Post on 11-May-2022
November 20, 2015
A Systems Approach to Exposure Modeling
(ExpoCast)John Wambaugh
National Center for Computational ToxicologyOffice of Research and Development
U.S. Environmental Protection Agency
FutureTox III: Bridges for TranslationArlington, Virginia
The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. EPA
ORCID: 0000-0002-4024-534X
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Introduction
• The timely characterization of the human and ecological risk posed by thousands of existing and emerging commercial chemicals is a critical challenge
• High throughput risk prioritization relies on three components:
1. high throughput hazard characterization2. high throughput exposure forecasts3. high throughput toxicocokinetics (i.e.,
dosimetry)• While advances have been made in HT toxicity
screening, exposure methods applicable to 1000s of chemicals are needed
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Scale of the Problem
Endocrine Disruptor Screening Program (EDSP) Chemical List
Number ofCompounds
Conventional Active Ingredients 838
Antimicrobial Active Ingredients 324
Biological Pesticide Active Ingredients 287
Non Food Use Inert Ingredients 2,211
Food Use Inert Ingredients 1,536
Fragrances used as Inert Ingredients 1,529
Safe Drinking Water Act Chemicals 3,616
TOTAL 10,341
EDSP Chemical Universe10,000
chemicals(FIFRA & SDWA)
EDSP List 2 (2013)
107Chemicals
EDSP List 1 (2009)
67 Chemicals
So far 67 chemicals have completed testing and an additional 107 are being tested
December, 2014 Panel: “Scientific Issues Associated with Integrated Endocrine Bioactivity and Exposure-Based Prioritization and Screening“ DOCKET NUMBER: EPA–HQ–OPP–2014–0614
• Park et al. (2012): At least 3221 chemicals in humans, many appear to be exogenous
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Concentration
Resp
onse
In vitro Assay AC50
Concentration (µM)
Assay AC50with Uncertainty
High-Throughput Bioactivity
Tox21: Examining >10,000 chemicals using ~50 assays intended to identify interactions with biological pathways (Schmidt, 2009)
ToxCast: For a subset (>1000) of Tox21 chemicals ran >500 additional assays (Judson et al., 2010)
Most assays conducted in dose-response format (identify 50% activity concentration –AC50 – and efficacy if data described by a Hill function)
All data is public: http://actor.epa.gov/
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High-Throughput Toxicokinetics
https://cran.r-project.org/web/packages/httk/Can access from the R GUI: “Packages” then “Install Packages”
“httk” R Package543 Chemicals to dateLead programmer Robert PearceWambaugh et al. (2015), Pearce et al. submitted
Inhaled Gas
Qliver
Qgut
Qgut
Kidney Blood
Gut BloodGut Lumen
QGFRKidney Tissue
Liver BloodLiver Tissue
Qrest
Lung BloodLung Tissue Qcardiac
Qmetab
Body Blood
Rest of Body
Qkidney
Arterial BloodVeno
us B
lood
Ora
l Equ
ival
ent D
aily
Dos
e
Steady-state Concentration (µM) = in vitro AC500
MedianPredicted CssLower 95%
Predicted Css
Upper 95%Predicted Css
Open source In Vitro-In Vivo Extrapolation and Physiological-
based Toxicokinetics
CNA
Biota
Neutrallipid
Acidicphospholipid
Proteins
Dust
Sediment
Air
Soil
EnvironmentalPartitioning
BiologicalPartitioning
water vapor
Water
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High Throughput Screening (HTS), High Throughput Toxicokinetics (HTTK), and Exposure
• For non-pesticide chemical space, there is a paucity of data for providing context to HTS data (Egeghy et al. (2012))
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Why “Systems Exposure”?
GENE GENE GENE GENE BIOMOLECULES
PATHWAYS
CELLS
PHENOTYPES
Systems Biology:Interactions on multiple scales integrated into a homeostatic system
see also Pleil and Shelden (2011)
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GENE GENE GENE GENE BIOMOLECULES
PATHWAYS
CELLS
PHENOTYPES
Chemical
Why “Systems Exposure”?
see also Pleil and Shelden (2011)
Systems Toxicology:Chemical perturbations of homeostasis
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Chemical ManufactureConsumer
Products, Articles, Building Materials Environmental
Release
Food Air, Soil, Water
Air, Dust, Surfaces
Near-FieldDirect
Near-Field Indirect
HumanEcological
Flora and Fauna
Dietary Far-Field
Direct Use(e.g., lotion)
Residential Use(e.g. ,flooring)
MONITORINGDATA
RECEPTORS
MEDIA
Biomarkers of Exposure
Biomarkers of Exposure
Media Samples
Ecological
Waste
Figure from Kristin Isaacs
Systems Exposure
see also Pleil and Shelden (2011)
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Chemical ManufactureConsumer
Products, Articles, Building Materials Environmental
Release
Food Air, Soil, Water
Air, Dust, Surfaces
Near-FieldDirect
Near-Field Indirect
HumanEcological
Flora and Fauna
Dietary Far-Field
Direct Use(e.g., lotion)
Residential Use(e.g. ,flooring)
MONITORINGDATA
RECEPTORS
MEDIA
EXPOSURE PATHWAY
(MEDIA + RECEPTOR)
Biomarkers of Exposure
Biomarkers of Exposure
Media Samples
Ecological
Waste
Exposure Pathways
see also Pleil and Shelden (2011) Figure from Kristin Isaacs
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Predicting Systematic Response
Prediction
Obs
erva
tion
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Consensus Exposure Predictions with the SEEM
Framework• Incorporate multiple models into consensus predictions for 1000s of chemicals within
the Systematic Empirical Evaluation of Models (SEEM) framework (Wambaugh et al., 2013, 2014)
• Evaluate/calibrate predictions with available monitoring data across as many chemical classes as possible to allow extrapolation
• Analogous efforts for both human and ecological exposures
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Chemical Use Identifies Relevant Pathways
Predictions with High Throughput Stochastic Human Exposure Dose Simulator (SHEDS-HT) (Isaacs et al., 2014)
>2000 chemicals with Material Safety Data Sheets (MSDS) in CPCPdb (Goldsmith et al., 2014)
105
NHA
NES
Che
mic
als
Chemical ManufactureConsumer
Products, Articles, Building Materials Environmental
Release
Food Air, Soil, WaterAir, Dust, Surfaces
Near-FieldDirect
Near-Field Indirect
HumanEcological
Flora and Fauna
Dietary Far-Field
Direct Use(e.g. lotion)
Residential Use(e.g. flooring)
MONITORINGDATA
RECEPTORS
MEDIA
EXPOSURE PATHWAY
(MEDIA + RECEPTOR)
Biomarkers of Exposure
Biomarkers of Exposure
Media Samples
Ecological
Waste
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Chem
icalsPredicting Chemical
Constituents
Functional use and weight fraction predictions for Tox21 chemical library
Isaacs et al. (submitted)
Unfortunately CPCPdb does not cover every chemical-product combination – using machine learning to fill in the rest
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Analytical Chemistry Methods
At least two methods are typically needed to quantify concentration of ToxCast chemicals• Liquid chromatography (LC) and gas chromatography (GC) mass spectrometry
(MS) Typically would have a calibration curve to relate MS signal to
concentration• HTTK in vitro assays designed to work using only ratios of signal, so no
calibration needed (in theory) Different non-targeted methods have been developed
• Can try to relate everything to signal for known standard chemical concentration
Different machines require different calibrations, but many aspects for a chemical should generalize (e.g., GC vs. LC)• Need to develop a methods database
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Suspect Screening and Non-Targeted Analytical
Chemistry
Mas
s
Retention Time
947 Peaks in an American Health Homes Dust Sample
Each peak corresponds to a mass of a chemical or (depending on technique) fragments of that compound
We are now expanding our identity libraries using reference samples of ToxCast chemicals
Multiple chemicals can have the same fragments or overall mass
Is chemical A present, chemical B, or both?
See poster “Linking High Resolution Mass Spectrometry Data with Exposure and Toxicity Forecasts to Advance High-
Throughput Environmental Monitoring” by Julia Rager
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Exposure Screening Tools for Accelerated Chemical Prioritization (ExpoCast)
Contracts were awarded (December, 2014) to Southwest Research Institute and Battelle
Phase I (Pilot) Examining capabilities and feasibilityAssay Unit Pilot Order Contractor Lead Researcher Lead EPA Post-Docs
High Throughput Screening-Level Physico-Chemical Properties Measurement (VP, pKa, Henry's Law, Kow)
compound 200 Alice Yau (SWRI) Chantel Nicolas and Kamel Mansouri
Determine Chemical Constituents of products, materials, articles (screening level)
test object 20 classes of product, 5 samples each
Alice Yau (SWRI) Katherine Phillips
Determine chemical emission rate from specific products, materials, articles
test object 100 Anne Louise Sumner and Tom Kelly (Battelle)
Chantel Nicolas
Screening for occurrence of large numbers of chemicals in sample acquired by contractor (biological media)
sample 500 blood samples (likely from Indianapolis)
Anne Gregg (Battelle) Caroline Ring
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Pilot 2: Determining Chemical
Constituents Broad screening for ToxCast chemical library compounds in consumer
products. Test objects will consist of five products selected by contractor in each of the following twenty consumer products and article of commerce categories
Research conducted by Southwest Research Institute (Alice Yau)1.Cotton Clothing (new shirt)2.Shampoo3.Toothpaste4. Skin Lotion5. Vinyl upholstery6. Fabric upholstery7. Hand Soap8. Baby Soap
9. Shaving cream10. Lipstick11. Indoor house paint12. Plastic children’s toys13. Glass cleaner14. Air freshener15. Deodorant
16. Shower curtains17. Breakfast cereal18. Carpet19. Carpet Padding20. Sunscreen
GC-MS with DCM Extraction One sample in each
category processed in duplicate
Surrogates and internal standards spiked into each sample
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Log10 (µg/g)
Product Scan withGC-MS
Results from Alice Yau (SWRI)
Com
mon
ly F
ound
Che
mic
als
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Pilot 4: Biomonitoring
Screening for occurrence of large numbers of chemicals in sample acquired by contractor (biological media)
Research Conducted by Battelle Memorial Institute (Anne Gregg) Cohort is a mixed gender and race group of adults from Indianapolis Sample Screening
• One extraction method resulting in two aliquots for analysis• Two analysis methods GCxGC TOFMS and LC-TOFMS
In addition to 200 priority ToxCast chemicals, we will look for NHANES chemicals as reference
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Consensus Exposure Predictions with the SEEM
Framework• Better chemical use data informs models predicting exposure
• Broader monitoring data informs evaluation of those predictions
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ToxCast-derived Receptor Bioactivity Converted to mg/kg/day with HTTK
ExpoCastExposure Predictions
December, 2014 Panel:“Scientific Issues Associated with Integrated Endocrine Bioactivity and Exposure-Based Prioritization and Screening“
DOCKET NUMBER:EPA–HQ–OPP–2014–0614
ToxCast ChemicalsPrioritization as in Wetmore et al. (2012) Bioactivity, Dosimetry, and Exposure Paper
Exposure for High Throughput Risk
Prioritization
Near FieldFar Field
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Life-stage and Demographic Specific Predictions
• Wambaugh et al. (2014) predictions of exposure rate for various demographic groups
• New version of httk R package (Ring et al., in preparation) allows prediction of parameters based on actual NHANES biometrics
Work by Caroline Ring (NCCT)
Change in Risk
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High Throughput Exposure (HTE)
The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. EPA
There are low levels of thousands of xenobiotic chemicals present in the metabolome, relating these to exposures and health effects is an important unsolved problem
Can use a combination of forward modeling and reverse inference from biomarkers of exposure to examine plausible exposures
• Must carefully consider predictive performance with statistical analysis• Predictive performance requires data
Toxicokinetics (TK) provides a bridge between HTS and HTE by predicting tissue concentrations due to exposure
New R package “httk” freely available on CRAN allows statistical and other analyses of 543 chemicals (ToxCast + pharmaceuticals)
NCCTChris GrulkeRichard JudsonDustin KapruanChantel NicolasRobert PearceJames RabinowitzAnn RichardCaroline RingWoody SetzerRusty ThomasJohn WambaughAntony Williams
NERLCraig BarberBrandy BeverlyDerya BiryolKathie Dionisio Peter Egeghy Kim GaetzBrandall IngleKristin IsaacsKatherine PhillipsPaul PriceMark StrynarJon SobusMike Tornero-VelezElin UlrichDan Vallero
*Trainees
**
Chemical Safety for Sustainability (CSS) Rapid Exposure and Dosimetry (RED)
Project
NHEERLJane Ellen SimmonsMarina EvansMike Hughes
Hamner InstitutesHarvey ClewellCory StropeBarbara Wetmore
University of North Carolina, Chapel HillAlex Tropsha
Netherlands Organisation for Applied Scientific Research (TNO)Sieto Bosgra
National Institute for Environmental Health Sciences (NIEHS)Mike DevitoSteve FergusonNisha SipesKyla TaylorKristina Thayer
Chemical Computing GroupRocky Goldsmith
NRMRLYirui LiangXiaoyu Liu
University of MichiganOlivier Jolliet
University of California, DavisDeborah Bennett
Arnot Research and ConsultingJon Arnot
*
Collaborators
Silent Spring InstituteRobin Dodson
*Research Triangle InstituteTimothy Fennell
*
*
*
**
The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. EPA
Battelle Memorial InstituteAnne Louise SumnerAnne Gregg
Southwest Research InstituteAlice YauKristin FavelaSummit ToxicologyLesa Aylward