Term
Factors that influence toxicity: |
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Definition
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The greater the amount of a
chemical taken up, the greater
the toxic response -
DOSE RESPONSE
It is not the dose but the
concentration of a toxicant
at the site or sites of action that
determines toxicity.
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Term
What determines the concentration of the toxicant at the site of the target tissue? |
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Definition
•Route of exposure
•Absorption
•Elimination
•Chemical Form
•Biotransformation (metabolism)
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Term
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Definition
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•The ROUTE (site) of exposure is an important determinant of the ultimate DOSE – different routes may result in different rates of absorption.
–Dermal (skin)
–Inhalation (lung)
–Oral (GI)
–Injection
•The ROUTE of exposure may be important if there are tissue-specific toxic responses.
ex. Snake Venom
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Term
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Definition
•HOW LONG an organism is exposed to a chemical is important
•DURATION and FREQUENCY contribute to DOSE. Both may alter toxic effects.
–ACUTE Exposure = usually entails a single exposure
–REPEATED Exposures = multiple exposures over time (Chronic)
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Term
Case in point: charcoal (Absorption) |
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Definition
•Charcoal is not absorbed in the gut, so oral administration exhibits no toxicity.
•Inhalation of aspiration of charcoal can produce lung edema and chronic lung disease.
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Term
Most important mode of elimination: |
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Definition
-Most compounds eliminated by kidneys
-Polar and ionic compounds
eliminated more readily
-Renal elimination can be exploited in the treatment of drug overdose
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Term
Chemical Form: Important in determining heavy metal toxicity. |
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Definition
Example: Chromium
Cr (III): Good
Cr(VI): Bad
Why?
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Term
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Definition
-At pharmacological doses of acetaminophen, mainly phase II metabolism occurs
-However, cytochrome P450 – mediated dehydrogenation yields a toxic metabolite.
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Term
Other Examples of Bioactivation |
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Definition
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Term
Chemical Interactions
(Drug-drug interactions)
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Definition
•Potentiation => one chemical causes a another chemical to have greater effect than if given alone
–Example: hepatotoxicity of acetaminophen is enhanced by ethanol
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Term
Specific toxicants: Carbon monoxide |
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Definition
•Binds reversibly with the O2 binding site on hemoglobin
•Binds with 220-fold higher affinity than O2
•Carboxyhemoglobin cannot transport O2
•Carboxyhemoglobin reduces O2 dissociation from the remaining sites where O2 is bound, leading to decreased oxygenation of tissues.
•Nonsmokers have ~1% carboxyhemoglobin normally
–Due to formation of CO through heme catabolism
•Smokers have ~5-10%
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Term
Clinical signs of CO poisoning: |
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Definition
•Hypoxia and progress from:
–Psychomotor impairment
–Headache and tightness in temporal area
–Confusion and loss of visual activity
–Tachycardia, syncope and coma
–Deep coma, convulsions, shock and respiratory failure
•Responses vary with individuals
•<15% carboxyhemoglobin unlikely to produce effects
•Above 40%: collapse and syncope
•Above 60%: death can occur
•Risk exacerbated by labor, high altitude, and high temperature.
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Term
Treatment of CO poisoning: |
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Definition
•Removal from source and administration of oxygen
•With 1 atm room air, elimination half life is 320 minutes!
•Half life at 100% oxygen = 80 min
•With hyperbaric oxygen (2-3 atm) = 20 min, though no firm indications for its use have been established.
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