1 sumol/august 21, 2002 toxicology& risk analysis sumol pavittranon, ph. d. dept. of medical...
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Toxicology& Risk Analysis
Sumol Pavittranon, Ph. D.
Dept. Of Medical Sciences
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RISK
Testing
Extrapolate
EXPOSURE
DOSE
SENSiTIVITY
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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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ความไม�รู้�เป็�นพิ�ษที่��สุ�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 extrapolationSafety assesmentRegulatory 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-rodentAvainFishAquatic invertibrateFerretnon primatesdograbbit
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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•BiochemicalNTEcAMP, cGMPGABADopamines
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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 modelLinear MultistageWeibullMultihitLogitProbit Model
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Dose - Response curve
0
20
40
60
80
100
0 20 40 60 80 100 120 140
Dose
Resp
onse
(/
)กา
รู้เก�ดโรู้
คพิ�ษ
NOEL
NOAEL
LOEL
LOAEL
Critical Points * NOAEL = No Observed Adverse Effect Level * End Point / การเก�ดพิ�ษ * 1 5 10 100 1000Uncertainty Factors ( , , , , ) * Exposure
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Risk AssessmentRisk ManagementRisk Communication
Public Hearing
Policy formulation
Standards / Implimentation
Public
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Data submission for registration
- Public health policy- -Socio economics-Politics
ReassessmentPost-marketingmonitoring and surveillance Reassessment
Toxicological dataMechanistic dataEpidemiological data
Exposure data Efficacy data
Adverse healtheffect
NOAEL Reference dose (Rfd, ADI )
Carcinogenic potency
Total exposure
Margin of safetyRisk (MRL, TI, )
Decision making
ApprovalFurther datarequired
Rejection
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Environmental Toxicology
Emission
Control
Transport
Monitor
Human response
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Environmental Toxicology
Water Pollution
ParametersBODPhysical propertyTotal solidsOil & greaseMetalsFree ChlorinePhosphateSulfideNitrogenBacteria
Ecology parameters
Environmental Exposure DataOctonal/ Water RatioEnvironmental fateAquatic toxicityBioaccumulationSensitivity andHigh 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 ToxicologyA. 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 EnvironmentUS Dept of Health, Education, and Welfare, DHEW Publication # NIH 77-1277