1 RISK CHARACTERIZATIONRISK CHARACTERIZATION Len Ritter Maged Younes (WHO) RISK CHARACTERIZATIONRISK CHARACTERIZATION SYNTHESIS OF INFORMATION RISK ESTIMATES FOR GIVEN EXPOSURE SCENARIOS EXPOSURE SCENARIOS UNCERTAINTIES VARIABLES TRANSPARENCY OF THE PROCESS RISK CHARACTERIZATION (1)RISK CHARACTERIZATION (1) A SUMMARY, INTEGRATION AND EVALUATION OF THE MAJOR SCIENTIFIC EVIDENCE, REASONING AND CONCLUSIONS OF A RISK ASSESSMENT. A CONCISE DESCRIPTION OF POTENTIAL RISK AND THE STRENGTHS AND WEAKNESSES OF THOSE ESTIMATES (US- EPA). FINAL STEP IN RISK ASSESSMENT SUPPORT TO RISK MANAGERSSUPPORT TO RISK MANAGERS RISK CHARACTERIZATION (RISK CHARACTERIZATION (22)) ANSWERS THE QUESTION: “WHAT IS THE EFFECT IN TERMS OF POTENTIAL OCCURRENCE OF ADVERSE OUTCOMES OR INCREASED RISK?” ADDRESSES UNCERTAINTIES IN THE ADDRESSES UNCERTAINTIES IN THE UNDERLYING DATA AND MODELS ADDRESSES ISSUES RELATED TO VARIABILITY IN SUSCEPTIBILITY AND RESPONSE ADDRESSES ISSUES RELATED TO COMPLETENESS, QUALITY AND CONSISTENCY OF DATA RISK CHARACTERIZATION (3)RISK CHARACTERIZATION (3) PROVIDES SENSE OF THE DEGREE OF CONFIDENCE IN DATA AND RISK ESTIMATES, PARTICULARLY : WHERE SUPPORTING DATA LIE ON THE CONTINUUM BETWEEN EVIDENCE BASED ON HUMAN DATA (OR HIGHLY RELEVANT TO HUMANS), AND EVIDENCE BASED ON ANIMAL OR IN VITRO EXPERIMENTS Component Component 44. Risk Characterization. Risk Characterization Hazard Identification Dose-Repsonse Exposure Risk Characterization 2 QUALITY OF DATAQUALITY OF DATA ADEQUATE, DETAILED ADEQUATE, DETAILED INFORMATIONINFORMATION ADEQUATE DOCUMENTATIONADEQUATE DOCUMENTATION ADEQUATE DOCUMENTATIONADEQUATE DOCUMENTATION COMPLIANCE WITH GLPCOMPLIANCE WITH GLP (For older studies: scientific rigour)(For older studies: scientific rigour) INTEGRITY OF STUDYINTEGRITY OF STUDY HUMAN DATAHUMAN DATA TEST METHODOLOGIESTEST METHODOLOGIES CHOICE OF SPECIES AND STRAINCHOICE OF SPECIES AND STRAIN GROUP SIZEGROUP SIZE SELECTION OF DOSE LEVELS, SELECTION OF DOSE LEVELS, INCLUDING SPACINGINCLUDING SPACING TEST DURATIONTEST DURATION HISTORICAL CONTROL DATAHISTORICAL CONTROL DATA ADEQUACY OF ADEQUACY OF EPIDEMIOLOGIC STUDIESEPIDEMIOLOGIC STUDIES Proper selection of exposed and control groups Lon g duration and follow u p gp Consideration of latent effects Valid cause of morbidity Detection of specific effects Determination of exposure and dose CRITICAL EFFECTCRITICAL EFFECT Often multiple effects observed Usually: Effect with lowest NOEL/LOEL Particularly severe effects Characterization of various effects may be Characterization of various effects may be necessary Some effects may be particularly relevant to certain population groups Detailed description of effect(s) required Classification schemes for some endpoints (carcinogens, allergens?) Carcinogen Classification Carcinogen Classification (IARC)(IARC) Criteria applied to classify carcinogens into one of the following categories: Group 1 : Agent (mixture) is carcinogenic to humans Group 2 A : A g ent (mixture) is probably carcinogenic to humans Group 2B : Agent (mixture) is possibly carcinogenic to humans Group 3 : Agent (mixture) is not classifiable as to its carcinogenicity to humans Group 4 : Agent (mixture) is probably not carcinogenic to humans Risk Characterization of Carcinogens Class of carcinogen Potency consideration (possibly risk figure) (possibly risk figure) Mode/mechanism of action Descriptive statement Particular exposure conditions/Vulnerable population groups 3 Mode/mechanism of action Mechanism of Toxicity A detailed understanding at the molecular level of all the steps involved in the carcinogenic process for a chemical chemical . Mode of Action A general description of the manner in which a chemical might act to produce its effect. Biological Plausibility Requires that evidence of a causal association fit with existing biological knowledge. Risk Characterization of NonRisk Characterization of Non carcinogenscarcinogens Safe level: Calculation of acceptable/tolerable exposures on basis of NOEL/LOEL and extrapolation Likelihood of exceeding guideline levels at given exposures Interpretation of consequences of exceeding such levels; Extrapolation to higher doses Risk Characterization of NonRisk Characterization of Non carcinogenscarcinogens Margin of Safety: Calculation of NOELs/LOELs/BMDs for critical effects; estimation of HBGV Comparison of level of exposure to these values Expert judgement concerning safety and potential risks Definition of risk management/risk reduction needs Potential Exposure Pathways in Potential Exposure Pathways in assessing Exposure of assessing Exposure of the General Publicthe General Public Air Milk Cattle Crops Soil Surface Water Ground Water Drinking Water Milk Humans Cattle Fish Crops Exposure ConsiderationsExposure Considerations Exposures from all sources and through various media Risk comparison of exposure via different routes ( e. g . inhalation vs. in g estion ) (g g ) Exposure under different conditions: Direct exposure Indirect exposure via the environment Occupational exposure Exposure of vulnerable groups Synthesis AREAS OF (PURE) AREAS OF (PURE) UNCERTAINTYUNCERTAINTY EXTRAPOLATION FROM SUBCHRONIC TO CHRONIC EXTRAPOLATION FROM LO(A)EL TO NO(A)EL DATABASE DEFICIENCIES: DATABASE DEFICIENCIES: ⌧DETERMINED BY NATURE, SITE, MODE OF ACTION, AND EXTENT OF EXPOSURE ⌧WHAT IS THE EVIDENCE THAT A “MISSING ENDPOINT IS MORE SENSITIVE? ⌧NO SIMPLISTIC APPROACH; SCIENTIFIC JUDGEMENT 4 AREAS OF UNCERTAINTY AREAS OF UNCERTAINTY ANDAND VARIABILITYVARIABILITY INTERSPECIES SCALING: ⌧APPROPRIATE DOSEMETRIC ⌧INCLUDES ELEMENTS OF TOXICOKINETICS AND TOXICODYNAMICS ⌧SPECIES-SPECIFIC DEFAULT VALUES? INTRASPECIES EXTRAPOLATION (HUMAN VARIABILITY): ⌧INCLUDES ELEMENTS OF TOXICOKINETICS AND TOXICODYNAMICS MECHANISTIC INFORMATION LIMITS OF OVERALL UNCERTAINTY SPECIFIC ISSUES OF SPECIFIC ISSUES OF CONCERNCONCERN ACCUMULATION ⌧PERSISTENT, LIPOPHILIC COMPOUNDS (e.g. PCBs, DIOXINS) ⌧PROTEIN BINDING / STORAGE ( e. g . HEAVY /(g METALS) ⌧BODY BURDEN CONSIDERATIONS CUMULATIVE EFFECTS ⌧COMMON MECHANISM OF TOXICITY (e.g. CHOLINESTERASE INHIBITION) ⌧BINDING TO SAME RECEPTOR (e.g. DIOXINS) USE OF MECHANISTIC DATA USE OF MECHANISTIC DATA ((11)) TOXICOKINETIC/TOXICODYNAMIC TOXICOKINETIC/TOXICODYNAMIC INFORMATION TO REPLACE DEFAULT INFORMATION TO REPLACE DEFAULT ASSUMPTIONS & REDUCE UNCERTAINTIESASSUMPTIONS & REDUCE UNCERTAINTIES USE OF SURROGATE DATA OR EARLYUSE OF SURROGATE DATA OR EARLY USE OF SURROGATE DATA OR EARLY USE OF SURROGATE DATA OR EARLY MARKERS OF EFFECTMARKERS OF EFFECT BETTER CHARACTERIZATION OF DOSEBETTER CHARACTERIZATION OF DOSE RESPONSE RELATIONSHIPRESPONSE RELATIONSHIP BETTER UNDERSTANDING OF CRITICAL BETTER UNDERSTANDING OF CRITICAL EFFECTS (RELEVANT ENDPOINT IN CASE OF EFFECTS (RELEVANT ENDPOINT IN CASE OF MULTIPLE ENDPOINTS)MULTIPLE ENDPOINTS) USE OF MECHANISTIC DATA USE OF MECHANISTIC DATA ((22)) PROVIDE BIOLOGICAL DATA RELEVANT FOR PROVIDE BIOLOGICAL DATA RELEVANT FOR PREDICTION, e.g. THROUGH QSARPREDICTION, e.g. THROUGH QSAR BIOLOGICAL BASIS FOR VARIABILITYBIOLOGICAL BASIS FOR VARIABILITY ESTIMATION OF TARGET ORGAN DOSEESTIMATION OF TARGET ORGAN DOSE ESTIMATION OF TARGET ORGAN DOSE ESTIMATION OF TARGET ORGAN DOSE (KINETIC/DYNAMIC MODELS)(KINETIC/DYNAMIC MODELS) MIXTURE EFFECTSMIXTURE EFFECTS DRIVE DESIGN OF TESTING DRIVE DESIGN OF TESTING METHODOLOGIESMETHODOLOGIES DIFFERENTIATE ETIOLOGY OF DIFFERENTIATE ETIOLOGY OF ENVIRONMENTAL DISEASESENVIRONMENTAL DISEASES TRANSPARENCY OF THE PROCESSTRANSPARENCY OF THE PROCESS ELEMENTS TO CONSIDERELEMENTS TO CONSIDER PURPOSE OF THE RISK ASSESSMENT EXTENT AND QUALITY OF THE DATABASE DATE OF LAST LITERATURE SEARCH HOW AND WHY ADJUSTMENT FACTORS FOR UNCERTAINTY AND VARIABILITY WERE APPLIED PROCESSES INVOLVED IN DECISION MAKING (SCIENTIFIC JUDGEMENT ELEMENTS, PEER- REVIEW PROCESS) QUESTIONS ASKED BY RISK QUESTIONS ASKED BY RISK MANAGERS (MANAGERS (11)) BOTTOM LINE OF RISK ASSESSMENT? SUFFICIENT INFORMATION TO SUPPORT A REGULATORY DECISION? RANGE OF UNCERTAINTY AROUND ESTIMATED EXPOSURE LEVEL AND PROJECTED NUMBER OF PEOPLE POSSIBLY EXPOSED! IS THERE A REASON FOR CONCERN? LIKELIHOOD OF ZERO RISK? 5 QUESTIONS ASKED BY RISK QUESTIONS ASKED BY RISK MANAGERS (MANAGERS (22)) WHAT DATA GAPS MAY ELICIT CRITICISM? ARE THERE ANY STUDIES UNDERWAY WHICH MAY ANSWER OPEN QUESTIONS? WHICH MAY ANSWER OPEN QUESTIONS? PEER REVIEW? PROCESS! KEY PARAMETERS THAT DRIVE THE ANALYSIS RATIONALE FOR EXCLUDING ANY STUDIES! IMPACT? . 1 RISK CHARACTERIZATIONRISK CHARACTERIZATION Len Ritter Maged Younes (WHO) RISK CHARACTERIZATIONRISK CHARACTERIZATION SYNTHESIS OF INFORMATION RISK ESTIMATES FOR GIVEN. POTENTIAL RISK AND THE STRENGTHS AND WEAKNESSES OF THOSE ESTIMATES (US- EPA). FINAL STEP IN RISK ASSESSMENT SUPPORT TO RISK MANAGERSSUPPORT TO RISK MANAGERS RISK CHARACTERIZATION (RISK CHARACTERIZATION. OR IN VITRO EXPERIMENTS Component Component 44. Risk Characterization. Risk Characterization Hazard Identification Dose-Repsonse Exposure Risk Characterization 2 QUALITY OF DATAQUALITY OF DATA ADEQUATE,