Unidentified Inert Ingredients in Pesticides: Implications for Human and Environmental Health

BACKGROUND: By statute or regulation in the United States and elsewhere, pesticide ingredients are divided into two categories: active and inert (sometimes referred to as other ingredients, adjuvants, or coformulants). Despite their name, inert ingredients may be biologically or chemically active and are labeled inert only because of their function in the formulated product. Most of the tests required to register a pesticide are performed with the active ingredient alone, not the full pesticide formulation. Inert ingredients are generally not identified on product labels and are often claimed to be confidential business information. OBJECTIVES: In this commentary, we describe the shortcomings of the current procedures for assessing the hazards of pesticide formulations and demonstrate that inert ingredients can increase the toxicity of and potential exposure to pesticide formulations. DISCUSSION: Inert ingredients can increase the ability of pesticide formulations to affect significant toxicologic end points, including developmental neurotoxicity, genotoxicity, and disruption of hormone function. They can also increase exposure by increasing dermal absorption, decreasing the efficacy of protective clothing, and increasing environmental mobility and persistence. Inert ingredients can increase the phytotoxicity of pesticide formulations as well as the toxicity to fish, amphibians, and microorganisms. CONCLUSIONS: Pesticide registration should require full assessment of formulations. Evaluations of pesticides under the National Environmental Policy Act, the Endangered Species Act, and similar statutes should include impact assessment of formulations. Environmental monitoring for pesticides should include inert ingredients. To enable independent research and risk assessment, inert ingredients should be identified on product labels

Far-Infrared Emission From E and E/S0 Galaxies

Studies of cold material through IRAS 60um and 100um observations indicated that half of ordinary E and E/S0 galaxies were detected above the 3 sigma level, indicating that cold gas is common, although no correlation was found between the optical and far- infrared fluxes. Most detections were near the instrumental threshold, and given an improved understanding of detection confidence, we reconsider the 60um and 100um detection rate. After excluding active galactic nuclei, peculiar systems, and background contamination, only 15 non-peculiar E and E/S0 galaxies from the RSA catalog are detected above the 98% confidence level, about 12% of the sample. An unusually high percentage of these 15 galaxies possess cold gas (HI, CO) and optical emission lines (Halpha), supporting the presence of gas cooler than 10E4 K. The 60um to 100um flux ratios imply a median dust temperature for the sample of 30 K, with a range of 23-38 K. These detections define the upper envelope of the optical to far-infrared relationship, F_fir propto F_B^0.24+/-0.08, showing that optically bright objects are also brighter in the infrared, although with considerable dispersion. A luminosity correlation is present with L_fir propto L_B^1.65+/-0.28, but the dust temperature is uncorrelated with luminosity. Models that contain large dust grains composed of amorphous carbon plus silicates come close to reproducing the typical 60um to 100um flux ratios, the far-infrared luminosity, and the L_fir - L_B relationship.Comment: 10 postscript pages, 2 tables, and 2 figure

Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation

Loss-of-function mutations of GNA11, which encodes G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in familial hypocalciuric hypercalcemia type 2 (FHH2). FHH2 is characterized by hypercalcemia, inappropriately normal or raised parathyroid hormone (PTH) concentrations, and normal or low urinary calcium excretion. A mouse model for FHH2 that would facilitate investigations of the in vivo role of Gα11 and the evaluation of calcimimetic drugs, which are CaSR allosteric activators, is not available. We therefore screened DNA from > 10,000 mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for GNA11 mutations and identified a Gα11 variant, Asp195Gly (D195G), which downregulated CaSR-mediated intracellular calcium signaling in vitro, consistent with it being a loss-of-function mutation. Treatment with the calcimimetic cinacalcet rectified these signaling responses. In vivo studies showed mutant heterozygous (Gna11+/195G) and homozygous (Gna11195G/195G) mice to be hypercalcemic with normal or increased plasma PTH concentrations and normal urinary calcium excretion. Cinacalcet (30mg/kg orally) significantly reduced plasma albumin-adjusted calcium and PTH concentrations in Gna11+/195G and Gna11195G/195G mice. Thus, our studies have established a mouse model with a germline loss-of-function Gα11 mutation that is representative for FHH2 in humans and demonstrated that cinacalcet can correct the associated abnormalities of plasma calcium and PTH

Measurement of H₂O₂ within living drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix

Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) is central to mitochondrial oxidative damage and redox signaling, but its roles are poorly understood due to the difficulty of measuring mitochondrial H<sub>2</sub>O<sub>2</sub> in vivo. Here we report a ratiometric mass spectrometry probe approach to assess mitochondrial matrix H<sub>2</sub>O<sub>2</sub> levels in vivo. The probe, MitoB, comprises a triphenylphosphonium (TPP) cation driving its accumulation within mitochondria, conjugated to an arylboronic acid that reacts with H<sub>2</sub>O<sub>2</sub> to form a phenol, MitoP. Quantifying the MitoP/MitoB ratio by liquid chromatography-tandem mass spectrometry enabled measurement of a weighted average of mitochondrial H<sub>2</sub>O<sub>2</sub> that predominantly reports on thoracic muscle mitochondria within living flies. There was an increase in mitochondrial H<sub>2</sub>O<sub>2</sub> with age in flies, which was not coordinately altered by interventions that modulated life span. Our findings provide approaches to investigate mitochondrial ROS in vivo and suggest that while an increase in overall mitochondrial H<sub>2</sub>O<sub>2</sub> correlates with aging, it may not be causative

Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy

Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2). ADH2 may cause symptomatic hypocalcemia with low circulating parathyroid hormone (PTH) concentrations. Effective therapies for ADH2 are currently not available and a mouse model for ADH2 would help in assessment of potential therapies. We hypothesised that a previously reported dark skin mouse mutant (Dsk7), which has a germline hypermorphic Gα11 mutation, Ile62Val, may be a model for ADH2 and allow evaluation of calcilytics, which are CaSR negative allosteric modulators, as a targeted therapy for this disorder. Mutant Dsk7/+ and Dsk7/Dsk7 mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 Gα11 to upregulate CaSR-mediated intracellular calcium and MAPK signaling, consistent with a gain-offunction. Treatment with NPS-2143, a calcilytic compound, normalised these signaling responses. In vivo, NPS-2143 induced a rapid and marked rise in plasma PTH and calcium concentrations in Dsk7/Dsk7 and Dsk7/+ mice, which became normocalcemic. Thus, these studies have established Dsk7 mice, which harbor a germline gain-of-function Gα11 mutation, as a model for ADH2; and demonstrated calcilytics as a potential targeted therapy

Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that plays a pivotal role in extracellular calcium homeostasis. The CaSR is also highly expressed in pancreatic islet α- and β-cells that secrete glucagon and insulin, respectively. To determine whether the CaSR may influence systemic glucose homeostasis, we characterized a mouse model with a germline gain-of-function CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf). Heterozygous- (CasrNuf/+) and homozygous-affected (CasrNuf/Nuf) mice were shown to have hypocalcemia in association with impaired glucose tolerance and insulin secretion. Oral administration of a CaSR antagonist compound, known as a calcilytic, rectified the glucose intolerance and hypoinsulinemia of CasrNuf/+ mice, and ameliorated glucose intolerance in CasrNuf/Nuf mice. Ex vivo studies showed CasrNuf/+ and CasrNuf/Nuf mice to have reduced pancreatic islet mass and β-cell proliferation. Electrophysiological analysis of isolated CasrNuf/Nuf islets showed CaSR activation to increase the basal electrical activity of β-cells independently of effects on the activity of the ATP-sensitive K+ (KATP) channel. CasrNuf/Nuf mice also had impaired glucose-mediated suppression of glucagon secretion, which was associated with increased numbers of α-cells and a higher α-cell proliferation rate. Moreover, CasrNuf/Nuf islet electrophysiology demonstrated an impairment of α-cell membrane depolarization in association with attenuated α-cell basal KATP channel activity. These studies indicate that the CaSR activation impairs glucose tolerance by a combination of α- and β-cell defects and also influences pancreatic islet mass. Moreover, our findings highlight a potential application of targeted CaSR compounds for modulating glucose metabolism

The diagnosis and management of systemic autoimmune rheumatic disease-related interstitial lung disease: British Society for Rheumatology guideline scope

Interstitial lung disease (ILD) is a significant complication of many systemic autoimmune rheumatic diseases (SARDs), although the clinical presentation, severity and outlook may vary widely between individuals. Despite the prevalence, there are no specific guidelines addressing the issue of screening, diagnosis and management of ILD across this diverse group. Guidelines from the ACR and EULAR are expected, but there is a need for UK-specific guidelines that consider the framework of the UK National Health Service, local licensing and funding strategies. This article outlines the intended scope for the British Society for Rheumatology guideline on the diagnosis and management of SARD-ILD developed by the guideline working group. It specifically identifies the SARDs for consideration, alongside the overarching principles for which systematic review will be conducted. Expert consensus will be produced based on the most up-to-date available evidence for inclusion within the final guideline. Key issues to be addressed include recommendations for screening of ILD, identifying the methodology and frequency of monitoring and pharmacological and non-pharmacological management. The guideline will be developed according to methods and processes outlined in Creating Clinical Guidelines: British Society for Rheumatology Protocol version 5.1.</p

Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health