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(part 2)
SANJAYADI
KEMAMPUAN AKHIR YANG DIHARAPKAN
Mahasiswa mampu mendefinisikan toksikologi dan menguraikan prinsip-prinsip toksikologi,
serta berpartisipsi aktif dalam berdiskusi mengenai prisnsip-prinsip toksikologi
TOPIK
1. Definisi dan ruang lingkup (area dan kategori) toksikologi
2. Karasteristik respon toksik
3. Klasifikasi agen toksik
4. Spektrum efek yang ditimbulkan agen toksik
5. Karakterisasi pemaparan
6. Hubungan antara dosis dan efek toksik yang ditimbulkan
7. Variasi respon toksik
8. Uji toksisitas ( akut, subkronik dan kronik)
9. Pengantar toksikogenomik
10. Glossary
Spektrum efek yang ditimbulkan agen toksik
• Allergic vs Idiosyncratic
• Immediate and delayed effects
• Reversible versus Irreversible Toxic Effects
• Local versus Systemic Toxicity
• Interaction of Chemicals
• tolerance
Allergic Reactions
• Allergic reaction (hypersensitivity/sensitization reaction) to a toxicant results from
previous sensitization to that toxicant or a chemically similar one.
• The chemical acts as a hapten and combines with an endogenous protein to form
an antigen, which in turn elicits the formation of antibodies.
• A subsequent exposure to the chemical results in an antigen–antibody
interaction, which provokes the typical manifestations of allergy.
• This reaction is different from the usual toxic effects:
1. a previous exposure is required
2. a typical sigmoid dose–response curve is usually not demonstrable with
allergic reactions allergic reactions are not dose-related
• sometimes very severe and may be fatal
• minor skin disturbance to fatal anaphylactic shock
Idiosyncratic Reactions
genetically determined abnormal reactivity to a chemical
Succinylcholine
In toxicology, irreversible effects are more important than reversible effects because the
former are chronic and difficult to treat
Local versus Systemic Toxicity
Local effects are those that occur at the site of fi rst contact between the biological
system and the toxicant
induced by
1. caustic substances acting on the gastrointestinal tract,
2. corrosive materials on the eyes or skin, and by irritant gases and vapors on the
respiratory tract.
Systemic effects result only after the toxicant has been absorbed and distributed to
other parts of the body
Most toxicants exert their main effects on one or a few organs. These organs are
referred to as the “target organs” of these toxicants.
A target organ does not necessarily have the highest concentration of the toxicants
in the organism. For example, the target organ of dichlorodiphenyltrichloroethane
(DDT) is the central nervous system, but it is concentrated in adipose tissues
Chemicals that cause systemic effects
Interaction of Chemicals
• it is important to consider how different chemicals may interact with each
other
Toxic effects in a
biological system are
not produced by a
chemical agent unless
that agent or its
metabolic breakdown
products reach
appropriate sites in the
body at a concentration
and for a length of time
sufficient to produce a
toxic manifestation.
TOXIC RESPONSE (TYPE OF EFFECT) DEPENDENT ON
• the chemical and physical properties of the agent,
• the exposure
• metabolism (biotransformation)
• concentration of the active form at the particular target site(s)
• susceptibility of the biological system or subject
dose–response
relationship
between different
dietary doses of
the
organophosphate
insecticide
chlorpyrifos
Quantal Dose–Response
Relationships
the dose–response relationships in a
population are by definition quantal—or “all
or none”—in nature, that is, at any given
dose, an individual in the population is
classified as either a “responder” or a
“nonresponder
Ex. mortality (LD50) and tumor formation
Quantal Dose–Response Relationships
Shape of the Dose–Response Curve
Hormesis
Shape of the Dose–Response Curve
Threshold-non threshold
Threshold
Shape of the Dose–Response Curve
Nonmonotonic Dose–Response Curves
Assumptions in Deriving the Dose–Response
Relationship
• the response is due to the chemical administered
• the magnitude of the response is in fact related to the dose
• there exist both a quantifiable method of measuring and a precise
means of expressing the toxicity
Comparison of Dose Responses
Therapeutic Index
The Therapeutic Index (TI) is used to compare the therapeutically effective dose to
the toxic dose of a pharmaceutical agent. The TI is a statement of relative safety of
a drug. It is the ratio of the dose that produces toxicity to the dose needed to
produce the desired therapeutic response. The common method used to derive
the TI is to use the 50% dose-response points, including TD50 (toxic dose)
and ED50 (effective dose)
MOS and MOE
Margin of Safety (MOS) is usually calculated as the ratio of the
toxic dose to 1% of the population (TD01) to the dose that is 99%
effective to the population (ED99)