Toxicology Flashcards
Most toxic substance
1) botulinus toxin
2) dioxin
Toxin
Toxic substance of bacterial, plant, animal
Organophosphate/carbamate
Anticholinergic
Toxic parent compound
Lead, carbon monoxide
Toxic metabolite
Carbon tetrachloride - phosgene
Ethylene glycol - oxalic acid
Reactive oxygen/nitrogen species
Pesticides
Oxygen radical, hydrogen peroxide, hydroxy radical, lipid perixidation
Oxidative stress if imbalance with radicals and antioxidant imbalance
Alzheimer’s, Parkinson’s, cancer, cardio
Radical detoxication
Oxygen radical SOD to H2O2 Glutathione peroxidase (GPO) to water with the help of glutathione
FDA
Federal food drug and cosmetics act
Environmental protection agency
Pesticides
Toxic control act
OSHA
CPSC
Occupational safety
Consumer product safety
Increases death by 1/million
Smoking
Living in a city - air pollution
Peanut butter
Charbroiled steaks
4 step Risk assessment
Hazard identification
Dose-response
Exposure
Risk characterization in exposed population
Saccharine
Artificial sweetener
Bladder tumors
Pre clinical tests
Animal tests for safety and efficacy
Acute toxicology - high dose, LD50
subchronic toxicity - adverse effects
carcinogenicity
Therapeutic index
LD50/ED50
10 is ideal
You want high lethal dose, low effective dose
Food additive no effect dose
100 times human consumption level
Phase 1 clinical trial
Toxicity profile in healthy volunteers
Phase 2 clinical trial
Safety and efficacy in patients
Phase 3 clinical trial
Establish dose-range and form
Larger number of patients hundreds
Phase 4 clinical trial
Post-market safety
Collections of additional data
Drug development facts
Cost >1 billion
12 years
Insecticides
Parathion
Carbaryl
DDT
Pyrethrum
Parathion
Most toxic organophosphate, activated to paraoxon by CYP
ACh accumulation at receptor sites via AChE blockage
Phosphate (binds to esteric site) can’t be rescued if ethyl groups are cleaved.
Increased cholinergic tone. SLUD
Salivation, lacrimation, urination, diarrhea
Chronic: sensory and motor neurotoxicity
ACh on nicotinic
Nm: striated muscle, cramps, weakness
Nn: tachycardia
Anxiety, insomnia, respiratory depression
Parathion treatment
Atropine followed by 2-PAM
Atropine for ACh symptoms
2-PAM binds to anionic site to cleave off phosphate group and rescue AChE
Carbamate
Less toxic than organophosphate
Like parathion but rapidly reversible
Treat with atropine only for symptoms
2-PAM may inhibit anionic site. AChE will be restored naturally over time
Pesticide but also used clinically for myasthenia gravis and glaucoma (relieve intraocular pressure) - physostigmine
DDT
Wide margin of safety between pests and humans
Toxic to fish, food chain, bald eagle shells thin through low estrogen, low Ca
More negative neuron membrane after causing prolonged action potential and repeated firing
Can cause breast cancer
DDT treatment
Anticonvulsant, diazepam
Pyrethrum
Active ingredient: Pyrethrin I most active
Affects action potential like DDT (CL- transport)
Neuron toxicity: convulsions, ataxia
Increases metabolism in mammals
Herbicides
Most active ingredients out of all pesticides
2,4 Dichlorophenoxy acetic acid
2,4,5 trichlorophenoxy acetic acid - banned b/c of carcinogenicity
2,4-D
Membrane damage
Interfere with acetyl CoA in metabolism
Uncoupling of oxidative phosphorylation
Less ATP produced
Treat with bicarbonate iv to alkinalize urine and ionize 2,4-D for excretion
2,4,5-T
Vietnamese population: birth defects
Toxic due to tetrachlorodibenzodioxin (TCDD)
Carcinogenic
Pentachlorophenol
Fungicide
Elevated body temperature
Mechanism: decreased H+ permeability
Short circuiting of ATP synthesis
Increased metabolic rate
Excessive heat generation
Treatment: cholestyramine
Rodenticide
Warfarin - teratogenic
Brodifacoum
Bleeding gums, bloody urine, hematoma
Warfarin weakens capillary walls causing hemorrhage and unable to clot by inhibiting vitamin K reductase
Treat with vitamin K
Cyanide
Fumigant, causes hypoxia, respiratory arrest
Bitter almond breath diagnostic
High affinity for Fe3+ on Cyt. Oxidase
Blocks oxygen utilization and inhibits cellular respiration, decreases ATP, and cell death
Can cause heart and brain damage
Cyanide treatment
1)Na-nitrite: methylHb(Fe3+) formation frees Cyt. Oxidase
Na-thiosulfate : frees MetHb(FeCN) and excretes SCN in urine
100% O2: maximizes recovery
Solvent toxicity factors
Low surface tension - spreading
Low viscosity - reaching distal airways
High volatility- vaporized & available for absorption
Lipid solubility- facilitation of absorption
Solvent - dissolution of membranes
Carbon tetrachloride (solvent)
Parent and metabolite are toxic
CCl3 radical leading to lipid peroxidation
Phosgene - covalent bonding to proteins and lipids
Stage 1: CNS, respiratory depression
Stage 2: hepatic damage
Stage 3: renal effects
Chronic toxicity: cirrhosis, liver cancer
Treatment - dialysis to remove metabolite
Methanol
Paint, varnish, aspartame in diet drinks
Metabolized by alcohol dehydrogenase
Hangs around more than ethanol (lower affinity for ADH)
Formaldehyde to formate acidosis toxicity
Diagnostic: urine has formaldehyde odor
Methanol treatment
Gastric lavage (remove unabsorbed toxin) Bicarbonate - neutralize acid formate Hemodialysis - clean blood Ethanol - competitive antagonist 4-Methyl Pyrazole (fomepizole) inhibits ADH and slows metabolism to formaldehyde
Ethylene Glycol
Forms oxalic acid and calcium oxalate crystals via ADH and GDH
Stage 1: NV, CNS depression, inebriation Stage 2 (most deadly) 12 hours: Ca-oxalate deposits in blood vessels, lungs, myocardium, CNS meninges causing tachycardia, CHF, pulmonary edema, hypocalcemia
Stage 3: renal tubular necrosis and oliguria from Ca-oxalate deposits
Ethylene glycol treatment
Drunkard w/o alcoholic breath
Gastric lavage
Fluids
Bicarbonate for acidosis
Ca-gluconate: to replace Ca deficiency
Competitive ADH inhibitor - ethanol, fomepizole
Propylene glycol
GRAS food additive
Benzene
Most toxic component in gasoline
Converts to phenol and phenoxyl radical leading to oxidative stress and bone marrow suppression
No antidote, only supportive care
Chronic: CNS effects, carcinogen, bone marrow cell production
Leukemia: chemotherapy
Aplastic anemia: bone marrow transplant
Metal toxicity mechanisms
Adventitious bind Oxidative stress Enzyme inhibition - arsenic to sulfur DNA damage Gene expression
Inhalation, poor GI absorption
Mercury
Dental amalgam, dental fillings, HgCl2
Thiomersal vaccines, Fish CH3Hg
Hg2+ has less absorption and cannot reach brain b/c of ion
In brain catalase converts Hg to toxic Hg2+
Neurotoxicity binds to BBB
Ionized excreted in the urine
Acute NVD via GI inflammation
Chronic mad hatter, renal damage, ataxia
Mechanism of mercury nephrotoxicity
Hg to SH groups of membrane proteins
Damage to glomerulus membrane
Causing glomerular nephritis and proximal tubular necrosis
USA Mercury
Salt water fish
New England
Pregnant women limit fish to once a week
Hair can tell history of exposure 1cm/month
Mercury treatment
Hg/Hg2+ : N-acetylpenicillamine to urine
CH3Hg : polythiol resin to feces or NAP
Lead (Pb2+)
Paint
Ultimately distributed to bones with a 32 year half-life
Inhibits heme biosynthesis (anemia), form lead-protein complexed in renal tubular cells, compete w/ calcium in bones
Chronic: brain damage in children
Lead treatment
Children: DMSA (metal chelation)
Adults: Ca, Na2-EDTA, replaces lead with calcium
Cadmium (Cd2+)
Ouch ouch
Inhalation, poor Gi absorption
Binds to metallothionein - t1/2 30 years
Damages kidney, VitD production
Chronic: lung cancer, renal dysfunction, breast cancer, osteomalacia, Ca deficiency
Treat osteomalacia with VitD
No effective chelating agent
Arsenic gas
Arsenite (3+)
Arsenate (5+)
Mono/dimethyl-arsenates
Short half life liver/kidney
Arsenate-arsenite-monomethyl-dimethyl-trimethylarsenate: causing oxidative damage
Acute: Arsenate 5+ mimics phosphate during glycolysis and causes uncoupled oxidative phosphorylation. No ATP produced
As3+ binds to SH groups on enzymes and inhibits pyruvate metabolism and decreases mitochondrial respiration ATP
Chronic: lipid peroxidation to cell death
Arsenic treatment
Breath has garlic odor
Multiple organ damage, anemia, cancer
Hemodialysis
Glucocorticoids
BAL, DMSA chelating agents
Pencillamine
Pulmonary toxicants
Small particles reach alveoli
Heavy particles get deposited in upper respiratory tract
Type 1 alveoli small cytoplasm, efficient gas exchange
Lung fibrosis
Inflammation leading to excess collagen to alveolar ducts
Lungs become stiff and smaller
Emphysema
Opposite of fibrosis
Type 1 alveolar cells destroyed and lose efficient gas exchange
Lungs become large, too compliant, and hyper inflated
Inefficient O2 CO2 gas exchange
Air pollution
60% automobiles
52% carbon monoxide (most abundant)
Smog = stagnant air
Sulfur dioxide to H2SO4 acid rain
Asthmatics most sensitive
H2SO4 / SO2
H2SO4More airway resistance, more clearance
Smaller particles more toxic
Acts on bronchial smooth muscle
Histamine release causing bronchial constriction
Chronic bronchitis: thickening of mucous layer
Gland hypertrophy
Metal chelating agents
For treatment
2 SH: DMSA, BAL, DMPS
SH & COOH: pencillamine, N-acetyl pencillamine
Nitrogen dioxide
Photochemical pollutant
Breaks down ozone UV protection
NO2 automobile exhaust
Pulmonary irritation
Lipid peroxidation
Damage to type 1 cells (emphysema)
Loss of celia, susceptible to infection
Formaldehyde
Irritant, automobile exhaust
Chronic: runny nose, sore throat, cough, headache
Ozone
Airline crew exposed
Dry throat, pulmonary irritation
Smog: limit outdoor activities and exertion
Chronic: O3 forms H2O2 lipid peroxidation, necrosis of type 1 cells-emphysema
Can cause compensatory fibrosis by increased collagen synthesis
Carbon monoxide
Heavy traffic, fires
Acute NV, afib, convulsions
Delayed neuropsych impairment, CVD
CO mechanism
1) reduced O2 in air for absorption
2) reduced O2 carrying capacity by Hb when bound by CO
3) reduced dissociation of O2 from COHb due to conformation change
4) reduced O2 transport in muscle/tissues
5) cytochrome-CO complexes lead to cellular hypoxia and lack cellular respiration
Carbon monoxide treatment
Diagnosis- Cyanic blue (CO-myo) when alive
Cherry red blood when dead
More toxic in high altitude (low air pressure), high ventilation (exercise), children
Treat 100% oxygen to dissociate COHb
Faster in hyperbaric chamber
Radon
Indoor air, basement
Chronic: lung, stomach cancer
Forms radioactive decay products (polonium)
Oxidative damage of nucleic acids and protein
ends at stable Pb lead
Seal basement, increase ventilation
Asbestos
Insulation
Lung cancer forms inside the lung
Pleural plaques scar and thicken lung walls
(Asbestosis) Progresses to Pleural mesothelioma outside lung lining
1) interaction with macromolecules
2) reactive oxygen species
3) inflammation
Treatment of malignant pleural mesothelioma
Surgery
Radiation
Pemetrexed antifolate
Cisplatin
Predifferentiation period
Up to day 17
Prenatal lethality if embryo unable to implant
Organogenesis period
Day 18-56
High susceptibility to teratogenesis
Histogenesis period
Day 50-90
Resistant to teratogenesis
growth retardation
Human development defects
20% genetic
5% drugs/chemicals
Teratogens
Thalidomide
Tobacco smoke
EtOH
Diethylstilbestrol
Thalidomide
Short/absent limbs
Sensitive 5-7 weeks
More toxic in humans than rabbits and mice
1) signal transduction interference
2) oxidative stress
3) intercalation with DNA in GC region
4) interfere with angiogenesis
Tobacco smoke
Cleft lip or palate
Low birth weight, slow growth
Learning disorders
300% sudden infant death syndrome
CO - hypoxia
HCN- cellular hypoxia (no respiration)
Cadmium - zinc deficiency
Nicotine- tachycardia
Ethyl alcohol
EtOH
Fetal alcohol syndrome
No threshold, one single drink can harm
Facial abnormalities
Growth retardation
Mental retardation neuro defect
Acetaldehyde decreases cell division and cell migration
Diethylstilbestrol
Synthetic steroidal estrogen
Indications: prostatic and breast cancer
No major malformations in infants
Post menopause mother 14x endometrial cancer
Boys - testicular defects, sperm abnormalities boys can reproduce healthy sperm
Girls - vaginal adenosis, adenocarcinoma
Risk of breast cancer after age 40
More age more egg exposure to DES
Reproductive study I
Single generation Toxicity study in rats
Drugs of short duration
For fertility and reproductive performance
Exposed prior to mating
Number of pregnancies and live fetuses
Reproductive study II
Perinatal - birth
Postnatal - after birth
Mid-gestation to lactation
Look for physical development
Behavioral effects
Reproductive Study III
Embryolethality
Teratology
Number of dead fetuses
Malformations in live fetuses
Multigeneration study
Required for:
1) drugs intended for chronic use
2) food additives & pesticides
Purpose:
1) transplacental carcinogenesis
2) germ cell mutations
Exposure throughout 2nd 3rd mating
Look for cancer, malformations, defects
Lipid peroxide
Cell degradation
Disrup lipid membrane I
