Environmental and Nutritional Diseases PDF

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See Targeted Therapy available online at studentconsult.com C H A P T E R Environmental and Nutritional Diseases 7 C H A P T E R CO N T E N T S Health Effects of Climate Change 269 Injury by Therapeutic Drugs and Drugs Injury Produced by Ionizing Radiation 289 Toxicity of Chemical and Physical of Abuse 282 Nutritional Diseases 293 Agents 271 Injury by Therapeutic Drugs: Adverse Drug Malnutrition 293 Environmental Pollution 272 Reactions 282 Protein-Energy Malnutrition 294 Air Pollution 272 Injury by Nontherapeutic Agents (Drug Anorexia Nervosa and Bulimia 295 Metals as Environmental Pollutants 273 Abuse) 284 Vitamin Deficiencies 296 Industrial and Agricultural Injury by Physical Agents 287 Obesity 302 Exposures 276 Mechanical Trauma 287 Diet and Systemic Diseases 306 Effects of Tobacco 277 Thermal Injury 288 Diet and Cancer 306 Effects of Alcohol 280 Electrical Injury 289 Many diseases are caused or influenced by environmental the Chernobyl nuclear accident in 1986, and the intentional factors. Broadly defined, the term environment encompasses contamination of Tokyo subways by the organophosphate the various outdoor, indoor, and occupational settings in pesticide sarin in 1995. Fortunately, these are unusual and which humans live and work. In each of these settings, the infrequent occurrences. Less dramatic, but much more air people breathe, the food and water they consume, and common, are diseases and injury produced by chronic the toxic agents they are exposed to are major determinants exposure to relatively low levels of contaminants. Several of health. Other environmental factors pertain to the indi- agencies in the United States set permissible levels of expo- vidual (“personal environment”) and include tobacco use, sure to known environmental hazards (e.g., the maximum alcohol ingestion, therapeutic and “recreational” drug con- level of carbon monoxide [CO] in air that is noninjurious sumption, diet, and the like. Factors in the personal envi- or the level of radiation exposure that is harmless or “safe”). ronment generally have a larger effect on human health But a host of factors, including complex interactions than that of the ambient environment, but new threats between pollutants producing multiplicative effects, as related to global warming (described later on) may change well as the age, genetic predisposition, and different tissue this equation. sensitivities of exposed persons, create wide variations in The term environmental disease refers to disorders caused individual sensitivity. Nevertheless, such “safe” levels are by exposure to chemical or physical agents in the ambient, useful for comparative studies of the effects of harmful workplace, and personal environments, including diseases agents between populations, and for estimating disease of nutritional origin. Environmental diseases are surpris- risk in heavily exposed persons. From this brief overview ingly common. The International Labor Organization has of the nature and magnitude of the problem, we turn to a estimated that work-related injuries and illnesses kill 1.1 consideration of mechanisms of toxicity and then some of million people per year globally—more deaths than are the more important environmental hazards. caused by road accidents and wars combined. Most of these work-related problems are caused by illnesses rather than accidents. The burden of disease in the general popu- lation created by nonoccupational exposures to toxic agents HEALTH EFFECTS OF is much more difficult to estimate, mostly because of the CLIMATE CHANGE diversity of agents and the difficulties in measuring the dose and duration of exposures. Whatever the precise Temperature measurements show that the earth has numbers, environmental diseases are major causes of dis- warmed at an accelerating pace over the last 50 years, ability and suffering and constitute a heavy financial perhaps at a rate greater than in any period during the burden, particularly in developing countries. preceding 1000 years. Since 1960 the global average tem- Environmental diseases are sometimes the conse­­­ perature has increased by 0.6°C, with the greatest increases quence of major disasters, such as the methyl mercury con- seen over land areas between 40°N and 70°N. These tamination of Minamata Bay in Japan in the 1960s, the changes have been accompanied by the rapid loss of glacial leakage of methyl isocyanate gas in Bhopal, India, in 1984, and sea ice, leading to predictions that the glaciers of 270 C H A P T E R 7 Environmental and Nutritional Diseases Glacier National Park in Montana and Mt. Kilimanjaro in end of this century—levels not experienced for tens of mil- Kenya will disappear by the year 2025, and that the Arctic lions of years. This increase stems not only from increased Ocean will be completely ice-free in summer by no later CO2 production but also from deforestation and the atten- than the year 2040. dant decrease in carbon fixation by plants. Depending on Although politicians quibble, among scientists there is a which computer model is used, increased levels of green- general acceptance that climate change is, at least in part, house gases are projected to cause the global temperature man-made. The culprit is the rising atmospheric level of to rise by 2°C to 5°C by the year 2100 (Fig. 7–1, B). Part of greenhouse gases, particularly carbon dioxide (CO2) the uncertainty about the extent of the temperature increase released through the burning of fossil fuels (Fig. 7–1, A), as stems from questions about the degree to which positive- well as ozone (an important air pollutant, discussed later) feedback loops will exacerbate factors driving the process. and methane. These gases, along with water vapor, produce Examples of such self-reinforcing loops are increases in the so-called greenhouse effect by absorbing energy radi- heat absorption due to loss of reflective ice and snow; ated from Earth’s surface that otherwise would be lost into increases in water vapor due to greater evaporation from space. The annual average level of atmospheric CO2 (about rivers, lakes, and oceans; large releases of CO2 and methane 387 ppm) in 2009 was higher than at any point in approxi- from organic matter in thawing Arctic “permafrost” and mately 650,000 years and, without changes in human submarine methane hydrates; and decreased sequestration behavior, is expected to increase to 500 to 1200 ppm by the of CO2 in oceans due to reduced growth of organisms, such as diatoms, that serve as carbon sinks. The health consequences of climate change will depend 1959-2009 Correlation Coefficient: 0.76903 on its extent and rapidity, the severity of the ensuing con- 400 sequences, and humankind’s ability to mitigate the damag- ing effects. Even in the best-case scenario, however, climate change is expected to have a serious negative impact on Mauna Loa CO2 level (ppm) 380 human health by increasing the incidence of a number of diseases, including Cardiovascular, cerebrovascular, and respiratory dis- 360 eases, all of which will be exacerbated by heat waves and air pollution. Gastroenteritis, cholera, and other food- and water- 340 borne infectious diseases, caused by contamination as a consequence of floods and disruption of clean water supplies and sewage treatment, after heavy rains and 320 other environmental disasters Vector-borne infectious diseases, such as malaria and 300 dengue fever, due to changes in vector number and –0.4 –0.2 0 0.2 0.4 0.6 geographic distribution related to increased tempera- A Global temperature anomaly (° C) tures, crop failures and more extreme weather variation (e.g., more frequent and severe El Niño events) Malnutrition, caused by changes in local climate that 5 disrupt crop production. Such changes are anticipated to be most severe in tropical locations, in which average 4 Temperature temperatures may already be near or above crop toler- anomaly ance levels; it is estimated that by 2080, agricultural pro- 3 (° C) ductivity may decline by 10% to 25% in some developing countries as a consequence of climate change. 2 Beyond these disease-specific effects, it is estimated that 1 melting of glacial ice, particularly in Greenland and other parts of the Northern Hemisphere, combined with the 0 thermal expansion of warming oceans, will raise sea levels by 2 to 6 feet by 2100. Approximately 10% of the world’s –1 population—roughly 600 million people—live in low-lying areas that are at risk for flooding even if the rise in ocean 1900 1950 2000 2050 2100 levels is at the low end of these estimates. The resulting B Year displacement of people will disrupt lives and commerce, Figure 7–1 Climate change, past and future. A, Correlation of CO2 levels creating conditions ripe for political unrest, war, and measured at the Mauna Loa Observatory in Hawaii with average global poverty, the “vectors” of malnutrition, sickness, and death. temperature trends over the past 50 years. “Global temperature” in any Both developed and developing countries will suffer the given year was deduced at the Hadley Center (United Kingdom) from consequences of climate change, but the burden will be measurements taken at over 3000 weather stations located around the greatest in developing countries, which are least culpable globe. B, Predicted temperature increases during the 21st century. Dif- for increases in greenhouse gases to date. This picture is ferent computer models plot anticipated rises in global temperatures of 2°C to 5°C by the year 2100. changing rapidly, however, owing to the growth of the (A, Courtesy of Dr. Richard Aster, Department of Earth and Environmental Science, New Mexico economies of India and China, which has recently sur- Institute of Mining and Technology, Socorro, New Mexico.) passed the United States to become the largest producer of  Toxicity of Chemical and Physical Agents 271 CO2 in the world. The urgent challenge is to develop new renewable energy resources that stem the production of greenhouse gases. Without immediate action, climate change stands to become the preeminent global cause of environmental disease in the 21st century and beyond. TOXICITY OF CHEMICAL Air Water Soil AND PHYSICAL AGENTS Toxicology is defined as the science of poisons. It studies the HUMAN EXPOSURE distribution, effects, and mechanisms of action of toxic agents. More broadly, it also includes the study of the effects of physical agents such as radiation and heat. GI tract Skin Lung Approximately 4 billion pounds of toxic chemicals, includ- ing 72 million pounds of known carcinogens, are produced each year in the United States. In general, however, little is known about the potential health effects of chemicals. Of the approximately 100,000 chemicals in use in the United States, less than 1% have been tested experimentally for health effects. In Europe the number of available chemicals is less than one-half that in the United States, but many of these chemicals are released into the environment as indus- trial products or discharged as human and animal wastes. We now consider some basic principles regarding the toxicity of exogenous chemicals and drugs. The definition of a poison is not straightforward. It is basi- Absorption into cally a quantitative concept strictly dependent on dosage. bloodstream The quote from Paracelsus in the 16th century that “all substances are poisons; the right dosage differentiates a poison from a remedy” is perhaps even more valid today, in view of the proliferation of therapeutic drugs with potentially harmful effects. Xenobiotics are exogenous chemicals in the environment that may be absorbed by the body through inhalation, ingestion, or skin contact (Fig. 7–2). Toxicity Distribution to tissues Storage Chemicals may be excreted in urine or feces or elimi- nated in expired air, or they may accumulate in bone, fat, brain, or other tissues. METABOLISM Excretion Chemicals may act at the site of entry, or they may be Figure 7–2 Human exposure to pollutants. Pollutants contained in air, transported to other sites. Some agents are not modified water, and soil are absorbed through the lungs, gastrointestinal tract, and upon entry in the body, but most solvents and drugs are skin. In the body, they may act at the site of absorption, but they generally metabolized to form water-soluble products (detoxifica- are transported through the bloodstream to various organs, where they tion) or are activated to form toxic metabolites. may be stored or metabolized. Metabolism of xenobiotics may result in the formation of water-soluble compounds, which are excreted, or in Most solvents and drugs are lipophilic, which facilitates activation of the agent, creating a toxic metabolite. their transport in the blood by lipoproteins and penetra- tion through lipid components of cell membranes. The reactions that metabolize xenobiotics into nontoxic xenobiotics into active compounds that cause cellular injury. products, or activate xenobiotics to generate toxic com- Both types of reactions may produce, as a byproduct, pounds (Fig. 7–3; see also Fig. 7–2), occur in two phases. reactive oxygen species (ROS), which can cause cellular In phase I reactions, chemicals can undergo hydrolysis, damage (discussed in Chapter 1). Examples of metabolic oxidation, or reduction. Products of phase I reactions activation of chemicals through the P-450 system are often are metabolized into water-soluble compounds the conversion of carbon tetrachloride to the toxic tri- through phase II reactions of glucuronidation, sulfation, chloromethyl free radical and the generation of a DNA- methylation, and conjugation with glutathione (GSH). binding metabolite from benzo[a]pyrene (BaP), a Water-soluble compounds are readily excreted. carcinogen present in cigarette smoke. The cytochrome The most important cellular enzyme system involved in P-450 system also participates in the metabolism of a phase I reactions is the cytochrome P-450 system, located large number of common therapeutic drugs such as acet- primarily in the endoplasmic reticulum (ER) of the liver aminophen, barbiturates, and anticonvulsants, and in but also present in skin, lungs, and gastrointestinal (GI) alcohol metabolism (discussed later). mucosa and in practically every organ. The system cata- P-450 enzymes vary widely in activity among different lyzes reactions that either detoxify xenobiotics or activate people, owing to both polymorphisms in the genes 272 C H A P T E R 7 Environmental and Nutritional Diseases sometimes stifles large cities such as Cairo, Los Angeles, Xenobiotic Elimination Houston, Mexico City, and São Paulo. It may seem that air pollution is a modern phenomenon. This is not the case; Nontoxic metabolite Seneca wrote in AD 61 that he felt an alteration of his dis- position as soon as he left the “pestilential vapors, soot, and heavy air of Rome.” The first environmental control law was proclaimed by Edward I in 1306 and was straightfor- Reactive metabolite ward in its simplicity: “Whoever should be found guilty of burning coal shall suffer the loss of his head.” What has changed in modern times is the nature and sources of air Effects on cellular molecules pollutants, and the types of regulations that control their (enzymes, receptors, membranes, DNA) emission. It could be argued that modern man has lost his head to drown himself in pollution! The lungs bear the brunt of the adverse consequences of air pollution, but air pollutants can affect many organ systems (as with the effects of lead poisoning and CO, discussed later). Except for some comments on smoking later in this chapter, pollutant-caused lung diseases are discussed in Chapter 12. Discussed here are the major Molecular and health effects of ozone, sulfur dioxide, particulates, and CO cellular repair (Table 7–1). Ozone is one of the most pervasive air pollutants, with levels in many cities exceeding EPA standards. It is a gas Toxicity formed by sunlight-driven reactions involving nitrogen (short- and long-term effects) oxides, which are released mostly by automobile exhaust. Together with oxides and fine particulate matter, ozone Figure 7–3 Xenobiotic metabolism. Xenobiotics can be metabolized to forms the familiar smog (from smoke and fog). Its toxicity nontoxic metabolites and eliminated from the body (detoxification). However, their metabolism also may result in activation of the chemical, leading to formation of a reactive metabolite that is toxic to cellular Table 7–1 Health Effects of Outdoor Air Pollutants components. If repair is not effective, short- and long-term effects develop. Populations at (Modified from Hodgson E: A Textbook of Modern Toxicology, 3rd ed, and Fig. 1–1. Hoboken, Pollutant Risk Effect(s) NJ, John Wiley & Sons, 2004.) Ozone Healthy adults Decreased lung function and children Increased airway reactivity Lung inflammation encoding the enzymes and interactions with drugs that Athletes, outdoor Decreased exercise capacity are metabolized through the system. The activity of the workers enzymes also may be decreased by fasting or starvation, Asthmatics Increased hospitalizations and increased by alcohol consumption and smoking. Nitrogen Healthy adults Increased airway reactivity dioxide Asthmatics Decreased lung function Children Increased respiratory ENVIRONMENTAL POLLUTION infections Sulfur dioxide Healthy adults Increased respiratory symptoms Air Pollution Patients with Increased mortality chronic lung The life-giving air that we breathe is also often laden with disease many potential causes of disease. Airborne microorgan- Asthmatics Increased hospitalization isms have long been major causes of morbidity and death. Decreased lung function More widespread are the chemical and particulate pollut- Acid aerosols Healthy adults Altered mucociliary ants found in the air, both in so-called “developed” and clearance “underdeveloped” countries. Specific hazards have been Children Increased respiratory recognized for both outdoor and indoor air. infections Asthmatics Decreased lung function Increased hospitalizations Outdoor Air Pollution Particulates Children Increased respiratory infections The ambient air in industrialized nations is contaminated Decreased lung function with an unsavory mixture of gaseous and particulate pol- Patients with Excess mortality lutants, more heavily in cities and in proximity to heavy chronic lung or industry. In the United States, the Environmental Protec- heart disease tion Agency (EPA) monitors and sets allowable upper Asthmatics Increased attacks limits for six pollutants: sulfur dioxide, CO, ozone, nitro- Data from Health effects of outdoor air pollution. Part 2. Committee of the Environ- gen dioxide, lead, and particulate matter. Together, some mental and Occupational Health Assembly of the American Thoracic Society. Am J Respir Crit Care Med 153:477, 1996. of these agents produce the well-known smog that  Environmental Pollution 273 stems from its participation in chemical reactions that gen- imparted by carboxyhemoglobin. If death occurs rapidly, erate free radicals, which injure the lining cells of the respi- morphologic changes may not be present; with longer sur- ratory tract and the alveoli. Low levels of ozone may be vival, the brain may be slightly edematous and exhibit punc- tolerated by healthy persons but are detrimental to lung tate hemorrhages and hypoxia-induced neuronal changes. function, especially in those with asthma or emphysema, These changes are not specific; they simply imply systemic and when present along with particulate pollution. Unfor- hypoxia. In victims who survive CO poisoning, complete tunately, pollutants rarely occur singly but combine to recovery is possible; however, sometimes impairments of create a veritable “witches’ brew.” memory, vision, hearing, and speech may remain. Sulfur dioxide, particles, and acid aerosols are emitted by coal- and oil-fired power plants and industrial processes burning these fuels. Of these, particles (although not well Indoor Air Pollution characterized chemically or physically) appear to be the As modern homes are increasingly “buttoned up” to main cause of morbidity and death. Particles less than exclude the environment, the potential for pollution of the 10 µm in diameter are particularly harmful, since when indoor air increases. The commonest pollutant is tobacco inhaled they are carried by the airstream all the way to the smoke (discussed later), but additional offenders are CO, alveoli. Here, they are phagocytosed by macrophages and nitrogen dioxide (already mentioned as outdoor pollut- neutrophils, causing the release of mediators and inciting ants), and asbestos (discussed in Chapter 12). A few com- an inflammatory reaction. By contrast, larger particles are ments about some other agents are presented here. removed in the nose or are trapped by the mucociliary Wood smoke, containing various oxides of nitrogen and “escalator” and as a result are less dangerous. carbon particulates, is an irritant that predisposes exposed Carbon monoxide (CO) is a nonirritating, colorless, persons to lung infections and may contain carcinogenic tasteless, odorless gas. It is produced by the incomplete polycyclic hydrocarbons. Radon, a radioactive gas derived oxidation of carbonaceous materials. Its sources include from uranium, is widely present in soil and in homes. automotive engines, industries using fossil fuels, home oil Although radon exposure can cause lung cancer in uranium burners, and cigarette smoke. The low levels often found miners (particularly in those who smoke), it does not in ambient air may contribute to impaired respiratory func- appear that low-level chronic exposures in the home tion but usually are not life-threatening. However, persons increase lung cancer risk, at least for nonsmokers. Bioaero- working in confined environments with high exposure to sols may contain pathogenic microbiologic agents, such as fumes, such as tunnel and underground garage workers, those that can cause Legionnaires’ disease, viral pneumo- may develop chronic poisoning. CO is included here as an nia, and the common cold, as well as allergens derived air pollutant, but it also is an important cause of accidental from pet dander, dust mites, and fungi and molds, which and suicidal death. In a small, closed garage, exhaust from can cause rhinitis, eye irritation, and even asthma. a running car engine can induce lethal coma within 5 minutes. CO is a systemic asphyxiant that kills by binding to hemoglobin and preventing oxygen transport. Hemo- S U M M A RY globin has a 200-fold greater affinity for CO than for O2. Environmental Diseases and Environmental Pollution The resultant compound, carboxyhemoglobin, is incapable of carrying oxygen. Hypoxia leads to central nervous Environmental diseases are conditions caused by expo- system (CNS) depression, which develops so insidiously sure to chemical or physical agents in the ambient, work- that victims may not be aware of their plight and indeed place, and personal environments. may be unable to help themselves. Systemic hypoxia Exogenous chemicals known as xenobiotics enter the appears when the hemoglobin is 20% to 30% saturated with body through inhalation, ingestion, and skin contact, and CO, and unconsciousness and death are probable with 60% can either be eliminated or accumulate in fat, bone, brain, to 70% saturation. and other tissues. Xenobiotics can be converted into nontoxic products, or activated to generate toxic compounds, through a two- MORPHOLOGY phase reaction process that involves the cytochrome P-450 system. Chronic poisoning by CO develops because carboxyhe- moglobin, once formed, is remarkably stable. As a result, The most common air pollutants are ozone (which in with low-level persistent exposure to CO, carboxyhemoglo- combination with oxides and particulate matter forms bin may accumulate to a life-threatening concentration in the smog), sulfur dioxide, acid aerosols, and particles less than blood. The slowly developing hypoxia can insidiously evoke 10 µm in diameter. widespread ischemic changes in the brain; these changes are Carbon monoxide is an air pollutant and important cause particularly marked in the basal ganglia and lenticular nuclei. of death from accidents and suicide; it binds hemoglobin With cessation of exposure to CO, the patient usually recov- with high affinity, leading to systemic asphyxiation associ- ers, but there may be permanent neurologic damage. The ated with CNS depression. diagnosis of CO poisoning is based on detection of high levels of carboxyhemoglobin in the blood. Acute poisoning by CO generally is a consequence of Metals as Environmental Pollutants accidental exposure or suicide attempt. In light-skinned Lead, mercury, arsenic, and cadmium, the heavy metals people, it is marked by a characteristic generalized cherry- most commonly associated with harmful effects in human red color of the skin and mucous membranes, a color populations, are considered here. 274 C H A P T E R 7 Environmental and Nutritional Diseases Lead BRAIN Lead exposure occurs through contaminated air and food. Adult: Headache, memory loss For most of the 20th century the major sources of lead in Child: Encephalopathy, mental the environment were house paints and gasoline. Although deterioration the use of lead-based paints and leaded gas has greatly GINGIVA diminished, many sources of lead persist in the environ- Lead line ment, such as mines, foundries, batteries, and spray paints, BLOOD all of which constitute occupational hazards. However, Anemia, red cell basophilic flaking lead paint in older houses and soil contamination stippling pose the major hazards for youngsters. Indeed, a single 1-cm2 chip of old leaded paint (pre-1977) contains about PERIPHERAL NERVES Adult: Demyelination 175 µg of lead; this amount, if consumed each day over time, will rapidly produce toxic lead levels. According to KIDNEY a 2008 report from the Environmental Protection Agency Chronic tubulointerstitial (EPA), 0.9% of American children had blood lead levels in disease excess of 10 µg/dL (the maximum allowable level). This percentage represents a decrease from 4.4% in the early GASTROINTESTINAL TRACT Abdominal pain 1990s. However, blood levels of lead in children living in homes containing lead-based paint or lead-contaminated dust generally exceed the maximum allowed levels. Chil- dren absorb more than 50% of lead from food, while adults absorb approximately 15%. A more permeable blood–brain barrier in children creates a high susceptibility to brain damage. The main clinical features of lead poisoning are shown in Figure 7–4. Most of the absorbed lead (80% to 85%) is taken up into bone and developing teeth; lead competes with calcium, BONES binds phosphates, and has a half-life in bone of 20 to 30 Child: Radiodense deposits years. About 5% to 10% of the absorbed lead remains in the in epiphyses blood, and the remainder is distributed throughout soft tissues. Excess lead causes neurologic effects in adults and chil- dren; peripheral neuropathies predominate in adults, while central effects are more common in children. The effects of chronic lead exposure in children include a lower intel- lectual capacity manifested by low intelligence quotient (IQ), behavioral problems such as hyperactivity, and poor organizational skills. Lead-induced peripheral neuropa- thies in adults generally remit with elimination of expo- SOURCES sure, but both peripheral and CNS abnormalities in children OCCUPATIONAL NONOCCUPATIONAL usually are irreversible. Excess lead interferes with the normal Spray painting Water supply remodeling of calcified cartilage and primary bone trabeculae Foundry work Paint dust and flakes in the epiphyses in children, causing increased bone density Mining and extracting lead Automotive exhaust detected as radiodense “lead lines” (Fig. 7–5). Lead lines Battery burning Urban soil of a different sort also may occur in the gums, where Figure 7–4 Pathologic features of lead poisoning. excess lead stimulates hyperpigmentation. Lead inhibits the healing of fractures by increasing chondrogenesis and delaying cartilage mineralization. Excretion of lead occurs diagnosis. In milder cases of lead exposure, anemia may be by way of the kidneys, and acute exposures may cause the only obvious abnormality. damage to proximal tubules. Lead has a high affinity for sulfhydryl groups and inter- feres with two enzymes involved in heme synthesis, ami- nolevulinic acid dehydratase and delta ferrochelatase. Iron M O R P H O LO G Y incorporation into heme is impaired, leading to anemia. Lead also inhibits sodium- and potassium-dependent The major anatomic targets of lead toxicity are the ATPases in cell membranes, an effect that may increase the blood, bone marrow, nervous system, GI tract, and kidneys fragility of red cells, causing hemolysis. The diagnosis of (Fig. 7–4). lead poisoning requires constant vigilance. It may be Blood changes are one of the earliest signs of lead suspected on the basis of neurologic changes in children accumulation and are characteristic, consisting of a micro- or unexplained anemia with basophilic stippling in red cytic, hypochromic anemia associated with a distinctive cells. Elevated blood lead and red cell free protopor­­ punctate basophilic stippling of red cells. These changes phyrin levels (greater than 50 µg/dL) or, alternatively, in the blood stem from the inhibition of heme synthesis in zinc-protoporphyrin levels, are required for definitive marrow erythroid progenitors. Another consequence of this  Environmental Pollution 275 Mercury Humans have used mercury in many ways throughout history, including as a pigment in cave paintings, a cos- metic, a remedy for syphilis, and a component of diuretics. Poisoning from inhalation of mercury vapors has long been recognized and is associated with tremor, gingivitis, and bizarre behavior, such as that of the “Mad Hatter” in Lewis Carroll’s Alice in Wonderland (mercury formerly was used in hat-making). Today, the main sources of exposure to mercury are contaminated fish and dental amalgams, which release mercury vapors. In some areas of the world, mercury used in gold mining has contaminated rivers and streams. Inor- ganic mercury from the natural degassing of the earth’s crust or from industrial contamination is converted to organic compounds such as methyl mercury by bacteria. Methyl mercury enters the food chain, and in carnivorous fish such as swordfish, shark, and bluefish, mercury levels may be a million times higher than in the surround- ing water. The consumption of contaminated fish from the release of methyl mercury in Minamata Bay and the Agano River in Japan, and the consumption of bread con- taining grain treated with a methyl mercury–based fungi- Figure 7–5 Lead poisoning. Impaired remodeling of calcified cartilage in cide in Iraq, caused widespread morbidity and many the epiphyses (arrows) of the wrist has caused a marked increase in their deaths. radiodensity, so that they are as radiopaque as the cortical bone. The medical disorders associated with the Minamata (Courtesy of Dr. G.W. Dietz, Department of Radiology, University of Texas Southwestern Medical School, Dallas, Texas.) episode became known as “Minamata disease” and include cerebral palsy, deafness, blindness, and major CNS defects in children exposed in utero. The developing brain is extremely blockade is that zinc-protoporphyrin is formed instead of sensitive to methyl mercury; for this reason, the Centers for heme. Thus, elevated blood levels of zinc-protoporphyrin or Disease Control and Prevention (CDC) in the United States its product, free red cell protoporphyrin, are important indi- has recommended that pregnant women avoid the con- cators of lead poisoning. sumption of fish known to contain mercury. There has been Brain damage is prone to occur in children. It may be much publicity about a possible relationship between thi- subtle, producing mild dysfunction, or it may be massive and merosal (a compound that contains ethyl mercury, used lethal. In young children, sensory, motor, intellectual, and until recently as a preservative in some vaccines) and the psychologic impairments have been described, including development of autism, but several large studies have reduced IQ, learning disabilities, retarded psychomotor failed to detect any association. development, and, in more severe cases, blindness, psycho- ses, seizures, and coma. Lead toxicity in the mother may be Arsenic the cause of impairment of prenatal brain development. The Arsenic was the favorite poison in Renaissance Italy, and anatomic changes underlying the more subtle functional defi- this application had some skilled practitioners among the cits are ill defined, but some of the defects may be perma- Borgias and Medicis. Deliberate poisoning by arsenic is nent. At the more severe end of the spectrum are brain exceedingly rare today, but exposure to arsenic is an impor- edema, demyelination of the cerebral and cerebellar white tant health problem in many areas of the world. Arsenic is matter, and necrosis of cortical neurons accompanied by found naturally in soil and water and is used in wood diffuse astrocytic proliferation. In adults, the CNS is less often preservatives, herbicides, and other agricultural products. affected, but frequently a peripheral demyelinating neu- It may be released into the environment by the mining and ropathy appears, typically involving motor neurons innervat- smelting industries. Large concentrations of inorganic ing the most commonly used muscles. Thus, the extensor arsenic are present in ground water in countries such as muscles of the wrist and fingers are often the first to be Bangladesh, Chile, and China. As many as 20 million affected, followed by paralysis of the peroneal muscles people in Bangladesh drink water contaminated by arsenic, (wristdrop and footdrop). constituting one of the largest environmental cancer risks The GI tract also is a locus for major clinical manifesta- yet identified. tions. Lead “colic” is characterized by extremely severe, The most toxic forms of arsenic are the trivalent com- poorly localized abdominal pain. pounds arsenic trioxide, sodium arsenite, and arsenic tri- The kidneys may develop proximal tubular damage with chloride. If ingested in large quantities, arsenic causes intranuclear lead inclusions. Chronic renal damage leads acute toxicity manifesting as severe gastrointestinal, car- eventually to interstitial fibrosis and possibly renal failure and diovascular, and central nervous system disturbances, findings suggestive of gout (“saturnine gout”). Other features often progressing to death. These effects may be attri­b­ of lead poisoning are shown in Figure 7–4. uted to the interference with mitochondrial oxidative 276 C H A P T E R 7 Environmental and Nutritional Diseases phos­phorylation. Chronic exposure to arsenic causes hyperpigmentation and hyperkeratosis of the skin, which Industrial and Agricultural Exposures may be followed by the development of basal and squa- More than 10 million occupational injuries occur annually mous cell carcinomas (but not melanomas). Arsenic- in the United States, and approximately 65,000 people die induced skin tumors differ from those induced by sunlight as a consequence of occupational injuries and illnesses. by appearing on palms and soles, and by occurring as Industrial exposures to toxic agents are as varied as the multiple lesions. Arsenic exposure also is associated with industries themselves. They range from merely annoying an increased risk of lung carcinoma. The mechanisms of irritations of respiratory airways by formaldehyde or arsenic carcinogenesis in skin and lung are uncertain. ammonia fumes to fatal lung cancers arising from exposure to asbestos, arsenic, or uranium mining. Human diseases Cadmium associated with occupational exposures are listed in Table In contrast with the metals already discussed, cadmium is 7–2. In addition to the toxic metals (which have already a relatively modern toxic agent. It is used mainly in nickel- been discussed), other important agents that contribute to cadmium batteries, which generally are disposed of as environmental diseases include the following: household waste. It can contaminate soil and plants directly Organic solvents are widely used in huge quantities or through fertilizers and irrigation water. Food is the worldwide. Some, such as chloroform and carbon tetra- most important source of exposure for the general popula- chloride, are found in degreasing and dry cleaning agents tion. Excessive cadmium intake can lead to obstructive and paint removers. Acute exposure to high levels of lung disease and renal toxicity, initially as tubular damage vapors from these agents can cause dizziness and confu- that may progress to end-stage renal disease. Cadmium sion, leading to CNS depression and even coma. Lower exposure can also cause skeletal abnormalities associated levels have toxicity for the liver and kidneys. Occupa- with calcium loss. Cadmium-contaminated water used to tional exposure of rubber workers to benzene and irrigate rice fields in Japan caused a disease in postmeno- 1,3-butadiene increases the risk of leukemia. Benzene is pausal women known as “itai-itai” (ouch-ouch), a com­ oxidized to an epoxide through hepatic CYP2E1, a com- bination of osteoporosis and osteomalacia associated ponent of the P-450 enzyme system already mentioned. with renal disease. A recent survey showed that 5% of The epoxide and other metabolites disrupt progenitor persons aged 20 years and older in the U.S. population cell differentiation in the bone marrow, causing marrow have urinary cadmium levels that, according to research aplasia and acute myeloid leukemia. data, may produce subtle kidney injury and increased Polycyclic hydrocarbons may be released during the com- calcium loss. bustion of coal and gas, particularly at the high tempera- tures used in steel foundries, and also are present in tar and soot. (Pott identified soot as the cause of scrotal cancers in chimney sweeps in 1775, as mentioned in Chapter 5.) Polycyclic hydrocarbons are among the most SUMMARY potent carcinogens, and industrial exposures have been implicated in the causation of lung and bladder cancer. Toxic Effects of Heavy Metals Organochlorines (and halogenated organic compounds in Lead, mercury, arsenic, and cadmium are the heavy metals general) are synthetic products that resist degradation most commonly associated with toxic effects in humans. and are lipophilic. Important organochlorines used as Children absorb more ingested lead than adults; the main pesticides are DDT (dichlorodiphenyltrichloroethane) and source of exposure for children is lead-containing paint. its metabolites and agents such as lindane, aldrin, and Excess lead causes CNS defects in children and peripheral dieldrin. Nonpesticide organochlorines include polychlo- neuropathy in adults. Excess lead competes with calcium rinated biphenyls (PCBs) and dioxin (TCDD [2,3,7,8- in bones and interferes with the remodeling of cartilage; tetrachlorodibenzo-p-dioxin]). DDT was banned in the it also causes anemia. United States in 1973, but more than half of the popula- The major source of exposure to mercury is contami- tion have detectable serum levels of p,p′-DDE, a long- nated fish. The developing brain is highly sensitive to lasting DDT metabolite, including those born after the methyl mercury, which accumulates in the brain and ban on DDT went into effect. PCB and TCDD also are blocks ion channels. present in the blood of most of the U.S. population. Exposure of the fetus to high levels of mercury in utero Acute DDT poisoning in humans causes neurologic tox- may lead to Minamata disease, characterized by cerebral icity. Most organochlorines are endocrine disruptors and palsy, deafness, and blindness. have antiestrogenic or antiandrogenic activity in labora- Arsenic is naturally found in soil and water and is a com- tory animals, but long-term health effects in humans ponent of some wood preservatives and herbicides. have not been firmly established. Excess arsenic interferes with mitochondrial oxidative Dioxins and PCBs can cause skin disorders such as fol- phosphorylation and causes toxic effects in the GI tract, liculitis and acneiform dermatosis known as chloracne, CNS, and cardiovascular system; long-term exposure which consists of acne, cyst formation, hyperpigmenta- causes skin lesions and carcinomas. tion, and hyperkeratosis, generally around the face and Cadmium from nickel-cadmium batteries and chemical behind the ears. It can be accompanied by abnormalities fertilizers can contaminate soil. Excess cadmium causes in the liver and CNS. Because PCBs induce the P-450 obstructive lung disease and kidney damage. enzyme system, workers exposed to these substances may show altered drug metabolism. Environmental  Effects of Tobacco 277 Table 7–2 Human Diseases Associated With Occupational Exposures Organ/System Effect(s) Toxicant(s) Cardiovascular system Heart disease Carbon monoxide, lead, solvents, cobalt, cadmium Respiratory system Nasal cancer Isopropyl alcohol, wood dust Lung cancer Radon, asbestos, silica, bis(chloromethyl)ether, nickel, arsenic, chromium, mustard gas Chronic obstructive lung disease Grain dust, coal dust, cadmium Hypersensitivity Beryllium, isocyanates Irritation Ammonia, sulfur oxides, formaldehyde Fibrosis Silica, asbestos, cobalt Nervous system Peripheral neuropathies Solvents, acrylamide, methyl chloride, mercury, lead, arsenic, DDT Ataxic gait Chlordane, toluene, acrylamide, mercury Central nervous system depression Alcohols, ketones, aldehydes, solvents Cataracts Ultraviolet radiation Urinary system Toxicity Mercury, lead, glycol ethers, solvents Bladder cancer Naphthylamines, 4-aminobiphenyl, benzidine, rubber products Reproductive system Male infertility Lead, phthalate plasticizers Female infertility Cadmium, lead Teratogenesis Mercury, polychlorinated biphenyls Hematopoietic system Leukemia Benzene, radon, uranium Skin Folliculitis and acneiform Polychlorinated biphenyls, dioxins, herbicides dermatosis Cancer Ultraviolet radiation Gastrointestinal tract Liver angiosarcoma Vinyl chloride DDT, dichlorodiphenyltrichloroethane. Data from Leigh JP, Markowitz SB, Fahs M, et al: Occupational injury and illness in the United States. Estimates of costs, morbidity, and mortality. Arch Intern Med 157:1557, 1997; Mitchell FL: Hazardous waste. In Rom WN (ed): Environmental and Occupational Medicine, 2nd ed. Boston, Little, Brown, 1992, p 1275; and Levi PE: Classes of toxic chemicals. In Hodgson E, Levi PE (eds): A Textbook of Modern Toxicology. Stamford, CT, Appleton & Lange, 1997, p 229. disasters in Japan and China in the late 1960s caused by occurs in the workplace. The increased risk of cancer as the consumption of rice oil contaminated by PCBs a result of asbestos exposure, however, extends to family during its production poisoned about 2000 people in members of asbestos workers and to other persons each episode. The primary manifestations of the disease exposed outside the workplace. Pneumoconioses and (yusho in Japan, yu-cheng in China) were chloracne and their pathogenesis are discussed in Chapter 12. hyperpigmentation of the skin and nails. Bisphenol A (BPA) is used in the synthesis of polycarbon- ate food and water containers and of epoxy resins that EFFECTS OF TOBACCO line almost all food bottles and cans; as a result, expo- sure to BPA is virtually ubiquitous in humans. BPA has Tobacco is the most common exogenous cause of human long been known as a potential endocrine disruptor. cancers, being responsible for 90% of lung cancers. The Several large retrospective studies have linked elevated main culprit is cigarette smoking, but smokeless tobacco in urinary BPA levels to heart disease in adult populations. its various forms (snuff, chewing tobacco) also is harmful In addition, infants who drink from BPA-containing to health and is an important cause of oral cancer. Not only containers may be particularly susceptible to its endo- does the use of tobacco products create personal risk, but crine effects. In 2010, Canada was the first country to list passive tobacco inhalation from the environment (“second- BPA as a toxic substance, and the largest makers of baby hand smoke”) can cause lung cancer in nonsmokers. Ciga- bottles and “sippy” cups have stopped using BPA in the rette smoking causes, worldwide, more than 4 million manufacturing process. The extent of the human health deaths annually, mostly from cardiovascular disease, risks associated with BPA remains uncertain, however, various types of cancers, and chronic respiratory problems. and requires further study. It is expected that there will be 8 million tobacco-related Exposure to vinyl chloride, used in the synthesis of poly- deaths yearly by 2020, the major increase occurring in vinyl resins, was found to cause angiosarcoma of the developing countries. Of people alive today, an estimated liver, a rare type of liver tumor. 500 million will die from tobacco-related illnesses. In the Inhalation of mineral dusts causes chronic, non-neoplastic United States alone, tobacco is responsible for more than lung diseases called pneumoconioses. This group of dis- 400,000 deaths per year, one third of these attributable to orders includes diseases induced by organic and inor- lung cancer. ganic particulates as well as chemical fume- and Smoking is the most preventable cause of human death. It vapor-induced non-neoplastic lung diseases. The most reduces overall survival in a dose-dependent fashion. common pneumoconioses are caused by exposures to While 80% of nonsmokers are alive at age 70, only about mineral dust: coal dust (in mining of hard coal), silica (in 50% of smokers survive to this age (Fig. 7–6). Cessation of sandblasting and stone cutting), asbestos (in mining, fab- smoking greatly reduces the risk of death from lung cancer, and rication, and insulation work), and beryllium (in mining it even has an effect, albeit reduced, on people who stop and fabrication). Exposure to these agents nearly always smoking at age 60. During the period 1998 to 2007 in the 278 C H A P T E R 7 Environmental and Nutritional Diseases Current cigarette smokers Never smoked regularly 100 Cancer of oral cavity 80 Cancer of larynx Cancer of esophagus 60 Cancer of lung Percent alive Chronic bronchitis, emphysema 40 Myocardial infarction Peptic ulcer 20 Cancer of pancreas 0 Systemic 40 55 70 85 100 atherosclerosis Age Figure 7–6 The effects of smoking on survival. The study compared age-specific death rates for current cigarette smokers with that of indi- Cancer of viduals who never smoke regularly (British Doctors Study). The difference bladder in survival, measured at age 75, between smokers and nonsmokers is 7.5 years. (Modified from Stewart BW, Kleihues P [eds]: World Cancer Report. Lyon, IARC Press, 2003.) United States, the incidence of smoking declined modestly, but approximately 20% of adults remained smokers. More Figure 7–7 Adverse effects of smoking. The more common are in boldface. disturbing, smoking in the world’s most populous country, China, is becoming the rule rather than the exception. It is estimated that more than 1 million people in China die each year of smoking-related diseases. Components of cigarette smoke, particularly polycyclic hydro- Discussed next are some of the agents contained in carbons and nitrosamines (Table 7–4), are potent carcinogens tobacco and diseases associated with tobacco consumption. in animals and probably are involved in the causation of Adverse effects of smoking in various organ systems are lung carcinomas in humans (see Chapter 12). The risk of shown in Figure 7–7. developing lung cancer is related to the intensity of The number of potentially noxious chemicals in tobacco exposure, frequently expressed in terms of “pack years” smoke is vast; Table 7–3 presents only a partial list (e.g., one pack daily for 20 years equals 20 pack years) and includes the type of injury produced by these agents. or in cigarettes smoked per day (Fig. 7–8). Moreover, Nicotine, an alkaloid present in tobacco leaves, is not a smoking multiplies the risk of disease associated with direct cause of tobacco-related diseases, but it is highly addictive. Nicotine binds to receptors in the brain and, through the release of catecholamines, is responsible for Table 7–3 Effects of Selected Tobacco Smoke Constituents the acute effects of smoking, such as increased heart rate and blood pressure, and increased cardiac contractility and Substance Effect(s) output. Tar Carcinogenesis The most common diseases caused by cigarette smoking Polycyclic aromatic Carcinogenesis involve the lung and include emphysema, chronic bronchitis, and hydrocarbons lung cancer, all discussed in Chapter 12. The mechanisms Nicotine Ganglionic stimulation and responsible for some tobacco-induced diseases are outlined depression, tumor promotion next. Phenol Tumor promotion; mucosal irritation Agents in smoke have a direct irritant effect on the tra- Benzopyrene Carcinogenesis cheobronchial mucosa, producing inflammation and Carbon monoxide Impaired oxygen transport and utilization increased mucus production (bronchitis). Cigarette smoke Formaldehyde Toxicity to cilia; mucosal irritation also causes the recruitment of leukocytes to the lung, Oxides of nitrogen Toxicity to cilia; mucosal irritation increasing local elastase production and subsequent injury to lung tissue that leads to emphysema. Nitrosamine Carcinogenesis  Effects of Tobacco 279 Table 7–4 Organ-Specific Carcinogens in Tobacco Smoke example of the carcinogenic interaction of these all too Organ Carcinogen(s) common vices is shown below for laryngeal cancer (Fig. 7–9). Lung, larynx Polycyclic aromatic hydrocarbons 4-(Methylnitrosoamino)-1-(3-pyridyl)- Maternal smoking increases the risk of spontaneous abortions 1-butanone (NNK) and preterm births and results in intrauterine growth 210 Polonium retardation (Chapter 6); however, birth weights of Esophagus N′-Nitrosonornicotine (NNN) infants born to mothers who stopped smoking before Pancreas NNK (?) pregnancy are normal. Bladder 4-Aminobiphenyl, 2-naphthylamine Exposure to environmental tobacco smoke (passive smoke inhalation) is also associated with detrimental effects. It Oral cavity: smoking Polycyclic aromatic hydrocarbons, NNK, NNN is estimated that the relative risk of lung cancer in non- smokers exposed to environmental smoke is about 1.3 Oral cavity: snuff NNK, NNN, 210polonium times that in nonsmokers who are not exposed to smoke. Data from Szczesny LB, Holbrook JH: Cigarette smoking. In Rom WH (ed): Environ- mental and Occupational Medicine, 2nd ed. Boston, Little, Brown, 1992, p 1211. In the United States, approximately 3000 lung cancer deaths in nonsmokers over the age of 35 years can be attributed each year to environmental tobacco smoke. Even more striking is the increased risk of coronary other carcinogens; well-recognized examples are the atherosclerosis and fatal myocardial infarction. Studies 10-fold higher incidence of lung carcinomas in asbestos report that every year, 30,000 to 60,000 cardiac deaths in workers and uranium miners who smoke than that in the United States are associated with passive exposure those who do not, and the interaction between tobacco to smoke. Children living in a household with an adult consumption and alcohol in the risk for oral cancers as who smokes have an increased frequency of respiratory described later on. illnesses and asthma. Passive smoke inhalation in non- Atherosclerosis and its major complication, myocardial infarc- smokers can be estimated by measuring the blood levels tion, are strongly linked to cigarette smoking. The causal of cotinine, a metabolite of nicotine. In the United States, mechanisms probably relate to several factors, including median cotinine levels in nonsmokers have decreased increased platelet aggregation, decreased myocardial by more than 60% during the last 15 years due to adop- oxygen supply (because of lung disease coupled with tion of non-smoking policies in public places. However, hypoxia related to CO in cigarette smoke) accompanied passive exposure to tobacco smoke in the home remains by increased oxygen demand, and a decreased threshold a major public health concern, particularly for children. for ventricular fibrillation. Almost one third of all heart It is clear that the transient pleasure a puff may give attacks are associated with cigarette smoking. Smoking comes with a heavy long-term price. has a multiplicative effect on risk when combined with hypertension and hypercholesterolemia. In addition to lung cancers, tobacco smoke contributes to Tobacco smoking (cigarettes/day) the development of cancers of the oral cavity, esophagus, pan- 0–7 8–15 16–25 26+ creas, and bladder. Table 7–4 lists organ-specific carcino- gens contained in tobacco smoke. The combination of tobacco (chewed or smoked) and 50 alcohol consumption has multiplicative effects on the risks of oral, laryngeal, and esophageal cancers. An 40 20 30 Relative risk 15 Relative risk 20 10 120+ 5 10 81–120 y) g/da n( tio 0 41–80 ump 0 ns 0 1 10 20 40 60 co hol Cigarettes smoked/day 0–40 Alco Figure 7–8 The risk of lung cancer is determined by the number of Figure 7–9 Multiplicative increase in the risk of laryngeal cancer from cigarettes smoked. the interaction between cigarette smoking and alcohol consumption. (Data from Stewart BW, Kleihues P [eds]: World Cancer Report. Lyon, IARC Press, 2003.) (Data from Stewart BW, Kleihues P [eds]: World Cancer Report. Lyon, IARC Press, 2003.) 280 C H A P T E R 7 Environmental and Nutritional Diseases or 6 ounces of whiskey (about 11 g of alcohol per ounce). SUMMARY Drowsiness occurs at 200 mg/dL, stupor at 300 mg/dL, Health Effects of Tobacco and coma, with possible respiratory arrest, at higher levels. Smoking is the most preventable cause of human death. The rate of metabolism affects the blood alcohol level. Persons with chronic alcoholism can tolerate levels as high Tobacco smoke contains more than 2000 compounds. as 700 mg/dL, due in part to accelerated ethanol metabo- Among these are nicotine, which is responsible for lism caused by a 5- to 10-fold increase in induction of the tobacco addiction and strong carcinogens—mainly, poly- hepatic cytochrome P-450 system, discussed next. cyclic aromatic hydrocarbons, nitrosamines, and aromatic Most of the alcohol in the blood is metabolized to acet- amines. aldehyde in the liver by three enzyme systems: alcohol Approximately 90% of lung cancers occur in smokers. dehydrogenase, cytochrome P-450 isoenzymes, and cata- Smoking is also associated with an increased risk of lase (Fig. 7–10). Of these, the main enzyme involved in alcohol cancers of the oral cavity, larynx, esophagus, stomach, metabolism is alcohol dehydrogenase, located in the cytosol of bladder, and kidney, as well as some forms of leukemia. hepatocytes. At high blood alcohol levels, however, the Cessation of smoking reduces the risk of lung cancer. microsomal ethanol-oxidizing system also has an impor- Smokeless tobacco use is an important cause of oral tant role. This system involves cytochrome P-450 enzymes, cancers. Tobacco consumption interacts with alcohol in particularly the CYP2E1 isoform, located in the smooth ER. multiplying the risk of oral, laryngeal, and esophageal Induction of P-450 enzymes by alcohol explains the cancer and increases the risk of lung cancers from occu- increased susceptibility of alcoholics to other compounds pational exposures to asbestos, uranium, and other agents. metabolized by the same enzyme system, which include Tobacco consumption is an important risk factor for drugs (acetaminophen, cocaine), anesthetics, carcinogens, development of atherosclerosis and myocardial infarction, and industrial solvents. Of note, however, when alcohol is peripheral vascular disease, and cerebrovascular disease. present in the blood at high concentrations, it competes In the lungs, in addition to cancer, it predisposes to emphy- with other CYP2E1 substrates and may delay the catabo- sema, chronic bronchitis, and chronic obstructive disease. lism of other drugs, thereby potentiating their effects. Cata- Maternal smoking increases the risk of abortion, prema- lase is of minor importance, being responsible for only ture birth, and intrauterine growth retardation. about 5% of alcohol metabolism. Acetaldehyde produced by these systems is in turn converted by acetaldehyde dehydrogenase to acetate, which is utilized in the mito- chondrial respiratory chain. Several toxic effects result from ethanol metabolism. Listed here are only the most important of these: EFFECTS OF ALCOHOL Alcohol oxidation by alcohol dehydrogenase causes a decrease in nicotinamide adenine dinucleotide (NAD+) and an Ethanol is consumed, at least partly, for its mood-altering increase in NADH (the reduced form of NAD+). NAD+ properties, but when used in moderation its effects are is required for fatty acid oxidation in the liver. Its defi- socially acceptable and not injurious. When excessive ciency is a main cause of fat accumulation in the liver of amounts are used, alcohol can cause marked physical and alcoholics. The increase in the NADH/NAD+ ratio in psychologic damage. Here we describe the lesions that are alcoholics also causes lactic acidosis. directly associated with the abuse of alcohol. Acetaldehyde has many toxic effects and may be respon- Despite all the attention given to illegal drugs, alcohol sible for some of the acute effects of alcohol. Acetalde- abuse is a more widespread hazard and claims many more hyde metabolism differs between populations because lives. Fifty percent of adults in the Western world drink of genetic variation. Most notably, about 50% of Asians alcohol, and approximately 5% to 10% have chronic alco- express a defective form of acetaldehyde dehydroge- holism. It is estimated that there are more than 10 million nase. After ingesting alcohol, such persons experience chronic alcoholics in the United States and that alcohol consump- flushing, tachycardia, and hyperventilation owing to the tion is responsible for more than 100,000 deaths annually. accumulation of acetaldehyde. Almost 50% of these deaths result from accidents caused by drunken driving and alcohol-related homicides and sui- Metabolism of ethanol in the liver by CYP2E1 produces cides, and about 25% are a consequence of cirrhosis of the reactive oxygen species and causes lipid peroxidation of cell liver. membranes. Nevertheless, the precise mechanisms that After consumption, ethanol is absorbed unaltered in the account for alcohol-induced cellular injury have not stomach and small intestine and then distributes to all of been well defined. the tissues and fluids of the body in direct proportion to Alcohol may cause the release of endotoxin (lipopoly- the blood level. Less than 10% is excreted unchanged in the saccharide), a product of gram-negative bacteria, from urine, sweat, and breath. The amount exhaled is propor- the intestinal flora. Endotoxin stimulates the release of tional to the blood level and forms the basis for the breath tumor necrosis factor (TNF) and other cytokines from test used by law enforcement agencies. A concentration of circulating macrophages and from Kupffer cells in the 80 mg/dL in the blood constitutes the legal definition of liver, causing cell injury. drunk driving in most states. For an average individual, The adverse effects of ethanol abuse can be categorized this alcohol concentration may be reached after consump- as acute or chronic. Acute alcoholism exerts its effects tion of about eight bottles of beer (6 to 16 g of alcohol per mainly on the CNS but also may induce reversible hepatic bottle), 12 ounces of wine (9 to 18 g of alcohol per glass), and gastric injuries. Even with moderate intake of alcohol,  Effects of Alcohol 281 Microsomes NADP+, H2O OH CH3CH NADPH + H+ OH + O2 CYP2E1 H2O Mitochondria Cytosol NAD+ ADH O CH3CH2OH ALDH CH3C Ethanol H NADH + H+ Acetaldehyde NAD+ NADH + H+ O CH3C OH Peroxisomes Acetic acid CATALASE H2O2 H 2O Figure 7–10 Metabolism of ethanol: oxidation of ethanol to acetaldehyde by three different routes, and the generation of acetic acid. Note that oxidation by alcohol dehydrogenase (ADH) takes place in the cytosol; the cytochrome P-450 system and its CYP2E1 isoform are located in the ER (microsomes), and catalase is located in peroxisomes. Oxidation of acetaldehyde by aldehyde dehydrogenase (ALDH) occurs in mitochondria. (Data from Parkinson A: Biotransformation of xenobiotics. In Klassen CD [ed]: Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed. New York, McGraw-Hill, 2001, p 133.) multiple fat droplets accumulate in the cytoplasm of hepa- deficiency are peripheral neuropathies and the Wernicke- tocytes (fatty change or hepatic steatosis). Gastric damage Korsakoff syndrome (see Table 7–9 and Chapter 22). occurs in the form of acute gastritis and ulceration. In the