Integrating Selection and Risk Assessment of Chemical Mixtures: A Novel Approach Applied to a Breast Milk Survey.

BACKGROUND: One of the main challenges of modern risk assessment is to account for combined exposure to the multitude of various substances present in food and the environment. OBJECTIVE: The present work proposes a methodological approach to perform chemical risk assessment of contaminant mixtures across regulatory silos regarding an extensive range of substances and to do so when comprehensive relevant data concerning the specific effects and modes of action of the mixture components are not available. METHODS: We developed a complete step-by-step approach using statistical methods to prioritize substances involved in combined exposure, and we used a component-based approach to cumulate the risk using dose additivity. The most relevant toxicological end point and the associated reference point were selected from the literature to construct a toxicological threshold for each substance. DISCUSSION: By applying the proposed method to contaminants in breast milk, we observed that among the 19 substances comprising the selected mixture, ∑DDT, ∑PCBi, and arsenic were main joint contributors to the risk of neurodevelopmental and thyroid effects for infants. In addition, ∑PCCD/F contributed to the thyroid effect and ∑aldrin-dieldrin to the neurodevelopmental effect. Our case study on contaminants in breast milk demonstrated the importance of crossing regulatory silos when studying mixtures and the importance of identifying risk drivers to regulate the risk related to environmental contamination. Applying this method to another set of data, such as human biomonitoring or in ecotoxicology, will reinforce its relevance for risk assessment. https://doi.org/10.1289/EHP8262.

Roadbumps at the Crossroads of Integrating Behavioral and In Vitro Approaches for Neurotoxicity Assessment.

With the appreciation that behavior represents the integration and complexity of the nervous system, neurobehavioral phenotyping and assessment has seen a renaissance over the last couple of decades, resulting in a robust database on rodent performance within various testing paradigms, possible associations with human disorders, and therapeutic interventions. The interchange of data across behavior and other test modalities and multiple model systems has advanced our understanding of fundamental biology and mechanisms associated with normal functions and alterations in the nervous system. While there is a demonstrated value and power of neurobehavioral assessments for examining alterations due to genetic manipulations, maternal factors, early development environment, the applied use of behavior to assess environmental neurotoxicity continues to come under question as to whether behavior represents a sensitive endpoint for assessment. Why is rodent behavior a sensitive tool to the neuroscientist and yet, not when used in pre-clinical or chemical neurotoxicity studies? Applying new paradigms and evidence on the biological basis of behavior to neurobehavioral testing requires expertise and refinement of how such experiments are conducted to minimize variability and maximize information. This review presents relevant issues of methods used to conduct such test, sources of variability, experimental design, data analysis, interpretation, and reporting. It presents beneficial and critical limitations as they translate to the in vivo environment and considers the need to integrate across disciplines for the best value. It proposes that a refinement of behavioral assessments and understanding of subtle pronounced differences will facilitate the integration of data obtained across multiple approaches and to address issues of translation.

Regulatory identification of BPA as an endocrine disruptor: Context and methodology.

BPA is one of the most investigated substances for its endocrine disruptor (ED) properties and it is at the same time in the center of many ED-related controversies. The analysis on how BPA fits to the regulatory identification as an ED is a challenge in terms of methodology. It is also a great opportunity to test the regulatory framework with a uniquely data-rich substance and learn valuable lessons for future cases. From this extensive database, it was considered important to engage in a detailed analysis so as to provide specific and strong evidences of ED while reflecting accurately the complexity of the response as well the multiplicity of adverse effects. An appropriate delineation of the scope of the analysis was therefore critical. Four effects namely, alterations of estrous cyclicity, mammary gland development, brain development and memory function, and metabolism, were considered to provide solid evidence of ED-mediated effects of BPA.