Prof Ball Flashcards
Alkaloid poisons
Aconitine
coniine
atropine
scopolamine
The Marsh Test
Arsenic poisoning - garlic smell
Three main areas of tox
Mechanistic
Regulatory
Descriptive
Descriptive tox
Tox testing
important for safety evaluation and regualtion
Mechanistic tox
elucidating mechanisms by which chemicals exert their toxic effects
Regulatory tox
deciding on basis of date providing by testing if drug poses a sufficiently low risk to be marketed for a stated purpose
Ways to classify a toxic agent (9)
Target organ usual designated use of the chemical source physical state chemical reactivity Chemistry (FG) effects poisoning potential biochemical mechanism of action
Toxins
Refer to toxic materials of natural origin
toxicants
materials of anthropogenic origin
What is Aflatoxin?
A Mycotoxin produced by fungus Aspergillus flavus
contaminates corn, peanuts, other grains
targets liver ultimately causing cancer
When is a toxic effect not observed?
If the chemical or its metabolic products do not reach an appropriate biological target
toxic agent must be present in a high enough concentration for a sufficient duration to produce an effect
Additive effects
1+1=2
toluene and xylene
chlorinated HCs
Controversial because of effects on environment + health
Choloform
Synergistic effects
1+1=10
tetrachloride+ethanol= hepatotoxic
Potentiation
0+3= 10
Antagonists
1+4=2
Local toxic effects
at site of contact with chemical
Systemic toxic effects
at various parts of the body- chemical mist be absorbed by the body
Acute effects
effects produced soon after exposure- up to 14 days
may not be fatal
effects easily related to the poison and the relationships between dose and effects can be determined
therefore, safe levels of the poison can be established
Methods of absorption
ingestion
inhalation
dermal- DMSO a powerful solvent
intraveneous inhalation intraperitoneal subcutaneous intramuscular oral dermal
occupational exposure
generally inhalation or dermal
define LD50
The dose, given all at once, which will kill 50% of the population exposed to it
based on body weight mg/kg
measured accurately for Animals- estimate for humans
fatal dose can only be obtained by
estimation- the amount of the chemical which will kill one member of the species
Weakness of LD50
Species dependent
does not tell about full spectrum of toxic effects
Low LD50
High toxicity
LC50
Lethal conc for 50%
LD01
lethal dose causing death of 1% of test animals
minimum lethal dose
LDLO
Lowest dose causing lethality
TDLO
Lowest dose causing a toxic effect
LD50 of copper sulfate in rats
30mg/kg
2.0mg/l for drinking water in humans
most toxic rating on Gosselin, Smith and Hodge
6
most toxic rating on Hodge and Sterner
1
describe dose response curve
show does on horizontal axis versus the cumulative % of deaths on vertical axis usually logarithmic
steeper curve more acute dangerous poison
Concerns about LD50 testing
lead to slow, painful deaths and poisons large number of animals
little info about chronic effects id obtained
animal and human LD50 have doubtful correlation
Alternatives to LD50
use fewer animals
use of bacteria
animal tests that do not have death as an endpoint
tissue cultures
Chronic effects
problems
exposure to small amounts of toxic substances over long period of time
symptoms can take years to show
difficult to track
HOW DO YOU KNOW that a particular chemical is responsible
May be many victims before toxicity becomes known
difficult to predict effects
Study of Chronic Toxic effects
Epidemiology
study of various factors relating to various diseases, illnesses etc
looks at factors that may affect he local distribution compared with the population as a whole
Increased incidence of bladder cancer
aromatic amines in dye industries
increased incidence of leukaemia
exposure to radioactive substances
mesothelioma
asbestos
lung cancer
smoking
Animal tests for chronic toxicity effects involve
large no. of animals more than one species multiple dose levels long term lifetime dosage examination of dosed animals and their ofspring for toxic symtoms
Problems in animal testing chronic effects
more expensive and time consuming than acute
specimen mus show same response as human
cost
can only be justified for drugs, food additives and important industrial and agricultural chemicals therefore, the majority of chemicals polluting the environment have not been subjected to full critical chronic toxicity testing
Animal testing depends on assumptions:
- the magnitude of the toxic effect is dose dependent
- there is a threshold dose, below which there are no toxic effects
- test animals show the same response as humasn
TLV
Threshold Limit Value
Measure of the max average safe levels of toxic chemicals in the at.
based on industrial exposure
comparing TLVs of substances provides a comparison of their toxic properties
Acceptable Daily Intake
ADI
one way of managing toxic risks for chemicals
daily intake of chemical for entire lifetime without appreciable risk
NOAEL
No observed adverse effect levels
for good data factor of 10
for less certain factor of 1000
Important agents causing chronic effects
carcinogens
mutagens
teratogens
sensitisers
Type 1 carcinogen
chemicals which are known to cause cancer in humans
type 2 carcinogens
chemicals which are known to cause cancer in animals and suspected of being carcinogenic in humans
type 3 carcinogens
chemicals that are not classifiable as to their carcinogenicity in humans
type 4 carcinogens
probably not carcinogenic to humans
action of carcinogens
reaction with DNA
possible for some carcinogens- no THdose
Mutagenic substance
causes chemical alteration of genetic material (DNA) in the nucleus of cells
may be no obvious effect immediate but in future generations
what can lead to mutations
chemicals, radiation
Ames Test
correlation between mutagenicity and carcinogenity has been estimated over 80%
Mutant strains of Salmonella Typhimurium
normal strains are histidine independent
mutant strains are histidine dependent
problems with Ames test
not perfect model for humans
compounds with low solubility or diffusion rates do not test well
dioxin tests negative but is carcinogen
visa versa
teratogen
damage fetus causing birth defects
thalidomide tragedy
Example of environmental teratogens
dioxins- produced by inceneration of waste from papermill wastes
persistent organic pollutants
Sensitisers
strong allergic reaction to various chemicals which are tolerated by the majority of people
Sensitisers- the allergic response
extreme allergic responses (hypersensitivity) due to anomlous reastions of the immune system
anaphylaxis
reaction of foreign material due to increased susceptibility following previous exposure to that material
examples of sensitisers
formaldehyde
pesticides
chronuim- printing
Risk Management
Balances beneficial effects of the chemical against adverse effects
DDT
Typhiod and Malaria
extinction of some bird species
3 Main sites of absorption
GIT
lungs
skin
GIT
chemical from GIT to bloodstream- pass through lipid membrane- transport active or passive
What does Fick’s Law tell you
Passive diffusion is a first order process
rate is poroprtional to the conc gradient across the membrane
thicker membranes lead to slower absorption
larger surface areas lead to faster absorption
Absorption rate of a toxic substance depends on
Magnitude of K, which depends on chem and phys properties of the compound
large K= rapidly absored
Acidic compounds tend to be absorbed in the
stomach
basic compounds absorbed in the
intestines
what size particle is usually exhaled- no retained
smalled than 0.2 um
what size particle is trapped in the trachea
larger than 60um
PM10
particle matter 10 micrometers or less in diameter
How do foreign substances enter cells
small molecules pass through pores in the membrane- formed by proteins embedded in the membrane
for passive diffusion (4)
conc gradient across membrane
foreign substance must be lipid-soluble
it must not be ionised
obeys Fick’s law
for Active Transport
Specific membrane carrier is required
metabolic energy required
can occur against conc gradient
sim substrates may compete for uptake
Facilitated Diffusion
Specific carrier in the membrane is required
conc gradient necessary
Process may be saturated at high substrate concentrations
glucose
Endocytosis
Two processes involve engulfment of foreign substances by cells
insoluble particles e.g. uranium dioxide and asbestos are absorbed into the lungs in this way
Phagocytosis
encapsulation of relatively large particles
pinocytosis
incorporation of small droplets
Absorption through skin mainly limited to lipid soluble compounds
solvents
absorption skin
IO poor
O may not be absorbed
Dimethyl sulfoxide greatly enhance absorption through the skin
surface area of lungs
50-100m^2
How are particles absorbed in the lungs
endocytosis
The rate of blood flow in the lungs is
the rate determining factor when a toxic material has low solubility in blood- blood is rapidly saturated and the only way for absorption to continue is to provide fresh blood.
Respiration rate is the rate determining factor when
a toxic material has high solubility in blood- toxic materials are continually removed from the air in the lungs
fast blood flow ensures that there is always a conc gradient favouring absorption
small intestine pH
stomach pH
mouth pH
6
2
7
Fate of toxic substance in the body
Metabolism
excretion
storage
storage in body organs
lead in bones
mercury in kidneys
DDt in fatty tissues
Dieldrin in Blood Proteins
What is directly excreted in urine
polar compounds e.g. organic acids
small water-soluble molecules
Metabolism
process of chemical reactions taking place in an organism which produces energy and leads to the synthesis of body molecules
catabolism
produces energy
protein–> amino acids
anabolism
synthesis of body molecules
amino acids–> body proteins
xenobiotics
chemicals which are not normally found in, or produced by an organism or which are found in much higher concentrations than usual
major site of metabolism
liver
enzymes
catalysts which drive all metabolic processes in the body
proteins made up of a linear combinations of amino acids
macromolecules whose molecular weights vary from 5000-1million
synthesised linear molecules folded into specific 3D shapes and tend to be globlar
levels of protein structure in amino acid
primary: aa sequence
secondary: localised 3D structure
tertiary: overall 3D structure
Quaternary: more than one peptide chain
each enzyme is coded by
a gene
prosthetic groups often contain
metals- Fe, Cu, Co, Mn
therefore, cytochromes contain Fe, Cu
active site
small part of the enzyme molecule involved in the catalytic process
contains active functional groups
efficiency of enzymes depends on
organisation of the FGs in the correct spatial arrangement
Chemical reactions catalysed by enzymes
hydrolysis synthesis/ coupling reactions oxidations and reductions molecular rearrangements time process 10^-6-10^-2 seconds
inhibition
toxic substances slow down/ stop normal catalytic function of the enzyme
binds to or blocks the active site in some manner
mechanisms for inhibition of enzyme activity
reversible- competitive and non inhibition
irreversible- form strong covalent onds to enzyme
poisons which are enzyme inhibitors
HCN, Organophosphorus insecticides, fluroacetate, heavy metals
how are xenobiotics eliminated in urine
metabolise din liver and made polar water- soluble metabolite then excreted in urine
2 processes of metabolism of xenobiotics
primary metabolism–> made water soluble, oxidations (most common), reductions, hydrolysis
secondary metabolism- primary metabolite linked to a highly water soluble molecule produced y the body
Cytochrome P450
enzyme system in the liver which oxidises a wide range of xenoiotics by introduction of Hydroxly groups
reduction examples
nitro compounds
azo compounds
secondary metabolism
3 examples
greatly enhances water solubility and hence urinary excretion
conjugation with glucuronic acid
conjugation with sulfate
conjugation with amino acids
effects of metabolism on the toxicity of xenobiotics
may or may not reduce toxicity
driving force is increasing water solubility
inherently not a detoxification mechanism
examples of metabolic deactivation
less toxic
toluene–>Hippuric acid
Parathion–> diethyl thiophosphoric acid
carbaryl–> methylamine
ethanol–> acetic acid
examples of metabolic deactivation
more toxic
benzene–> OH groups
Hecana–> one of the metabolites of hexans
–> N-Hydroxy metabolite
environmental substances activated by normal metabolism
polycuclic aromatic hydrocarbons- nitrosamines, alkylating agents, chlorinated solvents, polychlorinated biphenyls
ADI
if NOAEL dose for animal was 100mg/kg/dag
using 1000x uncertainty factor the NOAEL for humans would be 0.1mg/kg/day
for the average human (70kg) the ADI would be 70*0.1 mg/day (7mg/day)
