Toxicology& Risk Analysis

Sumol Pavittranon, Ph. D.

Dept. Of Medical Sciences

sumol@dmsc.moph.go.th

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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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 ่
ความไม่รู ้เป็ นพิษทีสุด
“ 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
100
LOEL
Response(การเกิดโรค/พิษ)
80
LOAEL
60

40

20

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)
* Exposure
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 Public Hearing

Risk Assessment
Risk Management
Risk Communi

Policy formulation Public

Standards / Implimentation
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 Data submission for registration

Toxicologica Exposure data Efficacy data

l data
Mechanistic
data
Epidemiolog
Adverse health NOAEL
Total
Reference dose (Rfd, ADI ) exposure
icaleffect
data
Carcinogenic potency

Margin of safety
Risk (MRL, TI, )
-Public health policy
-Socio-economics
-Politics
Decision making

Further data
Approval Rejection
required
Post-marketing
Reassessment
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monitoring and surveillance Reassessment21
 Environmental Toxicology

Emission

Control

Transport

Monitor

Human response
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 Environmental Toxicology

Water Pollution
Ecology parameters
Parameters
BOD
Physical property Environmental Exposure Data
Total solids Octonal/ Water Ratio
Oil & grease Environmental fate
Metals Aquatic toxicity
Free Chlorine Bioaccumulation
Phosphate Sensitivity and
Sulfide High risk group
Nitrogen
Bacteria
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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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