Expert opinion: Botanical Safety Consortium advances novel neurotoxicity screening
In a paper published in Expert Opinion on Drug Metabolism and Toxicology, the consortium’s Neurotoxicity Working Group explored the chemical complexity and potential neurotoxic effects of 16 botanicals as case study. It also outlines an initial selection of NAMs, which includes assays using primary rat cortical neurons, zebrafish embryos and Caenorhabditis elegans.
“The work outlined in the present paper represents a first step in the systematic evaluation of in vitro neurotoxicity screening methods for use with botanicals,” the authors wrote. “While the efforts of the BSC are currently focused on screening and hazard identification, the ultimate goal of the consortium is to develop a framework that can facilitate the evaluation of botanicals.”
The authors included leading authorities in toxicology, analytical chemistry, pharmacognosy and in vitro methods from the Food and Drug Administration, National Institutes of Health, Health and Environmental Sciences Institute, Oregon Health & Science University, Purdue University, American Botanical Council and Utrecht University.
The complexity and variability of botanicals
As the working group explained, the complexity and variability of botanicals—which are comprised of anywhere from hundreds to thousands of chemical constituents—can complicate the assessment of potential neurotoxic or neuroactive effects but that the selected assays may be used for relevant botanicals.
“The chemical composition of botanical-based products can vary depending on cultivation, processing and manufacturing conditions; combinations with other botanicals; and product/extract contamination or adulteration,” the experts wrote. “This complexity complicates the assessment of the potential toxicity of products in the market.”
Although botanical-induced neurotoxicity is assessed as uncommon, it may involve direct or indirect effects on neural cells in the peripheral or central nervous system—related to oxidative stress, neuroinflammation, disruption of neurotransmission, protein aggregation, autophagic flux disruption and/or interference with key enzymes.
As an initial step, the paper non-systematically summarized available data related to potential neuroactivity and neurotoxic effects of a set of well-characterized, data-rich botanicals including aconite, aristolochia, ashwagandha, Asian ginseng, blue cohosh, comfrey, ephedra, green tea dry decaffeinated extract, goldenseal, kratom, kava, milk thistle, oleander, Tripterygium, Usnea and yohimbe.
The selected assays and beyond
The working group noted that although many global regulatory frameworks mandate toxicity testing for botanicals, registrants often rely on history-of-use information to assess safety and that regulatory actions are typically prompted by adverse events.
Given the widespread and growing consumption of botanicals as dietary supplements, medicines and consumer products, the experts highlighted the important public health implications of having rapid, relevant, accessible, effective, comprehensive and cost-effective toxicity screening assays. In their opinion, this requires multiple NAMs to address the complexity of botanicals.
While the working group confirmed the evaluation of the assays is key, it also acknowledged that there are many steps between current knowledge and the end goal of developing a screening framework, both for the BSC and for the field of NAMs in general.
“A key area is a better understanding of toxicokinetics, absorption, distribution (including the potential to cross the blood-brain barrier), metabolism and excretion of chemical constituents [...],” the experts wrote. “Such an understanding would aid in in vitro to in vivo extrapolation, which would help with ensuring doses utilized in testing are at human-relevant concentrations and could aid in expanding NAM assessments of botanicals beyond the hazard/screening level.”
Next steps are to test the 16 botanicals using the selected assays as first assessment of suitable methods, evaluate the data, compare the results to the existing literature and develop a toolkit of assays to screen for neurotoxicity.
“In the future, the inclusion of more complex neuronal models with multiple cell types and neurons would help identify more specific effects and mechanisms of actions that these functional and whole organism assays do not provide and aid in developing a more robust framework,” the paper concluded.
“In addition, the inclusion of in vitro assays that cover key neurodevelopmental processes such as neuronal migration and differentiation and neurite outgrowth would aid in describing potential mechanisms of action of botanicals identified as potential developmental neurotoxicant in the whole organism assays evaluated.”
Source: Expert Opinion on Drug Metabolism & Toxicology
“Screening tools to evaluate the neurotoxic potential of botanicals: building a strategy to assess safety”
doi: 10.1080/17425255.2024.2378895
Authors: Jyotshna Kanungo et al.
