Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Pathobiology: Inhalant, Chemical and Drug Toxicity XENOBIOTIC METABOLISM: General: Xenobiotics: foreign, often lipophilic, potentially injurious chemicals that can be absorbed by inhalation, ingestion or skin contact Liver: primary site of metabolism General Process: o Deactivation to nontoxic, water-soluble metabolites that can be excreted (ie. urine, bile) o Activation into possibly toxic products Phase I Reactions: Examples of Phase I Reactions: oxidation, reduction and hydrolysis Examples of Enzymes Catalyzing Phase I Reactions: cytochrome p450 mixed-function oxygenases (CYPs) o Subject to induction and inhibition o Also a vast amount of genetic heterogeneity Phase II Reactions: Process: conjugation of the parent xenobiotics OR phase I metabolites with hydrophilic groups o Examples: glucuronic acid, inorganic sulfate, amino acids, glutathione, methyl groups Examples of Enzymes Catalyzing Phase II Reactions: o Glucuronyl transferases o Sulfotransferases o Glutathione transferases AIR POLLUTION: General: Greatest density in populated regions and near heavy industry Most significant effects on airways and lungs o Bronchial hyperreactivity, increased pulmonary infections, decreased pulmonary function o People with asthma and chronic lung disease are especially susceptible to these complications May also affect eyes, nose and throat Outdoor: Ground level ozone (O3): produces free-radical injury and secondary inflammation Sulfur and nitrogen oxides Particulates (soot): especially small particles that can be inhaled into the alveoli, causing an inflammatory rxn Indoor: Smoke: from tobacco, wood; also potentially carcinogenic Microbial-contaminated aerosols Allergens: dust mites, molds, pet dander Radon Formaldehyde: also carcinogenic TOBACCO ABUSE: General: Increased mortality: dose-dependent Synergistic carcinogenic effects: significantly amplifies carcinogenic effects of other agents (alcohol, asbestos) Quitting: results in slowing of loss of pulmonary function, and decreased mortality due to CV disease and lung carcinoma over time Secondhand smoke: also bad (esp. for children exposed in the home) Components: Nicotine: addictive; stimulates release of catecholamines (CV effects) Mucosal irritants: nitrogen oxides Carbon monoxide: results in decreased O2-carrying capacity Chemical carcinogens: both initiators and promoters o Examples: benzo[a]pyrene, polycyclic aromatic hydrocarbons, tar, phenol, nitrosamines Adverse Effects on Heath: Chronic Obstructive Pulmonary Disease (COPD): chronic bronchitis and emphysema Carcinomas: o Lung o Upper aerodigestive tract (lip, mouth, pharynx, larynx) - o Esophagus o Pancreas o Urinary bladder o Kidney o Uterine cervix Atherosclerosis Myocardial Infarction: due to decreased O2 supply AND increased O2 demand Pregnancy-related Complications: increased risk of miscarriages, premature infants and IUGR ETHANOL ABUSE: Metabolism of Ethanol: Location: liver Factors Affecting Individual Tolerance to Alcohol: o Genetic variability o Acquired induction of enzymatic action Contributors to Tissue Toxicity: injury to the liver and carcinogenic effects o Ethanol o Acetaldehyde (metabolic product of ethanol oxidation) Process: o Ethanol Acetaldehyde Primarily by alcohol dehydrogenase in cytosol Also by micorosomal ethanol-oxidizing system (high ethanol blood levels) Also some breakdown by catalase o Acetaldehyde Acetate Primarily by acetaldehyde dehyrodgenase Adverse Effects on Health: Acute: o Liver: Fatty change/steatosis (generally reversible) Increased: o Fatty acid uptake and synthesis o TG production Decreased: o Fatty acid oxidation o Lipoprotein secretion o Upper GI Tract: Acute gastritis Mallory-Weiss tears of lower esophagus (ie. due to vomiting) o CNS: Depressant Drowsiness Impaired motor and cognitive function Stupor Coma Respiratory arrest Chronic: o General: effects often associated with the following Protein-energy malnutrition Deficiencies in water soluble vitamins (ie. thiamine, folate) o Liver: Hepatocyte injury and necrosis (hepatitis) Mechanisms: o Direct toxic effects on cell membranes o Oxygen-derived free radical reactions o Immune-mediated damage directed against acetaldehyde modified cell surface molecules o Inflammatory cytokines o o o o o o Can lead to alcoholic hepatitis and cirrhosis (fibrosis, hyperplastic nodules) Associated complications: o Portal hypertension o Hepatic failure o Increased risk of hepatocellular carcinoma Liver injury can also go straight from steatosis to cirrhosis o Do not need to have hepatitis first GI Tract: conditions causing upper GI bleeding Gastritis Peptic ulcer disease Esophageal varices (due to portal hypertension) Pancreas: increased risk for acute and chronic pancreatitis CNS and PNS: Cerebral and cerebellar (esp. vermis) atrophy Thiamine deficiency can lead to peripheral neuropathy (dry beriberi) and WernickeKorsakoff’s syndrome CV System: Increased risk of atherosclerosis and HTN (with heavy alcohol intake) Dilated cardiomyopathy Carcinomas: increased incidence Upper aerodigestive tract (lip, mouth, pharynx, larynx) Esophagus Liver Fetal Alcohol Syndrome: due to alcohol consumption during pregnancy Microcephaly Impaired cognitive function Growth retardation Behavioral abnormalities Facial defects HEAVY METAL EXPOSURE: Lead (Pb) Toxicity: General: o Toxicity in children greater than adults: Increased intestinal absorption Less effective BBB Sources of Exposure: inhaled or ingested o Children: ingestion of lead-contaminated paint, dust or soil o Adults: certain occupations such as construction, manufacturing, mining, smelting, welding, radiator repair and work on firing ranges (lead in ammunition) Pathologic/Clinical Findings: o Matrix of Bone/Developing Teeth: lead competes with Ca++ for incorporation into osteoid Increased bone density (radiodense lead lines at the metaphyses of growing long bones) Decreased bone mineralization (poor bone growth and remodeling) Pregnancy can trigger release of lead from bone and into circulation (affect fetus) o Bone Marrow and Peripheral Blood: lead inhibits δ-aminolevulinic acid (ALA) dehydrogenase and ferrochelatase enzymes Result: decreased incorporation of iron into protoporphyrin, leading to increased levels of protoporphyrin (and ALA) and decreased synthesis of Hb Bone Marrow: ringed sideroblasts (RBC precursors with iron-laden mitochondria) Peripheral Blood: microcytic, hypochromic anemia with punctate basophilic stippling of RBCs o Nervous System: CNS: mostly in kids (wide range of symptoms) Learning disabilities, ADD, behavioral problems, poor motor coordination, impaired hearing, irritability, decreased intelligence (b/c of interference with Ca++ channels during nerve conduction?) Seizures, dementia, coma and death (w/ associated cerebral edema, neuronal necrosis and demyelination) PNS: mostly in adults Demyelinating motor neuropathy leading to muscle weakness o Examples: wrist drop, foot drop o GI Tract: severe abdominal pain (lead colic) o Kidneys: tubular injury (hyaline intranuclear lead inclusions) Decreased uric acid excretion (saturnine gout) Chronic kidney disease o Other: Blue-black lead lines at the gum margins Infertility Muscle and joint pain Mercury (Hg) Toxicity: Sources of Exposure: inhaled, ingested or absorbed through skin o Inorganic Mercury: Mining of mercury, gold and silver ores Manufacturing products containing mercury Fossil fuel combustion Solid waste incineration Volcanoes Fungicide o Elemental (Metallic) Mercury: liquid metal that vaporizes at room temperature Producing, using or breaking products containing mercury (thermometers, barometers, fluorescent light bulbs, electric switches, dental amalgams) o Organic Mercury (Methylmercury): most common source** Ingestion of contaminated fish and shellfish Inorganic/elemental mercury from the atmosphere and soil gain access to bodies of water Conversion by microorganisms (ie. bacteria) to methylmercury Concentrates up the food chain (bioaccumulation) Pathologic/Clinical Findings: o CNS: primarily causes CNS damage (esp. in children exposed in utero) Cognitive abnormalities Impaired hearing and vision Seizures Sensory and motor nerve dysfunction Fine tremor Personality changes o Other Organs Occasionally Involved: kidneys, GI tract, lungs, gingiva, skin, CV system Arsenic (As) Toxicity: Sources of Exposure: primarily ingested (but can also be inhaled or absorbed through skin) o Naturally occurring, inorganic arsenic found in soil and water o Increased contamination from industrial processes (mining, timber treatment, burning fossil fules) and agricultural runoff (pesticides, herbicides) Pathologic/Clinical Findings: o Acute Poisoning: Metallic taste in the mouth, garlic odor to the breath Hypersalivation Vomiting, abdominal pain, bloody diarrhea Hemolytic anemia Hypovolemic shock Seizures Delirium Coma and death o Chronic Low-Level Poisoning: Non-Malignant Disorders: Pigmentation abnormalities (raindrop pigmentation, Mees lines of nails) Hyperkeratosis (esp. palms and soles) Sensorimotor peripheral neuropathy Other (CV, pulmonary, hepatic, renal and bone marrow disorders) Malignancies: skin, lung, kidney, urinary bladder Cadmium (Cd) Toxicity: Sources of Exposure: o Inhalation of Aerosolized Products: Industrial workplaces (ore processing/smelting, handling of cadmium-containing batteries, incinerating waste) Cigarette smoking Hobbies (jewelry making, engraving, ceramics) o Ingestion: contaminated water or food (cereal grains, vegetables) Pathologic/Clinical Findings: o Kidneys: most severely affected* Worsening renal tubular dysfunction leading to glomerular damage and chronic kidney disease o Respiratory Tract: Acute: chemical pneumonitis and flu-like symptoms (can be lethal) Chronic: decreased pulmonary function, lung carcinoma, anosmia o Bones: Osteomalacia and osteoporosis (secondary to renal injury) ADDITIONAL HAZARDOUS CHEMICALS: Benzene Toxicity: General: organic solvent with aromatic ring structure Sources of Exposures: mostly inhaled as a vapor, but can be ingested and absorbed through the skin o Industrial emissions (manufacturing of styrofoam and other plastics, resins, nylon and rubber; gasolinerelated industries) o Incomplete combustion of carbon-rich materials (tobacco/wood smoke, motor vehicle exhaust, volcanoes) Pathologic/Clinical Findings: o Acute: mostly CNS effects (drowsiness, dizziness, confusion, LOC, even death) o Chronic: toxic metabolites affect the bone marrow pluripotent stem cells Produced by p450 enzymatic system Result in various cytopenias and malignancies (esp. AML) Vinyl Chloride: Industrial chemical used to produce PVC Prolonged exposure associated with hepatic angiosarcoma (rare liver malignancy) 2-Naphthylamine: Arylamine previously used in rubber and dye industries Increased risk of urothelial carcinoma of the urinary bladder ADVERSE DRUG REACTIONS: Hormone Replacement Therapy (HRT): General: variability in the risk to benefit ratio based on the following o Drug preparation o Route of administration o Patient age and medical history o Duration of treatment Benefits: o Decreased menopausal symptoms (ie. hot flashes, vaginal dryness) o Decreased bone loss (osteoporosis) and fractures o Decreased risk of colorectal carcinoma o Decreased risk of CV atherosclerotic disease when taken during early menopause (<60); unclear* Risks: o Increased thromboembolic complications (esp. in women with predisposing conditions like factor V Leiden mutations) o Increased breast carcinoma with continuous use and increased breast density (possibly false + mammograms) o Increased CV atherosclerotic disease when taken later in menopause (>60) o Increased gallbladder disease o Inconsistent results for risk of ovarian cancer and dementia Oral Contraceptives: General: health risks influenced by the following o Specific formulation o Mode of delivery o Age of the patient o Smoking history of the patient Increased Risk of the Following: o Thromboembolic events (esp. in patients with genetic predisposition for hypercoagulability) o CV disease (esp. in patients who smoke or are over 35) o Endometrial and ovarian carcinoma o Liver cell adenoma (benign tumor that can rupture and cause bleeding), esp. with prolonged use Anabolic Steroids: General: synthetic testosterone formulations, often taken at high doses to enhance athletic performance Adverse Effects: o Gynecomastia and testicular atrophy in men o Virilization in women o Stunted growth in adolescents o CV complications (HTN, tachycardia, alterations in lipid metabolism) o Psychiatric abnormalities (mood disorders) o Liver damage Acetaminophen: Metabolism: o Most detoxified by phase II enzymes and excreted in urine as glucuronate or sulfate conjugates o Small mount metabolized by CYP2E1 (which is also induced by alcohol), resulting in formation of NAPQ Formation of protein adducts and lipid peroxidation (liver failure) Can be removed via conjugation with GSH (process can become saturated) Toxicity: o Chronic alcohol abuse lowers the threshold o Hepatocellular necrosis leading to acute liver failure (most common cause of liver failure) Aspirin (Acetylsalicylic Acid): Toxicity: o Acid-base disturbances o Catabolic state with multiple metabolic abnormalities o GI effects (N/V, acute gastritis, ulceration) o Dehydration o Ototoxicity (tinnitus, hearing loss- due to neuronal toxicity) o CNS effects (anxiety, confusion, drowsiness, blurred vision, delirium, seizures, coma) o CV and hepatic abnormalities