Hepatic Toxicity

Because of a dual blood supply from the hepatic artery and the portal vein, the liver may be exposed to toxicants entering from the systemic circulation (e.g., via inhalation) or from the splanchnic circulation (absorbed from the gastrointestinal [GI] tract). The leaky capillary system of the hepatic sinusoids promotes the extraction of toxicants from the blood into the liver. The liver contains enzymes that metabolize many endogenous and exogenous chemicals (see Chapter 2). In some cases chemical modification produced by biotransformation results in bioactivation (production of toxic-reactive metabolites). This is exemplified by the bioactivation of chloroform to phosgene (Fig. 8-1). Compounds that enhance the activity of CYP2E1 (enzyme-inducing agents) or reduce the hepatic concentration of glutathione can exacerbate chloroform-induced liver injury. Other compounds that can cause liver injury after metabolism include several solvents (carbon tetrachloride, halogenated benzenes) and carcinogens (aflatoxin B, aromatic amines).

FIGURE 8–1 CYP2E1 converts chloroform to phosgene within the hepatocyte. Phosgene is highly reactive and has been used as a chemical warfare agent. GSH (glutathione) can conjugate with and detoxify phosgene. The liver is protected until the rate of formation of phosgene exceeds the rate of detoxification.

Neurotoxicity

Because neurons in the central nervous system (CNS) have a high metabolic rate that requires a sustained delivery of oxygen and nutrients, they are highly susceptible to injury. Chemicals that cause severe hypotension or hypoglycemia may result in neuronal cell death and CNS damage. Similarly, chemicals that interfere with oxidative metabolism (i.e., cyanide or dinitrophenol) can also compromise neuronal viability.

Axonal transport, which provides nerve terminals with proteins synthesized in neuronal cell bodies, is also a target of toxic compounds. Acrylamide and n-hexane produce peripheral neuropathies by interfering with axonal transport. Diketone metabolites of n-hexane can derivatize and cross-link neurofilaments in the axon, and as these cross-links accumulate with repeated exposure, axonal transport is retarded, ultimately causing axonal atrophy. Nerve terminals themselves are the target of several neurotoxins such as botulinus toxin, which interferes with the release of acetylcholine, and tetrodotoxin, which blocks sodium channels.

Pulmonary Toxicity

Injury to the lung results primarily from respiratory exposure to toxicants, although blood-borne compounds may also contribute. The pulmonary system is composed of the nasopharyngeal and tracheobronchial airways and the pulmonary parenchyma (alveoli). Airways are directly exposed to many gaseous or particulate toxicants. Gases may react with airway mucosal cells or penetrate to the alveoli. For example, chlorine gas reacts with upper airway fluids and produces hydrochloric acid, causing mucosal injury. Cyanide and chloroform penetrate to the alveoli, are well absorbed, and cause systemic, not pulmonary, toxicity. Particulates can also become impacted in the airway or, if small enough (less than 5 μm), can reach the alveoli. If trapped in the airway, they may be cleared by the mucociliary apparatus. Substances reaching the alveoli can be eliminated only by absorption into the blood, by macrophage phagocytosis, or by biotransformation. Macrophages phagocytose toxicants in particulate form and then enzymatically degrade them or simply transport them out of the alveolus. This function may actually underlie asbestos toxicity, because macrophages engulf but cannot degrade asbestos particles. When the macrophages ultimately die, they release degradative enzymes into the interstitium, which damage adjacent cells. Repetition of this process eventually leads to progressive fibrosis and restrictive respiratory dysfunction. The pulmonary biotransformation of chemicals may also lead to toxicity. The Clara cells, located in terminal bronchioles, and the alveolar type II cells possess cytochrome P450, which can produce toxic metabolites of certain chemicals. Inhalation of benzo[a]pyrene and other polycyclic aromatic hydrocarbons causes lung cancer by this mechanism.

The blood can serve as the route of exposure of the lung in the case of paraquat, a herbicide taken up by type II pneumocytes. Biotransformation in the lung yields a reactive intermediate that undergoes redox cycling, which produces reactive oxygen species that injure the cell. Although exposure to paraquat usually occurs after ingestion or skin contamination, death results from pulmonary injury. Similarly, certain pyrrolidine alkaloids are metabolized in the liver to compounds that circulate in the blood and produce toxicity in the lung. The actions of toxicants on pulmonary tissue are shown in Figure 8-2.

FIGURE 8–2 Summary of some toxicant actions on pulmonary tissues.

Renal Toxicity

The kidney is also susceptible to toxicants. The mechanisms of renal injury are similar to those in other organs but also include unique mechanisms. Delivery of blood-borne toxicants to the kidney is high, because the kidney receives 25% of cardiac output, and its functions include filtering, concentrating, and eliminating toxicants. As water is reabsorbed, the concentration of chemicals in the tubule can increase to toxic levels. In some cases the concentration may exceed the solubility of a chemical and lead to precipitation and obstruction of the affected area (Fig. 8-3).

FIGURE 8–3 Summary of some toxicant actions on the kidney.

The kidney also biotransforms chemicals, although to a lesser extent than the liver. Cytochrome P450 is located in the proximal tubule, which may explain the susceptibility of this region to chemical injury. For example, carbon tetrachloride and chloroform, two halogenated hydrocarbons that injure the proximal tubule, must be biotransformed by the cytochrome P450 system to be toxic. In addition, many heavy metals damage the proximal tubules. Because they are not metabolized by cytochrome P450, other mechanisms must be involved. Heavy metals may concentrate in renal tubular cells and may also injure blood vessels supplying the proximal tubule cells, a combination of direct and indirect toxicity.

The kidney can compensate for excessive chemical exposure because, like many organs, it has a reserve mass. Thus tissue injury equal to one entire kidney must occur before loss of function is clinically apparent. The kidney also replaces lost functional capacity by hypertrophy. In addition, the kidney has developed binding proteins to remove heavy metals. For example, metallothioneins avidly bind cadmium, protecting the kidney and other organs from toxicity. However, renal toxicity will develop if exposure exceeds the binding capacity or if a large amount of the cadmium-metallothionein complex accumulates.

Immunotoxicity

The immune system can be affected by a wide variety of toxicants. These agents often cause immunosuppression by interfering with cell growth or proliferation. Other compounds may directly destroy immune system components. Some chemicals distort normal signaling mechanisms that ultimately reduce the immune response. For example, benzene causes lymphocytopenia but also affects other bone marrow elements. The functional result is a deficiency in cell-mediated immunity. Workers exposed to benzene show decreased humoral immunity, as evidenced by depressed complement and immunoglobulin concentrations.

In humans, immunosuppression may lead to an increased incidence of bacterial, viral, and parasitic infections. Theoretically, immunosuppression may also interfere with the immune system’s surveillance function, resulting in an increased incidence of cancer, although this is still being investigated.

It is becoming increasingly apparent that activation and recruitment of phagocytic cells to sites of chemical-induced injury play a major role in the progression of tissue injury. Therapeutic interventions that could minimize the effects of these activated phagocytic cells include preventing the adhesion of phagocytic cells at the site of injury, reducing the release of cytotoxic factors, or inactivating these cytotoxic factors.

In addition to being a target for chemical-mediated injury, the immune system may mediate injury by producing hypersensitivity reactions—adverse events caused by an immune response to foreign antigens (see Chapter 6). Indeed, cell-mediated hypersensitivity initiated by T lymphocytes may lead to contact dermatitis as a consequence of exposure to nickel and several industrial chemicals.