Đang tải... (xem toàn văn)
BASIC PRINCIPLES a WHAT IS A THRESHOLD? IS A THRESHOLD? a CONSIDERATION OF TOXIC EFFECTS AT VARIOUS DOSE LEVELS a EFFECTS: GRADED AND MEASUREDGRADED AND MEASURED RESPONSE: QUANTAL AND COUNTEDQUANTAL AND COUNTED a SHAPE OF THE DOSE OF THE DOSERESPONSE CURVE CURVE a ESSENTIALITY CONSIDERATIONS a NO(A)EL DERIVATION vs. PROBABILISTIC APPROACHES aRisk assessment requires an evaluation of the full range of the doseresponse relationship aPrediction of risk at a given exposure aSafety assessment: Definition of a l l f b l hi h i k fevel of exposure below which risk of adverse effects is negligible aADITDI; RfDRfC (USEPA) DERIVATION OF THE ADITDI aCHARACTERIZATION OF CRITICAL EFFECT AND PIVOTAL STUDY aDETERMINATION OF THE NO OBSERVED(ADVERSE)EFFECT LEVEL (NOAEL) OR LO(A)EL aAPPLICATION OF SAFETYUNCERTAINTY FACTORS aCONSIDERATION OF 1 POINT ON DOSERESPONSE CURVE ONLYRESPONSE CURVE ONLY
12/5/2010 1 DOSEDOSE RESPONSE RESPONSE ASSESSMENTASSESSMENT (Threshold Effects)(Threshold Effects) Leonard Ritter Maged Younes/WHO BASIC PRINCIPLESBASIC PRINCIPLES WHAT IS A THRESHOLD?WHAT IS A THRESHOLD? WHAT IS A THRESHOLD?WHAT IS A THRESHOLD? CONSIDERATION OF TOXIC EFFECTS AT CONSIDERATION OF TOXIC EFFECTS AT VARIOUS DOSE LEVELSVARIOUS DOSE LEVELS EFFECTS:EFFECTS: GRADED AND MEASUREDGRADED AND MEASURED RESPONSE:RESPONSE: QUANTAL AND COUNTEDQUANTAL AND COUNTED SHAPE OF THE DOSESHAPE OF THE DOSE RESPONSE CURVERESPONSE CURVE SHAPE OF THE DOSESHAPE OF THE DOSE RESPONSE CURVERESPONSE CURVE ESSENTIALITY CONSIDERATIONSESSENTIALITY CONSIDERATIONS NO(A)EL DERIVATION vs. PROBABILISTIC NO(A)EL DERIVATION vs. PROBABILISTIC APPROACHESAPPROACHES 12/5/2010 2 12/5/2010 3 Basic PrinciplesBasic Principles Risk assessment requires an Risk assessment requires an evaluation of the full ran g e of the evaluation of the full ran g e of the dosedose response relationshipresponse relationship Prediction of risk at a given exposurePrediction of risk at a given exposure Safety assessment: Definition of a Safety assessment: Definition of a llf bl hihikfllf bl hihikf l eve l o f exposure b e l ow w hi c h r i s k o f l eve l o f exposure b e l ow w hi c h r i s k o f adverse effects is negligibleadverse effects is negligible ADI/TDI; RfD/RfC (USADI/TDI; RfD/RfC (US EPA)EPA) 12/5/2010 4 DERIVATION OF THE DERIVATION OF THE ADI/TDIADI/TDI CHARACTERIZATION OF CRITICAL CHARACTERIZATION OF CRITICAL EFFECT AND PIVOTAL STUDYEFFECT AND PIVOTAL STUDY DETERMINATION OF THE NODETERMINATION OF THE NO OBSERVEDOBSERVED (ADVERSE)(ADVERSE) EFFECT EFFECT LEVEL (NO[A]EL) OR LO(A)ELLEVEL (NO[A]EL) OR LO(A)EL APPLICATION OF APPLICATION OF SAFETY/UNCERTAINTY FACTORSSAFETY/UNCERTAINTY FACTORS CONSIDERATION OF 1 POINT ON CONSIDERATION OF 1 POINT ON DOSEDOSE RESPONSE CURVE ONLYRESPONSE CURVE ONLY 12/5/2010 5 ACCURACY ISSUESACCURACY ISSUES Dose spacing Dose spacing Information at different exposure levels Slope of the dose-response curve Shape of the dose - response curve: Shape of the dose response curve: linear, J-shaped, U-shaped 12/5/2010 6 ADI = NOAEL UNCERT. FACTOR Precision depends on the adequacy of the methods used. Guidelines for protocols and procedures ensure reliable data The value used depends on the adequacy of the safety database and whether the critical effect has been studied in humans 12/5/2010 7 Risk Assessment Factors Extrapolation Factors Inter- species Inhalation 3 Oral 10 Intra- species All routes 10 LOAEL to 310 Factors Database Factors LOAEL to NOAEL 3 or 10 Sub-chronic to chronic 3 or 10 Missing studies Temporary ADI 2 3 or 10 TDI FQPA 10 Teratogenicity 5 or 10 Non-genotoxic carcinogenicity 3 -10 Risk Management Factors Sub-group and Severity Factors SPECIES DIFFERENCES HUMAN V ARIABILITY The use of uncertainty or safety factors KINETICS DYNAMICSKINETICS DYNAMICS 10 10 Uncertainty or safety factors are used to extrapolate from a group of test animals to an average human and from average humans to potentially sensitive sub-populations. Up to an additional 10x to protect children 12/5/2010 8 US EPA Guidelines for Uncertainty Factors Guideline Factors Average Sensitive human <10x Animal Human < 10x LOAEL NOAEL < 10x Database Inadequacies < 10x Subchronic Chronic <10x Modifying factors < 10x 12/5/2010 9 UNCERTAINTY FACTORS UNCERTAINTY FACTORS COMMONLY USEDCOMMONLY USED INTERHUMAN / INTRASPECIESINTERHUMAN / INTRASPECIES INTERHUMAN / INTRASPECIESINTERHUMAN / INTRASPECIES EXPERIMENTAL ANIMAL TO HUMANEXPERIMENTAL ANIMAL TO HUMAN SUBCHRONIC TO CHRONICSUBCHRONIC TO CHRONIC LO(A)EL TO NO(A)ELLO(A)EL TO NO(A)EL INCOMPLETE DATABASEINCOMPLETE DATABASE INCOMPLETE DATABASEINCOMPLETE DATABASE MODIFYING FACTORS (MODIFYING FACTORS (TO ACCOUNT TO ACCOUNT FOR UNCERTAINTIES IN STUDY DESIGN)FOR UNCERTAINTIES IN STUDY DESIGN) 12/5/2010 10 ACCEPTABLE vs. TOLERABLE ACCEPTABLE vs. TOLERABLE INTAKESINTAKES PRIN C IPLE S F O R DERIVATI O N ARE THE PRIN C IPLE S F O R DERIVATI O N ARE THE PRINCIPLES FOR DERIVATION ARE THE PRINCIPLES FOR DERIVATION ARE THE SAMESAME ADI: USED FOR COMPOUNDS ADI: USED FOR COMPOUNDS INTRODUCED INTENTIONALLY TO FOOD, INTRODUCED INTENTIONALLY TO FOOD, e.g. FOOD ADDITIVES. ACCEPTABLE IN e.g. FOOD ADDITIVES. ACCEPTABLE IN VIEW OF BENEFICIAL AFFECTSVIEW OF BENEFICIAL AFFECTS TD(W)I: USED FOR COMPOUNDS TD(W)I: USED FOR COMPOUNDS TOLERATED IF NOT AVOIDABLE, e.g. TOLERATED IF NOT AVOIDABLE, e.g. CONTAMINATSCONTAMINATS ADI/TDI Exceeders ABOVE “ADi” DOSE REGION OF ADVERSE "SAFE" FOG OF UNCERTAINTY "NOT SAFE" REGION OF NO EFFECTS ADVERSE EFFECTS INCREASING DOSE “ADI” DOSE [...]... various exposure levels BENCHMARK DOSE BIOLOGICALLY BASED DOSEDOSERESPONSE MODELS (BBDR) ⌧Pharmacokinetics ⌧Mechanisms of action PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS (PBPK) BENCHMARK DOSE What is a Benchmark Dose (BMD)? at s e c a ose ( ) The statistical lower confidence limit on the dose producing a predetermined level of change in an adverse effect compared with the response in untreated animals... lower confidence on the dose that causes, for example, a 10% increase in the number of animals developing fatty liver compared with untreated animals A BMD is calculated by fitting a mathematical dose- response model to data 11 12/5/2010 Advantages of BMD Approach Not limited to doses tested experimentally; less p y; dependent on dose spacing Takes into account the shape of the doseresponse curve Provides... dependent on the model used Models for quantal data estimate the probability of response for each dose level Probability is assumed to increase as dose increases Models for continuous data estimate the mean response for each dose level compared to control control Mean response can either increase or decrease as a function of dose Goodness-of-fit analysis required to determine if a model adequately describes... increase may be appropriate for one response while a 1% increase is appropriate for a different response) Gives incentive to conduct better studies because more rigorous studies result in tighter uncertainty bands, and thus, higher BMDs 12 12/5/2010 Disadvantages to the BMD Possible to introduce error in model prediction of p BMD if the models are used to extrapolate to low doses without incorporating information... (ESPECIALLY TARGET ORGAN) CONSIST OF SEVERAL MASS BALANCE, DIFFERENTIAL EQUATIONS AROUND EACH COMPARTMENT DESCRIBING BLOOD FLOW PERMEABILITY 14 12/5/2010 EXTERNAL DOSE PB-PK MODEL INCLUDING LOCAL METABOLIC BIOACTIVATION TOXIC RESPONSE ABSORBED DOSE CLEARANCE CONCENTRATIONS IN GENERAL CIRCULATION INTRACELLULAR CHANGES DISTRIBUTION TO NON-TARGET TISSUES + - CONCENTRATIONS IN TARGET TISSUE INTERACTION WITH... NEEDED: ⌧PHYSIOLOGICAL INFORMATION ⌧PARTITION COEFFICIENTS ⌧METABOLIC RATES PROVIDES POSSIBILITY TO ACCOUNT FOR BIOLOGICAL PROCESSES 15 12/5/2010 USE OF PBPK MODELS STRENGTHS Estimates of target organ dose in humans can be based on in vitro data, without the need for administration to humans Species differences in blood flow to the target organ can be modelled to reflect Cmax Inclusion of organ blood... scaling of data for animals Blood:tissue affinities for humans are usually based on experimental data for animals, or octanol: water partitioning 16 12/5/2010 PROBABILISTIC APPROACHES Distribution of response and exposure Consider variability May be different for different groups of population Monte Carlo Approaches Probabilistic approaches to deriving ADI/TDI (or RfD/RfC) Probabilistic ADI/TDI The . 12/5/2010 1 DOSEDOSE RESPONSE RESPONSE ASSESSMENTASSESSMENT (Threshold Effects )(Threshold Effects) Leonard Ritter Maged Younes/WHO BASIC PRINCIPLESBASIC. ON DOSEDOSE RESPONSE CURVE ONLYRESPONSE CURVE ONLY 12/5/2010 5 ACCURACY ISSUESACCURACY ISSUES Dose spacing Dose spacing Information at different exposure levels Slope of the dose- response. exposure levels BENCHMARK DOSEBENCHMARK DOSE BIOLOGICALLY BASED DOSEBIOLOGICALLY BASED DOSE RESPONSE MODELS (BBDR )RESPONSE MODELS (BBDR) RESPONSE MODELS (BBDR )RESPONSE MODELS (BBDR) ⌧⌧PharmacokineticsPharmacokinetics ⌧⌧Mechanisms