2 Toxicology

MKH 1313 - Industrial Hygiene
Topic 2
Toxicology
1
Toxicology & Industrial Hygiene

Toxicology
A qualitative and quantitative study of the adverse
effects of toxicants on biological organism.
Industrial Hygiene
Industrial hygiene is the science of anticipating, recognizing,
evaluating, and controlling workplace conditions that may
cause workers' injury or illness.
Dr. AA, UTM, 2011
Page 1
Definition
Toxicology
The way toxicants enter biological
organism
The way toxicants are eliminated from
biological organism
The effect of toxicants on biological
organism
Dr. AA, UTM, 2011
Page 2
Fundamental Principle of
Toxicology
There are no harmless substance,

only harmless ways of using
substances
Toxicants
A chemical agents
A physical (dusts, fibers, noise, and radiation) agents,
e.g. asbestos
Toxicity is a property of toxicant that describe its
effect on biological organism.
Toxic hazards is the likelihood of damage to biological
organism based on exposure resulting from the
use/transport/storage of the toxicants (hazardous
material).
Dr. AA, UTM, 2011
Page 3
Toxic Effect can be classified

according to:
Reversible Vs Irreviersible
Acute Vs Chronic (Duration of Exposure)
local Vs systemic (Location of the effect)
Reversible/Irreversible
Irreversible
Carcinogen-cause cancer
Mutagen-cause chromosome (gene) damage
Teratogen- cause birth defects
May or may not be irreversible
Dr. AA, UTM, 2011
Dermatotoxic affects skin

Hemotoxic affects blood
Hepatotoxic- affects liver
Nephrotoxic affects kidneys
Neutotoxic affects nervous system
Pulmonotoxic- affects lungs
Page 4
Acute / Chronic
Acute exposure
High Dosage (e.g. due to accidental release
The effect is immediate
Chronic Exposure
Normally lower dose
The effect only noticed/detected following long
exposure
Sometimes, the worker could not recall the
exposure.
9
Local/Systemic
Local
Damage to the part of the body that comes in contact with
the substance.
Systemic
Chemical is absorbed by the body and attacks a target
organ.
Dr. AA, UTM, 2011
Page 5
Source of Toxicants
Toxic Release
Vapour/gas/liquid release from source
Fire and Explosion

Fire and radiation
Toxic release following explosion
11
Route of Entry
Dr. AA, UTM, 2011
Page 6
Route of Entry
Injection: through cuts or hypodermic needles into the
skin, usually cause highest blood level concentration.
Inhalation: through mouth/nose into the lungs
(respiratory system), 2nd highest blood level
concentration.
Ingestion: through mouth into stomach and
gastrointestinal tract, 2nd lowest in blood level
concentration.
Dermal (Skin) absorption: through skin membrane, lowest
in blood level concentration, note: absorption of phenol
could result in death
Route of Entry for Toxicants
ROUTE
*
*
ENTRY
CONTROL
Ingestion
mouth, stomach
rules on eating, drinking,

smoking
Inhalation
mouth, nose
ventilation, hoods,
protection equipment
Injection
cuts in skin
protective clothing
Dermal Absorption
skin
protective clothing
* industrially most significant
14
Dr. AA, UTM, 2011
Page 7
RESPIRATORY SYSTEM
Upper respiratory
Nose, sinuses, mouth, pharynx, larynx and tracea

Filtering, heating, and humidifying the air
Affected by toxicants that are soluble in water
These toxicants will react or dissolve in the mucus to form
acids or bases
E.g. hydrogen halides, oxides, hydroxides, sodium dusts
Human Respiratory System
Dr. AA, UTM, 2011
Page 8
Respiratory System: Lower Respiratory

System
Lungs (bronchial tubes and alveoli for gas exchange
with blood)
Toxicants affect the function of alveoli by blocking the
transfer of gases or by reaction with alveoli wall to
produce corrosive/toxic substances.
E.g. monomers (acrylonitrile), halides
(Chlorine),hydrogen sulfide, methyl cynaide etc
Dr. AA, UTM, 2011
Page 9
Respiratory System
Effect of dust and insoluble materials
The smaller the dust particles, the farther it
penetrate into respiratory system
Particles >5 m are filtered in the upper respiratory
system.
5m>Particles>2 m can reach bronchial system
Particles<1 m can reach the alveoli
How toxicant are eliminated from

biological organism
Excretion- through kidneys (blood to urine), liver
(selectively excrete certain chemicals indigestive tract to
bile), lungs , skin (sweats), hair, nail or other organ
Detoxification-change the chemical into something less
harmful by biotransformation through liver, can also occur
in blood, intestinal wall, skin, kidney
Storage- in fatty tissue. Can create problem when fatty
deposits are metabolized and released the toxic (e.g.
during reduced food supply). Also store in bone, blood,
liver, and kidney.
Massive exposure to hazardous chemical can damage major
organs (kidney, lung, liver), reduces their ability to excrete.
Dr. AA, UTM, 2011
Page 10
Kidney
Your kidneys receive
the blood from the
renal artery, process it,
return the processed
blood to the body
through the renal vein
and remove the wastes
and other unwanted
substances in the urine.
Urine flows from the
kidneys through the
ureters to the bladder.
Liver
Dr. AA, UTM, 2011
Page 11
Entry & Removal of Toxicants
Dose-Response
Relationships
Dr. AA, UTM, 2011
Page 12
"Dosis facit venenum" - The Dose

Makes the Poison
All substances are poisons; there is none which is
not a poison. The right dose differentiates a
poison." Paracelsus (1493-1541)
10 Grams Caffeine Usually Fatal
150 mg Stimulate Entire Spinal Cord

65 to 350 mg in 8 oz. of Coffee
55 mg in 12 oz Can of Mountain Dew
45 mg in 12 oz Can of Coke or Diet Coke
Key Factors Related to Dose

Response
The dose-response curve may differ for different
populations.
Individuals vary with regard to response to drugs or
toxins.
Dr. AA, UTM, 2011
Page 13
Dose-Response Curve
Dose-response curve graphically represents the

relationship between the dose of a stimulant (e.g.
chemicals, drugs) the response elicited
Responses - Toxicology
Toxicology:
Only toxic effects are of
concern.
Low doses NOEL
(no observable effect
level)
Greater than NOEL toxicity
Toxicity is the ability of a chemical to damage an

organ system, to disrupt a biochemical process, or
to disturb an enzyme system.
Dr. AA, UTM, 2011
Page 14
Responses (Pharmacology
Perspectives)
Low dose no observable
response
(subtherapeutic)
Increase dose leads to
increase in therapeutic
response (and side effects)
Greater than therapeutic
dose toxicity
Monty Herr
Dr. AA, UTM, 2011
Page 15
Factor Influencing a Dose-Response

Curve?
Species
Gender
Genetic strain
Age
Route of administration
Environmental conditions
Nutritional status
Effects of More Than One

Chemical
Additive Effect: the combined effect of the two
chemicals is equal to the sum of the effects of each
agent given alone. This is the most commonly
observed effect when two chemicals are given
together. (2 + 2 = 4)
Dr. AA, UTM, 2011
Page 16

Chemical Continued
Synergistic Effect:
occurs when the combined
effects of two chemicals are much greater than the
sum of the effects of each agent given alone.
CCl4 and ethanol are hepatotoxic alone but when given
together produce much more liver injury than the
mathematical sum of their individual effects. (2 + 2 = 20).
Smoking and asbestos exposure is another example.
Cocaine use with alcohol use is a third example.

Chemical Continued
Potentiation: occurs when one compound does not
have a toxic effect on a certain organ or system but
when added to another chemical makes that chemical
much more toxic.
CCl4 is hepatotoxic, isopropanol is not hepatotoxic, when
given together the effect of CCl4 is more than expected. (0 +
2 = 10)
Dr. AA, UTM, 2011
Page 17

Chemical Continued
Antagonism: occurs when two chemicals
administered together interfere with each others
action. Antagonistic interactions are very often
desirable in toxicology and are the basis of many
antidotes. (2 + (-2) = 0).
Types of Antagonism
Functional antagonism occurs when two chemicals
counterbalance each other by producing opposite
effects on the same physiological function.
Chemical antagonism is a chemical reaction between
two compounds that produces a less toxic product.
Example = a chelator and a metal.
Dr. AA, UTM, 2011
Page 18
Types of Antagonism-Continued
Dispositional antagonism occurs when the disposition
of a chemical is altered so that the concentration
and/or duration of the chemical at the target organ
are diminished. Ex. Metabolism is increased
Excretion is increased, therefore half-life is decreased
Receptor antagonism occurs when two chemicals that
bind to the same receptor produce less of an effect
when given together than the addition of their
separate parts. Receptor antagonists are often
termed blockers.
Determination
of Exposure Limits
Dr. AA, UTM, 2011
Page 19
Toxicology study
To quantify the effects of toxicant on target organism
Usually done on animals (lung, kidney, liver) and the
results are extrapolated to human. For genetic effect,
the study is on single-cell organism.
Different routes requires different toxicological study
Toxicological study
Involve identifying,
The toxicant
The target or test organism
The effect or response to be monitored
The dose range
Ingestion or injection , mg toxicant/kg of body weight
Gaseous Inhalation, ppm or mg/m3 air
Particle inhalation, millions of particle per cubic foot (mppcf) or
mg/m3 air
The period of the test (mostly acute tocixity study)
Acute toxicity, single exposure or series of exposure in a short
time
Chronic toxicity, multiple exposure over a long period of time,
also difficult to perform
Dr. AA, UTM, 2011
Page 20
Acute Exposure - Continued

Mouse and rat are the species most commonly used
for testing
Both sexes are used
Food is withheld the night before testing
The number of animals that reach a prescribed
endpoint at each dose are tabulated
10 animals per dose
5 dose levels
Acute Exposure - Continued

If larger animals are used the dose is increased in the
same animal until the prescribed endpoint is reached
Endpoints could be
Lethal dose (death)
Toxic dose (ex. Liver injury)
Effective dose (ex. Relief from itching)
Dr. AA, UTM, 2011
Page 21
Subchronic Testing
90 days is the most common test duration but 30 days
to 90 days can be used
Usually oral administration of the chemical via food;
also implant
Used to further characterize the specific organs
affected by test compound after repeated
administration of the chemical
Subchronic Exposure
At least 3 doses
A high dose that produces toxicity but death in less than
10% of the animals
A low dose that does not produce apparent toxic effects
during an acute exposure
An intermediate dose
Dr. AA, UTM, 2011
Page 22
For Drugs Under Development

Acute and Subchronic studies must be completed
before company can file an IND (Investigate New
Drug) application with the FDA (Food and Drug
Administration).
If the application is approved then Clinical Trials can
begin. Chronic tests can begin at the same time.
Chronic Exposure
Exposure to a chemical for a period longer than 3
months, usually 6 months to 2 years in rodents
Drug Testing 6 months
Food Additives with potential lifetime human
exposure 2 years required
Dr. AA, UTM, 2011
Page 23
Chronic Exposure - Continued

Designed to assess cumulative toxicity of chemicals
including consideration of carcinogenic potential
Mice 18 months to 2 years
Rats 2 to 2.5 years
Start with 60 animals/sex/dose to end up with 30
animals to survive study
Chronic Exposure - Continued

Highest administered dose = Estimated Maximum
Tolerable Dose (MTD) derived from subchronic study
The National Toxicology Program defines the MTD as
a dose that suppresses body weight slightly (i.e. 10%)
in a 90 day study
Also use MTD, MTD, and a control group
Dr. AA, UTM, 2011
Page 24
What Can Be Learned From A DoseResponse Curve?

LD50 Median Lethal Dose, quantity of the chemical
that is estimated to be fatal to 50% of the organisms
LD50 values are the standard for comparison of acute
toxicity between chemical compounds and between species
TD50 Median Toxic Dose

ED50 Median Effective Dose
LC50 Median Lethal Concentration
LD-50
100
%
affected
population
50
LD50 = 50% fatality
LD50
Dose
LD50 is commonly used for assessment of toxicity

50
Dr. AA, UTM, 2011
Page 25
Examples of LD50 Values
Mathematical Expression
for dose related event
E = magnitude of exposure
t2-t1 = exposure duration
a = availability factor
C(t) = exposure as a
function of time
IR = ingestion or
inhalation rate
f(t) = nonlinear absorption
function
Dr. AA, UTM, 2011
Page 26
Probit Analysis
Probit Analysis
The dose level of the various hazard events
against fatality can be conveniently determined
using Probit Analysis.
It is a graphical and Look-up Table approach to
determine probability of fatality
54
Dr. AA, UTM, 2011
Page 27
Probit Analysis
The probit variable Y is computed from:
Y = k1 + k2 ln V
Values of constants k1, k2 and causative
variable V (representing the dose) are
given in table
Once the probit is obtained, it can be
converted into % fatality
55
Probit: Toxic Release

Causative variable,
Probit Parameters
V=
Type of Injury
Ammonia Death
Carbon Monoxide Death
Chlorine Death
Ethylene Oxide Death
Hydrogen Chloride Death
Nitrogen Dioxide Death
Phosgene Death
Propylene Oxide Death
Sulfur Dioxide Death
Toluene
a
2.0
1.0
2.0
1.0
1.0
2.0
1.0
2.0
1.0
2.5
K1
-35.9
-37.98
-8.29
-6.19
-16.85
-13.79
-19.27
-7.42
-15.67
-6.79
K2
1.85
3.7
0.92
1.0
2.0
1.4
3.69
0.51
1.0
0.41
56
Dr. AA, UTM, 2011
Page 28
Probit: Fire and Explosion

Type of injury or damage
Causative
Probit parameters
Variable (V)
k1
k2
Burn deaths from flash fire
p0
-14.9
2.56
Burn deaths from pool burning
p0
-14.9
2.56
-77.1
6.91
Deaths from lung hemorrhage
-15.6
1.93
Eardrum ruptures
-46.1
4.82
Deaths from impact
p0
-39.1
4.45
Injuries from impact
p0
-27.1
4.26
Injuries from flying fragments
-23.8
2.92
Structural damages
-18.1
2.79
Fire
Explosion
Glass breakage
Here, te is the effective time duration (s), t is the time duration of pool burning
(sec), Ie is the effective radiation intensity (W/m2), I is the radiation intensity from
pool burning (W/m2), te is the effective time duration (s), p0 is peak overpressure
(N/m2), J is impulse (Ns/m2), C is concentration (ppm) and T is time interval (min).
57
Conversion of Probit to Fatality data

%
2.67
2.95
3.12
3.25
3.36
3.45
3.52
3.59
3.66
10
3.72
3.77
3.82
3.87
3.92
3.96
4.01
4.05
4.08
4.12
20
4.16
4.19
4.23
4.26
4.29
4.33
4.36
4.39
4.42
4.45
30
4.48
4.50
4.53
4.56
4.59
4.61
4.64
4.67
4.69
4.72
40
4.75
4.77
4.80
4.82
4.85
4.87
4.90
4.92
4.95
4.97
50
5.00
5.03
5.05
5.08
5.10
5.13
5.15
5.18
5.20
5.23
60
5.25
5.28
5.31
5.33
5.36
5.39
5.41
5.44
5.47
5.50
70
5.52
5.55
5.58
5.61
5.64
5.67
5.71
5.74
5.77
5.81
80
5.84
5.88
5.92
5.95
5.99
6.04
6.08
6.13
6.18
6.23
90
6.28
6.34
6.41
6.48
6.55
6.64
6.75
6.88
7.05
7.33
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
99
7.33
7.37
7.41
7.46
7.51
7.58
7.65
7.75
7.88
8.09
58
Dr. AA, UTM, 2011
Page 29

2 Toxicology

Hochgeladen von

Dokumentinformationen

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

2 Toxicology

Hochgeladen von

Copyright:

Verfügbare Formate

MKH 1313 - Industrial Hygiene

Toxicology & Industrial Hygiene

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

There are no harmless substance,

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Toxic Effect can be classified

May or may not be irreversible

Dr. AA, UTM, 2011

Dermatotoxic affects skin

MKH 1313 - Industrial Hygiene

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Fire and Explosion

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Route of Entry for Toxicants

rules on eating, drinking,

* industrially most significant

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Nose, sinuses, mouth, pharynx, larynx and tracea

Human Respiratory System

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Respiratory System: Lower Respiratory

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

How toxicant are eliminated from

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Entry & Removal of Toxicants

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

"Dosis facit venenum" - The Dose

150 mg Stimulate Entire Spinal Cord

Key Factors Related to Dose

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Dose-response curve graphically represents the

Toxicity is the ability of a chemical to damage an

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Factor Influencing a Dose-Response

Effects of More Than One

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Effects of More Than One

Effects of More Than One

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Effects of More Than One

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Dr. AA, UTM, 2011

MKH 1313 - Industrial Hygiene

Dr. AA, UTM, 2011