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Environmental context: Pesticides are critical to agriculture and food production but require ecological risk assessments. Although most risk assessments require data from vertebrate animal testing, we have developed an approach to assess risk to fish, birds and mammals using other means. This approach could help to ensure protection of the environment while minimising animal testing. Rationale: Recent directives to reduce animal testing have implications for ecological risk assessment, as several vertebrate tests are used to support these assessments. Therefore, a modern approach was devised to address these key knowledge needs without the use of chemical-specific vertebrate testing. Methodology: An ecological risk assessment for a novel acetyl-coenzyme A carboxylase (ACCase) inhibitor herbicide was conducted using alternative lines of evidence. For fish, chemical toxicity distributions were constructed to quantify the probability of effects, and these distributions were compared with exposure estimates for a representative use in soybeans. The effect distributions were further refined based on invertebrate toxicity and partitioning behaviour. For birds and mammals, a joint probability curve was constructed by integrating chemical toxicity distributions and Kenaga exposure distributions. Results: The lines of evidence presented in this predictive risk assessment suggest the intended use of a new ACCase inhibitor is unlikely to affect fish, birds, or mammals. Exposure was unlikely to exceed effect estimates, regardless of whether they were derived based on chemical-read across, invertebrate toxicity, or partitioning behaviour. Discussion: Key knowledge needs for ecological risk assessment can be informed by lines of evidence that do not require animal testing. The present study demonstrates such an approach by comparing predicted exposure and effects, which are expected to be protective. This predictive approach can be extended to other active ingredients and chemical classes, as well as other taxonomic groups of interest. Future research should aim to integrate new approach methods in a predictive risk assessment framework. Environmental context. Pesticides are critical to agriculture and food production but require ecological risk assessments. Although most risk assessments require data from vertebrate animal testing, we have developed an approach to assess risk to fish, birds and mammals using other means. This approach could help to ensure protection of the environment while minimising animal testing. This article belongs to the collection NAMs in Environmental Chemistry and Toxicology. [ABSTRACT FROM AUTHOR]

In 2019, the US EPA Administrator issued a directive directing the agency away from reliance on vertebrate tests by 2035, whilst maintaining high-quality human health and environmental risk assessments. There is no accepted approach to achieve this. The decade-long duration of the crop protection (CP) chemical R&D process therefore requires both the invention and application of a modernized approach to those CP chemical projects entering corporate research portfolios by the mid-2020s. We conducted problem formulation discussions with regulatory agency scientists which created the problem statement: "Develop, demonstrate, and implement a modern scientifically sound and robust strategy that applies appropriate and flexible exposure and effects characterization without chemical specific vertebrate tests to reliably address risk, uncertainties, and deficiencies in data and its interpretation with equivalent confidence as do the currently accepted test guidelines and meet the regulatory needs of the agencies". The solution must provide the knowledge needed to confidently conclude human health and environmental protective risk assessments. Exploring this led to a conceptual model involving the creation and parallel submission of a new approach without reliance on chemical-specific vertebrate tests. Assessment in parallel to a traditional package will determine whether it supports some, or all, of the necessary risk management actions. Analysis of any deficiencies will provide valuable feedback to focus development of tools or approaches for subsequent iterations. When found to provide sufficient information, it will form the technical foundation of stakeholder engagement to explore acceptance of a new approach to CP chemical risk assessment. Plain language summary The US EPA, and other regulatory agencies, aim to reduce the use of vertebrate animal tests for assessing risks of crop protection chemicals. There is currently no accepted way to do this. We outline a proposal to perform both the assessment using traditional vertebrate testing and a set of new non-animal methods. These data sets must each be combined with a calculated estimate of user exposure to the pesticide based on its intended use. Comparing the outcome of these two assessments will show whether the set of non-animal methods needs to be improved further. When the new approach appears to reliably predict the risks, the different stakeholders must be brought together to assess whether the non-animal methods package is acceptable and can replace the tests on vertebrate animals while maintaining the same level of protection of human health and the environment. [ABSTRACT FROM AUTHOR]

Progress in developing new tools, assays, and approaches to assess human hazard and health risk provides an opportunity to re-evaluate the necessity of dog studies for the safety evaluation of agrochemicals. A workshop was held where participants discussed the strengths and limitations of past use of dogs for pesticide evaluations and registrations. Opportunities were identified to support alternative approaches to answer human safety questions without performing the required 90-day dog study. Development of a decision tree for determining when the dog study might not be necessary to inform pesticide safety and risk assessment was proposed. Such a process will require global regulatory authority participation to lead to its acceptance. The identification of unique effects in dogs that are not identified in rodents will need further evaluation and determination of their relevance to humans. The establishment of in vitro and in silico approaches that can provide critical data on relative species sensitivity and human relevance will be an important tool to advance the decision process. Promising novel tools including in vitro comparative metabolism studies, in silico models, and high-throughput assays able to identify metabolites and mechanisms of action leading to development of adverse outcome pathways will need further development. To replace or eliminate the 90-day dog study, a collaborative, multidisciplinary, international effort that transcends organizations and regulatory agencies will be needed in order to develop guidance on when the study would not be necessary for human safety and risk assessment. [ABSTRACT FROM AUTHOR]

Use of molecular data in human and ecological health risk assessments of industrial chemicals and agrochemicals has been anticipated by the scientific community for many years; however, these data are rarely used for risk assessment. Here, a logic framework is proposed to explore the feasibility and future development of transcriptomic methods to refine and replace the current apical endpoint-based regulatory toxicity testing paradigm. Four foundational principles are outlined and discussed that would need to be accepted by stakeholders prior to this transformative vision being realized. Well-supported by current knowledge, the first principle is that transcriptomics is a reliable tool for detecting alterations in gene expression that result from endogenous or exogenous influences on the test organism. The second principle states that alterations in gene expression are indicators of adverse or adaptive biological responses to stressors in an organism. Principle 3 is that transcriptomics can be employed to establish a benchmark dose-based point of departure (POD) from short-term, in vivo studies at a dose level below which a concerted molecular change (CMC) is not expected. Finally, Principle 4 states that the use of a transcriptomic POD (set at the CMC dose level) will support a human health-protective risk assessment. If all four principles are substantiated, this vision is expected to transform aspects of the industrial chemical and agrochemical risk assessment process that are focused on establishing safe exposure levels for mammals across numerous toxicological contexts resulting in a significant reduction in animal use while providing equal or greater protection of human health. Importantly, these principles and approaches are also generally applicable for ecological safety assessment. [ABSTRACT FROM AUTHOR]

High-resolution [sup.1]H NMR spectroscopy is frequently used in the field of metabolomics to assess the metabolites found in biofluids or tissue extracts to define a metabolic profile that describes a given biological process. In this study, we aimed to increase the utility of NMR-based metabolomics by using advanced Bayesian modeling of the time-domain high-resolution 1D NMR free induction decay (FID). The improvement over traditional nonparametric binning is twofold and associated with enhanced resolution of the analysis and automation of the signal processing stage. The automation is achieved by using a Bayesian formalism for all parameters of the model including the number of components. The approach is illustrated with a study of early markers of acute exposure to different doses of a well-characterized nongenotoxic hepatocarcinogen, phenobarbital, in rats. The results demonstrate that Bayesian deconvolution produces a better model for the NMR spectra that allows the identification of subtle changes in metabolic concentrations and a decrease in the expected false discovery rate compared with approaches based on 'binning'. These properties suggest that Bayesian deconvolution could facilitate the biomarker discovery process and improve information extraction from high-resolution NMR spectra. 10.1021/ac100344m