PADMASHREE INSTITUTIONS OF MANAGEMENT AND SCIENCES

DOSE RESPONSE
RELATIONSHIPS

Submitted by:
V. Sri Lasya
B.Sc. CND
II Semester

Submitted to:
Dhanalakshmi
(Department of Biochemistry)
INTRODUCTION:
 The dose–response relationship, or exposure–response relationship, describes the
magnitude of the response of an organism, as a function of exposure (or doses) to a
stimulus or stressor (usually a chemical) after a certain exposure time.
 Dose–response relationships can be described by dose–response curves. This is
explained further in the following sections. A stimulus response function or stimulus
response curve is defined more broadly as the response from any type of stimulus, not
limited to chemicals.

DOSE RESPONSE RELATIONS:

 Dose response, is central to determining "safe", "hazardous" and (where relevant)
beneficial levels and dosages for drugs, pollutants, foods, and other substances to which
humans or other organisms are exposed.
 These conclusions are often the basis for public policy.
 The U.S. Environmental Protection Agency has developed extensive guidance and
reports on dose–response modelling and assessment, as well as software.
  The U.S. Food and Drug Administration also has guidance to elucidate dose–response
relationships during drug development.
 Dose response relationships may be used in individuals or in populations.
 The adage The dose makes the poison reflects how a small amount of a toxin has no
significant effect, while a large amount may be fatal. This reflects how dose–response
relationships can be used in individuals.
 In populations, dose–response relationships can describe the way groups of people or
organisms are affected at different levels of exposure.
 Dose response relationships modelled by dose response curves are used extensively in
pharmacology and drug development. In particular, the shape of a drug's dose–response
curve (quantified by EC50 and ymax parameters) reflects the biological activity and
strength of the drug.

STIMULUS AND RESPONSES:

 Some example measures for dose–response relationships are shown in the tables below.
 Each sensory stimulus corresponds with a particular sensory receptor, for instance the
nicotinic acetylcholine receptor for nicotine, or the mechanoreceptor for mechanical
pressure.
  Stimuli (such as temperatures or radiation) may also affect physiological processes
beyond sensation (and even give the measurable response of death).
 Responses can be recorded as continuous data (e.g. force of muscle contraction) or
discrete data (e.g. number of deaths).

EXAMPLES FOR STIMULUS

Example Stimulus Target

Agonist Biochemical receptors, Enzymes ,

(E.g. Nicotine and Isoprenaline) Transporters

Antogonist
(E.g. Ketamine and propranolol)

Allosteric Modulator
(E.g. Benzodiazepine)

EFFECTIVE DOSE:
 In pharmacology, an effective dose (ED) or effective concentration (EC) is a dose or
concentration of a drug that produces a biological response.
 The term effective dose is used when measurements are taken in vivo, while the term
effective concentration is used when the measurements are taken in vitro.
 It has been stated that any substance can be toxic at a high enough dose. This concept was
exemplified in 2007 when a California woman died of water intoxication in a contest
sanctioned by a radio station. 
 The line between efficacy and toxicity is dependent upon the particular patient, although
the dose administered by a physician should fall into the predetermined therapeutic
window of the drug.

ED50 value:
 The "median effective dose" is the dose that produces a quantal effect (all or nothing) in
50% of the population that takes it (median referring to the 50% population base.
  It is also sometimes abbreviated as the ED50, meaning "effective dose for 50% of the
population". The ED50 is commonly used as a measure of the reasonable expectancy of a
 drug effect, but does not necessarily represent the dose that a clinician might use. This
depends on the need for the effect, and also the toxicity.
 The toxicity and even the lethality of a drug can be quantified by the TD50 and
LD50 respectively. Ideally, the effective dose would be substantially less than either the
toxic or lethal dose for a drug to be therapeutically relevant.

ED95 value:
 The ED95 is the dose required to achieve the desired effect in 95% of the population.
 In anaesthesia, the term ED95 is also used when referring to the pharmacology of
neuromuscular blocking drugs. In this context, it is the dose which will cause 95%
depression of the height of a single muscle twitch, in half of the population.
 Put another way, it is the ED50 for 95% reduction in twitch height.
  The single twitch response occurs when a nerve stimulator is used to stimulate the ulnar
nerve, and the degree of twitch of the adductor pollicus muscle is measured.
 A more accurate nomenclature when used in this way would be "ED5095".

LETHAL DOSE 50%:

 The name LD50 is an abbreviation for "Lethal Dose, 50%" or median lethal dose. It is the
amount of the substance required (usually per body weight) to kill 50% of the test
population.
 The test was created by J.W. Trevan in 1927 but has been phased out. The U.S. Food and
Drug Administration has begun to approve non-animal alternatives to LD50, in response
to research cruelty concerns and the lack of validity/sensitivity of animal tests as they
relate to humans.

CONSTRUCTION OF DOSE RESPONSE CURVES:

 A dose–response curve is a coordinate graph relating the magnitude of a stimulus to the
response of the receptor.
 A number of effects (or endpoints) can be studied. The measured dose is generally
plotted on the X axis and the response is plotted on the Y axis.
 In some cases, it is the logarithm of the dose that is plotted on the X axis, and in such
cases the curve is typically sigmoidal, with the steepest portion in the middle.
 Biologically based models using dose are preferred over the use of log(dose) because the
latter can visually imply a threshold dose when in fact there is none.
A dose response curve showing the normalised tissue response to stimulation by an agonist. Low doses are
insufficient to generate a response, while high doses generate a maximal response. The steepest point of the curve
corresponds with an EC50 of 0.7 molar.

LIMITATIONS:
 The concept of linear dose–response relationship, thresholds, and all-or-nothing
responses may not apply to non-linear situations. A threshold model or linear no-
threshold model may be more appropriate, depending on the circumstances. A recent
critique of these models as they apply to endocrine disruptors argues for a substantial
revision of testing and toxicological models at low doses because of observed non-
monotonicity, i.e. U-shaped dose/response curves.
 Dose–response relationships generally depend on the exposure time and exposure route
(e.g., inhalation, dietary intake); quantifying the response after a different exposure time
or for a different route leads to a different relationship and possibly different conclusions
on the effects of the stressor under consideration. This limitation is caused by the
complexity of biological systems and the often unknown biological processes operating
between the external exposure and the adverse cellular or tissue response.

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