Transcript Method in Toxicology - Welcome To IIS 4.0!

Toxicology& Risk Analysis
Sumol Pavittranon, Ph. D.
Dept. Of Medical Sciences
[email protected]
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RISK
EXPOSURE
DOSE
SENSiTIVITY
Extrapolate
Testing
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Toxicology
“All substances are poisons;
there is none
which is not a poison.
The right dose differentiates
a poison and a remedy.”
Paracelsus (1493-1541)
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ความไม่ รู้ เป็ นพิษทีส่ ุ ด
“ Ignorance is the most toxic of all”
Sumol Pavittranon
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Toxic Agents
•Chemicals
•Food additives
•Drugs
•Pesticides
•Metals
•Solvents
•Radiation
•Toxin
•Pollutants
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Principle of toxicology
Obtaining, gathering data
to predict or hypothesize what happen
in the future to man and the environment
To do risk extrapolation
Safety assesment
Regulatory control
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Factors influence risk estimate
•Chemical property
•Biological System
•Effect or response
•Exposure situation
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Toxicity Testing
•Acute toxicity
•Subacute toxicity
•Chronic toxicity
•Reproductive toxicity
•Genotoxicity
•Neurotoxicity
•Immunotoxicity
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Acute toxicity testing
•Adverse effect within 24 hr
•Life threatening, accidental, overdose
•Define intrinsic toxicity of the chemical
•Oral, dermal, inhalation, skin, eye irritation
•Define LD50
•LD50 = Dose that cause 50 % mortality
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Sub chronic testing
•Repeated dose for up to 6 months
•10 % life span
•2 spp, rodent and non-rodent
•reflect cumulative effect, latent period
•and reversibility
•non-lethal parameter
•target organ arranged
•Data for chronic study
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Chronic toxicity testing
•Life span of animal, 2 year in rat
•18 months in mice
•Similar metabolism in man
•Same route of administration
•Exposure duration similar to man
•3 treatment groups
•Maximum tolerated dose
•Pathology data, bl. chem, urianalysis
•Good Laboratory practice
•To define safety factor
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Animals
Rodent and non-rodent
Avain
Fish
Aquatic invertibrate
Ferret
non primates
dog
rabbit
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Reproductive toxicity testing
•Reproductive efficiency, 2 generation
•Fertility profile 70 days
•Semen analysis
•Pathology, gross and histo
•Oogenesis
•In vitro method
•Teratogenetic
•Biochemistry parameters
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Genotoxicity testing
•Gene mutation assay (Ame’s assay)
•Chromosome effect
Sister chromatic exchange
Micronucleus test
•DNA interaction (DNA unscheduled synthesis)
•Neoplastic cell tranformation
BALB/3T3 cells
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Neurotoxicity testing
•Condition behaviors
•Unconditioned behaviors
•Affective behaviors
•Social behavior
•Motor acts
•Learning & Memory
•Biochemical
NTE
cAMP, cGMP
GABA
Dopamines
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Immunotoxicology testing
Immune disfunction
increase tumor susceptability
decrease host resistance
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Dose response Relationship
Assumptions
Response vary concentration
Concentration vary dose
dose related to response
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Low level risk estimate
One-hit model
Linear
Multistage
Weibull
Multihit
Logit
Probit Model
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Dose - Response curve
NOEL
NOAEL
Response (การเกิดโรค/พิษ)
100
LOEL
80
LOAEL
60
40
20
0
0
20
40
60
80
100
120
140
Dose
Critical Points
* NOAEL = No Observed Adverse Effect Level
* End Point / การเกิดพิษ
* Uncertainty Factors (1, 5, 10, 100, 1000)
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* Sumol/August
Exposure
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Public Hearing
Risk Assessment
Risk Management
Risk Communication
Policy formulation
Public
Standards / Implimentation
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Data submission for registration
Toxicological data
Mechanistic data
Epidemiological data
Adverse health
effect
Exposure data
Efficacy data
NOAEL
Reference dose (Rfd, ADI )
Carcinogenic potency
Total exposure
Margin of safety
Risk (MRL, TI, )
-Public health policy
-Socio-economics
-Politics
Decision making
Approval
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Reassessment
Post-marketing
monitoring and surveillance
Further data
required
Rejection
Reassessment
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Environmental Toxicology
Emission
Control
Transport
Monitor
Human response
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Environmental Toxicology
Water Pollution
Ecology parameters
Parameters
BOD
Physical property
Total solids
Oil & grease
Metals
Free Chlorine
Phosphate
Sulfide
Nitrogen
Bacteria
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Environmental Exposure Data
Octonal/ Water Ratio
Environmental fate
Aquatic toxicity
Bioaccumulation
Sensitivity and
High risk group
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“The Toxicologist may be able
to assess the risk of a compound,
but an acceptable risk level
will be set by the public”
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References
• Principles and Methods of Toxicology
A. Wallace Hayes, Student Edition
• Casarett and Doull’s Toxicology: The basic Sciences
of Poisons
J. Doull, C. D. Klaassen, and M. O. Amdur
• Human Health and the Environment
US Dept of Health, Education, and Welfare,
DHEW Publication # NIH 77-1277
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