Occupational health and toxicity

3/26/2018Dr. Ketna Atul Matkar 1
Basic Toxicology-LD50 and LC 50
Dr. Ketna Atul Matkar
Consultant-Environment Microbiologist
Trainer-Sustainable Environment Management
Occupational
Health

• Occupational hygiene (United States: industrial hygiene (IH)) is the
anticipation, recognition, evaluation, control and prevention of hazards
from work that may result in injury, illness, or affect the well being of
workers.
Occupational/Industrial Hygiene

• “Occupational
hygiene is about
the prevention of
ill-health from
work, through
recognizing,
evaluating and
controlling the
risks“…
– The British
Occupational
Hygiene Society
(BOHS)
Occupational/Industrial Hygiene
1. Recognizing
2.
Evaluating
3.
Controlling

• The risk of a health effect from a given stressor is a function of the
hazard multiplied by the exposure to the individual or group.
• For chemicals, the hazard can be understood by the dose
response profile most often based on toxicological studies or
models.
• Occupational hygienists work closely with toxicologists (see
Toxicology) for understanding chemical hazards, physicists (see
Physics) for physical hazards, and physicians and microbiologists
for biological hazards (see Microbiology Tropical medicine
Infection)
• Environmental and occupational hygienists are considered
experts in exposure science and exposure risk management.
Depending on an individual's type of job, a hygienist will apply
their exposure science expertise for the protection of workers,
consumers and/or communities.
Hazards/stressors
Biological
Chemical
Physical
Ergonomic
Psycosocial

• Occupational toxicology or Industrial toxicology is the application of the
principles and methodology of toxicology to understanding and
managing chemical and biological hazards encountered at work. The
objective of the occupational toxicologist is to prevent adverse health
effects in workers that arise from exposures in their work environment.
• The science of toxicology has many applications. One of these, relates to
exposure of people to noxious or hazardous agents during the course of
their work. Eg: secretary using typewriter correction fluid, loading and off-
loading of tanker trucks with thousands of gallons of gasoline.
• Field of occupational toxicology is the study of the adverse effects of
agents that may be encountered by workers during the course of their
employment.
Occupational/Industrial Toxicology

Decision
making
within
hierarchical
control
Setting
exposure
standards
for
workplace
chemicals
Biological
monitoring
for chemical
exposure
Occupational Toxicology: Role

• The measurement of a chemical, its metabolite, or a biochemical effect in
a biologic specimen for the purpose of assessing exposure.
• Biologic monitoring is an important tool to identify the nature and amount
of chemical exposures in occupational and environmental situations.
Biological Monitoring

• Toxicity is the degree to which a substance can damage an organism.
Toxicity can refer to the effect on a whole organism, such as an animal,
bacterium, or plant, as well as the effect on a substructure of the
organism, such as a cell (cytotoxicity) or an organ such as the liver
(hepatotoxicity).
• A central concept of toxicology is that the effects of a toxin are dose-
dependent; even water can lead to water intoxication when taken in too
high a dose, whereas for even a very toxic substance such as snake
venom there is a dose below which there is no detectable toxic effect.
Toxicity is species-specific, making cross-species analysis problematic.
Newer paradigms and metrics are evolving to bypass animal testing, while
maintaining the concept of toxicity endpoints.
Toxicity and Toxicology

Toxicants
Substances that produce adverse
biological effects of any nature
Chemical or physical in nature
Effects may be chronic, acute etc
Toxins
Specific proteins produced by living
organisms
Eg: Mushroom toxin, tetanus toxin
etc.
Exhibit immediate effects
Poisons
Cause immediate death or illness
Effects in very small quantities
Toxicology

Mechanistic
•Identifies
mechanism of
action of the
chemical on
organisms
Descriptive
•Toxicity testing,
gives
information for
safety
evaluation &
regulatory req.
Regulatory
•Decision
making based
on Mechanistic
and Descriptive
data, decides
upon the
warning and
caution
Types of Toxicology

• Chemical toxicants include inorganic substances such as, lead, mercury, hydrofluoric acid, and
chlorine gas, and organic compounds such as methyl alcohol, most medications, and poisons from
living things.
• While some weakly radioactive substances, such as uranium, are also chemical toxicants, more
strongly radioactive materials like radium are not, their harmful effects (radiation poisoning) being
caused by the ionizing radiation produced by the substance rather than chemical interactions with
the substance itself.
Types of Toxins
Chemical
Biological
Physical
Radiation

• Biological: Disease-causing microorganisms and parasites are toxic in a broad sense, but are
generally called pathogens rather than toxicants. The biological toxicity of pathogens can
be difficult to measure because the "threshold dose" may be a single organism. Theoretically
one virus, bacterium or worm can reproduce to cause a serious infection. However, in a host
with an intact immune system the inherent toxicity of the organism is balanced by the host's
ability to fight back; the effective toxicity is then a combination of both parts of the
relationship. In some cases, e.g. cholera, the disease is chiefly caused by a non-living
substance secreted by the organism, rather than the organism itself. Such non-living
biological toxicants are generally called toxins if produced by a microorganism, plant, or
fungus, and venoms if produced by an animal.
• Physical toxicants are substances that, due to their physical nature, interfere with biological
processes. Examples include coal dust, asbestos fibres or finely divided silicon dioxide, all of
which can ultimately be fatal if inhaled. Corrosive chemicals possess physical toxicity
because they destroy tissues, but they're not directly poisonous unless they interfere directly
with biological activity. Water can act as a physical toxicant if taken in extremely high doses
because the concentration of vital ions decreases dramatically if there's too much water in
the body. Asphyxiant gases can be considered physical toxicants because they act by
displacing oxygen in the environment but they are inert, not chemically toxic gases.
Types of Toxins

• Toxicity can be measured by its effects on the target (organism, organ,
tissue or cell).
• Because individuals typically have different levels of response to the same
dose of a toxic substance, a population-level measure of toxicity is often
used which relates the probabilities of an outcome for a given individual in
a population. One such measure is the LD50.
• The preclinical toxicity testing on various biological systems reveals the
species-, organ- and dose- specific toxic effects of an investigational
product/compound.
Measurement of toxicity

• The toxicity of substances can be observed by:
– (a) studying the accidental exposures to a substance
– (b) in vitro studies using cells/ cell lines
– (c) in vivo exposure on experimental animals.
– (d) in silico using computer simulation
• Since the late 1950s, the field of toxicology has sought to reduce or eliminate
animal testing under the rubric of "Three Rs" - reduce the number of
experiments with animals to the minimum necessary; refine experiments to
cause less suffering, and replace in vivo experiments with other types, or use
more simple forms of life when possible.
• Toxicity tests are mostly used to examine specific adverse events or specific
end points such as cancer, cardiotoxicity, and skin/eye irritation.
• Toxicity testing also helps calculate the No Observed Adverse Effect Level
(NOAEL) dose and is helpful for clinical studies.
Measurement of toxicity

• For substances to be regulated and handled appropriately they must be
properly classified and labelled. Classification is determined by approved
testing measures or calculations and have determined cut-off levels set by
governments and scientists (for example, no-observed-adverse-effect
levels, threshold limit values, and tolerable daily intake levels).
• Global classification looks at three areas: Physical Hazards (explosions and
pyrotechnics), Health Hazards and Environmental Hazards.
Classification

• Health Hazards:
– The types of toxicities where substances may cause lethality to the entire body,
lethality to specific organs, major/minor damage, or cause cancer.
• Environmental Hazards:
– An Environmental hazard can be defined as any condition, process, or state
adversely affecting the environment. These hazards can be physical or
chemical, and present in air, water, and/or soil. These conditions can cause
extensive harm to humans and other organisms within an ecosystem.
– Common types of Environmental Hazards:
Hazards
WaterWater
•Detergents, Fertilizer, Raw
Sewage, Prescription
Medication, Pesticides,
Herbicides, Heavy Metals,
PCBs
SoilSoil
•Heavy Metals, Herbicides,
Pesticides, PCBs
AirAir
•Particulate Matter, Carbon
Monoxide, Sulphur Dioxide
•Nitrogen Dioxide, Asbestos,
Ground Level Ozone, Lead

• Toxicity of a substance can be affected by many different factors, such
as:
• the pathway of administration (whether the toxin is applied to the skin,
ingested, inhaled, injected),
• the time of exposure (a brief encounter or long term),
• the number of exposures (a single dose or multiple doses over time),
• the physical form of the toxin (solid, liquid, gas),
• the genetic makeup of an individual,
• an individual's overall health, and many others.
Factors influencing toxicity

• Acute exposure
– A single exposure to a toxic substance which may result in severe biological
harm or death; acute exposures are usually characterized as lasting no longer
than a day.
• Chronic exposure
– Continuous exposure to a toxin over an extended period of time, often
measured in months or years; it can cause irreversible side effects.
• Subacute exposure
Types of response vs exposure

• Acute toxicity looks at
lethal effects following
oral, dermal or inhalation
exposure. It is split into
five categories of
severity where Category
1 requires the least
amount of exposure to
be lethal and Category
5 requires the most
exposure to be lethal.
The table below shows
the upper limits for each
category.
Acute Toxicity
Method of
administration
Category
1
Category 2 Category 3 Category 4 Category 5
Oral: LD50 measur
ed in mg/kg of
bodyweight
5 50 300 2 000 5 000
Dermal:
LD50 measured in
mg/kg of
bodyweight
50 200 1 000 2 000 5 000
Gas Inhalation:
LC50 measured in
ppmV
100 500 2 500 20 000 Undefined
Vapour
Inhalation:
LC50 measured in
mg/L
0.5 2.0 10 20 Undefined
Dust and Mist
Inhalation:
LC50 measured in
mg/L
0.05 0.5 1.0 5.0 Undefined

Sub-acute-1-
14 days
Chronic-
3m-2y
Acute-
single
dose/less
than 24h
Toxicology testing

Acute
• Single dose is used in each animal on one occasion only for the
determination of gross effect. Eg: LD50 or median lethal dose and LC50
Chronic
• Two species, one rodent and one non rodent are dosed daily for six
months
Sub-Acute
• Usually rats are dosed daily, starting at around expected therapeutic
level and increasing stepwise every two to three days until toxic signs
Toxicological testing

• The major routes (pathways) by which toxic agents gain access to the
body are:
• Gastrointestinal tract (ingestion)
• Lungs (inhalation)
• Skin (topical, percutaneous, or dermal)
• Other parenteral (other than intestinal canal) routes
• Toxic agents generally produce the greatest effect and the most rapid
response when they are introduced directly into the bloodstream (the
intravenous route)
Mode of exposure and administration of toxic
chemical compounds

Route of
administeration
Pentobarbital
(Mouse)
Isoniazid
(Mouse)
Procaine
(Mouse)
DFP (Rabbit)
Oral 280 142 500 4
Subcutaneous 130 160 800 1
Intramuscular 124 140 630 0.85
Intraperitoneal 130 132 230 1
Intravenous 80 153 45 0.34
Effect of route of administration (LD50 in mg/kg)
Data source: Loomis, T.A. (1968)-Essentials of Toxicology (Philadelphia: Lea & Febiger)

• LD stands for "Lethal Dose". LD50 is the amount of a material, given all at
once, which causes the death of 50% (one half) of a group of test animals.
The LD50 is one way to measure the short-term poisoning potential (acute
toxicity) of a material.
• Toxicologists can use many kinds of animals but most often testing is done
with rats and mice. It is usually expressed as the amount of chemical
administered (e.g., milligrams) per 100 grams (for smaller animals) or per
kilogram (for bigger test subjects) of the body weight of the test animal.
The LD50 can be found for any route of entry or administration but dermal
(applied to the skin) and oral (given by mouth) administration methods are
the most common.
LD50

• Chemicals can have a wide range of effects on our health. Depending on
how the chemical will be used, many kinds of toxicity tests may be required.
• Since different chemicals cause different toxic effects, comparing the toxicity
of one with another is hard. We could measure the amount of a chemical that
causes kidney damage, for example, but not all chemicals will damage the
kidney. We could say that nerve damage is observed when 10 grams of
chemical A is administered, and kidney damage is observed when 10 grams
of chemical B is administered. However, this information does not tell us if A or
B is more toxic because we do not know which damage is more critical or
harmful.
• Therefore, to compare the toxic potency or intensity of different chemicals,
researchers must measure the same effect. One way is to carry out lethality
testing (the LD50 tests) by measuring how much of a chemical is required to
cause death. This type of test is also referred to as a "quantal" test because it is
measures an effect that "occurs" or "does not occur".
Why study LD50

• In 1927, J.W. Trevan attempted to find a way to estimate the relative
poisoning potency of drugs and medicines used at that time. He
developed the LD50test because the use of death as a "target" allows for
comparisons between chemicals that poison the body in very different
ways. Since Trevan's early work, other scientists have developed different
approaches for more direct, faster methods of obtaining the LD50.
Concept formulation of LD50

• LD01 Lethal dose for 1% of the animal test population
• LD100 Lethal dose for 100% of the animal test population
• LDLO The lowest dose causing lethality
• TDLO The lowest dose causing a toxic effect
Other toxicity dose terms in common usage?

• Acute toxicity is the ability of a chemical to cause ill effects relatively soon
after one oral administration or a 4-hour exposure to a chemical in air.
"Relatively soon" is usually defined as a period of minutes, hours (up to 24)
or days (up to about 2 weeks) but rarely longer.
Why are LD50 and LC50 values a measure of
acute toxicity?

• LC stands for "Lethal Concentration". LC values usually refer to the
concentration of a chemical in air but in environmental studies it can also
mean the concentration of a chemical in water.
• According to the OECD (Organisation for Economic Cooperation and
Development) Guidelines for the Testing of Chemicals, a traditional
experiment involves groups of animals exposed to a concentration (or
series of concentrations) for a set period of time (usually 4 hours). The
animals are clinically observed for up to 14 days.
• The concentrations of the chemical in air that kills 50% of the test animals
during the observation period is the LC50 value. Other durations of
exposure (versus the traditional 4 hours) may apply depending on specific
laws.
LC50

• In nearly all cases, LD50 tests are performed using a pure form of the chemical.
Mixtures are rarely studied.
• The chemical may be given to the animals by mouth (oral); by applying on the skin
(dermal); by injection at sites such as the blood veins (i.v.- intravenous), muscles
(i.m. - intramuscular) or into the abdominal cavity (i.p. - intraperitoneal).
• The LD50 value obtained at the end of the experiment is identified as the LD50 (oral),
LD50 (skin), LD50 (i.v.), etc., as appropriate. Researchers can do the test with any
animal species but they use rats or mice most often. Other species include dogs,
hamsters, cats, guinea-pigs, rabbits, and monkeys. In each case, the LD50 value is
expressed as the weight of chemical administered per kilogram body weight of the
animal and it states the test animal used and route of exposure or administration;
e.g., LD50 (oral, rat) - 5 mg/kg, LD50 (skin, rabbit) - 5 g/kg. So, the example
"LD50 (oral, rat) 5 mg/kg" means that 5 milligrams of that chemical for every 1
kilogram body weight of the rat, when administered in one dose by mouth, causes
the death of 50% of the test group.
How are LD/LC50 tests done?

• If the lethal effects from breathing a compound are to be tested, the
chemical (usually a gas or vapour) is first mixed in a known concentration
in a special air chamber where the test animals will be placed. This
concentration is usually quoted as parts per million (ppm) or milligrams per
cubic metre (mg/m3).
• In these experiments, the concentration that kills 50% of the animals is
called an LC50 (Lethal Concentration 50) rather than an LD50. When an
LC50 value is reported, it should also state the kind of test animal studied
and the duration of the exposure, e.g., LC50 (rat) - 1000 ppm/ 4 hr or
LC50 (mouse) - 5mg/m3/ 2hr.
How are LD/LC50 tests done?

• Inhalation and skin absorption are the most common routes by which
workplace chemicals enter the body. Thus, the most relevant from the
occupational exposure viewpoint are the inhalation and skin application
tests.
• Despite this fact, the most frequently performed lethality study is the oral
LD50. This difference occurs because giving chemicals to animals by mouth
is much easier and less expensive than other techniques.
• However, the results of oral studies are important for drugs, food
poisonings, and accidental domestic poisonings.
• Oral occupational poisonings might occur by contamination of food or
cigarettes from unwashed hands, and by accidental swallowing.
Which LD50 information is the most important for
occupational health and safety purposes?

• In general, the smaller the LD50 value, the more toxic the
chemical is. The opposite is also true: the larger the LD50 value,
the lower the toxicity.
• The LD50 gives a measure of the immediate or acute toxicity of
a chemical in the strain, sex, and age group of a particular
animal species being tested.
• Changing any of these variables (e.g., type animal or age)
could result in finding a different LD50 value. The LD50 test was
neither designed nor intended to give information on long-
term exposure effects of a chemical.
How do I compare one LD50 value to another
and what does it mean to humans?

• Once you have an LD50 value, it can be
compared to other values by using a toxicity
scale. Confusion sometimes occurs because
several different toxicity scales are in use. The two
most common scales used are the "Hodge and
Sterner Scale" and the "Gosselin, Smith and Hodge
Scale". These tables differ in both the numerical
rating given to each class and the terms used to
describe each class. For example, a chemical
with an oral LD50 value of 2 mg/kg, would be rated
as "1" and "highly toxic" according to the Hodge
and Sterner Scale (Table 1) but rated as "6" and
"super toxic" according to the Gosselin, Smith and
Hodge Scale (Table 2). It is important to reference
the scale you used when classifying a compound.
• It is also important to know that the actual
LD50 value may be different for a given chemical
depending on the route of exposure (e.g., oral,
dermal, inhalation). For example, some LD50s for
dichlorvos, an insecticide commonly used in
household pesticide strips, are listed below:
• Oral LD50 (rat): 56 mg/kg
• Dermal LD50 (rat): 75 mg/kg
• Intraperitoneal LD50: (rat) 15 mg/kg
• Inhalation LC50 (rat): 1.7 ppm (15 mg/m3); 4-hour
exposure
• Oral LD50 (rabbit) 10 mg/kg
• Oral LD50 (pigeon:): 23.7 mg/kg
• Oral LD50 (rat): 56 mg/kg
• Oral (mouse): 61 mg/kg
• Oral (dog): 100 mg/kg
• Oral (pig): 157 mg/kg

• Differences in the LD50 toxicity ratings reflect the different routes of
exposure. The toxicity rating can be different for different animals. The
data above show that dichlorvos is much less toxic by ingestion in pigs or
dogs than in rats. Using Table 1, dichlorvos is moderately toxic when
swallowed (oral LD50) and extremely toxic when breathed (inhalation LC50)
in the rat. Using Table 2, dichlorvos is considered very toxic when
swallowed (oral LD50) by a rat.

Table 1: Toxicity Classes: Hodge and Sterner Scale
Routes of Administration
Oral LD50 Inhalation LC50 Dermal LD50
Toxicity Rating
Commonly
Used Term
(single dose to
rats) mg/kg
(exposure of
rats for 4 hours)
ppm
(single
application to
skin of rabbits)
mg/kg
Probable
Lethal Dose for
Man
1 Extremely Toxic 1 or less 10 or less 5 or less 1 grain (a
taste, a drop)
2 Highly Toxic 1-50 10-100 5-43 4 ml (1 tsp)
3 Moderately
Toxic
50-500 100-1000 44-340 30 ml (1 fl. oz.)
4 Slightly Toxic 500-5000 1000-10,000 350-2810 600 ml (1 pint)
5 Practically
Non-toxic
5000-15,000 10,000-100,000 2820-22,590 1 litre (or 1
quart)
6 Relatively
Harmless
15,000 or more 100,000 22,600 or more 1 litre (or 1
quart)

Table 2: Toxicity Classes: Gosselin, Smith and Hodge
Probable Oral Lethal Dose (Human)
Toxicity Rating or Class Dose For 70-kg Person (150 lbs)
6 Super Toxic Less than 5 mg/kg
1 grain (a taste - less than
7 drops)
5 Extremely Toxic 5-50 mg/kg
4 ml (between 7 drops
and 1 tsp)
4 Very Toxic 50-500 mg/kg
30 ml (between 1 tsp and
1 fl ounce)
3 Moderately Toxic 0.5-5 g/kg
30-600 ml (between 1 fl oz
and 1 pint)
2 Slightly Toxic 5-15 g/kg
600-1200 ml (between 1
pint to 1 quart)
1 Practically Non-Toxic Above 15 g/kg
More than 1200 ml (more
than 1 quart)

• In general, if the immediate toxicity is similar in all of the different animals
tested, the degree of immediate toxicity will probably be similar for
humans.
• When the LD50 values are different for various animal species, one has to
make approximations and assumptions when estimating the probable
lethal dose for man. Tables 1 and 2 have a column for estimated lethal
doses in man.
• Special calculations are used when translating animal LD50 values to
possible lethal dose values for humans. Safety factors of 10,000 or 1000 are
usually included in such calculations to allow for the variability between
individuals and how they react to a chemical, and for the uncertainties of
experiment test results.
Can animal LD50 data be applied to man?

• As an aid in developing emergency procedures in case of a major spill or accident.
• To help develop guidelines for the use of appropriate safety clothing and equipment. For example, if
the dermal LD50 value for a chemical is rated as extremely toxic, it is important to protect the skin with
clothing, gloves (etc.) made of the right chemical-resistant material before handling. Alternatively, if
a chemical has an inhalation LC50 value which indicates that it is relatively harmless, respiratory
protective equipment may not be necessary (as long as the oxygen concentration in the air is in the
normal range - around 18%).
• For the development of transportation regulations.
• As an aid in establishing occupational exposure limits.
• As a part of the information in Safety Data Sheets. Remember, the LD50 is only a ball park figure so
that lethal toxicity can be compared. It says nothing about levels at which other acute toxic, but
non-lethal, effects might occur.
• The LD50 is only one source of toxicity information. For a more thorough picture of the immediate or
acute toxicity of a chemical, additional information should be considered such as the lowest dose
that causes a toxic effect (TDLO), the rate of recovery from a toxic effect, and the possibility that
exposure to some mixtures may result in increasing the toxic effect of an individual chemical.
How should an LD50 value be used?

• The largest, single collection of LD50 and LC50 values is in the
database Registry of Toxic Effects of Chemical Substances (RTECS) that is
available by subscription on the Internet. Two other databases available
from CCOHS, CHEMINFO and the Hazardous Substances Data Bank
(HSDB), are in the CHEMpendium collection.
Where can I find LD50 and LC50 values?

• https://www.ccohs.ca/oshanswers/chemicals/ld50.html
• http://qu.edu.iq/ph/wp-content/uploads/2016/03/General-Principles-of-
Toxicology.pdf
• http://ec.europa.eu/health/ph_projects/2003/action3/docs/2003_3_09_a2
1_en.pdf
• http://web.nchu.edu.tw/pweb/users/jwliao/lesson/1842.pdf
References

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