8. ADME & Biomagnification Flashcards
What does ADME stand for?
- Absorption
- Distribution
- Metabolism
- Elimination
What is absorption
How the contaminant enters the body
Types of absorption (5)
- Inhalation through the respiratory system
- Dermal contact through the skin
○ Amphibians are sensible to it - Ingestion through GI system
- Maternal transfer
○ Oviparous animals - Diffusion across lipid membranes determined in part by log KOW
○ Can get taken up by cells
What is distribution?
It describes how the chemical moves through the body from the site of absorption
Examples of distribution (2)
- Often transported in blood or hemolymph
- Often absorbed in gut and transported directly to liver (key site of metabolism)
What are the key target organs? (2) (of distribution)
Liver and brain
What type of molecules can cross the blood-brain barrier?
lipophilic molecules (polar molecules CANNOT)
What is metabolism (or biotransformation)?
The chemical breakdown of a contaminant via enzymatic reactions inside an organism
What is the purpose of metabolism? (3)
- INCREASE polarity of the molecule (and solubility in water)
- PROMOTE excretion
- REDUCE toxicity
Can metabolism not work properly?
Yes, in some cases, metabolism can activate the contaminant and promote toxicity :(
Where does metabolism happen? (in the body)
Mainly in the liver
What is metabolism? (longer definition) (4 elements)
- Body’s defence against toxic substances
- Biological processes which transforms xenobiotics into water soluble form that can be excreted
- Uses an army of enzymes with broad substrate specificity (not specialized)
- One enzyme can metabolize many different things
What is elimination?
How the contaminant is removed (and how quickly)
Types of elimination (4)
- Across gills or skin (fish and amphibians)
○ Applies to water soluble and lipophilic contaminants - Through urine or bile (in feces)
○ Applies to metabolites of lipophilic contaminants or water soluble contaminants - In breast milk or eggs
○ Applies to lipophilic contaminants - Small amount of metals eliminated through hair and nails
How is methylmercury aborbed? (2)
- mainly through diet
- 95% of dietary MeHg is absorbed through the GI tract
How is MeHg distributed and where does it accumulate?
- through the bloodstream
- it accumulates in muscle and brain (cross blood-brain barrier)
How is MeHg metabolized?
It is slowly demethylated and excreted. Half life of around 80 days
How is MeHg eliminated?
Through feces. Biomarker in hair
Does MeHg biomagnify?
Yes
- Hg0 has a low log KOW of 0.62
- MeHg has a log KOW of 2.54
- MeHg biomagnifies because it gets trapped in proteins as methylmercury cysteine
How is TCDD (a dioxin) absorbed?
- mainly through diet
- more than 85% of dietary TCDD is absorbed through the GI tract
How is TCDD distributed and where does it accumulate?
- through bloodstream
- accumulates in liver and fat
How is TCDD metabolized?
Very slowly
it has a half life of 5-10 yeats
How is TCDD eliminated?
Mainly feces
Does TCDD biomagnify?
Yes
It has a log KOW of 6.8
→ when a contaminant doesn’t metabolize and has a high log KOW, it biomagnifies
What is Phase I biotransformation?
- Introduces or exposes a functional group
- small increase in hydrophylicity
What is Phase II biotransformation?
- Conjugation (e.g. glucuronic acid)
- large increase in hydrophilicity
In the hitch and trailer analogy, what is Phase I of biotransformation?
the hitch
In the hitch and trailer analogy, what is Phase II of biotransformation?
the trailer
In the hitch and trailer analogy, what is the chemical?
the truck
What are some examples of Phase I reactions? (3)
- hydrolysis
- reduction
- oxidation
What is hydrolysis?
Reaction with water that breaks a chemical bond
What is reduction?
Reaction that transforms a functional group to a reduced from (usually by the addition of hydrogen)
What is oxidation?
Reaction that increases the oxidation state of chemicals (usually by addition of oxygen)
Example of a enzyme that does metabolism
CYP1A
What are the 2 problems with the metabolism of DLCs by CYP1A?
- ‘Ineffective’
* PAHs are metabolized to carcinogenic epoxides
* Could be beneficial in the short term, but metabolite can be more toxic than parent compound
* Most PCBs are moderately well metabolized
* Dioxins and furans are very poor metabolized - ‘Dangerous’
* activating the AHR pathway is toxic in itself
* e.g. AHR knockout mice are insensitive to the toxic effects of TCDD
What can the metabolization of Benzo(a)pyrene (a PAH) result in?
A carcinogenic metabolite → epoxide
Why are relatively small amounts of chocolate toxic to dogs?
- This is related to the slow metabolism of a caffeine metabolite called theobromine (CYPA1 Phase I biotransformation)
- But also the LD50 of theobromine is smaller for dogs than for humans
How does this chocolate example apply to Risk = exposure x hazard?
It adds the term susceptibility to the paradigm. Susceptibility modifies the hazard term.
What is bioconcentration?
Build up of contaminant in an organism to a concentration that is higher than the concentration in the media to which it is exposed
What is bioaccumulation?
Build-up contaminant within the tissues of an organism (includes bioconcentration and dietary intake)
What is biomagnification?
Increase in concentration of contaminants as you move up the food chain
What is a trophic level
it is a position in the food web
How does the trophic level influence biomagnification?
Biomagnification increases as you increase the trophic level
What types of contaminant are more likely to biomagnify? (2 characteristics)
- high log kow
- resistant to metabolism
Why does biomagnification increase with trophic levels?
Each individual takes on the contaminant burden of all of its prey, and all of its prey’s prey, etc.
What happens if there were fewer trophic levels?
There would be less biomagnification.
What is δ15N (delta n 15)
- It is a measure that indicates trophic position
- a higher δ15N = higher trophic position
