Method in Toxicology

Method in Toxicology

Toxicology& Risk Analysis Sumol Pavittranon, Ph. D. Dept. Of Medical Sciences [email protected] Sumol/ August 21, 2002 1 RISK EXPOSURE DOSE SENSiTIVITY Extrapolate

Testing Sumol/ August 21, 2002 2 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)

Sumol/ August 21, 2002 3 Ignorance is the most toxic of all Sumol Pavittranon Sumol/ August 21, 2002 4 Toxic Agents Chemicals

Food additives Drugs Pesticides Metals Solvents Radiation Toxin Pollutants Sumol/ August 21, 2002 5 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 Sumol/ August 21, 2002 6 Factors influence risk estimate Chemical property Biological System Effect or response Exposure situation Sumol/

August 21, 2002 7 Toxicity Testing Acute toxicity Subacute toxicity Chronic toxicity Reproductive toxicity Genotoxicity Neurotoxicity Immunotoxicity Sumol/ August 21, 2002 8

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 Sumol/ August 21, 2002 9 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 Sumol/ August 21, 2002 10 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 Sumol/ August 21, 2002 11 Animals Rodent and non-rodent

Avain Fish Aquatic invertibrate Ferret non primates dog rabbit Sumol/ August 21, 2002 12 Reproductive toxicity testing Reproductive efficiency, 2 generation Fertility profile 70 days Semen analysis

Pathology, gross and histo Oogenesis In vitro method Teratogenetic Biochemistry parameters Sumol/ August 21, 2002 13 Genotoxicity testing Gene mutation assay (Ames assay) Chromosome effect Sister chromatic exchange Micronucleus test

DNA interaction (DNA unscheduled synthesis) Neoplastic cell tranformation BALB/3T3 cells Sumol/ August 21, 2002 14 Neurotoxicity testing Condition behaviors Unconditioned behaviors Affective behaviors Social behavior Motor acts Learning & Memory

Biochemical NTE cAMP, cGMP GABA Dopamines Sumol/ August 21, 2002 15 Immunotoxicology testing Immune disfunction increase tumor susceptability decrease host resistance Sumol/

August 21, 2002 16 Dose response Relationship Assumptions Response vary concentration Concentration vary dose dose related to response Sumol/ August 21, 2002 17 Low level risk estimate

One-hit model Linear Multistage Weibull Multihit Logit Probit Model Sumol/ August 21, 2002 18 Response(/) / )

Dose-Responsecurve NOEL NOAEL 100 LOEL 80 LOAEL 60 40 20

0 0 20 40 60 80 100 120

140 Dose al Points AEL = No Observed Adverse Effect Level Point / ertainty Factors (1, 5, 10, 100, 1000) Sumol/ osureAugust 21, 2002 19 Public Hearing

Risk Management Risk Communica sk Assessment Policy formulation Public Standards / Implimentation Sumol/ August 21, 2002 20 Data submission for registration Toxicologi Exposure data Efficacy data

cal data Mechanist ic data Adverse health NOAEL Epidemiol Total Reference dose (/)Rfd, ADI ) exposure effect ogical Carcinogenic potency data Margin of safety Risk (/)MRL, TI, ) -Public health policy

-Socio-economics -Politics Decision making Further data Approval required Rejection Post-marketing and surveillance Reassessment21 Sumol/ Reassessment August 21, 2002 monitoring Environmental Toxicology Emission Control

Transport Monitor Human response Sumol/ August 21, 2002 22 Environmental Toxicology Water Pollution Parameters BOD Physical property Total solids Oil & grease

Metals Free Chlorine Phosphate Sulfide Nitrogen Bacteria Sumol/ August 21, 2002 Ecology parameters Environmental Exposure Data Octonal/ Water Ratio Environmental fate Aquatic toxicity Bioaccumulation Sensitivity and

High risk group 23 The Toxicologist may be able to assess the risk of a compound, but an acceptable risk level will be set by the public Sumol/ August 21, 2002 24 References Principles and Methods of Toxicology

A. Wallace Hayes, Student Edition Casarett and Doulls 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 Sumol/ August 21, 2002 25

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