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Flashcards in Toxicology 1-3 Deck (112):

What is toxicology?

The study of harmful effects of chemicals on biological systems


What is a poison?

Any substance that can cause death, disease or injury, which can be just about anything in the right dose


What are the routes of exposure to poisons? Which will show the most rapid effect?

1. Oral (GI tract)
2. Parenteral (IV) - most rapid effect
3. Dermal (skin)
4. Inhalation (lungs)


What are the factors which determine the duration and intensity of poisoning?

1. Dose
2. Age (very young or very old more susceptible)
3. Personal habits
4. Genetics


What is toxicokinetics vs toxicodynamics?

Toxicokinetics - ADME of toxins
Toxicodynamics - The way that toxins interact with us and disturb vital functions


What is acute vs subacute vs chronic exposure?

Acute - single or multiple exposures in a 24 hr period
Subacute - multiple exposures in a 3 month period
Chronic - multiple exposures in a >3 month period


What are the two major categories of poisons?

1. Cumulative - i.e. lead, when total exposure is critical
2. Non-cumulative - readily detoxified by body, does not cause irreversible damage except at high doses


How is a zero-order rate constant calculated? What are its units?

k = slope of zero-order elimination process.

If A = concentration of drug A in blood

k = (A1-A0)/(t1-t0)

Since it is not dependent on the concentration of the drug in the rate law, Rate = k, and thus units are mg/hr typically.


What is the "transition period" in elimination kinetics?

As enzymes for metabolization become unsaturated, but still below Km, there is a transition period where the kinetics appear to be somewhere between zero order (saturated) and first order (dose-dependent elimination)


How does alcohol exhibit zero-order elimination?

Km of alcohol dehydrogenase is below one drink, so rapidly drinking two drinks will increase the BAC disproportionately (more than double it), since ADH will become saturated


How is aspirin metabolized? When is this saturated?

1. Acetylsalicylic acid -> hydrolyzed to salicylate by plasma esterases rapidly

2. Salicylate -> conjugated to glycine to form salicyluric acid

Saturated completely at 1g of aspirin (3 tablets), dose not become fully dose-dependent until 300 mg.


What are the toxic heavy metals of concern? Include atomic symbol.

1. Lead - Pb
2. Mercury - Hg
3. Arsenic - As
4. Cadmium - Cd


How, in general, are heavy metals toxic?

They are not metabolized, persist for long periods of time in the body, and combine with key amino acid residues on proteins (i.e. active sites of enzymes or structural proteins)


What does acute inorganic Pb poisoning cause?

Severe GI distress, progressing to CNS abnormalities


What does chronic inorganic Pb poisoning cause?

Weakness, CNS abnormalities, GI distress

most diagnostic: wrist drop (extensor muscle weakness)


What is the source of organic Pb poisoning and how can it be distinguished from inorganic Pb poisoning?

Organic generally due to tetraethyl or tetramethyl Pb from leaded gasoline

Distinguished from inorganic because few hematological abnormalities will be noticed, only CNS effects


How is Pb poisoning diagnosed?

Hematological abnormalities typically:

Blood lead concentration >0.5 mg/mL
Elevated free erythrocyte protoporphyrin test (FEP)


What compounds are elevated in lead poisoning?

1. Delta-aminolevulinate (delta-ALA) in urine
2. Coproporphyrinogen elevated in urine
3. Protoporphyrin 9 elevated in RBCs (without heme)


Why are these compounds elevated in lead poisoning?

Lead inhibits several SH-containing enzymes of heme biosynthesis, causing anemia by inhibiting hemoglobin synthesis (microcytic anemia).

Major enzyme blocked: Ferrochelatase -> build up of protoporphyrin 9

Secondary: delta-ALA dehydratase, and co-PPR oxidase


How are the symptoms of lead poisoning treated?

Treat seizures with diazepam
Treat cerebral edema with mannitol and dexamethasone
Maintain fluid and electrolyte balance


What chelators are used for lead poisoning?

Short-term: Dimercaprol and CaNa2EDTA

Long-term: Oral penicillamine


What are the three main forms of mercury?

1. Elemental mercury - a liquid
2. Inorganic mercury salts - HgCl2, previous used in healthcare
3. Organic mercurials - Methyl-mercuric chloride


What form of mercury is most easily absorbed, and which poses the greatest occupational hazard?

Organic mercurials -> most easily absorbed (like organic lead)

Elemental mercury - easily inhaled as vapor, greatest risk


Where does mercury tend to concentrate?

The kidneys and brain for a long period of time -> CNS effects and acute kidney damage


What are the shared symptoms of acute and chronic mercury intoxication?

Severe gingivitis, discolored gums, and metallic taste in mouth. (stomatitis)

Kidney damage

CNS effects in longterm


How does mercury exert its biochemical effect?

The ion forms covalent bods with SH group of intracellular porteins and precipitates them.


What is the treatment for mercury poisoning, and how is it monitored? What other heavy metal is this the same as?

Acute - dimercaprol
Chronic - add oral penicillamine

Monitored by urinary Hg levels to assess removal by chelators

Pretty much the same as both arsenic and lead!


Where is Arsenic commonly found, and what is it used for medically?

Commonly found as a contaminant of coal and metal ores.

Medically: used for treatment of certain tropical diseases and certain leukemias as chemotherapy


What is Arsenic used for non-medically?

Often found in herbicides and insecticides (weed killers!)


What is the primary enzyme affected by Arsenic, and by which form?

Trivalent form (As+3) binds sulfhydryl groups. Most commonly the SH groups of the lipoamide of pyruvate dehydrogenase -> forms a stable, 6-membered ring


What is the other form of arsenic and how is it toxic?

Pentavalent form (As+5), competes with inorganic phosphate in formation of ATP to uncouple oxidative phosphorylation


Why does Cadmium have a high environmental prevalence?

Less than 5% of it is recycled, so it is a pollutant (used in batteries). Also can be inhaled via cigarette smoking.


Where does Cadmium accumulate and why?

It is a cumulative exposure from the environment, accumulates in bones (competes with calcium). Half life is 10-30 years


What is the treatment for cadmium poisoning and what is contraindicated? Why?

Maybe EDTA, but really doesn't work well.

Contraindicated: dimercaprol, mobilizes cadmium, causing it to concentrate further in kidneys and produce nephrotoxicity


How do chelators actually chelate?

Use nitrogen, sulfur, and oxygen atoms (via electron pairs) to form coordinate-covalent bonds with the cationic metal atom. These must distribute to the sites of the body where the metal is, pick it up, and mobilize it from the body (urine)


What is one major challenge of designing a chelator?

It must chelate the heavy metals better than other divalent cations like calcium and zinc


What is BAL and what are its adverse effects? How has this been combatted?

Trade name of dimercaprol

Adverse effects: hypertension, tachycardia, nausea, vomiting, headache


How have the toxicities of dimercaprol been overcome?

More water soluble derivatives have been made which have less adverse effects: DMSA (succinate) and DMPS (propane sulfonate)


What is the primary adverse effect of edetate calcium disodium (CaNa2EDTA), and what metal can it not be used for?

Nephrotoxicity - do not use with poor renal function

CANNOT be used to treat mercury (Hg), all other heavy metals will displace the calcium just fine


What is penicillamine? Which form is less toxic?

A degradation product of penicillin, with D isomer being less toxic


What is penicillamine used for?

chelating copper (Wilson's disease), lead, mercury, and arsenic


What is the longterm safety of penillamine?

Same adverse effects longterm of penicillin: nephrotoxicity, hypersensitivity, eosinophilia


What is Deferoxamine (Desferal) used for primarily? Why is it super juicy?

Chelation of iron in iron poisoning

Juicy: does not interfere with iron in cellular proteins like hemoglobin or cytochromes


What is the toxicity of deferoxamine?

Renally eliminated -> nephrotoxicity. Also cataracts and GI side effects


What does arsenic poisoning cause in acute vs chronic causes?

Acute - GI symptoms + liver and renal injury

Chronic - neurological symptoms predominate, with secondary GI symptoms


What does CO form in blood, and who naturally has the highest levels?

Carboxyhemoglobin (binds with ~200x affinity of oxygen)

Smokers naturally have 5-10% carboxyhemoglobin, vs <1% for nonsmokers


What are the sources of CO?

Incomplete combustion, especially automobile exhaust, charcoal fires, and gas furnaces


What tissues are most affected by CO poisoning?

Brain and heart


What are the symptoms of CO poisoning?

Worsening CNS effects: Headache, weakness, nausea, vomiting, loss of muscular control, increased respiration

Worsening cardiac effects: Can cause arrythmias and MI due to hypoxia

Death by around 70% CO-Hb


What level of CO-Hb is considered safe?

<10% blood saturation


What are the common sources of HCN?

insecticides, rodenticides, burning nitrogen-containing plastics, and fruit seeds


How is HCN poisoning diagnosed?

1. By abruptness of onset of symptoms (within seconds of inhalation)
2. Almond odor on breath
3. Ataxia, convulsions, coma, nausea, vomiting


What is the mechanism of action of HCN poisoning?

Binds iron in the ferric (Fe+3) state, especially cytochrome oxidase, inhibiting cellular respiration


What are the treatments for HCN poisoning? What does this cause?

Amyl nitrite (NO2) - given via inhalation
Sodium nitrite - given IV

These will oxidize Hb-Fe+2 to Hb-Fe+3, and methemoglobin will compete for the CN on the cytochrome oxidases

Will cause methemoglobinemia


What enzyme is used in vivo to detoxify SCN?

Rhodanese - thiosulfate sulfurtransferase - detoxifies CN- to thiocyanate (SCN-)


What is methanol found in and why is it dangerous?

Found in antifreeze, solvents, paint remover, and used in chemical syntheses

Dangerous because it is more slowly oxidized in body than ethanol - early symptoms similar to ethanol


What is responsible for methanol toxicity? What do they cause?

The biproducts of oxidation are:

Formaldehyde - blindness -> damage retinal cells

Formic acid - Acidosis, cardiotoxic (cardiac depression)


How do you treat methanol toxicity?

Correct acidosis via sodium bicarbonate for survival

Secondly: Administer ethanol to competitively inhibit methanol oxidation (both use alcohol dehydrogenase)


What is the primary reservoir of ethylene glycol?

Found in antifreeze -> people may drink it


How is ethylene glycol toxic? What is the treatment?

Metabolized by alcohol dehydrogenase (like methanol).

1. Oxalate - produces crystals which cause kidney damage
2. Formic acid - causes acidosis like methanol

Treatment is same as methanol poisoning, with option for hemodialysis


How is acetaminophen (APAP) metabolized in typical doses?

Conjugation to glucuronide or sulfate


How does APAP poisoning occur?

Cytochrome P450 metabolizes it at high doses, creating reactive electrophile.

This must be depleted via glutathione (GSH), otherwise it will interact with proteins and cause cellular necrosis of liver (hepatotoxicity)


How is APAP overdose treated? How does this work?

N-acetylcysteine, which APAP reactive electrophile can bind rather than proteins or GSH, or will replenish the supply of GSH


Who tends to get vitamin poisoning, and by what vitamins?

Mostly children, vitamins A and D (less so E and K)


What is the most common mineral overdose?

Iron! treat with deferoxamine


How are arsenic and mercury used as pesticides?

Used in herbicides


How is cyanide used in pesticides?

As a fumigant to control insects (gaseous pesticide)


What are some examples of chlorinated hydrocarbon insecticides and what is their mechanism of action of toxicity?

DDT, chlordane, lindane

Interfere with the inactivation of sodium channel, thus causing repetitive firing in response to a single stimulus -> CNS stimulation and effects


What are the chemical properties of chlorinated hydrocarbon insecticides?

Low molecular weight, stable compounds, with poor water solubility (fat-soluble), so they concentrate in adipose tissue


What is an example of an organophosphorous insectide and what is its mechanism of toxicity?


Toxic by inhibiting acetylcholinesterase via phosphorylation -> acetylcholine hyperstimulation at nerve junctions


Why are organophosphorous compounds of concern and how do they differ from chlorinated hydrocarbons?

Unlike chlorinated hydrocarbons, they do not accumulate in tissues and are readily metabolized / excreted.

However, they do persist in the environment and have a high risk of acute toxicity (low doses can be fatal)


What is the mechanism of action of carbamate insecticides and how do they differ from organophosphorous compounds?

They inhibit acetylcholinesterase via carbamoylation of esteric site of enzyme. However, this is more reversible than organophosphorous.

Carbamates thus have a shorter duration of action and are less toxic.


Why are carbamates of less concern, aside from their lessened toxicity as compared to organophosphorous compounds?

They do not persist in the environment for very long.


Do herbicides and environmental pollutants exist?

Yes, they exist


What is a synergistic vs potentiating effect?

Synergistic - two toxic compounds amplify one another (2+2 = 20)

Potentiation - a compound not toxic alone causes a toxic compound to become more toxic
(2+0 = 20)


What is an antagonistic drug effect?

Addition of some compound with a toxic one reduces or eliminates its toxicity

(pharmacologic antagonists, used in reversal therapy)


Why is physiological antagonism difficult to use clinically?

Antidote (i.e. CNS stimulant for respiratory depression) may outlast the poison, causing complications (i.e. convulsions)


How do you treat coumarin poisoning?

It is an analog to vitamin K, works as an anticoagulant in humans and can cause hemorrhage. Treated via administering vitamin K


What is the major drug interaction of concern with alcohol?

Chronic alcohol use induces liver CYP450 isozymes, increasing metabolism of certain drugs. Can also competitively inhibit certain CYP450s


What is the major drug interaction of concern with caffeine?

Can interact with medications like benzodiazepines, oral contraceptives, and MAO inhibitors, induces some enzymes


What is the major drug interaction of concern with tobacco use?

Induces some drug-metabolizing enzymes like caffeine and alcohol, thus decreasing the effectiveness of some drugs like acetaminophen and same list as caffeine


Why are elderly patients often difficult to deal with and treat?

They often take 6-8 different drugs, and have compromised liver and kidney function -> monitor closely and consider benefit-to-risk ratio


What types of agents frequently bind DNA and are carcinogenic / mutagenic?

Alkylating agents -> hard electrophiles (Lewis acids)

i.e. carbonium ion


What are the unstable oxygen species?

Uncharged: Singlet oxygen, hydroxyl radical, hydrogen peroxide
Charged: Superoxide anion


What are two xenobiotics which can be bioactivated into stable but toxic metabolites? What are those? How?

Dichloromethane - A hydrogen is oxidized by CYP450, both chlorides leave, forming CO

Acetonitrile - A hydrogen on methane is oxidized by CYP450, CN leaves as a good leaving group


What is the most common bioactivation mechanism?

Biotransformation into reactive, electrophilic metabolites which react with DNA or proteins which are good nucleophiles


What is a hard vs soft base in vivo? How do they relate in terms of electronegativity, polarizability, and difficulty to oxidize?

Hard base = hard nucleophile
-> highly electronegative, hard to polarize or oxidize
-> in vivo, includes amino groups and oxygen-containing functional groups in DNA and protein

Soft base = soft nucleophile
-> low electronegativity, relative ease of polarization and oxidation
-> in vivo, includes thiol group of GSH / cysteine, protein sulfhydryl groups


What is Pearson's principle?

Hard electrophiles interact preferentially with hard nucleophiles, and soft electrophiles interact preferentially with soft nucleophiles


What are the features of a hard electrophile?

Small size, high positive charge, lacking unshared electrons in valence shell.

I.e. Alkyl carbonium ion -> highly mutagenic to DNA


What are the features of a soft electrophile? What do they tend to interact with?

Low positive charge, relatively large size, with unshared electron pairs in valence shell

They tend to interact with protein sulfhydryl groups


Is an electrophile a lewis acid or a lewis base?

Lewis acid! - they accept electrons and give protons


What is the functional difference between a hard and soft electrophile in terms of toxicity?

Hard electrophiles -> low dose, chronic carcinogens by mutating DNA

Soft electrophiles -> acute, high-dose toxicity by protein inhibition, but cannot cause mutations in DNA or cancer


What type of compound is the reactive intermediate of acetaminophen and what is its mechanism?

Quinone-imine, from CYP450 oxidation when glucuronide + sulfotransferase pathways are saturated.

When cellular GSH levels get too low to detoxify it, it reacts with membranes in liver causing hepatotoxicity. Also can cause nephrotoxicity via prostaglandin synthase activation.


What compound is one activated by CYP450 to an epoxide which can covalently bind macromolecules?



What is the benzopyrene activation mechanism and where is it found?

Found in tobacco smoke, is a carcinogen / mutagen, ring structure is activated much like bromobenzene by CYP450


What is the reactive intermediate of 2-acetylaminofluorene and what damage does this cause? How is it activated?

Activated via sulfate conjugation, which acts as a leaving group to form a nitrene intermediate which is a hard electrophile, binding DNA.

It is a liver carcinogen


Where is nitrosamine found and how is it activated?

Found in overcooked meat, activated by CYP450 to ultimately form a methyl carbonium ion, highly mutagenic hard electrophile


How can glutathione conjugates become nephrotoxic?

Activating trichloroethylene with GSH leads to the formation of two sulfur-containing reactants which work as both hard and soft electrophiles, causing kidney damage


What are the three stages of free radicals?

1. Initiation
2. Propagation
3. Termination


How can initiation of free radicals occur?

One electron oxidations or reductions, or homolytic sigma-bond cleavage


What atoms serve as centers for free radicals?

C, N, O, and S


What two mechanisms allow for the propagation of free radicals?

1. Abstraction of hydrogen from another compound, forming a free radical on that compound
2. Addition to another compound, forming a free radical on that compound


What are the three mechanisms of termination of free radicals?

1. Dimerization - Two free radicals form one adduct
2. Disproportionation - Two free radicals form two different species
3. Reaction with antioxidant (i.e. tocopherol)


What is one compound that often forms free radicals? How does this occur?

Carbon tetrachloride -> addition of one electron via CYP450 leads to carbontrichloride free radical formation, which can bind lipid in low O2 conditions which will not detoxify


What are the steps in the sequential reduction of oxygen? What are the intermediates considered?

Oxygen -> perhydroxyl radical (superoxide anion) -> hydrogen peroxide -> hydroxy radical -> water

Intermediates are considered reactive oxygen species


What are the main nonenzymatic and enzymatic sources of ROS?

Nonenzymatic - auto-oxidation of hemoglobin / myoglobin to Fe+3

Enzymatic - Flavin-containing oxidases (i.e. monoamine oxidase)


Give four compounds that produce toxicity via production of metabolic derangements, like inhibiting a pathway or producing a depletion of metabolic intermediate or coenzyme.

1. Galactosamine
2. Ethionine
3. Fructose
4. Fluoroacetate


How does galactosamine toxicity work?

It is hepatotoxic because it uses up hepatic UTP stores to form UDP-amino sugars


How does ethionine toxicity work?

Hepatotoxic via inhibition of RNA / protein synthesis, decreased cellular ATP and GSH concentrations.

It works as an antagonist of methionine to form S-adenosylethionine which does not participate in methylation reactions -> adenosyl trapping agent and depletes ATP


How does fructose toxicity work?

Depletes cellular ATP concentrations by being rapidly metabolized into fructose-1-phosphate via fructokinase


How does fluoroacetate toxicity work?

Lethal synthesis - similar structure to acetate and is made into fluoracetyl-CoA in the mitochondria, then forms fluorocitrate which will block aconitase -> citrate accumulates and mitochondrial energy is destroyed


How is Paraquat toxic?

It is an herbicide which is given an electron via flavoprotein to form a radical, reactive intermediate. This reacts with oxygen to form superoxide anion -> cause of pulmonary fibrosis