# 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 : • G enerating 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 Binding Aromatase 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 Responses Steroidogenesis x x x Organ weight x x x x x x Organ Histopathology x x x x x x Onset of Puberty x x x x Organism 2oSex 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