Download Toxicity

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
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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
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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
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Growth retardation
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Behavioral abnormalities
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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?)


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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
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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