Prediction of physicochemical and pharmacokinetic properties of botanical constituents by computational models.

Botanicals contain complex mixtures of chemicals most of which lack pharmacokinetic data in humans. Since physicochemical and pharmacokinetic properties dictate the in vivo exposure of botanical constituents, these parameters greatly impact the pharmacological and toxicological effects of botanicals in consumer products. This study sought to use computational (i.

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.

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.

New Approach Methodologies for the Endocrine Activity Toolbox: Environmental Assessment for Fish and Amphibians.

Multiple in vivo test guidelines focusing on the estrogen, androgen, thyroid, and steroidogenesis pathways have been developed and validated for mammals, amphibians, or fish. However, these tests are resource-intensive and often use a large number of laboratory animals. Developing alternatives for in vivo tests is consistent with the replacement, reduction, and refinement principles for animal welfare considerations, which are supported by increasing mandates to move toward an "animal-free" testing paradigm worldwide.

Ecological Thresholds of Toxicological Concern: A Review.

The ecological threshold of toxicological concern (ecoTTC) is analogous to traditional human health-based TTCs but with derivation and application to ecological species. An ecoTTC is computed from the probability distribution of predicted no effect concentrations (PNECs) derived from either chronic or extrapolated acute toxicity data for toxicologically or chemically similar groups of chemicals. There has been increasing interest in using ecoTTCs in screening level environmental risk assessments and a computational platform has been developed for derivation with aquatic species toxicity data (https://envirotoxdatabase.

Weight of evidence tools in the prediction of acute fish toxicity.

Acute fish toxicity (AFT) is a key endpoint in nearly all regulatory implementations of environmental hazard assessments of chemicals globally. Although it is an early tier assay, the AFT assay is complex and uses many juvenile fish each year for the registration and assessment of chemicals. Thus, it is imperative to seek animal alternative approaches to replace or reduce animal use for environmental hazard assessments.

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.

Investigating endocrine-disrupting properties of chemicals in fish and amphibians: Opportunities to apply the 3Rs.

Many regulations are beginning to explicitly require investigation of a chemical's endocrine-disrupting properties as a part of the safety assessment process for substances already on or about to be placed on the market. Different jurisdictions are applying distinct approaches. However, all share a common theme requiring testing for endocrine activity and adverse effects, typically involving in vitro and in vivo assays on selected endocrine pathways.

An evaluation framework for new approach methodologies (NAMs) for human health safety assessment.

The need to develop new tools and increase capacity to test pharmaceuticals and other chemicals for potential adverse impacts on human health and the environment is an active area of development. Much of this activity was sparked by two reports from the US National Research Council (NRC) of the National Academies of Sciences, Toxicity Testing in the Twenty-first Century: A Vision and a Strategy (2007) and Science and Decisions: Advancing Risk Assessment (2009), both of which advocated for "science-informed decision-making" in the field of human health risk assessment. The response to these challenges for a "paradigm shift" toward using new approach methodologies (NAMS) for safety assessment has resulted in an explosion of initiatives by numerous organizations, but, for the most part, these have been carried out independently and are not coordinated in any meaningful way.

Incorporating new approach methodologies in toxicity testing and exposure assessment for tiered risk assessment using the RISK21 approach: Case studies on food contact chemicals.

Programs including the ToxCast project have generated large amounts of in vitro high‒throughput screening (HTS) data, and best approaches for the interpretation and use of HTS data, including for chemical safety assessment, remain to be evaluated. To fill this gap, we conducted case studies of two indirect food additive chemicals where ToxCast data were compared with in vivo toxicity data using the RISK21 approach. Two food contact substances, sodium (2-pyridylthio)-N-oxide and dibutyltin dichloride, were selected, and available exposure data, toxicity data, and model predictions were compiled and assessed.

Mode of Action Classifications in the EnviroTox Database: Development and Implementation of a Consensus MOA Classification.

Multiple mode of action (MOA) frameworks have been developed in aquatic ecotoxicology, mainly based on fish toxicity. These frameworks provide information on a key determinant of chemical toxicity, but the MOA categories and level of specificity remain unique to each of the classification schemes. The present study aimed to develop a consensus MOA assignment within EnviroTox, a curated in vivo aquatic toxicity database, based on the following MOA classification schemes: Verhaar (modified) framework, Assessment Tool for Evaluating Risk, Toxicity Estimation Software Tool, and OASIS.

Creation of a Curated Aquatic Toxicology Database: EnviroTox.

Flexible, rapid, and predictive approaches that do not require the use of large numbers of vertebrate test animals are needed because the chemical universe remains largely untested for potential hazards. Development of robust new approach methodologies and nontesting approaches requires the use of existing information via curated, integrated data sets. The ecological threshold of toxicological concern (ecoTTC) represents one such new approach methodology that can predict a conservative de minimis toxicity value for chemicals with little or no information available.

An International Perspective on the Tools and Concepts for Effluent Toxicity Assessments in the Context of Animal Alternatives: Reduction in Vertebrate Use.

Since the 1940s, effluent toxicity testing has been used to assess potential ecological impacts of effluents and help determine necessary treatment options for environmental protection prior to release. Strategic combinations of toxicity tests, analytical tools, and biological monitoring have been developed. Because the number of vertebrates utilized in effluent testing is thought to be much greater than that used for individual chemical testing, there is a new need to develop strategies to reduce the numbers of vertebrates (i.

Practical advice for selecting or determining trophic magnification factors for application under the European Union Water Framework Directive.

European Union Directive 2013/39/EU, which amended and updated the Water Framework Directive (WFD; 2000/60/EC) and its daughter directive (2008/105/EC), sets Environmental Quality Standards for biota (EQS ) for a number of bioaccumulative chemicals. These chemicals pose a threat to both aquatic wildlife and human health via the consumption of contaminated prey or the intake of contaminated food originating from the aquatic environment. EU member states will need to establish programs to monitor the concentration of 11 priority substances in biota and assess compliance against these new standards for the classification of surface water bodies.

Qualitative approach to comparative exposure in alternatives assessment.

Most alternatives assessments (AAs) published to date are largely hazard-based rankings, thereby ignoring potential differences in human and/or ecosystem exposures; as such, they may not represent a fully informed consideration of the advantages and disadvantages of possible alternatives. Building on the 2014 US National Academy of Sciences recommendations to improve AA decisions by including comparative exposure assessment into AAs, the Health and Environmental Sciences Institute's (HESI) Sustainable Chemical Alternatives Technical Committee, which comprises scientists from academia, industry, government, and nonprofit organizations, developed a qualitative comparative exposure approach. Conducting such a comparison can screen for alternatives that are expected to have a higher or different routes of human or environmental exposure potential, which together with consideration of the hazard assessment, could trigger a higher tiered, more quantitative exposure assessment on the alternatives being considered, minimizing the likelihood of regrettable substitution.

Advancing the adverse outcome pathway framework-An international horizon scanning approach.

Our ability to conduct whole-organism toxicity tests to understand chemical safety has been outpaced by the synthesis of new chemicals for a wide variety of commercial applications. As a result, scientists and risk assessors are turning to mechanistically based studies to increase efficiencies in chemical risk assessment and making greater use of in vitro and in silico methods to evaluate potential environmental and human health hazards. In this context, the adverse outcome pathway (AOP) framework has gained traction in regulatory science because it offers an efficient and effective means for capturing available knowledge describing the linkage between mechanistic data and the apical toxicity end points required for regulatory assessments.

Alternative approaches to vertebrate ecotoxicity tests in the 21st century: A review of developments over the last 2 decades and current status.

The need for alternative approaches to the use of vertebrate animals for hazard assessment of chemicals and pollutants has become of increasing importance. It is now the first consideration when initiating a vertebrate ecotoxicity test, to ensure that unnecessary use of vertebrate organisms is minimized wherever possible. For some regulatory purposes, the use of vertebrate organisms for environmental risk assessments has been banned; in other situations, the number of organisms tested has been dramatically reduced or the severity of the procedure refined.

A framework for cumulative risk assessment in the 21st century.

The ILSI Health and Environmental Sciences Institute (HESI) has developed a framework to support a transition in the way in which information for chemical risk assessment is obtained and used (RISK21). The approach is based on detailed problem formulation, where exposure drives the data acquisition process in order to enable informed decision-making on human health safety as soon as sufficient evidence is available. Information is evaluated in a transparent and consistent way with the aim of optimizing available resources.

Problem formulation for risk assessment of combined exposures to chemicals and other stressors in humans.

When the human health risk assessment/risk management paradigm was developed, it did not explicitly include a "problem formulation" phase. The concept of problem formulation was first introduced in the context of ecological risk assessment (ERA) for the pragmatic reason to constrain and focus ERAs on the key questions. However, this need also exists for human health risk assessment, particularly for cumulative risk assessment (CRA), because of its complexity.

Use of the RISK21 roadmap and matrix: human health risk assessment of the use of a pyrethroid in bed netting.

The HESI-coordinated RISK21 roadmap and matrix are tools that provide a transparent method to compare exposure and toxicity information and assess whether additional refinement is required to obtain the necessary precision level for a decision regarding safety. A case study of the use of a pyrethroid, "pseudomethrin," in bed netting to control malaria is presented to demonstrate the application of the roadmap and matrix. The evaluation began with a problem formulation step.

Illustrative case using the RISK21 roadmap and matrix: prioritization for evaluation of chemicals found in drinking water.

The HESI-led RISK21 effort has developed a framework supporting the use of twenty-first century technology in obtaining and using information for chemical risk assessment. This framework represents a problem formulation-based, exposure-driven, tiered data acquisition approach that leads to an informed decision on human health safety to be made when sufficient evidence is available. It provides a transparent and consistent approach to evaluate information in order to maximize the ability of assessments to inform decisions and to optimize the use of resources.

It is time to develop ecological thresholds of toxicological concern to assist environmental hazard assessment.

The threshold of toxicological concern (TTC) concept is well established for assessing human safety of food-contact substances and has been reapplied for a variety of endpoints, including carcinogenicity, teratogenicity, and reproductive toxicity. The TTC establishes an exposure level for chemicals below which no appreciable risk to human health or the environment is expected, based on a de minimis value for toxicity identified for many chemicals. Threshold of toxicological concern approaches have benefits for screening-level risk assessments, including the potential for rapid decision-making, fully utilizing existing knowledge, reasonable conservativeness for chemicals used in lower volumes (low production volume chemicals (e.