Paradigm Shift in Risk Assessment
Uncertainty
factor
Hazard ID
Hazard characterisation
Exposure assessment
Risk characterisationR
esp
on
se
Dose
Risk Assessment in the 21st Century (RISK21)
• MISSION: Bring applicable, accurate, and resource
appropriate approaches to the evolving world of human
health risk assessment
• Convened experts from academia, industry, government
and other stakeholders
• RISK21 involved > 120 scientists from Europe and USA
• Developed a risk assessment approach that embraces
advances in scientific knowledge and methods
• Revised current thinking about how to approach the
science and art of risk assessment
How is RISK21 Different?
• Think about the problem that needs to be addressed; then select
sources of information which will have the most value
• RISK21 Principles:
– Problem-formulation based
– Exposure-driven
– Prior knowledge
– “Enough precision to make the decision”
• Provide a framework that is…
– Flexible
– Transparent
– Visual
Problem
Formulation ConcludeExposure?
Toxicity?
Risk? Safety?Mode of Action
In vivo
In vitro
QSAR/
TTC
1
4
Biomonitoring
Probabilistic
Deterministic
Minimal
Info
2
3
Problem
Formulation ConcludeExposure?
Toxicity?
Risk? Safety?Mode of Action
In vivo
In vitro
QSAR/
TTC
1
4
Biomonitoring
Probabilistic
Deterministic
Minimal
Info
2
Exposure
range
Toxicity range
3
Problem Formulation: The Starting Point
• Sets out:
– Objectives
– Scope
– Hypotheses
• Asks:
– what do you know?
– what do you need to know?
– How do you know when you’re done?
Enough precision to make a decision
Enough Precision for Exposure EstimateIn
cre
asin
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t
Estimate based on
samples from exposed
individuals
Detailed use
knowledge. Use
measurements
specifically relevant to
use
Use exposure
model(s) with
population,
exposure route,
environmental
fate, volume,
release, and
specific-use
information
Minimal information, such as
physical-chemical properties and
use knowledge. Estimate may
include :
Environmental background
Consumer Uses
Industrial Uses
Tier 3:
Biomonitoring
Tier 2:
Probabilistic
Tier 1:
Deterministic
Tier 0: Minimal
Info
Exposure Assessment
• Evaluation of the concentration of a particular agent that reaches a target – Nature
– Magnitude
– Frequency
– Duration
– Route
– Extent
• Describes the ways people come into contact with an agent
• Describes the relevant media and exposure routes
• Provides metrics of exposure to characterize health risks
• Determines if guidance value of an exposure concentration indicates need to perform a risk characterization
10
Sources of Information for Exposure Tiers
Tier DescriptionExamples of
tools/models/data
Tier 0 Limited substance and/or specific use knowledge.
Use of physical-chemical properties.
EPI Suite, look-up tables
from various models,
monitoring databases,
physical-chemical
properties, etc.
Tier 1
Limited use knowledge. Models with population,
exposure route, environmental fate, volume, release,
and specific-use information; geometric mean
monitoring values.
ECETOC TRA, USETox,
ConsExpo, EUSES, etc.
Tier 2
Detailed use knowledge. Specific contaminant
monitoring and measurement data for use in
probabilistic modeling.
PRZM-EXAMS, SHEDS, full
distribution of monitoring
data, etc.
Tier 3
Extensive use knowledge. Internal dose,
biomonitoring information, specific contaminant
monitoring and measurement data.
National Report on Human
Exposure to Environmental
Chemicals, NHANES, etc.11
Enough Precision for Toxicity Estimate
Structure & activity relationships
plus existing databases such as
Threshold of Toxicological
Concern (TTC)
Predictive assays plus in
vitro to in vivo
extrapolation (IVIVE)
Apical
endpoints
Dose-response for mode
of action, Key Events
Dose-Response
Framework (KEDRF)
Incre
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Tier 3:
Mode of Action
Tier 2:
In vivo
Tier 1:
In vitro
Tier 0:
QSAR/
TTC
Benefits of the RISK21 Framework
• Optimizes use of existing data and integration of new data,
using conventional or emerging methods, when relevant
• Gives appropriate weight to exposure and hazard
• Highly visual, flexible and very transparent
• Effective risk communications tool
• Multiple applications, e.g:
– Priority setting
– Evaluation of data needs
– Evaluation of new use or release scenario
– Comparison of different risk mitigation options
– Value of information analysis
• Can inform study design & resource allocation
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