Toxicity 5: Factors Affecting Toxicity
gas and vapours
-readily pass into the bloodstream -will keep being absorbed until gas and blood are at equilibrium -each gas/vapour has its own partition coefficient that indicates how quickly this equilibrium is reached (therefore how much is absorbed)
natural polymorphisms
-reduce DDT binding to channel and rose the resistance
synergistic interactions
-sum of the effect of two chemicals is much greater than the sum of the effects of the same agent given alone 2+2 =50 mercury and led salt
Additive interactions
-total amount of toxicity is the sum of the toxities of the two toxins 2+2= 4 Parathion and Malathion similar LD50 and targets of toxicity
toxicant storage: fat
-toxicants are mostly hydrophobic -readily partition into adipose tissue
antagonism interactions
-when two chemicals are encountered, and one counteracts the action of the other "basis of antidotes"
toxicokinetics pathway
1. Exposure 2. Absorption 3. Distribution and metabolism 4. Storage or excretion
mechanisms of resistance
1. selection for a polymorphism 2. selection for a new mutation 3. new gene picked up from environment 4. multiple copies of a gene
Factors affecting toxicity
1. specific toxicant 2. concentration of toxicant 3. form of toxicant 4. interactions between toxicants 5. duration of exposure 6. species of organism 7. age or life stage 8. genetics
cell types are often (4)
1. stratified epithelium of the skin 2. thin cell layers of epithelium of lungs and gastrointestinal tract 3. capillary endothelium 4. cells in the target organ/tissue
chronic doses can eventually reach toxic levels depending on :
1. the dose at each step of repeated exposure 2. how quickly the toxicant is metabolized or eliminated
many chemicals are excluded by the brain due to (2)
1. tight junctions (no pose in-between for paracellular diffusion) 2. MDR transporter which pump unwanted chemicals back into blood stream
very hydrophobic non ionic chemicals pas the BBB which correlates well with the ___ of the chemical
Kow
how toxicants are distributed between compartments is complex and dependent on the _____ of the toxicant
chemistry
transcellular diffusion
diffusion of toxicants through cells (membrane crossing)
paracellular diffusion
difusion of toxicants in-between cells
Larger toxicant enter cells through ____
endocytosis
intermediate polar toxicants can enter through ____ & _____
follicles and sweat glands
lungs are the site of _____ in the body
gas exchange
Resistance
genetically encoded ability for an organism to avoid toxic response when exposed to a toxicant
protein toxins are usually ___ made of the toxin (alpha subunit) and beta subunits
heterodimers
Transport is either passive if the toxicant is moving from _____
high to low concentration
toxicokinetics
how toxicants are absorbed, metabolized, distributed and eliminated
when does transcellular diffusion occur
if the cells are packed tightly with little space between them
Xenobiotics often contain ______ form the manufacturing process.
impurities
various transporters can move xenobiotics from the __ to the ___
intestine to bloodstream
sequencing genomes is getting ____
less expensive
all chemicals absorbed in the gut first go through the ______ via ___
liver via hepatic portal -major site of toxin metabolism -can excrete into bile
toxic effects may be ____ or ______
local (in a specific tissue) or systemic (throughout the organism)
transporter is active if moving from
low to high concentration (requires aTP)
toxicodynamics
what happens after the molecular target is altered -includes types of molecular, cellular and organ damage
absorption
when toxicants cross cell membranes and enter blood stream or lymph system
Multidrug resistance (MDR or MRP) and transporters can pump _____ back out of the epithelial cell
xenobiotics
toxicant absorption through the skin
-minor route -very hydrophobic molecules diffuse across skin
additive
-never encountering a toxin at one time -unpredictable results
deleterious effect
-only happens if the toxicant is at a sufficient concentration at the target
Tolerance
-prior exposure of a toxicant alters the metabolism or physiology of the organism can reduce the effect of the toxicant
toxicants move through membranes ________ or ______ via ____ & ___
toxicants move through membranes passively (diffusion) or actively via channels and transporters
toxicogenomics
-field of science that deals with gene and protein activity within a particular cell or tissue in response to a toxic substance
cell membranes are (3)
-lipid bilayers of phospholipids -contain proteins -coated in carbohydrates
Agent orange
-American military dumbed this herbicide and TCDD (teratogen) levels were super high
significance of karen wetterhahn
-Mercury is not toxic on its own but when it is in the environment it can be converted to its organic form (methyl mercury or dimethylmercury)
potentiation interactions
-a non toxic chemical makes a toxicant even more toxic
toxicant storage : blood
-albumin can absorb toxicants -is an abundant protein in the blood
warfarin
-anticoagulant -binds to albumin in blood -low dose carried by albumin can reach toxic levels in blood stream
receptor mediated endocytosis
-cells have receptors that recognize proteins -membrane forms a vesicle which contains the protein
Molecular target
-concept that somewhere in the body is a biomolecule that the toxicant can affect
genetics of the organism -polymorphisms -susceptibility factors -resistance factors
-differences in the DNA code of the genes are called polymorphisms *****
Age of the organism
-embroyo to adult goes through different developmental stages -sometimes a toxicant can have a greater effect at one of these stages
liver
-extract toxins and excrete them into bile
duck story in fat storage of toxicants
-female ducks died when laying eggs -due to dieldrin poisoning -dieldrin was stored in ducks fat reserves -fat reserves were mobilized to produce eggs = releasing dieldrin at toxic levels
toxicant storage: liver and kidney
-metabolism and excretion of toxicants and also as storage
if 2.5 um it will get stuck where
tracheobronchial
morphine is the _____ and naloxone is the ____.. meaning
agonist and antagonist -blocks the receptors
if <1 um it will get stuck where
alveolar
toxicants mostly defuse through tissues ____ entering the blood stream
before
The ____ ____ ____ can keep most toxicants out of the brain
blood brain barrier
beta subunits bind to ___ and tricks the cell into taking in the toxin
membrane components
if >5um it will get stuck where
nasopharyngeal
different types of transporters are involved in the uptake of nutrients because?
nutrients cannot diffuse across membranes
Stomach
pH 2 -degrade toxicants (proteins) -absorption of weak acids
small intestine
pH 6-7.5 -major area of nutrient intake -nutrients form gut into bloodstream
large intestine
pH6 -marjor area of water uptake -bacteria converts toxicants to different forms
most common path of hydrophobic toxicants
passive non mediated (straight thru membrane)
most common path of small hydrophilic
passive non mediated via channel
toxicants must pass through the ____ of many cells to reach its target
plasma membrane
acute does can give big effects ____
quickly
particulate
small chunk of solid matter
aerosol
small droplet of liquid
where they get stuck in the lung is dependent on ___
their size
half life of elimination (t1/2)
time required for the blood or plasma chemical concentration to decrease by one half