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Title: Use of Toxicological Pathways for Hazard Assessment in OECD (Q)SAR Toolbox:


1
Use of Toxicological Pathways for Hazard
Assessment in OECD (Q)SAR Toolbox
LMC, Bourgas University, Bulgaria Chemical
Management Center, NITE, Japan Fraunhofer
Institute for Toxicology and Experimental
Medicine, Germany OECD, Environment Directorate,
Paris International QSAR Foundation, USA
McKim Conference September 2008, Duluth, USA
2
Outline
  • Conceptual framework of QSAR
  • Categorization and QSAR
  • Predicting human health endpoints in Toolbox
  • Molecular initiating events and toxicological
    pathways
  • Case study with 28d RDT
  • Mechanism database in Toolbox

3
Outline
  • Conceptual framework of QSAR
  • Categorization and QSAR
  • Predicting human health endpoints in Toolbox
  • Molecular initiating events and toxicological
    pathways
  • Case study with 28d RDT
  • Mechanism database in Toolbox

4
Conceptual Framework of SAR/QSAR

Molecular Initiating Events
Chemical Speciation and Metabolism
Measurable System Effects
Adverse Outcomes
Parent Chemical
Rather than developing statistical models of
complex endpoints, key molecular initiating
events become the well-defined endpoints for
QSAR.
Gil Veith International QSAR Foundation
5
IQF Framework for QSAR
Adverse Outcomes
Parent Chemical
Black Box Models
Rapid but not mechanistically transparent
6
IQF Framework for QSAR
Molecular Initiating Events
Speciation and Metabolism
Measurable System Effects
Adverse Outcomes
Parent Chemical
QSAR
QSAR
Systems Biology
Chemistry/ Biochemistry
1. Identify Plausible Molecular Initiating
Events 2. Design Database for Abiotic
Binding Affinity/Rates 3. Explore Linkages
in Pathways to Downstream Effects 4. Develop
QSARs to Predict Initiating Event from Structure
7
Outline
  • Conceptual framework of QSAR
  • Categorization and QSAR
  • Predicting human health endpoints in Toolbox
  • Molecular initiating events and toxicological
    pathways
  • Case study with 28d RDT
  • Mechanism database in Toolbox

8
Categorization and QSAR
  • The categories concept is part of the historical
    description of QSARs
  • QSARs are quantitative models of key mechanistic
    processes which result in the measured activity

9
Categorization and QSAR
  • Each QSAR estimate is a result of two
    predictions
  • Qualitative prediction of predominant interaction
    mechanisms and hazard identification (defined by
    category)
  • Quantitative prediction of the intensity
    (potency) of the specific mechanisms of
    interaction (predicted by QSAR)
  • Wrong definition for the mechanism of underlying
    reaction could result in using of a wrong QSAR
    for the potency estimate

10
Categorization and QSAR
  • Example
  • Phenols are polar narcotics, uncouplers or
    electrophilic chemicals.
  • QSAR models for predicting acute effects for each
    mechanism have comparable uncertainty
  • The potency of the electrophilic mechanism can be
    orders of magnitude greater than polar narcotics
  • Wrong categorization of chemicals could cause
    significant errors in defining the potency

11
Categorization and QSAR Basic Assumption for
Regulatory Acceptance
  • The logic for selecting a specific model
    (category) for a specific chemical is the
    cornerstone of regulatory acceptance

OECD QSAR AD-Hoc group meeting, Madrid, April 2007
12
Outline
  • Conceptual framework of QSAR
  • Categorization and QSAR
  • Predicting human health endpoints in Toolbox
  • Molecular initiating events and toxicological
    pathways
  • Case study with 28d RDT
  • Mechanism database in Toolbox

13
Modelled human health endpoints in Toolbox
  • Sensitization
  • Lung
  • Skin
  • Genotoxicity
  • AMES bacterial mutagenicity
  • Chromosomal aberration
  • Irritation/corrosion
  • Eye
  • Skin

14
Commonality between the modelled endpoints
The effects could be characterized by
  • Single toxicological pathway
  • Strong dependency on initiating molecular events
    (e.g. on molecular structure)
  • Small impact of subsequent biological processes
    (short toxicological pathways)

15
QSAR Framework for modeled endpoint
Molecular Initiating Events
Speciation and Metabolism
Measurable System Effects
Adverse Outcomes
Parent Chemical
QSAR
QSAR
Biological processes
Initiating chemical/Biochemical Interactions
16
QSAR Framework for modeled endpoint
Molecular Initiating Events
Speciation and Metabolism
Adverse Outcomes
Parent Chemical
QSAR
QSAR
Initiating chemical/Biochemical Interactions
17
Mechanism of skin sensitization
  • Assumptions in the model
  • Chemicals always penetrate stratum corneum
  • Formation of protein conjugates is a premise for
    ultimate effect
  • Metabolism may play significant role in skin
    sensitization

Subject of modeling
18
Model Simulator of skin metabolism n QSAR models
Phase II
Reactive species
Metabolism
No sensitization
Parent
Reactive species
Phase II
Reactive species
19
Conclusion
The categorization of substances according to
chemical mechanisms governing the initiating
reaction with protein or DNA is good enough for
predicting human health effects resulting from
single and short toxicological pathways
20
Outline
  • Conceptual framework of QSAR
  • Categorization and QSAR
  • Predicting human health endpoints in Toolbox
  • Molecular initiating events and toxicological
    pathways
  • Case study with 28d RDT
  • Mechanism database in Toolbox

21
Toolbox logical sequence of components usage
Chemical input
Profiling
Category Definition
Filling data gap
Report
Endpoints
  • General characterization by the following
    grouping schemes
  • Substance information
  • Predefined
  • Mechanistic
  • Acute Toxicity MOA (OASIS)
  • Protein binding (OASIS)
  • DNA binding (OASIS)
  • Electron reach fragments (Superfragments) BioBite
  • Cramer Classification Tree (ToxTree)
  • Veerhar/Hermens reactivity rules (ToxTree)
  • Lipinski rules (MultiCase)

22
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29
Molecular Initiating Events and Toxicological
Pathways General Consideration
30
Molecular Level
Mechanism of chemical interactions
31
Molecular Level
Mechanism of chemical interactions
Mechanism 1 Mechanism 2 Mechanism 3
32
Molecular Level
Mechanism of chemical interactions
Mechanism 1 Mechanism 2 Mechanism 3
Distribution in lipid phase Protein binding
Arylcarboxylate aminolysis Michael-type
addition Schiff base formation DNA
binding Quinones Hydrazines
33
Molecular Level
Mechanism of chemical interactions
Receptor 1 Receptor 2 Receptor 3
Mechanism 1 Mechanism 2 Mechanism 3
Distribution in lipid phase Protein binding
Arylcarboxylate aminolysis Michael-type
addition Schiff base formation DNA
binding Quinones Hydrazines
34
Molecular Level
Mechanism of chemical interactions
Receptor 1 Receptor 2 Receptor 3
Mechanism 1 Mechanism 2 Mechanism 3
  • Initiating event/Receptor
  • Activation of AP-1?NF-kB?EpRE in hepatocyte
    ?Activation of JNK/AP-1 pathway
  • Activation of estrogen Signals ? Proliferation
    of bile duct cell and hepatocyte injury
  • Activation of MAPK Signals - Apoptosis

35
Chemistry/Biochemistry
Molecular Level
Mechanism of chemical interactions
Receptor 1 Receptor 2 Receptor 3
Mechanism 1 Mechanism 2 Mechanism 3
  • Initiating event/Receptor
  • Activation of AP-1?NF-kB?EpRE in hepatocyte
    ?Activation of JNK/AP-1 pathway
  • Activation of estrogen Signals ? Proliferation
    of bile duct cell and hepatocyte injury
  • Activation of MAPK Signals - Apoptosis

36
Chemistry/Biochemistry
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Receptor 1 Receptor 2 Receptor 3
Mechanism 1 Mechanism 2 Mechanism 3
37
Chemistry/Biochemistry
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Receptor 1 Receptor 2 Receptor 3
System 1 System 2 System 3 ...
Mechanism 1 Mechanism 2 Mechanism 3
38
Chemistry/Biochemistry
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Receptor 1 Receptor 2 Receptor 3
System 1 System 2 System 3 ...
Mechanism 1 Mechanism 2 Mechanism 3
  • System biology
  • Hepatotoxicity mechanism
  • Oxidant stress
  • Mitochondrial damage
  • Apoptosis
  • Degradation of membrane phospholipid
  • Aberration of ion channel
  • Increase of enzyme activition of drug
    metabolism
  • Inflammatory responses

39
Chemistry/Biochemistry
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Receptor 1 Receptor 2 Receptor 3
System 1 System 2 System 3 ...
Effect 1 Effect 2 Effect 3 ...
Mechanism 1 Mechanism 2 Mechanism 3
  • Cell Effects
  • Hepatocyte
  • Changes in the tubular epithelium

40
System biology
Chemistry/Biochemistry
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Receptor 1 Receptor 2 Receptor 3
System 1 System 2 System 3 ...
Effect 1 Effect 2 Effect 3 ...
Mechanism 1 Mechanism 2 Mechanism 3
41
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body Observed Effects
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Receptor 1 Receptor 2 Receptor 3
System 1 System 2 System 3 ...
Effect 1 Effect 2 Effect 3 ...
Mechanism 1 Mechanism 2 Mechanism 3
42
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body Observed Effects
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Tissue Effect 1 Effect 2 Effect 3 ...
Organ Effect 1 Effect 2 Effect 3 ...
Body Effect 1 Effect 2 Effect 3 ...
Receptor 1 Receptor 2 Receptor 3
System 1 System 2 System 3 ...
Effect 1 Effect 2 Effect 3 ...
Mechanism 1 Mechanism 2 Mechanism 3
43
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body Observed Effects
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Tissue Effect 1 Effect 2 Effect 3 ...
Organ Effect 1 Effect 2 Effect 3 ...
Body Effect 1 Effect 2 Effect 3 ...
Receptor 1 Receptor 2 Receptor 3
System 1 System 2 System 3 ...
Effect 1 Effect 2 Effect 3 ...
Mechanism 1 Mechanism 2 Mechanism 3
Molecular initiating event(s) and subsequent
downstream effects
44
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body Observed Effects
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Tissue Effect 1 Effect 2 Effect 3 ...
Organ Effect 1 Effect 2 Effect 3 ...
Body Effect 1 Effect 2 Effect 3 ...
Receptor 1 Receptor 2 Receptor 3
System 1 System 2 System 3 ...
Effect 1 Effect 2 Effect 3 ...
Mechanism 1 Mechanism 2 Mechanism 3
Molecular initiating event(s) and subsequent
downstream effects
45
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body Observed Effects
Cell Level
Molecular Level
Mechanism of chemical interactions
System biology/Effect
Tissue Effect 1 Effect 2 Effect 3 ...
Organ Effect 1 Effect 2 Effect 3 ...
Body Effect 1 Effect 2 Effect 3 ...
Receptor 1 Receptor 2 Receptor 3
System 1 System 2 System 3 ...
Effect 1 Effect 2 Effect 3 ...
Mechanism 1 Mechanism 2 Mechanism 3
Molecular initiating event(s) and subsequent
downstream effects
46
Conclusion
  1. One complex endpoint (e.g., 28days RDT) could be
    conditioned by more than one toxicological
    pathway (blood toxicity, liver damage, kidney
    damage)
  1. (Q)SAR models should be associated with a single
    toxicological pathway
  1. Chemicals which interact by different
    toxicological pathways should be out of the model
    mechanistic domain

47
Conclusion
  1. The categorization of substances according to
    chemical mechanisms governing the initiating
    reactions with protein or DNA is not enough for
    predicting human health effects resulting from
    multiple and complex toxicological pathways
  1. The link between chemical and toxicological
    mechanisms and respective categorization schemes
    needs to be identified

48
Outline
  • Conceptual framework of QSAR
  • Categorization and QSAR
  • Predicting human health endpoints in Toolbox
  • Molecular initiating events and toxicological
    pathways
  • Case study with 28d RDT
  • Mechanism database in Toolbox

49
Case study Twenty-eight day repeat dose oral
toxicity test of chemicals (28d RDT)
  • Data produced by
  • Safety examination of existing chemicals in NITE-
    Japan under Japanese Chemical Substances Control
    Law
  • Fraunhofer Institute for Toxicology and
    Experimental Medicine, Hanover, Germany
  • 2. Categorization of chemicals for predicting 28d
    RDT is based on analysis of data by NITE and LMC

50
28-day RDT tests conducted on male rats that
tested 14 aromatic amines
51
Categorization of Anilines
  • Based on their effects on two organs
  • Blood
  • Kidney

52
Categorization of Anilines
  • Based on their effects on two organs
  • Blood
  • Kidney

53
Blood Toxicity
  • Blood toxicity effects
  • decrease in erythrocyte count (RBC)
  • hemoglobin level (Hb)
  • Hematocrit (HTC)
  • glutamic-pyruvic transaminase (GPT)
  • increase in the number of reticulocytes
  • hemosiderin pigmentation in the spleen
  • increase in hematopoiesis
  • etc.

54
Toxicity scale of Intensity
  • Intensity scale basis of the number of effects
    indicative of toxicity
  • strong
  • medium
  • weak
  • non

55
Toxicity scale of Intensity
  • Example determining LOEL of N-ethylaniline
  • Test doses - 0, 5, 25, 125 mg/kg/day
  • Decrease in RBC only has been observed at 5 mg/kg
  • Decrease in RBC, Hb and HTCat 25 and 125 mg/kg
  • Hence, LOEL for hemolysis is 5mg/kg/day

56
Comparison of the intensities of anemia for 14
aromatic amines
Anemia findings ? 0, ? 1, 2, ? gt3 RBC?,
Hb?, HTC?, GPT ? Reticulocytes? hemosiderin
pigmentation in the spleen hematopoiesis? etc.
57
Relationships between NOEL for anemia and logKow
for 14 aromatic amines
NOELs for anemia RBC?, Hb?, HTC? Reticulocytes? h
emosiderin pigmentation in the
spleen hematopoiesis? etc.
Water soluble anilines (logKowlt0 ) have NO EFFECT
58
Relationships between LOEL for anemia and logKow
for 14 aromatic amines
Water soluble anilines (logKowlt0 ) have NO EFFECT
LOELs for anemia RBC?, Hb?, HTC? Reticulocytes? h
emosiderin pigmentation in the
spleen hematopoiesis? etc.
59
Mechanism underlying the toxic effects exerted by
anilines
Met Hb
Hb
Mechanism 1
CYP450 in the Liver
Adducts with DNA, Blood proteins Hb, Alb
Glucuronide and sulfate conjugation
Mechanism 2
Urine
These mechanisms of initiating reactions will be
used to develop toxicological mechanism based
categories
60
Relationships between LOEL for anemia and logKow
for 14 aromatic amines
LOELs for anemia RBC?, Hb?, HTC? Reticulocytes? h
emosiderin pigmentation in the
spleen hematopoiesis? etc.
Mechanism 2
Mechanism 1
61
Validation of Mechanism 1
Hemoglobin binding index (HBI)
HBI (mmole compound/mole Hb)/(mmole compound/kg
body weight)
E
Nitrenium ion
HBI f (?E)
?E
Reaction pathway
Sabbioni, Environ. Health Perspect. 102 (1994)
61-67.
62
Validation of Mechanism 1
Calculated HBI (?E eV) vs. change in RBC in
RDT test
63
Validation of Mechanism 1
in vitro, female rat liver R. Kato et al., Jpn.
J. Pharmacol., 19 (1969) 53 62

Rats 90 days lt150 mg/kg/day No Hemolysis Findings
Johnnsen et al., Toxicol. Lett., 30 (1986) 1-6.
Rats 28 days gt5 mg/kg/day Hemolysis (Japanese
CSCL)
Rats 28 days gt6 mg/kg/day Hemolysis (EU Risk
Assessment Report)
Repeated Dose Toxicity Test
Metabolite of N-methylanilines
64
Validation of Mechanism 1
Using HBI of the metabolite(Aniline)
65
Categorization of Anilines
  • Based on their effects on two organs
  • Blood
  • Kidney

66
Comparison of the effect on the kidney for 14
aromatic amines
Effect on the kidney ? Nothing ? Weak (Kidney
wt?) Medium (Other) ? Strong (Necrosis)
67
Relationships between LOEL for the kidney and
logKow for 14 aromatic amines
LOELs for the kidney
Different effect of the chemical as compared with
the anemia. This will be related with interaction
mechanism
68
Mechanism underlying the toxic effects exerted by
anilines
Met Hb
Hb
Adducts with DNA, Blood proteins Hb, Alb
CYP450 in the Liver
Glucuronide and sulfate conjugation
Urine
Mechanism 2
Mechanism underlying the toxic effects exerted by
anilines on kidney
69
Effect initiating mechanism
RDT Effect on the kidney
gt
Kidney, wt ? (720)
Basophilic tubule, proximal (100, 500) Necrosis,
Tubular epithelium, proximal (500)

binding with the SH proteins
70
Category building based on the link between
chemical and toxicological mechanisms
71
Category Building
Based on the link between chemical and
toxicological mechanisms
Category 1. Water soluble aromatic amines
logKow 0 no effect
Category 2. If 0ltlogKow 1 it is eliminated by
mechanism 2 and as parent or metabolite has
alerting groups interacting with
  • Proteins (such as quinone imines Mechanisms 2)
    strong kidney toxicity and weak blood toxicity
    (Category 2a)
  • DNA or blood proteins (Mechanisms 1) week
    blood toxicity (Category 2b)

72
Category Building
Based on the link between chemical and
toxicological mechanisms
Category 3. If logKow gt 1 and as parent or
metabolite has alerting groups interacting with
  • Proteins (Mechanisms 2) week kidney toxicity
    (Category 3a)
  • DNA (Mechanisms 1) strong blood toxicity
    (Category 3b)

73
Chemical
LogKowlt0
74
Chemical
LogKowlt0
Yes
No toxic effect
75
Chemical
LogKowlt0
No
Yes
No toxic effect
76
Chemical
LogKowlt0
No
Yes
Yes
Parent or metabolites have or form protein
binding alert
No toxic effect
77
Chemical
LogKowlt0
No
Yes
Yes
Parent or metabolites have or form protein
binding alert
No toxic effect
Yes
Strong kidney toxicity
78
Chemical
LogKowlt0
No
Yes
Yes
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Yes
Strong kidney toxicity
79
Chemical
LogKowlt0
No
Yes
Yes
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Yes
Strong kidney toxicity
Parent or metabolites have or form DNA binding
alert
80
Chemical
LogKowlt0
No
Yes
Yes
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Yes
Strong kidney toxicity
Parent or metabolites have or form DNA binding
alert
Yes
81
Chemical
LogKowlt0
No
Yes
Yes
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Yes
Strong kidney toxicity
Parent or metabolites have or form DNA binding
alert
No
Yes
82
Chemical
Parent or metabolites have or form protein
binding alert
LogKowlt0
No
No
Yes
Yes
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Yes
Strong kidney toxicity
Parent or metabolites have or form DNA binding
alert
No
Yes
83
Chemical
Parent or metabolites have or form protein
binding alert
LogKowlt0
No
No
Yes
Yes
Yes
Week kidney toxicity
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Yes
Strong kidney toxicity
Parent or metabolites have or form DNA binding
alert
No
Yes
84
Chemical
Parent or metabolites have or form protein
binding alert
LogKowlt0
No
No
No
Yes
Yes
Yes
Week kidney toxicity
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Yes
Strong kidney toxicity
Parent or metabolites have or form DNA binding
alert
No
Yes
85
Chemical
Parent or metabolites have or form protein
binding alert
LogKowlt0
No
No
No
Yes
Yes
Yes
Week kidney toxicity
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Parent or metabolites have or form alert
interacting with DNA
Yes
Strong kidney toxicity
Parent or metabolites have or form DNA binding
alert
No
Yes
86
Chemical
Parent or metabolites have or form protein
binding alert
LogKowlt0
No
No
No
Yes
Yes
Yes
Week kidney toxicity
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Parent or metabolites have or form alert
interacting with DNA
Yes
Strong kidney toxicity
Yes
Parent or metabolites have or form DNA binding
alert
No
Yes
87
Chemical
Parent or metabolites have or form protein
binding alert
LogKowlt0
No
No
No
Yes
Yes
Yes
Week kidney toxicity
Parent or metabolites have or form protein
binding alert
No toxic effect
No
Parent or metabolites have or form alert
interacting with DNA
No
Yes
Strong kidney toxicity
Yes
Parent or metabolites have or form DNA binding
alert
No
Yes
88
New Pilot Functionalities in Toolbox
Demonstrated by using RDT database, Fraunhover
ITEM, Hanover, Germany
89
Input chemical
90
Chemical category based on molecular initiating
event
91
Measured RDT and Genotoxicity data are extracted
from the OASIS genotox and RDT databases
92
OECD Toolbox
Endpoint
RDT Structure
Route
Organ/System
Species
NOEL
dermal
drinking water
feed
gavage
inhalation
oral unspecified
LOEL
rat
mouse
immune system
intestine
kidney
larynx
liver
lung
lymph node
mammary gland
nervous system
Effect/Tissue
weight decreased
weight increased
cell proliferation
changed enzyme activity
degeneration
inflammation
metaplasia
Specification
Alanine aminotransferase
Alkaline phosphatase
Lactate dehydrogenase
93
OECD Toolbox
New Filtering Functionality
Author(s) Title Source Date
Dermal Drinking water Feed Gavage
Filtering
Reference Study Endpoint Route Bioassay
(Species) Gender Exposure duration Organ/Tiss
ue Effect Study information Supplemental
Information
Rat Mouse
Immune system Intestine Kidney
Weight decreased Weight increased Cell
proliferation
Strain Study sex Effect sex Study duration,
days Study duration, categories Post
exposure Reliability
Items not in SIDS tree
94
Target endpoint LOEL, feed, rat
Damaged organs and effects are unknown before
chemical mechanism based categorization
95
Chemical grouping based on initiating molecular
reaction
96
Target endpoint LOEL, feed, rat
Damaged organs and effects should be defined
based on chemical mechanism based categorization
97
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Subcategorization based on chemical interaction
mechanisms and/or structure based similarity
99
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100
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101
Subcategorization based on toxicological
mechanisms resulting from underlying chemical
interaction mechanisms
102
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103
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104
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105
Missing information on organs expected to be
damaged as a result of initiating reaction
106
Missing information on effects expected on
damaged organs as a result of initiating reaction
107
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109
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110
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113
Assumed Toxicological Pathway
Aromatic Amines
Binding with DNA
Tumour formation in liver
Chemical Mechanisms
Toxicological Mechanisms
114
Defining toxicological pathway and building the
mechanism data base is critical for the Toolbox
project
Chemical Mechanisms
Toxicological Mechanisms
115
Grouping by Chemical Mechanisms
Grouping by Toxicological Mechanisms
Toxicological categorization
Chemical categorization
Predicted toxicological outcome for the target
chemical
Predicted initiating reactions for the target
chemical
116
Outline
  • Conceptual framework of QSAR
  • Categorization and QSAR
  • Predicting human health endpoints in Toolbox
  • Molecular initiating events and toxicological
    pathways
  • Case study with 28d RDT
  • Mechanism database in Toolbox

117
The Mechanism Database in the Toolbox Project
118
System biology
Symptomology
Chemistry/Biochemistry
119
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body
Molecular Level
Cell Level
120
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body
Cell Level
Molecular Level
Search / Collection of in vitro Test Information
121
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body
Cell Level
Molecular Level
Search / Collection of in vitro Test Information
  • Functions
  • Pathways
  • Processes

122
Chemistry/Biochemistry
System biology
Symptomology
Tissue, Organ and Body
Cell Level
Molecular Level
Search / Collection of in vitro Test Information
  • Functions
  • Pathways
  • Processes

Receptor 1 Receptor 2 Receptor 3 Receptor
4 ...
System 1 System 2 System 3 System 4 ...
Effect 1 Effect 2 Effect 3 Effect 4 ...
123
Chemistry/Biochemistry
System biology
Symptomology
Tissue, Organ and Body
Cell Level
Molecular Level
Search / Collection of in vitro Test Information
  • Functions
  • Pathways
  • Processes

Receptor 1 Receptor 2 Receptor 3 Receptor
4 ...
System 1 System 2 System 3 System 4 ...
Effect 1 Effect 2 Effect 3 Effect 4 ...
(Q)SAR
Categorization
124
Chemistry/Biochemistry
System biology
Symptomology
Tissue, Organ and Body
Cell Level
Molecular Level
Search / Collection of in vitro Test Information
  • Functions
  • Pathways
  • Processes

Receptor 1 Receptor 2 Receptor 3 Receptor
4 ...
System 1 System 2 System 3 System 4 ...
Effect 1 Effect 2 Effect 3 Effect 4 ...
(Q)SAR
Categorization
Chemical Mechanism Database
125
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body
Cell Level
Molecular Level
Search / Collection of in vitro Test Information
  • Functions
  • Pathways
  • Processes

Expert observation
Tissue Organ Body
Receptor 1 Receptor 2 Receptor 3 Receptor
4 ...
System 1 System 2 System 3 System 4 ...
Effect 1 Effect 2 Effect 3 Effect 4 ...
(Q)SAR
Response
Categorization
Chemical Mechanism Database
126
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body
Cell Level
Molecular Level
Search / Collection of in vitro Test Information
  • Functions
  • Pathways
  • Processes

Expert observation
Tissue Organ Body
Receptor 1 Receptor 2 Receptor 3 Receptor
4 ...
System 1 System 2 System 3 System 4 ...
Effect 1 Effect 2 Effect 3 Effect 4 ...
(Q)SAR
Response
Categorization
Toxicological Mechanism Database
Chemical Mechanism Database
127
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body
Cell Level
Molecular Level
Search / Collection of in vitro Test Information
  • Functions
  • Pathways
  • Processes

Expert observation
Tissue Organ Body
Receptor 1 Receptor 2 Receptor 3 Receptor
4 ...
System 1 System 2 System 3 System 4 ...
Effect 1 Effect 2 Effect 3 Effect 4 ...
(Q)SAR
Response
Categorization
Mechanism Knowledge Database
128
System biology
Symptomology
Chemistry/Biochemistry
Tissue, Organ and Body
Cell Level
Molecular Level
Search / Collection of in vitro Test Information
  • Functions
  • Pathways
  • Processes

Expert observation
Tissue Organ Body
Receptor 1 Receptor 2 Receptor 3 Receptor
4 ...
System 1 System 2 System 3 System 4 ...
Effect 1 Effect 2 Effect 3 Effect 4 ...
(Q)SAR
Response
Categorization
Mechanism Knowledge Database (Toxicological
pathways)
129
Contributors
130
Laboratory of mathematical Chemistry, Bourgas,
Bulgaria
O. Mekenyan S. Dimitrov T. Pavlov G. Chankov A.
Chapkanov
131
Chemical Management Center, NITE, Japan Case
study on RDT of aromatic amines Chemical vs.
toxicological mechanisms (Project of NEDO Japan)
Jun Yamada Yuki Sakuratani
132
Fraunhofer Institute for Toxicology and
Experimental Medicine, Department Chemical Risk
Assessment, Hanover, Germany Data from REPDOSE
Database (Project of CEFIC LRI) Inge
Mangelsdorf Sylvia Escher Annette Bitsch
133
Environment Directorate, OECD, Paris Bob
Diderich Terry Schultz
134
International QSAR Foundation, USA Gilman
Veith
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