FIFRA Scientific Advisory

Panel Meeting

New High Throughput Methods to

Estimate Chemical Exposure

FIFRA Scientific Advisory

Panel Meeting

New High Throughput Methods to

Estimate Chemical Exposure

Arlington, VA

July 29 ‐ August 1, 2014

Arlington, VA

July 29 ‐ August 1, 2014

Charge Questions
July 29 ‐ August 1, 2014 FIFRA Scientific Advisory Panel Meeting:

New High Throughput Methods to Estimate Chemical Exposure

Charge Questions

1. The Systematic Empirical Evaluation of Models (SEEM) Frame

Exposure PrioritizationThese charge questions address the science described in the S

entitled “Exposure Prioritization with ExpoCast Research.” The 

framework for evaluating high‐throughput exposure (HTE) inf

(including descriptors, exposure factors, mechanistic models, 

heuristics for thousands of chemicals) extrapolates from chem

monitoring data to those with no monitoring data. By compar

model predictions to exposure/doses inferred for the subset o

with monitoring data, we are able to empirically calibrate our 

model and provide an estimate of uncertainty in exposure pre

1.1) In the absence of sufficient exposure information to es

exposure for the majority of the chemicals of interest i

using EPA's historical low‐throughput methods, please 

on whether the SEEM approach is scientifically sound a

for using HTE methods to estimate relative levels of che

exposures and the associated uncertainty of these estim

consideration in a prioritization approach.
July 29 ‐ August 1, 2014 FIFRA Scientific Advisory Panel Meeting:

New High Throughput Methods to Estimate Chemical Exposure

Charge Questions

1. The Systematic Empirical Evaluation of Models (SEEM) Frame

Exposure Prioritization (continued)

1.2) Please suggest the most important steps for EPA that c

decrease uncertainties and increase confidence in usin

approach to predict exposures in various demographic 

(e.g., young children, women of child bearing age) for l

numbers of chemicals.
July 29 ‐ August 1, 2014 FIFRA Scientific Advisory Panel Meeting:

New High Throughput Methods to Estimate Chemical Exposure

Charge Questions

2. High Throughput Toxicokinetics (HTTK) and Reverse Toxicoki

These charge questions address the science described in the Section with the same nam

to provide an administered dose context to the concentrations showing bioactivity in th

related HTS assays.

A lack of data on the TK of chemicals in organisms is

a substantial im

providing this context. The recent development of HTTK methods provides

a solution to 

measuring key TK parameters for each chemical. To date, HTTK data have been gathered 

chemicals as part of the ExpoCast project. The HTTK assays can be incorporated into rela

vitro‐to‐in vivo extrapolation (IVIVE) computational models to predict steady‐state blood 

HTTK assays combined with physiological information and quantitative structure activity 

(QSAR) that predict tissue partitioning can be utilized in more complex, high‐throughput based TK (HTPBTK) models to predict relevant TK parameters such as area under the cur

maximum blood concentration (Cmax), and tissue and blood concentrations under non‐

conditions. For in vitro to in vivo extrapolation (IVIVE), reverse toxicokinetics (RTK) can b

using either simple or more complex HTPBPK models to predict the administered dose (

required to produce human tissue concentrations (μM) equal to concentrations that act

related in vitro assays (e.g., ToxCast, Tox21). Although current models based on HTTK dat

significantly higher throughput than traditional in vivo studies, as with ExpoCast predictand less data intensive predictions allowed by HTTK methods are associated with higher 

compared to in vivo methods. This higher uncertainty is due in part to the lack of availab

methods to capture biological processes important to toxicokinetics (e.g., active transpo

circulation, etc.).

2.1) In the absence of sufficient empirical toxicokinetics info

the thousands of EDSP relevant chemicals, please comm

approach of using HTTK, HTPBTK, IVIVE, and RTK for est

chemical TK to provide an administered dose context to 

concentrations showing bioactivity in the endocrine

‐re

assays.
July 29 ‐ August 1, 2014 FIFRA Scientific Advisory Panel Meeting:

New High Throughput Methods to Estimate Chemical Exposure

Charge Questions

2. High Throughput Toxicokinetics (HTTK) and Reverse Toxicoki

(continued)2.2) A comparison of the HTTK‐predicted steady‐state blood

concentrations with in vivo values from the literature s

the overall correlation is low, but that the discrepancy b

two can be predicted using a combination of chemical 

quantitative structure activity relationships (QSAR), and 

from the HTTK assays. Please comment on: a) how we

approach characterizes the uncertainty in the steady‐st

concentrations, and b) whether the identification of ch

classes that need additional TK investigation is useful in 

prioritization or initial screening context.
July 29 ‐ August 1, 2014 FIFRA Scientific Advisory Panel Meeting:

New High Throughput Methods to Estimate Chemical Exposure

Charge Questions

2. High Throughput Toxicokinetics (HTTK) and Reverse Toxicoki

(continued)2.3) Please comment on whether the assumptions made in 

models are appropriate given the current state of the s

data limitations.

2.4) Please suggest the most important steps EPA should ta

improve the various kinetic models to provide rapid an

effective predictions for large number of chemicals.

2.5) Please comment on the approaches presented in the p

White Paper for comparing RTK‐derived endocrine‐acti

ranges with exposure predictions from ExpoCast. Discu

strengths and limitations of these comparisons, and wh

or other approaches are suitable for clearly distinguish

chemicals with higher predicted doses from chemicals 

predicted RTK adjusted doses.
July 29 ‐ August 1, 2014 FIFRA Scientific Advisory Panel Meeting:

New High Throughput Methods to Estimate Chemical Exposure

Charge Questions

3. Future Directions

These charge questions address the science described in the S

the same name. Science is proceeding in three key areas to su

throughput exposure prioritization:

1. Near‐field (indoor or consumer use) exposures to human

2. Ecological exposures3. Refinement of high‐throughput toxicokinetics

For all three of these areas, ongoing science development effo

the need for rapid prioritization and initial screening of EDSP a

chemicals.3.1) Please comment on the three key areas including whet

are other areas that are of equal or higher priority to su

integrated activity/hazard and exposure based prioritiz

screening approach within the EDSP or other chemical 
July 29 ‐ August 1, 2014 FIFRA Scientific Advisory Panel Meeting:

New High Throughput Methods to Estimate Chemical Exposure

Charge Questions

3. Future Directions (continued)

3.2) We propose applying the ExpoCast framework to ecolo

exposures using aggregated water monitoring data to e

predictions of environmental fate and transport model

identify other data, models or environmental media th

of greater value in the initial model calibration and unc

analysis.

3.3) Please identify other relatively high‐throughput source

exposure‐related information that should be included i

three key areas and suggest how this information woul

to help prioritize chemicals.

3.4) For the HTTK work going forward, please comment on 

studies that could be performed or approaches that co

taken to improve rapid and cost efficient predictions of 

numbers of chemicals.