Animal testing is often used to evaluate the potential risks, uses, and environmental impacts of chemicals. New Approach Methodologies (NAMs) are technologies and approaches that can potentially provide the same hazard and risk assessment information without the use of animal testing. To further establish scientific confidence in these approaches, this study will review the variability and relevance of existing mammalian toxicity tests, specifically when it comes to human health risk assessment. The goal of this study is to set data-driven and science-based expectations for NAMs based on the variability and relevance of the traditional toxicity testing models.