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BASIC

TOXICOLOGY
The harmful effects of chemicals on
biological systems
DEFINITIONS
TOXICITY - the capacity of a chemical agent to
cause harm when absorbed into the body.
HAZARD - the toxicity, and the probability that the
chemical agent will be absorbed and cause harm
under a specified set of conditions.

Note that under some conditions of use a very toxic


chemical may represent a smaller risk or hazard than
a less toxic compound.
MEASUREMENT OF TOXICITY
DOSE-RESPONSE RELATIONSHIPS

The Dose-response relationship is a measure of


the number of individuals in a large group of
subjects which show a particular effect at a specific
level of exposure (dose).
The Dose-Response Relationship
70

60

50
Response

40

30

20

10

0
-3σ -2σ -1σ µ 1σ 2σ 3σ

Dose
ACUTE TOXICITY - ANIMAL STUDIES

The starting point in evaluation of toxicity of a chemical is the


determination of lethality (LD50)

LD50 - the dose that is estimated to kill 50% of a group of animals


after one dose or short exposure.
LC50 - the concentration (in air) of the agent estimated to kill 50%
of the test animals after one short exposure by inhalation.

LD50 is used as a method of comparing acute toxicities of different


chemicals. Because it only deals with one endpoint, death, it
cannot reveal anything about the chronic effects or other
toxic effects of the chemical.
TYPICAL TOXICITY CLASSIFICATION
BASED ON LD50

1. Extremely toxic 1 mg/kg or less


2. Highly toxic 1 - 50 mg/kg
3. Moderately toxic 50 - 500 mg/kg
4. Slightly toxic 0.5 - 5 gm/kg
5. Practically non-toxic 5 - 15 gm/kg
6. Relatively harmless more than 15gm/kg
Some Approximate Acute LD50s
Agent LD50 (mg/kg)
§ Ethyl alcohol 10,000
§ Sodium chloride 4,000
§ Ferrous Sulfate 1,500
§ Morphine sulfate 900
§ DDT 100
§ Strychnine sulfate 2
§ Nicotine 1
§ Tetrodotoxin 0.1
§ Dioxin 0.001
§ Botulinus toxin 0.00001
Comparison of Dose-Response Curves

50

40
Response

30
A B
20

10

Dose
Comparison of Dose-Response Curves

50

D
40
Response

30

20

10 C

Dose
SELECTIVE TOXICITY
Toxicological testing with animals is
complicated by the fact that different species
respond differently to the same chemicals.
This may be due to:

1. differences in surface area


2. differences in accumulation
3. differences in rate of biotransformation
4. differences in biochemical pathways
MALATHION
(relatively inactive)

rapid - insect slow - insect


rapid - mammal rapid - mammal

Oxidation hydrolysis
(microsomal enzymes) and binding

MALAOXON PRODUCTS
(active) (inactive)
hydrolysis
(A - esterases)
slow - insect
rapid - mammal
TOXIC EFFECTS
Local vs Systemic toxicology
Local - Irritant chemicals when inhaled produce
local toxic effects in the lungs. e.g. HCl, NH3

Systemic Toxicity - Many toxic substances


affect a number of organ systems well removed
from the site of absorption. Usually one or two
organs will suffer the greatest toxic effect.
These are the target organs for the toxicant.
Immediate vs Delayed toxicity
Immediate - HCN, CO, H2S

Delayed - phosgene, tri-orthocresyl


phosphate

Long Latency - carcinogenic compounds,


often have a latency
period of 20-30 years
ACUTE vs CHRONIC EXPOSURES
ACUTE - a single exposure or several exposures over
a short period of time
CHRONIC - repeated or continuous exposure over a
long period of time

ACUTE vs CHRONIC EFFECTS


Acute effects require higher concentrations of the agent
and are usually different from the effects produced by
chronic exposure
e.g. Lead - colic with acute exposure
- wrist drop with chronic exposure
FREQUENCY AND DURATION
OF EXPOSURE
• Frequency and duration of exposure is
important if some detoxification or elimination
of the agent occurs between exposures.
• Two consecutive 12 hour workday exposures
to a chemical are not equivalent to three
consecutive 8 hour workday exposures.
• An important consideration when applying
exposure levels designed for workers working
an 8 hour shift to graduate students.
CLASSIFICATION OF TOXICANTS

1. Irritants 6. Neurotoxic agents


a. primary 7. Hematopoietic
b. secondary toxicants
2. Asphyxiants 8. Fibrogenic agents
a. simple 9. Sensitizing agents
b. chemical 10. Mutagens
3. Narcotic agents 11. Carcinogens
4. Hepatotoxic agents 12. Teratogens
5. Nephrotoxic agents
ABSORPTION
Laboratory chemicals may be absorbed

1. Through the lung

2. Through the skin

3. Through the gastrointestinal tract


MECHANISMS OF TOXICITY
Absorbed chemicals may act as systemic
toxicants throughout the body, or may attack
specific target organs. Differences in
mechanism are due to:
1. Differences in ability to cross cell membranes
2. Solubility differences in different tissues
3. Blood supply to specific tissues
4. Differences in chemical reactivity
BIOTRANSFORMATION
• chemical transformations of a foreign chemical in an
organism
• chemical may be made more toxic, or less toxic
• e.g. ethyl alcohol is detoxified by oxidation to the
acetyl group which enters normal cellular metabolism
(the citric acid cycle)
• but, methyl alcohol is oxidized by the same enzyme
system to formaldehyde - more toxic than the alcohol.
• rate of these metabolic transformations varies
between individuals and between species
• accounts for SELECTIVE TOXICITY.
EXCRETION
The body may eliminate chemicals by way of:
1. exhaled air (the lung)
2. urine (the kidney)
3. feces (biliary excretion)
4. maternal milk
5. hair, nails
6. sweat, saliva
Many toxic chemicals can also cross the
placenta and enter the fetal circulation.
MEASURES OF TOXIC HAZARD
The LD50 is not very useful for assessing
risk of ongoing or chronic exposures.

To measure the exposure hazard


associated with airborne chemicals,
measures based on the concentration of
the chemical in air are used.
THE AMERICAN CONFERENCE OF
GOVERNMENTAL INDUSTRIAL
HYGIENISTS (ACGIH) Exposure Limits
TLV (Threshold Limit Value)
The concentration of an air contaminant to which
nearly all workers can be exposed 8 hrs a day
without significant adverse effect.

TLV-TWA (Time Weighted Average)


TLV-STEL (Short Term Exposure Limit)
TLV-C (Threshold Limit Value - Ceiling)
In Ontario:
TWAEV - Time Weighted Average Exposure Value
STEV - Short Term Exposure Value
CEV - Ceiling Exposure Value

These exposure limit values should not be taken as


quantitative measures of relative toxicity
They do not represent a clear cut dividing line
between safe and unsafe exposures
They are a useful, semi-quantitative guide to the
hazard presented by chemicals.
SOME EXPOSURE LIMITS IN ONTARIO
TWAEV
COMPOUND ppm mg/m3

acetone 500 1185


acetonitrile 40 67
carbon disulfide 10 31
toluene 50 376
benzene 0.5 1.6
toluene diisocyanate (TDI) 0.005 0.035
mercury (inorganic) 0.025
lead 0.05
THE OCCUPATIONAL HEALTH AND
SAFETY ACT
In Ontario, workplace exposures to hazardous chemical
and physical agents is regulated by the Occupational
Health and Safety Act and a series of specific
regulations made under this act.

The Designated Substance Regulations


Asbestos Isocyanates
Arsenic Lead
Acrylonitrile Mercury
Benzene Silica
Coke oven emissions Vinyl chloride
Ethylene Oxide
Chemical Engineering and Applied
Chemistry
requires that researchers using these substances
complete and post a Permit to Use a Designated
Substance in their laboratories. This permit describes
quantities to be used, room location and control
procedures that the researcher intends to use to limit
exposure.

This permit is also required for the use of a number of


other substances which have been designated by the
department. These include:
carbon disulfide carbon tetrachloride
formaldehyde styrene
The End