Advancing botanical safety: A strategy for selecting, sourcing, and characterizing botanicals for developing toxicological tools.

Increases in botanical use, encompassing herbal medicines and dietary supplements, have underlined a critical need for an advancement in safety assessment methodologies. However, botanicals present unique challenges for safety assessment due to their complex and variable composition arising from diverse growing conditions, processing methods, and plant varieties. Historically, botanicals have been largely evaluated based on their history of use information, based primarily on traditional use or dietary history. However, this presumption lacks comprehensive toxicological evaluation, demanding innovative and consistent assessment strategies. To address these challenges, the Botanical Safety Consortium (BSC) was formed as an international, cross-sector forum of experts to identify fit-for purpose assays that can be used to evaluate botanical safety. This global effort aims to assess botanical safety assessment methodologies, merging traditional knowledge with modern in vitro and in silico assays. The ultimate goal is to champion the development of toxicity tools for botanicals. This manuscript highlights: 1) BSC's strategy for botanical selection, sourcing, and preparation of extracts to be used in in vitro assays, and 2) the approach utilized to characterize botanical extracts, using green tea and Asian ginseng as examples, to build confidence for use in biological assays.

Neuroactivity screening of botanical extracts using microelectrode array (MEA) recordings.

Toxicity testing of botanicals is challenging because of their chemical complexity and variability. Since botanicals may affect many different modes of action involved in neuronal function, we used microelectrode array (MEA) recordings of primary rat cortical cultures to screen 16 different botanical extracts for their effects on cell viability and neuronal network function in vitro. Our results demonstrate that extract materials (50 µg/mL) derived from goldenseal, milk thistle, tripterygium, and yohimbe decrease mitochondrial activity following 7 days exposure, indicative of cytotoxicity. Importantly, most botanical extracts alter neuronal network function following acute exposure. Extract materials (50 µg/mL) derived from aristolochia, ephedra, green tea, milk thistle, tripterygium, and usnea inhibit neuronal activity. Extracts of kava, kratom and yohimbe are particularly potent and induce a profound inhibition of neuronal activity at the low dose of 5 µg/mL. Extracts of blue cohosh, goldenseal and oleander cause intensification of the bursts. Aconite extract (5 µg/mL) evokes a clear hyperexcitation with a marked increase in the number of spikes and (network) bursts. The distinct activity patterns suggest that botanical extracts have diverse modes of action. Our combined data also highlight the applicability of MEA recordings for hazard identification and potency ranking of botanicals.

Improving the rigor and utility of botanical toxicity studies: Recommended resources.

Interest in botanicals, particularly as dietary supplement ingredients, is growing steadily. This growth, and the marketing of new ingredients and combination products as botanical dietary supplements, underscores the public health need for a better understanding of potential toxicities associated with use of these products. This article and accompanying template outline the resources to collect literature and relevant information to support the design of botanical toxicity studies. These resources provide critical information related to botanical identification, characterization, pre-clinical and clinical data, including adverse effects and interactions with pharmaceuticals. Toxicologists using these resources should collaborate with pharmacognosists and/or analytical chemists to enhance knowledge of the botanical material being tested. Overall, this guide and resource list is meant to help locate relevant information that can be leveraged to inform on decisions related to toxicity testing of botanicals, including the design of higher quality toxicological studies.

Potential pharmacokinetic interactions with concurrent use of herbal medicines and a ritonavir-boosted COVID-19 protease inhibitor in low and middle-income countries.

The COVID-19 pandemic sparked the development of novel anti-viral drugs that have shown to be effective in reducing both fatality and hospitalization rates in patients with elevated risk for COVID-19 related morbidity or mortality. Currently, nirmatrelvir/ritonavir (Paxlovid™) fixed-dose combination is recommended by the World Health Organization for treatment of COVID-19. The ritonavir component is an inhibitor of cytochrome P450 (CYP) 3A, which is used in this combination to achieve needed therapeutic concentrations of nirmatrelvir. Because of the critical pharmacokinetic effect of this mechanism of action for Paxlovid™, co-administration with needed medications that inhibit or induce CYP3A is contraindicated, reflecting concern for interactions with the potential to alter the efficacy or safety of co-administered drugs that are also metabolized by CYP3A. Some herbal medicines are known to interact with drug metabolizing enzymes and transporters, including but not limited to inhibition or induction of CYP3A and P-glycoprotein. As access to these COVID-19 medications has increased in low- and middle-income countries (LMICs), understanding the potential for herb-drug interactions within these regions is important. Many studies have evaluated the utility of herbal medicines for COVID-19 treatments, yet information on potential herb-drug interactions involving Paxlovid™, specifically with herbal medicines commonly used in LMICs, is lacking. This review presents data on regionally-relevant herbal medicine use (particularly those promoted as treatments for COVID-19) and mechanism of action data on herbal medicines to highlight the potential for herbal medicine interaction Herb-drug interaction mediated by ritonavir-boosted antiviral protease inhibitors This work highlights potential areas for future experimental studies and data collection, identifies herbal medicines for inclusion in future listings of regionally diverse potential HDIs and underscores areas for LMIC-focused provider-patient communication. This overview is presented to support governments and health protection entities as they prepare for an increase of availability and use of Paxlovid™.

Plant vs. Kidney: Evaluating Nephrotoxicity of Botanicals with the Latest Toxicological Tools.

Botanicals can cause nephrotoxicity via numerous mechanisms, including disrupting renal blood flow, damaging compartments along the nephron, and obstructing urinary flow. While uncommon, there are various reports of botanical-induced nephrotoxicity in the literature, such as from aristolochia (Aristolochia spp.) and rhubarb (Rheum spp.). However, at present, it is a challenge to assess the toxic potential of botanicals because their chemical composition is variable due to factors such as growing conditions and extraction techniques. Therefore, selecting a single representative sample for an in vivo study is difficult. Given the increasing use of botanicals as dietary supplements and herbal medicine, new approach methodologies (NAMs) are needed to evaluate the potential for renal toxicity to ensure public safety. Such approaches include in vitro models that use layers of physiological complexity to emulate the in vivo microenvironment, enhance the functional viability and differentiation of cell cultures, and improve sensitivity to nephrotoxic insults. Furthermore, computational tools such as physiologically based pharmacokinetic (PBPK) modeling can add confidence to these tools by simulating absorption, distribution, metabolism, and excretion. The development and implementation of NAMs for renal toxicity testing will allow specific mechanistic data to be generated, leading to a better understanding of the nephrotoxic potential of botanicals.

The Botanical Safety Consortium: A public-private partnership to enhance the botanical safety toolkit.

Botanical dietary supplement use is widespread and growing, therefore, ensuring the safety of botanical products is a public health priority. This commentary describes the mission and objectives of the Botanical Safety Consortium (BSC) - a public-private partnership aimed at enhancing the toolkit for conducting the safety evaluation of botanicals. This partnership is the result of a Memorandum of Understanding between the US FDA, the National Institute of Environmental Health Sciences, and the Health and Environmental Sciences Institute. The BSC serves as a global forum for scientists from government, academia, consumer health groups, industry, and non-profit organizations to work collaboratively on adapting and integrating new approach methodologies (NAMs) into routine botanical safety assessments. The objectives of the BSC are to: 1) engage with a group of global stakeholders to leverage scientific safety approaches; 2) establish appropriate levels of chemical characterization for botanicals as complex mixtures; 3) identify pragmatic, fit-for-purpose NAMs to evaluate botanical safety; 4) evaluate the application of these tools via comparison to the currently available safety information on selected botanicals; 5) and integrate these tools into a framework that can facilitate the evaluation of botanicals. Initially, the BSC is focused on oral exposure from dietary supplements, but this scope could be expanded in future phases of work. This commentary provides an overview of the structure, goals, and strategies of this initiative and insights regarding our first objectives, namely the selection and prioritization of botanicals based on putative toxicological properties.

Comparing laboratory and field measured bioaccumulation endpoints.

An approach for comparing laboratory and field measures of bioaccumulation is presented to facilitate the interpretation of different sources of bioaccumulation data. Differences in numerical scales and units are eliminated by converting the data to dimensionless fugacity (or concentration-normalized) ratios. The approach expresses bioaccumulation metrics in terms of the equilibrium status of the chemical, with respect to a reference phase. When the fugacity ratios of the bioaccumulation metrics are plotted, the degree of variability within and across metrics is easily visualized for a given chemical because their numerical scales are the same for all endpoints. Fugacity ratios greater than 1 indicate an increase in chemical thermodynamic activity in organisms with respect to a reference phase (e.g., biomagnification). Fugacity ratios less than 1 indicate a decrease in chemical thermodynamic activity in organisms with respect to a reference phase (e.g., biodilution). This method provides a holistic, weight-of-evidence approach for assessing the biomagnification potential of individual chemicals because bioconcentration factors, bioaccumulation factors, biota-sediment accumulation factors, biomagnification factors, biota-suspended solids accumulation factors, and trophic magnification factors can be included in the evaluation. The approach is illustrated using a total 2393 measured data points from 171 reports, for 15 nonionic organic chemicals that were selected based on data availability, a range of physicochemical partitioning properties, and biotransformation rates. Laboratory and field fugacity ratios derived from the various bioaccumulation metrics were generally consistent in categorizing substances with respect to either an increased or decreased thermodynamic status in biota, i.e., biomagnification or biodilution, respectively. The proposed comparative bioaccumulation endpoint assessment method could therefore be considered for decision making in a chemicals management context.