Public Health Significance

Neurodevelopmental disorders such as autism and attention-deficit hyperactivity disorder (ADHD) are on the rise worldwide, and environmental exposures are likely contributing factors. Currently, almost no chemicals have been formally screened for developmental neurotoxicity (DNT) potential.

Current methods to evaluate the thousands of chemical compounds with unknown DNT potential remain inadequate and are rarely used. The complexity of neurodevelopment, which involves multiple key processes, one or more of which may be perturbed by a given environmental agent, requires a more modern and comprehensive approach.

It can take more than a decade for regulations to be put into effect from the time a compound is identified as potentially developmentally neurotoxic, due to the lack of emphasis on this health outcome and the insensitivity of traditional studies. In the interim, people continue to be exposed to environmental chemicals that may result in neurodevelopmental disorders.

An integrated testing strategy that incorporates novel, innovative methods and provides quicker results could better inform public health decisions and boost understanding of how to mitigate environmental contributions to neurodevelopmental disorders.

Research Objectives

Developmental Neurotoxicity Health Effects (DNT HE) research within the Division of Translational Toxicology (DTT) is structured around the following four objectives:

• Generate screening level information using new approach methodologies in compounds with unknown DNT potential as an interim means to evaluate hazard and prioritize further in-depth evaluation.
• Refine in vivo DNT testing by incorporating human-relevant mechanistic, behavioral, and brain network assessments to address complex neurodevelopmental issues.
• Contextualize in vitro and in vivo findings with human exposure using in vitro to in vivo extrapolation and in silico approaches to provide more relevant and translatable information that can be used to protect children’s health, working towards the additional goal of developing predictive DNT tools.
• Establish communication pipelines with stakeholders to spur progress in DNT research, enable knowledge generated by DTT to be used in further evaluations (e.g., for decision-making), and inform the public about the latest advancements through a range of diverse media.

An important aspect of this research is that it will complement global DNT research efforts and help move the field forward. Ultimately, this strategy is designed to provide more rapid identification of DNTs as well as mechanistic understanding of environmental contributions to neurodevelopmental disorders such as autism.

Background

DNT HE research is a high priority and aims to effectively develop a comprehensive method to evaluate environmental compounds with unknown DNT potential. There are concerns about the current framework of DNT assessment, which is largely based on rodent guideline studies that have been deemed inadequate. These studies are time- and resource-intensive and are performed only when there is an a priori trigger — for example, clinical observations or histopathological changes in the brain noted from acute or subchronic studies, and structural and/or use patterns of concern to known DNTs (such as extensive exposure to pesticides with an organophosphate backbone in children).

As a result, environmental compounds with unknown potential to cause DNT remain largely untested. Even in cases with guideline in vivo data, uncertainties remain in the current DNT test strategies due to limitations with respect to sensitivity, reproducibility, and relevance when extrapolating data from rodents to humans for complex diseases such as autism and ADHD.

To address some of these concerns, the DNT HE research will use novel, relevant tools and technologies that incorporate a tiered strategy in line with the DTT pipeline. This research will use new approach methodologies in conjuction with refined in vivo studies. The initiative also will use exposure information to provide reliable data to stakeholders for timely protection of children’s health.

The DNT-HE aligns with the NIEHS strategic plan and supports the goal of advancing predictive toxicology and the cross-divisional focus area of neuroscience. The development of innovative, human-relevant tools to predict potential hazards for regulators and the public in a timely manner aligns with the DTT mission.

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