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Despite the increasing interest in silver nanoparticles toxicity still few works dealt with the hazards of nanosized Ag in soils (either dissolved in pore water or coupled to colloids) although disposal of biosolids in landfills has been reported as the major source of silver nanoparticles in terrestrial environments. Presently, Eisenia fetida was used to assess the toxicity of 5 nm sized PVP-PEI coated silver nanoparticles in soil through the implementation of different exposure media Standard Toxicity Tests (Paper Contact and Artificial Soil –OECD-207- and Reproduction –OECD-222- Tests) together with cellular biomarkers measured in extruded coelomocytes. In order to decipher the mode of action of silver nanoparticles in soil and the uptake routes in earthworms, special attention was given to the Ag accumulation and distribution in tissues. High Ag accumulation rates, weight loss, and mortality due to the disruption of the tegument could be the result of a dermal absorption of Ag ions released from silver nanoparticles (Paper Contact Test). However, autometallography showed metals mainly localized in the digestive tract after Artificial Soil Test, suggesting that Ag uptake occurred mostly through soil ingestion. That is, silver nanoparticles attached to soil colloids seemed to be internalized in earthworms after ingestion of soil and transferred to the digestive gut epithelium where at high doses they have triggered severe effects at different levels of biological complexity.

Microbial toxicity tests play an important role in various scientific and technical fields including the risk assessment of chemical compounds in the environment. There is a large battery of normalized tests available that have been standardized by ISO (International Organization for Standardization) and OECD (Organization for Economic Co-operation and Development) and which are worldwide accepted and applied. The focus of this review is to provide information on microbial toxicity tests, which are used to elucidate effects in other laboratory tests such as biodegradation tests, and for the prediction of effects in natural and technical aqueous compartments in the environment. The various standardized tests as well as not normalized methods are described and their advantages and disadvantages are discussed. In addition, the sensitivity and usefulness of such tests including a short comparison with other ecotoxicological tests is presented. Moreover, the far-reaching influence of microbial toxicity tests on biodegradation tests is also demonstrated. A new concept of the physiological potential of an inoculum (PPI) consisting of microbial toxicity tests whose results are expressed as a chemical resistance potential (CRP) and the biodegradation adaptation potential (BAP) of an inoculum is described that may be helpful to characterize inocula used for biodegradation tests. Key points • Microbial toxicity tests standardized by ISO and OECD have large differences in sensitivity and applicability. • Standardized microbial toxicity tests in combination with biodegradability tests open a new way to characterize inocula for biodegradation tests. • Standardized microbial toxicity tests together with ecotoxicity tests can form a very effective toolbox for the characterization of toxic effects of chemicals.

The broad-spectrum herbicide glyphosate (common trade name “Roundup”) was first sold to farmers in 1974. Since the late 1970s, the volume of glyphosate-based herbicides (GBHs) applied has increased approximately 100-fold. Further increases in the volume applied are likely due to more and higher rates of application in response to the widespread emergence of glyphosate-resistant weeds and new, pre-harvest, dessicant use patterns. GBHs were developed to replace or reduce reliance on herbicides causing well-documented problems associated with drift and crop damage, slipping efficacy, and human health risks. Initial industry toxicity testing suggested that GBHs posed relatively low risks to non-target species, including mammals, leading regulatory authorities worldwide to set high acceptable exposure limits. To accommodate changes in GBH use patterns associated with genetically engineered, herbicide-tolerant crops, regulators have dramatically increased tolerance levels in maize, oilseed (soybeans and canola), and alfalfa crops and related livestock feeds. Animal and epidemiology studies published in the last decade, however, point to the need for a fresh look at glyphosate toxicity. Furthermore, the World Health Organization’s International Agency for Research on Cancer recently concluded that glyphosate is “probably carcinogenic to humans.” In response to changing GBH use patterns and advances in scientific understanding of their potential hazards, we have produced a Statement of Concern drawing on emerging science relevant to the safety of GBHs. Our Statement of Concern considers current published literature describing GBH uses, mechanisms of action, toxicity in laboratory animals, and epidemiological studies. It also examines the derivation of current human safety standards. We conclude that: (1) GBHs are the most heavily applied herbicide in the world and usage continues to rise; (2) Worldwide, GBHs often contaminate drinking water sources, precipitation, and air, especially in agricultural regions; (3) The half-life of glyphosate in water and soil is longer than previously recognized; (4) Glyphosate and its metabolites are widely present in the global soybean supply; (5) Human exposures to GBHs are rising; (6) Glyphosate is now authoritatively classified as a probable human carcinogen; (7) Regulatory estimates of tolerable daily intakes for glyphosate in the United States and European Union are based on outdated science. We offer a series of recommendations related to the need for new investments in epidemiological studies, biomonitoring, and toxicology studies that draw on the principles of endocrinology to determine whether the effects of GBHs are due to endocrine disrupting activities. We suggest that common commercial formulations of GBHs should be prioritized for inclusion in government-led toxicology testing programs such as the U.S. National Toxicology Program, as well as for biomonitoring as conducted by the U.S. Centers for Disease Control and Prevention.

Target-specific, mechanism-oriented in vitro assays post a promising alternative to traditional animal toxicology studies. Here we report the first comprehensive analysis of the Tox21 effort, a large-scale in vitro toxicity screening of chemicals. We test ∼10,000 chemicals in triplicates at 15 concentrations against a panel of nuclear receptor and stress response pathway assays, producing more than 50 million data points. Compound clustering by structure similarity and activity profile similarity across the assays reveals structure–activity relationships that are useful for the generation of mechanistic hypotheses. We apply structural information and activity data to build predictive models for 72 in vivo toxicity end points using a cluster-based approach. Models based on in vitro assay data perform better in predicting human toxicity end points than animal toxicity, while a combination of structural and activity data results in better models than using structure or activity data alone. Our results suggest that in vitro activity profiles can be applied as signatures of compound mechanism of toxicity and used in prioritization for more in-depth toxicological testing. Large-scale in vitro assays may reduce the number of toxicological tests carried out in animals. Here, Huang et al . report a large dataset containing results of in vitro tests of approximately 10,000 chemicals, and use these data to create models that can potentially predict toxicity in humans.

Machine learning classification algorithms are widely used for the prediction and classification of the different properties of molecules such as toxicity or biological activity. The prediction of toxic vs. non-toxic molecules is important due to testing on living animals, which has ethical and cost drawbacks as well. The quality of classification models can be determined with several performance parameters. which often give conflicting results. In this study, we performed a multi-level comparison with the use of different performance metrics and machine learning classification methods. Well-established and standardized protocols for the machine learning tasks were used in each case. The comparison was applied to three datasets (acute and aquatic toxicities) and the robust, yet sensitive, sum of ranking differences (SRD) and analysis of variance (ANOVA) were applied for evaluation. The effect of dataset composition (balanced vs. imbalanced) and 2-class vs. multiclass classification scenarios was also studied. Most of the performance metrics are sensitive to dataset composition, especially in 2-class classification problems. The optimal machine learning algorithm also depends significantly on the composition of the dataset.

Microplastics (synthetic polymers; <5 mm) are ubiquitous, in the environment and in the news. The associated effects of microplastics on flora and fauna are currently only established through laboratory-based exposure trials; however, such studies have come under scrutiny for employing excessive concentrations with little environmental relevance. This critical review is intended to summarize key issues and approaches for those who are considering the need for local microplastics research, both in terms of environmental pollution and the impacts on aquatic species. A meta-analysis of results from published experimental (n = 128) and environmental (n = 180) studies allowed us to compare the reported impacts from experiments that expose organisms to microplastics, and the concentrations of environmental microplastics found in the wild. The results of this meta-analysis highlight three issues that should be modified in future work (1) use of extreme dosages, (2) incompatible and incomparable units, and (3) the problem of establishing truly informative experimental controls. We found that 5% of exposure trials examined did not use any control treatment, and 82% use dramatically elevated dosages without reference to environmental concentrations. Early studies in this field may have been motivated to produce unequivocal impacts on organisms, rather than creating a robust, environmentally relevant framework. Some of the reported impacts suggest worrying possibilities, which can now inspire more granular experiments. The existing literature on the extent of plastic pollution also has limited utility for accurately synthesizing broader trends, as has been raised in previous reviews; environmental extraction studies use many different units, among which only 76% (139/180) could be plausibly converted for comparison. Future research should adopt the units of microparticles/kg (of sediment) or mp/L (of fluid) to improve comparability. Now that the global presence of microplastic pollution is well established, with more than a decade of research, new studies should focus on comparative aspects rather than the presence of microplastics. Robustly designed, controlled, hypothesis-driven experiments based on environmentally relevant concentrations are needed now to understand our future in the new plastic world.

Nonclinical testing has served as a foundation for evaluating potential risks and effectiveness of investigational new drugs in humans. However, the current two‐dimensional (2D) in vitro cell culture systems cannot accurately depict and simulate the rich environment and complex processes observed in vivo, whereas animal studies present significant drawbacks with inherited species‐specific differences and low throughput for increased demands. To improve the nonclinical prediction of drug safety and efficacy, researchers continue to develop novel models to evaluate and promote the use of improved cell‐ and organ‐based assays for more accurate representation of human susceptibility to drug response. Among others, the three‐dimensional (3D) cell culture models present physiologically relevant cellular microenvironment and offer great promise for assessing drug disposition and pharmacokinetics (PKs) that influence drug safety and efficacy from an early stage of drug development. Currently, there are numerous different types of 3D culture systems, from simple spheroids to more complicated organoids and organs‐on‐chips, and from single‐cell type static 3D models to cell co‐culture 3D models equipped with microfluidic flow control as well as hybrid 3D systems that combine 2D culture with biomedical microelectromechanical systems. This article reviews the current application and challenges of 3D culture systems in drug PKs, safety, and efficacy assessment, and provides a focused discussion and regulatory perspectives on the liver‐, intestine‐, kidney‐, and neuron‐based 3D cellular models.

The U.S. EPA's Endocrine Disruptor Screening Program (EDSP) screens and tests environmental chemicals for potential effects in estrogen, androgen, and thyroid hormone pathways, and it is one of the only regulatory programs designed around chemical mode of action. This review describes the EDSP's use of adverse outcome pathway (AOP) and toxicity pathway frameworks to organize and integrate diverse biological data for evaluating the endocrine activity of chemicals. Using these frameworks helps to establish biologically plausible links between endocrine mechanisms and apical responses when those end points are not measured in the same assay. Pathway frameworks can facilitate a weight of evidence determination of a chemical's potential endocrine activity, identify data gaps, aid study design, direct assay development, and guide testing strategies. Pathway frameworks also can be used to evaluate the performance of computational approaches as alternatives for low-throughput and animal-based assays and predict downstream key events. In cases where computational methods can be validated based on performance, they may be considered as alternatives to specific assays or end points. A variety of biological systems affect apical end points used in regulatory risk assessments, and without mechanistic data, an endocrine mode of action cannot be determined. Because the EDSP was designed to consider mode of action, toxicity pathway and AOP concepts are a natural fit. Pathway frameworks have diverse applications to endocrine screening and testing. An estrogen pathway example is presented, and similar approaches are being used to evaluate alternative methods and develop predictive models for androgen and thyroid pathways. https://doi.org/10.1289/EHP1304.

Assessing chemicals for their potential to cause male reproductive toxicity involves the evaluation of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in hazard identification and evidence integration, the process of identifying, screening and analyzing mechanistic studies and outcomes is a challenging exercise due to the diversity of research models and methods and the variety of known and proposed pathways for chemical-induced toxicity. Ten key characteristics of carcinogens provide a valuable tool for organizing and assessing chemical-specific data by potential mechanisms for cancer-causing agents. However, such an approach has not yet been developed for noncancer adverse outcomes. The objective in this study was to identify a set of key characteristics that are frequently exhibited by exogenous agents that cause male reproductive toxicity and that could be applied for identifying, organizing, and summarizing mechanistic evidence related to this outcome. The identification of eight key characteristics of male reproductive toxicants was based on a survey of known male reproductive toxicants and established mechanisms and pathways of toxicity. The eight key characteristics can provide a basis for the systematic, transparent, and objective organization of mechanistic evidence relevant to chemical-induced effects on the male reproductive system. https://doi.org/10.1289/EHP5045.

The pharmaceutical industry is developing increasing numbers of drugs and diagnostics based on nanoparticles, and evaluating the immune response to these diverse formulations has become a challenge for scientists and regulatory agencies alike. An international panel of scientists and representatives from various agencies and companies reviewed the imitations of current tests at a workshop held at the National Cancer Institute in Frederick, Maryland. This article outlines practical strategies for identifying and controlling interferences in common evaluation methods and the implications for regulation.