Section 7:

Future Directions

Steven Knott, Director

Exposure Assessment Coordination and Policy Division

Office of Science Coordination and Policy

Office of Chemical Safety and Pollution Prevention

Slide 1 of 8
Presentation Roadmap

Introduction

Estrogen Receptor 

Bioactivity

Androgen Receptor 

Bioactivity

Exposure

Toxicokinetics/Dosimetry

Integrated Bioactivity 

Exposure Ranking

Future Directions

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 2 of 8
Major Points

ToxCast

ExpoCast

IBER 

Prioritization

Tier 1 

Substitution

/WoE

HTTK/RTK

ER

ER & AR

ToxCast

ExpoCast

IBER 

Prioritization

Tier 1 

Substitution

/WoE

HTTK/RTK

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 3 of 8

July 2014 FIFRA SAP

December 2014 FIFRA SAP

Future FIFRA SAP

• Continue to adopt computational tools in a fit-forpurpose approach for androgen and thyroid 

o prioritization, 

o contributing to WoE, 

o and substitution of Tier 1.

EAT

EAT
Future Directions

 ER

• Additional chemicals for bioactivity

• Inclusion of metabolically competent in vitro assays

• Better discrimination of cell-stress/cytotoxicity related assay interference

 AR

• Expanded in vitro and in vivo reference chemicals across a range of potencies

• Additional chemicals for bioactivity

• Inclusion of metabolically competent in vitro assays

• Better discrimination of cell-stress/cytotoxicity related assay interference

• Development of QSAR model similar to ER QSAR effort

 Exposure

• Next generation models that include other sources of exposure (e.g., ground water and drinking 

water), 

• New models (e.g. SHEDS-HT) and data sources

• Additional partnerships with CDC to target mid and high concentration chemicals not currently 

measured in NHANES

• Develop exposure models for ecological species (e.g., fish)

 HTTK

• More chemicals

• Model population variability 

• Expand beyond current human and mammalian models

• Refining models and QSAR 

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 4 of 8
 Modeling the thyroid pathway: 

• Generate HTS data around targets in the thyroid pathway

• Build models to understand the consequences of perturbing thyroid targets 

• Particular targets include: 

– Thyroid hormone receptor

– Thyroid releasing hormone

– Sodium-iodide symporter

– Multiple dioidinases

– Thyroid peroxidase

• Models are being parameterized for both human and rat

 Modeling the steroidogenesis pathway: 

• Generating HTS data using a modified variant of the EDSP Tier 1 T47D guideline 

assay

– Generates concentration-response profiles on almost all intermediate and final metabolites in 

steroidogenesis pathway. 

• Raw data for the first 1000 chemicals is in house 

• A whole-pathway model is being developed to better predict where in pathway 

a chemical is causing disruption

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 5 of 8

Future Directions
Additional Consideration

 July 2014 FIFRA SAP report commented:

“[High throughput exposure] HTE may not only 

be used simultaneously with High Throughput 

(HTP) bioassays for screening, but may provide 

environmentally relevant dosages for Tier 1 

studies (or additional HTP bioassays) that would 

avoid overt toxicity that confounds endocrine 

responses in vivo.”

 The same may be true for high throughput 

bioactivity

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 6 of 8
Estrogen Adverse Outcome Pathway

Study Type

HTS 

in vitro 

in silico Tier 1 Tier 2

Endpoint

QSAR

ToxCast

ER Binding

ERTA

Aromatase

Steroidogenesis

Uterotrophic

Pubertal

FSTRA

Rat 2-gen/EOGRT 

MEOGRT

LAGDA

Quail

Physicochemical x x Toxicant

ER binding x x x

Molecular

Interactions

ER activation x x x

DNA Binding x x

Cell proliferation x

Protein production x x x x

Cellular 

Responses Biochemistry x x x x x

Steroidogenesis x x x

Organ weight x December 2014 x x x x x

Organ Histopathology x x x x x x

Onset of Puberty x x x x

Organisms Estrous Cyclicity x x

Fertility/Fecundity x x x x x

Population Development 2015 x x x x x x

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 7 of 8
Androgen Adverse Outcome Pathway

Study Type

HTS 

in vitro 

in silico Tier 1 Tier 2

Endpoint

QSAR

ToxCast

AR BindingAromatase

Steroidogenesis

Hershberger

Pubertal

FSTRA

Rat 2-gen/EOGRT 

MEOGRT

LAGDA

Quail

Physicochemical x x Toxicant

AR binding x x x Molecular

Interactions AR activation x x

DNA Binding x x

Biochemistry x x x x x x Cellular 

Steroidogenesis x x x Responses

Organ weight x x x x x x

Organ

Histopathology x x x x x x

Onset of Puberty x x x x

Organism

2

oSex characteristics x x x

Fertility/Fecundity x x x x x

Population

Development 2015 x x x x x x

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 8 of 8