Applications of

Toxicogenomics
 Toxicology is multidispliniary field

 It is quantitative & qualitative study of adverse

effects of chemicals on living organisms
 Toxicity is the adverse biological response to a
chemical reaction
 Toxicogenomics provides valuable information on the
effects of drugs and chemicals at a molecular level,
providing a more complete understanding of their
potential toxic effects
 Following the law of mass action, the rate if a
chemical reaction depends on concentrations
of 2 reactants.
 The active toxicant and the biological
response/target
 The more active toxicant present, the greater is
the dose,
 More toxicity, the greater is the response
 This is dose-response relationship
 Exposure to a single high conc. Will elicit an
immediate (acute) response that is qualitative
different from repeated exposure (chronic) to the
same chemical at much lower conc.
 For ex.a single exposure to 1 mg of afatoxin B1 to a
rat, will result in killing of large numbers of liver
cells and death due to liver failure within 5-6 days.
 Exposure to few nanograms for several months does
not kill liver cells but results liver cancer

 Dose response relationship
 Wide quantitative variations in drug responses
occur b/w diff species and within same species
with diff condition
 Each drug has a characteristic response curve
for a specified set of conditions.
 The dose response curve forms S-shaped or
sigmoid type.
 2 types of relationship
 2 types of relationship

 Graded or quantitative dose-response

relationship

 Quantal or quantitative dose-response

relationship
 Graded or quantitative dose-
response relationship
 This type relates the size of the response in a single
biological unit to the dose of the drug.
 As the dose administered to a tissue is increases, the
pharmacological response will also increase in graded
fashion provided the dose has not exceeded the
threshold dose.
 The degree of response produced by increasing the
doses of a drug eventually reaches a steady level
termed as ceiling response.
 And the dose is called a celing dose
 If the dose exceed the ceiling dose, there is no
futher increase in the therapeutic effect.
 Such dose have undesirable responses.
 The ceiling dose allows to compare the
therapeutic efficacy of various
pharmacologically active compds.
Qualtal or all or none dose-response
relationship
 This curve shows the frequency with which any dose
of drug evokes a stated, fixed(all or none) response.
 It is a frequency distribution of the responders to
different doses of drug.
 Each animal is categorized as responding or none.
 In case of lethal toxicity tests, each animal is
classified as dead or alive at specified time after the
drug treatment.
 Some animals will respond to smaller doses of drug
and some are resistant and need large doses.
 The sensitivity of animals to diff doses of a drug is
distributed normally with respect to the logarithm of
the dose.
 For a given dose, if log is plotted on the horizontal
axis, a gaussian(normal) distribution is obtained.
 The curve represents the distribution of sensitivity of
a group of animals to the given drug.
 The curve….
 The quantal dose response curve will not
always bell-shaped.
 But may show skewing or truncation.
 This shows that inter-coupled events and
experimental limitations influence the quantal
dose response curve.
 The median lethal dose or LD50
 This is the dose(mg/kg) which would be
expected to kill one-half of an unlmited
population of the same species and strain.
 The median effective dose or ED50
 This is the dose(mg/kg) which produces a
desired response in 50 percent of the test
population.
 Therapeutic index(TI)
 It is approximate assessment o the safety of the
drug.
 It is ration of LD and ED
 Margin of safety
 It is the difference between the therapeutic and lethal
dose of a drug.
 As the drug metabolism varies from species to
species, the therapeutic index will also vary.
 The larger the therapeutic index the safer is the drug.
 For safe therapeutic application, the TI must be more
than one.
 Such drugs will have v.little dose-related toxicity.
 The TI gives only a rough idea about the
safety.
 Depending upon its clinical use, a drug may
have many TI.
 Eg. The margin of safety of aspirin if used for
headache is far greater than its margin of
safety of athritic pain or rhematic fever,
 This is because the latter required larger dose.