Sandy Raimondo Mace G. Barron Office of Research and Development/NHEERL Gulf Ecology Division 2...
-
Upload
gilbert-jenkins -
Category
Documents
-
view
217 -
download
0
Transcript of Sandy Raimondo Mace G. Barron Office of Research and Development/NHEERL Gulf Ecology Division 2...
Sandy RaimondoMace G. Barron
Office of Research and Development/NHEERLGulf Ecology Division
2 November 2005
Development and Improvement Development and Improvement of ICE/ACE of ICE/ACE
for Predictive Toxicologyfor Predictive Toxicology
OverviewOverview
• Background: ICE/ACE development
• Current Research: ICE/ACE Validation and Improvement
ICE and ACE Software DevelopmentICE and ACE Software Development
Developed by Sonny Mayer (GED) and Colleagues
ICE (Interspecies Correlation Estimation)
Estimates acute toxicity for a species, genus or family from a surrogate species
ACE (Acute to Chronic Estimation)
Estimates chronic toxicity from raw acute toxicity data
Significance:
• Addresses second largest source of variation in toxicity data – variation of species within a chemical
• Fills data gaps by estimating toxicity of untested species
ICE: Interspecies Correlation Estimations
How ICE worksHow ICE works
LC50: concentration that
kills 50% of organisms
LD50: dose that kills 50%
Uses existing correlations of toxicity values (LC50, LD50) between a surrogate species and a predicted taxa (species, genus, or family)
Acute toxicity estimates using Acute toxicity estimates using interspecies correlationsinterspecies correlations
1.0 2.0 3.0 4.0
1.0
2.0
3.0
Rainbow Trout (log 96-h LC50)
Cap
e F
ear
shin
er (
log
96-
h L
C50
)
X = -0.025 + 1.098Xr = 0.991
2 1
1.0 2.0 3.0 4.0
1.0
2.0
3.0
Rainbow Trout (log 96-h LC50)
Cap
e F
ear
shin
er (
log
96-
h L
C50
)
X = -0.025 + 1.098Xr = 0.991
2 1
ICE estimates LC50 from surrogate species LC50 and available species correlation
Current ICE Uses: EPA Program Offices
• Office of Water (OW): draft Ambient Water Quality Criteria (AWQC) guidelines, endangered species
• Office of Pesticide Programs (OPP): qualitative use in risk assessment currently being implemented.
Ecological Risk Assessment (ERA)• Generate species sensitivity distribution• Define risk management level
Endangered Species Risk Assessment• Surrogate test species are toxicologically
representative of endangered species (Mayer et al.)• ICE can be used to estimate toxicity to T&E species
using existing correlations (147 LC50s; 20 species)
ICE: Applications
Provides estimated chronic toxicity for species with only acute data
ACE: Acute to Chronic Estimations
Significance:
Acute: ie.96-hour LC50/ LD50
Chronic: long-term, sublethal
• Reduced reliance on acute to chronic ratios based on multiple species and chemicals
• Being considered by OPP for qualitative use in risk assessment
ACE: Acute to Chronic Estimations
Application:
How ACE Works
ACE Chronic Mortality PredictionACE Chronic Mortality Prediction
a=NOEC
0.010 0.021 0.0421/tim e (h)
10
8.0
6.0
4.0
2.0
Lo
gN
OE
C(µ
g/L
)at
each
tim
ep
erio
d
a=NOEC
0.010 0.021 0.0421/tim e (h)
10
8.0
6.0
4.0
2.0
Lo
gN
OE
C(µ
g/L
)at
each
tim
ep
erio
d
a=NOEC
0.010 0.021 0.0421/tim e (h)
10
8.0
6.0
4.0
2.0
Lo
gN
OE
C(µ
g/L
)at
each
tim
ep
erio
d
10
8
6
4
2
00.140
12.01.0
0.080.06DOSE
(ug/L)TIM E (DAY)
EXTRA RESPONSE
(% )
0.040.02
0.0 020
4060
80100
Linear Regression Analysis (LRA)
Accelerated Life Testing (ALT)
Uses raw survival data to estimate chronic mortality
Limitations of ICE and ACE
• validation and uncertainty (ICE, ACE)
• data poor (e.g., ICE wildlife)
• flexibility-power (ICE)
Expand Datasets(QA/QC)
New Software
ICE
Validation, Refinement, Expansion
ACE
Validation
Improved Tool Functionality
Future Direction of ICE/ACE
1. Model Validation: Regression analysis
2. Model Refinement: Stepwise regression
3. Model Expansion: Power and number of models
4. QA/QC: Bootstrap validation
5. Defining Assumptions / Developing user guidelines: multivariate analyses
6. New Software
ICE Improvement Procedure
ICE Improvement Procedure
1. Model Validation: Assessment of existing significant correlations
Aquatic ICE models (P<0.01)• Species: 565• Genus: 195• Family: 291
Validation dataset for aquaticsAmbient Water Quality Criteria (AWQC) data
• 88 chemicals (12 pesticides)• 279 species• 1458 new data points
ICE Validation ExampleRainbow Trout Surrogate - Pesticides only
R2 = 0.95
-2
-1
0
1
2
3
4
5
6
-1 0 1 2 3 4 5
Log10 ICE predicted LC50
Lo
g1
0 A
ctu
al L
C5
0
< 3x difference
> 3x difference
2. Model Refinement
Stepwise Regression• Finds the best fit model• Quality of data• Power of model• Mode of action
Model improvement through reduction (filter by MOA, species, data quality)
Rainbow Trout Surrogate - Pesticides only
R2 = 0.95
-2
-1
0
1
2
3
4
5
6
-1 0 1 2 3 4 5
Log10 ICE predicted LC50
Lo
g1
0 A
ctu
al L
C5
0
ICE Improvement Procedure
3. Model ExpansionIncrease power of the models
• Many existing models have N=3• More data increases likelihood of significant correlations
Increase the number of significant correlations
ICE Wildlife Correlations (P ≤ 0.01)
Original Current
62 152
ICE Improvement Procedure
Model improvement through addition (species, chemical)
ICE Improvement Procedure
4. QA/QC of all refined and improved modelsBootstrap validation of all improved models
Rainbow Trout Surrogate - Pesticides only
R2 = 0.95
-2
-1
0
1
2
3
4
5
6
-1 0 1 2 3 4 5
Log10 ICE predicted LC50
Lo
g1
0 A
ctu
al L
C5
0
• data points are randomly removed
• model is recreated• removed data are used
to validate model• up to 1000 replicates
Multivariate Analysis• mode of action• chemical class• species• life history
• model fit (yes or no)• degrees of freedom• model R2, p-value
Rainbow Trout Surrogate - Pesticides only
R2 = 0.95
-2
-1
0
1
2
3
4
5
6
-1 0 1 2 3 4 5
Log10 ICE predicted LC50
Lo
g1
0 A
ctu
al L
C5
0
User Guidance
ICE Improvement Procedure
6. Updated Software (2007)
Selectable datasets
Interactive program
user can enter in new dataset for species not in ICE (ie. endangered species) and ICE will build predictive model based on internal data
Broader applicability
Wider user base
ICE Improvement Procedure
ACE Validation and User Guidance
Validate using expanded dataset• Original validation used 30 fish acute: chronic data pairs• Expanded validation dataset
>150 datasets
Define where models are robust• MOA• Chemical Classes• Species
Develop new user guidance• Multivariate Analyses• Improve value to user
R2 = 0.95
-2
-1
0
1
2
3
4
5
-4 -2 0 2 4 6
Log10 ACE ALT
Log1
0 S
urvi
val M
AT
C
< 5x difference
> 5x difference
• Manuscript: Wildlife Toxicity Estimation• Manuscript: Validation of ICE• Manuscript: Validation of ACE• Technology transfer
2007: Updated ICE Software
2006 Anticipated Products & Outcomes: