Guidance Document 116 on the Conduct and Design of Chronic Toxicity and Carcinogenicity Studies, Supporting Test Guidelines 451, 452 and 453

Abstract

Biomarker: A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.Carcinogenicity: Substances are defined as carcinogenic if they induce tumours (benign or malignant), increase its incidence or shorten the time of tumour, when inhaled, ingested, dermally applied or injected. CES: Critical Effect SizeChronic Toxicity: Toxicity (adverse effect) after an exposure period of 12 months or longer due to a test article that has been ingested inhaled, dermally applied or injected.

Incorporating human exposure information in a weight of evidence approach to inform design of repeated dose animal studies

“…This latter concern is a general limitation of using animal models to derive human risk assessment endpoints, and it is not specific to any one of the approaches for top dose selection. Rather than a reason to dismiss the use of TK data, such a concern makes it even more critical to take into account any existing TK data collected from shorter-term studies before embarking on the design of longer-term animal studies ( OECD, 2012 ). Also, efforts to understand the TK differences between test species and humans (e.g., comparing in vitro clearance) are necessary to ensure that animal studies provide a rational basis for human health risk assessment ( Lewis and Botham, 2013 ; OECD, 2012 ).…”

“…Rather than a reason to dismiss the use of TK data, such a concern makes it even more critical to take into account any existing TK data collected from shorter-term studies before embarking on the design of longer-term animal studies ( OECD, 2012 ). Also, efforts to understand the TK differences between test species and humans (e.g., comparing in vitro clearance) are necessary to ensure that animal studies provide a rational basis for human health risk assessment ( Lewis and Botham, 2013 ; OECD, 2012 ). In addition to in vivo studies, a range of in vitro and in silico methods are available to characterize both qualitative and quantitative differences in TK across species ( Madden, 2019 ; OECD, 2021 ).…”