Use of new approach methodologies (NAMs) to meet regulatory requirements for the assessment of industrial chemicals and pesticides for effects on human health.

New approach methodologies (NAMs) are increasingly being used for regulatory decision making by agencies worldwide because of their potential to reliably and efficiently produce information that is fit for purpose while reducing animal use. This article summarizes the ability to use NAMs for the assessment of human health effects of industrial chemicals and pesticides within the United States, Canada, and European Union regulatory frameworks. While all regulations include some flexibility to allow for the use of NAMs, the implementation of this flexibility varies across product type and regulatory scheme. This article provides an overview of various agencies' guidelines and strategic plans on the use of NAMs, and specific examples of the successful application of NAMs to meet regulatory requirements. It also summarizes intra- and inter-agency collaborations that strengthen scientific, regulatory, and public confidence in NAMs, thereby fostering their global use as reliable and relevant tools for toxicological evaluations. Ultimately, understanding the current regulatory landscape helps inform the scientific community on the steps needed to further advance timely uptake of approaches that best protect human health and the environment.

Alkyne Cycloadditions Mediated by Tetrabutylammonium Fluoride: A Unified and Diversifiable Route to Isoxazolines and Pyrazolines.

A versatile approach to isoxazolines and pyrazolines by the cyclization of alkyne substrates using tetrabutylammonium fluoride (TBAF) is described. The reported diheteroatom cycles were produced under mild reaction conditions and with broad product scope. Evidence is also provided for a vinyl anion intermediate produced under unusually mild conditions, which was trapped in situ as part of a tandem cyclization/aldehyde addition sequence. Finally, a deprotection/functionalization method is described, leading to a substituted pyrazoline in good diastereoselectivity.

Synthesis and Characterization of Urofuranoic Acids: In Vivo Metabolism of 2-(2-Carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic Acid (CMPF) and Effects on in Vitro Insulin Secretion.

CMPF (2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid) is a metabolite that circulates at high concentrations in type 2 and gestational diabetes patients. Further, human clinical studies suggest it might have a causal role in these diseases. CMPF inhibits insulin secretion in mouse and human islets in vitro and in vivo in rodents. However, the metabolic fate of CMPF and the relationship of structure to effects on insulin secretion have not been significantly studied. The syntheses of CMPF and analogues are described. These include isotopically labeled molecules. Study of these materials in vivo has led to the first observation of a metabolite of CMPF. In addition, a wide range of CMPF analogues have been prepared and characterized in insulin secretion assays using both mouse and human islets. Several molecules that influence insulin secretion in vitro were identified. The molecules described should serve as interesting probes to further study the biology of CMPF.

Ammonium catalyzed cyclitive additions: evidence for a cation-π interaction with alkynes.

The addition of carbamate nitrogen to a non-conjugated carbon-carbon triple bond is catalyzed by an ammonium salt leading to a cyclic product. Studies in homogeneous systems suggest that the ammonium agent facilitates nitrogen-carbon bond formation through a cation-π interaction with the alkyne unit that, for the first time, is directly observed by Raman spectroscopy.

Haemorrhagic nephritis and enteritis of geese: pathomorphological investigations and proposed pathogenesis.

Haemorrhagic nephritis and enteritis of geese as a new disease was first described in Hungary in 1969. The authors identified the causative agent of the outbreaks occurring in 1969 as a polyomavirus by PCR in 2001. In order to study the pathogenesis of the virus, one-day-old goslings were infected with tissue homogenate that tested positive for polyomavirus by PCR. Morphological, light and transmission electron microscopic (TEM) examinations have revealed that goose haemorrhagic polyomavirus replicates in the endothelial cells of the blood vessels and capillaries of diseased birds. Infection causes damage and necrosis of the endothelial cells. The virus was not observed in the parenchymal cells. Oedema and haemorrhages found throughout the body may be due to the dysfunction or functional deficiency of endothelial cells damaged by the virus.

Pathology of goose haemorrhagic polyomavirus infection in goose embryos.

Goose embryos were infected with goose haemorrhagic polyomavirus (GHPV) onto the chorioallantoic membrane (CAM) in order to examine the effect of GHPV on the embryos and to obtain data on whether embryos could develop into infected, virus-shedding goslings, as well as to present an accurate biological method for virus titration. The reported method of infection could offer a possibility to express the virus titre as the median embryo infective dose (EID(50)). As a special pathological feature of the disease, extensive cerebral haemorrhages were observed, which protruded the skullcap in many cases. Some embryos infected with 10(1.25) or 10(0.25) EID(50)/0.2 ml were able to hatch; however, they were in poor physical condition and died by post-hatching day 4 showing haemorrhagic nephritis and enteritis of geese. Virus shedding was revealed by polymerase chain reaction. The ability of some of the infected goose embryos to hatch may indicate the potency of GHPV to spread vertically, although this needs further study for confirmation.