Developmental neurotoxicity testing – the need for a new approach

Professor Lein discusses developmental neurotoxicity and the critical need for a new approach to identifying and regulating chemicals that interfere with normal brain development

We are witnessing an alarming increase in neurodevelopmental disorders in children. In the United States, parents report that 1 in 6 children, an increase of 17% over the past decade, have a developmental disability, including learning disabilities, attention deficit hyperactivity disorder (ADHD), autism and other intellectual developmental delays. Similar increases have been documented in other countries around the world. These are complex disorders with multiple causes, including genetic, social, and environmental. Human, animal and mechanistic data increasingly implicate toxic chemicals as factors that increase risk for neurodevelopmental disorders. The “snowballing” evidence that common chemical exposures can derail brain development has triggered scientific stakeholders from regulatory agencies, academia, the health profession, children’s health advocacy groups, and industry to recently issue consensus statements1 calling for a new framework to assess the potential for chemicals in the human environment to cause developmental neurotoxicity (DNT).

Counting the costs

The individual, family and societal costs of neurodevelopmental disorders provide a compelling reason to invest in this endeavor. In the United States, the cost to educate a child with a learning or behavioral disability is, on average, twice that for a neurotypical child. A 2015 study in the European Union of the costs associated with the loss of IQ points due to exposure to neurotoxic chemicals, in particular polybrominated diphenyl ether (PBDE) flame retardants and organophosphate (OP) pesticides, were estimated to be 155.44 billion euros annually. In the United States, a 2009 analysis concluded that for every $1 spent to reduce exposures to the potent developmental neurotoxicant, lead, society would benefit by $17-$221. The fact that environmental factors are modifiable risk factors, in contrast to currently irreversible genetic causes of neurodevelopmental disorders, suggests that regulating or replacing chemicals identified to be toxic to the developing brain is a rational approach for the primary prevention of these developmental disabilities.

DNT Testing

Humans are exposed to tens of thousands of man-made chemicals, but only a very small percentage of these (less than one-tenth of a percent) have been tested for DNT. While the United States Environmental Protection Agency (USEPA) and the Organization for Economic Co-operation and Development (OECD) have guidelines for DNT studies, testing for DNT is not routine in the United States or in the European Union. DNT testing is not required by law unless chemical toxicity testing in adult animals indicate neurotoxic or endocrine effects. Based on decades of data indicating that the developing brain is significantly more vulnerable than the mature brain to the toxic effects of chemicals, these current regulatory requirements are likely not sufficiently protective of the developing brain.

In addition to a change in the regulatory framework, there is a critical need for a paradigm shift in how DNT studies are conducted. The classic approach of testing a chemical for DNT potential in a rodent animal model is extremely resource intensive with respect to time, money and number of animals. Thus, it is not feasible to close the DNT data gap using the current test guidelines. The past decade has seen the emergence of a variety of in vitro and in silico testing platforms that enable rapid, efficient and scientifically valid toxicity testing. Integrating these methods into the testing and regulatory strategies for DNT will be critical to meeting the goal of protecting healthy brain development to ensure the sustainability of society.

 

1Project TENDR: Targeting Environmental Neuro-Developmental Risks. The TENDR Consensus Statement. Environ Health Perspect. 2016 Jul 1;124(7):A118-22. doi: 10.1289/EHP358.

 

Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes. Toxicol Appl Pharmacol. 2018 Feb 12. pii: S0041-008X(18)30043-7. doi: 10.1016/j.taap.2018.02.004.

 

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