Philip Sasi
Background
• The field of toxicology is a broad-based
multidisciplinary science that examines the
harmful effects of substances on living
organisms, including humans.
• Mechanistic toxicology
– is focused on determining the mechanisms by
which substances exert toxic effects
• Regulatory toxicology
– uses toxicologic data to establish policies
regarding exposure limits for toxic substances.
• Toxicant
– is a general term that refers to any
harmful substance and is generally
interchangeable with poison.
• Toxicodynamics
• refers to the general concepts of
pharmacodynamics (interaction with molecular
targets and mechanisms of effects) as applied to
interactions and mechanisms that generate toxic
effects
• Toxicokinetics
• refers to the general concepts of
pharmacokinetics (absorption, distribution,
biotransformation, and elimination) as applied to
toxic substances
General Mechanisms of Toxicity
• Toxicity can be caused by both therapeutic
and nontherapeutic substances.
• In terms of therapeutic drugs, toxicity may
arise from a direct extension of the drug’s
primary action. For example, central nervous
system (CNS) depression or coma may occur
with excessive doses of barbiturates used in
the treatment of epilepsy.
• The toxic effect may also be unrelated to the
primary therapeutic effect but related to the
general pharmacology of the drug
(nonsteroidal antiinflammatory agents may
increase edema in heart failure patients).
• Mutagenic (carcinogenic)
• Toxicants alter DNA structure or function
sufficiently to cause mutations (benzene) or
initiate and promote the development of cancers
(polycyclic aromatic hydrocarbons such as
benzo[a]pyrene, found in cigarette smoke).
• Immunologic
• Toxicant may trigger an immune response that
leads to cellular damage (e.g., penicillin-induced
hemolytic anemia) or conversely suppresses the
immune system, causing an increased
susceptibility to infection (e.g., procainamide-
induced agranulocytosis).
• Teratogenic
• Toxicant alters fetal development, resulting in
birth defects (e.g., phenytoin is associated with
development of cleft lip)
Target Organs
• Toxicity may be systemic, affecting the whole
body, or it may be largely confined to select
target organs, the so-called toxic effect organs.
Brain
•Central homeostatic regulator
Heart
•High blood flow Lungs
•Large surface area
Kidneys •High blood flow
•High blood flow •Exposed to atmospheric
•Toxicants concentrated in urine toxicants
Risk Assessment
• Poisoning remains a significant public health
issue that affects up to approximately 5% of
the population per year in industrialized
countries.
• Many countries have established national
poison control centers that can serve as
valuable sources of information.
• The World Health Organization maintains a
directory of these centers (see Websites).
• Because virtually all substances are potentially
toxic, key questions in toxicology are:
– how much risk is associated with a particular
substance and under what conditions does this
risk become apparent?
Dose Response
•Do toxic effects exhibit a dose Risk
dependent response relationship Assessment
•What are the critical plasma
concentrations