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Toxicology& Risk Analysis

Toxicology& Risk Analysis. Sumol Pavittranon, Ph. D. Dept. Of Medical Sciences sumol@dmsc.moph.go.th. RISK. EXPOSURE. standards. DOSE SENSiTIVITY. Extrapolate. Testing. Toxicology. “All substances are poisons; there is none which is not a poison.

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Toxicology& Risk Analysis

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  1. Toxicology& Risk Analysis Sumol Pavittranon, Ph. D. Dept. Of Medical Sciences sumol@dmsc.moph.go.th

  2. RISK EXPOSURE standards DOSE SENSiTIVITY Extrapolate Testing

  3. 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)

  4. ความไม่รู้เป็นพิษที่สุดความไม่รู้เป็นพิษที่สุด “ Ignorance is the most toxic of all” Sumol Pavittranon

  5. Toxic Agents • Chemicals • Food additives • Drugs • Pesticides • Metals • Solvents • Radiation • Toxin • Pollutants

  6. 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

  7. Factors influence risk estimate • Chemical property • Biological System • Effect or response • Exposure situation

  8. Toxicity Testing • Acute toxicity • Subacute toxicity • Chronic toxicity • Reproductive toxicity • Genotoxicity • Neurotoxicity • Immunotoxicity

  9. 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

  10. 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

  11. 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

  12. Animals Rodent and non-rodent Avain Fish Aquatic invertibrate Ferret non primates dog rabbit

  13. Reproductive toxicity testing • Reproductive efficiency, 2 generation • Fertility profile 70 days • Semen analysis • Pathology, gross and histo • Oogenesis • In vitro method • Teratogenetic • Biochemistry parameters

  14. 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

  15. Neurotoxicity testing • Condition behaviors • Unconditioned behaviors • Affective behaviors • Social behavior • Motor acts • Learning & Memory • Biochemical • NTE • cAMP, cGMP • GABA • Dopamines

  16. Immunotoxicology testing Immune disfunction increase tumor susceptability decrease host resistance

  17. Dose response Relationship Assumptions Response vary concentration Concentration vary dose dose related to response

  18. Low level risk estimate One-hit model Linear Multistage Weibull Multihit Logit Probit Model

  19. NOEL NOAEL LOEL LOAEL Critical Points * NOAEL = No Observed Adverse Effect Level * End Point / การเกิดพิษ * Uncertainty Factors (1, 5, 10, 100, 1000) * Exposure

  20. Public Hearing Risk Assessment Risk Management Risk Communication Public Policy formulation Standards / Implimentation

  21. Data submission for registration Toxicological data Mechanistic data Epidemiological data Exposure data Efficacy data NOAEL Reference dose (Rfd, ADI ) Carcinogenic potency Adverse health effect Total exposure Margin of safety Risk (MRL, TI, ) -Public health policy -Socio-economics -Politics Decision making Further data required Rejection Approval Post-marketing monitoring and surveillance Reassessment Reassessment

  22. Environmental Toxicology Emission Control Transport Monitor Human response

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

  24. “The Toxicologist may be able to assess the risk of a compound, but an acceptable risk level will be set by the public”

  25. 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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