Dose response relationship

A.P. Dr Mohd Khan Ayob
PPSKTM, FST,
UKM,
43600 Bangi
25/05/2010 1Kursus Toksikologi Makanan IKU 31Mei-4Jun 2010

INTRODUCTION
The science of toxicology is based on the principle that
there is a relationship between a toxic reaction (the
response) and the amount of poison received (the dose).
“The right dose differentiates a poison from a remedy.”
Important assumptions in this relationship
there is almost always a dose below which no response
occurs or can be measured.
once a maximum response is reached any further increases
in the dose will not result in any increased effect.

Dose-response relationship = the cause and effect
relationship between chemical exposure and illness.
Allergic reactions are special kinds of changes in the
immune system; they are not really toxic responses.
 Not always comply with D-R assumptions
Allergies vs. toxic reactions
 A toxic effect : results of the toxic chemical acting on cells.
 Allergic responses : result of a chemical stimulating the body
to release natural chemicals which are in turn directly
responsible for the effects seen.

MEASURES OF EXPOSURE
Exposure to poisons can be intentional or
unintentional.
The effects of exposure to poisons vary with the
amount of exposure, "the dose.“
Contamination of food or water with chemicals can also
provide doses of chemicals each time we eat or drink.
Some commonly used measures for expressing levels
of contaminants are listed in Table 1.

Table 1. Measurements for Expressing Levels of
Contaminants in Food and Water.
Dose Abbrev. Metric
equivalent
Abbrev. Approx. amt. in
water
parts per
million
ppm milligrams
per kilogram
mg/kg 1 teaspoon per
1,000 gallons
parts per
billion
ppb micrograms
per kilogram
ug/kg 1 teaspoon per
1,000,000 gallons

25/05/2010 6
Dose
the amount of a substance administered at one
time.
other parameters - to characterize the exposure to
xenobiotics.
the number of doses, frequency, and total time period
of the treatment.
For example:
650 mg Tylenol as a single dose
500 mg Penicillin every 8 hours for 10 days
10 mg DDT per day for 90 days
Kursus Toksikologi Makanan IKU 31Mei-4Jun 2010

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Type of Doses

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Units of Dose
The units used in toxicology - the same as those
used in medicine.
The gram is the standard unit.
smaller quantities of exposures - milligram
(mg)
E.g., the common adult dose of Tylenol is 650 mg.
A common dose measurement - mg/kg (mg of
substance per kg of body weight.
Dosage unit, mg/kg/day – includes exposure duration.

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Units of Dose (2)

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Environmental exposure units
expressed as the amount of a xenobiotic in a unit
of the media.
mg/liter (mg/l) for liquids
mg/gram (mg/g) for solids
mg/cubic meter (mg/m3
) for air
µg/ml, parts per million (ppm), parts per billion
(ppb) and parts per trillion (ppt).

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Fractionating the Dose
Fractionating a total dose - decreases the risk of
toxicity.
Total dose, harmful if received all at once, is non-
toxic when administered over a period of time.
E.g., 30 mg of strychnine swallowed at once could be
fatal to an adult whereas 3 mg of strychnine swallowed
each day for ten days would not be fatal.

What is a Response?
Toxic effects - changes from normal state
molecular, cellular, organ, or organism level
Local or Systemic
Reversible or Irreversible
Immediate or Delayed
Graded or Quantal

Toxicity – Toxic effects
Toxicity can result from adverse cellular, biochemical, or
macromolecular changes. Examples are:
cell replacement, such as fibrosis
damage to an enzyme system
disruption of protein synthesis
production of reactive chemicals in cells
DNA damage
Some xenobiotics may also act indirectly by:
modification of an essential biochemical function
interference with nutrition
alteration of a physiological mechanism

Dose and Dose-Response
Relationship
Dose-response relationship - a fundamental concept
in toxicology which describes the quantitative
relationship between the amount of exposure
(dose) to a toxicant and the incidence of adverse
effects (response).
Sources of Information::
Animal studies
Human epidemiology studies
Generally, the higher the dose, the more severe the
response

Dose Response to Toxins / Toxicants
Within a population, most responses to a toxic
substance are similar; however, a variety of responses
will be encountered.

Dose Response with Threshold
- Used for non cancerous risk
 Data from exposure of test organism to doses of toxic
substance. (e.g. mg/day)
 Response is % of individuals with symptoms.
 Dose-response curve -- typical shape for non carcinogenic
toxins.25/05/2010 17Kursus Toksikologi Makanan IKU 31Mei-4Jun 2010

Threshold dose: where toxicity first appears; this
occurs where body’s ability to detoxify or repair
effects is exceeded.

Shape and Slope
Major differences among toxicants:
 the point at which the threshold is reached
 the percent of population responding per unit change in dose
(i.e., the slope).
 Shape and slope of dose-response curves is important for predicting
toxicity at specific dose levels.

Dose Estimates Toxic Effects
(from lab or epidemiological data)
• NOAEL -- No observed adverse effect level; highest data point at
which no observed adverse/toxic effect.
• LOAEL -- Low observed adverse effect level; lowest point at
which an observed effect.
LD50

Dose Estimates of Toxic Effects
Dose-response curves are used to derive dose
estimates of chemical substances.
A common dose estimate for acute toxicity is the
LD50 (Lethal Dose 50%).
This is a statistically derived dose at which 50% of the
individuals will be expected to die.
The figure below illustrates how an LD50 of 20 mg is
derived.

Toxic Thresholds

LD50 Comparison
 Different toxicants can be compared: lowest dose is most
potent
Chemical LD50 (mg/kg)
Ethyl Alcohol 10,000
Sodium Chloride 4,000
Ferrous Sulfate 1,500
Morphine Sulfate 900
Strychnine Sulfate 150
Nicotine 1
Black Widow 0.55
Curare 0.50
Rattle Snake 0.24
Dioxin (TCDD) 0.001
Botulinum toxin 0.0001

 Other dose estimates
 LD0 = dose (just below the threshold) at which no individuals are
expected to die (lethality).
 LD10 = dose at which 10% of the individuals will die.
 Inhalation toxicity, exposure values  air concentrations.
 LC50 = Lethal Concentration 50%, the calculated concentration of
a gas lethal to 50% of a group.
 LC0 and LC10.

 Effective Doses (EDs) - indicate the effectiveness of a
substance.
 refers to a beneficial effect (relief of pain).
 for a harmful effect (paralysis).
 The usual terms are:

 Toxic Doses (TDs) are utilized to indicate doses that cause adverse
toxic effects. The usual dose estimates are listed below:

Effective & Toxic Doses
Therapeutic Index (TI)
= Toxic Dose/Therapeutic Dose

Therapeutic Index (TI)
a statement of relative safety of a drug.
to compare the therapeutically effective dose to the
toxic dose.
the ratio, toxic dose : therapeutic dose.
to derive the TI
use the 50% dose-response points.
Eg: LD50 is 200, ED50 = 20 mg;  TI = 10 (200/20).
 A clinician would consider a drug safer if it had a TI of
10 than if it had a TI of 3.

Comparison of toxic effects -
Potency and Efficacy
Potency
Range of doses over which a chemical produces
increasing responses
Efficacy
Maximum response
Limit / plateau of dose-response curve on the
response axis.

Scales of Toxicities
 Potency of a chemical is related
to the dose required to achieve
the toxic effect under study.
 In the extreme, toxic response is
expressed in terms of lethality.
 It is also related to the animal
used to perform the toxicity
experiments.

Potency of a poison
The potencies of poisons are often compared using
signal words or categories as shown in the example in
Table 2.
25/05/2010 Kursus Toksikologi Makanan IKU 31Mei-4Jun 2010 32

Table 2. Toxicity Rating Scale and Labeling Requirements
for Pesticides.
Category Signal word
required on
label
LD50 oral
mg/kg(ppm)
LD50
dermal
mg/kg(ppm)
Probable
oral lethal
dose
I
highly toxic
DANGER-
POISON
(skull and
crossbones)
less than 50 less than 200 a few drops
to a
teaspoon
II
moderately
toxic
WARNING 51 to 500 200 to 2,000 over 1
teaspoon to
1 ounce
III
slightly toxic
CAUTION over 500 over 2,000 over 1 ounce
IV
practically
non-toxic
none
required
- - -

Scale of Toxicities
Classifications are arbitrary!
A typical scale of toxicities:
Extremely toxic ………. 50 mg/kg or less
Moderately toxic ……..50 – 500 mg/kg
Slightly toxic ……………0.5 – 5 g/kg
Relatively harmless … 5 g/kg or more

Margin of Safety (MOS)
The MOS calculation
the ratio; dose within the lethal range (LD01): dose
that is 99% effective (ED99)
MOS = LD01/ED99.
A physician must use caution in prescribing a drug in
which the MOS is less than 1.

Margin of Safety
Margin of Safety
(MOS) = LD(01)/ED(99)

Dose-Response Relationship
Previous curves are examples of traditional dose
responses (monotonic)
Non-traditional dose response curves (non-
monotonic)
U-shaped dose response - essential nutrients
Hormesis - hormones/hormonally active chemicals;
various other chemicals

U-Shaped Dose-Response
(Essential Nutrients: Metals, Vitamins, etc.)

Hormetic Dose-Response
Relationship
 Hormesis: Concept that xenobiotics may cause stimulatory
(beneficial?) effects at low dose, but adverse effects at high
dose

Cancer dose response is usually assumed to
be linear, intercepting 0,0 (any exposure
increases the risk).
Increase in Cancer Risk
y = 0.0001x
0.000
0.002
0.004
0.006
0.008
0.010
0.012
0 50 100 150
Exposure, µg/d
Slope factor

• Carcinogen risk assessment is the cancer slope factor.
• a toxicity value that quantitatively defines dose-response
relationship.
• a plausible upper-bound estimate of the probability that an
individual will develop cancer if exposed to a chemical for a
lifetime (70 years).
• expressed as mg/kg/day.
25/05/2010 41

Dose response relationship

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