Integrated Activity and Exposure

Based Prioritization and Screening

Integrated Activity and Exposure

Based Prioritization and Screening

Presented by Steven Knott

Endocrine Disruptor Screening Program

Office of Science Coordination & Policy

Office of Chemical Safety and Pollution Prevent

Presented by Steven Knott

Endocrine Disruptor Screening Program

Office of Science Coordination & Policy

Office of Chemical Safety and Pollution Prevent
Presentation Roadmap

Future App

Exposure Estimation with

ExpoCast Research

High Throughput

Toxicokinetics (HTTK) and

Reverse Toxicokinetics (RTK)

Ongoing Research

Introduction
Why an Integrated Activity –

Exposure Approach for EDSP

 EDSTAC recommendation (August 1998)“Data resulting from HTPS will be combined with exposure‐related information, and w

effects‐related information that is available, for each chemical for the purpose of setti

T1S”

 Lists 1 and 2

• Based primarily on exposure considerations• Not presumed to interfere with the endocrine systems of humans o

 Other chemicals could have higher priority for EDSP screening a

bioactivity considerations are joined with exposure consideratiointegrated approach

10000

67109

176

EDSP Universe List 1 List 2
Why an Integrated Activity –

Exposure Approach for TSCA

 Mandate to address both existing and new chemicals Limited existing and available data (next to nil for new substanc

• Historically, have relied on analog and read‐across analysis, catego

and predictive modeling (e.g., QSAR)

 Could serve in evaluating new chemicals and in prioritizing assessmen

existing chemicals

> 84,000

1,000

Existing Chemicals Approximate # of New Chemicals / Year
Capturing Critical Points Alo

the Source to Outcome Path

Physicochemical

Properties

High Through Put

Exposure

HTS and QSAR

Activity

Broader

Universe

EDSP Universe

EDSP List 2

•H

•Lo

•H

•Lo

•H

•Lo
Integrating Activity and Exp

 in vitro chemical dose

bioactivity data are us

potential biological ta

 HTTK methods are the

determine the human for each chemical to atargets in vivo

 putative bioactive dos

directly compared to 

to estimate likelihood 

that cause bioactive d

Chemicals where the putative human bioactive dose is comparable to 

predictions become targets for further investigationOverall approach will be the subject of a future FIFRA SAP review

Potential Exposure

from ExpoCast

mg/kg BW/day

In vitro Bioactivity from

ToxCast with Reverse

Toxicokinetics

LowPriority

MedPriority

HigherPriority
High Throughput Exposure Methods a

Reverse Toxicokinetics for Screening and Prio

 HTE Methods and RTK

• Rapid exposure estimation based on

readily available chemical use and

production data

• Use toxicokinetics to bridge in vitro,

concentration‐based ToxCast data toin vivo, dose‐based Exposures from

ExpoCast

RTK

ToxCast

HTE

Methods

 ToxCast

• Expanding use of CompTox (Phys‐

chem properties, QSARS, etc.) tosupport screening and prioritization

• Transparent and collaborative

This SAP
Fit for Purpose

 High Throughput Exposure (HTE) IS

• HTE estimation is “fit” to be used in an integrated

activity‐exposure approach to rank chemicals.

• That is, HTE exposure estimates are “fit” to discern

chemicals with higher potential exposure from

chemicals with lower potential exposure.

• This in turn will be considered along with bioactivity to

prioritize and screen chemicals for traditional low‐

throughput assessment methods.