Chair:

David Hines, RTI International

Co-Chair:

Cynthia Rider, NIEHS

Primary Endorser: Regulatory and Safety Evaluation Specialty Section


Endorser(s): In Vitro and Alternative Methods Specialty Section


Endorser(s): Mixtures Specialty Section

Characterizing toxicity and risk for complex chemical mixtures poses unique challenges. Mixtures of interest for risk assessment can include combined exposure to environmental contaminants (e.g., Superfund sites) or commercial products with multiple ingredients. Some mixture constituents that may be unknown but are present at varying concentrations have different kinetics and may affect multiple mechanistic pathways leading to one or more biological outcomes. Furthermore, mixture components may contribute to chemical interactions that can result in synergy or antagonism. New approach Methodologies (NAMs) have emerged as nonanimal alternatives to traditional toxicology test methods but have yet to be widely implemented in regulatory risk assessment. These NAMs include in vitro assays that can generate one or more mechanistic outputs to characterize toxicity, as well as computational and statistical approaches that can be used to integrate, evaluate, and interpret in vitro results. This Workshop identifies the current usefulness and limitations of NAMs related to informing regulatory risk assessment of mixtures. It also discusses emerging methodologies used to address these challenges in chemical spaces, which range from household products to pharmaceuticals. This session will focus specifically on progressing toward the application of NAMs in regulatory settings for mixtures in the US and other countries. The session will begin with a brief introductory presentation by the session Chair to provide an outline of the Workshop and highlight the importance of extending NAMs to mixtures regulatory applications. The second speaker will provide a regulatory perspective on the needs and potential uses for NAMs that are relevant to mixtures. This presentation will focus on what questions NAMs should address so that they are useful in regulatory settings. The third speaker will discuss the advantages and challenges of NAMs compared with traditional regulatory risk assessment approaches, focusing specifically on mixtures applications. This presentation will highlight certain capabilities of current NAM approaches to filling knowledge gaps and facilitating mixtures analysis as well as identifying their limitations. The fourth speaker will provide an example application of NAMs analysis of mixtures by discussing cell-based toxicogenomic studies conducted on natural product mixtures. The floor will then be open for discussion to facilitate conversation focused on addressing current limitations and progressing NAMs toward regulatory application in risk assessment. The discussion will include the questions (1) how can emerging NAMs help to address these limitations and inform mixtures risk assessments, (2) how can NAMs provide advantages over traditional regulatory risk assessment approaches, (3) can NAMs be used to inform on undefined mixtures, such as those from natural products or ingredient breakdown, and (4) what NAM resources are currently available to help managers assess mixtures?