Background and Purpose: Monosodium glutamate (MSG) is a well-studied food additive. In addition to numerous authoritative assessments of safety, a substantial volume of research is ongoing with MSG; this includes a growing volume of research assessing the ameliorating potential of various substances against purported MSG-induced toxicity. This work set out to develop a framework for evaluating the combined reliability and relevance of these types of investigations as part of ingredient safety assessments, and subsequently, to apply such to a case study of MSG publications involving co-exposures with other substances. Methods: For the development of the framework, key aspects related to internal, external, construct and biological validity were considered with particular focus on the safety of food ingredients. As the evidence base for some food ingredients often contains non-guideline studies, SciRAP was chosen to assess reliability (internal and construct validity) due to its specific development to focus on such studies. To assess the relevance (external and biological validity) study attributes that are fundamental for a food safety risk assessment were considered to ensure the most relevant studies were found. The study attributes included the study design (ensuring relevant and meaningful results), route of exposure (potentially allows for more relevant food exposures), outcomes assessed (apical or complex responses often considered when setting an ADI), and dosing regimen (chronic studies and those at levels below understood NOAELs often provide more insight than high dose acute studies). A categorization scheme was developed for both the reliability and relevance evaluation as well as an aggregate study quality categorization. After development of the framework, a case study was conducted on a unique set of publications related to MSG. Specifically, these studies involved a co-exposure investigating a potential ameliorating effect for a wide range of chemicals. Results: The approach assesses the reliability of the studies utilizing SciRAP, and the relevance in context of study design, dose relevance, and biological validity, resulting in an overall categorization of the informativeness of an individual study, or study quality. In a case study application to 39 studies assessing MSG toxicity and ameliorative properties of a variety of substances, no publications were deemed of ‘high’ study quality for the purpose of assessing safety, due primarily to low relevance to human safety (e.g., use of an acute high dose during neonatal life stages) and limited reliability in study conduct and reporting. Consideration of the biological plausibility of the reported endpoints further determined the limited informativeness of the studies in understanding MSG safety. Conclusions: In all, this work developed an approach for evaluating the combined reliability and relevance of these types of investigations as part of ingredient safety assessments, and subsequently, was applied to a case study of MSG publications involving co-exposures with other substances. Such a framework has applicability to a wide range of food ingredients and offers an approach to thoroughly and reproducibly evaluate the scientific literature. Additionally, the case study did not determine any studies to be of “high” quality indicating limited utility in informing MSG safety.