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Hazard
identification

In vivo animal experiments


Endpoint assays (mortality)
Epidemiological studies
Environmental monitoring

Chemical characterization
Toxicity pathway identification
Some targeted animal testing
Population context

Dose-response
assessment

Extrapolation of in vivo
animal results to humans

Modeling based on a battery


of in vitro assays, systems
biology and reverse
toxicokinetics

Exposure
assessment

Receptors
Pathways of exposure
Concentration, duration
Internal dose

Population data
Exposure data (biomonitoring
and personal exposure
monitoring)

Risk
characterization

Quantitative risk
assessment models

Biologically relevant health


risk assessment

Emerging Technologies

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Chemical
Characterization

Hazard Identification

Toxicity Profiling

Cluster Analysis
Cell Population
Kinetics

Risk
Characterization

Mode of Action

Population
Exposure

PLOT OF EC EFFICIENCY BY EC ADOPTATION BY EC RATE


cluster: CLUSTER ONE
CLUSTER TWO
CLUSTER THREE
CLUSTER FOUR
CLUSTER FIVE
CLUSTER SIX
CLUSTER SEVEN

EC Efficiency
2.34

0.99

-0.36

-1.71

Mutagenicity
Assay

-3.05

-4.99

-4.40
9.69

-2.32
6.48

0.35
3.26

EC RATE

3.03

0.05

EC Adoptation

5.70

-3.16
-6.38 8.37

Reverse
Toxicokinetics

Mean Graph
Mean Graph For
CytochalasinB

Chemicals
VSMC

SKNS

HEPG

BEAS

Dose-Response

ARPE

A549

Cytochalasin B - VSMC
-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

150
24 hr
48 hr
72 hr
96 hr

100

50

Toxic Effect

In Vitro Dose

GHS Classification

In Vivo LD50
LD50 (mmol/kg) vs KC50 (mM)_geomean in 6 Human Cell Lines

-50
2

-100

-150
-4

-3

-2

-1

Log10 concentration (uM)

log LD50 Rat (mmol/kg)

Metabolites

HTS Cell
Panel

Exposure
Standards;
Health Risk
Assessment

-2

-4

Specialized
Assays

-6
-10

-8

-6

-4

-2

log KC50 (mM)_geomean


logLD50 (mmol/kg) = 0.560xlogKC50 + 0.155
regression line (r = 0.86, r2 = 0.74)
RC(12) Prediction Line (r =0.87, r2 = 0.77)
Log-5 (RC12)
Log +5 (RC12)
RC(282) Prediction line (r = 0.67, r2 = 0.45)

Bioinformatics

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1. Human exposure standards


2. Prediction of in vivo starting doses
3. GHS Classification of chemicals

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Cytochalasin B - VSMC
150
24 hr
48 hr
72 hr
96 hr

100

Toxic Effect

50

-50

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PLOT OF EC EFFICIENCY BY EC ADOPTATION BY EC RATE
cluster: CLUSTER ONE
CLUSTER TWO
CLUSTER THREE
CLUSTER FOUR
CLUSTER FIVE
CLUSTER SIX
CLUSTER SEVEN

EC Efficiency
2.34

0.99

-0.36

-1.71

-3.05

-4.99

-4.40
9.69

-2.32
6.48

0.35
3.26

EC RATE

3.03

0.05

5.70

-3.16
-6.38 8.37

EC Adoptation


 %)' +&
Mean
Me
an Graph
Gra
raph
p For
ph
For
CytochalasinB

Mean
Me
an Graph
Gra
raph
p For
ph
For
CytochalasinD

VSMC
VSMC

VSMC

SKNS
SKNS

SKNS

H
EPG
HEPG

HEPG

B
EAS
BEAS

BEAS

ARPE
ARPE

ARPE

A549

A549

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

-0.8

-0.6

-0.4

Mean Graph For


LatrunculinA

VSMC

SKNS
SKNS

SKNS

HEPG
HEPG

HEPG

B
EAS
BEAS

BEAS

ARPE
A
RPE

ARPE

A549

A549

-2.0

-1.5

-1.0

-0.5

0.0

0.0

0.2

0.4

0.6

0.5

1.0

1.5

Mean Graph For


LatrunculinB

VSMC
VSMC

-2.5

-0.2

0.5

1.0

1.5

-2.0

-1.5

-1.0

-0.5

0.0

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Slope Intercept

RTCA
Dose
Finding

RTCA
RTCA
Definitive Definitive

Measure

IC50

IC50

KC50

KC50

KC50

Cell Line

HNK

9 Human
Geomean

ACHN

HepG2

Chemical

347

51

12

12

12

40%

29%

50%

42%

36%

Over-predicted

34%

40%

50%

50%

46%

Under-predicted

26%

31%

0%

8%

9%

0.68

0.64
0.91(*

0.84

0.69

RC (374) 0.435

0.625

Correlation with LD50


values ( r )
JIACHN

RC-IC NRU

0.67

r = 0.91, HepG2 r = 0.64

) + &%&  C?


LD50 ((mmol/kg)
mmol
ol/k
l/kg)) vs
vs KC50 ((mM)_geomean
mM)
mM
M)_ge
geom
ge
omea
om
ean
ea
n in
in 6 Human
Hum
uman
an Cell
Cel
ellll Lines
Line
Li
ness
ne
4

LD50

log L
log
LD50 Rat (mmol/kg)
mmol
ol/k
l/kg))

-2

-4

-6
-10

-8

-6

-4

-2

log KC50 (mM)_geomean


logLD50 (mmol/kg) = 0.560xlogKC50 + 0.155
regression line (r = 0.86, r2 = 0.74)
RC(12) Prediction Line (r =0.87, r2 = 0.77)
Log-5 (RC12)
Log +5 (RC12)
RC(282) Prediction line (r = 0.67, r2 = 0.45)

* % 
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Molecular
initiating
event

Receptor binding
Ligands
Protein adducts
DNA adducts

Organelle
responses

Cellular
effects
Systems
biology

Injury
Stress
Gene activation
Apoptosis
Protein production
Autophagy
Signaling
Necrosis
Transformation

Gene mutation
Ligand binding
Reporter gene
Enzyme activity
Gene expression
Co-activators
Biomarkers
Chemical x-actions

Biochemical assayss Molecular assayss

Cytotoxicity
Flow cytometry
Imaging

Cellular assays

Point of
departure
concentration
in vitro

Acceptable
concentration
in vitro
(g/l)

Reverse
toxicokinetics

In vivo human
exposure
standard
(mg/kg/day)

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