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General Principles of Toxicology
I
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Toxicology is a study of adverse effects of chemical agents on living organisms
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Different areas of toxicology:
i
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They have specialized training in emergency medicine and
poison management
...
Experimental toxicology: study harmful effects of chemical substances on living animals
(mechanism of action, disposition, analytical procedures)
iii
...
Food toxicology: possible deleterious effects of chemicals in food for human consumption
(residue level)
v
...
They use chemical analysis to
determine cause and circumstances of death in postmortem investigation
...
Poison is also called as toxicant
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A disease state that results from exposure to poison is called toxicosis/poisoning/intoxication
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Toxin is a poisonous substance produced by living organism
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Plant: phytotoxin
ii
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Microbes: bacteriotoxin
f
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Biologic origin: nicotine, botulinum toxin
ii
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Manufactured chemicals (pesticides)
iv
...
Synthetic does not mean toxic or poisonous
2
...
Exposure is the actual contact of chemical substance with biological organism (contact with
hazardous substance)
...
Hazard is a chemical substance, physical agent, or biological agent that can harm people’s health
...

i
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Risk = Hazard x Exposure
j
...

k
...

l
...

m
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n
...

o
...

i
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It is
normally expressed as
milligrams of chemical
substance per kilogram of
animal body weight
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TD50 (median toxic dose) is the
dose that causes toxic effect to
happen in 50% of population
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Each chemical also has their NOAEL and LOAEL
i
...

ii
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EXPOSURE TO TOXIC AGENTS
a
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Ingestion: gastrointestinal tract
ii
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Topical: skin
iv
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Injection routes
1
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Intraperitoneal
3
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Intramuscular
5
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Different route of exposure may have different TD or LD
c
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Acute: <24 hours, can be single administration
or repeated exposure during 24 hours
ii
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Subchronic: 1-3 months
iv
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Repetitive exposure: the degree toxicity of any
substance depends on how much it enters the body and
over what period of time it is eliminated

III
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Local vs systemic toxicity
i
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Examples: caustic agents, irritants

ii
...

1
...

2
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Reversible vs irreversible toxicity
i
...
Example: liver tissue
ii
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Example: central
nervous system (CNS), teratogenic and carcinogenic effects

IV
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Immediate vs delayed toxicity
i
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Example: cyanide toxicity
ii
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Example: carcinogenicity
SPECIFIC TYPES OF TOXIC RESPONSES
a
...
Immunologic response
ii
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Severity of response is dose related for an individual (not population)
iv
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Example: anaphylaxis in response to penicillin
b
...
Genetically determined abnormal reactivity to a chemical

ii
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NADH-methemoglobin reductase catalyzes the reduction of methemoglobulin (oxidized
haemoglobin) to haemoglobin

iv
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Abnormal sensitivity to nitrites
c
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that causes methemoglobin
formation
Interaction of chemicals
i
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Synergistic
iii
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Antagonistic

DOSE-RESPONSE RELATIONSHIP
a
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Advantages of semi logarithmic dose-response curve
1
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g if there are set of

b
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d
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values between 1 to 100, therefore the log values
would fall only in range of 0 to 2
2
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The middle portion (25-75%) of curve is linear
4
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Characterized by a dose-related increase in severity of
response
...

ii
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Dose-response relationship in population
ii
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Substances that are required for normal physiological
function and survival has U-shaped dose-response
relationship
ii
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ED50, TD50, LD50
1
...

2
...
It is normally
expressed as milligrams of chemical substance
per kilogram of animal body weight
...
TD50 (median toxic dose) is the dose that causes
toxic effect to happen in 50% of population
ii
...
A ratio that compares the dose in which a drug
causes therapeutic effect to dose that causes
death (in animal) or toxicity (in human)
2
...
TI doesn’t provide information about shape of dose-response curve
iii
...
The zone between surely effective dose (ED 99) and the lowest lethal dose (LD1) or
lowest toxic dose (TD1)
2
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MOS is useful for drugs, but not useful for non-beneficial agents
iv
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Potency: capability of drug to start showing effect
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Efficacy: highest effect that can be achieved by drug
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MECHANISMS OF TOXICITY
a
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Intensity of a toxic effect depends primarily on
concentration and persistence of ultimate toxicant
at its site of action
ii
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Absorption
a
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Majority of chemicals will traverse
epithelial barriers diffuse through
cells and reach blood capillaries
c
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Distribution: distribution of chemicals
from blood circulation into target organ
...
Redistribution: storage of toxicants in
another organs
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Metabolism/biotransformation
a
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Toxication: biotransformation to
more harmful products
c
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Excretion
a
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For non-volatile compounds
through renal glomeruli
c
...

b
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Most prevalent and toxicologically relevant targets are macromolecules such as nucleic acid
(DNA) and proteins
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These targets have reactivity towards toxicants by covalent or non-covalent reactions
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Results
1
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Destruction of target molecules by cross-linking, fragmentation

c
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3
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Toxicant with no target molecules alter biological microenvironment physically, for
example:
a
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b
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Effect to cell regulation (signaling)
1
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Inappropriate cell division: neoplasia, teratogenesis
b
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Inappropriate protein synthesis example: peroxisome proliferation
2
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Inappropriate neuromuscular activity
i
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Narcosis, paralysis, paresthesia
ii
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Impaired internal maintenance
a
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Impaired calcium ion (Ca2+) regulation
Cell injury/death
c
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Impaired microtubular function
e
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Impaired external maintenance
a
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Inappropriate repair and adaptation
i
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Molecular: protein, lipid, DNA repairs
2
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Tissue: apoptosis, cell reproduction, ECM reproduction
ii
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Systematic scientific evaluation of potential adverse health effects resulting from human exposures to
hazardous agents/situation
b
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Protect human and ecological health
1
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Balance risks and benefits
1
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Pesticides
iii
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Food contamination
2
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Set priorities for program activities
1
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Manufacturers
3
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Estimate residual risks and extent of risk reduction after steps are taken to reduce risks

c
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Toxicology is the study of adverse effects of chemical agents on living organisms
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Different areas of toxicology include clinical, experimental, environmental, food, and forensic toxicology
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Toxic response are affected by site of contact between toxicant and target sites, the regeneration ability of
target site, and the period taken to show toxic effects
4
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5
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Mechanisms of toxicity includes delivery of chemicals (absorption, distribution, redistribution,
metabolism/biotransformation, excretion), reaction with target, cellular dysfunction and resultant toxicities,
and inappropriate repair and adaptation
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Risk assessment is a systemic scientific evaluation of potential adverse health effects resulting from human
exposures due to hazardous agents/situation

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