Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment
Autor: | David J. Miller, James Nguyen, Harvey J. Clewell, Monique M. Perron, Rachel Brunner, Pankaj Gulati, Nicole Kleinstreuer, Rhian B. Cope, Anna Lowit, Alan R. Boobis, Jeffrey M. Minucci, Elizabeth Mendez, Jeffrey Dawson, Alicia Paini, Yu-Mei Tan, Kelly Lowe, Hua Qian, Philip Villanueva, Jeanne Y. Domoradzki, Michelle R. Embry, John F. Wambaugh, Katherine Phillips, Hugh A. Barton, Brandall Ingle, Tharacad S. Ramanarayanan, Fiona Sewell, Peter P. Egeghy |
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Rok vydání: | 2021 |
Předmět: |
Weight of evidence
Dose-Response Relationship Drug Maximum Tolerated Dose Carcinogenicity Tests Mechanism (biology) General Medicine Toxicology Risk Assessment Toxicokinetics Human health Risk analysis (engineering) Maximum tolerated dose Toxicity Tests Maximum dose Animals Risk assessment Dose selection |
Zdroj: | Regulatory Toxicology and Pharmacology. 127:105070 |
ISSN: | 0273-2300 |
Popis: | 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 intention 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. |
Databáze: | OpenAIRE |
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