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ILSI Health and

Environmental Sciences

Institute

HESI'S RISK21 Program

Roadmap

and

Matrix

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

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eso

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re

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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)

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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

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