Robert A. Bays, DDS

• Professor and Chairman (Retired) Division of Oral and
• Maxillofacial Surgery,
• Department of Surgery, School of Medicine
• Emory University
• Atlanta, Georgia

The hyperthermia is accompanied by marked generalized vasodilation coronary heart group order generic propranolol, with peripheral pooling of blood and a decreased effective circulating blood volume coronary heart disease effective 80 mg propranolol. Particularly important cardiovascular system includes purchase propranolol online pills, however coronary heart zones order on line propranolol, are sustained contractions of skeletal muscle that can exacerbate the hyperthermia and lead to muscle necrosis (rhabdomyolysis) aqueduct 11 capillaries cheap propranolol 20 mg with amex. In affected individuals arteries shoulder buy propranolol master card, exposure to certain anesthetics during surgery triggers a rapid rise in calcium levels in skeletal muscle, leading to muscle rigidity and increased heat production. The resulting hyperthermia has a mortality rate of approximately 80% if untreated, but this falls to less than 5% if the condition is recognized and muscle relaxants are administered promptly. Electrical Injury Electrical injuries, which are often fatal, can arise from contact with low-voltage currents. Injuries are of two types: (1) burns and (2) ventricular fibrillation or cardiac and respiratory center failure, resulting from disruption of nerve impulse conduction. The type of injury and the severity and extent of burns depend on the strength (amperage), duration, and path of the electric current within the body. Voltage in the household and workplace (120 or 220 V) is high enough that with low resistance at the site of contact (as when the skin is wet), sufficient current can pass through the body to cause serious injury, including ventricular fibrillation. If the current flow is sustained, it may generate enough heat to produce burns at the site of entry and exit as well as in internal organs. An important characteristic of alternating current, the type supplied to most homes, is that it induces tetanic muscle spasm, so that when a live wire or switch is grasped, irreversible clutching is likely to occur, prolonging the period of current flow. This results in a greater likelihood of developing extensive electrical burns and, in some cases, spasm of the chest wall muscles, producing death from asphyxia. Currents generated from high-voltage sources cause similar damage; however, because of the large current flows generated, these are more likely to produce paralysis of medullary centers and extensive burns. Hypothermia Prolonged exposure to low ambient temperature leads to hypothermia, a condition seen all too frequently in homeless persons. High humidity and wet clothing, sometimes exacerbated by dilation of superficial blood vessels due to ingestion of alcohol, hasten the lowering of body temperature. Hypothermia causes injury by two mechanisms: Direct effects are probably mediated by physical disruptions within cells by high salt concentrations caused by the Injury Produced by Ionizing Radiation Radiation is energy that travels in the form of waves or high-speed particles. Radiation has a wide range of energies that span the electromagnetic spectrum; it can be divided into nonionizing and ionizing radiation. By contrast, ionizing radiation has sufficient energy to remove tightly bound electrons. Injury by physical agents Collision of electrons with other molecules releases electrons in a reaction cascade, referred to as ionization. The main sources of ionizing radiation are (1) x-rays and gamma rays (electromagnetic waves of very high frequencies), (2) highenergy neutrons, alpha particles (composed of two protons and two neutrons), and (3) beta particles, which are essentially electrons. At equivalent amounts of energy, alpha particles induce heavy damage in a restricted area, whereas x-rays and gamma rays dissipate energy over a longer, deeper course and produce considerably less damage per unit of tissue. It is indispensable in medical practice, being used in the treatment of cancer, in diagnostic imaging, and in therapeutic or diagnostic radioisotopes, but it also produces adverse short-term and long-term effects such as fibrosis, mutagenesis, carcinogenesis, and teratogenesis. Thus, fractionated doses of radiant energy have a cumulative effect only to the extent that repair during the "recovery" intervals is incomplete. Radiation therapy of tumors exploits the general capability of normal cells to repair themselves and recover more rapidly than tumor cells and thus not sustain as much cumulative radiation damage. The body can sustain relatively high doses of radiation when delivered to small, carefully shielded fields, whereas smaller doses delivered to larger fields may be lethal. Understandably, therefore, tissues with a high rate of cell division, such as gonads, bone marrow, lymphoid tissue, and the mucosa of the gastrointestinal tract, are extremely vulnerable to radiation, and the injury is manifested early after exposure. Several somewhat confusing terms are used to describe radiation dose, which can be quantified according to the amount of radiation emitted by a source, the amount of radiation that is absorbed by a person, and the biologic effect of the radiation. Commonly used terms are as follows: Curie (Ci) represents the disintegrations per second of a radionuclide (radioisotope); 1 Ci is equal to 3. A centigray (cGy), which is the absorption of 100 erg/g of tissue, is equivalent to 100 Rad (radiation absorbed dose), abbreviated as R. For the same absorbed dose, various types of radiation produce different amounts of damage. The equivalent dose controls for this variation and thereby provides a uniform measure of biologic dose. The equivalent dose (expressed in Sieverts) corresponds to the absorbed dose (expressed in Grays) multiplied by the relative biologic effectiveness of the radiation. The relative biologic effectiveness depends on the type of radiation, the type and volume of the exposed tissue, the duration of the exposure, and some other biologic factors (discussed next). Poorly vascularized tissues with low oxygenation, such as the center of rapidly growing tumors, are generally less sensitive to radiation therapy than nonhypoxic tissues. Damage to endothelial cells, which are moderately sensitive to radiation, may cause narrowing or occlusion of blood vessels leading to impaired healing, fibrosis, and chronic ischemic atrophy. The mitotic spindle often becomes disorderly, and polyploidy and aneuploidy may be encountered. Nuclear swelling and condensation and clumping of chromatin may appear; disruption of the nuclear membrane may also be noted. Giant cells with pleomorphic nuclei or more than one nucleus may appear and persist for years after exposure. At extremely high doses of radiant energy, indicators of cell death, such as nuclear pyknosis and lysis, appear quickly. Vascular changes and interstitial fibrosis are also prominent in irradiated tissues. With time or with higher doses, a variety of degenerative changes appear, including endothelial cell swelling and vacuolation, or even necrosis and dissolution of the walls of small vessels such as capillaries and venules. Still later, endothelial cell proliferation and collagenous hyalinization and thickening of the intima are seen in irradiated vessels, resulting in marked narrowing or even obliteration of the vascular lumens. At this time, an increase in interstitial collagen in the irradiated field usually becomes evident, leading to scarring and contractions. Exposure of large areas of the body to even very small doses of radiation may have devastating effects. However, higher levels of exposure cause health effects known as acute radiation syndromes, which at progressively higher doses involve the hematopoietic, gastrointestinal, and central nervous systems. The syndromes extremely susceptible to radiation injury and deserve special mention. With high dose levels and large exposure fields, severe lymphopenia appears within hours along with shrinkage of the lymph nodes and spleen. Radiation kills lymphocytes directly, both in the circulation and in tissues (nodes, spleen, thymus, gut). With sublethal doses of radiation, regeneration from viable precursors is prompt, leading to restoration of a normal blood lymphocyte count within weeks to months. Hematopoietic precursors in the bone marrow are also quite sensitive to radiant energy, which produces a dose-dependent marrow aplasia. The acute effects of marrow irradiation on peripheral blood counts reflect the kinetics of turnover of the formed elements, the granulocytes, platelets, and red cells, which have half-lives of less than a day (granulocytes), 10 days (platelets), and 120 days (red cells). After a brief rise in the circulating neutrophil count, neutropenia appears within several days. Neutrophil counts reach their nadir, often at counts near zero, during the second week. If the patient survives, recovery of a normal granulocyte count may require 2 to 3 months. Understandably, higher doses of radiation produce more severe cytopenias and more prolonged periods of recovery. Very high doses kill hematopoietic stem cells and induce permanent aplasia (aplastic anemia) marked by a failure of blood count recovery, whereas with lower doses the aplasia is transient. A common consequence of radiation therapy for cancer is the development of fibrosis in the tissues included in the irradiated field. Fibrosis may occur weeks or months after irradiation as a consequence of the replacement of dead parenchymal cells by connective tissue, leading to the formation of scars and adhesions. Vascular damage, the death of tissue stem cells, and the release of cytokines and chemokines that promote inflammation and fibroblast activation are the main contributors to the development of radiation-induced fibrosis. Common sites of fibrosis after radiation treatment are the lungs, the salivary glands after radiation therapy for head and neck cancers, and colorectal and pelvic areas after treatment for cancer of the prostate, rectum, or cervix. In surviving cells, simple defects may be repaired by various enzyme systems present in most mammalian cells. Any cell capable of division that has sustained a mutation has the potential to become cancerous. Thus, an increased incidence of neoplasms may occur in any organ after exposure to ionizing radiation. The level of radiation required to increase the risk of cancer development is difficult to determine, but there is little doubt that acute or prolonged exposures that result in doses of greater than 100 mSv cause serious consequences, including cancer. Proof of this risk is found in the increased incidence of leukemias and solid tumors in several organs. The long-term cancer risks caused by radiation exposures in the range of 5 to 100 mSv are much more difficult to establish because accurate measurements of risks require large population groups ranging from 50,000 to 5 million people. It is believed that the risk of secondary cancers following irradiation is greatest in children. Nutritional diseases Increased risk of cancer development may also be associated with occupational exposures. Its carcinogenic effects are largely attributable to two decay products, polonium 214 and polonium 218 (or "radon daughters"), which emit alpha particles. Polonium 214 and polonium 218 produced from inhaled radon tend to deposit in the lung, and chronic exposure in uranium miners may give rise to lung carcinomas. Risks are also present in homes in which the levels of radon are very high, comparable to those found in mines. It is suspected that lower levels of household radon may also contribute to lung cancer development, particularly in those who also smoke tobacco. By contrast, secondary malnutrition results from malabsorption, impaired utilization or storage, excess loss, or increased need for nutrients. Homeless persons, aged individuals, and children of the poor often suffer from severe malnutrition as well as trace nutrient deficiencies. In lower income countries, poverty, crop failures, livestock deaths, and drought, often in times of war and political upheaval, create the setting for the malnourishment of children and adults. The basal metabolic rate rises in many illnesses, resulting in increased daily requirements for all nutrients. Alcoholic persons may sometimes suffer from malnutrition but more frequently have deficiencies of vitamins, especially thiamine, pyridoxine, folate, and vitamin A, as a result of poor diet, defective gastrointestinal absorption, abnormal nutrient utilization and storage, increased metabolic needs, and an increased rate of loss. A failure to recognize the likelihood of thiamine deficiency in persons with chronic alcoholism may result in irreversible brain damage. Even the affluent may fail to recognize that infants, adolescents, and pregnant women have increased nutritional needs. Some examples are iron deficiency in infants fed exclusively artificial milk diets; thiamine deficiency in diets in which polished rice is the mainstay; and lack of iodine from food and water in regions removed from the oceans, unless supplementation is provided. Anorexia nervosa, bulimia, and less overt eating disorders affect individuals who are concerned about body image and are obsessed with body weight (anorexia and bulimia are discussed later). Additional causes of malnutrition include gastrointestinal diseases and malabsorption syndromes, genetic diseases, specific drug therapies (which block uptake or utilization of particular nutrients), and inadequate total parenteral nutrition. Millions of people in lower income nations are malnourished or living on the cruel edge of starvation. In the higher income world and, more recently, also in some lower income countries, obesity has become a major public health problem due to its association with diseases such as diabetes, atherosclerosis, and cancer. Particular attention is devoted to childhood malnutrition, anorexia nervosa and bulimia, deficiencies of vitamins and trace minerals, obesity, and the relationships of diet to cancer and atherosclerosis. Other nutrients and nutritional issues are discussed in the context of specific diseases. It is common in low income countries, where as many as 25% of children may be affected and where it is a major contributor to the high death rates among the very young. In addition to loss of life, wars also exact a heavy toll on refugees who live in abject poverty. In recent years, camps set up for refugees from Syria, as many as 20% of the children are severely or moderately malnourished. Note the loss of muscle mass and subcutaneous fat; the head appears to be too large for the emaciated body. The infant shows generalized edema, seen as ascites and puffiness of the face, hands, and legs. It should be noted that from a functional standpoint, there are two protein compartments in the body: the somatic compartment, represented by proteins in skeletal muscles, and the visceral compartment, represented by protein stores in the visceral organs, primarily the liver. The somatic compartment is affected more severely in marasmus, and the visceral compartment is depleted more severely in kwashiorkor. Clinical assessment of undernutrition is discussed next, followed by descriptions of marasmus and kwashiorkor. In mild to moderate forms, the usual approach is to compare the body weight for a given height against standard tables; other helpful parameters are fat stores, muscle mass, and levels of certain serum proteins. With a loss of fat, measured skinfold thickness (which includes skin and subcutaneous tissue) is reduced. If the somatic protein compartment is catabolized, the resultant reduction in muscle mass is reflected by reduced circumference of the midarm. Measurement of serum proteins (albumin, transferrin, and others) provides an estimate of the adequacy of the visceral protein compartment.

At the center of the granuloma is the schistosome egg coronary heart 0 texas generic propranolol 40mg without a prescription, which contains a miracidium; this degenerates over time and calcifies cardiovascular associates of east texas 20mg propranolol. The granulomas are composed of macrophages cardiovascular system role in homeostasis purchase propranolol 40mg mastercard, lymphocytes cardiovascular system nclex questions cheap propranolol 80 mg without prescription, neutrophils cardiovascular disease jeopardy purchase 20mg propranolol free shipping, and eosinophils coronary artery ecg territories generic 40mg propranolol amex, which are distinctive for helminth infections. The liver is darkened by regurgitated heme-derived Schistosomiasis Schistosomiasis is estimated to infect approximately 230 million persons and kill more than 200,000 individuals annually. Schistosoma flukes require passage through freshwater snails that live in the slow-moving water of tropical rivers, lakes, and irrigation ditches, ironically linking agricultural development with spread of the disease. Acute schistosomiasis in humans can be a severe febrile illness that peaks about 2 months after infection. Pathogenesis Much of the pathology of schistosomiasis is caused by host inflammatory reactions to different stages of the parasite. After release from snails, ciliated miracidium larvae mature into infectious larvae (cercariae) that swim through fresh water and penetrate human skin with the aid of powerful proteolytic enzymes that degrade the keratinized layer. High magnification (B) demonstrates miracidium-containing eggs (arrow), prominent eosinophils, histiocytes, and giant cells. Mosquitoes that bite infected individuals take up the microfilariae and can transmit the disease. In addition, symbiotic Wolbachia bacteria infect filarial nematodes and contribute to pathogenesis of disease. As is the case with leprosy and leishmanial infections, some of the different disease manifestations caused by lymphatic filariae are likely related to variations in host T-cell responses to the parasites. In chronic lymphatic filariasis, damage to the lymphatics is caused directly by the adult parasites and by a Th1-mediated immune response, which stimulates the formation of granulomas around the adult parasites. Hypersensitivity to microfilaria in the lungs is thought to be associated with tropical pulmonary eosinophilia. The surface of the liver is bumpy, and cut surfaces reveal granulomas and widespread fibrosis and portal enlargement without intervening regenerative nodules. Because these fibrous tracts resemble the stem of a clay pipe, the lesion is named pipe-stem fibrosis. The fibrosis often obliterates the portal veins, leading to portal hypertension, severe congestive splenomegaly, esophageal varices, and ascites. Schistosome eggs, diverted to the lung through portal collaterals, may produce granulomatous pulmonary arteritis with intimal hyperplasia, progressive arterial obstruction, and ultimately heart failure (cor pulmonale). On histologic examination, arteries in the lungs show disruption of the elastic layer by granulomas and scars, luminal organizing thrombi, and angiomatoid lesions similar to those of idiopathic pulmonary hypertension (Chapter 15). Patients with hepatosplenic schistosomiasis also have an increased frequency of mesangioproliferative or membranous glomerulopathy (Chapter 20) in which glomeruli contain deposits of immunoglobulin and complement but rarely schistosome antigen. Later, the granulomas calcify and develop a sandy appearance, which, if severe, may line the wall of the bladder and cause a dense concentric rim (calcified bladder) on radiographic films. There is also an association between urinary schistosomiasis and squamous cell carcinoma of the bladder (Chapter 21). In severe and long-lasting infections, chylous weeping of the enlarged scrotum may ensue, or a chronically swollen leg may develop tough subcutaneous fibrosis and epithelial hyperkeratosis, termed elephantiasis. Elephantoid skin shows dilation of the dermal lymphatics, widespread lymphocytic infiltrates, and focal cholesterol Lymphatic Filariasis Lymphatic filariasis is transmitted by mosquitoes and is caused by closely related nematodes, Wuchereria bancrofti and Brugia spp. Foci of epidermal atrophy and elastic fiber breakdown may alternate with areas of hyperkeratosis, hyperpigmentation with pigment incontinence, dermal atrophy, and fibrosis. The subcutaneous onchocercoma is composed of a fibrous capsule surrounding adult worms and a mixed chronic inflammatory infiltrate that includes fibrin, neutrophils, eosinophils, lymphocytes, and giant cells. The progressive eye lesions begin with punctate keratitis along with small, fluffy opacities of the cornea caused by degenerating microfilariae, which evoke an eosinophilic infiltrate. This is followed by a sclerosing keratitis that opacifies the cornea, beginning at the scleral limbus. Keratitis is sometimes accentuated by treatment with antifilarial drugs (Mazzotti reaction). Microfilariae in the anterior chamber cause inflammation of the anterior chamber of the eye and ciliary body (iridocyclitis) and glaucoma, whereas involvement of the choroid and retina results in atrophy and loss of vision. Adult filarial worms-live, dead, or calcified-are present in the draining lymphatics or nodes, surrounded by (1) mild or no inflammation, (2) an intense eosinophilia with hemorrhage and fibrin (recurrent filarial funiculoepididymitis), or (3) granulomas. In the testis, hydrocele fluid, which often contains cholesterol crystals, red cells, and hemosiderin, induces thickening and calcification of the tunica vaginalis. Lung involvement by microfilariae is marked by eosinophilia caused by Th2 responses and cytokine production (tropical eosinophilia) or by dead microfilariae surrounded by stellate, hyaline, eosinophilic precipitates embedded in small epithelioid granulomas (Meyers-Kouwenaar bodies). Onchocerciasis Onchocerca volvulus is a filarial nematode that is the leading cause of preventable blindness in sub-Saharan Africa. It is transmitted by black flies and affects 17 million people in Africa, South America, and Yemen. An aggressive campaign of ivermectin treatment has dramatically reduced the incidence of Onchocerca spp. The disease attributable to onchocerciasis is primarily due to inflammation induced by microfilaria. Inseminated females produce microfilariae, which accumulate in the skin and disseminate to the eye chambers. Although the increased risk among these groups is partially due to unsafe sexual practices, limited access to health care is often a contributing factor. The infectious causes of some diseases were not new, but previously unrecognized because some of the infectious agents are difficult to culture; examples include H. Finally, infectious diseases that are common in one area may be introduced into a new area. For example, West Nile virus was common in Europe, Asia, and Africa for years before it was described in the United States. Annual outbreaks of Nipah virus infection have occurred in Bangladesh due to consumption of date palm sap. Bats, which shed the virus in their saliva and urine, are thought to contaminate the sap by feeding on it while it is being collected from the tree. Because these pathogens are novel, humans lack immunity and so these infections can quickly spread through the population as pandemics, as was seen with influenza A H1N1 in 2009. Bioterrorism is the use of biologic or chemical agents as weapons, and microorganisms are classified based on an assessment of which pose the greatest danger. For example, smallpox is a category A agent because of its high transmissibility, case mortality rate of 30% or greater, and lack of effective antiviral therapy. Because vaccination ended in the United States in 1972 and immunity has waned, the population is highly susceptible to smallpox. Concern that smallpox could be used for bioterrorism has led to a return of vaccination for selected groups. Many infectious agents, however, are best visualized by special stains that identify organisms on the basis of particular characteristics of their cell wall or coat or by staining with specific antibodies (Table 8. Organisms are typically easiest to identify at the advancing edge of a spread by person-to-person contact, and by transmission from pigs to people. Reforestation of the eastern United States has led to massive increases in the populations of deer and mice, which carry the ticks that transmit Lyme disease, babesiosis, and ehrlichiosis. Acute infections can be diagnosed serologically by detecting pathogen-specific antibodies in the serum. The presence of specific IgM antibody shortly after the onset of symptoms is diagnostic. Alternatively, specific antibody titers can be measured during the early infection and again 4 to 6 weeks later; a fourfold rise in titer is considered diagnostic. These molecular diagnostic assays have become routine for diagnosis of gonorrhea, chlamydial infection, tuberculosis, and herpes encephalitis. Next-generation sequencing can be used to detect bacteria, viruses, parasites, or fungi directly in patient specimens. This method currently has limited clinical application, but is likely to become increasingly important and common in the future. Grote A, Lustigman S, Ghedin E: Lessons from the genomes and transcriptomes of filarial nematodes, Mol Biochem Parasitol 215:23, 2017. Ramirez-Toloza G, Ferreira A: Trypanosoma cruzi evades the complement system as an efficient strategy to survive in the mammalian host: the specific roles of host/parasite molecules and Trypanosoma cruzi calreticulin, Front Microbiol 8:1667, 2017. Broadly defined, the term environment encompasses the various indoor, outdoor, and occupational settings in which human beings live and work. In each of these settings, the air people breathe, the food and water they consume, and the toxic agents they are exposed to are major determinants of health. The environmental factors that influence our health pertain to individual behavior ("personal environment") and include tobacco use, alcohol ingestion, recreational drug consumption, diet, and the like, or the external (ambient and workplace) environment. In general, in higher income countries personal behavior has a larger effect on health than the ambient environment, but new threats related to global warming (described later) may change this equation. The term environmental disease refers to conditions caused by exposure to chemical or physical agents in the ambient, workplace, and personal environment, including diseases of nutritional origin. The International Labour Organization estimates that work-related injuries and illnesses kill approximately 2. In the United States in 2018, there were nearly 3 million occupational injuries and illnesses. In 2019, it was estimated that 795 million people were malnourished-one in every nine persons worldwide. Children are disproportionately affected by undernutrition, which accounts for approximately 50% of childhood mortality worldwide. Estimating the burden of disease in the general population caused by nonoccupational exposures to toxic agents is complicated by the diversity of agents and difficulties in determining the extent and duration of exposures. But whatever the precise numbers, it is clear that environmental diseases are major causes of disability and suffering and constitute a heavy financial burden, particularly in low income countries. In this chapter, we first consider the emerging problem of the health effects of climate change. We then discuss the mechanisms of toxicity of chemical and physical agents and address specific environmental disorders, including those of nutritional origin. Global temperature measurements show that the earth has warmed significantly since the early 20th century and especially since the mid-1960s. Record-breaking global temperatures have become common, and the 5 years from 2014 to 2018 have been the warmest since 1880. Mean global ocean temperatures also continue to warm, with the annual average temperature in 2018 being 0. The rising atmospheric and oceanic temperatures have led to a large number of effects that include changes in storm frequency, drought, and flood, as well as large-scale ice losses in Greenland, Antarctica, and the vast majority of the other glaciated regions on earth, as well as dramatic thinning or disappearance of Arctic Ocean sea ice. Although politicians quibble, among scientists there is a general acceptance that climate change is in large part man-made. This number does not include morbidity and disruption of health services from extreme changes in weather. Even in the best-case scenario, however, climate change is expected to have a serious negative impact on human health by increasing the incidence of a number of diseases including the following: Cardiovascular, cerebrovascular, and respiratory diseases, all of which will be exacerbated by heat waves and air pollution. Global temperature in any given year was deduced at the Hadley Center (United Kingdom) from measurements taken at more than 3000 weather stations located around the globe. Richard Aster, Department of Geophysics, Colorado State University, Fort Collins, Colo. Such changes are anticipated to be most severe in tropical locations, in which average temperatures may already be near or above crop tolerance levels; it is estimated that by 2080, agricultural productivity may decline by 10% to 25% in some low income countries as a consequence of climate change. Toxicity of chemical and physical agents Beyond these disease-specific effects, it is estimated that the melting of glacial ice, particularly in Greenland and other parts of the Northern Hemisphere, combined with the thermal expansion of warming oceans will raise sea levels by 2 to 6 feet by 2100. The resulting displacement of people will disrupt lives and commerce, creating conditions ripe for political unrest, war, and poverty-the "vectors" of malnutrition, sickness, and death. Chemicals may be excreted in urine or feces; eliminated in expired air; or accumulate in bone, fat, brain, or other tissues. Chemicals may act at the site of entry or at other sites following transport through the blood. Most solvents and drugs are lipophilic, which facilitates their transport in the blood by lipoproteins and their penetration through the plasma membrane into cells. Most solvents, drugs, and xenobiotics are metabolized to form inactive water-soluble products (detoxification) or are activated to form toxic metabolites. More broadly, it also includes the study of the effects of physical agents such as radiation and heat. Of the approximately 100,000 chemicals in commercial use in the United States, only a small proportion has been tested experimentally for health effects. Several agencies in the United States set permissible levels of exposure to known environmental hazards. Factors such as the complex interaction between various pollutants and the age, genetic predisposition, and different tissue sensitivities of exposed persons create wide variations in individual sensitivity to toxic agents, limiting the value of establishing "safe levels" for entire populations. Nevertheless, such cutoffs are useful for comparative studies of the effects of agents between specific populations and for estimating risk of disease in heavily exposed individuals. We now consider some basic principles relevant to the effects of toxic chemicals and drugs. The quote from Paracelsus in the 16th century that "all substances are poisons; the right dosage differentiates a poison from a remedy" is still valid today, given the number of pharmaceutical drugs with potentially harmful effects. In the body they may act at the site of absorption, but are generally transported through the bloodstream to various organs where they may be stored or metabolized. Xenobiotics may be metabolized to watersoluble compounds that are excreted or to toxic metabolites, a process referred to as activation.

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Infarcts also are common in markedly enlarged spleens heart disease joint pain order 80 mg propranolol visa, regardless of cause cardiovascular disease question and answer buy 80 mg propranolol overnight delivery, presumably because the blood supply is tenuous and easily compromised 2 blocked arteries cheap 80mg propranolol with mastercard. Miscellaneous Disorders Amyloidosis Primary neoplasms and cysts Secondary neoplasms encroach on and virtually efface the lymphoid follicles cardiovascular system amazing facts purchase propranolol without a prescription. Neutrophils cardiovascular disease symptoms generic 40mg propranolol with mastercard, plasma cells heart disease women symptoms buy discount propranolol 20mg, and occasionally eosinophils are usually present throughout the white and red pulp. At times the white pulp follicles may undergo necrosis, particularly when the causative agent is a hemolytic streptococcus. Congestive Splenomegaly Chronic venous outflow obstruction causes a form of splenic enlargement referred to as congestive splenomegaly. Venous obstruction may be caused by intrahepatic disorders that retard portal venous drainage or extrahepatic disorders that directly impinge upon the portal or splenic veins. Systemic, or central, venous congestion is encountered in cardiac decompensation involving the right side of the heart, as can occur in tricuspid or pulmonic valvular disease, chronic cor pulmonale, or following leftsided heart failure. In septic infarcts this appearance is modified by the development of suppurative necrosis. Accessory spleens (spleniculi) are common, being present singly or multiply in 20% to 35% of postmortem examinations. They are small, spherical structures that are histologically and functionally identical to the normal spleen. Accessory spleens are of clinical importance in some hematologic disorders, such as hereditary spherocytosis (Chapter 14), where splenectomy may be used as a treatment. If an accessory spleen is overlooked, the therapeutic benefit of removal of the definitive spleen may be reduced or lost entirely. Multiple well-circumscribed infarcts are present in this spleen, which is massively enlarged (2820 g; normal: 150 to 200 g) by extramedullary hematopoiesis secondary to a myeloproliferative neoplasm (myelofibrosis). Recent infarcts are hemorrhagic, whereas older, more fibrotic infarcts are a pale yellow-gray color. Such "spontaneous ruptures" never involve truly normal spleens but rather stem from some minor physical insult to a spleen made fragile by an underlying condition. The most common predisposing conditions are infectious mononucleosis, malaria, typhoid fever, and lymphoid neoplasms, which may cause the spleen to enlarge rapidly, producing a thin, tense capsule that is susceptible to rupture. This dramatic event often precipitates intraperitoneal hemorrhage, which must be treated by prompt splenectomy to prevent death from blood loss. Chronically enlarged spleens are unlikely to rupture because of the toughening effect of extensive reactive fibrosis. Benign fibromas, osteomas, chondromas, lymphangiomas, and hemangiomas may arise in the spleen. Of these, lymphangiomas and hemangiomas are most common and often cavernous in type. The thymus is embryologically derived from the third and, inconstantly, the fourth pair of pharyngeal pouches. It grows until puberty, achieving a maximum weight of 20 to 50 g, and thereafter undergoes progressive involution to little more than 5 to 15 g in older adults. Fibrous extensions of the capsule divide each lobe into numerous lobules, each with an outer cortical layer enclosing the central medulla. Diverse types of cells populate the thymus, but thymic epithelial cells and immature T lymphocytes, also called thymocytes, predominate. Epithelial cells in the cortex are polygonal in shape and have an abundant cytoplasm with dendritic extensions that contact adjacent cells. In contrast, the epithelial cells in the medulla are densely packed, often spindle-shaped, and have scant cytoplasm devoid of interconnecting processes. Whorls of medullary epithelial cells create Hassall corpuscles, with their characteristic keratinized cores. During adulthood the thymic production of T cells slowly declines as the organ atrophies. Macrophages, dendritic cells, a minor population of B lymphocytes, rare neutrophils and eosinophils, and scattered myoid (muscle-like) cells are also found within the thymus. The myoid cells are of particular interest because they likely play some role in the development of myasthenia gravis, a musculoskeletal disorder of immune origin. As discussed in Chapter 5, DiGeorge syndrome is often associated with other developmental defects as part of the 22q11 deletion syndrome. They rarely exceed 4 cm in diameter, can be spherical or arborizing, and are lined by stratified to columnar epithelium. The fluid contents can be serous or mucinous and are often modified by hemorrhage. While isolated cysts are not clinically significant, neoplastic thymic masses (whatever their origin) compress and distort adjacent normal thymus and sometimes cause cysts to form. Therefore the presence of a cystic thymic lesion in a symptomatic patient should provoke a thorough search for a neoplasm, particularly a lymphoma or a thymoma. Thymomas account for 20% to 30% of tumors in the anterosuperior mediastinum, which is also a common location for certain lymphomas. Most are encapsulated, but 20% to 25% of tumors penetrate the capsule and infiltrate perithymic tissues and structures. Noninvasive thymomas are most often composed of medullary-type epithelial cells or a mixture of medullary- and cortical-type epithelial cells. There is usually a sparse infiltrate of thymocytes, which often recapitulate the phenotype of medullary thymocytes. In mixed thymomas there is an admixture of polygonal cortical-type epithelial cells and a denser infiltrate of thymocytes. Although follicular hyperplasia can occur in a number of chronic inflammatory and immunologic states, it is most frequently encountered in myasthenia gravis, in which it is found in 65% to 75% of cases (Chapter 27). Similar thymic changes are sometimes encountered in Graves disease, systemic lupus erythematosus, scleroderma, rheumatoid arthritis, and other autoimmune disorders. In other instances, a morphologically normal thymus is simply large for the age of the patient. As mentioned, the size of the thymus varies widely, and whether this constitutes a true hyperplasia or is merely a variant of normal is unclear. The main significance of this form of thymic "hyperplasia" is that it may be mistaken radiologically for a thymoma, leading to unnecessary surgical procedures. We instead use a classification that relies on the most important prognostic features, the surgical stage and the presence or absence of overt cytologic features of malignancy. In this simple system there are only three histologic subtypes: Tumors that are cytologically benign and noninvasive Tumors that are cytologically benign but invasive or metastatic Tumors that are cytologically malignant (thymic carcinoma) In all categories the tumors usually occur in adults older than 40 years of age; thymomas are rare in children. Most tumors arise in the anterior superior mediastinum, but sometimes they occur in the neck, thyroid, pulmonary hilus, or elsewhere. The neoplastic epithelial cells are arranged in a swirling pattern and have bland, oval to elongated nuclei with inconspicuous nucleoli. The neoplastic epithelial cells are polygonal and have round to oval, bland nuclei with inconspicuous nucleoli. The morphologic appearance of this tumor is identical to that of benign thymomas of the cortical type. In this case, however, the tumor was locally aggressive, invading adjacent lung and pericardium. Tumors that have a substantial proportion of medullary-type epithelial cells are usually noninvasive. Invasive thymoma refers to a tumor that is cytologically benign but locally invasive. The epithelial cells are most commonly of the cortical variety, with abundant cytoplasm and rounded vesicular nuclei. In some cases the neoplastic cells show cytologic atypia, a feature that correlates with a propensity for more aggressive behavior. By definition, invasive thymomas penetrate through the capsule into surrounding structures. The extent of invasion has been subdivided into various stages, which are beyond our scope. With minimal invasion, complete excision yields a 5-year survival rate of greater than 90%, whereas extensive invasion is associated with a 5-year survival rate of less than 50%. Macroscopically, they are usually fleshy, obviously invasive masses, sometimes accompanied by metastases to sites such as the lungs. Another distinctive variant is lymphoepithelioma-like carcinoma, a tumor composed of sheets of cells that bears a close histologic resemblance to nasopharyngeal carcinoma. A variety of other, less common histologic patterns of thymic carcinoma have been described; all exhibit cytologic atypia seen in other carcinomas. White Cell Neoplasms Clinical Features About 40% of thymomas present with symptoms stemming from impingement on mediastinal structures. Another 30% to 45% are detected in the course of evaluating patients with myasthenia gravis. The rest are discovered incidentally during imaging studies or cardiothoracic surgery. In addition to myasthenia gravis, other associated autoimmune disorders include hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dermatomyositispolymyositis, and Cushing syndrome. Hence it seems likely that abnormalities in the selection or "education" of T cells maturing within the environment of the neoplasm contribute to the development of diverse autoimmune disorders. Arber A, Orazi A, Hasserjian R et al: the 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia, Blood 127:2391, 2016. Schmitz R, Ceribelli M, Pittaluga S et al: Oncogenic mechanisms in Burkitt lymphoma, Cold Spring Harb Perspect Med 4:a014282, 2014. Vainchenker W, Kralovics R: Genetic basis and molecular pathophysiology or classical myeloproliferative neoplasms, Blood 129:667, 2017. By far, the most common and important are the anemias, red cell deficiency states that usually have a nonneoplastic basis. We will then complete our review of blood diseases by discussing the major bleeding disorders and complications of blood transfusion. Anemia reduces the oxygen-carrying capacity of the blood, leading to tissue hypoxia. In practice, the measurement of red cell mass is not easy, and anemia is usually diagnosed based on a reduction in the hematocrit (the ratio of packed red cells to total blood volume) and the hemoglobin concentration of the blood to levels that are below the normal range. These values correlate with the red cell mass except when there are changes in plasma volume caused by fluid retention or dehydration. A second clinically useful approach classifies anemia according to alterations in red cell morphology, which often point to particular causes. Morphologic characteristics that provide etiologic clues include red cell size (normocytic, microcytic, or macrocytic); degree of hemoglobinization, reflected in the color of red cells (normochromic or hypochromic); and shape. Microcytic hypochromic anemias are caused by disorders of hemoglobin synthesis, and macrocytic anemias often stem from abnormalities that impair the maturation of erythroid precursors in the bone marrow. Normochromic, normocytic anemias have diverse etiologies; in some of these anemias, characteristic abnormalities of red cell shape provide an important clue as to the cause. Red cell shape is assessed through visual inspection of peripheral smears, whereas as other red cell indices are determined in clinical laboratories with special instrumentation. Whatever its cause, when sufficiently severe anemia leads to manifestations related to the diminished hemoglobin and oxygen content of the blood. Patients appear pale and often report weakness, malaise, easy fatigability, and dyspnea on mild exertion. On occasion, myocardial hypoxia manifests as angina pectoris, particularly when complicated by pre-existing coronary artery disease. With acute blood loss and shock, oliguria and anuria can develop as a result of renal hypoperfusion. Central nervous system hypoxia can cause headache, dimness of vision, and faintness. Anemias of Blood Loss Acute Blood Loss the effects of acute blood loss are mainly due to the loss of intravascular volume, which if massive can lead to cardiovascular collapse, shock, and death. The clinical features depend on the rate of hemorrhage and whether Anemias Table 14. This process appears to be triggered by age-dependent changes in red cell surface proteins, which lead to their recognition and removal by phagocytes. In the great majority of hemolytic anemias, the premature destruction of red cells also occurs within phagocytes, an event that is referred to as extravascular hemolysis. If persistent, extravascular hemolysis leads to a hyperplasia of phagocytes manifested by varying degrees of splenomegaly. Extravascular hemolysis is most commonly caused by alterations that make red cells less deformable. Extreme changes in shape are required for red cells to navigate the splenic sinusoids successfully. Reduced deformability makes this passage difficult, leading to red cell sequestration and phagocytosis by macrophages located within the splenic cords. Regardless of the cause, the principal clinical features of extravascular hemolysis are anemia, splenomegaly, and jaundice. Some hemoglobin inevitably escapes from phagocytes, which leads to variable decreases in plasma haptoglobin, an 2-globulin that binds free hemoglobin and prevents its excretion in the urine. Because much of the premature destruction of red cells occurs in the spleen, individuals with extravascular hemolysis often benefit from splenectomy. Intravascular hemolysis of red cells may be caused by mechanical injury, complement fixation, intracellular parasites.

The main drugs reported to cause chronic hepatitis and/or cirrhosis are listed in Box 27 cardiovascular system lab discount propranolol online. The clinicobiological pattern is usually that of cholestatic or mixed liver injury [88 arteries carry blood away from the heart and lungs best order for propranolol,90 cardiovascular disease grants order propranolol 20 mg visa,170] cardiovascular genetics buy propranolol master card. Only histological examination enables the demonstration of small bile duct lesions [88 cardiovascular disease uk cheap propranolol 40mg with mastercard,90 coronary heart disease quotes buy propranolol 80mg free shipping,170]. Allopurinol Amiodarone Amoxicillin-clavulanate Aprindine Aspirin Azathioprine Carbamazepine Carbimazole Carbutamide Cephalexin Chlorpromazine Clindamycin Clofibrate Cotrimoxazole Cyclofenil Dapsone Dapsone Diazepam Diclofenac Dicloxacillin Difebarbamate Diflunisal Diltiazem Disopyramide Enflurane Estroprogestatives Feprazone Flucloxacillin Fluconazole Flumequine Glibenclamide Glyburide Gold salts Halothane Hydralazine Isoniazid Ketoconazole Lovastatin Mesalazine Methimazole Methotrexate Methyldopa Minocycline Naproxen Nitrofurantoin Nomifensine Ofloxacin Oxacillin Oxyphenbutazone Papaverine Penicillin Penicillamine Perhexiline Phenazone Phenindione Phenprocoumon Phenylbutazone Phenytoin Piroxicam Procainamide Procarbazine Quinidine Quinine Ranitidine Sulfadiazine Sulfadimethoxine Sulfadoxine Sulfamethoxazole Sulfanilamide Sulfathiazole Sulfasalazine Tacrine Ticlopidine Tocainide Tolbutamide Troglitazone Box 27. The main agents reported to cause vascular lesions of the liver are listed in Box 27. Despite a clinicopathological picture similar to primary biliary cholangitis, the clinical course of drug-induced prolonged cholestasis is overall much better [90,92,93,170]. The main drugs reported to cause acute and chronic cholangitis are listed in Box 27. Benign and malignant tumors There are few drugs that have been established to cause liver tumors. Acepromazine Ajmaline Allopurinol Amitriptyline Amoxicillin-clavulanate Ampicillin Azathioprine Barbiturate Candesartan cilexetil Carbamazepine Carbutamide Cefoperazone Chlorothiazide Chlorpromazine Chlorpropamide Cimetidine Ciprofloxacin Clometacin Cyamemazine Cyproheptadine Dantrolene Diazepam Difetarsone Doxycycline Erythromycin + chlorpropamide Etretinate Fenofibrate Flucloxacillin Glibenclamide Gold salts Haloperidol Hydralazine Imipramine Interleukin-2 Methahexamide Methyltestosterone Norandrostenolone Penicillamine Phenylbutazone Phenytoin Prochlorperazine Propoxyphene (dextropropoxyphene) Ramipril Rosiglitazone Sulindac Tenoxicam Terbinafine Tetracycline Thiabendazole Ticlopidine Tiopronin Tolbutamide Trimethoprim-sulfamethoxazole Troleandomycin Xenylamine Box 27. The increasing attraction of herbal medicines is partly explained by the return to natural products occurring along with the ecological movement in industrialized countries [173]. The enhanced use of herbal medicines may be also related to the limited efficacy or important side effects of conventional treatments for various chronic diseases [173]. Several studies focused on the use of herbal medicines in chronic hepatitis C in occidental countries are particularly demonstrative of this [166,175]. A prospective inquiry carried out in France, based on outpatients seen for chronic liver diseases, has revealed that there was herbal medicine intake for at least one month in 30% of patients with hepatitis C [176]. Patients may find these products in various stores, some of them specializing in herbal products but also in pharmacy stores. Furthermore, herbal medicines may produce interactions with liver drug metabolizing enzymes [177]. In part to avoid these side effects, utilization of "natural medicine" is increasingly being controlled in many countries. Marketing authorization has been given for plants considered efficient and innocuous. Hepatotoxicity of herbal remedies is particularly difficult to demonstrate [23,173]because of the usual difficulties in assessing a relationship between an adverse event and the intake of a drug largely caused by the absence of clinical specificity [173]. There may be additional difficulties because of the frequency ofself-medication and the reputation of safety so that patients often forget to mention herbal medicine ingestion to the physician [173]. In addition, there are specific risks contributing to the hepatotoxicity of herbal remedies [173]: misidentification of the plant, selection of the wrong part of the medicinal plant, inadequate storage modifying the native product, adulteration during processing, and mislabeling of the final product [173]. Another instance is Herbalife hepatotoxicity, reported in Israel and Switzerland in 2007 [179,180]. Interestingly, it seems that the complex composition of the products marketed under this brand name in these two countries was not exactly the same [179,180]. Another difficulty is that the real composition of the herbal preparation may remain unclear [23,173]. A safe herbal product may be contaminated by a toxic compound leading to hepatotoxicity. This may result from adulteration with heavy metals, pesticides, herbicides, microorganisms, and even classical pharmaceutical products [23,173]. A recent illustration is a product marketed in Scandinavian countries under the brand name Fortodol, normally containing Curcuma longa (turmeric) as a gentle pain-killer [181,182]. It turned out that it also contained nimesulide, a nonsteroidal anti-inflammatory compound, well documented as causing acute liver injury [181,182]. The degree of evidence of toxicity is variable, as for classical pharmaceutical agents. Herbal medicines with the highest level of evidence of hepatotoxicity are plants containing pyrrolizidine alkaloids, germander (Teucrium chamaedris), Atractylis gummifera, plants containing pennyroyal oil (Mentha pulegium, Hedeoma pulegioides), greater celandine (Chelidonium majus), kava-kava (Piper methysticum), black cohosh (Actaea racemosa), and several Asian medicinal preparations (Table 27. Pyrrolizidine alkaloids are a remarkable illustration of the difficulties encountered with herbal medicine hepatotoxicity and the particular need to develop biomarkers to identify the problem. The main species implicated are Heliotropium, Senecio, Crotalaria [23,173], and Symphytum (comfrey) and, more recently, Gynura segetum [23,67,184]. Pyrrolizidine poisoning is endemic in areas such as Africa and Jamaica, where toxic alkaloids are ingested as infusions, herbal teas or decoctions, or used as an enema [23,173]. Contamination of flour by plants containing pyrrolizidine alkaloids has also caused epidemic intoxications in India and Afghanistan [173]. Hepatotoxicity of pyrrolizidine alkaloids is reproducible and doserelated in laboratory animals [23]. It has been related to the biotransformation of unsaturated alkaloids into unstable, toxic metabolites, probably pyrrolic derivatives, by cytochrome P450, leading mainly to lesions of endothelial cells and, to a lesser extent, of hepatocytes [23]. Another example in which the mechanism of hepatotoxicity has been clearly elucidated is germander (Teucrium chamaedrys) [23], in which it is possible to make the diagnosis with a biological marker. A product containing vitamin A associated with thyroid hormones commercialized as Plethoryl for weight loss has been responsible for acute hepatitis, cholestasis, chronic hepatitis, and cirrhosis [187,188]. Its toxicity has been recognized for 30 years in France, where its use has been forbidden [187,188] However, its use has continued and caused liver injuries in other countries [186]. Furthermore, the illicit use of androgen-anabolic steroids is increasing markedly for body-building and improving fitness and exercise performance [24,186]. These compounds may lead to a wide variety of liver lesions, from acute hepatitis to adenoma and hepatocarcinoma [24,186]. Illegal and recreational compounds Recreational and illicitly used products are increasingly frequently responsible for liver toxicity. Cocaine abuse is a worldwide problem with medical, social, economic, and legal issues. It has been reported that 22 million Americans have used cocaine at least once and 5 million use it regularly [189]. Fifteen percent of nonparenteral cocaine users who have been hospitalized exhibit mild liver enzyme elevation [43]. Acute cocaine intoxication may lead to a severe syndrome with associated fever, arterial hypotension, disseminated Chapter 27: Drug-induced Hepatotoxicity Table 27. Main herbal preparation Pyrrolizidine alkaloids Crotalaria Senecio Heliotropium Symphytum officinale (comfrey) Teucrium chamaedrys (germander) Teucrium polium Atractylis gummifera L. Acute hepatitis occurs within 2 days and is characterized by marked transaminase elevation and liver lesions consisting of pericentral coagulative necrosis and peripheral microvesicular steatosis [190]. Hypertension, arterial vasospasm, and hyperthermia may contribute to the liver injury with this syndrome. Also, confusion with enzyme elevations from rhabdomyolysis may lead to misdiagnosis of liver injury. Animal models have shown that cocaine toxicity is dose-dependent and involves an oxidative reaction mediated by the cytochromes P450 [191]. Cocaine is biotransformed by cytochrome P450 into norcocaine, which is further transformed to N-hydroxynorcocaine, norcocaine nitroxide, and norcocaine nitrosonium ion. These free radical metabolites may cause oxidative stress and lipid peroxidation in hepatocytes [191]. In animals, toxicity is increased by inducers (phenobarbital, ethanol) of cytochrome P450 and is prevented by its inhibitors [191]. Amphetamine and methamphetamine hepatotoxicity mainly appears to be related to hyperthermia. Ecstasy (3,4-methylenedioxymetamphetamine) is an illicit synthetic amphetamine derivative increasingly used as a recreational drug. Ecstasy use should be specifically sought in all young patients with unexplained jaundice. Ecstasy hepatotoxicity can also be caused by another mechanism, the contamination of the product by other hepatotoxic substances. This morphine analog has been used as a drug to help patients to stop drug addiction. When used via the oral route at recommended doses, the risk of hepatotoxicity appears extremely low [16,25,197]. In contrast, when used via the intravenous or intranasal route, this compound is responsible for to hepatotoxic reactions [16,197]. Experimental studies support that the mechanism may be related to mitochondrial dysfunction [198]. Hepatotoxicity may be further increased when there is simultaneous intake of another drug that may cause mitochondrial dysfunction, such as is observed with aspirin [26]. Other drugs misused as psychostimulating agents and causing hepatotoxicity are methylphenidate [199,200]. Hepatotoxicity can be related to the sniffing of organic solvents with an aromatic odour, for instance a combination of trichloroethylene andcarbon tetrachloride, chloroform, or toluene [6]. Another type type of hepatotoxicity derives from the use of a medicinal herb for recreational purposes [17]. This herb from the Pacific Islands was initially used for its relaxing and slightly euphoric properties at low doses in infusion. In occidental countries its misuse as psychostimulant has led to an epidemic of acute hepatitis including liver failure with transplantation and death [17,201,202]. Cannabis, which is widely used, has recently been shown to increase steatosis and fibrosis formation in patients with hepatitis C [203]. Overall, the frequency of hepatotoxicity of recreational and illegal compounds is likely markedly underestimated and increasing. The diagnosis is particularly difficult because intake is usually misrepresented by the user and the product may be adulterated by another toxic product [9]. Hepatotoxicity of chemicals and industrial products Pollution related to exposure to chemical products, which is a well-known burden in traditionally industrialized countries, is now rapidly extending worldwide with a magnitude and toxicological consequences which are difficult to evaluate [56,204]. Although the risk has been reduced for some chemical toxicities, it is generally much more difficult to evaluate than for drugs [56,204]. Indeed, the collection of data on toxic side effects of chemicals is not organized as efficiently as for drugs with pharmacovigilance networks. Furthermore, the long-term effects of intermittent exposures to chemicals remain largely ignored. Indeed, the latency period between exposure and the expression of hepatotoxicity may be several years [56,204]. Epidemiological aspects the assessment of risk requires systematic and combined analyses between epidemiology, toxicology, and clinical evaluations. Zimmermann underlined that the toxicity of chemical agents was insufficiently characterized [43]. A decade later, less than 30% of potentially toxic chemicals were adequately tested, with persisting exposure in the environment and workplace to known hepatotoxins such as vinyl chloride and yet-tobe-identified hepatotoxic chemicals, as reported in petrochemical workers in Brazil [205,206]. Indeed, the structure and liposolubility of chemical products are major determinants of their transport through the cellular membranes. Industrial exposure occurs primarily through inhalation and skin contact, while environmental exposure occurs primarily through Chapter 27: Drug-induced Hepatotoxicity 767 inhalation and ingestion [204].