Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment.

Animals Carcinogenicity Tests / methods Dose-Response Relationship, Drug Maximum Tolerated Dose Risk Assessment Toxicity Tests / methods Toxicokinetics
Dose selection KMD Toxicokinetics Weight of evidence

Journal

Regulatory toxicology and pharmacology : RTP
ISSN: 1096-0295
Titre abrégé: Regul Toxicol Pharmacol
Pays: Netherlands
ID NLM: 8214983

Informations de publication

Date de publication:
Dec 2021
Historique:
received: 16 08 2021
revised: 18 10 2021
accepted: 25 10 2021
pubmed: 1 11 2021
medline: 20 1 2022
entrez: 31 10 2021
Statut: ppublish

Résumé

Top dose selection for repeated dose animal studies has generally focused on identification of apical endpoints, use of the limit dose, or determination of a maximum tolerated dose (MTD). The intent is to optimize the ability of toxicity tests performed in a small number of animals to detect effects for hazard identification. An alternative approach, the kinetically derived maximum dose (KMD), has been proposed as a mechanism to integrate toxicokinetic (TK) data into the dose selection process. The approach refers to the dose above which the systemic exposures depart from being proportional to external doses. This non-linear external-internal dose relationship arises from saturation or limitation of TK process(es), such as absorption or metabolism. The importance of TK information is widely acknowledged when assessing human health risks arising from exposures to environmental chemicals, as TK determines the amount of chemical at potential sites of toxicological responses. However, there have been differing opinions and interpretations within the scientific and regulatory communities related to the validity and application of the KMD concept. A multi-stakeholder working group, led by the Health and Environmental Sciences Institute (HESI), was formed to provide an opportunity for impacted stakeholders to address commonly raised scientific and technical issues related to this topic and, more specifically, a weight of evidence approach is recommended to inform design and dose selection for repeated dose animal studies. Commonly raised challenges related to the use of TK data for dose selection are discussed, recommendations are provided, and illustrative case examples are provided to address these challenges or refute misconceptions.

Identifiants

DOI: 10.1016/j.yrtph.2021.105070 PMID: 34718074 PMC: PMC9229944
pubmed: 34718074
pii: S0273-2300(21)00211-7
doi: 10.1016/j.yrtph.2021.105070
pmc: PMC9229944
mid: NIHMS1807634
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

105070

Subventions

Organisme : Intramural EPA
ID : EPA999999
Pays : United States

Informations de copyright

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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Auteurs

Yu-Mei Tan (YM)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Durham, NC, USA.

Hugh A Barton (HA)

Independent Consultant, Mystic, CT, USA.

Alan Boobis (A)

Imperial College London, London, UK.

Rachel Brunner (R)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Durham, NC, USA.

Harvey Clewell (H)

Ramboll US Consulting, Inc., Monroe, LA, USA.

Rhian Cope (R)

Australian Pesticides and Veterinary Medicines Authority, Sydney, NSW, Australia.

Jeffrey Dawson (J)

U.S. Environmental Protection Agency, Office of Chemical Safety and Pollution Prevention, Washington, DC, USA.

Jeanne Domoradzki (J)

Corteva Agriscience, Indianapolis, IN, USA.

Peter Egeghy (P)

U.S. Environmental Protection Agency, Office of Research & Development, Durham, NC, USA.

Pankaj Gulati (P)

Australian Pesticides and Veterinary Medicines Authority, Sydney, NSW, Australia.

Brandall Ingle (B)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Durham, NC, USA.

Nicole Kleinstreuer (N)

National Toxicology Program, Interagency Center for the Evaluation of Alternative Toxicological Methods, Research Triangle Park, NC, USA.

Kelly Lowe (K)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Washington, DC, USA.

Anna Lowit (A)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Washington, DC, USA.

Elizabeth Mendez (E)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Washington, DC, USA.

David Miller (D)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Washington, DC, USA.

Jeffrey Minucci (J)

U.S. Environmental Protection Agency, Office of Research & Development, Durham, NC, USA.

James Nguyen (J)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Washington, DC, USA.

Alicia Paini (A)

European Commission, Joint Research Centre, Ispra, Italy.

Monique Perron (M)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Washington, DC, USA.

Katherine Phillips (K)

U.S. Environmental Protection Agency, Office of Research & Development, Durham, NC, USA.

Hua Qian (H)

ExxonMobil Biomedical Sciences, Inc., Annandale, NJ, USA.

Tharacad Ramanarayanan (T)

Syngenta, Ltd., Greensboro, NC, USA.

Fiona Sewell (F)

National Centre for the Replacement, Refinement, and Reduction of Animals in Research, London, UK.

Philip Villanueva (P)

U.S. Environmental Protection Agency, Office of Pesticide Programs, Washington, DC, USA.

John Wambaugh (J)

U.S. Environmental Protection Agency, Office of Research & Development, Durham, NC, USA.

Michelle Embry (M)

Health and Environmental Sciences Institute, Washington DC, USA. Electronic address: membry@hesiglobal.org.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Opportunities and challenges related to...
questionsmedicales.fr › Techniques d'investigation › Tests de toxicité › Tests de cancérogénicité › Opportunities and challenges related to...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › Opportunities and challenges related to...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Dose maximale tolérée › Opportunities and challenges related to...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Appréciation des risques › Opportunities and challenges related to...
questionsmedicales.fr › Techniques d'investigation › Tests de toxicité › Opportunities and challenges related to...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Toxicocinétique › Opportunities and challenges related to...