Principles of Toxicology 2

Question 0

what has hormesis lead to the suggestion that….

Answer 0

humans need to be exposed to small amounts of xenobiotics and radiation to live long and healthy lives

Question 1

what is hormesis ?

Answer 1

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

Question 2

what graphs do essential vitamins produce?

Answer 2

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

Question 3

what does too much or too little vitamin D cause ?

Answer 3

too much= hypervitaminosis-= renal stones and damage to the kidney
too little= ricketts

Question 4

what is RFD ?

Answer 4

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

Question 5

what effects does biochanin A have ?

Answer 5

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

Question 6

what effects does bromodeoxyuridine do ?

Answer 6

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

Question 7

when do organisms come into contact with toxicants and toxins?

Answer 7

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

Question 8

what are the 4 aspects to exposure ?

Answer 8

the route
intensity
frequency
duration

Question 9

what is the “RULE OF 2”?

Answer 9

substances with HIGH LIPID SOLUBILITY and HIGH EXPOSURE are the most likely to enter an organism and cause harm

Question 10

what is the 1st step in the induction of toxicity ?

Answer 10

exposure to the toxicant and its entry into the body by absorption

Question 11

what are the routes of entry for a toxicant ?

Answer 11

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

Question 12

what is “bioavailability”?

Answer 12

for a chemical to cause toxic effects it needs to enter into an organism

Question 13

what law does the rate and extent of absorption of a toxicant by diffusion obey ?

Answer 13

ficks law
influenced by the physico-chemical properties of the toxicant and biological factors such as membrane thickness and surface area

Question 14

what is the key property of the toxicant for rate and extent of absorption ?

Answer 14

lipid solubility

highly lipid soluble compounds have the potential to rapidly penetrate into the organism

Question 15

what is the difference between transcellular and paracellular diffusion |?

Answer 15

transcellular means through the cell whereas paracellular involves diffusion through the gaps between the cells

Question 16

what does efficient metabolism cause ?

Answer 16

metabolism and/or excretion of a toxicant will reduce exposure of the target cells and this will protect against a toxic response

Question 17

what does the accumulation of a toxicant in a non-target tissue cause ?

Answer 17

accumulation in adipose tissue

it will be protective because this process will reduce the amount of toxicant reaching the target cells

Question 18

why is paracetamol different ?

Answer 18

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

Question 19

what 3 things can happen to the toxicant once it is present in the blood ?

Answer 19

• 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

Question 20

what happened in the 60s and 70s with soaps?

Answer 20

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

Question 21

what does paraquat do ?

Answer 21

it is a toxicant which is selectively transported into and concentrates in epithelial cells in the lung - cells are selectively killed by paraquat

Question 22

what are targets for toxicants ?

Answer 22

cells
subcellular organelles
molecular components of a cell

Question 23

what happened to eider ducks and dieldin ?

Answer 23

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

Question 24

when is cell injury sub lethal ?

Answer 24

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

Question 25

what happens normally when a chemical attack is lethal ?

Answer 25

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

Question 26

what adult organs only have a small stem cell population and what effect does this have ?

Answer 26

CNS and heart

this means that even death of a small population of cells will have adverse effects on organ functio

Question 27

what effect can mutations have ?

Answer 27

they may not have an immediate consequences by themselves but in the long term they may lead to developmental abnormalities and/or cancer

Question 28

what are the 4 consequences of toxicant-target interactions ?

Answer 28

• 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

Question 29

what are SAPICS?

Answer 29

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

Question 30

what are the 2 forms of cell death ?

Answer 30

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

Question 31

how can toxicants/toxins interact with their targets ?

Answer 31

form a covalent bond or they can break a covalent bond

Question 32

what is similar about sarin and edrophonium ?

Answer 32

they have the same target acetylcholineesterase

Question 33

what does sarin do to its target ?

Answer 33

phosphorylates its target and covalently modifies it causing irreversible damage - this effect can last for many weeks, until the body can resynthesise ache

Question 34

why are edrophoniums effects on AChE different to sarin ?

Answer 34

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