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