Developmental neurotoxicity – Challenges in the 21st Century and In Vitro Opportunities

Abstract

Summary In recent years neurodevelopmental problems in children have increased at a rate that suggests lifestyle factors and chemical exposures as likely contributors. When environmental chemicals contribute to neurodevelopmental disorders developmental neurotoxicity (DNT) becomes an enormous concern. But how can it be tackled? Current animal test-based guidelines are prohibitively expensive, at $1.4 million per substance, while their predictivity for human health effects may be limited, and mechanistic data that would help species extrapolation are not available. A broader screening for substances of concern requires a reliable testing strategy, applicable to larger numbers of substances, and sufficiently predictive to warrant further testing. This review discusses the evidence for possible contributions of environmental chemicals to DNT, limitations of the current test paradigm, emerging concepts and technologies pertinent to in vitro DNT testing and assay evaluation, as well as the prospect of a paradigm shift based on 21st century technologies.

Integrated testing strategies (ITS) for safety assessment

“…In future this can be even further expanded by considering the corresponding human response (Basketter et al, 2014). While highlighting the importance of defining a set of reference substances for ITS development, this fact also highlights the difficulties in compiling a proper list of reference substances for other endpoints, such as reproductive toxicity, (developmental)neurotoxicity (Smirnova et al, 2014) and so on, when only in vivo animal data are available.…”

OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes

“…This was referred to as a "process control" based testing strategy for DNT. In addition, they clearly underlined the regulatory benefit of testing biological processes directly linked to toxicity endophenotypes based on the assumption that nervous system development is impaired when key biological processes are disturbed (Lein et al, 2005;Smirnova et al, 2014). To put this principle into action, a case study was presented for the DNT compound methylmercury that was tested across a large variety of DNT assays covering different neurodevelopmental processes (KEs) and identifying the most sensitive endpoint from those.…”

Evolution of toxicological science: the need for change

“…Possible examples of continuously increasing health problems include atherosclerosis, male infertility and other possible manifestations of endocrine disruption, autism and other developmental behavioural disorders (Smirnova et al, 2014), immunotoxicity (Hartung and Corsini, 2013), childhood asthma and other obstructive lung diseases, obesity, and diabetes. This is not to suggest that these health problems are caused by environmental chemicals, but that their unclear etiology and, in most cases, increasing numbers, suggest the need for testing.…”