Principles of Toxicology 2 Flashcards
what has hormesis lead to the suggestion that….
humans need to be exposed to small amounts of xenobiotics and radiation to live long and healthy lives
what is hormesis ?
it is the term used to describe U or J shaped log dose response curves
- evidence that exposure to small amounts of chemicals can be protective- then as the exposure increases the beneficial effects decrease
what graphs do essential vitamins produce?
they give rise to U shaped exposure repsonse cirves
- dietary deficiencies cause adverse effects but diminish as intake increases until sufficient amounts are present
- but excessive intake may cause harm
what does too much or too little vitamin D cause ?
too much= hypervitaminosis-= renal stones and damage to the kidney
too little= ricketts
what is RFD ?
reference dose/ exposure
- daily level of exposure that we anticipate to be without harm to the organism
= NOAEL (from most sensitive organism)/SF (safety factor)
SF= UF (uncertainty factor) * MF (modifying factor)
UF= differences in sensitivities between 2 species (x10)
MF= x10
what effects does biochanin A have ?
at low levels of exposure it has beneficial effects in breast cancer by acting like estrogen, enabling a protective mechanism against cell proliferation but at higher levels it has an anti-estrogenic effect and causes damage
what effects does bromodeoxyuridine do ?
its an anti cancer drug
pregnant mice were exposed to it and at low levels it had a protective mechanism causing a reduction in fetal deaths but this is only up to about 250mg/Kg/day
when do organisms come into contact with toxicants and toxins?
OCCUPATIONAL- at work - especially chemical industry
DOMESTIC- chemicals at home such as bleach, detergents and washing powder
ENVIRONMENT- pollutants both man made and natural- they can be in the air, water and on land
TREATMENT OF ILLNESSES- pharmaceuticals
EXPOSURE CAN BE INTENTIONAL OR ACCIDENTAL
what are the 4 aspects to exposure ?
the route
intensity
frequency
duration
what is the “RULE OF 2”?
substances with HIGH LIPID SOLUBILITY and HIGH EXPOSURE are the most likely to enter an organism and cause harm
what is the 1st step in the induction of toxicity ?
exposure to the toxicant and its entry into the body by absorption
what are the routes of entry for a toxicant ?
ingestion- followed by absorption from the gut - small intestine has a large surface area and the epithelial layer is only one cell thick so easy for lipid soluble toxicants to cross and if they are not lipid soluble they can cross b carrier mediated transport - cant cross by paracellular diffusion, only by transcellular
inhalation- followed by absorption from the lungs - particularly gases and volatile liquids
dermal/topical followed by absorption through the skin- striatum cornum is several layers of dead cells
what is “bioavailability”?
for a chemical to cause toxic effects it needs to enter into an organism
what law does the rate and extent of absorption of a toxicant by diffusion obey ?
ficks law
influenced by the physico-chemical properties of the toxicant and biological factors such as membrane thickness and surface area
what is the key property of the toxicant for rate and extent of absorption ?
lipid solubility
highly lipid soluble compounds have the potential to rapidly penetrate into the organism
what is the difference between transcellular and paracellular diffusion |?
transcellular means through the cell whereas paracellular involves diffusion through the gaps between the cells
what does efficient metabolism cause ?
metabolism and/or excretion of a toxicant will reduce exposure of the target cells and this will protect against a toxic response
what does the accumulation of a toxicant in a non-target tissue cause ?
accumulation in adipose tissue
it will be protective because this process will reduce the amount of toxicant reaching the target cells
why is paracetamol different ?
it is not detoxified by metabolism- infact it produces a toxic metabolite which is chemically reactive and is able to cause hepatotoxicity in large doses
what 3 things can happen to the toxicant once it is present in the blood ?
- accumulate in tissue- eg in adipose tissue - lipid soluble substances will dissolve in adipose tissue and accumulate, this can occur over a lifetime producing significant accumulation - during starvation, this these toxins can cause toxicity
- metabolism to inactivate or activate metabolites
- excretion in urine, bile or exhaled in air
what happened in the 60s and 70s with soaps?
all soaps and talcs for neonates contained hexachlorophene which is used to prevent bacterial infection of the skin
however in france there were talcs containing 6% hexachlorophene and this was a sufficient amount to cause neurotoxicity - led to death or disability such as cognitive impairment
what does paraquat do ?
it is a toxicant which is selectively transported into and concentrates in epithelial cells in the lung - cells are selectively killed by paraquat
what are targets for toxicants ?
cells
subcellular organelles
molecular components of a cell
what happened to eider ducks and dieldin ?
female ducks died while incubating their eggs due to dieldrin
the dieldrin had built up in their fat stores and then while th ducks were incubating their eggs they were using up energy stores (like starvation) and this caused the release of dieldrin which killed them
when is cell injury sub lethal ?
when the targte can be regenerated by a transient reversible interaction with a toxicant- quickly resynthesised or is protected by a chemical defence so its biological functions are not disrupted
what happens normally when a chemical attack is lethal ?
necrotic cell death occurs
this is not too bad in organs such as the liver where stem cells are active and can replace the dead cells so organ function is not affected as long as not too many cells are killed
what adult organs only have a small stem cell population and what effect does this have ?
CNS and heart
this means that even death of a small population of cells will have adverse effects on organ functio
what effect can mutations have ?
they may not have an immediate consequences by themselves but in the long term they may lead to developmental abnormalities and/or cancer
what are the 4 consequences of toxicant-target interactions ?
- transient disruption of cell biology with recovery
- disruption of cell biology with no recovery leading to death
- organ/tissue dysfunction
- irreversible changes to DNA/chromosomes - give rise to mutagenesis and cancer
what are SAPICS?
stress activated protein kinases
- their initial response is to try and over come the damage caused by the chemical
they are involved in triggering cell death if the damage is not transient
what are the 2 forms of cell death ?
APOPTOSIS- this occurs if the cell has lots of ATP- responds to noxious stimuli by shrinking and undergoing phagocytosis- this is efficient and clean
NECROSIS- this occurs if there is little ATP - the cell swells and bursts and releases its contents into the extracellular fluid - some of this is proinflammatory and causes an inflammatory reaction leading to further cell death
how can toxicants/toxins interact with their targets ?
form a covalent bond or they can break a covalent bond
what is similar about sarin and edrophonium ?
they have the same target acetylcholineesterase
what does sarin do to its target ?
phosphorylates its target and covalently modifies it causing irreversible damage - this effect can last for many weeks, until the body can resynthesise ache
why are edrophoniums effects on AChE different to sarin ?
it is not sufficiently lipid soluble from the GIT so its effects only last a few minutes
actions are short because the actions are irreversible and the strength of binding is weak and also it is readily excreted by the kidney
