Environmental Diseases Lecture Notes PDF

PATHOLOGY | TRANS 01 LE Environmental Diseases EVETTE LILYBELLE A.DEMAISIP, MD, FPSP, MP H. MIMHoA | Lecture Date (09/...

PATHOLOGY | TRANS 01 LE Environmental Diseases EVETTE LILYBELLE A.DEMAISIP, MD, FPSP, MP H. MIMHoA | Lecture Date (09/14/2024) | Version #1 02 OUTLINE → Traditionally, the focus of public health work has been I. Environmental Pollutants IV. Drugs concerned with local health hazards such as air, land, A. Environment A. Therapeutic Drugs and water pollution B. Toxicity of Chemical & B. Injury by Therapeutic ▪ However, in the recent years, there has been a Physical Agents Drugs (ADRs) growing concern for global hazards such as ozone C. Environmental Pollution C. Injury by Non-Therapeutic depletion and climate change D. Key Concepts Agents (Drug Abuse) → Type of environmental influence that populations suffer II. Tobacco Smoking D. Key Concepts A. Tobacco Smoking V. Physical Agents from are broadly related to inequitable socioeconomic B. Effects of Tobacco A. Mechanical Trauma development which lead to variations in environmental C. Quitting Smoking B. Thermal Injury disease type and magnitude among different countries D. Secondhand Smoke C. Electrical Injury → Greatest burden of disease: E. Electronic Cigarettes D. Ionizing Radiation Injury ▪ Unsafe drinking water F. Thirdhand Smoke E. Key Concepts ▪ Poor sanitation and hygiene G.Other Effects of Tobacco VI. Review Questions ▪ Indoor and outdoor air pollution H. Key Concepts VII. References ▪ Climate change III. Alcohol VIII. Self Assessment A. Effects of Alcohol IX. Appendix − WHO: unless we don’t take action, climate change B. Metabolism of Ethanol will be the foremost cause of environmental C. Injurious Effects of Alcohol diseases in the 21st century and beyond. D. Key Concepts − Meteorological studies have shown that: o Past 5 years (2014-2018) have been the Must Lecturer Book Previous Youtube warmest since 1880 ❗️ Know 💬 📖 📋 Trans 🔺 Video o Mean global ocean temperatures continue to warm URTI SUMMARY OF ABBREVIATIONS Upper respiratory tract infection 🔺Youtube Video: The Greenhouse Effect CAD Coronary artery disease The Greenhouse Effect → Most common cause of climate change ESRD End-stage renal disease → Gas in the atmosphere, such as water vapor, carbon CdMT Cadmium-Metallothionein complex dioxide, methane, nitrous oxide and LEARNING OBJECTIVES chlorofluorocarbons, let the sun's light in but keep some At the end of the lesson, the students should be able to: of the heat from escaping, like the glass walls of a ✔ Describe the health effects of climate changes greenhouse. ✔ Discuss toxicity of chemical and physical agents in → Human activities, like the burning of fossil fuels, have general increased the amount of CO2 in the atmosphere by ✔ Differentiate effects of environmental pollutants as: more than a third since the industrial revolution, leading air pollution (outdoor and indoor) & metals (lead, to increased warming of the planet in an alarming rate mercury, arsenic, cadmium) → Climate change has consequences for our oceans, our ✔ Discuss occupational Health Risks related to Industrial weather, our food sources and our health. and Agricultural Exposures: Tobacco ▪ Water from glaciers, once melted, causes sea level to ✔ Discuss the health effects of alcohol rise and to spill out of the oceans, flooding coastal regions. I. ENVIRONMENTAL POLLUTANTS ▪ More extreme weather including intense major A. ENVIRONMENT storms, floods, snowfall, and more frequent droughts. Ambient Environment ▪ Agricultural problems: difficulties in growing crops → Encompasses all factors and conditions external to the and displacement of animals. human host that affect peoples’ lives ▪ Decreased water supplies → Includes physicochemical, biological, social, and cultural → Problems on physical health factors which, individually or in combination, influence ▪ In urban areas, the warmer atmosphere creates an human health and wellbeing environment that traps and increases the amount of Personal Environment smog → Pertains more to an individual - our own environment − smog contains ozone particles which increase → Refers to the things we do to our body such as: rapidly at higher temperatures. ▪ Habits - Smoking and drug intake − exposure to higher levels of smog could lead to ▪ Activities - exercise or the lack thereof health problems such as asthma, heart disease, ▪ Nutrition and lung cancer Environmental Diseases → While the rapid rate of climate change is caused by → Conditions caused by exposure to chemical and humans, humans are also the ones who can combat it. physical agents in the ambient and personal ▪ Via usage of renewable energy sources such as solar environment and wind which don’t produce greenhouse gas. LE 2 TG 12 & 13 | Juaini, Justiniano, Jose, Justo, TE | Khong Hun, Lagazo AVPAA | R. Manalili PAGE 1 of 26 TRANS 1 Kang, Laceda, Lacsaman, Laguardia, Landicho, VPAA | A. Escolano Gedorio PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP B. TOXICITY OF CHEMICAL & PHYSICAL AGENTS 2 types of metabolism Toxicology → Detoxification → Defined as the science of poisons ▪ Xenobiotic is converted to a less toxic form → Studies the distribution, the effects and mechanisms of ▪ Natural defense mechanism of the organism action of toxic agents ▪ Generally involves conversion of lipid soluble compounds to polary or water soluble compounds TOXICOLOGY PRINCIPLES → Bioactivation DOSAGE ▪ Xenobiotic may be converted into more reactive Most important in determining if a substance is toxic metabolites that are toxic to cell components Length of time of exposure determines whether the effect ▪ If repair is not effective, short and long term effects is either acute or chronic develop All chemicals can be acute toxicants if sufficiently large 2 phases of Xenobiotic Metabolism doses during a short period of time are administered → Phase 1: Hydrolysis, reduction, oxidation Toxic mechanisms in target organs are different for acute ▪ Chemicals undergo hydrolysis, oxidation or reduction and chronic toxicity → Phase 2: Glucuronidation, sulfation, methylation, → Ethanol conjugation ▪ Acute Toxic Effects: May cause CNS depression if ▪ Products of phase 1 reactions are often metabolized taken at large quantities at one time into water soluble compounds through phase 2 ▪ Chronic Toxic Effects: May cause liver cirrhosis if reactions taken continuously for a long period of time → Water soluble compounds are now readily excreted in → Arsenic the kidney. ▪ Acute Toxic Effects : GI damage → Drug metabolizing enzymes - enzymes that catalyze ▪ Chronic Toxic Effects: Skin/liver cancer the biotransformation of xenobiotics and drugs EXPOSURE ROUTE Cytochrome P450 Defined as the way that an individual comes in contact with → Most important enzyme catalyst of phase 1 reactions a toxic substance → Large family of enzymes that use iron to oxidize Xenobiotics Xenobiotics to convert harmful substances by making → Exogenous chemicals in the environment in air, water, them more water soluble or hydrophilic food, and soil that may be absorbed into the body → Many of the drugs are primarily cleared by the through inhalation, ingestion and skin contact cytochrome P450 enzymes → May be highly toxic by one route, but not in others ▪ Adding of a hydroxyl group to a xenobiotic is part of ▪ Due to differences in absorption and distribution the body’s strategy to get rid of toxic substances within the body ▪ Often followed by conjugation to increase the ▪ Ex. Ingested chemicals, when absorbed from the solubility even further intestine, distribute first to the liver and may → Primarily expressed in hepatocytes (endoplasmic immediately be detoxified or rendered inactive, while reticulum) inhaled toxicants immediately enter the general blood ▪ Can also be found in the skin, the lungs, circulation and can distribute through all the body gastrointestinal mucosa, and other organs prior to being detoxified by the liver. → The name cytochrome P450 enzymes is derived due to their several characteristics METABOLISM ▪ Cyto - Bound to cell membrane AKA biotransformation ▪ Cytochrome - colored cells → Process of conversion of a chemical from one form to − Color the liver cells dark red as they contain iron another by a biological organism ▪ P450 → Metabolites - products of metabolism − P - Pigment − 450 - when bound to carbon monoxide, produces a spectrum with a wavelength at approximately 450nm → Catalyzes reactions that either detoxify xenobiotics or, less commonly, convert xenobiotics into active compounds that cause cell injury ▪ Both reactions may produce a byproduct reactive oxygen species (ROS) which can cause cell damage → Examples of metabolic activation of chemicals through cytochrome P450 include the following: 1. Production of the toxic trichloromethyl free radical from carbon tetrachloride in the liver 2. Generation of a DNA binding metabolite from benzo[a]pyrene which is a known carcinogen present in cigarette smoke 3. Cytochrome P450 enzymes participate in the Figure 1. 2 Types of Metabolism. (L) Detoxification of metabolism of a large number of common therapeutic Xenobiotics; (R) Bioactivation of Xenobiotics drugs such as acetaminophen, barbiturates, warfarin, and anticonvulsants → Also involved in the metabolism of alcohol PATHOLOGY Environmental Diseases PAGE 2 of 26 PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP Table 1. Cytochrome P450 Inducers and Inhibitors Inducers Inhibitors Environmental chemicals Fasting/Starving Drugs Drugs Smoking Alcohol Hormones Increased rate of drug Decreased rate of drug metabolism → Effect is metabolism → Drug not reduced converted → Drug level in 💬 body increased → adverse When inducing agent is or harmful effect Figure 3. Passive diffusion and filtration of xenobiotics prescribed with another EXCRETION medication, the dosage of Elimination of xenobiotics and it is metabolized by specific the other medication needs excretory organs to be adjusted → Polar (hydrophilic) substances are more likely than lipid Activity of Cytochrome P450 enzymes solubles toxicants to be eliminated from the body → Greatly varies among individuals → Chemicals must pass through membranes in order to → Variations are due to genetic polymorphism in the leave the body structure of the Cytochrome P450 → Excretory organs: → Commonly are due to exposure to drugs or chemicals ▪ Kidneys (primary) that induce or diminish cytochrome P450 activity ▪ GIT 💬CYTOCHROME P450 SUMMARY ▪ Lungs (for gasses) ▪ Sweat, tears, and milk → Lipid soluble toxicants are reabsorbed and concentrated in kidney cells → Impaired kidney function causes slower elimination of toxicants and increases their toxic potential C. ENVIRONMENTAL POLLUTION AIR POLLUTION: OUTDOOR Figure 2. Summary of Cytochrome P450 Ambient or surrounding air in industrialized nations is It belongs to a superfamily of enzymes contaminated with noxious mixture of gaseous and Mostly located in the endoplasmic reticulum and cell particulate pollutants which are heavily concentrated in membranes cities and factories Present in large amount in the liver which is color red → Most well known and studied pollutants are: because of the heme group in cytochrome P450 enzymes ▪ Sulfur dioxide Catalyzes mainly oxidation reactions in Phase 1 ▪ Carbon monoxide metabolism in xenobiotics ▪ Ozone DISTRIBUTION ▪ Nitrogen dioxide Distribution of toxic substance and metabolites within the ▪ Lead body ▪ Particulate Matter → Ultimately determines the sites where toxicity occurs ▪ Collectively, they produce smog Lipid Solubility → Regulatory agencies like US EPA monitors and sets → Major determinant of whether a toxic substance or allowable upper limits for ambient pollutants toxicant will damage the cell → Lipid soluble toxicants (lipophilic) readily penetrate cell membrane Most solvents and drugs are lipophilic → Facilitates their transport in the blood by lipoproteins and their penetration the plasma membrane in to the cells Body fat,liver, kidney, and bone: Most common storage sites of toxicants Blood: Main avenue of distribution Lymph also distributes some materials In general, highly ionized chemicals have low lipid solubility and pass with difficulty through the lipid membranes Figure 4. Health effects of outdoor air pollutants Respiratory system- primary target of harmful effects of air pollutants PATHOLOGY Environmental Diseases PAGE 3 of 26 PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP OZONE (O3) When released into the air, the gasses will now combine Produced by the interaction of UV radiation and oxygen with water molecules in the atmosphere to form acid rain. in the stratosphere Acid Rain Formation Good Ozone → O3 + sulfur dioxide (from combustion of oil and coal, ▪ Naturally accumulates in ozone layer about 10-30 copper smelting, paper mill) + particulates → Sulfuric miles above earth’s surface acid + water → acid ▪ Produced by the interaction of UV radiation and → Nitrogen oxide also contribute to acid rain ( nitric acid) oxygen in the stratosphere → Note: Normal Rainwater pH 5-5.5 while Acid rain pH is ▪ Protects life on earth by absorbing harmful UV 4.0 radiation emitted by the sun Bad Ozone ▪ Accumulates in the low atmosphere → Ground Level Ozone ▪ One of the most destructive air pollutants ▪ Gas formed by the reaction of nitrogen oxides and volatile organic compounds in the presence of sunlight ▪ They are release by industrial emission and motor vehicle exhaust During the past 35 years, stratospheric ozone layer decreased in both thickness and extent due to the widespread use of chlorofluorocarbon gasses in air conditioners, refrigerators and as aerosol propellants Figure 6. Acid rain formation of airplanes Acid Rain Effects ▪ When released into the atmosphere, they drift up to → Direct Effects on Humans the stratosphere and react in the presence of UV light ▪ Sulfuric acid and sulfur trioxide causes a burning that destroys the ozone sensation in the nose, throat and skin. ▪ Depletions are most pronounced in polar ▪ Accelerated respiratory problems, e.g. asthma and regions,particularly over Antarctica during winter bronchitis in susceptible individuals months → Dissolve marble statues ▪ International air force banned the use of → Corrode metal chlorofluorocarbon that started in 1987 which resulted in → Dull car finishes reduced ozone hole over Antarctica → Damage buildings PARTICULATE MATTER (SOOT) emitted by coal- and oil-fired power plants, fuel combustion, diesel exhaust. Causes pulmonary inflammation and secondary cardiovascular effects. US studies: 0.5% increase in overall daily mortality per 10 mg/m3 increase in 10 μm particles in outdoor air due to aggravation of pulmonary and cardiac disease. Fine or ultrafine particles with 10μm in diameter cause less damage Figure 5. Ozone because they are generally removed in the nose or trapped by the mucociliary epithelium of the airways OZONE TOXICITY Mediated by the release of free radicals which damage the respiratory epithelial cells and type I alveolar cells and cause the release of inflammatory mediators Healthy individuals that are exposed to ozone experience URTI, mild symptoms (decreased lung function and chest discomfort) Worsens asthma or emphysema O3 + sulfur dioxide (from burning of coal & oil, copper smelting, paper mill) & particulates ​Air pollutants often combine with other agents such as sulfur dioxide and particulates. Nitrogen oxides-produced naturally by lightning strikes Sulfur dioxides -formed when volcanoes explode and are produced by power plants, burning coal, and oil from Figure 7. Particulate matter copper smelting and as a byproduct of paper mills. PATHOLOGY Environmental Diseases PAGE 4 of 26 PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP CARBON MONOXIDE Table 2. Levels of carboxyhemoglobin (CO-Hb) saturation Systemic asphyxiant (%) and symptoms. Cause of accidental and suicidal death. CO-Hb (%) Clinical Symptom 📋 Non irritating, colorless,tasteless, odorless gas 60 are carcinogens (tar, polycyclic aromatic POLLUTION hydrocarbons, benzo[a]pyrene, nitrosamine) Environmental diseases are conditions caused by Benzo[a]pyrene is the most studied among the four exposure to chemical or physical agents in the → Produced when organic matter such as tobacco leaf is ambient, workplace, and personal environments. burnt Exogenous chemicals known as xenobiotics enter the → Benzopyrene becomes a powerful DNA disruptor body through inhalation, ingestion, and skin contact producing mutations that can lead to cancer and can either be eliminated or accumulate in fat, bone, → Processed by cytochrome P450 enzymes to make it brain, and other tissues. water soluble and excreted in urine Xenobiotics can be converted into nontoxic products Benzopyrene epoxides - the water soluble form of or activated to generate toxic compounds through a benzo[a]pyrene two-phase reaction process that involves the → Specially good at binding to DNA cytochrome P-450 system. → Form adducts that bend DNA out of shape The most common and important air pollutants are → Cells can remove these adducts easily with specialized ozone (which in combination with oxides and particulate DNA enzymes but occasionally, the adducts remain matter forms smog), sulfur dioxide, acid aerosols, and stuck to DNA and leads to a cascade of problems particles less than 10 um in diameter. Nicotine and nitrosamine are not directly cause of CO poisoning is an important cause of death from tobacco related diseases, but it is strongly addictive accidents and suicide; it binds hemoglobin with high → Without these, it will be easy for smokers to quit affinity, leading to systemic asphyxiation associated with → Nicotine binds to nicotinic acetylcholine receptors in the CNS depression. brain and stimulate the release of catecholamine from A variety of pollutants including smoke, bioaerosols, sympathetic neurons radon, and formaldehyde may accumulate in indoor ▪ Leads to acute effects of smoking (increased air and cause disease. HR,BP,CO) TOXIC EFFECTS OF HEAVY METALS B. EFFECTS OF TOBACCO Lead, mercury, arsenic, and cadmium are the heavy Increased risk in developing cancer in various organs metals most commonly associated with toxic effects in Increased risk for heart diseases humans. The ill effects of tobacco smoke depends on the following Children absorb more ingested lead than adults; the → Number of years a person smoked main source of exposure for children is lead-containing → How much the person smokes or is exposed to (in paint in older housing and lead-containing drinking second hand smoke) water. Decreases the survival rate of smokers Excess lead causes CNS defects in children and Survival rate (SR) is expressed as peripheral neuropathy in adults. It also interferes with → SR in pack-years = ave. no. of cigarette packs smoked the remodeling of cartilage and causes anemia by each day x no. of years smoking. interfering with hemoglobin synthesis. If the smoker stops smoking within 5 years, overall The major source of exposure to mercury is mortality and the risk of death from cardiovascular contaminated fish. The developing brain is highly diseases is greatly reduced sensitive to methyl mercury, which accumulates in the → Lung cancer mortality decreases by 25% within 5 years CNS. → Excess risks persist for 30 years Exposure of the fetus to high levels of mercury in utero 75% of non smokers are expected to be alive at age 70 may lead to Minamata disease, characterized by compared to smokers where only about 50% survive to cerebral palsy, deafness, and blindness. that age Arsenic is naturally found in soil and water and is a Lungs, mouth and bladder are common sites of smoking component of some wood preservatives and induced cancer herbicides. Excess arsenic interferes with → This is where epoxides are made or where they travel mitochondrial oxidative phosphorylation and the C. QUITTING TOBACCO SMOKING function of a variety of proteins. It causes toxic Quitting can be hard for some people because of effects in the gastrointestinal tract, CNS, and withdrawal symptoms cardiovascular system; long-term exposure causes skin → Irritability lesions and carcinomas. → Headache PATHOLOGY Environmental Diseases PAGE 9 of 26 PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP → Intense nicotine cravings → WHO urges restriction on e-cigarettes as it produces Even if quitting is a challenge, the benefits on physical aerosol that contains harmful ingredients such as and mental health are worth it glycols, aldehydes, volatile organic compounds, → Improves circulation, increases oxygen levels and polycyclic aromatic hydrocarbon, tobacco specific lowers inflammation giving the immune system a boost nitrosamines → Within 1 month of quitting, many nicotine receptors in F. THIRDHAND SMOKE the brain will be back to normal, breaking the cycle of Residual tobacco smoke addiction Particles from ETS can settle in dust and on surfaces → Within 3 months, lung function may start to improve (i.e fabric, walls, furnitures, toys) → remain there long after with decreased cough, sinus congestion, fatigue, and the smoke is gone → combine with gasses in air to form shortness of breath cancer-causing compounds that settle onto surfaces → Within 1 year, risk of stroke is now as low as Hazards of thirdhand smoke are not as well documented someone who stopped smoking 5-15 years ago as the hazards of secondhand smoke → As for cancers, it may take a few years after quitting, but Particles can last for months you will lower your risk of cancer among others Harmful chemicals from thirdhand smoke: NNK → You will have cleaner teeth and mouth (nicotine-derived nitrosamine ketone) and PAHs ▪ Smoking yellows teeth, causes bad breath, and (polycyclic aromatic hydrocarbons) increases risk of oral infection → Known carcinogens causing lung cancer found in dust ▪ Within a week of quitting, you will already see a samples taken from homes of smokers difference in your mouth G. OTHER EFFECTS OF TOBACCO D. SECONDHAND SMOKE Irritants: formaldehyde, phenols, nitric oxide that can Exposure to tobacco smoke, not from smoking, but from cause emphysema →damage to the air sacs (alveoli) in being exposed to someone else’s cigarette lungs. Also called environmental tobacco smoke (ETS) or Atherosclerosis, myocardial infarction passive/involuntary smoking → related to factors including increased platelet Produces same detrimental effects from active smoking aggregation, decreased myocardial oxygen supply Relative risk of lung cancer in non smokers exposed is because of significant lung disease, coupled with 1.3x higher than the relative risk of nonsmokers not hypoxia related to carbon monoxide content of cigarette exposed smoke, accompanied by increased oxygen demand. Frequently, we are exposed to passive smoke at home, → smoking greatly increases the risk for myocardial workplace, bars and nightclubs or when using public infarction when combined with hypertension and transportation hypercholesterolemia Mainstream smoke Maternal smoking: increases the risk of fetal hypoxia, → Smoke that is inhaled and exhaled from the smokers spontaneous abortion, preterm birth which can result in lungs intrauterine growth retardation. Sidestream smoke → The smoke that comes from the lighted end of a cigarette, pipe, cigar, or tobacco burning in a hookah → Burning end of a cigarette is not hot enough to proceed to the complete combustion of the tobacco ▪ Some chemicals are favored by this incomplete burning, undiluted sidestream smoke contains higher concentrations of several chemicals than the Figure 13. Other effects of tobacco[Lecturer’s PPT] mainstream smoke → Chemicals inhaled in sidestream smoke are H. KEY CONCEPTS 📖 naphthylamine, nitrosodimethylamine and carbon Smoking is the most prevalent preventable cause of monoxide among others human death. → Sidestream smoke is said to be more toxic than Tobacco smoke contains more than 7000 mainstream smoke compounds. Among these are nicotine, which is → Has smaller particles than mainstream smoke responsible for tobacco addiction, and potent → Passive smoke in non smokers can be measured by carcinogens-- mainly, PAH, NKK, and aromatic amines. blood levels of cotinine, a metabolite of nicotine Nicotine also has other adverse effects particularly on → Smoking at home remains a major public concern fetal development, and is associated with preterm birth particularly for children who may develop respiratory and stillbirth. diseases and asthma approximately 90% of lung cancers occur in smokers. Smoking is also associated with an increased risk of E. ELECTRONIC CIGARETTES (VAPING) cancers of the oral cavity, larynx, esophagus, stomach, Simulate cigarette smoking by delivering vaporized bladder, and kidney, some forms of leukemia, as well as nicotine and flavorings liver and colorectal cancer. Cessation of smoking 2019: Outbreak of vaping-associated acute lung injury reduces the risk of lung cancer. that occured in the US Smokeless tobacco use is an important cause of oral → By the end of 2019, close to 2000 cases had been cancers. Tobacco consumption interacts with alcohol in reported to CDC with 42 fatalities multiplying the risk of oral, laryngeal, and esophageal → Pathogenesis of this outbreak is still under study cancer and increases the risk of lung cancers from No WHO advisory on usefulness in quitting smoke occupational exposures to asbestos, uranium, and other agents. PATHOLOGY Environmental Diseases PAGE 10 of 26 PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP Tobacco use is an important risk factor for development of atherosclerosis and myocardial infarction, peripheral vascular disease, and cerebrovascular disease. In the lungs, in addition to cancer, it predisposes to emphysema, chronic bronchitis, and COPD. Maternal smoking increases the risk of spontaneous abortion, premature birth, and intrauterine growth retardation. III. ALCOHOL A. EFFECTS OF ALCOHOL Ethanol consumption in moderate amounts in generally not harmful and may even protect against some disorders → A glass a day may do little damage to your overall health. But if that habit grows, or if you find yourself Figure 14. Alcohol metabolism [Lecturer’s PPT] having a hard time stopping after just one glass, the C. INJURIOUS EFFECTS OF ALCOHOL cumulative effects can add up. The oxidation of ethanol produces toxic metabolites and Drinking too much alcohol can lead to short-term, and disrupts certain metabolic pathways long-term physical and psychological effects Ethanol is absorbed in stomach & small intestine unaltered Distributed to all tissues and fluids of the body in direct proportion to blood level Only less than 10% is excreted unchanged in the urine, sweat, and breath Amount exhaled proportional to blood level → basis of the breath test Drunk: 80 mg/dL → legal definition of drunk driving in the US → 3 beer bottles or 15 oz of wine for an average individual Drowsiness: 200 mg/dL Stupor: 300 mg/dL Figure 15. Oxidation of ethanol [Lecturer’s PPT] Coma and respiratory arrest: >300 mg/dL Acetaldehyde Chronic alcoholics can tolerate up to 700mg/dL → Direct product of alcohol oxidation B. METABOLISM OF ETHANOL → Responsible for acute effects of alcohol and for oral Most of the alcohol in the blood is metabolized into cancers acetaldehyde in the liver by three (3) enzyme systems: → Efficiency of alcohol metabolism varies between (1) microsomal ethanol-oxidizing system populations; depending on: (2) alcohol dehydrogenase ▪ Expression levels of alcohol dehydrogenase and ▪ main enzyme system located in the cytosol of acetaldehyde dehydrogenase isozymes hepatocytes ▪ Genetic variants that alter enzyme activity (3) catalase ▪ 50% of asians w/ very low alcohol dehydrogenase At high blood alcohol levels the microsomal ethanol activity ~ (substitution of lysine for glutamine(Normal oxidizing system participates in its metabolism allele = ALDH2*1; inactive variant = ALDH2*2) Catalase, which uses hydrogen peroxide (H2O2) as its ▪ ALDH2*2 protein has dominant-negative activity, such substrate, is of minor importance, metabolizing no more that even one copy of the ALDH2*2 allele reduces than 5% of alcohol in the liver. acetaldehyde dehydrogenase activity significantly Acetaldehyde produced by alcohol metabolism is ▪ Some asians who are homozygous for ALDH2*2 allele: converted into acetate by acetaldehyde dehydrogenase completely unable to oxidize acetaldehyde -> which is the utilized by mitochondrial respiratory system cannot tolerate alcohol experiencing nausea, The microsomal oxidation system involves CYP450 flushing, tachycardia, and hyperventilation after its enzymes, particularly CYP2E1, located in the smooth ER. ingestion. Alcohol induces the CYP450 enzymes which increase the Alcohol oxidation by alcohol dehydrogenase causes the susceptibility of alcoholics to other compounds that are reduction of NAD to NADH, with a consequent decrease metabolized by the same enzyme systems including drugs, in NAD and increase in NADH anesthetics, carcinogens, and industrial solvents Fatty liver: fat accumulation due to decreased level of When alcohol is present in the blood at high NAD (needed for fatty acid oxidation and conversion of concentrations, it competes with other CYP2E1 substrates lactate to pyruvate) and delays drug catabolism and potentiates the depressing Increase NADH:NAD ratio -> lactic acidosis effects of narcotics, sedatives, and psychoactive drugs in Alcohol induces: CYP450 (CYP2E1) enzymes -> the CNS. production of ROS -> release of endotoxin cytokine (inflammation) Injurious effects of alcohol depend on how long and how much you have consumed, your health, and other factors ACUTE Fatty liver, gastritis, and ulcer, CNS depression PATHOLOGY Environmental Diseases PAGE 11 of 26 PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP CNS: Alcohol is a depressant, first affecting the subcortical structures that modulate cerebral cortical activity. Consequently, there is stimulation and disordered cortical motor and intellectual behavior → At the progressively higher blood levels, cortical neurons and the lower medullary centers are depressed, including those that regulate respiration and so respiratory arrest may follow CHRONIC Liver: fatty change, hepatitis, cirrhosis, increased risk for Cancer GIT: gastritis, ulcer (bleed), esophageal varices (which are associated with cirrhosis) CVS: dilated cardiomyopathy (alcoholic cardiomyopathy), increased BP, decreased HDL Pancreas: pancreatitis Cancer: increased risk - oral, esophagus, liver, breast Figure 17. Fetal Alcohol Syndrome causing damage to the 💬 (tumor promoters) It is thought that acetaldehyde DNA adducts have been midline structures of the face and brain [Lecturer’s PPT] detected in some tumors from these tissues Neurologic effects D. KEY CONCEPTS 📖 Acute alcohol abuse causes drowsiness at blood → Thiamine (Vitamin B1) deficiency is common in levels of approximately 200 mg/dL. Stupor and coma chronic alcoholics. develop at higher levels. → The principal lesions resulting from this deficiency are Alcohol is oxidized to acetaldehyde in the liver by peripheral neuropathies and Wernicke-Korsakoff alcohol dehydrogenase, by the cytochrome P-450 syndrome. system, and by catalase, which is of minor importance. → Cerebral atrophy, cerebellar degeneration, and optic Diminished ability to metabolize acetaldehyde is neuropathy may also occur associated with acute toxicity and an increased risk of certain cancers. Alcohol oxidation by alcohol dehydrogenase depletes NAD, leading to accumulation of fat in the liver and metabolic acidosis. The main effects of chronic alcoholism are fatty liver, alcoholic hepatitis, and cirrhosis, which leads to portal hypertension and increases the risk for development of hepatocellular carcinoma. Chronic alcoholism can cause bleeding from gastritis and gastric ulcers, peripheral neuropathy associated with thiamine deficiency, alcoholic cardiomyopathy, and acute and chronic pancreatitis. Chronic alcoholism is a major risk factor for cancers of the oral cavity, larynx, and esophagus. The risk is greatly increased by concurrent smoking or use of smokeless tobacco. IV. DRUGS A. THERAPEUTIC DRUGS (MEDICATIONS) Some common therapeutic drugs: → Oral Contraceptives (BCPs) Figure 16. Thiamine Deficiency and Associated Symptoms → Hormone Replacement Therapy (HRT) [Lecturer’s PPT] → Acetaminophen Fetal Alcohol Syndrome: microcephaly, CNS and CVS, → Aspirin GUT → During pregnancy, the use of alcohol can cause fetal B. INJURY BY THERAPEUTIC DRUGS (ADRs) alcohol syndrome (FAS) characterized by Adverse drug reactions (ADRs) microcephaly, growth retardation, facial → untoward effects of drugs that are given in conventional abnormalities in the newborn, and reduction in mental functions as the child grows older 💬 therapeutic settings ADRs are direct harmful, unfavorable, noxious, and unintended effects of drugs which occur at doses given → It is difficult to establish the minimal amount of alcohol consumption that can cause FAS but consumption normally for treatment either for prophylaxis (vaccines), during the first trimester of pregnancy is particularly for diagnosis (dyes injected in radiology for better harmful visualization) or most commonly, for treatment. → It has been estimated that the prevalence of frequent → Note: There is a causal link between a drug and an and binge-drinking among pregnant women is adverse drug reaction approximately 6% and FAS affects 1 to 48 per 1000 children born in the U.S. PATHOLOGY Environmental Diseases PAGE 12 of 26 PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP MENOPAUSAL HORMONE THERAPY (MHT) / ▪ OCs have protective effect that may last for HORMONE REPLACEMENT THERAPY (HRT) decades following cessation of OCs Given to postmenopausal women and women who → Thromboembolic events underwent hysterectomy to counteract the undesirable ▪ DVT and Pulmonary Embolism increased symptoms of menopause associated with a marked − Most studies show that OCs, including the new decrease in ovarian estrogen production low-dose formulations containing 35 y.o. and reduction in breast cancer risk women who smoke ▪ There is no increase in risk for ovarian cancer ▪ Ischemic stroke increased regardless of age or → Atherosclerosis and Coronary Artery Disease (CAD) smoking ▪ MHT may have a protective effect on → Liver tumors atherosclerosis and CAD in women 106°F, over 110°F have contact with hot surfaces, hot liquids, steam, or flame been reported, high mortality → Classification of burns − Most serious heat-related illness ▪ Classified by the degree depending on how deeply − Occurs when the body can no longer control its and severely they penetrate the skin’s surface temperature ▪ May be impossible to classify a burn immediately − The body temperature rises rapidly, the sweating when it occurs as it can progress over time, so you mechanism fails, and the body is unable to may not know the full extent for a day or two cooldown ▪ First-degree burn − When heatstroke occurs, the body temperature − Superficial burns which affect only the outer layer can rise to higher than 100°F or higher within 10 to of the skin, the epidermis 15 minutes − Burn site is red, painful, dry, and has no blisters − Hyperthermia is accompanied by marked, o Example: Mild sunburn generalized vasodilation with peripheral pooling of − Long term tissue damage is rare and often blood, and a decrease in effective circulating blood consists of an increase or decrease in the skin volume color − Hyperkalemia, tachycardia, and arrhythmia are ▪ Second degree systemic effects that are commonly seen in − Partial thickness burns which involve the heatstroke epidermis and part of the lower layer of the → Malignant hyperthermia skin, the dermis ▪ Severe reaction to certain drugs used for anesthesia − The burn site looks red with blisters, and may be ▪ Dangerously high body temperature, rigid muscles or swollen and painful spasms, a rapid heart rate, and other symptoms ▪ Third degree ▪ Complications caused by malignant hyperthermia can − Full thickness burns which involve the epidermis be fatal and dermis Hypothermia − May go into the innermost layer of the skin, the → Prolonged exposure to low ambient temperature subcutaneous tissue → Often in setting of homelessness or alcoholism or both − The burn site may look white or blackened and ▪ 1000 REM unstable genomes survive and may expand as ▪ Intractable nausea and vomiting abnormal clones that eventually transform into cancer. ▪ Confusion, somnolence, convulsions ▪ Death in 14-36 hr THERAPEUTIC RADIATION External radiation is delivered to malignant neoplasms at fractionated doses up to 40 to 70 Gy (4000 to 7000 rad), with shielding of adjacent normal tissues Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people exposed to alkylating agents Radiation therapy can effectively treat many types of cancer. Like other cancer treatments, it often causes side effects. These are some common possible side effects of radiation therapy: → Fatigue, nausea, and vomiting frequently → Bone marrow suppression may occur, especially with chest or abdominal radiation Side effects vary from one person to another depending on Figure 32. Effects of ionizing radiation on DNA and its the following: consequences [Lecturer’s PPT] → Type of cancer → Location of cancer The cells of hematopoietic and lymphoid systems are → Radiation therapy dose extremely susceptible to radiation injury → General health of the individual With high dose levels and larger exposure fields, severe lymphopenia (decrease in lymphocytes) occur within DELAYED RADIATION INJURY hours, together with shrinkage of lymph nodes in the Any cell capable of division that has sustained a mutation spleen has the potential to become cancerous and can be carried Radiation kills lymphocytes directly both in the circulation from one generation to another and the tissues like the nodes, the spleen, the thymus, and Thus, an increase incidence in neoplasms may occur in the GI tract any organ after exposure to ionizing radiation History has shown that acute or prolonged exposures cause serious consequences, foremost of which is cancer Carcinogenesis (atom bomb survivors) → Myeloid leukemias peak 5 to 7 years after exposure → Breast and thyroid cancers may show greater latency → No germline mutations noted in progeny of survivors Vascular effects → Endothelial necrosis followed by intimal and medial fibrosis Figure 33. The single most radiosensitive cell in your body → Capillaries may become thrombosed and obliterated or [Lecturer’s PPT] ectatic Parenchymal atrophy and fibrosis ACUTE EFFECTS OF IONIZING RADIATION Specific Effects → Free radical generation ▪ Ionizing radiation + H2O → H3O+ + OH → DNA Damage ▪ Double-stranded DNA breaks needed to kill cell (mammalian cells can repair single-stranded breaks) PATHOLOGY Environmental Diseases PAGE 20 of 26 PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP 2. The mechanism of disease productions of bisphenol A (BPA) is: a. Chemical irritation of sensitive cells and tissues b. Disruption of hematopoietic cell differentiation c. Potential endocrine disruptor 3. A small child with fever of a few days duration and reduced food intake and mild dehydration and took an overdose of acetaminophen, the child then developed nausea, vomiting and diarrhea and after a few days had jaundice. The ratio behind this manifestations is: a. Acute erosive gastritis Figure 34. Delayed Radiation Injury [Lecturer’s PPT] b. Hepatic Necrosis c. Metabolic acid / base imbalance 4. Heat wave and air pollution in climate change will impact human health on: a. Cardiovascular, cerebrovascular, and respiratory diseases b. Increase in spread of vector: Malaria and dengue c. Gastroenteritis, cholera, foodborne, and waterborne diseases 5. Drug of abuse that cause excessive psychomotor stimulation that may lead to cardiac arrhythmia and Figure 35. Radiation Effects on Tissue. Acute (vasculitis, respiratory arrest are the following EXCEPT: possibly “fibrinoid” necrosis); Chronic (fibrosis) [Lecturer’s PPT] a. Opiates b. Ecstasy (MDMA) c. Cocaine ANS: 1. c. Wood smoke contains polycyclic hydrocarbons (also seen in cigarette smoke) which is a carcinogen 2. c. Used in manufacturing food and water containers and epoxy resins. A potential endocrine disruptor 3. b. Overdose of acetaminophen leads to hepatocellular necrosis 4. a. Cardiovascular and cerebrovascular disease are Figure 36. Vascular changes and fibrosis of salivary glands worsened by heat waves and respiratory diseases are produced by radiation therapy of the neck region. (A) Healthy worsened by air pollution salivary gland; (B) fibrosis caused by radiation; (C) vascular 5. a. Opioid narcotics cause euphoria, hallucination, changes consisting of fibrointimal thickening and arteriolar somnolence, and sedation. sclerosis. I, Thickened intima; V, vessel lumen. (A–C, Courtesy of Dr. Melissa Upton, Department of Pathology, VII. REFERENCES University of Washington, Seattle, Washington.) [Robbins & Kumar: Kumar, V., Abbas A., Aster, J., Deyrup, A., & Das, A.(2023). Robbins & Basic Pathology, 11th ed, p. 255] Kumar: Basic Pathology. (11th ed.). Elsevier, Inc. KEY CONCEPTS: RADIATION INJURY 📖 Ionizing radiation may injure cells directly or indirectly by generating free radicals from water or molecular oxygen Ionizing radiation damages DNA; therefore rapidly dividing cells such as germ cells and those in the bone marrow and gastrointestinal tract are very sensitive to radiation injury DNA damage that is not adequately repaired may result in mutations that predispose affected cells to neoplastic transformation Ionizing radiation may cause vascular damage and sclerosis, resulting in ischemic necrosis of parenchymal cells and their replacement by fibrous tissue VI. REVIEW QUESTIONS 1. A man working as a cook for many years in a dirty kitchen that uses firewood was diagnosed with cancer of the lungs. A probable cause is: a. Pet dander and dust mites b. Carbon monoxide c. Polycyclic hydrocarbons PATHOLOGY Environmental Diseases PAGE 21 of 26 ANATOMY | LE 1 Title of Lecture | Name of Professor VIII. SELF ASSESSMENT PART 1: POLLUTANTS Question & Choices Answer & Rationale 1. Which of the following mechanisms best explains Ozone Toxicity how ozone contributes to respiratory disease? Mediated by the release of free radicals which damage the a. Ozone inhibits the production of alveolar surfactant, respiratory epithelial cells and type I alveolar cells and cause leading to atelectasis the release of inflammatory mediators b. Ozone generates free radicals that damage epithelial B cells and trigger inflammation c. Ozone binds to hemoglobin, reducing oxygen transport d. Ozone directly destroys type I pneumocytes, causing acute respiratory failure 2. Which of the following best defines a xenobiotic? Xenobiotics a. An endogenous compound produced by the body Exogenous chemicals in the environment in air, water, food, under pathological conditions and soil that may be absorbed into the body through b. A foreign chemical compound not produced by the inhalation, ingestion and skin contact body, including drugs and environmental toxins B c. A dietary nutrient metabolized by normal human enzymes d. A microorganism that infects the body and causes disease 3. Which of the following best describes the function 2 phases of xenobiotic metabolism of Phase I reactions in xenobiotic metabolism? Phase 1: Hydrolysis, reduction, oxidation a. Formation of reactive oxygen species to neutralize Chemicals undergo hydrolysis, oxidation or reduction toxins Phase 2: Glucuronidation, sulfation, methylation, conjugation B b. Hydrolysis, reduction, and oxidation to introduce or expose functional groups c. Direct excretion of xenobiotics in the urine or bile d. Conjugation of xenobiotics with hydrophilic molecules 4. Phase II metabolism of xenobiotics primarily 2 phases of xenobiotic metabolism involves which of the following reactions? Phase 1: Hydrolysis, reduction, oxidation a. Hydrolysis of lipid-soluble toxins to increase their Chemicals undergo hydrolysis, oxidation or reduction solubility C Phase 2: Glucuronidation, sulfation, methylation, conjugation b. Reduction of xenobiotics to less reactive forms c. Conjugation with glucuronic acid, sulfate, or glutathione d. Oxidation by cytochrome P450 enzymes Cytochrome P450 Most important enzyme catalyst of phase 1 reactions 5. Which of the following enzymes is most commonly Large family of enzymes that use iron to oxidize Xenobiotics involved in the Phase I metabolism of xenobiotics? to convert harmful substances by making them more water a. Glutathione S-transferase D soluble or hydrophilic b. alcohol dehydrogenase Many of the drugs are primarily cleared by the cytochrome c. Sulfotransferase P450 enzymes d. Cytochrome P450 Adding of a hydroxyl group to a xenobiotic is part of the body’s strategy to get rid of toxic substances PART 2: TOBACCO Question & Choices Answer & Rationale 1.Which of the following is the primary mechanism Tobacco contains benzo(a)pyrene which can be a powerful DNA by which tobacco smoke contributes to the disruptor producing mutations that can lead to cancer development of lung cancer? a. Decreased production of surfactant in alveolar cells Benzopyrene epoxides - the water soluble form of b. Increased clearance of toxins by ciliary action in the benzo(a)pyrene which is especially good at binding to DNA. It respiratory tract D form adducts that bend DNA out of shape c. Direct stimulation of bronchial smooth muscle hyperplasia d. Induction of chronic inflammation and oxidative DNA damage LE 2 TG 12 & 13 | Juaini, Justiniano, Jose, Justo, TE | Khong Hun, Lagazo AVPAA | R. Manalili PAGE 22 of TRANS 1 Kang, Laceda, Lacsaman, Laguardia, Landicho, VPAA | A. Escolano 26 Gedorio PATHOLOGY | LE 2 Environmental Diseases | EVETTE LILYBELLE A. DEMAISIP, MD, FPSP 2. Which of the following is the primary carcinogenic Tobacco smoke contains more than 7000 compounds. Among agent in tobacco smoke responsible for lung cancer? these are nicotine, which is responsible for tobacco addiction, a. Nicotine and potent carcinogens-- mainly, polycyclic aromatic b. Carbon monoxide D hydrocarbons (PAHs), NKK, and aromatic amines. c. Formaldehyde d. Polycyclic aromatic hydrocarbons (PAHs) Effects of Tobacco 3. Which of the following mechanisms best explains Atherosclerosis, myocardial infarction the increased cardiovascular risk associated with Related to factors including increased platelet aggregation, chronic smoking? decreased myocardial oxygen supply because of significant a. Vasodilation due to chronic nicotine exposure B lung disease, coupled with hypoxia related to carbon b. Endothelial dysfunction and increased atherosclerosis monoxide content of cigarette smoke, accompanied by c. Decreased platelet aggregation increased oxygen demand. d. Enhanced oxygen-carrying capacity of hemoglobin PART 3: ALCOHOL Question & Choices Answer & Rationale 1. Which of the following enzymes plays the primary Most of the alcohol in the blood is metabolized into role in the metabolism of alcohol in the liver? acetaldehyde in the liver by three (3) enzyme systems: a. Acetaldehyde dehydrogenase 1. microsomal ethanol-oxidizing system D b. CYP2E1 2. alcohol dehydrogenase (main enzyme system located in the c. Catalase cytosol of hepatocytes) d. Alcohol dehydrogenase 3. catalase 2. Chronic alcohol consumption leads to fatty liver Alcohol oxidation by alcohol dehydrogenase causes the primarily due to which of the following reduction of NAD to NADH, with a consequent decrease in NAD mechanisms? and increase in NADH. The decreased level of NAD (needed for a. Decreased mitochondrial beta-oxidation of fatty acids A fatty acid oxidation and conversion of lactate to pyruvate) leads b. Inhibition of gluconeogenesis to fatty liver c. Increased acetaldehyde production d. Increased bile acid production 3. A 50-year-old man with a history of chronic Thiamine (Vitamin B1) deficiency is common in chronic alcoholism presents with symptoms of confusion, alcoholics.The principal lesions resulting from this deficiency are ataxia, and ophthalmoplegia. Which of the peripheral neuropathies and the Wernicke-Korsakoff syndrome. following deficiencies is most likely responsible for Cerebral atrophy, cerebellar degeneration, and optic neuropathy his symptoms? A may also occur a. Thiamine (Vitamin B1) b. Vitamin D c. Folate d. Vitamin C PART 4: DRUGS AND PHYSICAL AGENTS Question & Choices Answer & Rationale Effects of OCPs: Breast cancer and other cancers 1.Which of the following is a known risk associated no increase in breast cancer with long-term use of oral contraceptive pills Endometrial and ovarian cancers (OCPs)? OCs have protective effect that may last for decades a. Increased risk of breast cancer following cessation of OCs b. Increased risk of ovarian cancer C Thromboembolic events c. Increased risk of venous thromboembolism DVT and Pulmonary Embolism increased d. Increased risk of endometrial cancer Most studies show that OCs, including the new low-dose formulations containing