Lecture 1: Toxicology I Flashcards
List the Halogenated Hydrocarbons that can cause intoxication
- Carbon tetrachloride (CCl4)
- Chloroform (CHCl3)
List the Aromatic Hydrocarbons that can cause intoxication
- Benzene
- Toluene
List the Alcohols that cause intoxication
- Methanol
- Ethylene glycol
List the Pesticides that cause intoxication
- Organophosphates
- Carbamates
- Pyrethroids
- Rotenone
List the Rodenticides that cause intoxication
- Brodifacoum
- Difenacoum
List the Metals that cause intoxication (6)
- Lead (Pb)
- Mercury (Hg)
- Cadmium (Cd)
- Arsenic (As)
- Iron (Fe)
- Copper (Cu)
List all the Antidotes and Treatments that treat different intoxications
- N-acetylcysteine
- Flumazenil
- O2
- Na Thiosulfate
- Fomepizole
- Succimer
- Dimercaprol
- Naloxane
- Atropine
- Pralidoxime
- Penicillamine
- Deferoxamine
- Charcoal
Define Toxicology
Study of the adverse effects of xenobiotics (foreign bodies) on living systems
What differentiates a poison from a remedy?
Right dose
How many patients in the USA present with acute poisoning?
8 million patients; Accounting for 10-20% of hospital admissions
True or False. Chronic toxicity from low-dose toxicants may take years to develop a clinical presentation
True
What causes the highest poison exposure for all group w/ fatal outcomes?
Medications
What other substances can cause poison exposure in all age groups?
Low yield
- Cosmetic, personal care items
- Cleaning substances (fatal outcome)
- Pesticides (fatal outcome)
- Art & crafts, office supples
- Alcohols (fatal outcome)
- Food products
- Plants
- Gas, fumes, chemicals (fatal outcome)
- Automotive products (fatal outcome)
What types of medications are most frequently involved in human poisoning exposures?
Analgesics (Aspirin, Ibuprofen, Acetaminophen)
What are the three ways to get exposed to a toxicant?
- Skin contact
- Ingestion
- Inhalation
What occurs in the body when exposed to a toxicant?
Distributed throughout the body, activated or inactivated, interacts with cells which can result in toxicity
What organ is affected by inhaled gases/particles?
Lungs
What organ(s) are affected by ingested chemicals? (4)
- Liver (Bioactivation or inactivation)
- Brain (Lipophilic)
- Kidney
- Heart (disruption of ion gradients)
Which compounds have selective toxicity?
- Enzymes
- Receptors (helps choose antibodies)
Which compounds have non-selective toxicity?
- Acids
- Bases
What outcome occurs with immediate toxicity?
Skin damage
What outcome occurs with delayed toxicity?
Cancer (Chronic exposure)
What method of toxicant exposure occurs with Halogenated hydrocarbons (CCl4 & CHCl3)?
Carbon tetrachloride (CCl4)
Chloroform (CHCl4)
Inhalation/Ingestion
True or False. Halogenated hydrocarbons (CCl4 & CHCl3) can penetrate the blood-brain barrier (BBB).
Carbon tetrachloride (CCl4)
Chloroform (CHCl4)
True.
b/c lipid soluble
How do most Halogenated hydrocarbons (CCl4 & CHCl3) affect the CNS?
Carbon tetrachloride (CCl4)
Chloroform (CHCl4)
- Depress the CNS w/ acute high exposure
What is the treatment for Halogenated hydrocarbons (CCl4 & CHCl3)?
Carbon tetrachloride (CCl4)
Chloroform (CHCl4)
- Support treatment for acute intoxication
- Support tx (ABCD): Airway, Blood Pressure, Circulation, Decontamination
What is Support Treatment for toxicity?
Support tx: ABCD
Maintainance of the Airway, Blood Pressure, Circulation and Decontamination of the patient
How can you get exposed to Carbon Tetrachloride (CCl4)?
Halogenated hydrocarbons
Contaminated drinking H2O
What side effects does CCl4 have at low concentrations? high concentrations?
Low concentrations
- Irritating to eyes & respiratory system
High concentrations
- Nausea, Vomiting, Stupor, Seizures,Coma, Death (CNS depression)
How is CCl4 bioactivated?
By cytochrome P450 (CYP) which produces free radicals that can cause damage to macromolecules, e.g., lipid peroxidation
What are the side effects of acute nonlethal exposure to CCl4?
- Produce liver and kidney damage
- Can occur in several hours to days
What side effects occur when exposed to Chloroform (CHCl3)?
- Similar to CCl4
- Dizziness, Headaches, Facilitated catecholamine-induced arrhythmias
Describe the normal pathway for CHCl3 detoxification. And what occurs to cause toxicity?
Normal Pathway
- CHCl3 (cholorform) →CYP2E1 (biotransformation)→Phosgene (Reactive metabolite)→GSH-Glutathione Transferase (protects organ damage)→Detoxified product
Toxicity
- GSH gets saturated and can NO longer inactive Phosgene →Hepatotoxicity
How can you get exposed to Aromatic Hydrocarbons?
Benzene, Toluene
Inhalation/Ingestion
What side effects occur with high acute exposure to Aromatic Hydrocarbons?
Benzene, Toluene
- CNS depression
- Catecholamine-induced arrhythmias
What is the treatment for Aromatic hydrocarbons?
Benzene, Toluene
Support treatment (ABCD) for acute intoxication
What ways can you be exposed to Benzene
Aromatic hydrocarbons
- 1/2 national exposure via tobacco smoke
- Combustion of fossil fuels/contaminated H2O
What diseases can chronic exposure to Benzene cause?
Aromatic hydrocarbons
Hematopoietic toxicity:
- Agranulocytosis
- Leukemia (AML)
Note: AML=
- M3 subtype: Promyelocytic leukemia
- M5 subtype: Monocytic leukemia
In what ways can you be exposed to Toluene?
Aromatic hydrocarbons
- Gasoline (1°)
- Degreasers
- Paint
- Furniture polish
- Abuse: Bagging/huffing feeling Euphoric
What side effects does exposure to Toluene cause?
Aromatic Hydrocarbons
- CNS depression→drowsiness, ataxia, tremors, impaired speech, hearing loss
- Chronic exposure-Liver and kidney damage
- High concentrations- Death
Hydrocarbons
- Toxicant exposure
- Physiological Effect
- Treatment
Halogenated and Aromatic
- Inhaled/Ingested
- Depress CNS
- Treatment is Supportive
List characteristics that you need to know for Halogenated hydrocarbons
- CHCl3
- CCl4
- Both penetrate BBB
- CHCl3 (Choloform):
- CYP2E1 bioactivated, Phosgene toxic metabolite
- CCl4 (Carbon tetrachloride):
- Contaminated H2O
- Eye irritant, resp. decrease
- Depress CNS
- CYP450 bioactivated
For Aromatic hydrocarbons: (Benzene, Toluene) explain:
- Way of exposure
- Physiological effects
- Benzene
- Tobacco smoke, fossil fuels, contaminated H2O
- AML (Leukemia)
- Toluene
- Gas/Paint/Polish
- Acute: decrease CNS, Chronic: liver and kidney damage→death
A 55-year-old man who has worked in a chemical plant for 25 years has been chronically exposed to benzene. Which of the following is the most likely toxicity of chronic benzene exposure?
A. Hepatotoxicity
B. Nephrotoxicity
C. Leukemia
D. Parkinson disease
c. Leukemia
What are common side effects caused by the toxicity of alcohol?
Methanol (wood alcohol)
Ethylene glycol (in antifreeze)
- CNS sedation
- Oxidized to toxic metabolites→can cause coma, seizure, hyperpnea & hypertension→(Sedation)
What side effects occur due to Methanol toxicity?
Methanol (wood alcohol)
Methanol →Formic acid→Retinal injury/blindness
What side effects occur due to Ethylene glycol toxicity?
Ethylene glycol (in antifreeze)
Ethylene glycol→Renal failure
What is the treatment for Alcohol toxicity?
Methanol
Ethylene glycol
Fomepizole
What is the mechanism of Fomepizole (tx for alcohol toxicity) and the side effects?
- Inhibits alcohol dehydrogenase
- Renal elimination of parent compounds
- Side effects: burning at injection site, nausea, headache, dizziness
Explain how Fomepizole stops the oxidation of the toxic metabolite of Methanol
Normal Pathway of Methanol toxicity
- Methanol→alcohol dehydrogenase→Formaldehyde→aldehyde dehydrogenase→Formic acid →Retinal injury/permanent blindness
Pathway with Tx: Fomepizole
- Methanol→Fomepizole inhibts alcohol dehydrogenase= Formic acid never formed
Explain how Fomepizole stops the oxidation of the toxic metabolite of Ethylene glycol
Normal Pathway of Ethylene glycol toxicity
- Ethylene glycol→alcohol dehydrogenase→Glycoladehyde→aldehyde dehydrogenase→Glycolate→glycolate oxidase→Glyoxylate→glycolate oxidase→Calcium oxate crystals→Renal failure
Pathway with Tx: Fomepizole
- Ethylene glycol→Fomepizole inhibts alcohol dehydrogenase= calcium oxalate crystals never form
List characteristics (side effects, MOA, tx, etc) that you need to know about:
- Methanol
- Ethylene glycol
- Methanol
- CNS sedation
- Toxic metabolite: Formic acid
- Retinal injury/blindness
- Tx: Fomepizole
- Ethylene glycol
- CNS Sedation
- Toxic metabolite: Calcium oxalate crystals
- Renal failure
- Tx: Fomepizole
What do the Organophosphate and carbamate insecticides inhibit?
Pesticides
- Inhibit Acetylcholinesterase→increase acetylcholine
What side effects do Organophosphate and carbamate insecticides toxicity cause?
- Salivation
- Lacrimation
- Perspiration
- Miosis
- Nausea, Vomitng
- Bronchospasm
- Seizures
- Coma
What is the treatment(s) for Organophosphate and carbamate insectides toxicity?
- Supportive (breathing)
- Decontamination
- Pralidoxime
- Atropine
Explain the mechanism of Pralidoxime and Atropine
Treatmenf for Organophosphate and carbamate insectides toxicity
- Pralidoxime: reactivates cholinesterase, usually for organphosphates, side effects: muscle paralysis/spasm
- Atropine: Muscarinic receptor antagonist
Pralidoxime side effects may be due to rapid infusion
For Pesticides: Organophosphates & carbamata insecticides
- Mechanism of action
- Treatment
- MOA: Inhibit acetylcholinesterase →↑ acetylcholine
- Treatment: Atropine, Pralidoxime
For the pesticide: Pyrethroids:
- Mechanism of action
- Physiological effects
- Treatment
LOW yield
Pyrethroids (chrysanthematic, pyrethric acids)
- MOA: Extend the opening time of sodium channels in the CNS and PNS
- Physiological effects: Loss of coordination, seizures, burning/itching sensation, contact dermatitis, asthma-like symptoms
- Supportive treatment for acute intoxication
For the pesticide, Rotenone explain the mechanism of action
HIGH yield
- MOA: Inhibits NADH-coenzyme Q reductase (complex 1)→stops oxidative phosphorylation
FYI: CO is toxic to cytochromes but the amount required is 1000X the lethal dose & thus plays no role in clinical poisoning
For the pesticide, Rotenone explains the side effects and treatments
HIGH yield
- Physiological effects: Nausea/Vomitting, Seziures, Death @ at very high doses
- Treatment: Supportive treatment for acute intoxication
What are Rodenticides structurally similar to?
Brodifacoum
Difenacoum
- Structurally similar to warfin (More lipophilic)
- Can have longer half-life (effects clotting factors: 2,7,9, 10)
For Rodenticides: Brodifacoum, Difenacoum:
- Ingestion:
- Toxicity effects:
- Treatment:
- Ingestion: Can occur w/ intentional poisoning & suicide
- Toxicity effects: Bleeding
- Treatment: Fresh frozen plasma & phytonadione (VIT K)
Which metals are Heavy metals?
- Lead (Pb)
- Mercury (Hg)
- Cadmium (Cd)
For Heavy metals; Pb, Hg, Cd
- Explain exposure
- Treatment
- Public health concern; Chronic low dose exposure (a concern)
- Tx: Chelators
Treatment for Lead (Pb) poisoning
Chelators
- CaNa2 EDTA: Ca2+ will be replace with Lead
What poisoning does Succimer treat?
Chelators
Tx for Lead (Pb) and Mercury (Hg) poisoning
What poisoning does Dimercaprol treat?
Chelators
Tx for Lead (Pb), Mercury (Hg), Arsenic (As) and Copper (Cu)
What poisoning does Penicillamine treat?
Tx for Copper (Cu) poisoning
What metal is a contraindication to all the chelator treatment?
Cadmium (Cd)
What ways can you be exposed Lead (Pb)?
Ubiquitous in environment
- Old paint
- Drinking water (lead paint)
- Industrial pollution
- Food
- Dust
Elimination from gasoline and paint in the late→↓Pb exposure in the USA
Who absorbs more of the ingested dose of Pb, Adults or Children?
- Children absorbed 40% of ingested dose
- Adults absorb 10%
Where in the body is Inorganic Pb distributed?
- Initially distributes to soft tissues
- Redistributes to bone (MAINLY), teeth and hair (can be detected by X-ray)
How long does Pb stay in blood and bone?
- Blood: t1/2 about 1-2 months
- Bone: t1/2 about 20-30 years
t1/2=half life
What are the Physiological effects of Pb toxicity?
- CNS toxicity or Pb encephalopathy: HA, confusion, clumisness, insomnia, fatigue and impaired concentration
Enpathalopathy: Disrupts Ca2+ homeostasis which disrupts neurotransmitters
Who is more susceptible to CNS toxicity caused by Pb and what are the effects?
- Children which can lower IQ (estimated 9% of children may have blood conc. more than 10 μg/dL)
What are symptoms of Gastrointestinal (GI) toxicity caused by Pb exposure?
- Sx: Discomfort, constipation, or diarrhea
- Higher doses can cause painful intestinal spasms which can be treated with IV calcium gluconate
What are the effects of Blood toxicity caused by Pb exposure?
- Disrupts heme synthesis→shortens RBC life span, Hypochromic, microcytic anemia
- ↑ δ-aminolevulinic acid (ALA) & protoporphyrin IX blood concentration by inhibition of δ-aminolevulinic acid dehydratase & ferrochetalase
- Blood concentration>25 μg/dL, Diagnostic for Pb intoxication
Explain the function and side effects of the tx: Dimercaprol for Pb toxicity
- Antidote w/ edatate calcium disodium
- Chelator which forms a coordinated bond w/ cationic metal & the complex renally excerted
- Side effecs: ↑ blood pressure & heart rate
Developed during WWII as an antidote to arsenical war gas or Lewisite
Which two chelators are a treatment for high Pb toxicity?
Dimercaprol + EDTA
(Prevents Pb from entering CNS)
Explain the function and side effects of tx: Succimer for Pb toxicity
- Antidote for Pb including children
- Side effects: ↑ hepatic enzymes, nausea/vomiting/diarrhea (N/V/D), loss of appetite
Explain the function and side effects of tx: Edetate calcium disodium (EDTA) for Pb toxicity
- Antidote for Pb
- Can be combined w/ Dimpercaprol
- Side Effects: nephrotoxicity
What treatment is used for Pb toxicity based on the conentration of Pb listed below:
- 45-54 μg/dL=
- 55-69 μg/dL=
- 70-100 μg/dL=
- 45-54 μg/dL= Succimer
- 55-69 μg/dL= EDTA
- 70-100 μg/dL= EDTA + Dimercaprol
For Heavy Metal: Lead (Pb)
- Exposure
- Mechanism of action
- Physiological effects
- Treatment
- Exposure: Old paint, drinking water
- MOA: Blocks heme synthesis
- Physiological effects: CNS toxicity, Pb encephalopathy, GI toxicity, Blood toxicity
- Treatment: Dimercaprol, Succimer, EDTA
List the three ways Mercury (Hg) can exist as toxin
- Elemental Hg
- Inorganic Hg (mercuric chloride)
- Organic Hg ( methyl mercury)
Explain exposure and side effects of Elemental Hg toxicity
- Exposure: Inhaled vapors
- SE: Tremors, depression, memory loss, ↓verbal skills, renal inflammation
- High concentration →Corrosive to lungs
What are the clinical presentations of Inorganic Hg (mercuric chloride)?
Corrosive: mucosal mouth damage, renal damage
Explain the chemical properties and exposure of Organic Hg ( methyl mercury)
- Chemical properties: Very lipid solubility and less corrosive than inorganic Hg
- Exposure: Contaminated fish
What are the neurological symptoms of Organic Hg toxicity?
- Visual disturbances
- Parasthesia
- Ataxia
- Hearing loss
- Mental deterioration
- Muscle tremors
- Movement disorders
What occurs at very high doses of Organic Hg?
- Paralysis and death (especially toxic to the unborn child)
- Misdiagnosed Alzheimers or Parkinson disease in elderly
What are the treatments for Mercury (Hg) toxicity?
- Dimercaprol
- Succimer
Chelating agents
For Hard Metal: Mercury (Hg)
- Exposure
- Physiological effects
- Treatment
Exposure:
- Inhaled vapors (Elemental Hg)
- Contaminated fish (Organic Hg)
Physiological effects:
- Tremors,depression,memory loss (Elemental Hg)
- Corrosive (Inorganic Hg)
- Neurological symptoms (Organic Hg)
Treatment:
- Dimercaprol, Succimer (for All types)
How can you get exposed to the heavy metal, Cadmium (Cd)?
- Ingestion or inhalation
- Contaminated plants
- Cigarrette smoke
- Burning of fossil fuels
- Industrial exposure,e.g., welding, smelting
- Greater absorption with inhalation
Where is Cd mainly distributed? and the half life?
- To the liver and kidney by binding to metallothionein
- t1/2=10-30 years
What organ(s) is Cd especially toxic to?
Kidney and liver, also carcinogenic
What is the treatment for Cadmium (Cd)?
- Supportive tx for acute intoxication
- No evidence of chelation therapy effectiveness
- Dimercaprol, penicillamine & EDTA contraindicated→↑risk of nephrotoxicity (kidney toxicity)
A MSP3 student who plans on applying to medical school or pharmacy school is studying the effects of toxicants on human cell lines at the MCOM. Which of the following most likely disrupts electron transfer during oxidative phosphorylation?
A. Chloroform
B. Lead
C. Rotenone
D. Brodifacoum
C. Rotenone
- Which of the following is NOT treated by supported treatment?
a. Carbon tetrachloride
b. Chloroform
c. Toluene
d. Ethylene Glycol
d. Ethylene Glycol
- A patient comes to the ER after ingesting the rodenticide: Brodifacoum. Which of the following would be administered to the patient due to the toxicity?
a. Penicillamine
b. Phytonadione
c. Pralidoxime
d. Atropine
b. Phytonadione (Vit K)
- Which of the following is NOT a metal that is a public health concern?
a. Arsenic
b. Lead
c. Mercury
d. Cadmium
a. Arsenic
- A child has been experiencing headaches, confusion, and struggling with schoolwork. When reviewing his labs, you note that the urine sample contained high amounts of ALA and protoporphyrin. Which of the following would be a possible treatment?
a. Succimer
b. Penicillamine
c. Phytonadione
d. Fomepizole
a. Succimer
- Which of the following can present as symptoms of Parkinson’s when exposed to a toxic dose?
a. Toluene
b. Methanol
c. Lead
d. Mercury
d. Mercury (Hg)