ORD's Tiered Toxicity Testing Strategy for - PFAS
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ORD’s Tiered Toxicity Testing Strategy for PFAS EPA Executive BOSC Meeting September 29, 2021 Rusty Thomas Director, Center for Computational Toxicology and Exposure Office of Research and Development The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of the U.S. EPA
Quick Review of the State of the Science
• There continues to be an evolving definition of what constitutes a PFAS.
• The EPA needs to evaluate a large number of PFAS for potential human and
ecological effects.
• Most PFAS have limited or no toxicity data.
• There is emerging consensus on the need to use category/grouping-based
approaches to evaluate PFAS for a range of decision contexts.
• In a category/grouping approach, one or more data rich analogs is used to read-
across toxicity values for the remaining data poor substances within the group.
• Historically, for human health assessment within EPA, PFAS analogs and/or groups
were based on a combination of chain-length and functional groups.
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Office of Research
and Development
It Starts With Chemistry… Curating Names,
Structures, and Identifiers
DTXSID Substance_Name Substance Source_Name (incorrect or Source_CASRN Source_Acronym Unique_Acronym
_CASRN ambiguous) (incorrect or (incorrect or
invalid) ambiguous)
DTXSID20874028 2H,2H,3H,3H-Perfl uorooctanoi c a ci d 914637-49-3 5:3 Pol yfl uori na ted a ci d 914637-49-3 5:3 a ci d 5:3 PFOA
DTXSID7027831 N-Methyl -N-(2- 24448-09-7N-Methyl NMeFOSE, MeFOSE NMeFOSE
hydroxyethyl )perfl uorooctanes ul fona mi de perfl uorooctanes ul fona mi deoetha nol
DTXSID10892352 Perfl uoro-2-{[perfl uoro-3-(perfl uoroethoxy)- 749836-20-2
Etha nes ul foni c a ci d, 2-[1-[di fl uoro(1,2,2,2- 749836-20-2 PFESA Byproduct 2 PFESA Byproduct 2
2-propa nyl ]oxy}etha nes ul foni c a ci d tetra fl uroroethoxy)methyl ]-1,2,2,2-
tetra fl uoroethoxy]-1,1,2,2-tetra fl uoro
DTXSID70892479
DTXSID8071354
Lists from EPA Regulatory Offices and
Perfl uoropentanes ul fona te
Ammoni um perfl uoropentanes ul fona te
175905-36-9 Perfl uoropenta ns ul fona te
68259-09-6 Ammoni um perfl uoropenta ns ul fona te
2706-91-4
68259-09-6
PFPeS PFPeS_i on
APFPeS
DTXSID40881350 4,8-Di oxa -3H-perfl uoronona noi c a ci d 919005-14-4 2,2,3-Tri fl uoro-3-(1,1,2,2,3,3-hexa fl uoro-3- 919005-14-4 ADONA ADONA pa rent a ci d
DTXSID00874026 Regions
Ammoni um 4,8-di oxa -3H-
perfl uoronona noa te
(tri fl uoromethoxy)propoxy)propa noi c a ci d
958445-44-8 Ammoni um 4,8-di oxa -3H-
perfl uoronona noa te
958445-44-8 ADONA ADONA
DTXSID3037707 Potas s i um perfl uorobutanes ul fona te 29420-49-3 Potas s i um perfl uoro-1-butanes ul fona te PFBS PFBS-K
DTXSID5030030 Perfl uorobutanes ul foni c a ci d 375-73-5 Perfl uorobutanes ul foni c a ci d 375-73-5 PFBS PFBS
DTXSID60873015 Perfl uorobutanes ul fona te 45187-15-3 Perfl uorobutanes ul fona te 375-73-5 PFBS PFBS_i on
DTXSID3040148 Perfl uorodeca nes ul foni c a ci d 335-77-3 Perfl uorodeca nes ul foni c a ci d PFDS PFDS
DTXSID00873014 Perfl uorodeca nes ul fona te 126105-34-8 Perfl uorodeca nes ul fona te 335-77-3 PFDS PFDS_i on
DTXSID60892443 Sodi um perfl uorodeca nes ul fona te 2806-15-7 Sodi um perfl uoro-1-deca nes ul fona te PFDS PFDS-Na
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Office of Research Antony Williams, Ann Richard, and Chemical Curation Team
and Development
It Starts With Chemistry… Curating Names,
Structures, and Identifiers
Currently >10,000 PFAS and >30 lists
DTXSID Substance_Name Substance Source_Name (incorrect or Source_CASRN Source_Acronym Unique_Acronym
_CASRN ambiguous) (incorrect or (incorrect or
invalid) ambiguous)
DTXSID20874028 2H,2H,3H,3H-Perfl uorooctanoi c a ci d 914637-49-3 5:3 Pol yfl uori na ted a ci d 914637-49-3 5:3 a ci d 5:3 PFOA
DTXSID7027831 N-Methyl -N-(2- 24448-09-7N-Methyl NMeFOSE, MeFOSE NMeFOSE
hydroxyethyl )perfl uorooctanes ul fona mi de perfl uorooctanes ul fona mi deoetha nol
DTXSID10892352 Perfl uoro-2-{[perfl uoro-3-(perfl uoroethoxy)- 749836-20-2
Etha nes ul foni c a ci d, 2-[1-[di fl uoro(1,2,2,2- 749836-20-2 PFESA Byproduct 2 PFESA Byproduct 2
2-propa nyl ]oxy}etha nes ul foni c a ci d tetra fl uroroethoxy)methyl ]-1,2,2,2-
tetra fl uoroethoxy]-1,1,2,2-tetra fl uoro
DTXSID70892479
DTXSID8071354
Lists from EPA Regulatory Offices and
Perfl uoropentanes ul fona te
Ammoni um perfl uoropentanes ul fona te
175905-36-9 Perfl uoropenta ns ul fona te
68259-09-6 Ammoni um perfl uoropenta ns ul fona te
2706-91-4
68259-09-6
PFPeS PFPeS_i on
APFPeS
DTXSID40881350 4,8-Di oxa -3H-perfl uoronona noi c a ci d 919005-14-4 2,2,3-Tri fl uoro-3-(1,1,2,2,3,3-hexa fl uoro-3- 919005-14-4 ADONA ADONA pa rent a ci d
DTXSID00874026 Regions
Ammoni um 4,8-di oxa -3H-
perfl uoronona noa te
(tri fl uoromethoxy)propoxy)propa noi c a ci d
958445-44-8 Ammoni um 4,8-di oxa -3H-
perfl uoronona noa te
958445-44-8 ADONA ADONA
DTXSID3037707 Potas s i um perfl uorobutanes ul fona te 29420-49-3 Potas s i um perfl uoro-1-butanes ul fona te PFBS PFBS-K
DTXSID5030030 Perfl uorobutanes ul foni c a ci d 375-73-5 Perfl uorobutanes ul foni c a ci d 375-73-5 PFBS PFBS
DTXSID60873015 Perfl uorobutanes ul fona te 45187-15-3 Perfl uorobutanes ul fona te 375-73-5 PFBS PFBS_i on
DTXSID3040148 Perfl uorodeca nes ul foni c a ci d 335-77-3 Perfl uorodeca nes ul foni c a ci d PFDS PFDS
DTXSID00873014 Perfl uorodeca nes ul fona te 126105-34-8 Perfl uorodeca nes ul fona te 335-77-3 PFDS PFDS_i on
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DTXSID60892443 Sodi um perfl uorodeca nes ul fona te 2806-15-7
https://comptox.epa.gov/dashboard
Sodi um perfl uoro-1-deca nes ul fona te PFDS PFDS-Na
Office of Research Antony Williams, Ann Richard, and Chemical Curation Team
and Development
It Starts With Chemistry… Curating Names,
Structures, and Identifiers
• Attempted to procure ~3,000 based on chemical
diversity, Agency priorities, and other
considerations
• Obtained 480 unique chemicals
• 430/480 soluble in DMSO (90%)
• Initially selected 150 PFAS in two phases for
testing
• Currently, over 100 have passed QC and are
undergoing Tier 1 testing and available for Tier 2
and other testing
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Office of Research Kathy Coutros, Ann Richard, Barbara Wetmore, and Analytical Chemistry Team
and DevelopmentSelecting a Subset of PFAS for Tiered Toxicity and
Toxicokinetic Testing
• Developed initial structural categories based on Buck et al., 2011
• Selected 150 substances to support refinement of categories and read-across evaluation.
• Testing substances in a range of assays to characterize mechanistic and toxicokinetic properties.
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Office of Research
and DevelopmentTier 1 In Vitro Toxicity and Toxicokinetic Testing
Summary of Tier 1 toxicity and toxicokinetic testing
will be provided by Richard and Barbara in Breakout
Meetings…
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Office of Research
and DevelopmentLegacy In Vivo Toxicity Study Data Curation
Summary of in vivo toxicity study data curation
activities will be provided by Richard and Kris in
Breakout Meetings…
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Office of Research
and DevelopmentDevelop and Refine PFAS Categories for Hazard
Assessment in Collaboration with OCSPP
Develop Initial PFAS Categories
Chemistry Curation
(Structure-Based)
Activities
In Vivo Studies to Fill Gaps
In Vivo Toxicity Study Identify PFAS Categories with
• ORD studies
Curation Activities Data Gaps
• TSCA Test Orders
Refine PFAS Categories Using
In Vitro Toxicity and
Mechanistic, Toxicokinetic, and In Vivo
Toxicokinetic Testing
Testing Data
Activities
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Office of Research Antony Williams, Grace Patlewicz, Richard Judson, and OPPT Collaborators
and DevelopmentDevelop Initial PFAS Structural Categories for
Hazard Assessment in Collaboration with OCSPP
Tertiary categorization
performed only on
Secondary Categories with
structural diversity greater
than the threshold
Primary Secondary Tertiary
DSSTox Structural
Structural Structural Structural
Database Filters
Categories* Categories Categories
~906K
substances 1. Contains -CF2 1. PFAS derivatives 1. Greater than or equal to 8
2. Apply ‘OPPT working 2. PFAAs carbons
definition’ 3. Perfluoro PFAA 2. Less than 8 carbons
3. Remove radicals, charge precursors 3. Volatile (>100 mmHg
imbalanced 4. Non-PFAA Perfluoroalkyls Vapor Pressure)
4. Remove specific types of 5 5. FASA-based PFAA
and 6 membered rings Precursors
(aromatic, containing 6. Fluorotelomer PFAA
double bonds, precursors
heterocycles) 7. Silicon PFAS
8. Side-chain fluorinated
aromatic PFAS
*Based
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on Su and Rajan, 2021 9. Other aliphatic PFAS
Office of Research Antony Williams, Grace Patlewicz, Richard Judson, and OPPT Collaborators
and DevelopmentStructural Diversity ‘Within’ and ‘Between’ Secondary
Categories Used to Set Diversity Threshold
Secondary Category C
Secondary Category A ‘Between’ and ‘Within’ Category Pairwise Distance Distributions
Diversity Characteristic #2
‘Within’
Category
Distances
Density
‘Between’
Category
Distances
Secondary Category B
Median Pairwise Distances
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Diversity Characteristic #1
Office of Research Antony Williams, Grace Patlewicz, Richard Judson, and OPPT Collaborators
and DevelopmentCentroids Calculated for Each Terminal Category to
Help Select Most Representative PFAS for Testing
Terminal Category A
Diversity Characteristic #2
Centroid
‘Centroids’ used to
Mean of the chemical identify the most
Terminal Category B fingerprint matrix representative
used to identify the substance for the
‘centroid’. group
Centroid
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Diversity Characteristic #1
Office of Research Antony Williams, Grace Patlewicz, Richard Judson, and OPPT Collaborators
and DevelopmentDevelop and Refine PFAS Categories for Hazard
Assessment in Collaboration with OCSPP
Develop Initial PFAS Categories
Chemistry Curation
(Structure-Based)
Activities
In Vivo Studies to Fill Gaps
In Vivo Toxicity Study Identify PFAS Categories with
• ORD studies
Curation Activities Data Gaps
• TSCA Test Orders
Refine PFAS Categories Using
In Vitro Toxicity and
Mechanistic, Toxicokinetic, and In Vivo
Toxicokinetic Testing
Testing Data
Activities
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Office of Research Antony Williams, Grace Patlewicz, Richard Judson, and OPPT Collaborators
and DevelopmentTake Home Messages
• ORD undertaking a multi-pronged strategy to characterize the chemistry,
toxicity, and toxicokinetic properties of the broader class of PFAS.
• A category-based strategy is being used to identify candidate PFAS for further
in vivo testing and provide toxicity values for the constituent substances.
• Initial structural categories will be refined using the mechanistic and
toxicokinetic data.
• ORD is working closely with OCSPP to develop the strategy for regulatory
application.
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Office of Research
and DevelopmentQuestions?
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