in a variety of acute and chronic toxic effects in the respiratory system, including irritation, aggravation of preexisting conditions (e.g., asthma), structural damage leading to chronic diseases (e.g., pulmonary fibrosis and emphysema), and cancer. For example, the effects of inhaling gases such as Cl2, SO2, and H2S which are subject to accidental and routine release to the environment range from coughing to difficulty in breathing to death, depending on the exposure. Ozone aggravates asthma and increases the severity of respiratory infections. Particulate matter, asbestos, arsenic, and nickel are known lung carcinogens.

10.2.3.3 Cardiovascular, Lymphatic, and Immune Systems The cardiovascular and lymphatic systems serve as a means of physical transport of biologically important substances (i.e., oxygen, nutrients, waste products, hormones, disease-fighting cells, etc.) throughout a series of interconnected fluid transfer systems. These substances are circulated within bodily fluids such as blood, lymph, and intracellular fluid. Although both blood and lymphatic fluid circulate throughout the body, the motive force for the two systems is different. Blood is circulated through arteries (blood-supplying tubes), veins (blood collection tubes), and capillaries (the blood distribution network comprising very narrow tubes) via the pumping action of the heart, whereas the lymphatic fluid has no centralized pump to force circulation. Intracellular fluid originates from blood plasma that is forced through the capillary walls by hydrostatic pressure, leaving the larger blood cells within the capillaries. This interstitial fluid is transported from the interstices of body tissues through lymphatic capillaries to lymphatic ducts that are typically at a lower pressure than the interstitial fluid. The lymphatic fluid is then returned from the ducts to the bloodstream, forming plasma.

Blood serves several vital functions in the body in its role as a chemical transport and communication system. Among the most important functions are transport of dissolved substances in the blood plasma; oxygen transfer by hemoglobin in red blood cells; and resistance to disease associated with white blood cells. New blood cells are continuously produced in the marrow of long bones to replace old cells (~120 days), which are destroyed in the liver and spleen. Thus, damage to the bone marrow typically results in clinical effects being observed in the affected person's blood chemistry. The circulatory system also plays an important role in heat regulation by varying the size of capillaries near exterior surfaces of the body, resulting in the ability to control the transfer of heat from the body to outside air. In conjunction with the white blood cells (leukocytes), the lymphatic system provides the body with the ability to recognize and eliminate harmful agents (thereby conferring immunity) by both adapting white blood cells formed in the bone marrow and generation of lymphocytes. Key components of the immune system are the lymphocytes and macrophages, which encapsulate foreign substances for their subsequent destruction or excretion, and antibodies, which are proteins that attach to foreign substances and trigger an immune reaction.

Toxic insults to the blood and immune system can occur in a variety of ways. Some chemicals affect the ability of the hemoglobin in red blood cells to transfer oxygen. Carbon monoxide, which binds readily to hemoglobin, is well known for reducing oxygen transfer by the blood. A wide array of environmental contaminants has been implicated in interfering with immune system function. Benzene, halogenated hydrocarbons, dioxins, pesticides, and metals are all known to suppress the immune system. Organic compounds such as vinyl chloride, TCE, and PCE, and metals such as gold and mercury can cause an autoimmune response (i.e., an immune response to a person's own tissue). Many contaminants, including organic solvents and metals such as beryllium and mercury, can induce allergic responses.

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