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Although the United States Food & Drug Administration (FDA) has provided guidance on the control of drug degradants for prescription drugs, there is less guidance on how to set degradant specifications for FDA OTC monograph drugs. Given that extensive impurity testing was not part of the safety paradigm in original OTC monographs, a weight of evidence (WOE) approach to qualify OTC degradants is proposed. This approach relies on in silico tools and read-across approaches alongside standard toxicity testing to determine safety. Using several drugs marketed under 21 CFR 341 as case studies, this research demonstrates the utility of a WOE approach across data-rich and data-poor degradants. Based on degradant levels ranging from 1 to 4% of the maximum daily doses of each case study drug and 10th percentile body weight data for each patient group, children were recognized as having the highest potential exposure relative to adults per body mass. Depending on data availability and relationship to the parent API, margins of safety (MOS) or exposure margins were calculated for each degradant. The findings supported safe use, and indicated that this contemporary WOE approach could be utilized to assess OTC degradants. This approach is valuable to establish specifications for degradants in OTCs. • There is a need to establish safety profiles of common degradants in OTC drugs. • In silico tools were integrated with traditional safety data to evaluate degradants. • Approaches used applied to data-rich and data-poor degradants. • A weight-of-evidence approach was used to establish safety of common OTC cough/cold degradants. [ABSTRACT FROM AUTHOR]

A history of safe use is a backbone of safety assessments for many current probiotic species, however, there is no global harmonization regarding requirements for establishing probiotic safety for use in foods and supplements. As probiotic manufacturers are increasingly seeking to use new strains, novel species, and next-generation probiotics, justification based on a significant history of use may be challenged. There are efforts underway by a variety of stakeholders, including the United States Pharmacopeia (USP), to develop best practices guidelines for assessing the quality and safety of probiotics. A current initiative of the USP seeks to provide expert advice specific to safety considerations for probiotics. Toward this goal, this review provides a helpful summary guide to global regulatory guidelines. We question the suitability of traditional animal toxicology studies designed for testing chemicals for relevance in assessing probiotic safety. This includes discussion of the use of excessive dose levels, the length of repeated dose toxicity studies needed, and the most suitable animal species used in toxicology studies. In addition, the importance of proper manufacturing practices with regard to final product safety are also included. Thus, an outline of essential parameters of a comprehensive safety assessment for a probiotic are provided. • United States Pharmacopeia (USP) expert advice specific for safety considerations for probiotics. • Summary guide of global regulatory guidelines for assessing probiotic safety. • Suitability of traditional animal toxicology studies for use in studying the safety of probiotics. • Essential parameters of a comprehensive safety assessment for a probiotic dietary supplement product. [ABSTRACT FROM AUTHOR]

The use of natural products (NPs), including herbal medicines and other dietary supplements, by North Americans continues to increase across all age groups. This population has access to conventional medications, with significant polypharmacy observed in older adults. Thus, the safety of the interactions between multi-ingredient NPs and drugs is a topic of paramount importance. Considerations such as history of safe use, literature data from animal toxicity and human clinical studies, and NP constituent characterization would provide guidance on whether to assess NP-drug interactions experimentally. The literature is replete with reports of various NP extracts and constituents as potent inhibitors of drug metabolizing enzymes, and transporters. However, without standard methods for NP characterization or in vitro testing, extrapolating these reports to clinically-relevant NP-drug interactions is difficult. This lack of a clear definition of risk precludes clinicians and consumers from making informed decisions about the safety of taking NPs with conventional medications. A framework is needed that describes an integrated robust approach for assessing NP-drug interactions; and, translation of the data into formulation alterations, dose adjustment, labelling, and/or post-marketing surveillance strategies. A session was held at the 41st Annual Summer Meeting of the Toxicology Forum in Colorado Springs, CO, to highlight the challenges and critical components that should be included in a framework approach. [ABSTRACT FROM AUTHOR]

In its review of the U.S. Environmental Protection Agency's toxicological review of inorganic arsenic (iAs), the National Academy of Sciences identified carcinogenic endpoints among the highest priority health effects of concern and stated the need to consider evidence that early life exposures may increase the risk of adverse health effects. Recent studies in mice suggest that in utero exposure to arsenic increases susceptibility to cancer later in life. These data are striking in light of the general lack of evidence for carcinogenicity in rodents exposed to iAs. To evaluate the transplacental carcinogenic potential of iAs, a detailed analysis of the toxicology literature evaluating the role of in utero arsenic exposure in carcinogenesis was conducted. Bladder, lung, and skin tumors, which are the tumor types most consistently reported in humans exposed to high arsenic levels, were not consistently increased in mouse studies. There was also a lack of concordance across studies for other tumor types not typically reported in humans. Therefore, we considered methodological and other critical issues that may have contributed to variable results and we suggest additional studies to address these issues. It was concluded that the available data do not provide evidence of a causal link between in utero arsenic exposure and cancer or indicate early life-stage susceptibility to arsenic-induced cancer, particularly at environmentally relevant doses. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Assessing the safety of botanicals in dietary supplements is a public health need. • Discussion of resources and guidelines for high-quality botanical toxicity studies. • Systematic approach to literature reviews with a template. [ABSTRACT FROM AUTHOR]

Recently Bergman et al. (2015) took issue with our comments (Lamb et al., 2014) on the WHO-UNEP 1 report entitled the “State of the Science of Endocrine Disrupting Chemicals – 2012” (WHO 2013a). We find several key differences between their view and ours regarding the selection of studies and presentation of data related to endocrine disrupting chemicals (EDCs) under the WHO-IPCS 2 definition (2002). In this response we address the factors that we think are most important: 1. the difference between hazard and risk; 2. the different approaches for hazard identification (weight of the evidence [WOE] vs. emphasizing positive findings over null results); and 3. the lack of a justification for conceptual or practical differences between EDCs and other groups of agents. [ABSTRACT FROM AUTHOR]

Highlights: [•] We critically review the WHO-UNEP 2012 report on endocrine disruptors. [•] WHO-UNEP report is not an update of the WHO-IPCS 2002 state-of-the-science review. [•] WHO-UNEP report should not guide evidence-based decisions on endocrine disruption. [•] A balanced and objective review of all available literature is needed. [•] An update must note controversies, data gaps, and provide supported conclusions. [Copyright &y& Elsevier]

During the 25 years since the US Congress passed the Dietary Supplement Health and Education Act (DSHEA), the law that transformed the US Food and Drug Administration's (FDA's) authority to regulate dietary supplements, the dietary supplement market has grown exponentially. Retail sales of herbal products, a subcategory of dietary supplements, have increased 83% from 2008 to 2018 ($4.8 to $8.8 billion USD). Although consumers often equate "natural" with "safe", it is well recognized by scientists that constituents in these natural products (NPs) can result in toxicity. Additionally, when NPs are co-consumed with pharmaceutical agents, the precipitant NP can alter drug disposition and drug delivery, thereby enhancing or reducing the therapeutic effect of the object drug(s). With the widespread use of NPs, these effects can be underappreciated. We present a summary of a symposium presented at the Annual Meeting of the Society of Toxicology 2019 (12 March 2019) that discussed potential toxicities of NPs alone and in combination with drugs. • In the past 25 years, the dietary supplement market has grown from 4000 to more than 80,000 products. • Consumers equate "natural" with "safe"; some natural products (NPs) can cause drug interactions. • Cannabinoid compounds can cause hazardous drug interactions with other anti-seizure drugs. • In vitro techniques can be used to evaluate inhibition or induction of drug metabolizing enzymes. • NIH-funded center will provide guidance on conduct/translation of NP-drug interaction studies. [ABSTRACT FROM AUTHOR]