Toxicology Flashcards
Toxicology
Science of adverse effects of chemicals on living organisms
Major areas of toxicology
Descriptive- toxicity testing in cells, animals, humans
Mechanistic- how chemicals cause adverse effects and how the body protects against them
Regulatory- rule making and compliance
Food and Drug Administration (FDA)
Drugs, medical devices, cosmetics, food additives
Environmental Protection Agency (EPA)
Pesticides, toxic chemicals, hazardous wastes, and toxic pollutants in water and air
Occupational Safety and Health Administration (OSHA)
Determines whether or not employers are providing working conditions that are safe for employees
Forensic toxicology
Combines analytical chemistry and fundamental toxicology to investigate postmortem the cause or circumstances of death, concerned with medicolegal aspects of chemicals
Clinical toxicology
Treat patients who are poisoned by drugs and other chemicals and develop new techniques for diagnosis and treatment of intoxications
Signs and symptoms can be caused by toxic chemicals
From administered therapeutic agents and/or the environment
Dose-response relationship in individual
Graded dose-response relationship
Dose-response relationship in population
Quantal dose-response relationship, extremely important in toxicology, LD50 is determined experimentally
Shape of dose-response curve in individual
Shape of graded dose response relationship in an individual is U-shaped, low doses have high level adverse effect, too high of a dose has different adverse effect
Hormesis
Nonnutritional toxic substances that may impart beneficial or stimulatory effects at low doses but produce adverse effects at high doses (ex- alcohol)
Dose-response curve of alcohol
Chronic consumption increases risks of esophageal, stomach, and liver cancer, low-moderate consumption may reduce incidence of coronary heart disease and stroke
Therapeutic index (TI)
TD50 / ED50
Margin of safety
LD1 / ED99
Mechanism of toxicity- delivery
Toxication- biotransformation to harmful products
Detoxication- biotransformation that eliminates the ultimate toxicant or prevent formation
Mechanism of toxicity- reaction
Reaction of toxicant with target molecule or biological microenvironment
Mechanism of toxicity- cellular dysfunction and resulting toxicities
Cell regulation (signaling), cell maintenance (survival)
Cell regulation (signaling)
Dysregulation of gene expression- inappropriate cell division, apoptosis, or protein synthesis
Dysregulation of ongoing cell function- inappropriate neuromuscular activity, tremors, convulsion, arrhythmia, paresthesia
Cell maintenance (for survival)
Impaired internal maintenance- ATP synthesis, membrane function, protein synthesis
Impaired external maintenance- impaired function of integrated systems
Mechanism of toxicity- repair or disrepair
Repair- molecular, cellular, tissue repair
Disrepair- necrosis, fibrosis, carcinogenesis
Prevention of acute poisonings
Most poisonings from drugs can be prevented by physicians providing common sense instructions, patients or parents of patients accepting the advice
Division of toxic agents
Those for which specific treatment antidote exist
Those for which there is no treatment- majority of drugs and chemicals, require medical care that supports vital functions
Supportive therapy
Most important aspect of treatment of drug poisoning
Strategy for treatment of poisoned patient
Clinical stabilization of patient, clinical evaluation, prevention of further toxic absorption, enhance toxin elimination, administration of antidote, supportive care and clinical follow-up
Stabilization
First priority, assessment of vital signs and respiration/circulation, ventilation support, circulation support, oxygenation, in critically ill, treatment interventions must be initiated before patient is stable
Clinical evaluation
Determine the substance and time of exposure, get information from family, EMT, etc, assume maximal level of exposure, unobtainable history proceeds as unknown ingestion poisoning
Physical examination
Assess patient’s condition, mental status, trauma, infection, initiation of rational treatment based on most likely toxin responsible
Laboratory evaluation
Some drugs or chemicals are available for immediate measurement in a hospital facility, number of agents is limited
Anion gap
Difference between concentrations of serum Na ion and the sum of serum Cl and HCO3 ion, normal is <12, metabolic acidosis and elevated anion gap suggest toxicity
Osmol gap
Numerical difference between the measured and calculated serum osmolality, normal is <10 mOsm, elevated osmol gap suggests presence of osmotically active substances in the plasma not accounted for by Na, glucose, or BUN
Radiographic examination
Use is limited, may detect ingested substances, may detect lesions to specific organs
Prevention of further toxin absoprtion
Toxins from inhalation- remove patient from environment
Toxins from contact- remove clothing, wash skin
Toxins from ingestion- methods of emesis, gastric lavage (dilution), charcoal administration, whole bowel irrigation
Enhance toxin elimination
Alkalinization of urine, hemodialysis, hemoperfusion, hemofiltration, hemodiafiltration, plasma exchange or exchange transfusion, serial oral activated charcoal
Alkalinization of the urine
Ionize weak acids for elimination
Hemodialysis
Remove toxins by passing blood through semipermeable dialysis membrane
Hemoperfusion
Remove toxins by passing blood through a cartridge containing absorptive material
Hemofiltration
Removal of ultrafiltrate of plasma and replacement with sterile solutions
Hemodiafiltration
Hemodialysis plus removal of ultrafiltrate of plasma and replacement with sterile solutions
Plasma exchange or exchange transfusion
Removal of plasma and replacement with frozen donor plasma, albumin, or both
Serial oral activated charcoal
Remove toxins by serving as “sink” for toxins
Administration of antidote
Small number of specific antidotes are available clinically in the treatment of poisoning, antidotes may be chelators, antagonists, reactive chemicals to increase detoxifying capacity for the toxins
Supportive care
Some toxins have delayed toxicity, some exhibit multiple phases of toxicity, close monitoring can detect later-phase complications, psychiatric assessment to prevent future poisoning
Environmental toxicants
Air pollutants, pesticides, plant toxins
Pollutants that account for most of air pollution
Carbon monoxide, sulfur oxides, nitrogen oxides, volatile organic compounds, particulate matter
Reducing type of pollution
Sulfur dioxide and smoke from incomplete combustion of coal and by conditions of fog and cool temperatures
Oxidizing type of pollution
Hydrocarbons, oxides of nitrogen, photochemical oxidants from automobile exhaust in areas with intense sunlight, causing photochemical reactions
Carbon monoxide (CO)
Colorless, odorless, tasteless, nonirritating gas from incomplete combustion of organic matter, produced from forest fires, ocean microorganisms, inadequate furnace venting, automobiles, cigarette smoke
Toxicology of carbon monoxide
Binding site of hemoglobin is ferrous heme that can reversibly bind oxygen, CO prevents oxygen binding by forming a bond with ferrous heme significantly stronger than oxygen-heme bond
Mechanism of CO poisoning
When 50% of O2 binding sites on hemoglobin are occupied by CO, no more than 50% saturation of O2, at tissue, hemoglobin saturation is still over 35%, less than 15% of heme sites can deliver O2 to tissues
CO2 poisoning
In addition to interference with O2 delivery, CO binds to cellular cytochromes in respiratory enzymes and myoglobin and interfere with enzyme function, anemic individuals are more susceptible, signs of CO poisoning mimic hypoxia
Pathology of CO poisoning
Tissues most affected are those most sensitive to O2 deprivation- permanent damage to brain and heart, headache due to cerebral edema and increased intracranial pressure
Diagnosis of CO poisoning
Facilitated by circumstantial evidence, living patient is commonly cyanotic and pale, “cherry-red cyanosis” seen only at autopsy (CO hemoglobin is cherry-red)
Excretion of CO
Once exposure to CO is terminated, it will be excreted from lungs, CO concentration of blood decreases with half-time of 320 min in room air, 100% O2 is 80 min, hyperbaric is <25 min
Treatment of CO poisoning
Transfer patient to fresh air, artificial respiration if respiration failed, 100% oxygen or hyperbaric oxygen
Prolonged low-level CO exposure
Shift from aerobic to anaerobic metabolism, increased incidence of atherosclerosis, impaired vigilance test, long term exposure can cause development of polycythemia
CO exposure and fetus
Fetus is susceptible, gas readily crosses the placenta, gross damage to brain, neurological sequelae
Toxicity of sulfur dioxide
Burning of fossil fuels contains sulfur, water soluble upper airway irritant, stimulates mucus secretion and bronchoconstriction
Mechanism of sulfur dioxide toxicity
Portion of SO2 converted in atmosphere to sulfuric acid (H2SO4), ammonium sulfate, and other sulfates, sulfuric acid irritates upper airway due to acidity- more bronchoconstriction than SO2, chronic exposure injuries phagocytes and endothelial cells, can cause bronchitis
Donora fog
Mainly comprised of ammonium sulfate, more bronchoconstriction than SO2, associated with increased mortality
Toxicity of nitrogen dioxide (NO2)
Deep lung irritant, can produce pulmonary edema if inhaled at high concentrations, causes bronchiole inflammation, high concentration damages bronchiole epithelial cells and cause loss of ciliated cells and secretory granules
Volatile organic compounds (VOC)
Gases emitted from certain solids or liquids under normal indoor pressure and temp, higher concentration indoors, cause eye and respiratory tract irritation, headaches, dizziness, visual disorders, memory impairment
Sources of VOC
Paints and lacquers, paint strippers, cleaning supplies, pesticides, building materials, furnishings, office equipment, craft materials, tobacco smoke
Formaldehyde
Act via sensory nerves that signal through trigeminal nerve, induce bronchoconstriction through vagus nerve, associated with nasopharyngeal cancer in humans, linked to leukemia and sinonasal cancer
Sources of formaldehyde
Product of construction materials such as plywood, furniture, polymerized urea-formaldehyde from insulation
Particulate matter
Combination of organic, inorganic, biological material, causes pneumoconiosis- restrictive lung diseases caused by inhalation of dust particles
Pneumoconiosis
Most common is silicosis, macrophages proliferate and migrate to site of reaction to release cytokines and other growth factors, cause replication of fibroblasts and collagen synthesis
Asbestos
Long-term inhalation of dust, causes three forms of lung disease: asbestosis, bronchial lung cancer, malignant mesothelioma
Asbestosis
Pulmonary fibrosis, develops first in areas adjacent to bronchioles, formation of fibrous pleuritis, dyspnea, tachypnea, cough
Bronchial lung cancer
Occur 20-30 years after exposure, increased incidence with cigarette smoking
Malignant mesothelioma
Cancer of thin cell wall lining internal organs, occurs 25-40 years after exposure
Pesticides
Include insecticides, rodenticides, fungicides, herbicides, fumigants, major insecticides: organochlorine, organophosphorus
Organochlorine
Chlorophenothane (DDT)- highly lipophilic, stored in fat, major environmental effect, declining bird population, banned form US in 1972
Organophosphates
Parathion, malathion- do not persist in environment, low carcinogenic potential, inhibits cholinesterases through phosphorylation of esteratic active site
Signs and symptoms of organophosphate toxicity
Cholinergic symptoms- sweating, salivating, bronchiole secretion and constriction, miosis, increased GI motility, diarrhea, tremors, muscle twitching, severe poisoning may cause respiratory collapse
Treatment of organophosphate toxicity
IV atropine to prevent excessive muscarinic action and pralidoxime to prevent aging
Agent orange
Herbicide, used in Vietnam war to defoliate forests, causes vomiting, burning of mouth, abdominal pain, hypotension, and CNS effect including coma, causes soft-tissue sarcoma, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia
Paraquat
Accumulates in lungs and kidney, poorly metabolized and excreted unchanged in urine
Paraquat toxicity
Damages alveolar epithelial cells within 24 hours, leads to loss of alveolar epithelium, alveolar edema, interstitial inflammatory cells infiltration, death due to anoxia
Signs of paraquat toxicity
1st phase- extensive proliferation of fibroblasts in the lung
2nd phase- attempted alveolar epithelium regeneration, intensive fibrosis
Rodenticides
Compound 1080, causes CNS and heart toxicity, anticoagulants- warfarin/coumarin derivatives, dispersed in grain-based baits
Fumigants
Active against insects, mites, nematodes, weed seeds, fungi, rodents, liquids readily vaporize, may cause respiratory, GI, neurologic symptoms
Plant toxins- skin
Allergic dermatitis caused by plants, flower growers at risk, major allergen in natural rubber latex from rubber tree
Plant toxins- respiratory tract
Pollen causes summer rhinitis (hay fever, pollinosis), workers that handle peppers- capsaicin depletes neuropeptide P, increase incidence of cough
Plant toxins- GI system
Nausea, vomiting, diarrhea, cholchicine is major alkaloid in autumn crocus- Gi effects, antimitotitic, confusion, delirium, hematuria, neuropathy, bone marrow aplasia, renal failure
Plant toxins- cardiovascular system
Cardioactive glycosides (digitalis)- found in plants, when eaten may present with nausea, vomiting, cardiac arrhythmias, ergots- fungus parasitics on grains of rye, cause vasoconstriction in extremities followed by gangrene
Plant toxins- liver
Most deaths from mushroom poisoning are due to liver damage, A. phalloides has phalloidin- combines with muscle cell actin to interfere with muscle function (diarrhea), and amatoxins- strong affinity for hepatocytes where it binds to RNA polymerase II, inhibiting protein synthesis, liver failure, death
Plant toxins- bladder
Bracken fern contains carcinogen ptaquiloside, alkylates adenines and guanines of DNA, increased incidence of epithelial and bladder tumor, esophageal and stomach cancers
Plant toxins- kidney
Woodland fungi cause acute degenerative tubular lesions with inflammatory interstitial fibrosis, acute renal failure
Plant toxins- nervous system
Cicuta maculata (water hemlock)- contains cicutoxin, binds GABA-gated chloride channels, cause tonic-clonic convulsions, some mushrooms- muscarine, causes parasympathetic stimulation, some plants- anticholinergic alkaloids, parasympathetic blockade
Plant toxins- skeletal muscle
Some plants contain nicotine- prolonged depolarization of NMJ, causes muscle weakness, respiratory compromise, muscle spasm, GI irritation, curare- neuromuscular blocking agent, stops respiration, blocks AChR
