TOXICOLOGY

“THE STUDY OF POISONS” DR ROSLYNN BAATJIES

 INTRODUCTION TO
TOXICOLOGY
 Toxicology is the study of the potential of a substance to
produce adverse health effects on a living organism and the
likelihood that the effects might occur under specified
exposure conditions.
 Historically toxicology was the art and science of poisoning.

 It is a discipline which makes use of information developed

by a wide range of chemical, physical, biological and
medical sciences in order to predict the likely adverse
effects on man of an ever‑increasing range of substances to
which he is exposed.
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FUNDAMENTALS OF
TOXICOLOGY
"All substances are poisons, there is none
which is not a poison. The right dose
differentiates a poison
and a remedy" – Paracelsus (1525).

Any chemical may be toxic if the dose is high

enough
 ANY CHEMICAL MAY BE
TOXIC IF THE DOSE IS HIGH
ENOUGH
This concept is fundamental to understanding the
•
principles of toxicology
• It is also important when trying to protect workers
• However, it is often difficult to link the cause and
effect of a disease
PROBLEMS LINKING CAUSE
AND EFFECT
•The effect may not occur at time of exposure
•By the time it occurs the person may not be working
with the substance–long latency periods before
symptoms are obvious–examples?
•People vary insusceptibility (react differently)
•Variations may be due to age, gender, health status
etc.
PROBLEMS LINKING CAUSE
AND EFFECT
• Complications of combined effects
- Exposure to different substances
- Exposure to alcohol, tobacco or prescribed drugs
• Detailed toxicological information is often not
available for many substances
BASIC TOXICOLOGICAL
TERMS
Acute effects
Occur immediately on exposure or soon after
Usually from relatively high dose
Usually of short duration
Usually reversible

Chronic effects
Occur some time after exposure
Usually from repeated lower doses over many months / years
Usually irreversible
TERMS CONTINUED
Local effects
Occur at the point of contact e.g.
Xylene causes de-fatting of skin
Sulphuric acid causes irritation / burns on skin
Chlorine causes pulmonary inflammation

Systemic effects
Occur at target organ remote from point of contact e.g.
Xylene causes dizziness / unconsciousness
Xylene causes damage to liver / CNS
Cadmium causes damage to kidney
Lead causes damage to blood forming process in bones
BASIC TERMS CONT…
Xenobiotic
- terms for a substance not normally found or produced in a
person, meaning it is foreign to the body
- xenobiotics include drugs, industrial chemicals, naturally
occurring poisons etc
MAIN TYPES OF COMBINED
EFFECTS
Additive effect
Combined effect of two substances is equal to the
sum of the individual effects(1+3=4):
•Toluene and xylene–both are irritant and narcotic,
similar chemicals, affect the same target organs
•Organo-phosphorus insecticides–all organo-
phosphorous pesticides inhibit cholinesterase
activity
MAIN TYPES OF COMBINED
EFFECTS
Independent effects
Toxic effects of each substance are unaffected by
simultaneous exposure
(1+2=1+2):
e.g. Lead and xylene
MAIN TYPES OF COMBINED
EFFECTS
Synergistic effects
Combined effect is greater than the sum of the
individual effects if each substance encountered
alone e.g.(2+2=20):
•Carbon tetrachloride and ethanol–both are
hepatoxic (causing liver damage)–but total liver
damage by combined exposure is much greater than
expected

•Smoking and Asbestos–greatly increased lung

cancer risk
MAIN TYPES OF COMBINED
EFFECTS
Potentiation
A substance has no toxic effect, but when
simultaneous exposure occurs with a second
substance, the toxicity of the second chemical is
enhanced.
An example is:
•Carbon tetrachloride and iso-propanol –isopropanol
alone is not hepatoxic, but it increases the
hepatoxicity of carbon tetrachloride.
MAIN TYPES OF COMBINED
EFFECTS
Antagonism
this is where the combined effect of two substances
is less than the sum of the individual effects if each
substance was encountered alone. An example is:
•Phenobarbitone and paradoxon (an organo-
phosphorous pesticide) –phenobarbitone increases
the rate of metabolism of paradoxon and reduces its
toxicity.
QUESTION 1:
Which is more toxic: water or benzene? Which
of the two is the more hazardous?
ANSWER
Benzene is the more toxic substance. When
considering the hazard which substances present, it
depends entirely on conditions of exposure and use.
For a fisherman, water is much more hazardous than
a bottle of benzene in a cabinet in the ship’s engine
room
TOXICOLOGY: TERMINOLOGY
Blood Haem Haematology
Lung Pneumo Pneumoconiosis
Liver Hepa Hepatoxic
Kidney Neph Nephron
Skin Dermal Dermatitis
CNS Neural Neurosis

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INFO WHEN ASSESSING OCCUPATIONAL
EXPOSURE OR DISEASES ARE ASSESSED
• Concentration;
• Route(s) of exposure;
• Form of the substance;
• Duration and frequency of exposure;
• Additive or synergistic effects with other hazardous substances;
• Duration until onset of symptoms?
• acute onset – single exposure or,
• chronic onset from multiple low dose exposures.

• Biological exposure indicating body burden-

• Directly – by measuring the level of the contaminant present in blood or urine or;
• Indirectly - by measuring a metabolic product are determining the effect on a
system or activity i.e. the enzyme cholinesterase level in blood from exposure to
organophosphate pesticides;

• Additional medical test i.e. liver function, lung function etc.

OTHER…….
• Controls in place
• Rate of generation
• Probability of exposure
• Form of substance
• Effect of substance
• LD/ LC values
• Number of persons exposed
• Combined effects of various HCSs
• Individual differences
• Health status of persons
• Work rate – breathing, blood flow
TOXICOKINETICS:
THE CONCENTRATION OF A TOXIN
AND ITS EFFECTS DEPEND ON THE
FOLLOWING:
Effect of a hazardous substance depends on the level or
concentration of the substance that is present in the body’s
systems–this will depend on rates (or kinetics) of:
• Rate of Absorption of the hazardous substance
• Distribution in the body
• Rate of biotransformation (Metabolism)
• Toxicity of metabolites
• Rate of excretion (Elimination)
Study of these processes is called toxicokinetics (sometimes
referred to as pharmacokinetics)
ROUTES OF ENTRY
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ABSORPTION
Both the concentration and lipid solubility of the
toxic substance determine the rate of absorption.
Increased blood flow and large surface areas of
exposure increase the rate of absorption.
Common routes of absorption are the
gastrointestinal tract, respiratory tract and skin or
dermal system.
The most common route of exposure in occupational
settings is the respiratory tract.
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ROUTE OF ENTRY / ABSORPTION

Ingestion: Ingestion is the least significant route of

entry in industry while in environmental toxicology it is
the most.
Inhalation: Particles less than 10 micron in diameter
may reach the alveoli. If soluble, approximately 40% are
then absorbed. Inhalation accounts for approximately
90% of industrial poisoning.
The Skin: In the skin there is again no selective uptake.
Fat-soluble compounds are absorbed readily as are
organic solvents.
Injection: May be possible e.g. needlestick injuries or
grease gun injection into skin.
THE DIAGRAM BELOW REFLECTS THE ROUTE OF
MAXIMUM ABSORPTION OVER TIME – MOST
EFFECTIVE ROUTE OF ABSORPTION -
RESPIRATORY ROUTE
DOSE RESPONSE CURVES
Paracelsus stated that "all substances are poisons;
there is none which is not. Only the dose differentiates
a poison from a remedy".
One of the basic tenets of toxicology is the dose
response relationship which results from measurement
of outcomes over various dosages.
Dose response tables and graphs typically result from
laboratory animal testing over high dose levels.
On relatively rare occasions dose response data can
be derived from human toxicity data.
DOSE RESPONSE CURVES

Dose response curves can show a number of points

including:
◦The ‘no effect level’ where no effect occurs or no
effect is detectable
◦The threshold dose of the substance–the level at
which the effect starts to occur
◦The levels at which the effect occurs in a set
percentage or all of the test animals
 The typical sigmoid curve of the percent of
observed subjects (laboratory animals), with
evidence of a toxic effect over the different
dosages studied.
Note that response here means
the percentage of subjects affected in a
defined way (e.g. death)
In general, the higher the dose, the more
severe the response.
For most effects, small doses are not toxic.
Most physiologic responses follow a sigmoidal
or "S" shaped curve, with an initially low slope
of incremental response with increasing dose
which increases to a maximal slope in the mid
dose range and plateaus again to a low slope
at maximal range.
TYPICAL There may or may not be a threshold, a dose
below which no observable effect is expected.
SIGMOID CURVE In the hypothetical curve above in Figure 1 ,
no toxicity occurs at 10 mg whereas at 35 mg
100% of the individuals experience toxic
effects.
 The shape and slope of the dose-
response curve is helpful in predicting

DOSE RESPONSE the risk or toxicity of a substance at

specific dose levels.

CURVES Major differences among toxicants may

exist not only in the dose at which the
toxicity is seen but also in the percent of
population responding per unit change in
dose (i.e., the slope).

As illustrated in Figure 4, Toxicant A has

a higher threshold but a steeper slope
than Toxicant B, the implication being
that comparatively, Toxicant B is more
toxic at lower dosages and Toxicant
A more toxic at higher dosages.

A threshold for toxic effects occurs at

the point where the body's ability to
detoxify a xenobiotic or repair toxic injury
has been exceeded.

The threshold may also be referred to as

 Dose effect relationships

INDICES: B
Death
Medical
Indices
Sub- E C Diagnosable illness
clinical F
Toxicology
Indices
F
Detectable disease
E pre cursors
Pshyco C Earliest
A = Linear physio T demonstrable
B = Hyperbolic logical change
C = Sigmoidal indices
No change
A

D O S E [concentration X time]
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RESPONSE CURVE TYPES – see previous figure
Linear response:
Typically substances awarded OEL‑TWA values. As the dose increase the effects
increase.

Hyperbolic response:
Substances awarded OEL‑TWA and STEL values show this response. There is an
increase in the effect as the dose increases but there is no correlation between the
dose and effect.

Sigmoidal response:
Substances awarded ceiling limits show Sigmoidal response. These type
substances have an all or nothing effect, thus as the dose increase there is no
drastic increase in the effect until such a point where a slight increase in the dose
could lead to a very drastic effect (e.g. death).

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DISTRIBUTION

•Once substances have entered the body they can distributed

around the body through the blood supply.
•They may concentrate differentially in the organs.
•Blood is the primary method of distribution with some of the toxic
substances being removed by the lymph and lung macrophages.
Distribution depends on:
 Physiological properties
 Physiochemical properties
 Lipid solubility – assist with penetration
 Active transport – binding to cellular protein
 pH gradient differences – HCS accumulates in a site
 Molecular affinity – CO for hemoglobin!
METABOLISM
Substances which are distributed through the body then tend to be
metabolised.
The main site of metabolism is the liver, although the kidneys, lungs
and skin can metabolise some chemicals.
Metabolism can convert a toxic substance to a non-toxic one and
vice versa.
EXCRETION
This takes place via;
 Kidneys
 Bile,
 Lungs,
 Gastric juices,
 Breast milk,
 Skin (iron).

The more rapidly excretion takes place the less likely is a toxin to
damage the body.
Excretion products are often used to monitor work exposure.
HALF-LIFE - AN IMPORTANT TOXICOKINETIC CONCEPT

An important concept is that of half-life of a substance. This is

relevant, for example, to biological monitoring. It is also relevant to
the interpretation of disciplinary alcohol or drug monitoring
undertaken by some employers.
(It is critical in forensic medicine in estimating when someone may
have ingested a toxin, or how much they must have ingested, e.g.
alcohol.)
Half-life (t½) = time to eliminate half of the starting load.
Acetone 3 hr. Hydrogen sulphide <20 min.
Ammonia <20min. Iron oxide fume 12 hr.
Aniline 2 - 9 hr. Lead 25-40 days
Benzene 3 - 5 hr. Mercury 5 wk.
Cadmium 7-30 yr. Methanol 7 hr.
Carbon di-sulphide 0.9 hr. Mineral dust > 6 mo.
Carbon monoxide 1 - 4 hr. Nitro-benzene Nitrogen 86 hr.
Carbon tetrachloride Chlorine 3 hr. dioxide Phenol 1 hr.
Chloroform DDT < 20min. p-Nitro phenol Styrene 3.4 hr.
Di-chloro di-fluoro methane 15-30 min. Sulphur dioxide 1 hr.
Ethyl acetate 1-3 yr. Tetrachloroethylene 0.5-8 hr.
Ethyl alcohol 9 min. Toluene < 20 min.
Ethyl benzene 2 hr. Trichloroethylene 27-70 hr.
Fluorides 1.5-10 hr. Vinyl chloride 12 hr.
Hexane isomers 5 hr. Xylene 24 hr.
8 hr. 3 hr.
3 hr. 3 - 8 hr

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TOXICITY
Particular points on dose response curves can also include toxicity:
LD50 (Lethal dose, 50%) the dose (Oral) that kills 50% of the test
population
LC50 (Lethal concentration, 50%) the concentration (inhalation)
that kills 50% of the test population
TD50 (Toxic dose, 50%) the dose that causes a particular effect in
50% of the test population
TC50 (Toxic concentration, 50%) the concentration that causes a
particular effect in 50% of the test population
TOXICITY
Single values give no indication of curved slopes
LD 50 value CURVE A is more potent than
LD 50 CURVE B.
From the curves B is more potent at lower doses
LD 50

Response
LD 10
B A

Dose

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 TOXICITY
The largest single collection of LD and LC values is in the database Registry of Toxic
effects of Chemical substances (RTECS)

LD; LC …….
Category/ LD 50 orally LC 50 skin LC 50 Gas
Group mg/kg mg/kg mg/kg
Very toxic 1a < 25 < 50 < 0,5
Toxic 1b < 25 - 200 < 50 - 400 < 0,5 – 2
Harmful 2 > 200 - 2000 > 400 - 2000 > 2 - 20

 Substances ability to pass membranes increase their toxicity

 Lipid soluble substances cross the blood, brain and placental barrier
 Molecular size of substance
 Non ionized substances
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RISK PHRASES
R01 Explosive when dry.
R02 Risk of explosion by shock, friction, fire or other sources of ignition
R03 Extreme risk of explosion by shock, friction, fire or other sources ignition.

R04 Forms very sensitive explosive metallic compounds

R05 Heating may cause an explosion
R06 Explosive with or without contact with air
R07 May cause fire
R08 Contact with combustible material may cause fire
R09 Explosive when mixed with combustible material
R10 Flammable
R11 Highly Flammable
R12 Extremely Flammable
R14 Reacts violently with water
R15 Contact with water liberates extremely flammable gases
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RISK PHRASES
RISK PHRASES
TOXICOLOGICAL
CLASSIFICATION
TOXICOLOGICAL CLASSIFICATION
P112-
Asphyxiant
Irritants
Anesthetic/ narcotic
Systemic: Liver ; Kidney; Lungs etc.
Carcinogenic – Mutagenic – Teratogenic
Allergens

47
Substances which
produce lack of
oxygen in the blood
thus preventing
oxygen from reaching
organs

48
Prevent oxygen
distribution:
= interfere with
absorption of oxygen
into the blood
= or in the exchange
of oxygen at the
tissues

49
Primary or contact irritants
reacts with the body’s
tissues on contact.

Mucous membranes, skin,

eyes, upper respiratory
tract, lower respiratory
tract.

Many, probably most,

complaints among workers
working with chemical
substances fall into this
category, and may
interfere with quality of
life.

Irritative symptoms may

also be the first indication
of excessive exposure. 50
Rapidly penetrate blood brain
barrier and cause CNS
excitation or depression

Slows down the functioning of

the CNS initially starting with
symptoms such as headache
and fatigue

51
Materials are carried in
the bloodstream to
some specific action
site.

The toxic substance

acts on the body by
depressing or
stimulating of enzyme
systems

See classification by
organ system.
Examples include:
Hepatotoxins -
tetrachloroethane
Neurotoxins (peripheral
or central) - mercury,
lead, solvents,
pesticides
Nephrotoxins
36 - heavy
metals 52
53
NOW FOR REAL!

54
Asphyxiants: Substances which produce lack of oxygen (Anoxia)
in the blood and tissues thus preventing oxygen from reaching
the body.
Inert gases which displaces O2 from the air
Examples: Methane, Nitrogen and CO2
asphyxiants Oxygen levels should never be below 18%
Simple

Prevent oxygen distribution inside the body. Act by:

-Interfere with the absorption of oxygen into the blood
or
-in the exchange of oxygen at the tissues
EXAMPLES:
- CO Has great affinity for sites on haemoglobin where
xiants

O2 is normally carried. Therefore blood transports

lower quantity of O2. 55
IRRITANTS:
Primary or contact irritants reacts with the body's tissues on
contact
Irritant Ammonia, chloride, fluorine, phosgene, nitrogen
gases dioxide, NO2 SO2
Irritant Vapours of- formaldehyde, bromine, methylene
liquids chloride, resins
Irritant Dusts, fibres
solids
Symptoms:
- Eyes: Itchy, sore, red and dry/ runny:
- Nose : Itchy, stuffy or runny;
- Upper airways: Coughing and sneezing, difficult breathing;
- Skin: Red, blotchy in contact area;
- Dermatitis: Develops in exposed area;
- Corrosion: Is extreme irritation prognosis for recovery is
poor. 56
ANAESTHETICS OR NARCOTICS:
Substances probably affect the permeability of nerve cell
membranes by acting on fat containing areas.
This penetration of the "blood-brain" barrier affects the
performance of the nerve cell.
Slows down the functioning of the central nervous system
initially starting with symptoms such as headaches and
fatigue.
Progressive symptoms: Examples:
- Impaired judgement - motor - Acetylene, ethylene, ethyl
co-ordination; ether, propane
- Confusion - excitement; - Nearly all organic solvent
- Convulsions; vapours have some
- Immobility, muscles relaxed, anaesthetic effect.
reflexes regressed, coma - The more volatile the
greater the risk of an effect
57
 Materials that are carried in the bloodstream to some
specific action site
The toxic substance acts on the body by depressing or
stimulating of enzyme systems
Blood and blood forming Benzene, phenol, lead, arsine
system
Visceral organs (liver, Hydrocarbons, cadmium, Cr, Hg,
SYSTEMIC POISONS

kidneys) PB
Nervous system Organic phosphate insecticides
Brain Lead, Mercury, Manganese
Lungs Cadmium, Asbestos, Silica
quartz
Reproduction Ethylene oxide

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 Act on unborn off-spring to produce congenital

S
TERRATOGEN
malformations
Embryo-toxic materials act on unborn off-spring to
produce abortion
Thalidomide, X-ray, lead

Mutagenesis is broadly defined as the induction of DNA

damage:
- gene mutations: changes in one/few DNA base pairs
(mutagens)
- chromosome aberrations gross changes in
chromosome structure (clastogens)
Substance that damages chromosomal structures, are
known as genotoxic i.e. Vinyl chloride
Various processes have also been shown to produce
mutagens:
AGENS

- incomplete combustion (benzo-a-pyrene)

- cooking and normal processing of food 59
 Cancer is characterised by abnormal cell division and growth,
producing tumours or neoplasms
They may be either benign of malignant:
- benign neoplasms include warts, polyps and fibroids - they
can be removed surgically and do not normally recur
CARCINOGENIC - malignant tumours can spread (to metastasis) through the
SUBSTANCES body, invading other tissues.

60
 CARCINOGENIC
CLASSIFICATION
Category Explanation
Group 1 The agent is carcinogenic to humans. The
exposure circumstances entails exposures
that are carcinogenic to humans
Group 2A The agent is probably carcinogenic to humans.
The exposure circumstances entails exposures
that are probable carcinogenic to
humans
Group 2B The agent is possible carcinogenic to humans.
The exposure circumstances entails exposures
that are possibly carcinogenic to
humans
Group 3 The agent is not classified as to it’s
carcinogenicity to humans
Group 4 The agent is probably not carcinogenic to 61
Nickel Species Classifying Agency

EPA - ‘86 IARC - ‘90 EU - ‘90 ACGIH- 98 TERA - ‘99

Metallic Ni - 3 3 5 -

Soluble Ni - 1 0.125 4 4

Oxidic Ni - 1 1 1 -

Sulphidic Ni 1 1 1 1 -

Ni Carbonyl 2 1 3 - -

• Soluble Ni [Ni salts] include: 1 = Known human carcinogen

Ni chloride & Ni sulphate 2 = Probable human carcinogen

• Oxidic Ni include: 3 = Possible human carcinogen

Ni oxides, Ni hydroxide, 4 = Intermediate human carcinogen

Ni carbonate 5 = Not carcinogenic to humans

• Sulphidic Ni include:

Ni sulphides & Ni subsulphides A=Does not include nickel chloride

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 - Antibodies may be produced against unfamiliar substances,
including
- soluble toxin released by bacteria and molecules on the surface

SENSITISERS
of bacteria,
- any large unfamiliar molecule, not only bacterial products.
- When the immune system reacts with unnecessary enthusiasm
to an unfamiliar material an allergy or hypersensitivity results.
- On exposure there will be skin or the respiratory effects

Chlorine Flour Dust mite Microorganisms

SO2 Mouldy hay droppings Spores
Platinum salts, Dander Endotoxins
Chromium, Feathers
Di-isocyanate

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FOR NEXT CLASS - THAT
MEANS TOMORROW!
Divide into groups
Scan the remaining topics
CANCERS:
Identify causes 1.
Identify Types 2.
What is REPRODUCTIVE EFFECTS & 3.
What is mutagenesis? 4.

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STILL TOMORROW!
SENSITISERS:
 What is inflammation 5
 What reactions occur 5
 CAUSES OF RESP ALLERGENS
 Allergies from inorganic dust 6
 Allergies from organic dust
 Allergies and ventilation systems
 Allergies from animal protein
 OCCUPATIONAL ASTHMA 7
 Bysinnosis 8
 EAA 9
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NOPE THAT’S NOT THE END!
• 9 Sections were listed above
• Generate 2 MCQ questions per topic per group (no copying)
• THUS: 9x2 = 18 MCQs Add 2 extra total 20
• MCQs must be mailed to ME!
• See overleaf for format:

66
THIS IS THE END TODAY!!!!
Section 1 (ANSWER *)
1. The OELs are found in:
A. Facebook
B. *HCS regulations
C. The hymn book
D. ABSA bank

2. OHS is
 Simply the best
 Demanding
 Stimulating
 *All of the above

SECTION 2:
3. ………………..

67
SAFETY DATA SHEETS
Much of the work involved in accessing workplace hazards can be
carried out by accessing Safety Data Sheets (SDS) (previously
called Material Safety Data Sheets or MSDS). The SDS is a standard
way of communicating toxicology and other relevant information
about substances.
In many countries it is a legal requirement or common practice that
a company supplies an SDS for each of the products that they sell.
SAFETY DATA SHEETS
The content of the SDS will vary depending upon local
legislative requirements but is likely to contain the following
information:
Composition/Data on components: This gives
details of the different chemicals contained within
the material. It will often list the Chemical
Abstracts Service (CAS) number for each chemical
is contains. The CAS number is a unique number
which is assigned to most of the chemicals used in
industry.
Identification of substance: This includes the
trade name, as well as manufacturer/supplier
details. It may also give emergency information
such as contact names and telephone numbers.
 SAFETY DATA SHEETS
Hazards identification: The material will be classified under a
number of categories and described with pictograms.

First aid measures: Advice about how to deal with workers who have
been exposed under different circumstances.

Fire fighting measures: Do’s and don’ts of fire extinguishing e.g.

what type of fire extinguisher to use.

Accidental release measures: The procedures to be followed in case

of accidental release of the chemical, including methods to be used to
clean up spills.

Handling and storage: Giving information on the precautions such as

flammables cabinets and temperature limitations.
SAFETY DATA SHEETS
Exposure controls and personal protection: Outlines
requirements such as Personal Protective Equipment and ventilation.
Physical and chemical properties: e.g. the form (solid/liquid/gas),
colour, odour, melting and boiling points.
Stability and reactivity: Properties such as thermal decomposition
and conditions to be avoided.
Toxicological information: Details such as acute and chromic
effects on man and animals.
Ecological information: How the material might affect the
environment if it is released beyond the workplace.
Disposal considerations: Any special requirements associated with
disposal of the material.
SAFETY DATA SHEETS
Transport information: generally as a list of
codes indicating the dangers associated with the
chemical.

Regulations: Relevant legislation for the

country in which the material is used.

Other information: Any information which is

relevant.