[ascct] Member webinar: Using new technologies for risk assessment

  • From: Kristie Sullivan <KSullivan@xxxxxxxx>
  • To: "ascct@xxxxxxxxxxxxx" <ascct@xxxxxxxxxxxxx>
  • Date: Tue, 7 Aug 2012 13:55:33 -0400

You are invited to an ASCCT member webinar:

Incorporating New Technologies into Toxicity Testing and Risk Assessment:  
Moving from 21st Century Vision to a Data-Driven Framework

Russell S. Thomas, The Hamner Institutes for Health Sciences

See below for a description of the presentation.

Meeting Subject:  Member webinar: Using new technologies for risk assessment
Meeting Date:   Thu Aug 16 2012
Meeting Time:   02:00:00 PM (GMT-05:00) US/Eastern

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Incorporating New Technologies into Toxicity Testing and Risk Assessment:  
Moving from 21st Century Vision to a Data-Driven Framework

Russell S. Thomas, The Hamner Institutes for Health Sciences
The release of the National Research Council’s Report “Toxicity Testing in the 
21st Century: A Vision and a Strategy” in 2007 initiated a broad-based movement 
in the toxicology community to re-think how toxicity testing and risk 
assessment are performed.  Since the release of the report, efforts such as the 
Human Toxicology Project, Risk21, and others have added to the momentum, but 
the majority of these efforts have focused more on a vision of how things 
should be done rather than the development of a data-driven paradigm.  The 
focus on vision has been due to a lack of adequate datasets that would be 
required to develop a data-driven paradigm.  This lack of data is gradually 
changing with the release of the ToxCast Phase I data, the development of 
high-throughput dosimetry approaches, and the collection of short-term in vivo 
transcriptomic studies.
This webinar will briefly cover a series of studies that together inform what 
could be seen as a basis for a new data-driven paradigm to toxicity testing and 
risk assessment.  The first study is a comprehensive cross-validation model 
comparison to evaluate the predictive performance of the more than 600 in vitro 
assays from the ToxCast Phase I screening effort across 60 in vivo endpoints 
using 84 different statistical classification methods.  The predictive 
performance of the in vitro assays was compared to that of chemical structure 
descriptors.  The results showed that the current suite of ToxCast 
high-throughput toxicity assays have limited applicability for predicting in 
vivo chemical hazards using standard statistical classification methods.  
However, if viewed as a survey of potential molecular initiating events and 
interpreted as risk factors for toxicity, the assays may still be useful for 
chemical prioritization.  The second study involves the development of 
high-throughput methods for estimating pharmacokinetics for in vitro studies.  
Hepatic metabolic clearance and plasma protein binding were experimentally 
measured for a subset of the ToxCast Phase I chemicals using rat hepatocytes 
and plasma. Computational pharmacokinetic models used these results to estimate 
the rat daily oral dose necessary to produce steady-state in vivo blood 
concentrations equivalent to the AC50 values obtained in the 600 in vitro 
ToxCast assays. The estimated rat daily oral doses associated with the in vitro 
assays were compared to the low effect levels (LEL) for apical responses 
obtained from in vivo rodent studies.  The results showed that the daily oral 
dose equivalent for the most sensitive in vitro assay provided a conservative 
estimate of the in vivo LEL value.  The third study involves short-term in vivo 
transcriptomic measurements that were performed in dose-response and a multiple 
time points.  When transcriptomic changes were grouped by pathway, the 
transcriptional dose-response changes were strongly correlated with both 
noncancer- and cancer-related apical endpoints and the correlations appeared 
stable over time and target tissue.  In addition, transcriptional 
points-of-departure for the most sensitive pathway differed by less than an 
order of magnitude from the points-of-departure based on traditional apical 
Together the three studies argue for a new tiered toxicity testing framework 
that is not based on the traditional model of hazard identification in animals. 
 Rather, the new paradigm identifies a region of the dose-response curve where 
no significant biological perturbations are expected.  A comparison of the 
region of safety with human exposure estimates provides a means to eliminate 
chemicals from further testing or transition chemicals to higher tiers while at 
the same time providing points-of-departure for risk assessment.
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Kristie Sullivan, MPH
American Society for Cellular and Computational Toxicology

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