Expected Results Benefits, Outputs and Outcome There is a critical lack of information concerning the
effects of chemicals on the developing brain. Current animal based approaches
cost $1.4 million per substance. Experts have recommended the development of
screening approaches based on alternative in vitro methods. The project aims to
comply with this recommendation by developing a rapid systems biology approach
for the assessment of developmental neurotoxicity. Expected results will
demonstrate the significance of a systems biology approach to assess developmental
neurotoxicity in a faster, more scientific and more humane manner. The impact
of the project will be the increase in understanding of the developing brain
and how chemicals interact with brain development (in vitro and in vivo).
Possibly new pathways of developmental neurotoxicity will be identified and
biomarkers for its prediction. Moreover, by demonstrating the proof of concept
for the systems biology approach, companies or institutes might implement
systems biology to replace, reduce or refine animal studies for regulatory DNT
assessment. Since the project includes a human cell system, it
might show that human cell systems provide better predictions for human heath
effects. Further simplifying the model with reporter gene transfected cells and
then in silico modeling will demonstrate whether a feasible battery of in vitro
and in silico tests can be envisaged. Toxicology has to undergo a transition in
order to meet the challenges of the 21st century. The
vision of a toxicity pathway-based approach has been put forward by the NAS
[NRC 2007]. It is necessary to create a proof-of-principle. Reproductive toxicity
is a key aspect of risk assessment, consuming a large part of resources and
animals for the regulation of environmental chemicals. The dimensions of the
funding available versus the complexity of the reproductive cycle require
focusing on a key area; it is proposed to address DNT, which qualifies as a
stand-alone hazard assessment demand and because of its key role in the current
change from a two-generation to an extended one-generation study for regulatory
purposes.
By bringing together carefully prioritized highly
quality-controlled in vitro models, with pathway identification by systems
toxicology, with molecular biology derived reporter gene assays, with
state-of-the-art in silico modeling and with supervision/advice from leading
toxicologist involved in the paradigm shift of toxicology, a unique feasibility
study shall be carried out. If successful, this study will serve as a role
model for a novel approach to regulatory toxicology.
The proposed work shall: -
Establish a center ReTox-21c at Johns Hopkins.
Results
and benefits: expand the existing competence
center in a prime academic environment to leverage for setting into practice
the NAS vision; link formally to nationally leading groups
-
Focus on carefully selected models,
which reflect crucial mechanisms and targets of DNT, and a list of priority
chemicals. A homogenous dataset shall be produced, which allows identification
of key cellular pathways. Results and benefits: Sufficiently large and homogenous
datasets in relevant, quality-controlled in vitro models to allow meaningful in
silico modeling. -
This requires a combination of
state-of-the art, quality-controlled cell culture with various omic
technologies and bioinformatics to establish a systems toxicology approach. Results and benefits: translate systems
biology to toxicology; objective interpretation of results from
information-rich systems
-
Selected pathways shall then be
established as reporter gene cells (or acquired where such cells have been already
constructed). The original substance set plus a broader selection identified in
a consensus process with the DNT consortium shall be tested, taking into
consideration the needs of later modeling. Results
and benefits: pathways identified without pre-knowledge
/ prejudice by systems toxicology shall be modeled first in vitro to allow
higher through-put screening without confounding parallel pathways; optimal
conditions for model development by early alignment of needs, large and easily
interpretable datasets.
-
The standardized datasets are used
for modeling. Results
and benefits: optimal start conditions to model
in silico relatively simple systems in order to reduce labor and costs of
information generation.
-
Additional standardized data are
produced for model validation. Results and benefits: independent external
validation of models by a second dataset with the same quality.
-
The process will be monitored as a
case study to develop a pathway-based toxicology and in vitro testing
strategies for DNT. Opportunities for extension to other mechanisms of DNT,
reproductive toxicology in general or other areas of toxicology shall be
assessed in workshops and the DNT-4 conference planned for 2014. Results and benefits: extension beyond the actual projects as a test
case for the novel approach by accompanying analysis of process and
limitations; maximum stakeholder and expert input for the test case.
-
A link to pertinent projects in
Europe shall be maintained. Results
and benefits: synergy for developing new approaches; opening up for possible
later evaluation / acceptance of new approaches.
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