Prof Ball Flashcards
(116 cards)
1
Q
Alkaloid poisons
A
Aconitine
coniine
atropine
scopolamine
2
Q
The Marsh Test
A
Arsenic poisoning - garlic smell
3
Q
Three main areas of tox
A
Mechanistic
Regulatory
Descriptive
4
Q
Descriptive tox
A
Tox testing
important for safety evaluation and regualtion
5
Q
Mechanistic tox
A
elucidating mechanisms by which chemicals exert their toxic effects
6
Q
Regulatory tox
A
deciding on basis of date providing by testing if drug poses a sufficiently low risk to be marketed for a stated purpose
7
Q
Ways to classify a toxic agent (9)
A
Target organ usual designated use of the chemical source physical state chemical reactivity Chemistry (FG) effects poisoning potential biochemical mechanism of action
8
Q
Toxins
A
Refer to toxic materials of natural origin
9
Q
toxicants
A
materials of anthropogenic origin
10
Q
What is Aflatoxin?
A
A Mycotoxin produced by fungus Aspergillus flavus
contaminates corn, peanuts, other grains
targets liver ultimately causing cancer
11
Q
When is a toxic effect not observed?
A
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
12
Q
Additive effects
A
1+1=2
toluene and xylene
13
Q
chlorinated HCs
A
Controversial because of effects on environment + health
Choloform
14
Q
Synergistic effects
A
1+1=10
tetrachloride+ethanol= hepatotoxic
15
Q
Potentiation
A
0+3= 10
16
Q
Antagonists
A
1+4=2
17
Q
Local toxic effects
A
at site of contact with chemical
18
Q
Systemic toxic effects
A
at various parts of the body- chemical mist be absorbed by the body
19
Q
Acute effects
A
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
20
Q
Methods of absorption
A
ingestion
inhalation
dermal- DMSO a powerful solvent
intraveneous inhalation intraperitoneal subcutaneous intramuscular oral dermal
21
Q
occupational exposure
A
generally inhalation or dermal
22
Q
define LD50
A
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
23
Q
fatal dose can only be obtained by
A
estimation- the amount of the chemical which will kill one member of the species
24
Q
Weakness of LD50
A
Species dependent
does not tell about full spectrum of toxic effects
25
Low LD50
High toxicity
26
LC50
Lethal conc for 50%
27
LD01
lethal dose causing death of 1% of test animals
| minimum lethal dose
28
LDLO
Lowest dose causing lethality
29
TDLO
Lowest dose causing a toxic effect
30
LD50 of copper sulfate in rats
30mg/kg
| 2.0mg/l for drinking water in humans
31
most toxic rating on Gosselin, Smith and Hodge
6
32
most toxic rating on Hodge and Sterner
1
33
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
34
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
35
Alternatives to LD50
use fewer animals
use of bacteria
animal tests that do not have death as an endpoint
tissue cultures
36
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
37
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
38
Increased incidence of bladder cancer
aromatic amines in dye industries
39
increased incidence of leukaemia
exposure to radioactive substances
40
mesothelioma
asbestos
41
lung cancer
smoking
42
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
```
43
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
44
Animal testing depends on assumptions:
1. the magnitude of the toxic effect is dose dependent
2. there is a threshold dose, below which there are no toxic effects
3. test animals show the same response as humasn
45
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
46
Acceptable Daily Intake
ADI
one way of managing toxic risks for chemicals
daily intake of chemical for entire lifetime without appreciable risk
47
NOAEL
No observed adverse effect levels
for good data factor of 10
for less certain factor of 1000
48
Important agents causing chronic effects
carcinogens
mutagens
teratogens
sensitisers
49
Type 1 carcinogen
chemicals which are known to cause cancer in humans
50
type 2 carcinogens
chemicals which are known to cause cancer in animals and suspected of being carcinogenic in humans
51
type 3 carcinogens
chemicals that are not classifiable as to their carcinogenicity in humans
52
type 4 carcinogens
probably not carcinogenic to humans
53
action of carcinogens
reaction with DNA
| possible for some carcinogens- no THdose
54
Mutagenic substance
causes chemical alteration of genetic material (DNA) in the nucleus of cells
may be no obvious effect immediate but in future generations
55
what can lead to mutations
chemicals, radiation
56
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
57
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
58
teratogen
damage fetus causing birth defects
| thalidomide tragedy
59
Example of environmental teratogens
dioxins- produced by inceneration of waste from papermill wastes
persistent organic pollutants
60
Sensitisers
strong allergic reaction to various chemicals which are tolerated by the majority of people
61
Sensitisers- the allergic response
extreme allergic responses (hypersensitivity) due to anomlous reastions of the immune system
62
anaphylaxis
reaction of foreign material due to increased susceptibility following previous exposure to that material
63
examples of sensitisers
formaldehyde
pesticides
chronuim- printing
64
Risk Management
Balances beneficial effects of the chemical against adverse effects
65
DDT
Typhiod and Malaria
| extinction of some bird species
66
3 Main sites of absorption
GIT
lungs
skin
67
GIT
chemical from GIT to bloodstream- pass through lipid membrane- transport active or passive
68
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
69
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
70
Acidic compounds tend to be absorbed in the
stomach
71
basic compounds absorbed in the
intestines
72
what size particle is usually exhaled- no retained
smalled than 0.2 um
73
what size particle is trapped in the trachea
larger than 60um
74
PM10
particle matter 10 micrometers or less in diameter
75
How do foreign substances enter cells
small molecules pass through pores in the membrane- formed by proteins embedded in the membrane
76
for passive diffusion (4)
conc gradient across membrane
foreign substance must be lipid-soluble
it must not be ionised
obeys Fick's law
77
for Active Transport
Specific membrane carrier is required
metabolic energy required
can occur against conc gradient
sim substrates may compete for uptake
78
Facilitated Diffusion
Specific carrier in the membrane is required
conc gradient necessary
Process may be saturated at high substrate concentrations
glucose
79
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
80
Phagocytosis
encapsulation of relatively large particles
81
pinocytosis
incorporation of small droplets
82
Absorption through skin mainly limited to lipid soluble compounds
solvents
83
absorption skin
IO poor
O may not be absorbed
Dimethyl sulfoxide greatly enhance absorption through the skin
84
surface area of lungs
50-100m^2
85
How are particles absorbed in the lungs
endocytosis
86
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.
87
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
88
small intestine pH
stomach pH
mouth pH
6
2
7
89
Fate of toxic substance in the body
Metabolism
excretion
storage
90
storage in body organs
lead in bones
mercury in kidneys
DDt in fatty tissues
Dieldrin in Blood Proteins
91
What is directly excreted in urine
polar compounds e.g. organic acids
| small water-soluble molecules
92
Metabolism
process of chemical reactions taking place in an organism which produces energy and leads to the synthesis of body molecules
93
catabolism
produces energy
| protein--> amino acids
94
anabolism
synthesis of body molecules
| amino acids--> body proteins
95
xenobiotics
chemicals which are not normally found in, or produced by an organism or which are found in much higher concentrations than usual
96
major site of metabolism
liver
97
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
98
levels of protein structure in amino acid
primary: aa sequence
secondary: localised 3D structure
tertiary: overall 3D structure
Quaternary: more than one peptide chain
99
each enzyme is coded by
a gene
100
prosthetic groups often contain
metals- Fe, Cu, Co, Mn
| therefore, cytochromes contain Fe, Cu
101
active site
small part of the enzyme molecule involved in the catalytic process
contains active functional groups
102
efficiency of enzymes depends on
organisation of the FGs in the correct spatial arrangement
103
Chemical reactions catalysed by enzymes
```
hydrolysis
synthesis/ coupling reactions
oxidations and reductions
molecular rearrangements
time process 10^-6-10^-2 seconds
```
104
inhibition
toxic substances slow down/ stop normal catalytic function of the enzyme
binds to or blocks the active site in some manner
105
mechanisms for inhibition of enzyme activity
reversible- competitive and non inhibition
irreversible- form strong covalent onds to enzyme
106
poisons which are enzyme inhibitors
HCN, Organophosphorus insecticides, fluroacetate, heavy metals
107
how are xenobiotics eliminated in urine
metabolise din liver and made polar water- soluble metabolite then excreted in urine
108
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
109
Cytochrome P450
enzyme system in the liver which oxidises a wide range of xenoiotics by introduction of Hydroxly groups
110
reduction examples
nitro compounds
| azo compounds
111
secondary metabolism
| 3 examples
greatly enhances water solubility and hence urinary excretion
conjugation with glucuronic acid
conjugation with sulfate
conjugation with amino acids
112
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
113
examples of metabolic deactivation
| less toxic
toluene-->Hippuric acid
Parathion--> diethyl thiophosphoric acid
carbaryl--> methylamine
ethanol--> acetic acid
114
examples of metabolic deactivation
| more toxic
benzene--> OH groups
Hecana--> one of the metabolites of hexans
--> N-Hydroxy metabolite
115
environmental substances activated by normal metabolism
polycuclic aromatic hydrocarbons- nitrosamines, alkylating agents, chlorinated solvents, polychlorinated biphenyls
116
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)
