chemical category formation: toxicology and reach dr steven enoch liverpool john moores university...
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Chemical Category Formation: Toxicology and REACH
Dr Steven Enoch
Liverpool John Moores University
14th May 2009
Is Regulatory Toxicology Important?
• Number of stories about the toxicity of chemicals
Is Regulatory Toxicology Important?
• Number of stories about the toxicity of chemicals
• Many chemicals have little or no toxicological data
• Concerns about the potential toxicity of chemicals
• New REACH legislation regarding chemical safety
• Applies to excipients, intermediates etc
• Cosmetics directive prohibits animal testing
REACH and Intelligent Testing Strategies
Risk Assessment
In vivo
In silico In chemico
In vitro
In-silico Category Formation
• Structural
• Mechanistic
• Toxicological
• Qualitative and quantitative predictions
OHOH
ON
OH
OH
OH
OH
In-silico Category Formation
• Structural
• Mechanistic
• Toxicological
• Qualitative and quantitative predictions
OHOH
ON
OH
OH
OH
OH
Mechanistic Category Formation – Skin Sensitisation
• Six key chemical reactions have been defined for protein reactivity1
• All known skin sensitising chemicals can be assigned to one of these mechanisms
• SMARTS based rules have been developed2
1Aptula AO and Roberts DW (2006) Chem Res Toxicol 19; 1097-11052Enoch SJ et al (2008) SAR QSAR Environ Sci 19; 555-578
Electrophilic Reaction Chemistry
X XNu
ProteinProteinNu
-carbon
-carbon
X = electron withdrawing substituent e.g. CO, CHO, NO2, CO2R.
Mechanism for Michael Addition
O
NO2
O
O
O O
O
O
O
N
O
Br
O
OMe
I
O
Mechanistic Category Formation
• Qualitative read-across using only mechanistic assignment
• Quantitative read-across using the electrophilicity index () to model protein reactivity within a category3
• Electrophilic index calculated from HOMO and LUMO using DFT
3Enoch SJ et al (2008) Chem Res Toxicol 21; 513-520
Read-Across within a Mechanistic Category
Cl
Cl O
O N
O O
O
O
Increasing electrophilicity ()
Increasing skin sensitising potential (pEC3)
pEC3 = NC, = 1.10 pEC3 = 0.55, = 1.49 pEC3 = 1.82, = 1.55
pEC3 = 1.25, = 1.61 pEC3 = 1.64, = 2.10 pEC3 = 4.04, = 3.90
Quantitative Electrophilicity () Ranking
O Chemical A:
= 1.61, EC3 = 5.5, pEC3 = 1.25
O
Chemical B:
= 1.80, EC3 = 7.5, pEC3 = 1.30
O
O
Chemical X:
= 1.73 Pred. pEC3 = 1.29 (1.31)
Pred. EC3 = 9.87 (9.30)
Quantitative Read-Across Predictions
Toxicological Category Formation - Developmental Toxicity
• Mechanistic read-across requires a priori mechanistic knowledge
• What about category formation when we don’t know about the mechanism of action?
• Can we use chemical similarity to form categories?4
Read-Across within a Toxicological Category
4Enoch SJ et al (2009) QSAR Comb Sci in-press
OO
OO
ethynodiol diacetate
Read-across prediction (atom environment similarity): D / XActual classification: D
Qualitative Read-AcrossOH
OH
ethynodiol (D)
OH
lynestrenol (D)
OH
O
norethindrone (X)
Read-across prediction (fingerprint similarity): BActual classification: B
Qualitative Read-Across
ON
O
N S
O
O
NO
O O
S N
N
cefotaxime
ON
O
N S
NO
O O
S N
N
ceftizoxime (B)
ON
O
N S
O N
O
NO
O O
Ocefuroxime (B)
O
ON
SN
O
S
N
OO
Ocephapirin (B)
Regulatory QSAR Tools
4http://www.oecd.org/document/23/0,3343,en_2649_34377_33957015_1_1_1_1,00.html5http://ecb.jrc.ec.europa.eu/qsar/qsar-tools/
• OECD QSAR Application Toolbox4
• Chemical category formation
• Read-across and trend analysis
• Regulatory reporting for ECHA
• Toxmatch and Toxtree5
• Similarity based category formation
• Rule based category formation
Conclusions
• REACH envisages intelligent testing of chemicals
• In silico developed chemical categories play a central role
• Qualitative and quantitative predictions of toxicity used to fill data gaps
• In silico methods must be transparent and simple in order for regulatory acceptance from EChA
The Future – Intelligent Testing Strategies
Risk Assessment
In vivo
In silico In chemico
In vitro
?
Acknowledgements
• The funding of the European Chemicals Agency (EChA) Service Contract No. ECHA/2008/20/ECA.203 is gratefully acknowledged