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Correlation between the results of in vitro and in vivo chromosomal damage tests in consideration of exposure levels of test chemicals

INTRODUCTION: We examined the correlation between the results of in vitro and in vivo chromosomal damage tests by using in-house data of 18 pharmaceutical candidates that showed positive results in the in vitro chromosomal aberration or micronucleus test using CHL/IU cells, and quantitatively analyz...

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Detalles Bibliográficos
Autores principales: Yamamura, Eiji, Aruga, Chinami, Muto, Shigeharu, Baba, Nobuyuki, Uno, Yoshifumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838998/
https://www.ncbi.nlm.nih.gov/pubmed/29556374
http://dx.doi.org/10.1186/s41021-018-0094-3
Descripción
Sumario:INTRODUCTION: We examined the correlation between the results of in vitro and in vivo chromosomal damage tests by using in-house data of 18 pharmaceutical candidates that showed positive results in the in vitro chromosomal aberration or micronucleus test using CHL/IU cells, and quantitatively analyzed them especially in regard to exposure levels of the compounds. FINDINGS: Eight compounds showed that the exposure levels [maximum plasma concentration (C(max)) and AUC(0-24h)] were comparable with or higher than the in vitro exposure levels [the lowest effective (positive) concentration (LEC) and AUC(vitro) = LEC (μg/mL) × treatment time (h)]. Among them, 3 compounds were positive in the in vivo rodent micronucleus assays using bone marrow cells. For 2 compounds, cytotoxicity might produce false-positive results in the in vitro tests. One compound showed in vitro positive results only in the condition with S9 mix which indicated sufficient concentration of unidentified active metabolite(s) might not reach the bone marrow to induce micronuclei. CONCLUSION: These facts suggested that the in vivo exposure levels being equal to or higher than the in vitro exposure levels might be an important factor to detect in vivo chromosomal damage induced by test chemicals.