RISK CHARACTERIZATIONLen Ritter Maged Younes WHO RISK CHARACTERIZATION SYNTHESIS OF INFORMATION RISK ESTIMATES FOR GIVEN EXPOSURE SCENARIOS UNCERTAINTIES VARIABLES TRANSPARENCY OF THE PR
Trang 1RISK CHARACTERIZATION
Len Ritter
Maged Younes (WHO)
RISK CHARACTERIZATION
SYNTHESIS OF INFORMATION RISK ESTIMATES FOR GIVEN EXPOSURE SCENARIOS UNCERTAINTIES VARIABLES TRANSPARENCY OF THE PROCESS
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 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)
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
Trang 2QUALITY OF DATA
ADEQUATE, DETAILED
INFORMATION
ADEQUATE DOCUMENTATION
COMPLIANCE WITH GLP
(For older studies: scientific rigour)
INTEGRITY OF STUDY
HUMAN DATA
TEST METHODOLOGIES
CHOICE OF SPECIES AND STRAIN GROUP SIZE
SELECTION OF DOSE LEVELS, INCLUDING SPACING
TEST DURATION HISTORICAL CONTROL DATA
ADEQUACY OF
EPIDEMIOLOGIC STUDIES
Proper selection of exposed and
control groups
Long duration and follow up g p
Consideration of latent effects
Valid cause of morbidity
Detection of specific effects
Determination of exposure and dose
CRITICAL 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
(IARC)
Criteria applied to classify carcinogens
into one of the following categories:
Group 1: Agent (mixture) is carcinogenic to
humans
Group 2A: Agent (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) Mode/mechanism of action Descriptive statement Particular exposure conditions/Vulnerable population groups
Trang 3Mode/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 Non Risk Characterization of Non carcinogens
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 Non
Risk Characterization of
Non carcinogens
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 assessing Exposure of the General Public
Air
Milk Cattle
Crops
Soil Surface Water Ground Water
Drinking Water
Milk
Humans Cattle
Fish Crops
Exposure Considerations
Exposures from all sources and through
various media
Risk comparison of exposure via different
routes (e.g inhalation vs ingestion) ( g g )
Exposure under different conditions:
Direct exposure
Indirect exposure via the environment
Occupational exposure
Exposure of vulnerable groups
Synthesis
AREAS OF (PURE) UNCERTAINTY 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
Trang 4AREAS OF UNCERTAINTY
AND
AND VARIABILITY VARIABILITY
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 CONCERN
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
((11))
TOXICOKINETIC/TOXICODYNAMIC
INFORMATION TO REPLACE DEFAULT
ASSUMPTIONS & REDUCE UNCERTAINTIES
USE OF SURROGATE DATA OR EARLY
USE OF SURROGATE DATA OR EARLY
MARKERS OF EFFECT
BETTER CHARACTERIZATION OF DOSE
BETTER CHARACTERIZATION OF
DOSE RESPONSE RELATIONSHIP
BETTER UNDERSTANDING OF CRITICAL
EFFECTS (RELEVANT ENDPOINT IN CASE OF
MULTIPLE ENDPOINTS)
USE OF MECHANISTIC DATA ((22))
PROVIDE BIOLOGICAL DATA RELEVANT FOR PREDICTION, e.g THROUGH QSAR
BIOLOGICAL BASIS FOR VARIABILITY ESTIMATION OF TARGET ORGAN DOSE ESTIMATION OF TARGET ORGAN DOSE (KINETIC/DYNAMIC MODELS)
MIXTURE EFFECTS DRIVE DESIGN OF TESTING METHODOLOGIES
DIFFERENTIATE ETIOLOGY OF ENVIRONMENTAL DISEASES
TRANSPARENCY OF THE PROCESS
ELEMENTS 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 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?
Trang 5QUESTIONS ASKED BY RISK
MANAGERS (
MANAGERS (22))
WHAT DATA GAPS MAY ELICIT
CRITICISM?
ARE THERE ANY STUDIES UNDERWAY
WHICH MAY ANSWER OPEN QUESTIONS?
PEER REVIEW? PROCESS!
KEY PARAMETERS THAT DRIVE THE
ANALYSIS
RATIONALE FOR EXCLUDING ANY
STUDIES! IMPACT?