ILSI Health and

Environmental Sciences

Institute

HESI'S RISK21 Program

Roadmap

and

Matrix

Paradigm Shift in Risk Assessment

Uncertainty

factor

Hazard ID

Hazard characterisation

Exposure assessment

Risk characterisationR

esp

on

se

Dose

Paradigm Shift in Risk Assessment

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

g r

eso

urc

es a

nd

re

fin

em

en

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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fin

em

en

t

Tier 3:

Mode of Action

Tier 2:

In vivo

Tier 1:

In vitro

Tier 0:

QSAR/

TTC

WEB-Based Tool

Use of RISK21 Matrix

MOE set at 1:100

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

Critical Reviews in Toxicology, 2014; 44(S3): 1–5Critical Reviews in Toxicology, 2014; 44(S3): 6–16Critical Reviews in Toxicology, 2014; 44(S3): 17–43

OPEN ACCESS!