Search

Octahydro-tetramethyl-naphthalenyl-ethanone (OTNE) is a synthetic fragrance ingredient. OTNE was evaluated in repeated-dose toxicological studies. Target organs via oral and dermal routes were the liver and skin/liver, respectively. Effects were observed on the thyroid and thyroid hormones, suggesting hypothalamic-pituitary-thyroid axis perturbation. We investigated the molecular initiating event(s) (MIEs), key events (KEs), and adverse outcomes of OTNE-induced thyroid perturbation within an adverse outcome pathway (AOP). Data were generated using new approach methodologies (NAMs) on human, mouse, and/or rat receptors exploring MIEs using in vitro receptor ligand-binding assays for androstane receptor variant 3 (CAR), farnesoid X receptor (FXR), liver X receptor alpha (LXRα), peroxisome proliferator-activated receptors alpha, delta, and gamma (PPARα, δ, and γ), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AhR). These data inform an AOP network where CAR, FXR, and PXR activation serve as MIEs with thyroid perturbation occurring as secondary effects. These data represent a robust evaluation using NAMs for mapping OTNE-induced thyroid effects and identifying activation of receptor-ligand binding as MIEs in lieu of additional in vivo experimentation. These data indicate the observed thyroid effects are secondary to liver effects and the thyroid effects, therefore, should not be the basis for assessing potential OTNE-induced human health hazards. • OTNE induced dose-dependent agonist increases on human/mouse CAR variant 3 and human/mouse/rat FXR and PXR. • OTNE did not exhibit agonist or antagonist activity on human/mouse/rat LXRα and PPARα, γ, or δ, or human/rat AhR. • OTNE caused statistically significant increases in liver weight following repeated oral and dermal administration in rodents. • OTNE caused statistically significant increases in rat thyroid weights after repeated oral administration in an EOGRT study. • I n vitro studies assessing MIEs within an AOP suggests OTNE produces thyroid effects in rodent studies via secondary effects on the liver. [ABSTRACT FROM AUTHOR]

Carbon tetrachloride (CCl4) is routinely used as a model compound for eliciting centrilobular hepatotoxicity. It can be bioactivated to the trichloromethyl radical, which causes extensive lipid peroxidation and ultimately cell death by necrosis. Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) can rapidly reduce the levels of β-nicotinamide adenine dinucleotide and adenosine triphosphate and ultimately promote necrosis. The aim of this study was to determine whether inhibition of PARP-1 could decrease CCl4-induced hepatotoxicity, as measured by degree of poly(ADP-ribosyl)ation, serum levels of lactate dehydrogenase (LDH), lipid peroxidation, and oxidative DNA damage. For this purpose, male ICR mice were administered intraperitoneally a hepatotoxic dose of CCl4 with or without 6(5 H)-phenanthridinone, a potent inhibitor of PARP-1. Animals treated with CCl4 exhibited extensive poly(ADP-ribosyl)ation in centrilobular hepatocytes, elevated serum levels of LDH, and increased lipid peroxidation. In contrast, animals treated concomitantly with CCl4 and 6(5 H)-phenanthridinone showed significantly lower levels of poly(ADP-ribosyl)ation, serum LDH, and lipid peroxidation. No changes were observed in the levels of oxidative DNA damage regardless of treatment. These results demonstrated that the hepatotoxicity of CCl4 is dependent on the overactivation of PARP-1 and that inhibition of this enzyme attenuates the hepatotoxicity of CCl4. [ABSTRACT FROM AUTHOR]

Brominated benzylpolystyrene (BrBPS) is a fire safety polymer, which imparts flame retardancy in a variety of styrenic polymers and resins. In this study, the individual components of BrBPS were evaluated using a novel screening process to inform various endpoints relevant for assessing risks to the environment and human health. For this purpose, representative components were created using the B3LYP density functional method to generate the energetically optimal bromine substitution patterns of the parent molecules toluene, ethylbenzene, and cumene. Representative low energy conformations of the components were identified by using repetitive short bursts of Molecular Dynamics, followed by Molecular Mechanics minimization. The resulting structures were energy minimized at the quantum mechanical Becke-Perdew GGA density functional level. Thereafter, octanol:water partition coefficients, maximum molecular lengths, average maximum diameters, and cross-sectional diameters were calculated to inform parameters on environmental fate, bioaccumulation, and mammalian and ecological toxicity. The relevance of these data for informing risk assessment is discussed. [ABSTRACT FROM AUTHOR]

The United States Environmental Protection Agency's Integrated Risk Information System (IRIS) includes hazard identification and dose-response assessment values developed by Agency scientists. Uncertainty factors (UFs) are used in the development of IRIS values to address the lack of information in five main areas. The standard UFs account for interspecies uncertainty (UFA) and intraspecies variability (UFH). The UFA addresses uncertainty related to the extrapolation of data from animals to humans, whereas the UFH addresses variability amongst individuals (i.e., intrahuman). Additional UFs have been employed to account for database incompleteness, extrapolations from a lowest-observed-adverse-effect level in the absence of a no-observed-adverse-effect level (UFL), and subchronic-to-chronic extrapolation (UFS). A sixth UF designated as "other uncertainty factors" (UFO) has also been applied in place of the UFL to account for uncertainty with the adversity of points of departure obtained using benchmark dose modeling. This review will discuss how UFL, UFS, and UFO have been applied in IRIS assessments, along with the rationale used to describe the choice of UF values that deviate from the standard default of 10. [ABSTRACT FROM AUTHOR]

Nitrobenzene (CASRN: 98-95-3) has been shown to induce cancers in many tissues including kidney, liver, and thyroid, following chronic inhalation in animals. However, with a few exceptions, genotoxicity assays using nitrobenzene have given negative results. Some DNA binding/adduct studies have brought forth questionable results and, considering the available weight of evidence, it does not appear that nitrobenzene causes cancer via a genotoxic mode of action. Nitrobenzene produces a number of free radicals during its reductive metabolism, in the gut as well as at the cellular level, and generates superoxide anion as a by-product during oxidative melabolism. The reactive species generated during nitrobenzene metabolism are considered candidates for carcinogenicity. Furthermore, several lines of evidence suggest that nitrobenzene exerts its carcinogenicity through a non-DNA reactive (epigenetic) fashion, such as a strong temporal relationship between non-, pre-, and neoplastic lesions leading to carcinogenesis. In this report, we first describe the absorption, distribution, metabolism, and excretion of nitrobenzene followed by a summary of the available genotoxicity studies and the only available cancer bioassay. We subsequently refer to the mode of action framework of the U.S. Environmental Protection Agency's 2005 Guidelines for Carcinogen Risk Assessment as a basis for presenting possible modes of action for nitrobenzene-induced cancers of the liver, thyroid, and kidney, as supported by the available experimental data. The rationale(s) regarding human relevance of each mode of action is also presented. Finally, we hypothesize that the carcinogenic mode of action for nitrobenzene is multifactorial in nature and reflective of free radicals, inflammation, and/or altered methylation. [ABSTRACT FROM AUTHOR]

Determination of the promutagenic base 8-hydroxy-2′-deoxyguanosine (oxo8dG) has been the hallmark of studies aimed to determine oxidative damage to DNA. Different techniques including HPLC, GC–mass spectrometry, DNA sensitive sites and histology have been used to quantify oxo8dG levels in samples from different sources. The most accepted and well-established methods are based on HPLC and the ability of oxo8dG to be oxidized with an electrochemical detector. Considerable concerns have been raised in the ability of different labs to utilize a process of DNA extraction that reduces the levels of artifactual oxo8dG formed during sample workup. Here, we present a fully detailed protocol that has been extensively used in our Lab to extract and analyze DNA and has little or no impact in the basal levels of oxo8dG. Additionally, this protocol allows for the determination of the activity of mOgg1, the enzyme responsible for the initial step in the repair of the accumulated oxo8dG, in the same sample in which oxo8dG is detected. [Copyright &y& Elsevier]

Adult male ICR mice were treated by intraperitoneal injection with 250 mg/kg of bodyweight of commercial malathion (a dose corresponding to 1/12 the LD 50 ). After 6 h, acetylcholinesterase (AChE) activity in blood, liver, and six brain regions was determined. A statistically significant inhibition was observed in whole blood (23%), liver (21%), and, in particular, the central nervous system; the greatest degree of AChE inhibition was observed in the cerebellum (45%), followed by the hippocampus (29%). There was no significant change in AChE activity in the caudate putamen, frontal cortex, midbrain, or pons medulla. These results demonstrate that the magnitude of AChE inhibition in peripheral tissues does not accurately reflect the central-inhibitory effects of malathion on AChE activity in specific brain regions. [ABSTRACT FROM AUTHOR]

Ethylene dibromide (EDB) has been used as a model compound for eliciting hepato- and nephrotoxicity. Conjugation with glutathione (GSH) has been shown to play a role in the bioactivation of EDB. The aim of this study was to determine whether activation of α1-adrenergic receptors, which causes a decrease in cellular GSH levels, could modulate the nephrotoxicity of EDB. For this purpose, male ICR mice were treated with EDB and/or the α-adrenergic agonist, phenylephrine (Pe), or the α-adrenergic antagonist, phentolamine (Phe). Animals treated with EDB (40 mg/kg, i.p.) had a 9.3-fold increase in urinary γ-glutamyltranspeptidase (GGTP: EC 2.3.2.2) activity and a 38% decrease in renal non-protein bound sulfhydryl (NPSH) levels; however, animals co-treated with EDB and Pe (50 mg/kg, i.p.) exhibited a 27.8-fold increase in urinary GGTP activity and a 60% decrease in NPSH levels. The enhanced presence of urinary GGTP and decrease in cellular levels of NPSH was nearly blocked by treating animals concomitantly with EDB and Phe (10 mg/kg, i.p.) or EDB, Pe, and Phe. Histopathological examination revealed the enhanced degree of tissue damage and necrosis following treatment with EDB and Pe, and the protective effect of Phe at ameliorating EDB toxicity. These results indicate that factors that can influence α-adrenergic receptors may be critical in assessing dose–response data used in the risk assessment process. [Copyright &y& Elsevier]

Inhalation is a major route by which human exposure to substances can occur. Resources have therefore been dedicated to optimize human-relevant in vitro approaches that can accurately and efficiently predict the toxicity of inhaled chemicals for robust risk assessment and management. In this study—the IN vitro Systems to PredIct REspiratory toxicity Initiative—2 cell-based systems were used to predict the ability of chemicals to cause portal-of-entry effects on the human respiratory tract. A human bronchial epithelial cell line (BEAS-2B) and a reconstructed human tissue model (MucilAir, Epithelix) were exposed to triethoxysilane (TES) and trimethoxysilane (TMS) as vapor (mixed with N2 gas) at the air-liquid interface. Cell viability, cytotoxicity, and secretion of inflammatory markers were assessed in both cell systems and, for MucilAir tissues, morphology, barrier integrity, cilia beating frequency, and recovery after 7 days were also examined. The results show that both cell systems provide valuable information; the BEAS-2B cells were more sensitive in terms of cell viability and inflammatory markers, whereas MucilAir tissues allowed for the assessment of additional cellular effects and time points. As a proof of concept, the data were also used to calculate human equivalent concentrations. As expected, based on chemical properties and existing data, the silanes demonstrated toxicity in both systems with TMS being generally more toxic than TES. Overall, the results demonstrate that these in vitro test systems can provide valuable information relevant to predicting the likelihood of toxicity following inhalation exposure to chemicals in humans. [ABSTRACT FROM AUTHOR]

We evaluated the available pharmacokinetic data and human and animal toxicity data for 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether (BDE-209) (CASRN 1163-19-5) with the objective of deriving a reference dose (RfD) based on the best available science. The available studies for deriving an RfD were first screened using the Klimisch criteria and further evaluated using the United States Environmental Protection Agency’s general assessment factors for data quality and relevance (i.e., soundness, applicability and utility, clarity and completeness, uncertainty and variability, and evaluation and review). The chronic 2-year dietary feeding study conducted by the United States National Toxicology Program (NTP, 1986, Technical Report Series No. 309) was selected for RfD derivation. Hepatocellular degeneration in male rats was chosen as the critical endpoint in the development of an RfD. For dose-response characterization, we applied benchmark-dose modeling to animal data and determined a point of departure (the 95% lower confidence limit for a 10% increase in hepatocellular degeneration) of 419 mg/kg-day for oral exposures. Based on the similar pharmacokinetic characteristics of BDE-209 across species, this value was converted to a human equivalence dose of 113 mg/kg-day by applying a dosimetric adjustment factor based on body weight scaling to the ¾ power. An oral RfD of 4 mg/kg-day was calculated by using a composite uncertainty factor of 30, which consisted of 10 for intraspecies uncertainty, 3 for interspecies uncertainty (i.e., 3 for toxicodynamics × 1 for toxicokinetics), and 1 for deficiencies with the database. We consider the RfD to be adequately protective of sensitive subpopulations, including women, their fetuses, children, and people with hepatocellular diseases. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article “Flame retardants in placenta and breast milk and cryptorchidism in newborn boys,” by K.M. Main et al. in the vol. 115, 2007 issue.

Neuronal cells injured by ischemia and reperfusion to a certain extent are committed to death in necrotic or apoptotic form. Necrosis is induced by gross ATP depletion or ‘energy crisis’ of the cell, whereas apoptosis is induced by a mechanism still to be defined in detail. Here, we investigated this mechanism by focusing on a DNA damage-sensor, poly(ADP-ribose) polymerase-1 (PARP-1). A 2-h oxygen and glucose deprivation (OGD) followed by reoxygenation (Reox) induced apoptosis, rather than necrosis, in rat cortical neurons. During the Reox, PARP-1 was much activated and autopoly(ADP-ribosyl)ated, consuming the substrate, NAD+. Induction of apoptosis by OGD/Reox was suppressed by overexpression of Bcl-2, indicating mitochondrial impairment in this induction process. Mitochondrial permeability transition (MPT), or membrane depolarization, and a release of proapoptotic proteins, i.e. cytochrome c, apoptosis-inducing factor and endonuclease G, from mitochondria were observed during the Reox. These apoptotic changes of mitochondria and the nucleus were attenuated by PARP-1 inhibitors, 1,5-dihydroxyisoquinoline and benzamide, and also by small interfering RNA specific for PARP-1. These results indicated that PARP-1 plays a principal role in inducing mitochondrial impairment that ultimately leads to apoptosis of neurons after cerebral ischemia. [ABSTRACT FROM AUTHOR]

Male Sprague Dawley® rats were administered a vitrified material obtained from the former Charleston Naval Shipyard (Charleston, SC, USA) by gavage once daily for 32 days. Group mean body weight of treated animals was within ±5.4% of controls. No gross or histopathological changes were observed when animals were treated with 67, 174, or 370 mg/kg per day. Analysis of heavy metals revealed a statistically significant increase only in the concentration of arsenic in the livers of animals treated with 174 or 370 mg/kg per day versus controls. Although there was a statistically significant increase in liver arsenic levels, the concentrations were far below mean soil concentrations for western and eastern United States. If the standard assumption of 100% absorption is used, the concentrations observed in the present study are about 20 times less than the average background soil levels in these regions. Based on this, it is concluded that the vitrified material would not pose a public health risk for its intended use as an additive for asphalt and glass beams. [Copyright &y& Elsevier]

In this article the authors discuss aspects of the report "Comparative Tissue Distribution, Biotransformation and Associated Biological Effects by Decabromodiphenyl Ethane and Decabrominated Diphenyl Ether in Male Rats after a 90-Day Oral Exposure Study," by F. Wang and colleagues that appeared in a 2010 issue of "Environmental Science & Technology." They discuss the biological relevance of the claims made by Wang and colleagues regarding the bioaccumulative effects of DBDPE and BDE-209.

A letter to the editor is presented in reponse to an article "Polybrominated diphenylether (PBDE) flame retardants and thyroid hormone during pregnancy," by Jonathan Chevrier, Kim G. Harley, Asa Bradman, and Brenda Eskenazi. A response from the article authors is also included.

A letter to the editor is presented in response to the article "Prenatal exposure to PBDEs and neurodevelopment," by J. B. Herbstman and colleagues.

A letter to the editor is presented in response to the article "PBDE concentrations in women's serum and fecundability," by Kim G. Harley.

In this article the authors discuss aspects of a report within the issue on research investigating the use of brominated flame retardants (BFRs) in children's toys. The authors raise several important questions about the research including the researchers' assumption that flame retardants were present in the material of the toys investigated; the lack of molecular ion detection methods, and the researchers' use of outdated data from a previous BFR study.

A letter to the editor is presented in response to the article "Elevated House Dust and Serum Concentrations of PBDEs in California: Unintended Consequences of Furniture Flammability Standards?,” by A.R. Zota, R.A. Rudel, R.A Morello-Frosch, and J.G. Brody in an issue of 2008.

The authors comment on the article "Alternate and New Brominated Flame Retardants Detected in U.S. House Dust" by Heather M. Stapleton and others. They focus on the exposure of nonpolybrominated diphenyl ether and brominated flame retardants in dust and examine the values in context from a toxicology and risk assessment perspective. They examine the values for hexabromocyclododecane (HBCD) and suggest that the amount of HBCD that a child might consume before appreciable risk is far in excess of the amount of dust a child would consume in a single day and cites soil ingestion values from the U.S. Environmental Protection Agency as a surrogate for dust ingestion. They state that the research findings demonstrate that the benefits of having flame-retarded products far outweigh the risk.