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Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment

Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose–response data (Gollapudi et al., 2013), here we present...

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Autores principales: Johnson, G.E., Soeteman‐Hernández, L.G., Gollapudi, B.B., Bodger, O.G., Dearfield, K.L., Heflich, R.H., Hixon, J.G., Lovell, D.P., MacGregor, J.T., Pottenger, L.H., Thompson, C.M., Abraham, L., Thybaud, V., Tanir, J.Y., Zeiger, E., van Benthem, J., White, P.A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710644/
https://www.ncbi.nlm.nih.gov/pubmed/24801602
http://dx.doi.org/10.1002/em.21870
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author Johnson, G.E.
Soeteman‐Hernández, L.G.
Gollapudi, B.B.
Bodger, O.G.
Dearfield, K.L.
Heflich, R.H.
Hixon, J.G.
Lovell, D.P.
MacGregor, J.T.
Pottenger, L.H.
Thompson, C.M.
Abraham, L.
Thybaud, V.
Tanir, J.Y.
Zeiger, E.
van Benthem, J.
White, P.A.
author_facet Johnson, G.E.
Soeteman‐Hernández, L.G.
Gollapudi, B.B.
Bodger, O.G.
Dearfield, K.L.
Heflich, R.H.
Hixon, J.G.
Lovell, D.P.
MacGregor, J.T.
Pottenger, L.H.
Thompson, C.M.
Abraham, L.
Thybaud, V.
Tanir, J.Y.
Zeiger, E.
van Benthem, J.
White, P.A.
author_sort Johnson, G.E.
collection PubMed
description Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose–response data (Gollapudi et al., 2013), here we present analyses of 1‐ethyl‐1‐nitrosourea (ENU) and 1‐methyl‐1‐nitrosourea (MNU) dose–response data and additional approaches for the determination of genetic toxicity point‐of‐departure (PoD) metrics. We previously described methods to determine the no‐observed‐genotoxic‐effect‐level (NOGEL), the breakpoint‐dose (BPD; previously named Td), and the benchmark dose (BMD(10)) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non‐linear slope‐transition‐dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL(10) and BMDL(1SD) PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL(10) values were often lower than the other PoDs, and the distribution of BMDL(10) values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making. Environ. Mol. Mutagen. 55:609–623, 2014. © 2014 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.
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spelling pubmed-67106442019-08-29 Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment Johnson, G.E. Soeteman‐Hernández, L.G. Gollapudi, B.B. Bodger, O.G. Dearfield, K.L. Heflich, R.H. Hixon, J.G. Lovell, D.P. MacGregor, J.T. Pottenger, L.H. Thompson, C.M. Abraham, L. Thybaud, V. Tanir, J.Y. Zeiger, E. van Benthem, J. White, P.A. Environ Mol Mutagen Research Articles Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose–response data (Gollapudi et al., 2013), here we present analyses of 1‐ethyl‐1‐nitrosourea (ENU) and 1‐methyl‐1‐nitrosourea (MNU) dose–response data and additional approaches for the determination of genetic toxicity point‐of‐departure (PoD) metrics. We previously described methods to determine the no‐observed‐genotoxic‐effect‐level (NOGEL), the breakpoint‐dose (BPD; previously named Td), and the benchmark dose (BMD(10)) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non‐linear slope‐transition‐dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL(10) and BMDL(1SD) PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL(10) values were often lower than the other PoDs, and the distribution of BMDL(10) values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making. Environ. Mol. Mutagen. 55:609–623, 2014. © 2014 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. John Wiley and Sons Inc. 2014-10 2014-05-06 /pmc/articles/PMC6710644/ /pubmed/24801602 http://dx.doi.org/10.1002/em.21870 Text en © 2014 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Johnson, G.E.
Soeteman‐Hernández, L.G.
Gollapudi, B.B.
Bodger, O.G.
Dearfield, K.L.
Heflich, R.H.
Hixon, J.G.
Lovell, D.P.
MacGregor, J.T.
Pottenger, L.H.
Thompson, C.M.
Abraham, L.
Thybaud, V.
Tanir, J.Y.
Zeiger, E.
van Benthem, J.
White, P.A.
Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment
title Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment
title_full Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment
title_fullStr Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment
title_full_unstemmed Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment
title_short Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment
title_sort derivation of point of departure (pod) estimates in genetic toxicology studies and their potential applications in risk assessment
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710644/
https://www.ncbi.nlm.nih.gov/pubmed/24801602
http://dx.doi.org/10.1002/em.21870
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