OSIRIS Webtool: AnintegratedFrameworkfor non ... · OSIRIS Webtool: AnintegratedFrameworkfor non-testingmethods Dinant Kroese TNO| knowledge for business. 2 ... Fetogenesis Postnatal

TNO| knowledge for business

OSIRIS W

ebtool:

AnintegratedFramework

for

non-testingmethods

Dinant Kroese

2

Focus:

not on the webtoolprimarily

on human health endpoints

OSIRIS StakeholderWS, March1st , Berlin 2010

3

Outline

Context: REACH, ITS & ‘Non-Testing’

Objectives O

SIRIS / W

ebtool

WoEapproaches

Conclusions / Next steps


4

REACH context O

SIRIS StakeholderWS, March1st , Berlin 2010

•The Chemical Safety Assessmentis the tool used to determine the

safety of the chemical

•The Chemical Safety Reportis the tool used to record/document

the Assessment to EChA

•The Safety D

ata Sheetis the tool used to communicate

safe use

to downstream users (DU)

Core tools under REACH


Chemical Safety

Assessment

C&L assessment (PBT & vPvB)

and

DNEL/DMEL derivation (PNEC)

has 2 m

ajor objectives..

to determ

ine

the safety of the chemical


7

1. G

ather and share available inform

ation

2. Consider inform

ation requirements

cftonnage-bands(Annexes VII-X)

3. Identify inform

ation gaps

4. G

enerate new testing data / propose testing strategy

(Annexes VII & VIII / Annexes IX & X)

Chemical Safety Assessment

(Annex VI)


WoEITS HumanToxicologyWoEITS HumanToxicology

8

Tonnage

Human Health

1 –

10 tpa

Annex VII

•In vitro

skin and eye irritation

•Skin sensitization

•In vitro

mutagenicity

•Acute toxicity (one route)

10 –

100 tpa

Annex VIII

•In vivoskin and eye irritation

•Further in vitro

mutagenicity

•Acute toxicity (2nd route)

•Sub acute toxicity (28d)

•Reproductive toxicity screen

100 –

1000 tpa

Annex IX

•Further mutagenicitytests

•Sub-chronic toxicity (90d)

•Reproductive toxicity tests

>1000 tpa

Annex X


•Further reproductive toxicity tests

•Carcinogenicity m

ay

•Chronic toxicity m

ay

REACH Standard Inform

ation Requirements

(Annexes VII –

X)


WoEITS HumanToxicologyWoEITS HumanToxicology

9

Tonnage

Human Health

1 –

10 tpa

Annex VII

•In vitro

skin and eye irritation


•In vitro

mutagenicity

•Acute toxicity (one route)

10 –

100 tpa

Annex VIII

•In vivoskin and eye irritation

•Further in vitro

mutagenicity

•Acute toxicity (2nd route)

•Sub acute toxicity (28d)

•Reproductive toxicity screen

100 –

1000 tpa

Annex IX


•Sub-chronic toxicity (90d)


>1000 tpa

Annex X


•Further reproductive toxicity tests


ay

•Chronic toxicity m

ay


ation Requirements

(Annexes VII –

X)

(REACH

art.13, 25

& Annex XI)

Anim

al tests

as last

resort!



ation Requirements

General rules for adaptation

(Annex XI)

1. Testingdoes notappear scientifically

necessary

2. Testingis technically notpossible

3. Substance-tailored exposure-driven testing


11

Strategy to efficiently gather required inform

ation

Magic w

ord = ITS


12

Non-Testing (NT) inform

ation

Available sources of inform

ation

(Q)SAR

Human data

In vitro

Exposure

(-based waiving)

Grouping &

read across


ITS

13

Step 1: G

ather all available Testing and Non-Testing inform

ation

If notsufficient for C&Land RC cfREACH

Step 2: Is Exposure-Based W

aiving an option?

(Testing is technically possible)

If notpossible

Step 3: Perform

/ Propose Testing as last resort!!

Strategy to efficiently gather required inform

ation


14

ITS: 3 starting situations (per endpoint)

OECD/GLP study

available

Perform

ed:

non

OECD/GLP

study

Reliability

OK;

(relevanceof certain

effects?)

Howto

judgethis

test?

“Ideal endpoint inform

ation”

“Accepted by REACH”

No

test inform

ation

at all

Generate

NT

inform

ation

etc..

Additional NT

inform

ation needed?


NT and reprotox

15

REACH objectives

C&L, RC

How to weight & combine inform

ation from different sources?

sufficient ???

Non-GLP/ Non-OECD

Available inform

ation

+=

+ +

=sufficient ???

=sufficient ???


NT and reprotox

16

•Weightinform

ation

•from

tests

•from

models / m

ethods

•from

categoriesapproaches

•etc.

•Canaddweights

of different sourcesof inform

ation

•Candecideiftotalweightof inform

ationis “sufficient”

•Ifnot→

help findmost efficientwayof filling“inform

ationgap”

We needtoolsthat:


NT and reprotox

17

OSIR

IS

Optimized Strategies for Risk Assessm

ent of Industrial

Chem

icals through Integration of Non-Test and Test

Inform

ation

2007-2011

This is the central objective of:


Ultim

ate goal: O

SIRIS webtool

WP 4.2 Tool

sorts to type of info

adds weight to type of info

or

asks (expert) input

makes an assessment:

compares with ‘golden standard’

inform

ation, and concludeson:

C & L

RA

concludes on additional

inform

ation needed

consults ITS and library of options

ITS

library of

options

Available inform

ation input by user

Output

Proposal for new test

Pre

de

fin

ed

qu

est

ion

air

e?

OK!

TTC/EBW


19

At the firstStakeholderWorkshop (Stuttgart 07):

Focus onmost criticalendpoints: CMRS!

Generating focus within O

SIRIS

At subsequentOSIRIS M

eetings:

Focus onProof-of-Conceptinsteadof concrete ITSsesforCMRS!


20

At interpillarmeeting in Liverpool 08:

P-o-C

fora categorical, and fora continuousdataset!

Categoricaldataset: sensitisation

(as m

odel C&L endpoint)

Continuousdataset: repeateddosetoxicity

(as m

odel RC endpoint)

Main

reason: availability

of data and expertise!


Generating focus within O

SIRIS

NT and reprotox

21

•Weights

inform

ation

•from

tests

•from

models / m

ethods

•from


•etc.

•Canaddweights


ation



•Ifnot→


ationgap”

How to develop a

toolfor a categorical endpointthat:


NT and reprotox

22

ProbabilisticoneusingBayesianstatistics:

“Whatis the probability

that

a predictedresponse thatthe substanceis a sensitizerornot, is true?”

Approach chosen:


NT and reprotox

23

1. Score of the substancein a test:

‘yes’or‘no’(i.e. sensitizing)

& Score of thattest relativeto

therequiredOECD/G

LPtest as ‘GS’

(‘Gold Standard’)

Approach chosen:

2. ‘Qualityfactor’score of thattest:

describingperform

ance of specifictest and its

result

-no. of anim

als

-applicability

domain

-reporting..

‘Sensitivity/Specificity cross table’

~ Klim

ischrating

National Institute

for Public Health

and the

Environment


OSIRIS W

P4.2. meets

WP4.4

24

Tonnage

Human H

ealth

1 –

10 tpa

Annex VII


•In vitro

mutagenicity

10 –

100 tpa

Annex VIII

•Further in vitro

mutagenicity

•Reproductive toxicity

screen

100 –

1000 tpa

Annex IX



>1000 tpa

Annex X


•Further reproductive

toxicity tests


ay be

required

‘Gold Standard’

LLNA, OECD 429

GM Bacteria, OECD 471

CA/M

N M

amm

cells, O

ECD 473/487

GM M

amm

cells, O

ECD 476

Reprotoxscreen, O

ECD 421

If pos in vitro: in vivo, OECD 474/475

Prenatal developm

tox, OECD 414

(2-gen tox, OECD 416)

If pos in vitro: in vivo, OECD 474/475

2-gen tox, OECD 416

Carcinogenicity, O

ECD 451

Categorical CMRS endpoints and ‘GS’

(Annexes VII –

X)


NT and reprotox

25

•Weights

inform

ation

•from

tests

•from

models / m

ethods

•from


•etc.

•Canaddweights


ation



•Ifnot→


ationgap”

How to develop a

toolfor a continuousendpoint that:


NT and reprotox

26

ProbabilisticoneusingBayesianstatistics:

“Whatis the probability

that

the observedNOAEL (LOAEL) is the trueNOAEL (LOAEL) ?”

Approach chosen:


NT and reprotox

27

repeateddose toxicity

databaseanalysis

Target organsmostfrequentlydeterm

iningNOAEL:

Liver

Body w

eight

Clinicalsymptoms

Kidney

Blood

Providesa w

ay to assign

weightto anynon-O

ECD/

GLP test data

…!

and evenNon-testdata?!


NT and reprotox

28

1. Score of the substancein a test:

‘NOAEL’or‘LOAEL’

& Score of thattest relativeto

therequiredOECD/G

LPtest as ‘GD’

(‘Gold Standard’)

Approach chosen:

2. ‘Qualityfactor’score of the specifictest:

describingperform

ance of specifictest and its

result

-no. of anim

als

-‘applicability

domain’

-reporting..

‘Organ-coverage statistics’

~ Klim

ischrating

National Institute

for Public Health

and the

Environment


Progress so far?

NT and reprotox

29


30

Using the ITS structure as template:

Step 1: G

ather all available Testing and Non-Testing inform

ation

If notsufficient for C&Land RA cfREACH

Step 2: Is Exposure-Based W

aiving an option?

(Testing is technically possible)

If notpossible

Step 3: Perform

/ Propose Testing as last resort!!


Tools for CMRS ITSsesto be developed

Ref-lunch22 febr2010


Complex R

eproductive Cycle

Teamoverleg 29 sept09

Sexual Maturation

Gamete production

Fertilization

Preimplantation

embryogenesis

Transport of the

zygote

Implantation

Placental

development/

barrier function

Postimplantation

embryogenesis

Fetogenesis

Birth

Postnatal

developmentGrowth and

development


Coverage approach

for repro:

Dang et al,

Reproduct.Toxicol.

2009

ReProTect(FP6)

ChemScreen(FP7)

Tools for CMRS ITS to be developed

What are the NT

options?

What are options?

What are options?


34


•A clear focusand template

for our objectives (given data, time …

.).

statisticians, toxicologists, software engineers, chemists etc…

. their languages and hobbies….


35


•A clear focusand template

for our objectives (given data, time …

.).

•WoEapproach for categoricalendpoints: nearly finished.

•WoEapproach for continuous endpoints identified; yet to m

ake

statistically-founded.

•ITSsesfor sensitisation, mutagenicity, BCF, and aquatic toxare

introduced in the webtool(http://osiris.sim

mple.com; not yet public).

One continuous human health endpointneeds to be incorporated

asap(to allow validation by P5).

•Adaptedin vivotesting: what are the options?

•TTCs/ Exposure-based W

aiving options need to be incorporated.


•What is an acceptable probability (weight)?

TNO The Netherlands T

+31 30 694 45 80 F

+31 30 694 40 99

Einfo-kvl@

tno.nlwww.tno.nl/alternatives

Thank you for your attention

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OSIRIS Webtool: AnintegratedFrameworkfor non ... · OSIRIS Webtool: AnintegratedFrameworkfor non-testingmethods Dinant Kroese TNO| knowledge for business. 2 ... Fetogenesis Postnatal