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Eugene DemchukAgency for Toxic Substances and Disease Registry
Frederick, MD - 08/25/2011
Chemical Toxicity Databases at NCEH/ATSDR
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Topics
• EH Portfolio external dose
• NHANES internal dose
• Doch/QSAR: the QSAR Database Of Consistent Health guidance values
~ 60,000,00
0syntheticchemicals
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Environmental Pollutants
3,000 – 4,000
Information about a Chemical200,000
records inEH Portfolio
Chemicals
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EH PortfolioATSDR’s Integrated Knowledge Base
Former
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Hazardous Waste Sites
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EH Portfolio System Interfaces
EH Portfolio
MISB Personnel (MS SQL Server)
MISB UFMS(MS SQL server)
UFMS (unix)
GIS
EPA
TopHat
GIS Mapping
CERCLISLOAD
Mapping Interface(proposed)
Data out via WebService(requested)
Demographics batch
sftp
UFMS process
Data downloadData download
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Site / Event
Comparison Values
Health Studies
SubstancePublications
Cost Recovery
ASA
Abstracts
Toll Free
Health Education
Contaminants
EH Portfolio Relationships Diagram
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ATSDR Functions Supported
EH Portfolio was deemed Critical or Significant to the following ATSDR Functions:
• Liaison Function (Washington Office)• Budget Development and Justification (Washington Office)• State Cooperative Agreement Project Management (DHAC)• ATSDR Internal and External Technical Support (DHAC)• Development of CERCLA Hazardous Substances Priority List• Development of Toxicological Profiles• Development of Research Data Needs• Mixtures Research• Dissemination of Information
* Indicates Congressionally Mandated Function
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log LOAELs Categorized by Source
oral data from Doch/QSAR
-8.0
-6.0
-4.0
-2.0
0.0
2.0lo
g(L
OA
EL
)
IRIS OPP ATSDR Others
Count 85 13 70 12
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National Health and Nutrition Examination
Survey (NHANES)
• NHANES IV survey conducted during 1981-2008 by NCHS • Cross-sectional survey designed by NCHS• Multi-stage probability sampling design that includes 49 pseudo geographic
strata and two Primary Sampling Unit (PSU)
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MEC of the NCHS
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CDC measures more than 300 environmental chemicals
in blood and urine (biomonitoring)
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Doch/QSARthe QSAR Database of
consistent health guidance values (HGVs)
Need: because of large uncertainty error bar on empirical tox data, the data for CQDB have to be carefully selected and classified to avoid possible internal contradictions
• Components
• Intended for cross-chemical extrapolation
Oral Ingestion
Inhalation
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Is it possible to extrapolate
from a small number of chemicals?
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Power Analysis
Number of Points in the Training Set
R2 ALL data
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Criteria and Data Evaluation
• Eliminate developmental toxicity• Select most recent assessment• Chronic studies preferred over intermediate studies
Primary Data SourcesATSDR and IRIS
Multiple HGVs
RfD, Chronic MRL, Intermediate MRL
No HGV
EPA-OPP, IPCS-CICADS, Health Canada, RIVM,
U.S. Army
Consistent HGV
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What impacts power?
• Quantity• Uniformity/quality
of the data
Target Organ
Critical effect
Mode of action
Mechanism of action
Gene/enzyme
Binding site
N
0.0
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LOAEL ~ Species
Decreasing of LOAELs with increasing body weight of tested species.
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0
100
200
300
400
500
600
700
362
157
6219 26
Other species
Human
Mouse
Dog
Rat
Nu
mb
er
of
ch
em
icals
0
100
200
300
400
500
600
700
308
159
8551
19LEL
BMDL
LOAEL
NOEL
NOAEL
Nu
mb
er
of
ch
em
icals
Oral data in Doch/QSAR
POD SpeciesData source
627 data records for 499 unique chemicals
329 Chronic 186 Intermediate 112 Others(289 unique chem.) (178 unique chem.)
0
100
200
300
400
500
600
700
315
127
160
22Other Source
ATSDR
OPP
IRIS
Nu
mb
er
of
ch
em
icals
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Rat oral chronic LOAELs
All oral chronic LOAELs
300400200456
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Rat oral chronic LOAELs
All oral chronic LOAELs
300400200456
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Current ATSDR oral LOAEL modelMethod used: Partial Least Squares Regression
Number of compounds: 100Response variable: log LOAEL [mmol/kg]Final predictors used: 53Number of PLS factors: 10Cross-validation: 20-fold
Cross-validated Q-Square
RSS PRESS
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0 5 10 15 20 25 30 35 400
500
1000
1500
2000
2500
3000
3500
Estimated Rat Chronic LOAEL (mg/kg)
Polynomial (Es-timated Rat Chronic LOAEL (mg/kg) )
TOPKAT Est. Rat Chronic LOAEL (mg/kg)
Linear (TOPKAT Est. Rat Chronic LOAEL (mg/kg))
Number of Carbon Atoms
Esti
mate
d R
at
Ora
l C
hro
nic
LO
AEL
(mg/k
g)
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Validationby bioavailability of ingested aliphatic hydrocarbons
“Studies in rats show that absorption of ingested aliphatic hydrocarbons is inversely related to molecular weight, ranging from complete absorption at the lower end of the molecular weight range to about 60% for C14 hydrocarbons, 5% for C28 hydrocarbons, and essentially no absorption for aliphatic hydrocarbons with >32 carbons”
Toxicological Profile for Total Petroleum Hydrocarbons, ATSDR, 1999
ATSDR HGV/ LOAEL model shaped similar to mouse LDlo/LD50 experimental data
2814
60% for C14 5% for C28 absorption for no>32
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Comparison to MRDD modelfrom ACD/Labs
0 5 10 15 20 25 30 35 40 45 500
50
100
150
200
250
No. of Carbon
MR
DD
(m
g/K
g/d
ay)
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Current ATSDR Inhalation model
(AEGL-1, 8 Hour) Apply the
model to: training data
(blue) external data
(red)
The model was trained with 121 compounds and processed 12 of 13 compounds in the external validation set
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Current ATSDR Inhalation model
(AEGL-2, 8 Hour) Apply the
model to: training data
(blue) external data
(red)
The model was trained with 176 compounds and processed 18 of 19 compounds in the external validation set
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Current ATSDR Inhalation model
(AEGL-3, 8 Hour) Apply the
model to: training data
(blue) external data
(red)
The model was trained with 175 compounds and processed 14 of 19 compounds in the external validation set
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Message
• You were shown several databases that are developed at CDC/NCEH/ATSDR
• One of them, Doch/QSAR consists of carefully selected high-quality toxicity data
• These data can be used for toxicological cross-chemical extrapolations
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DisclaimerThe findings and conclusions in this presentation have not been formally disseminated by the Agency for Toxic Substances and Disease Registry and should not be construed to representany agency determination or policy.
