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Introduction Pulmonary dysfunction (PD) and its associated hypoxia present a complication to the care of many service members and can arise intrinsically via comorbidities or extrinsically by infection or combat-related trauma (burn, smoke inhalation, and traumatic acute lung injury). Current supportive treatments (e.g., ventilation and supplemental oxygen) relieve hypoxia but carry a significant risk of further lung injury that drives mortality. Ox66 is a novel, solid-state oxygenating compound capable of delivering oxygen via intravenous infusion. Materials and Methods Male Sprague Dawley rats (N = 21; 250-300 g) were surgically prepared for cardiovascular monitoring, fluid infusion, mechanical ventilation, and intravital and phosphorescence quenching microscopy (interstitial oxygen tension; PISFO2) of the spinotrapezius muscle. Baselines (BL) were collected under anesthesia and spontaneous respiration. PD was simulated via hypoventilation (50% tidal volume reduction) and was maintained for 3 hours. Groups were randomized to receive Ox66, normal saline (NS; vehicle control), or Sham (no treatment) and were treated immediately following PD onset. Arterial blood samples (65 µL) and intravital images were taken hourly to assess blood gases and chemistry and changes in arteriolar diameter, respectively. Significance was taken at P Results PD reduced PISFO2 for all groups; however, by 75 minutes, both NS and Sham were significantly lower than Ox66 and remained so until the end of PD. Serum lactate levels were lowest in the Ox66 group—even decreasing relative to BL—but only significant versus Sham. Furthermore, all Ox66 animals survived the full PD challenge, while one NS and two Sham animals died. No significant vasoconstrictive or vasodilative effect was noted within or between experimental groups. Conclusion Treatment with intravenous Ox66 improved interstitial oxygenation in the spinotrapezius muscle—a recognized bellwether for systemic capillary function—suggesting an improvement in oxygen delivery. Ox66 offers a novel approach to supplemental oxygenation that bypasses lung injury and dysfunction.

Human exposures to perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been linked to several diseases associated with adverse health outcomes. Animal studies have been conducted, though these may not be sufficient due to the inherent differences in metabolic processes between humans and rodents. Acquiring relevant data on the health effects of short-chain PFAS can be achieved through methods supported by in vitro human cell-based models. Specifically, cytotoxicity assays are the crucial first step to providing meaningful information used for determining safety and providing baseline information for further testing. To this end, we exposed human cell lines representative of six different tissue types, including colon (CaCo-2), liver (HepaRG), kidney (HEK293), brain (HMC-3), lung (MRC-5), and muscle (RMS-13) to five short-chain PFAS and two legacy PFAS. The exposure of the individual PFAS was assessed using a range of concentrations starting from a low concentration (10

Exposure to combustion-derived particulate matter (PM) such as diesel exhaust particles (DEP) is a public health concern because people in urban areas are continuously exposed, and once inhaled, fine and ultrafine DEP may reach the brain. The blood-brain barrier (BBB) endothelial cells (EC) and the perivascular microglia protect the brain from circulating pathogens and neurotoxic molecules like DEP. While the BBB-microglial interaction is critical for maintaining homeostasis, no study has previously evaluated the endothelial-microglial interaction nor comprehensively characterized these cells’ inflammatory marker profiles under ultrafine DEP exposures in vitro. Therefore, the goal of this study was to investigate the in vitro rat EC-microglial co-culture under acute (24 h.) exposure to ultrafine DEP (0.002–20 μg/mL), by evaluating key mechanisms associated with PM toxicity: lactate dehydrogenase (LDH) leakage, reactive oxygen species (ROS) generation, cell metabolic activity (CMA) changes, and production of 27 inflammatory markers. These parameters were also evaluated in rat microglial and endothelial monocultures to determine whether the EC-microglial co-culture responded differently than the cerebrovasculature and microglia alone. While results indicated that ultrafine DEP exposure caused concentration-dependent increases in LDH leakage and ROS production in all groups, as expected, exposure also caused mixed responses in CMA and atypical cytokine/chemokine profiles in all groups, which was not expected. The inflammation assay results further suggested that the microglia were not classically activated under this exposure scenario, despite previous in vitro studies showing microglial activation (priming) at similar concentrations of ultrafine DEP. Additionally, compared to the cerebrovasculature alone, the EC-microglia interaction in the co-culture did not appear to cause changes in any parameter save in pro-inflammatory marker production, where the interaction appeared to cause an overall downregulation in cytokine/chemokine levels after ultrafine DEP exposure. Finally, to our knowledge, this is the first study to evaluate the influence of microglia on the BBB’s ultrafine DEP-induced cytotoxic and inflammatory responses, which are heavily implicated in the pathogenesis of PM-related cerebrovascular dysfunction and neurodegeneration.

Human exposure to environmental nanoparticles (NPs) may result in systemic distribution and accumulation of NPs. Depending on exposure conditions and their physiochemical properties, NPs could cross biological barriers and reach vital organs. This method describes an analytical technique that quantifies the nanoparticles’ translocation through a sample human airway barrier. Silver nanoparticles (AgNPs) were used as the example nanoparticles due to their common use in nanotechnology. The analytical method introduced in this study allows mass measurements of both cellular uptake and translocation of AgNPs through the modeled barrier. Additionally, cytotoxicity was evaluated using a convenient assay to investigate adverse effects from AgNPs treatment. The assay measures cellular injury from each layer in the barrier independently. The assay does not engage cells physically for chemical reaction, therefore it is non-destructive to the model, and the model can be used for other purposes subsequently. To conclude, this study provides researchers with measurable tools for evaluating the translocation, cellular trafficking, uptake and toxic effects of metallic nanoparticles in the in vitro barrier format.•Quantitative evaluation of nanoparticles translocation through human airway barrier•Non-invasive and quantifiable toxicity evaluation for co-culture models, Graphical abstract Image, graphical abstract

Ox66™ is a novel solid state oxygenating compound. In order to support the use of Ox66™ as a potential oxygenating supplement to injured cells, this study evaluated the safety of Ox66™, its ability to withstand the conditions in the digestive tract, and its potential to increase oxygenation in the mesentery in rats. The toxicity of Ox66™ was evaluated by performing acute (10-day) and chronic (90-day) feeding studies on rats, the stability of the compound in the digestive tract was evaluated via ex vivo simulated digestion and subsequent CFDA viability assay on gut epithelial cells, and its capacity for oxygenation in the mesenteric microcirculation was determined by interstitial fluid pressure (PISF) O2 measurements upon injection into the small intestine of rats. No toxicity was found associated with acute or chronic oral administration of the compound in rats, and the compound was able to withstand the environment of the digestive tract in vitro. Based on the acute animal feeding study, the NOAEL was considered to be 1000 mg/kg/day. This proof-of-concept study further demonstrates the potential of Ox66™ to function as an oxygenating supplement that might be useful for treating either pathological hypoxic-related conditions or to improve oxygenation levels during or after exercise under healthy conditions.

Polycyclic aromatic hydrocarbons (PAHs) have been labeled contaminants of concern due to their carcinogenic potential, insufficient toxicological data, environmental ubiquity, and inconsistencies in the composition of environmental mixtures. The Environmental Protection Agency is reevaluating current methods for assessing the toxicity of PAHs, including the assumption of toxic additivity in mixtures. This study was aimed at testing mixture interactions through in vitro cell culture experimentation, and modeling the toxicity using quantitative structure-activity relationships (QSAR). Clone-9 rat liver cells were used to analyze cellular proliferation, viability, and genotoxicity of 15 PAHs in single doses and binary mixtures. Tests revealed that many mixtures have nonadditive toxicity, but display varying mixture effects depending on the mixture composition. Many mixtures displayed antagonism, similar to other published studies. QSARs were then developed using the genetic function approximation algorithm to predict toxic activity both in single PAH congeners and in binary mixtures. Effective concentrations inhibiting 50% of the cell populations were modeled, with R(2) = 0.90, 0.99, and 0.84, respectively. The QSAR mixture algorithms were then adjusted to account for the observed mixture interactions as well as the mixture composition (ratios) to assess the feasibility of QSARs for mixtures. Based on these results, toxic addition is improbable and therefore environmental PAH mixtures are likely to see nonadditive responses when complex interactions occur between components. Furthermore, QSAR may be a useful tool to help bridge these data gaps surrounding the assessment of human health risks that are associated with PAH exposures.

Traumatic brain injury (TBI) is a leading cause of death and disability in every developed country in the world and is believed to be a risk factor in the later development of depression, anxiety disorders and neurodegenerative diseases including chronic traumatic encephalopathy (CTE), Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). One challenge faced by those who conduct research into TBI is the lack of a verified and validated biomarker that can be used to diagnose TBI or for use as a prognostic variable which can identify those at risk for poor recovery following injury or at risk for neurodegeneration later in life. Neuroimaging continues to hold promise as a TBI biomarker but is limited by a lack of clear relationship between the neuropathology of injury/recovery and the quantitative and image based data that is obtained. Specifically lacking is the data on biochemical and biologic changes that lead to alterations in neuroimaging markers. There are multiple routes towards developing the knowledge required to more definitively link pathology to imaging but the most efficient approach is expanded leveraging of in vivo human blood, serum, and imaging biomarkers with both in vivo and ex vivo animal findings. This review describes the current use and limitations of imaging in TBI including a discussion of currently used animal injury models and the available animal imaging data and extracted markers that hold the greatest promise for helping translate alterations in imaging back to injury pathology. Further, it reviews both the human and animal TBI literature supporting current standards, identifies the remaining voids in the literature, and briefly highlights recent advances in molecular imaging. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.

A proposed primary pathway through which polybrominated diphenyl ethers (PBDEs) disrupt normal biological functions is oxidative stress. In the present study, 4 PBDE congeners were evaluated for their potential to initiate oxidative stress in zebrafish during development: BDE 28, BDE 47, BDE 99, and BDE 100. N-acetylcysteine (NAC) was used to increase intracellular glutathione concentrations and only decreased the effects of BDE 28 at 10 ppm and 20 ppm and BDE 47 at 20 ppm. N-acetylcysteine coexposure did not alter the rates of mortality or curved body axis compared with PBDE exposure alone. The activity of glutathione-S-transferase (GST) was not altered at 24 h postfertilization (hpf), but increased following 10 ppm BDE 28 exposure at 120 hpf. Transcription of several genes associated with stress was also evaluated. At 24 hpf, cytochrome c oxidase subunit 6a (COX6a) transcription was up-regulated in embryos exposed to BDE 99, and BDE 28 exposure up-regulated the transcription of Glutathione-S-transferase-pi (GSTpi). At 24 hpf, glutamate-cysteine ligase (GCLC) was slightly down-regulated by all congeners evaluated. At 120 hpf, TNF receptor-associated protein 1 (TRAP1) and COX6A were up-regulated by all congeners, however GSTpi was down-regulated by all congeners. The results of quantitative real-time transcription polymerase chain reaction are mixed and do not strongly support a transcriptional response to oxidative stress. According to the authors' data, PBDEs do not induce oxidative stress. Oxidative stress may occur at high exposure concentrations; however, this does not appear to be a primary mechanism of action for the PBDE congeners tested.

Surface-functionalized silver nanoparticles (AgNPs) are the most deployed engineered nanomaterials in consumer products because of their optical, antibacterial and electrical properties. Almost all engineered nanoparticles are coated with application-specific capping agents (i.e. organic/inorganic ligands on particle surface) to enhance their stability in suspension or increase their biocompatibility for biomedicine. The aim of this study was to investigate the contribution of the selected capping agents to their observed health impacts using realistic dose ranges. AgNPs capped with citrate, polyvinylpyrrolidone (PVP) and tannic acid were studied with human bronchoalveolar carcinoma (A549) and human colon adenocarcinoma (Caco-2) cell lines and compared against exposures to Ag ions. Cellular uptake and cytotoxicity were evaluated up to 24 h. Tannic acid capped AgNPs induced higher cellular uptake and rate in both cell lines. Citrate-capped and PVP-capped AgNPs behaved similarly over 24 h. All three of the capped AgNPs penetrated more into the A549 cells than Caco-2 cells. In contrast, the uptake rate of Ag ions in Caco-2 cells (0.11 ± 0.0001 µg h–1) was higher than A549 cells (0.025 ± 0.00004 µg h–1). The exposure concentration of 3 mg l–1 is below the EC50 value for all of the AgNPs; therefore, little cytotoxicity was observed in any experiment conducted herein. Exposure of Ag ions, however, interrupted cell membrane integrity and cell proliferation (up to 70% lysed after 24 h). These findings indicate cellular uptake is dependent on capping agent, and when controlled to realistic exposure concentrations, cellular function is not significantly affected by AgNP exposure. Copyright © 2015 John Wiley & Sons, Ltd.

Embryonic zebrafish were used to compare the uptake and metabolism of six polybrominated diphenyl ether (PBDE) congeners (BDEs 28, 47, 99, 100, 153, and 183) and identified metabolites from static exposures at 24 and 120 h postfertilization (hpf). An inverse relationship was observed between uptake of PBDEs and their octanol-water partitioning coefficients (uptake of BDEs 28 and 47>99 and 100>153 and 183). Debromination metabolites were identified in all congeners (excluding BDE 28) tested in the 120-hpf tissue samples. Interestingly, BDE 153 underwent meta-debromination, forming BDEs 47 and 99. Gene transcription analysis was conducted at 120 hpf to identify potential metabolic pathways for the PBDEs examined in the present study (gstpi, deiodinases 1 and 2, cyp1a1, cyp1b1, and ugt5g). The greatest induction was of ugt5g for all congeners and deiodinase transcription was also upregulated by BDEs 28, 47, and 183. The cyp1a1 and cyp1b1 were upregulated by BDEs 28, 47, 99, and 183. The least alterations in gene transcription were in the BDE 153-exposed embryos. A clear primary pathway of debromination metabolism was not identified; however, upregulation of these different genes indicated that fish were responding to exposure of PBDEs. Furthermore, the present study demonstrated that the most bioavailable congeners are also those with the highest reported toxicity.

Non-gaseous oxygen therapeutics are emerging technologies in regenerative medicine that aim to sidestep the undesirable effects seen in traditional oxygen therapies, while enhancing tissue and wound regeneration. Using a novel oxygenating therapeutic (Ox66™) several in vitro models including fibroblast and keratinocyte monocultures were evaluated for potential drug toxicity, the ability of cells to recover after chemical injury, and cell migration after scratch assay. It was determined that in both cell lines, there was no significant cytotoxicity found after independent treatment with Ox66™. Similarly, after DMSO-induced chemical injury, the health parameters of cells treated with Ox66™ were improved when compared to their untreated counterparts. Particles were also characterized using scanning electron microscopy and electron dispersive spectroscopy both individually and in conjunction with fibroblast growth. The data in this study showed that the novel wound healing therapeutic has potential in advancing the treatment of various types of acute and chronic wounds.

Polybrominated diphenyl ethers (PBDEs) have become ubiquitous environmental contaminants with potential for bioaccumulation and maternal-fetal transfer that has led to regulatory bans and/or phasing out of several technical mixtures of PBDEs. In the present study, six PBDE congeners (BDE 28, BDE 47, BDE 99, BDE 100, BDE 153, BDE 183) were evaluated for developmental effects on embryonic zebrafish. These congeners were chosen because they are environmentally relevant and cover a wide range of physical-chemical properties. Alterations in behavior, physical malformations, and mortality were scored daily until 168 h postfertilization (hpf). A concentration-dependent increase in spontaneous movement indicated an early onset of behavioral responses to PBDE exposures. Spontaneous movement was affected the most by BDE 47 and BDE 28, whereas BDE 183 did not alter behavior at any concentration tested. Swimming rates were significantly increased by BDE 28 at 96 and 120 hpf, but decreased swimming activity at 168 hpf. Additionally, BDE 47 significantly decreased the swimming rate at 168 hpf. Other endpoints included malformations and mortality. Congeners with fewer bromines (BDE 28, 47, 99, and 100) also induced a curved body axis starting around 120 hpf, which was followed by mortality. BDEs 153 and 183, however, did not elicit these adverse effects. A relationship was found between log KOW and median lethal concentration (LC50) and median effective concentration (EC50). Structure–activity relationships in this study suggest that PBDE acute toxicity results from a receptor-mediated effect and further studies are necessary to determine these pathways. Environ. Toxicol. Chem. 2011; 30:1865–1872. © 2011 SETAC

Risk assessments for mixtures of polycyclic aromatic hydrocarbons (PAH) are problematic due to the lack of available potency and toxicity data on individual compounds and mixtures. This article examines the toxicity of parent compounds and designed mixtures of PAH in order to bridge the gap between component assessment and mixture assessment for this class of ubiquitous compounds. The objective for this study was to test seven parent PAH compounds and four PAH mixtures in a set of three bioassays to evaluate the toxicity of parent compound PAH and binary mixtures of PAH. PAH and mixtures were examined in the Salmonella/microsome mutagenicity assay, a Gap Junction Intercellular Communication assay, and the 7-ethoxyresorufin-O-deethylase assay. These assays were chosen for their ability to measure specific toxic endpoints related to the carcinogenic process (i.e. initiation, promotion, and progression). Two compounds similar in structure, benzo(a) pyrene (BAP) and benzanthracene, consistently produced posit...

Polybrominated diphenyl ethers (PBDE) are flame retardants found in many industrial components, such as furniture foam, consumer electronics, plastics, and textiles and levels have increased in human beings over the past few decades. PBDE (1) produce adverse neurotoxic effects in mice, (2) are lipophilic, and (3) bioaccumulate in fish. Consequently, PBDE biomagnification may occur, which may be transferred to human beings in amounts that may exert adverse health effects. This investigation uses in vitro models to calculate bioassay-based reference doses in order to develop a human health risk assessment based on the consumption of PBDE-contaminated fish, using in vitro to in vivo extrapolation. The toxicity effects of 10 PBDE congeners were examined and compared among those developed using traditional in vivo mouse studies and in vitro models in this investigation employing rat (Clone-9), HEPG2 and zebrafish liver cells to determine the feasibility of using alternative approaches to develop toxicity metrics to evaluate human health risk.

Ethanol is metabolized by Alcohol Dehydrogenase (ADH) to acetaldehyde and then irreversibly oxidized by Aldehyde Dehydrogenase (ALDH) to nontoxic acetate. In individuals expressing the ALDH2*2 variant enzyme, the rate of conversion from acetaldehyde to acetate is reduced and leads to flushing, nausea, and tachycardia due to increased blood levels of acetaldehyde. The ALDH2*2 variant has a lowered NAD+ coenzyme binding affinity, which results in a lowered clearance capacity toward acetaldehyde. This polymorphism is caused by the substitution of glutamate for lysine at position 487 within the catalytic active site of ALDH2, resulting in effects on subunit and quaternary complex activity. ALDH2*2 alleles are dominant over ALDH2*1 and therefore are expected to contribute to the formation of inactive heterotetramers decreased enzymatic activity in both homozygous and heterozygous individuals. Consequently, a higher susceptibility to various diseases such as Alzheimer’s, osteoporosis, and acute coronary syndrome has been associated with ALDH2*2 carriers. Additionally, the polymorphism seems to affect the efficacy of Glyceryl Trinitrate (GTN), a drug intended to treat coronary heart disease, in carriers of ALDH2*2 alleles. However, the polymorphism is believed to afford a protective effect against alcoholism as the side effects of acetaldehyde build-up are undesirable. Disulfiram, a drug historically used to treat alcohol dependency, induces the same undesirable physiological effects as the variant enzyme in non-carriers by inhibiting the normal functioning of ALDH2 enzyme.

Deterministic risk assessments provide a single point estimate of risk at a site of concern, while probabilistic risk assessment methods generate a range of values from probability distribution functions (PDFs). This study compares deterministic and probabilistic risk assessment methods for two different sites using uncertainty analysis and evaluates the use of toxic equivalency factors (TEFs) for polycyclic aromatic hydrocarbons (PAHs) in each method. The use of TEFs allowed more of the PAHs to be included which resulted in higher risk estimates for both adults and children at both study sites. Exposure factor variability generated greater uncertainty in risk estimates than sample heterogeneity or toxicity estimates. TEFs allowed for a more complete representation of the toxicity contributions from PAH species present at the study sites. Exposure factor distributions together with TEF estimations for toxicity of PAH species provide an assessment that can reduce and account for uncertainty. Probabilistic risk estimates provide a sensible improvement to deterministic risk estimates by generating a range of risk values, along with an average estimate and the degree of conservatism of those estimates.

Polycyclic aromatic hydrocarbons (PAHs) have been labeled contaminants of concern due to their carcinogenic potential, insufficient toxicological data, environmental ubiquity, and inconsistencies in the composition of environmental mixtures. The Environmental Protection Agency is reevaluating current methods for assessing the toxicity of PAHs, including the assumption of toxic additivity in mixtures. This study was aimed at testing mixture interactions through in vitro cell culture experimentation, and modeling the toxicity using quantitative structure-activity relationships (QSAR). Clone-9 rat liver cells were used to analyze cellular proliferation, viability, and genotoxicity of 15 PAHs in single doses and binary mixtures. Tests revealed that many mixtures have nonadditive toxicity, but display varying mixture effects depending on the mixture composition. Many mixtures displayed antagonism, similar to other published studies. QSARs were then developed using the genetic function approximation algorithm to predict toxic activity both in single PAH congeners and in binary mixtures. Effective concentrations inhibiting 50% of the cell populations were modeled, with R(2) = 0.90, 0.99, and 0.84, respectively. The QSAR mixture algorithms were then adjusted to account for the observed mixture interactions as well as the mixture composition (ratios) to assess the feasibility of QSARs for mixtures. Based on these results, toxic addition is improbable and therefore environmental PAH mixtures are likely to see nonadditive responses when complex interactions occur between components. Furthermore, QSAR may be a useful tool to help bridge these data gaps surrounding the assessment of human health risks that are associated with PAH exposures.

There is an increasing need to prevent or mitigate known exposures, extrapolate environmental remediation knowledge, and share lessons of effective risk communication from industrialized countries with less developed areas of the world. To facilitate this process, global health concerns resulting from environmental exposures need to be addressed universally. Additionally, the global scientific community must commit to working together to help find solutions to these health issues as they are experienced throughout the world. If the next generation of health scientists is to act as stewards of the environment, this group must place more emphasis on sharing existing knowledge with all nations, specifically by collaborating with other nations that are dealing with the same environmental challenges. The International Central and Eastern European Health Conference was held in Prague, Czech Republic, in October 2004. This location was selected because current social, political, and economic transitions in this region have resulted in a dramatic impact on environmental and occupational exposures. During the past two decades, the period of political change, inadequate/aging infrastructure, and a lack of economic resources in Eastern and Central Europe have resulted in increased pollution and public health risk (Bell 2000; Organization for Economic Cooperation and Development 1999). A lack of regulation of environmental pollution and an increase in poor industrial and agricultural practices have resulted in increased air and water pollution as well as soil contamination (Jedrychowski 1995; Woolfson 2006). The purpose of this commentary is to summarize some of the main conference themes that were identified by the international graduate students who participated in the platform discussions at the conference. These students were asked to share their opinions and to prioritize the predominant environmental issues facing their respective countries, and to provide potential solutions for them. These forums identified societal and political issues as a potential challenge to implementing environmental reforms, whereas education and training were described as some of the most immediate ways to initiate action on these issues. Additionally, these two groups also emphasized the prominent need to address children’s health issues, because children are often considered the most susceptible subgroup of any population. We hope that this commentary will highlight the international nature of current environmental health problems and underscore the vital need to increase the exchange of information across borders and scientific disciplines.

Soluble in the extracellular matrix experience a crowded environment. However, most of the biophysical studies performed to date have focused on concentrations within the dilute regime (well below the mM range). Here, we systematically studied the interaction of model cell membrane systems (giant unilamellar vesicles and supported bilayers) with soluble globular , bovine serum albumin, and lysozyme at physiologically relevant concentrations. To mimic the extracellular environment more closely, we also used fetal bovine serum as a good representative of a biomimetic mixture. We found that regardless of the used (and thus of their biological function), the interactions between a model cell membrane and these are determined by their physico-chemical characteristics, mainly their dipolar character (or charged patches). In this paper we discuss the specificity and reversibility of these interactions and their potential implications on the living cells. In particular, we report initial evidence for an additional role of in cell membranes: that of reducing the effects of non-specific of soluble on the cell membrane.

A proposed primary pathway through which polybrominated diphenyl ethers (PBDEs) disrupt normal biological functions is oxidative stress. In the present study, 4 PBDE congeners were evaluated for their potential to initiate oxidative stress in zebrafish during development: BDE 28, BDE 47, BDE 99, and BDE 100. N-acetylcysteine (NAC) was used to increase intracellular glutathione concentrations and only decreased the effects of BDE 28 at 10 ppm and 20 ppm and BDE 47 at 20 ppm. N-acetylcysteine coexposure did not alter the rates of mortality or curved body axis compared with PBDE exposure alone. The activity of glutathione-S-transferase (GST) was not altered at 24 h postfertilization (hpf), but increased following 10 ppm BDE 28 exposure at 120 hpf. Transcription of several genes associated with stress was also evaluated. At 24 hpf, cytochrome c oxidase subunit 6a (COX6a) transcription was up-regulated in embryos exposed to BDE 99, and BDE 28 exposure up-regulated the transcription of Glutathione-S-transferase-pi (GSTpi). At 24 hpf, glutamate-cysteine ligase (GCLC) was slightly down-regulated by all congeners evaluated. At 120 hpf, TNF receptor-associated protein 1 (TRAP1) and COX6A were up-regulated by all congeners, however GSTpi was down-regulated by all congeners. The results of quantitative real-time transcription polymerase chain reaction are mixed and do not strongly support a transcriptional response to oxidative stress. According to the authors' data, PBDEs do not induce oxidative stress. Oxidative stress may occur at high exposure concentrations; however, this does not appear to be a primary mechanism of action for the PBDE congeners tested.

Surface-functionalized silver nanoparticles (AgNPs) are the most deployed engineered nanomaterials in consumer products because of their optical, antibacterial and electrical properties. Almost all engineered nanoparticles are coated with application-specific capping agents (i.e. organic/inorganic ligands on particle surface) to enhance their stability in suspension or increase their biocompatibility for biomedicine. The aim of this study was to investigate the contribution of the selected capping agents to their observed health impacts using realistic dose ranges. AgNPs capped with citrate, polyvinylpyrrolidone (PVP) and tannic acid were studied with human bronchoalveolar carcinoma (A549) and human colon adenocarcinoma (Caco-2) cell lines and compared against exposures to Ag ions. Cellular uptake and cytotoxicity were evaluated up to 24 h. Tannic acid capped AgNPs induced higher cellular uptake and rate in both cell lines. Citrate-capped and PVP-capped AgNPs behaved similarly over 24 h. All three of the capped AgNPs penetrated more into the A549 cells than Caco-2 cells. In contrast, the uptake rate of Ag ions in Caco-2 cells (0.11 ± 0.0001 µg h(-1) ) was higher than A549 cells (0.025 ± 0.00004 µg h(-1) ). The exposure concentration of 3 mg l(-1) is below the EC50 value for all of the AgNPs; therefore, little cytotoxicity was observed in any experiment conducted herein. Exposure of Ag ions, however, interrupted cell membrane integrity and cell proliferation (up to 70% lysed after 24 h). These findings indicate cellular uptake is dependent on capping agent, and when controlled to realistic exposure concentrations, cellular function is not significantly affected by AgNP exposure.

Polybrominated diphenyl ethers (PBDEs) are known as effective flame retardants and have vast industrial application in products like plastics, building materials and textiles. They are found to be structurally similar to thyroid hormones that are responsible for regulating metabolism in the body. Structural similarity with the hormones poses a threat to human health because, once in the system, PBDEs have the potential to affect thyroid hormone transport and metabolism. This study was aimed at designing quantitative structure-activity relationship (QSAR) models for predicting toxic endpoints, namely cell viability and apoptosis, elicited by PBDEs in mammalian cells. Cell viability was evaluated quantitatively using a general cytotoxicity bioassay using Janus Green dye and apoptosis was evaluated using a caspase assay. This study has thus modelled the overall cytotoxic influence of PBDEs at an early and a late endpoint by the Genetic Function Approximation method. This research was a twofold process including running in vitro bioassays to collect data on the toxic endpoints and modeling the evaluated endpoints using QSARs. Cell viability and apoptosis responses for Hep G2 cells exposed to PBDEs were successfully modelled with an r(2) of 0.97 and 0.94, respectively.

Embryonic zebrafish were used to compare the uptake and metabolism of six polybrominated diphenyl ether (PBDE) congeners (BDEs 28, 47, 99, 100, 153, and 183) and identified metabolites from static exposures at 24 and 120 h postfertilization (hpf). An inverse relationship was observed between uptake of PBDEs and their octanol-water partitioning coefficients (uptake of BDEs 28 and 4799 and 100153 and 183). Debromination metabolites were identified in all congeners (excluding BDE 28) tested in the 120-hpf tissue samples. Interestingly, BDE 153 underwent meta-debromination, forming BDEs 47 and 99. Gene transcription analysis was conducted at 120 hpf to identify potential metabolic pathways for the PBDEs examined in the present study (gstpi, deiodinases 1 and 2, cyp1a1, cyp1b1, and ugt5g). The greatest induction was of ugt5g for all congeners and deiodinase transcription was also upregulated by BDEs 28, 47, and 183. The cyp1a1 and cyp1b1 were upregulated by BDEs 28, 47, 99, and 183. The least alterations in gene transcription were in the BDE 153-exposed embryos. A clear primary pathway of debromination metabolism was not identified; however, upregulation of these different genes indicated that fish were responding to exposure of PBDEs. Furthermore, the present study demonstrated that the most bioavailable congeners are also those with the highest reported toxicity.

The ubiquitous spread of polybrominated diphenyl ethers (PBDEs) has led to concerns regarding the metabolites of these congeners, in particular hydroxylated PBDEs. There are limited studies regarding the biological interactions of these chemicals, yet there is some concern they may be more toxic than their parent compounds. In this study three hydroxylated PBDEs were assessed for toxicity in embryonic zebrafish: 3-OH-BDE 47, 5-OH-BDE 47, and 6-OH-BDE 47. All three congeners induced developmental arrest in a concentration-dependent manner; however, 6-OH-BDE 47 induced adverse effects at lower concentrations than the other congeners. Furthermore, all three induced cell death; however apoptosis was not observed. In short-term exposures (24-28 hours post fertilization), all hydroxylated PBDEs generated oxidative stress in the region corresponding to the cell death at 5 and 10 ppm. To further investigate the short-term effects that may be responsible for the developmental arrest observed in this study, gene regulation was assessed for embryos exposed to 0.625 ppm 6-OH-BDE 47 from 24 to 28 hpf. Genes involved in stress response, thyroid hormone regulation, and neurodevelopment were significantly upregulated compared to controls; however, genes related to oxidative stress were either unaffected or downregulated. This study suggests that hydroxylated PBDEs disrupt development, and may induce oxidative stress and potentially disrupt the cholinergic system and thyroid hormone homeostasis.

Quantitative structure-activity relationships (QSAR) offer a reliable, cost-effective alternative to the time, money, and animal lives necessary to determine chemical toxicity by traditional methods. Additionally, humans are exposed to tens of thousands of chemicals in their lifetimes, necessitating the determination of chemical toxicity and screening for those posing the greatest risk to human health. This study developed models to predict toxic endpoints for three bioassays specific to several stages of carcinogenesis. The ethoxyresorufin O-deethylase assay (EROD), the Salmonella/microsome assay, and a gap junction intercellular communication (GJIC) assay were chosen for their ability to measure toxic endpoints specific to activation-, induction-, and promotion-related effects of polycyclic aromatic hydrocarbons (PAH). Shape-electronic, spatial, information content, and topological descriptors proved to be important descriptors in predicting the toxicity of PAH in these bioassays. Bioassay-based toxic equivalency factors (TEF(B)) were developed for several PAH using the quantitative structure-toxicity relationships (QSTR) developed. Predicting toxicity for a specific PAH compound, such as a bioassay-based potential potency (PP(B)) or a TEF(B), is possible by combining the predicted behavior from the QSTR models. These toxicity estimates may then be incorporated into a risk assessment for compounds that lack toxicity data. Accurate toxicity predictions are made by examining each type of endpoint important to the process of carcinogenicity, and a clearer understanding between composition and toxicity can be obtained.