Lecture 1: Principles of Toxicology Flashcards Preview

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1

Toxicology

Toxicology is the study of adverse effects of xenobiotics
on organisms, including:
•Mechanisms of action and exposure to chemicals as a cause of
acute and chronic illness.
•Understanding physiology and pharmacology by using toxic
agents.
•Recognition, identification, quantification of hazards from
occupational exposure to chemicals.
•Discovery of new drugs and pesticides.
•Development of standards and regulations to protect humans and
environment from adverse effects of chemicals.

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Branches of Toxicology

1. Mechanistic—cellular, biochemical and
molecular mechanisms by which
chemicals cause toxic responses
2. Forensic—cause of death, legal aspects
3. Clinical—treatments for poisonings and
xenobiotic injuries
4. Environmental—environmental
pollutants, effects on flora and fauna
5. Food—adverse effects of processed or
natural food components
6. Regulatory—assigns risk to substances
of commercial importance.

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Origins of Toxicology

Earliest humans who used animal venoms and plant
extracts for hunting, warfare and assassination.
•400 BC: Hippocrates compiled a listing of a number of
poisons and outlined some clinical toxicology principles.
•1493-1541: Paracelsus—physician and philosopher
•All substances are poisons; the right dose
differentiates a poisons from a remedy.
•“Dose determines toxicity.”
•1775: Percival Pott found that soot was causing scrotal
cancer in chimney sweeps. Much later found due to
polycyclic aromatic hydrocarbons.

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Dose-Response

• The relationship between the degree of
response of the biological system and the
amount of toxicant administered.
• There are two types of dose-response
curves:
1.Individual dose-response
2.Quantal dose-response

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1. Individual dose-response

-Response of an individual organism to varying doses of a chemical
(also called “graded” response because effect is continuous over a
dose range) (e.g. enzyme activity, blood pressure).
-Y-axis: % of max. response
(linear in middle range)
-X-axis: dose (e.g. mg/kg)
(plotted as log base 10)
-Can derive ID50 values
from D-R data.
-IC50 determined from
concentration-response.

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2. Quantal dose-response

-Characterizes distribution of responses
to different doses in a population of
organisms (responders or nonresponders).
-Cumulative/sigmoidal responses are
used to determine LD50 (lethal dose
50%) and NOAEL (no observable
adverse effect level).

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Dose-Response Curves for Beneficial Substances

•For substances required for normal physiological function and
survival, the dose-response curves will be U-shaped.
•At very low doses, there is an adverse effect (deficiency), which
decreases with increasing dose (homeostasis). At very high
doses, an adverse response appears from toxicity.
•For example, vitamin A can cause liver toxicity and birth defects
at high doses and vitamin A deficiency is lethal.

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Hormesis: Hormetic Dose-
Response

•Non-nutritional toxic
substances may also impart
beneficial or stimulatory effects
at low doses but produce
toxicity at higher doses.
•Chronic alcohol consumption
at high doses causes
esophageal and liver cancer,
whereas low doses can reduce
coronary heart disease.

9

Evaluating Dose-Response Relationships

-ED50: dose at which 50% of population therapeutically responds.
(In this example, ED50=1 mg/kg)
-TD50: dose at which 50% of population experiences toxicity (TD50=10 mg/kg).
-LD50: dose at which 50% of population dies (LD50=100 mg/kg).
-NOAEL: no observed adverse effect level
-LOAEL: lowest observed adverse effect
level

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Comparing Toxicity of Compounds

Therapeutic Index (TI)
TI = LD50/ED50
or TI = TD50/ED50
•TI is the ratio of the doses of the toxic and the desired
responses.
• TI is used as an index of comparative toxicity of two different
materials; approximate statement of the relative safety of a
drug.
•The larger the ratio, the greater the relative safety.

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Disadvantages of Using TI

Therapeutic index does not take into account the slope
of the dose-response curves.

12

Margin of Safety

-Margin of safety can overcome this deficiency by using ED99 for
the desired effect and LD1 for the undesired effect.
-Margin of safety = LD1/ED99