Cargando…

Toxic Responses Induced at High Doses May Affect Benchmark Doses

To derive reference points (RPs) for health-based guidance values, the benchmark dose (BMD) approach increasingly replaces the no-observed-adverse-effect level approach. In the BMD approach, the RP corresponds to the benchmark dose lower confidence bounds (BMDLs) of a mathematical dose–response mode...

Descripción completa

Detalles Bibliográficos
Autores principales: Zarn, Jürg A., Zürcher, Ursina A., Geiser, H. Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175069/
https://www.ncbi.nlm.nih.gov/pubmed/32341684
http://dx.doi.org/10.1177/1559325820919605
_version_ 1783524753994153984
author Zarn, Jürg A.
Zürcher, Ursina A.
Geiser, H. Christoph
author_facet Zarn, Jürg A.
Zürcher, Ursina A.
Geiser, H. Christoph
author_sort Zarn, Jürg A.
collection PubMed
description To derive reference points (RPs) for health-based guidance values, the benchmark dose (BMD) approach increasingly replaces the no-observed-adverse-effect level approach. In the BMD approach, the RP corresponds to the benchmark dose lower confidence bounds (BMDLs) of a mathematical dose–response model derived from responses of animals over the entire dose range applied. The use of the entire dose range is seen as an important advantage of the BMD approach. This assumes that responses over the entire dose range are relevant for modeling low-dose responses, the basis for the RP. However, if part of the high-dose response was unnoticed triggered by a mechanism of action (MOA) that does not work at low doses, the high-dose response distorts the modeling of low-dose responses. Hence, we investigated the effect of high-dose specific responses on BMDLs by assuming a low- and a high-dose MOA. The BMDLs resulting from modeling fictitious quantal data were scattered over a broad dose range overlapping with the toxic range. Hence, BMDLs are sensitive to high-dose responses even though they might be irrelevant to low-dose response modeling. When applying the BMD approach, care should be taken that high-dose specific responses do not unduly affect the BMDL that derives from low doses.
format Online
Article
Text
id pubmed-7175069
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher SAGE Publications
record_format MEDLINE/PubMed
spelling pubmed-71750692020-04-27 Toxic Responses Induced at High Doses May Affect Benchmark Doses Zarn, Jürg A. Zürcher, Ursina A. Geiser, H. Christoph Dose Response Original Article To derive reference points (RPs) for health-based guidance values, the benchmark dose (BMD) approach increasingly replaces the no-observed-adverse-effect level approach. In the BMD approach, the RP corresponds to the benchmark dose lower confidence bounds (BMDLs) of a mathematical dose–response model derived from responses of animals over the entire dose range applied. The use of the entire dose range is seen as an important advantage of the BMD approach. This assumes that responses over the entire dose range are relevant for modeling low-dose responses, the basis for the RP. However, if part of the high-dose response was unnoticed triggered by a mechanism of action (MOA) that does not work at low doses, the high-dose response distorts the modeling of low-dose responses. Hence, we investigated the effect of high-dose specific responses on BMDLs by assuming a low- and a high-dose MOA. The BMDLs resulting from modeling fictitious quantal data were scattered over a broad dose range overlapping with the toxic range. Hence, BMDLs are sensitive to high-dose responses even though they might be irrelevant to low-dose response modeling. When applying the BMD approach, care should be taken that high-dose specific responses do not unduly affect the BMDL that derives from low doses. SAGE Publications 2020-04-21 /pmc/articles/PMC7175069/ /pubmed/32341684 http://dx.doi.org/10.1177/1559325820919605 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Article
Zarn, Jürg A.
Zürcher, Ursina A.
Geiser, H. Christoph
Toxic Responses Induced at High Doses May Affect Benchmark Doses
title Toxic Responses Induced at High Doses May Affect Benchmark Doses
title_full Toxic Responses Induced at High Doses May Affect Benchmark Doses
title_fullStr Toxic Responses Induced at High Doses May Affect Benchmark Doses
title_full_unstemmed Toxic Responses Induced at High Doses May Affect Benchmark Doses
title_short Toxic Responses Induced at High Doses May Affect Benchmark Doses
title_sort toxic responses induced at high doses may affect benchmark doses
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175069/
https://www.ncbi.nlm.nih.gov/pubmed/32341684
http://dx.doi.org/10.1177/1559325820919605
work_keys_str_mv AT zarnjurga toxicresponsesinducedathighdosesmayaffectbenchmarkdoses
AT zurcherursinaa toxicresponsesinducedathighdosesmayaffectbenchmarkdoses
AT geiserhchristoph toxicresponsesinducedathighdosesmayaffectbenchmarkdoses