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are developing IVIVE models for specific
compounds, such as phthalates, parabens,
carbaryl and arsenic (Choi et al., 2011).
Training
Hamner staff from our Center for Human
Health Assessment (CHHA), led by Dr.
Harvey Clewell, held week-long courses,
one in 2010 and the second in 2011,
that included lectures on using PBPK
modelling to conduct IVIV extrapolation for
cell-based toxicity testing (thehamner.org/
about-the-hamner/education-training/pbpkmodeling/#2011).
The course material
is available on the website. The Hamner
group also led a continuing education
course (CEC) on IVIVE at the 2011 SOT
meeting. A Hamner-led proposal for a
CEC on early life dosimetry and vulnerable
populations has been accepted for the
2012 SOT meeting.
Conclusions
Progress in developing case studies
requires careful selection of prototype
compounds and prototype pathways. In
addition, contributions are necessary
from a trans-disciplinary staff with
diverse skills—assay design, genomics/
bioinformatics, computational modelling,
pharmacokinetics and human health risk
assessment. Our programmes are moving
forward with resources that are targeted
to specific technical areas and slowly
expanding to develop several case studies
that span all the key technical areas
required for success with any individual
pathway assay. We are furthest along with
case studies for the p53-DNA damage and
the PPAR-a pathways. Work with these
prototypes provides activities covering
each aspect of risk assessment based on
in vitro test results (Figure 1).
The case study approach offers several
advantages. First, it does not worry
excessively over all challenges required to
make a wholesale change in toxicity testing,
focusing instead on the process by which
in vitro toxicity information will/could be
used for setting regulatory standards in
specific instances. Second, it proposes
learning by doing. Many key issues in use
of the information will become apparent
by moving ahead with the process. We
can look tour own history and suggest
that only a couple of successes with case
studies will make the entire process go
along much more easily. The two authors
of this report were among a small group
who brought PBPK modelling forward for
use in risk assessment in the 1980s. It is
an area that now has contributed widely to
human health risk assessment. Based on
our experience, the majority of challenges
required to implement PBPK modelling to
a diverse set of compounds were clearly
defined with the application to the first
two compounds—styrene and methylene
chloride (Ramsey & Andersen, 1984;
Andersen et al., 1987). History is likely to
repeat itself with toxicity testing in the 21 st
century. After completing the first two or
three pathway case studies, most of the
issues will become clear and expansion
of the testing to other pathways will be
greatly accelerated.
AXLR8-2 WORKSHOP REPORT
Progress Report 2011 & AXLR8-2 Workshop Report
319