1 Sumol/August 21, 2002 Toxicology& Risk Analysis Sumol Pavittranon, Ph. D. Dept. Of Medical Sciences

2 Sumol/August 21, 2002 RISK Testing Extrapolate EXPOSURE DOSE SENSiTIVITY

3 Sumol/August 21, 2002 Toxicology “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” Paracelsus ( )

4 Sumol/August 21, 2002 ความไม่รู้เป็นพิษที่สุด “ Ignorance is the most toxic of all” Sumol Pavittranon

5 Sumol/August 21, 2002 Toxic Agents Chemicals Food additives Drugs Pesticides Metals Solvents Radiation Toxin Pollutants

6 Sumol/August 21, 2002 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 Sumol/August 21, 2002 Factors influence risk estimate Chemical property Biological System Effect or response Exposure situation

8 Sumol/August 21, 2002 Toxicity Testing Acute toxicity Subacute toxicity Chronic toxicity Reproductive toxicity Genotoxicity Neurotoxicity Immunotoxicity

9 Sumol/August 21, 2002 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 LD 50 LD 50 = Dose that cause 50 % mortality

10 Sumol/August 21, 2002 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 Sumol/August 21, 2002 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 Sumol/August 21, 2002 Animals Rodent and non-rodent Avain Fish Aquatic invertibrate Ferret non primates dog rabbit

13 Sumol/August 21, 2002 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 Sumol/August 21, 2002 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 Sumol/August 21, 2002 Neurotoxicity testing Condition behaviors Unconditioned behaviors Affective behaviors Social behavior Motor acts Learning & Memory Biochemical NTE cAMP, cGMP GABA Dopamines

16 Sumol/August 21, 2002 Immunotoxicology testing Immune disfunction increase tumor susceptability decrease host resistance

17 Sumol/August 21, 2002 Dose response Relationship Assumptions Response vary concentration Concentration vary dose dose related to response

18 Sumol/August 21, 2002 Low level risk estimate One-hit model Linear Multistage Weibull Multihit Logit Probit Model

19 Sumol/August 21, 2002 NOEL NOAEL LOEL LOAEL Critical Points * NOAEL = No Observed Adverse Effect Level * End Point / การเกิดพิษ * Uncertainty Factors (1, 5, 10, 100, 1000) * Exposure

20 Sumol/August 21, 2002 Risk Assessment Risk ManagementRisk Communication Public Hearing Policy formulation Standards / Implimentation Public

21 Sumol/August 21, 2002 Data submission for registration -Public health policy -Socio-economics -Politics Reassessment Post-marketing monitoring and surveillance Reassessment Toxicologic al data Mechanistic data Epidemiolo gical data Exposure dataEfficacy data Adverse health effect NOAEL Reference dose (Rfd, ADI ) Carcinogenic potency Total exposure Margin of safety Risk (MRL, TI, ) Decision making Approval Further data required Rejection

22 Sumol/August 21, 2002 Environmental Toxicology Emission Control Transport Monitor Human response

23 Sumol/August 21, 2002 Environmental Toxicology Water Pollution Parameters BOD Physical property Total solids Oil & grease Metals Free Chlorine Phosphate Sulfide Nitrogen Bacteria Ecology parameters Environmental Exposure Data Octonal/ Water Ratio Environmental fate Aquatic toxicity Bioaccumulation Sensitivity and High risk group

24 Sumol/August 21, 2002 “The Toxicologist may be able to assess the risk of a compound, but an acceptable risk level will be set by the public”

25 Sumol/August 21, 2002 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