Toxicology Flashcards
(82 cards)
0
Q
Most toxic substance
A
1) botulinus toxin
2) dioxin
1
Q
Toxin
A
Toxic substance of bacterial, plant, animal
2
Q
Organophosphate/carbamate
A
Anticholinergic
3
Q
Toxic parent compound
A
Lead, carbon monoxide
4
Q
Toxic metabolite
A
Carbon tetrachloride - phosgene
Ethylene glycol - oxalic acid
5
Q
Reactive oxygen/nitrogen species
A
Pesticides
Oxygen radical, hydrogen peroxide, hydroxy radical, lipid perixidation
Oxidative stress if imbalance with radicals and antioxidant imbalance
Alzheimer’s, Parkinson’s, cancer, cardio
6
Q
Radical detoxication
A
Oxygen radical SOD to H2O2 Glutathione peroxidase (GPO) to water with the help of glutathione
7
Q
FDA
A
Federal food drug and cosmetics act
8
Q
Environmental protection agency
A
Pesticides
Toxic control act
9
Q
OSHA
CPSC
A
Occupational safety
Consumer product safety
10
Q
Increases death by 1/million
A
Smoking
Living in a city - air pollution
Peanut butter
Charbroiled steaks
11
Q
4 step Risk assessment
A
Hazard identification
Dose-response
Exposure
Risk characterization in exposed population
12
Q
Saccharine
A
Artificial sweetener
Bladder tumors
13
Q
Pre clinical tests
A
Animal tests for safety and efficacy
Acute toxicology - high dose, LD50
subchronic toxicity - adverse effects
carcinogenicity
14
Q
Therapeutic index
A
LD50/ED50
10 is ideal
You want high lethal dose, low effective dose
15
Q
Food additive no effect dose
A
100 times human consumption level
16
Q
Phase 1 clinical trial
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Toxicity profile in healthy volunteers
17
Q
Phase 2 clinical trial
A
Safety and efficacy in patients
18
Q
Phase 3 clinical trial
A
Establish dose-range and form
Larger number of patients hundreds
19
Q
Phase 4 clinical trial
A
Post-market safety
Collections of additional data
20
Q
Drug development facts
A
Cost >1 billion
12 years
21
Q
Insecticides
A
Parathion
Carbaryl
DDT
Pyrethrum
22
Q
Parathion
A
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
23
Q
ACh on nicotinic
A
Nm: striated muscle, cramps, weakness
Nn: tachycardia
Anxiety, insomnia, respiratory depression
24
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
25
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
26
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
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DDT treatment
Anticonvulsant, diazepam
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Pyrethrum
Active ingredient: Pyrethrin I most active
Affects action potential like DDT (CL- transport)
Neuron toxicity: convulsions, ataxia
Increases metabolism in mammals
29
Herbicides
Most active ingredients out of all pesticides
2,4 Dichlorophenoxy acetic acid
2,4,5 trichlorophenoxy acetic acid - banned b/c of carcinogenicity
30
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
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2,4,5-T
Vietnamese population: birth defects
Toxic due to tetrachlorodibenzodioxin (TCDD)
Carcinogenic
32
Pentachlorophenol
Fungicide
Elevated body temperature
Mechanism: decreased H+ permeability
Short circuiting of ATP synthesis
Increased metabolic rate
Excessive heat generation
Treatment: cholestyramine
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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
34
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
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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
36
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
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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
38
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
39
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
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40
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
41
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
42
Propylene glycol
GRAS food additive
43
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
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Metal toxicity mechanisms
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Adventitious bind
Oxidative stress
Enzyme inhibition - arsenic to sulfur
DNA damage
Gene expression
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Inhalation, poor GI absorption
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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
46
Mechanism of mercury nephrotoxicity
Hg to SH groups of membrane proteins
Damage to glomerulus membrane
Causing glomerular nephritis and proximal tubular necrosis
47
USA Mercury
Salt water fish
New England
Pregnant women limit fish to once a week
Hair can tell history of exposure 1cm/month
48
Mercury treatment
Hg/Hg2+ : N-acetylpenicillamine to urine
CH3Hg : polythiol resin to feces or NAP
49
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
50
Lead treatment
Children: DMSA (metal chelation)
Adults: Ca, Na2-EDTA, replaces lead with calcium
51
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
52
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
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Arsenic treatment
Breath has garlic odor
Multiple organ damage, anemia, cancer
Hemodialysis
Glucocorticoids
BAL, DMSA chelating agents
Pencillamine
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Pulmonary toxicants
Small particles reach alveoli
Heavy particles get deposited in upper respiratory tract
Type 1 alveoli small cytoplasm, efficient gas exchange
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Lung fibrosis
Inflammation leading to excess collagen to alveolar ducts
Lungs become stiff and smaller
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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
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Air pollution
60% automobiles
52% carbon monoxide (most abundant)
Smog = stagnant air
Sulfur dioxide to H2SO4 acid rain
Asthmatics most sensitive
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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
59
Metal chelating agents
For treatment
2 SH: DMSA, BAL, DMPS
SH & COOH: pencillamine, N-acetyl pencillamine
60
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
61
Formaldehyde
Irritant, automobile exhaust
Chronic: runny nose, sore throat, cough, headache
62
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
63
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
64
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
65
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
66
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
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Treatment of malignant pleural mesothelioma
Surgery
Radiation
Pemetrexed antifolate
Cisplatin
68
Predifferentiation period
Up to day 17
Prenatal lethality if embryo unable to implant
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Organogenesis period
Day 18-56
High susceptibility to teratogenesis
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Histogenesis period
Day 50-90
Resistant to teratogenesis
growth retardation
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Human development defects
20% genetic
| 5% drugs/chemicals
72
Teratogens
Thalidomide
Tobacco smoke
EtOH
Diethylstilbestrol
73
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
74
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
75
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
76
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
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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
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Reproductive study II
Perinatal - birth
Postnatal - after birth
Mid-gestation to lactation
Look for physical development
Behavioral effects
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Reproductive Study III
Embryolethality
Teratology
Number of dead fetuses
Malformations in live fetuses
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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
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Lipid peroxide
Cell degradation
Disrup lipid membrane I
