Investigating the Relationship between in Vitro–in Vivo Genotoxicity: Derivation of Mechanistic QSAR Models for in Vivo Liver Genotoxicity and in Vivo Bone Marrow Micronucleus Formation Which Encompass Metabolism

Strategic testing as part of an integrated testing strategy
(ITS) to maximize information and avoid the use of animals where possible
is fast becoming the norm with the advent of new legislation such
as REACH. Genotoxicity is an area where regulatory testing is clearly
defined as part of ITS schemes. Under REACH, the specific information
requirements depend on the tonnage manufactured or imported. Two types
of test systems exist to meet these information requirements, in vivo
genotoxicity assays, which take into account the whole animal, and
in vitro assays, which are conducted outside the living mammalian
organism using microbial or mammalian cells under appropriate culturing
conditions. Clearly, with these different broad experimental categories,
results for a given chemical can often differ, which presents challenges
in the interpretation as well as in attempting to model the results
in silico. This study attempted to compare the differences between
in vitro and in vivo genotoxicity results, to rationalize these differences
with plausible hypothesis in concert with available data. Two proof
of concept (Q)­SAR models were developed, one for in vivo genotoxicity
effects in liver and a second for in vivo micronucleus formation in
bone marrow. These “mechanistic models” will be of practical
value in testing strategies, and both have been implemented into the
TIMES software platform (http://oasis-lmc.org) to help
predict the genotoxicity outcome of new untested chemicals.