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The Dietary Supplement Health and Education Act (DSHEA) of 1994 defined the FDA's statutory authority to regulate dietary supplement products as a category of food in the United States. As we celebrate 30 years post-DSHEA, it is important to reflect on its significance for public health, influence on the continuously evolving and expanding product category, the current regulatory framework, and potential opportunities or modernizing oversight to ensure a strong and well-regulated marketplace. An estimated three-fourths of U.S. consumers report use of dietary supplements, and the product market has grown substantially since the passage of DSHEA, from approximately 4,000 products in 1994 to 80,000+ present day. This growth represents a current $60 billion domestic and $200 billion international market for dietary supplements. Scientists, public health officials, health care providers, patients, consumer advocacy organizations, and the U.S. Food and Drug Administration have all called for reform to what has been described as 'outdated' regulation of dietary supplements. Advancing at an even faster rate is published scientific evidence in the space. This special issue of the Journal of Dietary Supplements comprises a collection of articles authored by academicians, legal scholars, representatives of U.S. government agencies, and industry scientists that critically examine the successes, challenges, and opportunities for improving specific aspects of DSHEA and domestic health policy. This editorial provides historical context and milestones of dietary supplement regulation in the U.S. post-DSHEA and offers an overview of the research contained within the special issue. Advancing toward a more transparent and safer marketplace requires trustworthy supply chains, increased adherence to quality standards, additional labeling requirements, and enhancement of post-market surveillance. This special issue seeks to contribute to the broader understanding of dietary supplement regulation and its future direction.

Botanical supplements, herbal remedies, and plant-derived products are used globally. However, botanical dietary supplements are rarely subjected to robust safety testing unless there are adverse reports in post-market surveillance. Botanicals are complex and difficult to assess using current frameworks designed for single constituent substances (e.g. small molecules or discrete chemicals), making safety assessments costly and time-consuming. The liver is a primary organ of concern for potential botanical-induced hepatotoxicity and botanical-drug interactions as it plays a crucial role in xenobiotic metabolism. The NIH-funded Drug Induced Liver Injury Network noted that the number of botanical-induced liver injuries in 2017 nearly tripled from those observed in 2004-2005. New approach methodologies (NAMs) can aid in the rapid and cost-effective assessment of botanical supplements for potential hepatotoxicity. The Hepatotoxicity Working Group within the Botanical Safety Consortium is working to develop a screening strategy that can help reliably identify potential hepatotoxic botanicals and inform mechanisms of toxicity. This manuscript outlines the Hepatotoxicity Working Group's strategy and describes the assays selected and the rationale for the selection of botanicals used in case studies. The selected NAMs evaluated as a part of this effort are intended to be incorporated into a larger battery of assays to evaluate multiple endpoints related to botanical safety. This work will contribute to a botanical safety toolkit, providing researchers with tools to better understand hepatotoxicity associated with botanicals, prioritize and plan future testing as needed, and gain a deeper insight into the botanicals being tested.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus responsible for the COVID-19 pandemic that can lead to severe respiratory distress requiring hospitalization and can be fatal. Media have reported that various dietary supplements (DS) or their combination with different medications can prevent infection or decrease disease severity. Here, we analyzed data collected from 15,830 patient follow-up telephone interviews from the University of Arkansas for Medical Sciences COVID-19 testing sites from March 15 to August 1, 2020. Within the REDCap database, we recorded patient demographics and DS and medication use. In total, data on DS and medication use was available for 8,150 study participants, of whom 21.9% and 4.1% reported using DS or medications, respectively, to either prevent or treat COVID-19. The majority of respondents were female (64%) and non-Hispanic whites (44.5%). Most individuals (64.5%) who took DS were younger than 50 years of age. Products such as vitamin C (1,013, 33.2%), multivitamins (722, 23.6%), and vitamin D (294, 9.6%) were the most commonly used DS among the responders. Analysis of the DS use and symptom scores association did not provide a strong evidence of beneficial health effects of DS. The results of this study demonstrate that a significantly higher proportion of study participants considered usage of DS to mitigate or prevent COVID-19-related symptoms compared to those who preferred medications. However, lack of observable health benefits associated with ingestion of DS suggests that more rigorous research is needed to substantiate the label claims.

Methylsulfonylmethane (MSM), a natural organosulfur compound, is a popular dietary supplement sold both as a single product and as a constituent of multi-ingredient products. It has been postulated that MSM may serve as a donor for methyl groups for various cellular processes; however, studies have yet to demonstrate this. Therefore, the goal of this study was to determine whether or not MSM, supplemented to fully differentiated human HepaRG cells at physiologically-relevant concentrations, can serve as a donor for methyl groups for DNA methylation. For this purpose, methyl groups in the MSM molecule were labeled with deuterium (deuterated) and incorporation of the labeled 5-methylcytosine into the HepaRG cell DNA was evaluated using liquid chromatography/mass spectrometry (LC-MS/MS). We report that MSM supplementation resulted in significant incorporation of deuterated product into DNA in a time- and dose-dependent fashion. These changes were not associated with increased 5-methylcytosine content, did not result in changes of DNA methylation or re-distribution of DNA methylation patterns between the retrotransposons LINE-1 and HERV18, and were not associated with cytotoxicity. In conclusion, short-term supplementation with MSM in vitro demonstrates that MSM can serve as a donor of methyl groups for methylation of DNA, but does not affect the levels of DNA methylation globally and does not lead to redistribution of the DNA methylation patterns within the most abundant repetitive elements. Future studies will be needed to validate these findings in vivo and to investigate whether or not MSM can restore normal DNA methylation patterns within the hypomethylated phenotype.

Cannabidiol (CBD) is a non-psychotropic constituent of Cannabis sativa that has grown in popularity during the last decade. CBD is the active component of EPIDIOLEX®, a U.S. Food and Drug Administration (FDA)-approved drug designed for the treatment of drug-resistant pediatric epileptic seizures associated with several rare syndromes. Furthermore, CBD has been proposed as a treatment for a number of other diseases for which clinical trials are now ongoing. Accumulating evidence indicates that the number of "CBD-containing" products, available mostly online, is growing exponentially. However, the U.S. FDA currently prohibits sales of CBD as a dietary supplement (DS) or ingredient in conventional food. Further, clear federal regulatory and quality oversight does not exist, which has led to an uncontrolled CBD market that, in turn, threatens to result in negative health effects experienced by a trusting public. Thus, there are open questions demanding answers in the very near future: For which medical purposes is CBD provably effective? Can it be used safely as a non-prescription product? At what level? Is a hemp extract that contains CBD a different ingredient than isolated CBD? Is CBD safe for everyone? What is a future path for hemp products with CBD as well as for other cannabinoids? Should CBD be allowed as a drug only, or is there a way for hemp extracts to be listed as a dietary supplement and food ingredient? This Special Issue, the first of its kind on CBD and other phytocannabinoids, is devoted to answering those and other questions by publishing articles in the fields of pharmacology, toxicology, and regulation.

The proliferation in the last few years of cannabidiol (CBD)-containing products in the U.S. markets has been greatly accelerated by changes in the regulatory environment, and by perceptions of their health benefits and presumed safety. The result has been aggressive marketing of many types of products, some of dubious quality, making or implying drug-type claims. The recent approval by the U.S. Food and Drug Administration (FDA) of CBD in the form of Epidiolex®, further complicates the regulatory picture. In addition, a number of studies suggest that, at least at high doses, there may be serious adverse effects or drug interactions associated with CBD. At present, CBD-containing products do not meet the strict definition of dietary supplements, but the FDA is continuing to consider some framework under which they might be allowed. Meanwhile, FDA has adopted a "risk-based" enforcement policy. Possible approaches to a new framework for regulation of CBD products as dietary supplements are discussed here, including expanded research emphasis, a robust corporate stewardship program, and a rigorous adverse event reporting program.

Cannabidiol (CBD) is the major non-psychotropic phytocannabinoid present in Cannabis sativa . In 2018, Congress designated certain C. sativa plant material as "hemp," thus removing it from the DEA's list of controlled substances. As a result, CBD-containing hemp extracts and other CBD products are now widely available and heavily marketed, yet their FDA regulatory status is still hotly debated. The goal of this study was to investigate the effects of a cannabidiol-rich cannabis extract (CRCE) on the gut microbiome and associated histomorphological and molecular changes in the mouse gut mucosa. Male C57BL6/J mice were gavaged with either 0, 61.5, 184.5, or 615   mg/kg/bw of CRCE in sesame oil for 2   weeks (Mon-Fri). Substantial CRCE-induced increases in the relative abundance of A. muciniphila , a bacterial species currently accepted as probiotic, was observed in fecal samples at all doses. This was paralleled by decreases in the relative abundance of other gut bacterial species. Coincident with the observed changes in gut ecology were multiple pro-inflammatory responses, including increased expression of cytokines and chemokines- Il1ß , Cxcl1 , and Cxcl2 in the colon tissue. Furthermore, dramatic increases in the relative abundance of A. muciniphila significantly decreased expression of Muc2- a gene intimately associated with gut integrity. Taken together, these findings raise concerns about the safety of long-term CBD usage and underline the need for additional well-designed studies into its tolerability and efficacy.

Evidence continues to grow on potential environmental health hazards associated with engineered nanomaterials (ENMs). While the geno- and cytotoxic effects of ENMs have been investigated, their potential to target the epigenome remains largely unknown. The aim of this study is two-fold: 1) determining whether or not industry relevant ENMs can affect the epigenome in vivo and 2) validating a recently developed in vitro epigenetic screening platform for inhaled ENMs. Laser printer-emitted engineered nanoparticles (PEPs) released from nano-enabled toners during consumer use and copper oxide (CuO) were chosen since these particles induced significant epigenetic changes in a recent in vitro companion study. In this study, the epigenetic alterations in lung tissue, alveolar macrophages and peripheral blood from intratracheally instilled mice were evaluated. The methylation of global DNA and transposable elements (TEs), the expression of the DNA methylation machinery and TEs, in addition to general toxicological effects in the lung were assessed. CuO exhibited higher cell-damaging potential to the lung, while PEPs showed a greater ability to target the epigenome. Alterations in the methylation status of global DNA and TEs, and expression of TEs and DNA machinery in mouse lung were observed after exposure to CuO and PEPs. Additionally, epigenetic changes were detected in the peripheral blood after PEPs exposure. Altogether, CuO and PEPs can induce epigenetic alterations in a mouse experimental model, which in turn confirms that the recently developed in vitro epigenetic platform using macrophage and epithelial cell lines can be successfully utilized in the epigenetic screening of ENMs.

Extensive incorporation of engineered nanomaterials (ENMs) into industrial and biomedical applications increases the risks of exposure to these potentially hazardous materials. While the geno- and cytotoxic effects of ENMs have been investigated, the potential of ENMs to target the cellular epigenome remains largely unknown. Our goal was to determine whether industry relevant ENMs can affect the epigenome at low cytotoxic doses. A panel of cells relevant to inhalation exposures such as human and murine macrophages (THP-1 and RAW264.7, respectively) and human small airway epithelial cells (SAEC) were exposed to printer-emitted engineered nanoparticles (PEPs), mild steel welding fumes (MS-WF), copper oxide (CuO) and titanium dioxide nanoparticles. Toxicological effects, including cytotoxicity, oxidative stress and inflammatory responses were assessed, taking into consideration in vitro dosimetry. The effects of ENMs on cellular epigenome were determined by addressing the global and transposable elements (TEs)-associated DNA methylation and expression of DNA methylation machinery and TEs. The percentage of ENMs-induced cytotoxicity for all cell lines was in the range of 0-15%. Oxidative stress was evident in SAEC after exposure to PEPs and in THP-1 when exposed to CuO. In addition, exposure to ENMs resulted in modest alterations in DNA methylation of two most abundant TEs in mammalian genomes, LINE-1 and Alu/SINE, their transcriptional reactivation, and decreased expression of DNA methylation machinery in a cell-, dose- and ENM-dependent manner. These results indicate that exposure to ENMs at environmentally relevant concentrations, aside from the geno- and cytotoxic effects, can also affect the epigenome of target cells.

Introduction: MicroRNAs (miRNAs) comprise a family of short non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. Rapidly growing evidence indicates that miRNAs play a key role in drug (xenobiotic) metabolism., Areas Covered: This review summarizes the current knowledge of the role of miRNAs in the regulation of drug (xenobiotic) metabolizing genes and the cellular responses to exposure to exogenous toxicants. The literature search was performed using the PubMed database (up to March 2012)., Expert Opinion: miRNAs play a major role in control of the proper functioning of the cellular drug metabolizing system. Emerging evidence indicates that exposure to environmental and occupational toxicants and therapeutic drugs may alter the expression of miRNAs, including those that regulate the expression of drug metabolizing genes. This suggests that drug-induced (xenobiotic-induced) miRNA abnormalities may be one of the underlying mechanisms in the pathogenesis of exposure-related pathologies, and that miRNAs may be potential non-invasive biomarkers of exposure and indicators of the severity of tissue injury induced by toxicants. Also, the evaluation of the expression of miRNAs may be applied for the chemical and drug safety assessment. Additionally, differences in the expression of miRNAs that target drug metabolizing genes may be important determinants for inter-individual differences in sensitivity to toxicants and can serve as critical biomarkers for identifying subpopulations sensitive to exposure.

Recent advances in field of cancer research have established that all major human cancers, in addition to having a large number of genetic alterations, exhibit prominent epigenetic abnormalities that can be used as biomarkers for the molecular diagnosis of cancer. Currently, epigenetic markers have shown promise in establishing the diagnosis and prognosis of all major human cancers. Additionally, accumulating evidence suggests that epigenetic alterations may be early indicators of genotoxic and non-genotoxic carcinogenic exposure and may be used as biomarkers in the assessment of the carcinogenic potential of environmental chemical and physical agents. This review presents current evidence on the role of epigenetic alterations in chemical carcinogenesis and highlights a number of advantages of epigenetic biomarkers over traditionally used methods in cancer risk assessment.