Mind the gaps: Prioritizing activities to meet regulatory needs for acute systemic lethality.

Efforts are underway to develop and implement nonanimal approaches which can characterize acute systemic lethality. A workshop was held in October 2019 to discuss developments in the prediction of acute oral lethality for chemicals and mixtures, as well as progress and needs in the understanding and modeling of mechanisms of acute lethality. During the workshop, each speaker led the group through a series of charge questions to determine clear next steps to progress the aims of the workshop.

Structural insights into assembly of the ribosomal nascent polypeptide exit tunnel.

The nascent polypeptide exit tunnel (NPET) is a major functional center of 60S ribosomal subunits. However, little is known about how the NPET is constructed during ribosome assembly. We utilized molecular genetics, biochemistry, and cryo-electron microscopy (cryo-EM) to investigate the functions of two NPET-associated proteins, ribosomal protein uL4 and assembly factor Nog1, in NPET assembly.

Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity.

New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity.

Alternative approaches for acute inhalation toxicity testing to address global regulatory and non-regulatory data requirements: An international workshop report.

Inhalation toxicity testing, which provides the basis for hazard labeling and risk management of chemicals with potential exposure to the respiratory tract, has traditionally been conducted using animals. Significant research efforts have been directed at the development of mechanistically based, non-animal testing approaches that hold promise to provide human-relevant data and an enhanced understanding of toxicity mechanisms. A September 2016 workshop, "Alternative Approaches for Acute Inhalation Toxicity Testing to Address Global Regulatory and Non-Regulatory Data Requirements", explored current testing requirements and ongoing efforts to achieve global regulatory acceptance for non-animal testing approaches.

Evaluation of OASIS QSAR Models Using ToxCast™ in Vitro Estrogen and Androgen Receptor Binding Data and Application in an Integrated Endocrine Screening Approach.

Background: Integrative testing strategies (ITSs) for potential endocrine activity can use tiered in silico and in vitro models. Each component of an ITS should be thoroughly assessed.

Objectives: We used the data from three in vitro ToxCast™ binding assays to assess OASIS, a quantitative structure-activity relationship (QSAR) platform covering both estrogen receptor (ER) and androgen receptor (AR) binding.

Evaluation of TOPKAT, Toxtree, and Derek Nexus in Silico Models for Ocular Irritation and Development of a Knowledge-Based Framework To Improve the Prediction of Severe Irritation.

Assessment of ocular irritation is an essential component of any risk assessment. A number of (Q)SARs and expert systems have been developed and are described in the literature. Here, we focus on three in silico models (TOPKAT, BfR rulebase implemented in Toxtree, and Derek Nexus) and evaluate their performance using 1644 in-house and 123 European Centre for Toxicology and Ecotoxicology of Chemicals (ECETOC) compounds with existing in vivo ocular irritation classification data.

Acute Toxicity Prediction in Multiple Species by Leveraging Mechanistic ToxCast Mitochondrial Inhibition Data and Simulation of Oral Bioavailability.

There is great interest in assessing the in vivo toxicity of chemicals using nonanimal alternatives. However, acute mammalian toxicity is not adequately predicted by current in silico or in vitro approaches. Mechanisms of acute toxicity are likely conserved across invertebrate, aquatic, and mammalian species, suggesting that dose-response concordance would be high and in vitro mechanistic data could predict responses in multiple species under conditions of similar bioavailability.

Evaluation of reproductive development following intravenous and oral exposure to DEHP in male neonatal rats.

Di-(2-ethylhexyl)phthalate (DEHP) was administered to 3- to 5-day-old male Sprague-Dawley rats by daily intravenous injections of 60, 300, or 600 mg/kg/day or by daily oral gavage of 300 or 600 mg/kg/day for 21 days. Histopathological evaluation and organ weight measurements were performed on some animals after 21 days of dosing (primary group) and later on the recovery group animals that were held without further treatment until sexual maturity at approximately 90 days of age. No effects of any type were observed in animals treated intravenously with 60 mg/kg/day.

Comparative metabolism of methyl isobutyl carbinol and methyl isobutyl ketone in male rats.

Methyl isobutyl carbinol (MIBC) is an oxygenated solvent that is metabolized to methylisobutyl ketone (MIBK) and then to 4-hydroxymethyl-4-methyl-2-pentanone (HMP). Plasma levels of MIBC, MIBK and HMP were determined up to 12 h after a single oral 5 mmol/kg dose of MIBC or MIBK to male rats. The major material in the plasma in both cases was HMP, with similar areas-under-the-curve (AUC) and C(max) at 9 h after dosing.