Environmental and Nutritional Diseases PDF

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Environmental and Nutritional Diseases 9...

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Environmental and Nutritional Diseases 9 CHAPTER CONTENTS Health Effects of Climate Injury by Therapeutic Drugs and Thermal Injury 427 Change 406 Drugs of Abuse 420 Thermal Burns 427 Toxicity of Chemical and Physical Injury by Therapeutic Drugs (Adverse Hyperthermia 428 Agents 407 Drug Reactions) 420 Hypothermia 428 Environmental Pollution 408 Anticoagulants 421 Electrical Injury 428 Air Pollution 408 Menopausal Hormone Therapy 421 Injury Produced by Ionizing Radiation 428 Outdoor Air Pollution 408 Oral Contraceptives 422 Nutritional Diseases 433 Indoor Air Pollution 410 Acetaminophen 422 Dietary Insufficiency 433 Metals as Environmental Pollutants 411 Aspirin (Acetylsalicylic Acid) 423 Severe Acute Malnutrition 433 Lead 411 Injury by Nontherapeutic Agents (Drug Anorexia Nervosa and Bulimia 435 Mercury 412 Abuse) 423 Vitamin Deficiencies 436 Arsenic 413 Cocaine 423 Vitamin A 436 Cadmium 413 Opioids and Opiates 424 Vitamin D 438 Occupational Health Risks: Amphetamines and Related Drugs 425 Vitamin C (Ascorbic Acid) 442 Industrial and Agricultural Marijuana 425 Obesity 444 Exposures 414 Other Drugs 426 Clinical Consequences of Obesity 447 Effects of Tobacco 415 Injury by Physical Agents 426 Obesity and Cancer 448 Effects of Alcohol 418 Mechanical Trauma 426 Diet and Cancer 449 Diet and Systemic Diseases 450 Many diseases are caused or influenced by environmental (more deaths than are caused by road accidents and wars factors. Broadly defined, the term environment encompasses combined). In the United States in 2018, there were nearly the various indoor, outdoor, and occupational settings in 3 million occupational injuries and illnesses. Disease related which human beings live and work. In each of these settings, to malnutrition is even more pervasive. In 2019, it was the air people breathe, the food and water they consume, estimated that 795 million people were malnourished—one and the toxic agents they are exposed to are major deter- in every nine persons worldwide. Children are dispropor- minants of health. The environmental factors that influence tionately affected by undernutrition, which accounts for our health pertain to individual behavior (“personal environ- approximately 50% of childhood mortality worldwide. ment”) and include tobacco use, alcohol ingestion, recre- Estimating the burden of disease in the general population ational drug consumption, diet, and the like, or the external caused by nonoccupational exposures to toxic agents is (ambient and workplace) environment. In general, in higher complicated by the diversity of agents and difficulties in income countries personal behavior has a larger effect determining the extent and duration of exposures. But on health than the ambient environment, but new threats whatever the precise numbers, it is clear that environmental related to global warming (described later) may change this diseases are major causes of disability and suffering and equation. constitute a heavy financial burden, particularly in low The term environmental disease refers to conditions income countries. caused by exposure to chemical or physical agents in the In this chapter, we first consider the emerging problem ambient, workplace, and personal environment, including of the health effects of climate change. We then discuss the diseases of nutritional origin. The International Labour mechanisms of toxicity of chemical and physical agents and Organization estimates that work-related injuries and ill- address specific environmental disorders, including those nesses kill approximately 2.3 million people per year globally of nutritional origin. 405 406 CHAPTER 9 Environmental and Nutritional Diseases 1958–2018 Correlation Coefficient: 0.92269 HEALTH EFFECTS OF 420 CLIMATE CHANGE 400 Mauna Loa CO2 Level (ppm) Without immediate action, climate change stands to become the preeminent global cause of environmental disease in 380 the 21st century and beyond. Global temperature measure- ments show that the earth has warmed significantly since 360 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 340 since 1880. During 2018, the global land temperature was 1.1°C warmer than the 20th century average. Mean global 320 ocean temperatures also continue to warm, with the annual average temperature in 2018 being 0.66°C warmer than the 300 20th century average. –0.4 –0.2 0 0.2 0.4 0.6 0.8 The rising atmospheric and oceanic temperatures have A Global Temperature Anomaly (°C) led to a large number of effects that include changes in storm frequency, drought, and flood, as well as large-scale 5 ice losses in Greenland, Antarctica, and the vast majority of the other glaciated regions on earth, as well as dramatic 4 Temperature thinning or disappearance of Arctic Ocean sea ice. The anomaly melting of land-based glacial ice and the thermal expan- 3 (° C) sion of the warming oceans has produced approximately 2 13–20 cm of global average sea level rise since 1900, and the sea level currently is rising at a global average rate of 1 3.5 ± 0.4 mm/year. Although politicians quibble, among scientists there is 0 a general acceptance that climate change is in large part man-made. The culprit is the rising atmospheric level of –1 greenhouse gases, particularly carbon dioxide (CO2) released through the burning of fossil fuels (Fig. 9.1A), ozone (an 1900 1950 2000 2050 2100 important air pollutant, discussed later), and methane. B Year These gases, along with water vapor, produce the so-called Figure 9.1 Climate change, past and future. (A) Correlation of carbon greenhouse effect by absorbing energy radiated from Earth’s dioxide (CO2) levels measured at the Mauna Loa Observatory in Hawaii surface that otherwise would be lost into space. The annual with average global temperature trends over the past 60 years. Global average level of atmospheric CO2 (about 410 ppm) in 2019 temperature in any given year was deduced at the Hadley Center (United was higher than at any point in approximately 650,000 years Kingdom) from measurements taken at more than 3000 weather stations and, without changes in human behavior, is expected to located around the globe. (B) Predicted temperature increases during the increase to 500 to 1200 ppm by the end of this century—levels 21st century. Different computer models plot anticipated rises in global temperatures of 2°C to 5°C by the year 2100. (A, Courtesy Dr. Richard not experienced for tens of millions of years. This increase Aster, Department of Geophysics, Colorado State University, Fort Collins, stems not only from increased CO2 production but also Colo.) from deforestation and the attendant decrease in carbon fixation by plants. Depending on the computer model used, increased levels of greenhouse gases are projected to cause the global temperature to rise by 2°C to 5°C by the year 2100 Gastroenteritis, cholera, and other foodborne and water- (Fig. 9.1B). borne infectious diseases, caused by contamination as a The health consequences of climate change will depend consequence of floods and disruption of clean water on its extent and rapidity, the severity of the ensuing conse- supplies and sewage treatment after heavy rains and quences, and humankind’s ability to mitigate the damaging other environmental disasters. effects. The World Health Organization (WHO) estimates Vector-borne infectious diseases such as malaria and dengue that approximately 250,000 deaths would occur annually fever resulting from changes in vector number and between 2030 and 2050 as a consequence of climate change. geographic distribution related to increased temperatures, This number does not include morbidity and disruption of crop failures, and more extreme weather variation (e.g., health services from extreme changes in weather. Even in more frequent and severe El Niño events). the best-case scenario, however, climate change is expected Malnutrition, caused by changes in local climate that to have a serious negative impact on human health by disrupt crop production. Such changes are anticipated increasing the incidence of a number of diseases including to be most severe in tropical locations, in which average the following: temperatures may already be near or above crop tolerance Cardiovascular, cerebrovascular, and respiratory diseases, all levels; it is estimated that by 2080, agricultural productiv- of which will be exacerbated by heat waves and air ity may decline by 10% to 25% in some low income pollution. countries as a consequence of climate change.  Toxicity of chemical and physical agents 407 Beyond these disease-specific effects, it is estimated that the body through inhalation, ingestion, and skin contact the melting of glacial ice, particularly in Greenland and (Fig. 9.2). other parts of the Northern Hemisphere, combined with Chemicals may be excreted in urine or feces; eliminated the thermal expansion of warming oceans will raise sea in expired air; or accumulate in bone, fat, brain, or other levels by 2 to 6 feet by 2100. Approximately 10% of the tissues. world’s population—roughly 600 million people—live in Chemicals may act at the site of entry or at other sites low-lying areas that are at risk for flooding even if the rise following transport through the blood. in ocean levels is at the low end of these estimates. For Most solvents and drugs are lipophilic, which facilitates their example, a rise in sea level by 1.5 feet will submerge 70% transport in the blood by lipoproteins and their penetra- of the land mass of the Maldive islands, while a 3-foot rise tion through the plasma membrane into cells. will inundate 100% of all of the islands, changes in sea level Most solvents, drugs, and xenobiotics are metabolized that are projected to occur by 2100. The resulting displace- to form inactive water-soluble products (detoxification) ment of people will disrupt lives and commerce, creating or are activated to form toxic metabolites. The reactions conditions ripe for political unrest, war, and poverty—the “vectors” of malnutrition, sickness, and death. Worldwide recognition of the potentially catastrophic effects of climate change led in late 2015 to a historic meeting of 196 countries in Paris, France, at which the participating countries agreed to the following objective: To hold the increase in the global average temperature to well below 2°C above preindustrial levels and to pursue efforts to limit the temperature increase to 1.5°C above preindustrial levels, recognizing that this would significantly reduce the risks and impacts of climate change. However, in 2017 the United States decided to withdraw from this agreement as of 2020, Air Water Soil leading to uncertainty about the world’s ability to meet the goals established in the Paris accord. HUMAN EXPOSURE TOXICITY OF CHEMICAL AND PHYSICAL AGENTS Skin Lung GI tract Toxicology is defined as the science of poisons. It studies the 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. 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 (e.g., the maximum level of carbon monoxide [CO] in air that is noninjurious or the tolerable levels of radiation that are “safe”). Factors such as the Absorption into complex interaction between various pollutants and the age, bloodstream genetic predisposition, and different tissue sensitivities of exposed persons create wide variations in individual sensitiv- ity 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 Toxicity Distribution to tissues Storage effects of toxic chemicals and drugs. The definition of a poison is not straightforward. It is basi- cally a quantitative concept that depends on dosage. The METABOLISM Excretion quote from Paracelsus in the 16th century that “all substances are poisons; the right dosage differentiates a Figure 9.2 Human exposure to pollutants. Pollutants in the air, water, and poison from a remedy” is still valid today, given the soil are absorbed through the lungs, gastrointestinal (GI) tract, and skin. In the body they may act at the site of absorption, but are generally number of pharmaceutical drugs with potentially harmful transported through the bloodstream to various organs where they may effects. be stored or metabolized. Xenobiotics may be metabolized to water- Xenobiotics are exogenous chemicals in the environment soluble compounds that are excreted or to toxic metabolites, a process in air, water, food, and soil that may be absorbed into referred to as activation. 408 CHAPTER 9 Environmental and Nutritional Diseases Xenobiotic Xenobiotic Phase I reactions: Hydrolysis Reduction Nontoxic metabolite Oxidation Primary metabolite Reactive metabolite Phase II reactions: Glucuronidation Sulfation Methylation Effects on cellular molecules Conjugation (enzymes, receptors, membranes, DNA) Secondary metabolite Molecular and cellular repair Elimination in urine, Toxicity bile, or feces (short- and long-term effects) A B Figure 9.3 Xenobiotic metabolism. (A) Xenobiotics can be metabolized to nontoxic metabolites and eliminated from the body (detoxification). (B) Xenobiotic metabolism may also result in the formation of a reactive metabolite that is toxic to cellular components. If repair is not effective, short-term and long-term effects develop. (Based on Hodgson E: A textbook of modern toxicology, ed 3, Hoboken, NJ, 2004, Wiley.) that metabolize xenobiotics into nontoxic products or chemicals, drugs, smoking, alcohol, and hormones. In that activate xenobiotics to generate toxic compounds contrast, fasting or starvation can decrease CYP activity. (Figs. 9.2 and 9.3) occur in two phases. In phase I reactions, Inducers of CYP act by binding to specific nuclear receptors, chemicals undergo hydrolysis, oxidation, or reduction. which then heterodimerize with the retinoic X receptor (RXR) Products of phase I reactions are often metabolized into to form a transcriptional activation complex that associates water-soluble compounds through phase II reactions, with promoter elements located in the 5′-flanking region which include glucuronidation, sulfation, methylation, of CYP genes. Nuclear receptors participating in CYP induc- and conjugation with glutathione (GSH). Water-soluble tion include the aryl hydrocarbon receptor, the peroxisome compounds are readily excreted. proliferator-activated receptors (PPARs), and two orphan The most important catalyst of phase I reactions is the nuclear receptors, constitutive androstane receptor (CAR) cytochrome P-450 enzyme system. Cytochrome P-450 and pregnane X receptor (PXR). enzymes (CYPs) are a large family of heme-containing This brief overview of the general mechanisms of toxicity enzymes, each with preferred substrate specificities. provides the background for the discussion of environmental These enzymes are primarily expressed in hepatocytes, diseases presented in this chapter. in which they localize to the endoplasmic reticulum, but can also be found in skin, lungs, gastrointestinal mucosa, and other organs. The P-450 system catalyzes reactions ENVIRONMENTAL POLLUTION that either detoxify xenobiotics or, less commonly, convert xenobiotics into active compounds that cause Air Pollution cellular injury. Both types of reactions may produce, as a by-product, reactive oxygen species (ROS), which can Air pollution is a significant cause of morbidity and cause cellular damage (Chapter 2). Examples of metabolic mortality worldwide, particularly among at-risk individuals activation of chemicals through CYPs are the production with preexisting pulmonary or cardiac disease. Air is of the toxic trichloromethyl free radical from carbon precious to life, but can also carry many potential causes tetrachloride in the liver and the generation of a DNA- of disease. Airborne microorganisms have long been major binding metabolite from benzo[a]pyrene, a carcinogen causes of morbidity and mortality, especially in low income present in cigarette smoke, in the lung. CYPs participate countries. More widespread are airborne chemical and in the metabolism of alcohol (discussed later) and a large particulate pollutants, especially in high income nations. number of common therapeutic drugs, such as acetamino- Here we consider these hazards in outdoor and indoor air. phen, barbiturates, warfarin, and anticonvulsants. Outdoor Air Pollution There is great variation in the activity of CYPs among The ambient air in industrialized nations is contaminated individuals. The variation may be a consequence of genetic with an unsavory mixture of gaseous and particulate pol- polymorphisms in specific CYPs, but more commonly it is lutants, more heavily in cities and in proximity to heavy due to exposure to drugs or chemicals that induce or diminish industry. In the United States, the Environmental Protection CYP activity. Known CYP inducers include environmental Agency monitors and sets allowable upper limits for six  Environmental pollution 409 pollutants: sulfur dioxide, CO, ozone, nitrogen dioxide, lead, accumulates in the so-called ozone layer 10 to 30 miles above and particulate matter. Collectively, these agents produce the earth’s surface. This layer protects life on earth by the well-known smog (smoke and fog) that sometimes stifles absorbing the most dangerous UV radiation emitted by the large cities such as Beijing, Los Angeles, Houston, Cairo, sun. In 1985, it was discovered that ozone was nearly New Delhi, Mexico City, and São Paulo. It may seem that completely depleted over Antarctica and was thinned air pollution is a modern phenomenon, but this is hardly elsewhere, a dire effect stemming from the widespread use the case. John Evelyn wrote in 1661 that inhabitants of of chlorofluorocarbon gases in air conditioners and refrigera- London suffered from “Catharrs, Phthisicks and Consump- tors and as aerosol propellants. When released into the tions” (bronchitis, pneumonia, and tuberculosis) and breathed atmosphere, these gases drift up into the stratosphere and “nothing but an impure and thick mist, accompanied by a participate in chemical reactions that destroy ozone. Due fuliginous and filthy vapour, which renders them obnoxious to prevailing stratospheric air currents, the resulting depletion to a thousand inconveniences, corrupting the lungs, and is most profound in polar regions, particularly over Ant- disordering the entire habit of their bodies.” The first arctica during the winter months. Recognition of the problem environmental control law, proclaimed by Edward I in 1306, led in 1987 to the Montreal Protocol, international agreements was straightforward in its simplicity: “whoever should be that call for a complete phase-out of chlorofluorocarbon use found guilty of burning coal shall suffer the loss of his by 2020 in higher income countries and by 2040 in lower head.” What has changed in modern times is the nature income countries. Decreased use of chlorofluorocarbons over and sources of air pollutants and the types of regulations the past 30 years has reduced the size of the yearly ozone that control their emission. “hole” over Antarctica, indicating that this global environ- Although the lungs bear the brunt of the adverse con- mental challenge is being met successfully. sequences, air pollutants can affect many organ systems. In contrast to the “good” ozone in the stratosphere, ozone Except for some comments on smoking, pollutant-caused that accumulates in the lower atmosphere (ground-level lung diseases are discussed in Chapter 15. Major health effects ozone) is one of the most pernicious air pollutants. Ground- of outdoor pollutants are summarized in Table 9.1. Ozone, level ozone is a gas formed by the reaction of nitrogen sulfur dioxide, particulates, and CO are discussed here. oxides and volatile organic compounds in the presence of Ozone (O3) is produced by interaction of ultraviolet (UV) sunlight. These chemicals are released by industrial emissions radiation and oxygen (O2) in the stratosphere and naturally and motor vehicle exhaust. Ozone toxicity is in large part mediated by the production of free radicals, which injure epithelial cells along the respiratory tract and type I alveolar Table 9.1 Health Effects of Outdoor Air Pollutants cells and cause the release of inflammatory mediators. Populations at Healthy individuals exposed to ozone experience upper Pollutant Risk Effects respiratory tract inflammation and mild symptoms (decreased Ozone Healthy adults and Decreased lung function lung function and chest discomfort), but exposure is much children Increased airway more dangerous for people with asthma or emphysema. reactivity To make matters worse, ozone often combines with other Lung inflammation agents such as sulfur dioxide and particulates to create a Athletes, outdoor Decreased exercise veritable “witches’ brew” of pollutants. Sulfur dioxide is workers capacity produced by power plants burning coal and oil, from copper Asthmatics Increased hospitalizations smelting, and as a by-product of paper mills. Released into Nitrogen Healthy adults Increased airway the air, it may be converted into sulfuric acid and sulfuric dioxide reactivity trioxide, which cause a burning sensation in the nose and Asthmatics Decreased lung function Children Increased respiratory throat, difficulty in breathing, and asthma attacks in sus- infections ceptible individuals. Sulfur Healthy adults Increased respiratory Particulate matter (known as “soot”) is a particularly dioxide symptoms important cause of morbidity and mortality related to Individuals with chronic Increased mortality pulmonary inflammation and secondary cardiovascular lung disease effects. Based on studies of large cities in the United States, Asthmatics Increased hospitalization it is estimated that there is a 0.5% increase in overall daily Decreased lung function mortality for every 10 mg/m3 increase in 10-µm particles Acid Healthy adults Altered mucociliary in outdoor air, mainly due to exacerbations of pulmonary aerosols clearance and cardiac disease. Particulates are emitted by coal- and Children Increased respiratory oil-fired power plants, by industrial processes burning these infections Asthmatics Decreased lung function fuels, and by diesel exhaust. Although the particles have Increased hospitalizations not been well characterized chemically or physically, fine or ultrafine particles less than 10 µm in diameter are the Particulates Children Increased respiratory infections most harmful. They are readily inhaled into the alveoli, Individuals with chronic Decreased lung function where they are phagocytosed by macrophages and neutro- lung or heart disease phils, which respond by releasing a number of inflammatory Asthmatics Excess mortality mediators. In contrast, particles that are greater than 10 µm Increased attacks in diameter are of lesser consequence because they are From Bascom R, et al: Health effects of outdoor air pollution, Am J Respir Crit generally removed in the nose or trapped by the mucociliary Care Med 153:477, 1996. epithelium of the airways. 410 CHAPTER 9 Environmental and Nutritional Diseases CO is a systemic asphyxiant that is an important cause polycyclic aromatic hydrocarbons generated by cooking oils of accidental and suicidal death. CO is a nonirritating, and coal burning are important indoor pollutants in lower colorless, tasteless, odorless gas that is produced during income parts of the world, particularly parts of Asia. Only any process that results in the incomplete oxidation of a few comments about other agents are made here. hydrocarbons. From the standpoint of human health, the Smoke from burning of organic materials, containing various most important environmental source of CO is the burning oxides of nitrogen and carbon particulates, is an irritant of carbonaceous materials, as occurs in automotive engines, that predisposes exposed persons to lung infections and furnaces, and cigarettes. CO is short-lived in the atmosphere, may contain carcinogenic polycyclic hydrocarbons. It is being rapidly oxidized to CO2; thus elevated levels in ambient estimated that one-third of the world’s people burn air are transient and occur only in close proximity to sources carbon-containing material such as wood, dung, or of CO. Chronic poisoning may occur in individuals working charcoal in their homes for cooking, heating, and light. in environments such as tunnels, underground garages, and Bioaerosols range from microbiologic agents capable of highway toll booths with high exposures to automobile causing infectious diseases such as legionnaires’ disease, fumes. Of greater concern is acute toxicity. In a small, closed viral pneumonia, and the common cold to less threatening garage, the average running car can produce sufficient CO but nonetheless distressing allergens derived from pet to induce coma or death within 5 minutes, and CO concentra- dander, dust mites, fungi, and molds that are variously tions can also rapidly rise to toxic levels with improper use responsible for rhinitis, eye irritation, and asthma. of gasoline-powered generators (e.g., during power outages) Radon, a radioactive gas derived from uranium widely or following mine fires. CO kills in part by inducing central present in soil and in homes, can cause lung cancer in nervous system (CNS) depression, which appears so insidi- uranium miners. It is also suspected that low-level chronic ously that victims are often unaware of their plight. exposures in the home increase lung cancer risk, particu- Hemoglobin has 200-fold greater affinity for CO than for larly in those who smoke tobacco. Radon is the number oxygen, and the resultant carboxyhemoglobin cannot carry one cause of lung cancer among nonsmokers, according O2. Systemic hypoxia develops when the hemoglobin is 20% to EPA estimates. Overall, radon is the second leading to 30% saturated with CO; unconsciousness and death are cause of lung cancer. Radon is responsible for about 21,000 likely with 60% to 70% saturation. lung cancer deaths every year. About 2,900 of these deaths occur among people who have never smoked. Formaldehyde is used in the manufacture of building MORPHOLOGY materials (e.g., cabinetry, furniture, adhesives) and may accumulate in the air in poorly ventilated housing. At Chronic poisoning by CO develops because carboxyhemoglobin, concentrations of 0.1 ppm or higher, it causes breathing once formed, is remarkably stable. Even with low-level, but difficulties and a burning sensation in the eyes and throat persistent, exposure to CO, carboxyhemoglobin may rise to and can trigger asthma attacks. Formaldehyde is classified life-threatening levels in the blood. The slowly developing hypoxia as a carcinogen for humans and animals. can insidiously evoke widespread ischemic changes in the CNS; The so-called sick building syndrome remains an elusive these are particularly marked in the basal ganglia and lenticular problem; it may be a consequence of exposure to one or nuclei. With cessation of exposure to CO, the patient usually more indoor pollutants, possibly due to poor ventilation. recovers, but there may be permanent neurologic sequelae, such as impairment of memory, vision, hearing, and speech.The diagnosis is made by measuring carboxyhemoglobin levels in the blood. KEY CONCEPTS Acute poisoning by CO is generally a consequence of ENVIRONMENTAL DISEASES AND accidental exposure or suicide attempt. In light-skinned individuals, ENVIRONMENTAL POLLUTION acute poisoning is marked by a characteristic generalized cherry-red color of the skin and mucous membranes, which Environmental diseases are conditions caused by exposure to results from high levels of carboxyhemoglobin. This effect of CO chemical or physical agents in the ambient, workplace, and on coloration may result in a failure to recognize the oxygen-starved personal environments. state of the victim (and is used by the meat industry in the United Exogenous chemicals known as xenobiotics enter the body States to keep meat appearing fresh—caveat emptor!). If death through inhalation, ingestion, and skin contact and can either occurs rapidly, morphologic changes may not be present; with be eliminated or accumulate in fat, bone, brain, and other tissues. longer survival, the brain may be slightly edematous, with punctate Xenobiotics can be converted into nontoxic products or hemorrhages and hypoxia-induced neuronal changes. The mor- activated to generate toxic compounds through a two-phase phologic changes are not specific and stem from systemic hypoxia. reaction process that involves the cytochrome P-450 system. The most common and important air pollutants are ozone (which in combination with oxides and particulate matter forms Indoor Air Pollution smog), sulfur dioxide, acid aerosols, and particles less than 10 µm in diameter. As we increasingly “button up” our homes to exclude the CO poisoning is an important cause of death from accidents environment, the potential for pollution of the indoor air and suicide; it binds hemoglobin with high affinity, leading to increases. The most common pollutant is tobacco smoke systemic asphyxiation associated with CNS depression. (discussed later), but additional offenders are CO, nitrogen A variety of pollutants including smoke, bioaerosols, radon, and dioxide (both already mentioned as outdoor pollutants), formaldehyde may accumulate in indoor air and cause disease. and asbestos (Chapter 15). Volatile substances containing  Environmental pollution 411 Metals as Environmental Pollutants Lead, mercury, arsenic, and cadmium are the heavy metals µg/mL most commonly associated with harmful effects in humans. 150 Death 2 + Lead Pb Lead is a readily absorbed metal that binds to sulfhydryl 100 Encephalopathy Pb 2+ Nephropathy groups in proteins and interferes with calcium metabolism, Frank anemia effects that lead to hematologic, skeletal, neurologic, Pb2+ Colic gastrointestinal, and renal toxicities. Lead exposure may occur through contaminated air, food, and water. For most 50 of the 20th century the major sources of lead in the environ- 2+ Pb ment were lead-containing house paints and gasoline. 40 Decreased hemoglobin synthesis Although limits have been set for the amounts of lead Pb 2 contained in residential paints and use of leaded gasoline + in road vehicles was banned in the United States in 1996, 30 lead contamination remains an important health hazard, particularly for children. There are many sources of lead 20 Decreased nerve conduction velocity in the environment such as from mining, foundries, batteries, Pb 2+ Increased level of erythrocyte protoporphyrin and spray painting that constitute occupational hazards. Altered vitamin D metabolism However, flaking lead paint in older houses and soil con- Altered calcium homeostasis tamination pose major hazards to youngsters. Blood levels 10 Developmental toxicity of lead in children living in older homes containing lead- Pb 2+ Decreased IQ level Decreased hearing based paint or lead-contaminated dust often exceed 5 µg/ Decreased growth dL, the level at which the Centers for Disease Control and 0 Impaired peripheral nerve function Prevention (CDC) recommends that measures be taken to Fetal effects by transplacental transfer limit further exposure. A dramatic case of lead contamination of drinking water occurred in Flint, Michigan, in 2014–2016. Figure 9.4 Effects of lead poisoning in children related to blood levels. The Flint water crisis occurred when the source of water (Modified from Bellinger DC, Bellinger AM: Childhood lead poisoning: the supply to the city was changed from Lake Huron to the tortuous path from science to policy, J Clin Invest 116:853; 2006.) Flint River. Because water from the Flint River had a higher chloride concentration than the lake waters, it leached lead from century-old lead pipes. This caused an increase in lead levels in tap water above the acceptable limit of 15 parts Lead also affects many other tissues. Excess lead inter- per billion (ppb) in about 25% of the homes and in some feres with the normal remodeling of calcified cartilage cases as high as 13,200 ppb. As a result, 6000 to 12,000 resi- and primary bone trabeculae in the epiphyses in children, dents developed very high lead levels in their blood. Ingested causing increased bone density detected as radiodense lead is particularly harmful to children because they absorb lead lines (Fig. 9.6). Lead lines of a different sort also more than 50% of lead from food, whereas adults absorb may occur in the gums, where excess lead stimulates approximately 15%. A more permeable blood–brain barrier hyperpigmentation. Lead inhibits the healing of fractures in children creates a high susceptibility to brain damage. by increasing chondrogenesis and delaying cartilage The main clinical features of lead poisoning in children and mineralization. Excretion of lead occurs by way of the adults are shown in Figs. 9.4 and 9.5. kidneys, and acute exposures may cause damage to proximal Most absorbed lead (80% to 85%) is taken up into develop- tubules. ing teeth and into bone, where it competes with calcium, Lead has a high affinity for sulfhydryl groups and binds phosphates, and has a half-life of 20 to 30 years. About interferes with two enzymes involved in heme synthesis: 5% to 10% of the absorbed lead remains in the blood, and delta-aminolevulinic acid dehydratase and ferrochelatase. the remainder is distributed throughout soft tissues. Excess Iron incorporation into heme is impaired, leading to micro- lead is toxic to nervous tissues in adults and children; cytosis (small red cells) and anemia. Lead also inhibits peripheral neuropathies predominate in adults, whereas sodium- and potassium-dependent adenosine triphosphatases central effects are more common in children. The effects of (ATPases) in cell membranes, an effect that may increase chronic lead exposure in children may be subtle, producing the fragility of red cells, causing hemolysis. The diagnosis mild dysfunction, including reduced IQ, learning disabilities, of lead poisoning requires constant vigilance. It may be and delayed psychomotor development. At higher doses, suspected on the basis of neurologic changes in children or however, the results can be devastating, taking the form of unexplained microcytic anemia with basophilic stippling blindness, psychoses, seizures, coma, and even death. Lead- in red cells in adults and children. Elevated blood lead and induced peripheral neuropathies in adults generally remit red cell free protoporphyrin levels (greater than 50 µg/dL) with the elimination of exposure, but both peripheral nervous or, alternatively, zinc protoporphyrin levels, are required system and CNS abnormalities in children usually are for definitive diagnosis. In milder cases of lead exposure, irreversible. anemia may be the only abnormality. 412 CHAPTER 9 Environmental and Nutritional Diseases BRAIN described. Lead toxicity in a pregnant woman may impair brain Adult: Headache, memory loss Child: Encephalopathy, mental development in the fetus. The anatomic changes underlying the deterioration subtle functional deficits are ill-defined, but there is concern that these defects may be permanent. At the more severe end of GINGIVA Lead line the spectrum there is marked brain edema, demyelination of the cerebral and cerebellar white matter, and necrosis of cortical neurons BLOOD accompanied by diffuse astrocytic proliferation. In adults the CNS Anemia, red cell basophilic is less often affected, but frequently a peripheral demyelinating stippling neuropathy appears, typically involving the motor nerves of the PERIPHERAL NERVES most commonly used muscles. Thus the extensor muscles of the Adult: Demyelination wrist and fingers are often the first to be affected (causing wristdrop), followed by paralysis of the peroneal muscles (causing footdrop). KIDNEY The gastrointestinal tract is also a major source of clinical Chronic tubulointerstitial disease manifestations. Lead colic is characterized by severe, poorly localized abdominal pain. GASTROINTESTINAL TRACT Kidneys may develop proximal tubular damage associated Abdominal pain with intranuclear inclusions consisting of protein aggregates. Chronic renal damage leads eventually to interstitial fibrosis and renal failure. Decreases in uric acid excretion can lead to gout (saturnine gout). Mercury BONES Like lead, mercury binds to sulfhydryl groups in certain Child: Radiodense deposits proteins with high affinity, leading to damage in the CNS and in epiphyses the kidney. Mercury has had many uses throughout history, for example, as a pigment in cave paintings, a cosmetic, a remedy for syphilis, and a component of diuretics. Alchemists tried (without much success) to produce gold from mercury. SOURCES OCCUPATIONAL NONOCCUPATIONAL Spray painting Water supply Foundry work Paint dust and flakes Mining and extracting lead Automotive exhaust Battery manufacturing Urban soil Figure 9.5 Pathologic features of lead poisoning in adults. MORPHOLOGY The major anatomic targets of lead toxicity are the bone marrow and blood, nervous system, gastrointestinal tract, and kidneys (see Fig. 9.5). Blood and marrow changes occur fairly rapidly and are characteristic. The inhibition of ferrochelatase by lead may result in the appearance of a few ring sideroblasts, red cell precursors with iron-laden mitochondria that are detected with a Prussian blue stain. In the peripheral blood the defect in hemoglobin synthesis appears as a microcytic, hypochromic anemia that is often accompanied by mild hemolysis. Even more distinctive Figure 9.6 Lead poisoning. Impaired remodeling of calcified cartilage in is a punctate basophilic stippling of the red cells. the epiphyses (arrows) of the wrist has caused a marked increase in their Brain damage is prone to occur in children. In young radiodensity so that they are as radiopaque as the cortical bone. children, sensory, motor, intellectual, and psychologic have been (Courtesy Dr. G. W. Dietz, Department of Radiology, University of Texas Southwestern Medical School, Dallas, Tex.)  Environmental pollution 413 Poisoning from inhalation of mercury vapors has long been preservers and herbicides and other agricultural products. recognized and is associated with tremor, gingivitis, and It may be released into the environment from mines and bizarre behavior, such as that displayed by the Mad Hatter smelting industries. Arsenic is present in Chinese and Indian in Alice in Wonderland. There are three forms of mercury: herbal medicine, and high concentrations of inorganic arsenic metallic mercury (also referred to as elemental mercury), are present in groundwater in countries such as Bangladesh, inorganic mercury compounds (mostly mercuric chloride), Chile, and China. It is estimated that 40 million people and organic mercury (mostly methyl mercury). Today, the in Bangladesh drink water contaminated with arsenic, main sources of exposure to mercury are contaminated constituting one of the greatest environmental cancer risks fish (methyl mercury) and mercury vapors released from yet uncovered. metallic mercury in dental amalgams, a possible occupational The most toxic forms of arsenic are the trivalent com- hazard for dental workers. In some areas of the world, pounds arsenic trioxide, sodium arsenite, and arsenic tri- mercury used in gold mining has contaminated rivers and chloride. If ingested in large quantities, arsenic causes acute streams. gastrointestinal, cardiovascular, and CNS toxicities that are Inorganic mercury from the natural degassing of the often fatal. These effects may be attributed in part to interfer- earth’s crust or from industrial contamination is converted ence with mitochondrial oxidative phosphorylation, since to organic compounds such as methyl mercury by bacteria. trivalent arsenic can replace the phosphates in ATP. However, Methyl mercury enters the food chain, and in carnivorous arsenic also has pleiotropic effects on the activity of a number fish such as swordfish, shark, and bluefish, mercury levels of other enzymes and ion channels, and these too may may be 1 million times higher than in the surrounding water. contribute to certain toxicities. Almost 90% of ingested methyl mercury is absorbed in the Neurologic effects usually occur 2 to 8 weeks after exposure gastrointestinal tract. The consumption of fish contaminated and consist of a sensorimotor neuropathy that causes by the release of methyl mercury from industrial sources paresthesias, numbness, and pain. in Minamata Bay and the Agano River in Japan caused Cardiovascular effects include hypertension and prolonged widespread mortality and morbidity. Acute exposure Q-Tc interval with ventricular arrhythmias. through consumption of bread made from grain treated Skin changes consisting of hyperpigmentation and hyper- with a methyl mercury–based fungicide in Iraq in 1971 keratosis occur with chronic exposure. resulted in hundreds of deaths and thousands of hospitaliza- Increased risk for the development of cancers is the most tions. The medical disorders associated with the Minamata serious consequence of chronic exposure, particularly of episode became known as Minamata disease and include the lung, bladder, and skin. Arsenic-induced skin tumors cerebral palsy, deafness, blindness, intellectual disability, differ from those induced by sunlight; they are often and major CNS defects in children exposed in utero. The multiple and usually appear on the palms and soles. The lipid solubility of methyl mercury and metallic mercury mechanisms of arsenic carcinogenesis in skin and lung facilitates their accumulation in the brain, disturbing neu- have not been elucidated but may involve defects in romotor, cognitive, and behavioral functions. Intracellular nucleotide excision repair mechanisms that protect against GSH, by acting as a sulfhydryl donor, is the main protec- DNA damage. tive mechanism against mercury-induced CNS and kidney damage. Cadmium Mercury continues to be released into the environment Cadmium is preferentially toxic to the kidneys and the by power plants and other industrial sources, and there are lungs through uncertain mechanisms that may involve serious concerns about the effects of chronic low-level exposure increased production of ROS. In contrast to the other metals to methyl mercury in the food supply. To protect against discussed in this section, cadmium toxicity is a relatively potential fetal brain damage, the CDC has recommended modern problem. It is an occupational and environmental that pregnant women avoid consumption of fish known pollutant generated by mining, electroplating, and production to contain high levels of mercury. Ingested mercury can of nickel-cadmium batteries, which are usually disposed of injure the gut and cause ulcerations and bloody diarrhea. as household waste. Cadmium can contaminate the soil In the kidneys, mercury can cause acute tubular necrosis and plants directly or through fertilizers and irrigation water. and renal failure. Chronic exposure can cause nephrotic Food is the most important source of cadmium exposure syndrome. for the general population. Its toxic effects require its uptake into cells via transporters such as ZIP8, which normally Arsenic serves as a transporter for zinc. Arsenic salts interfere with several aspects of cellular The principal toxic effects of excess cadmium are a metabolism, leading to toxicities that are most prominent form of obstructive lung disease caused by necrosis of in the gastrointestinal tract, nervous system, skin, and alveolar epithelial cells and renal tubular damage that may heart. Arsenic was the poison of choice in Renaissance Italy, progress to end-stage renal disease. Cadmium exposure with members of the Borgia and Medici families being highly can also cause skeletal abnormalities associated with skilled practitioners of the art of its use. Because of its favored calcium loss. Cadmium-containing water used to irrigate use as an instrument of assassination among royal families, rice fields in Japan caused a disease in postmenopausal arsenic has been called “the poison of kings and the king women known as itai-itai (“ouch-ouch”), a combination of of poisons.” Deliberate poisoning is rare today, but unin- osteoporosis and osteomalacia associated with renal disease. tentional exposure to arsenic is an important health problem Cadmium exposure is also associated with an elevated risk in many areas of the world. Arsenic is found naturally in of lung cancer, which has been demonstrated in workers soils and water and is used in products such as wood exposed occupationally and in populations living near zinc 414 CHAPTER 9 Environmental and Nutritional Diseases smelters. Cadmium is not directly genotoxic and most likely produces DNA damage through the generation of ROS OCCUPATIONAL HEALTH RISKS: (Chapter 2). INDUSTRIAL AND AGRICULTURAL EXPOSURES KEY CONCEPTS More than 10 million occupational injuries occur annually TOXIC EFFECTS OF HEAVY METALS in the United States, and approximately 65,000 people die as a consequence of occupational injuries and illnesses. Lead, mercury, arsenic, and cadmium are the heavy metals most About 10% of these deaths occur due to falls and other commonly associated with toxic effects in humans. traumatic injuries, while the remainder are secondary to Children absorb more ingested lead than adults; the main source toxic exposures that lead to cancer, lung disease, and other of exposure for children is lead-containing paint in older housing potentially fatal conditions. Industrial exposures to toxic and lead-containing drinking water. agents are as varied as the industries themselves. They range Excess lead causes CNS defects in children and peripheral neu- from merely annoying irritations of respiratory airways by ropathy in adults. It also interferes with the remodeling of cartilage formaldehyde or ammonia fumes to lung cancers arising and causes anemia by interfering with hemoglobin synthesis. from exposure to asbestos, arsenic, or uranium. Human The major source of exposure to mercury is contaminated diseases associated with occupational exposures are listed fish. The developing brain is highly sensitive to methyl mercury, in Table 9.2. In addition to toxic metals (already discussed), which accumulates in the CNS. other important agents that contribute to environmental Exposure of the fetus to high levels of mercury in utero may diseases include the following: lead to Minamata disease, characterized by cerebral palsy, Organic solvents are widely used in huge quantities world- deafness, and blindness. wide. Some, such as chloroform and carbon tetrachloride, are Arsenic is naturally found in soil and water and is a component found in degreasing and dry cleaning agents and paint of some wood preservatives and herbicides. Excess arsenic removers. Acute exposure to high levels of these agents interferes with mitochondrial oxidative phosphorylation and can cause dizziness and confusion, CNS depression, and the function of a variety of proteins. It causes toxic effects in even coma. Lower levels may cause liver and kidney toxic- the gastrointestinal tract, CNS, and cardiovascular system; ity. Occupational exposure to benzene and 1,3-butadiene long-term exposure causes skin lesions and carcinomas. increases the risk of leukemia. Benzene is oxidized to an Cadmium from nickel-cadmium batteries and chemical fertilizers epoxide through hepatic CYP2E1, a component of the can contaminate soil. Excess cadmium causes obstructive lung P-450 enzyme system already mentioned. The epoxide and disease and kidney damage. other metabolites disrupt progenitor cell differentiation Table 9.2 Human Diseases Associated With Occupational Exposures Organ/System Effect Toxicant 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, uranium Chronic obstructive pulmonary 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 CNS depression Alcohols, ketones, aldehydes, solvents Cataracts Ultraviolet radiation Urinary system Renal toxicity Mercury, lead, glycol ethers, solvents Bladder cancer Naphthylamines, 4-aminobiphenyl, benzidine, rubber products Reproductive system Male infertility Lead, phthalate plasticizers, cadmium Female infertility Lead, mercury Stillbirths Lead, mercury Teratogenesis Mercury, polychlorinated biphenyls Hematopoietic system Leukemia Benzene Skin Folliculitis and acneiform dermatosis Polychlorinated biphenyls, dioxins, herbicides Cancer Ultraviolet radiation Gastrointestinal tract Liver angiosarcoma Vinyl chloride CNS, Central nervous system; DDT, dichlorodiphenyltrichloroethane. Data from Leigh JP, 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, editor: Environmental and Occupational Medicine, ed 2, Boston, 1992, Little, Brown, p 1275; and Levi PE: Classes of toxic chemicals. In Hodgson E, Levi PE, editors: A Textbook of Modern Toxicology, Stamford, Conn, 1997, Appleton & Lange, p 229.  Occupational health risks: industrial and agricultural exposures 415 in the bone marrow and may lead to marrow aplasia cutting), asbestos (in mining, fabrication, and insulation and acute myeloid leukemia. work), and beryllium (in mining and fabrication). Expo- Polycyclic hydrocarbons are released during the combustion sure to these agents nearly always occurs in the workplace. of coal and gas, particularly at the high temperatures The increased risk of cancer as a result of asbestos used in steel foundries, and also are present in tar and exposure, however, extends to family members of asbestos soot. (Pott identified soot as the cause of scrotal cancers workers and to other persons exposed outside the in chimney sweeps in 1775, as mentioned in Chapter 7). workplace. Pneumoconioses and their pathogenesis are Polycyclic hydrocarbons are among the most potent discussed in Chapter 13. carcinogens, and industrial exposures have been impli- cated in the causation of lung and bladder cancer. Effects of Tobacco Organochlorines (and halogenated organic compounds in Smoking is the most readily preventable cause of death general) are synthetic products that resist degradation in humans. The main culprit is cigarette smoking, but and are lipophilic. Organochlorines used as pesticides smokeless tobacco (e.g., snuff, chewing tobacco) is also are dichlorodiphenyltrichloroethane (DDT) and its metabolites harmful to health and an important cause of oral cancer. and agents such as lindane, aldrin, and dieldrin. Non- The use of tobacco products not only creates personal risks, pesticide organochlorines include polychlorinated biphenyls but passive tobacco inhalation from the environment (second- (PCBs) and dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin hand smoke) can cause lung cancer in nonsmokers. More [TCDD]). DDT was banned in the United States in 1973. than 20 million US residents have died of smoking-related Acute DDT poisoning in humans causes neurologic diseases since the 1964 Surgeon General’s report on the toxicity. Most organochlorines are endocrine disruptors adverse effects of smoking. Of these, almost 2.5 million died and have antiestrogenic or antiandrogenic activity in as a result of inhalation of second-hand smoke. More than laboratory animals, but long-term health effects in humans 10 times as many people in the United States have died as have not been firmly established. a result of cigarette smoking than have died in all the wars Nonpesticide organochlorines include PCBs and dioxin fought by the United States in its entire history. Annually, (TCDD). Dioxins and PCBs can cause skin disorders such tobacco is responsible for more than 400,000 deaths in the as folliculitis and acneiform dermatosis known as chlor- United States, one-third of these due to lung cancer. Indeed, acne, which consists of acne, cyst formation, hyperpig- tobacco is the leading exogenous cause of human cancers, mentation, and hyperkeratosis, generally around the face including 90% of lung cancers. and behind the ears. It can be accompanied by abnormali- Worldwide, two-thirds of smokers live in 10 countries, ties in the liver and CNS. Because PCBs induce the P-450 led by China, which accounts for nearly 30%, and India enzyme system, workers exposed to these substances with about 10%, followed by Indonesia, Russia, the United may show altered drug metabolism. Environmental States, Japan, Brazil, Bangladesh, Germany, and Turkey. disasters in Japan and China in the late 1960s caused by From 1998 to 2007 in the United States, the incidence of the consumption of rice oil contaminated by PCBs poi- smoking declined modestly, but this trend failed to continue, soned about 2000 people in each episode. The primary and approximately 20% of adults remain smokers. More manifestations of the disease (yusho in Japan, yu-cheng disturbing, the world’s most populous country, China, has in China) were chloracne and hyperpigmentation of the become the world’s largest producer and consumer of ciga- skin and nails. rettes. China has approximately 350 million smokers who Bisphenol A (BPA) is used in the synthesis of polycarbonate in aggregate consume about 33% of all cigarettes smoked food and water containers and of epoxy resins that line worldwide. It is estimated that more than 1 million people almost all food bottles and cans; as a result, exposure to in China die each year of smoking-related diseases; this rate BPA is virtually ubiquitous in humans. BPA has long is projected to rise to 8 million deaths each year by 2050. been known as a potential endocrine disruptor. Several Worldwide, cigarette smoking causes more than 4 million large retrospective studies have linked elevated urinary deaths annually, mostly from cardiovascular disease, various BPA levels to heart disease in adult populations. In types of cancers, and chronic respiratory problems. These addition, infants who drink from BPA-containing contain- figures are expected to rise to 8 million tobacco-related deaths ers may be particularly susceptible to the endocrine effects by 2020, the major increase occurring in lower income of BPA. In 2010, Canada was the first country to list BPA countries. Of people alive today, an estimated 500 million as a toxic substance, and the largest makers of baby bottles will die of tobacco-related illnesses. and “sippy” cups have stopped using BPA in the manu- Tobacco reduces overall survival through dose-dependent facturing process. The extent of the human health risks effects that are often expressed as pack-years, the average associated with BPA remains uncertain. number of cigarette packs smoked each day multiplied by Vinyl chloride, used in the synthesis of polyvinyl resins, the number of years of smoking. The cumulative effects of can cause angiosarcoma of the liver, a rare type of liver smoking over time are striking. For instance, while about tumor. 75% of nonsmokers are alive at age 70, only about 50% of Inhalation of mineral dusts causes chronic, nonneoplastic smokers survive to that age (Fig. 9.7). The only good news lung diseases called pneumoconioses. This group of dis- is that cessation of smoking greatly reduces, within 5 years, orders includes diseases induced by organic and inorganic overall mortality and the risk of death from cardiovascular particulates as well as chemical fume- and vapor-induced diseases. Lung cancer mortality decreases by 21% within 5 nonneoplastic lung diseases. The most common pneu- years, but the excess risk persists for 30 years. moconioses are caused by exposures to coal dust (in The number of potentially noxious chemicals in tobacco mining of hard coal), silica (in sandblasting and stone smoke is extraordinary. Tobacco smoke contains a complex 416 CHAPTER 9 Environmental and Nutritional Diseases Current cigarette smokers Table 9.4 Suspected Organ-Specific Carcinogens in Tobacco Smoke Never smoked regularly 100 Organ Carcinogen Lung, larynx Polycyclic aromatic hydrocarbons 4-(Methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) 80 Polonium 210 Esophagus N′-Nitrosonornicotine (NNN) Pancreas NNK 60 Bladder 4-Aminobiphenyl, 2-naphthylamine Oral cavity Polycyclic aromatic hydrocarbons, NNK, NNN % alive (smoking) Oral cavity (snuff) NNK, NNN, polonium 210 40 Data from Szczesny LB, Holbrook JH: Cigarette smoking. In Rom WH, editor: Environmental and Occupational Medicine, ed 2, Boston, 1992, Little, Brown, p 1211. 20 include effects on the fetus, as nicotine, exposure affects fetal brain development and contributes to preterm birth and still birth. 0 40 55 70 85 100 Smoking and Lung Cancer. Agents in smoke have a direct Age irritant effect on the tracheobronchial mucosa, producing Figure 9.7 Effects of smoking on survival. The study compared age- increased mucus production (bronchitis). Components of specific death rates for current cigarette smokers with death rates of cigarette smoke, particularly polycyclic hydrocarbons and individuals who never smoked regularly (British Doctors Study). Measured nitrosamines (Table 9.4), are potent carcinogens in animals at age 75, the difference in survival between smokers and nonsmokers is and are directly involved in the development of lung cancer 7.5 years. (Modified from Stewart BW, Kleihues P, editors: World Cancer in humans. CYPs (cytochrome P-450 phase I enzymes) and Report, Lyon, 2003, IARC Press.) phase II enzymes increase the water solubility of the car- cinogens, facilitating their excretion. However, some intermediates produced by CYPs are electrophilic and form mixture of 7000 chemicals, more than 60 of which have been DNA adducts that are repaired by error-prone mechanisms, identified as carcinogens. Table 9.3 provides only a partial leading to potentially oncogenic mutations (Chapter 7). Most list and includes various types of injuries produced by these tellingly, deep sequencing of the genomes of lung cancers agents. that occur in smokers has revealed the presence of thousands Nicotine, an alkaloid present in tobacco leaves, is strongly of mutations of a type that is produced by carcinogens in addictive. Nicotine binds to nicotinic acetylcholine receptors tobacco smoke in experimental settings. The risk of develop- in the brain, and stimulates the release of catecholamines ing lung cancer is related to the number of pack-years or from sympathetic neurons. This activity is responsible for cigarettes smoked per day (Fig. 9.8). Moreover, smoking the acute effects of smoking, such as the increase in heart increases the risk of other carcinogenic influences. Witness rate and blood pressure and the elevation in cardiac con- the 10-fold higher incidence of lung carcinomas in asbestos tractility and output. Recent studies indicate that in addition workers and uranium miners who smoke over those who to being addictive, nicotine has other untoward effects. These do not smoke and the interaction between tobacco consump- tion and alcohol in the development of oral and laryngeal cancers (Fig. 9.9). Table 9.3 Effects of Selected Tobacco Smoke Constituents Substance Effect Smoking and Other Diseases. In addition to lung cancer, Tar Carcinogenesis smoking is linked to many other malignant and nonmalignant disorders that affect numerous organ systems (Fig. 9.10). Polycyclic aromatic hydrocarbons Carcinogenesis Cigarette smoking is associated with cancers of the esopha- Nicotine Ganglionic stimulation and gus, pancreas, bladder, kidney, cervix, and bone marrow. To depression; tumor promotion this list, the latest report of the US Surgeon General has Phenol Tumor promotion; mucosal added carcinomas of the liver and colon; the latter is the irritation second most common cause of cancer deaths. Benzo[a]pyrene Carcinogenesis The toll taken by nonmalignant conditions associated with Carbon monoxide Impaired oxygen transport and smoking is even more terrible. Agents in smoke have a utilization direct irritant effect on the tracheobronchial mucosa, Formaldehyde Toxicity to cilia; mucosal irritation producing inflammation and increased mucus production Nitrogen oxides Toxicity to cilia; mucosal irritation (bronchitis). Cigarette smoke also causes the recruitment of leukocytes to the lung, with increased local elastase Nitrosamine Carcinogenesis production and subsequent injury to lung tissue, leading  Occupational health risks: industrial and agricultural exposures 417 CANCERS CHRONIC DISEASES 20 Stroke Blindness, cataracts, 15 age-related macular degeneration Relative risk Oropharynx Orofacial clefts (maternal smoking) 10 Larynx Periodontitis Esophagus Aortic aneurysm, Trachea, 5 atherosclerosis bronchus, lung Coronary artery disease Acute 0 myeloid Pneumonia, 0 1 10 20 40 60 leukemia asthma, COPD, tuberculosis, Cigarettes smoked/day Liver other respiratory Stomach effects Figure 9.8 The risk of lung cancer is determined by the number of cigarettes smoked. (Modified from Stewart BW, Kleihues P, editors: World Pancreas Diabetes Cancer Report, Lyon, 2003, IARC Press.) Kidney, ureter Reduced fertility (women) Colorectal to emphysema, chronic bronchitis, and chronic obstructive Ectopic pregnancy pulmonary disease, conditions that are discussed in Cervix Chapter 15. Smoking exacerbates asthma and increases Bladder Hip fractures the risk for pulmonary tuberculosis. Erectile Cigarette smoking is strongly linked to the development of dysfunction atherosclerosis and its major complications, myocardial (men) infarction and stroke. The causal mechanisms probably Rheumatoid relate to several factors including increased platelet arthritis aggregation, decreased myocardial oxygen supply Decreased immune function, overall diminished health Figure 9.10 Health consequences causally linked to smoking. Items in red Tobacco smoking (cigarettes/day) are new diseases added in the 2016 report from the Surgeon General (US 0–7 8–15 16–25 26+ Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, Ga, 2016, US Department of Health and Human Services, Centers for 50 Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health). COPD, Chronic obstructive pulmonary disease. 40 (because of significant lung disease coupled with the hypoxia related to the CO content of cigarette smoke) 30 accompanied by increased myocardial oxygen demand Relative risk and a decreased threshold for ventricular fibrillation. Smoking has a multiplicative effect on the incidence of myocardial infarction when combined with hypertension 20 and hypercholesterolemia. Smoking also harms the developing fetus. Maternal smoking increases the risk of spontaneous abortions and preterm 120+ births and results in intrauterine growth retardation 10 (Chapter 10). Birth weights of infants born to mothers