Much of the work carried out by DTT is in support of the National Toxicology Program (NTP), an interagency partnership of the Food and Drug Administration, National Institute for Occupational Safety and Health, and NIEHS.
Public Health Significance
Neurodevelopmental disorders such as autism and attention-deficit hyperactivity disorder (ADHD) are on the rise worldwide, and environmental exposures may be contributing factors.
Current methods to evaluate the thousands of chemical compounds with unknown developmental neurotoxicity (DNT) potential remain largely ineffective. That is due to the complexity of neurodevelopment, which involves multiple key processes, one or more of which may be perturbed by a given environmental agent.
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 rigor required for decision-making and the length of time for traditional studies. In the interim, susceptible populations 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 the origins of neurodevelopmental disorders.
The Developmental Neurotoxicity Health Effects Innovation (DNT HEI) Program 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 program is that it will complement global DNT research efforts and help move the field forward. Ultimately, this strategy is designed to provide biological and mechanistic understanding of environmentally related neurodevelopmental disorders while reducing animal use.
The DNT HEI program is a high-priority initiative that 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. 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 in vivo data, uncertainties remain in the current DNT test guidelines 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 HEI program will use novel, relevant tools and technologies that incorporate a tiered strategy in line with the DTT pipeline. The program will use new approach methodologies that allow high throughput, short-term in vivo studies. The initiative also will use exposure information to provide reliable data to stakeholders for timely protection of children’s health.
This program aligns with the NIEHS 2018–2023 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.
|DNT screening assay battery
|Cover key neurodevelopmental events to prioritize compounds with DNT potential
Neuroimmune cells as targets for neurotoxicity assessments
Assess microglia and astrocyte functional changes contributing to chemical-induced neurotoxicity
Assessing outcomes from prophylactic use of HIV therapeutics
Study neurovascular, neuroinflammation processes in rats exposed during development, aging
|Modified One-Generation 18 months Neurotoxic Assessment study number MOG18001D
|Incorporating genetic susceptibility into DNT screening
|Evaluate role of genetic diversity in susceptibility to neurotoxicity
|Tox21 Cross Partner Project
|Population-wide toxicodynamic variability, mode of action of methyl mercury for protecting sensitive subpopulations
|Investigate variability of genetically diverse mouse cells in response to methyl mercury, using transcriptomics
|Parkinson’s disease; associations with environmental exposures
|Scoping review to systematically map evidence between exposures to environmental chemicals and Parkinson’s disease
|Health Assessment and Translation Project on Parkinson’s Disease
|Fluoride developmental neurotoxicity
|Systematic review to evaluate potential neurobehavioral effects from exposure to fluoride