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

Abstract

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.

Toxicological evaluation of ametryn effects in Wistar rats

“…In contrast with in vitro tests, metabolism, pharmacokynetic and toxicokynetic factors (such as absorption, distribution, metabolism and excretion) are all inherent features in the in vivo genotoxicity tests such as the MN test. With two different experimental categories-in vivo and in vitro-results for a given chemical can often differ, which presents challenges in their interpretation (Mekenyan et al, 2012). In relation to ametryn, in vitro and in vivo assays presented the same response and our results corroborate results obtained with others experimental models.…”

“…Appropriate in vivo experimental test systems used to evaluate genotoxicity include the bone marrow in vivo micronucleus test (MN) (Mekenyan et al, 2012). MN test is the preferred in vivo analysis because this assay presents both wide mutagenicity range assessment (clastogenicity and aneugenicity) and high specificity in concordance with the genotoxic carcinogenicity model (Mekenyan et al, 2012).…”

“…MN test is the preferred in vivo analysis because this assay presents both wide mutagenicity range assessment (clastogenicity and aneugenicity) and high specificity in concordance with the genotoxic carcinogenicity model (Mekenyan et al, 2012). For this propose, the femur was removed and the epiphysis was cut to wash the medullary canal with fetal bovine serum (FBS) (Cultilab, Campinas, Brazil).…”

A feasibility study: Can information collected to classify for mutagenicity be informative in predicting carcinogenicity?

“…This so-called extrapolation workflow was used to facilitate the development of new genotoxicity models in the Tissue Metabolism Simulator (TIMES) platform and to help direct strategic testing (Mekenyan et al, 2012). Two (Q)SAR models, namely for in vivo genotoxicity in liver and in vivo micronucleus formation in bone marrow were developed.…”

“…Therefore carcinogenicity has been the subject of many different efforts to both develop short-term tests and non-testing approaches capable of predicting genotoxic carcinogenic potential. In our previous publication (Mekenyan et al, 2012) we presented an in vitro-in vivo extrapolation workflow to help investigate the differences between in vitro and in vivo genotoxicity tests. The outcomes facilitated the development of new (Q)SAR models and for directing testing.…”