Showing papers in "Journal of Toxicology in 2012"
TL;DR: The nature of ROS-induced damage on key cellular targets of oxidative stress is examined and evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity is reviewed.
Abstract: Reactive oxygen species (ROS) are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.
542 citations
TL;DR: Emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology.
Abstract: Exposure to ambient air pollution is a serious and common public health concern associated with growing morbidity and mortality worldwide. In the last decades, the adverse effects of air pollution on the pulmonary and cardiovascular systems have been well established in a series of major epidemiological and observational studies. In the recent past, air pollution has also been associated with diseases of the central nervous system (CNS), including stroke, Alzheimer's disease, Parkinson's disease, and neurodevelopmental disorders. It has been demonstrated that various components of air pollution, such as nanosized particles, can easily translocate to the CNS where they can activate innate immune responses. Furthermore, systemic inflammation arising from the pulmonary or cardiovascular system can affect CNS health. Despite intense studies on the health effects of ambient air pollution, the underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology. A better understanding of the mediators and mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system and mental health.
489 citations
TL;DR: It is demonstrated that silver nanoparticles are lethal to zebrafish by demonstrating increased rate of operculum movement and surface respiration after nanosilver exposure, suggesting respiratory toxicity.
Abstract: The influence of water chemistry on characterised polyvinyl pyrrolidone- (PVP-) coated silver nanoparticles (81 nm) was investigated. NaCl solution series of 100–800 mg L−1 lead to initial and temporal increase in nanoparticles size, but agglomeration was limited. pH variation (5–8) had only minor influence on the hydrodynamic particle size. Acute toxicity of nanosivler to zebrafish (Danio rerio) was investigated in a 48-hour static renewal study and compared with the toxicity of silver ions (AgNO3). The nanosilver and silver ion 48-hour median lethal concentration (LC50) values were 84 μg L−1 and 25 μg L−1, respectively. To investigate exposure-related stress, the fish behaviour was observed visually after 0, 3, 6, 12, 24, 27, 30, and 48 hours of both nanosilver and ionic silver treatments. These observations revealed increased rate of operculum movement and surface respiration after nanosilver exposure, suggesting respiratory toxicity. The present study demonstrates that silver nanoparticles are lethal to zebrafish.
197 citations
TL;DR: This paper summarizes the evidence for metal interactions with synaptic transmission and synaptic plasticity and indicates that the multiple effects of metals might occur simultaneously and are based on the specific metal species, metal concentrations, and the types of neurons involved.
Abstract: Metal neurotoxicity is a global health concern. This paper summarizes the evidence for metal interactions with synaptic transmission and synaptic plasticity. Presynaptically metal ions modulate neurotransmitter release through their interaction with synaptic vesicles, ion channels, and the metabolism of neurotransmitters (NT). Many metals (e.g., Pb2+, Cd2+, and Hg+) also interact with intracellular signaling pathways. Postsynaptically, processes associated with the binding of NT to their receptors, activation of channels, and degradation of NT are altered by metals. Zn2+, Pb2+, Cu2+, Cd2+, Ni2+, Co2+, Li3+, Hg+, and methylmercury modulate NMDA, AMPA/kainate, and/or GABA receptors activity. Al3+, Pb2+, Cd2+, and As2O3 also impair synaptic plasticity by targeting molecules such as CaM, PKC, and NOS as well as the transcription machinery involved in the maintenance of synaptic plasticity. The multiple effects of metals might occur simultaneously and are based on the specific metal species, metal concentrations, and the types of neurons involved.
92 citations
TL;DR: This study provides the first report of genotoxic and cytotoxic effects in PBL following in vitro exposure to commercial neonicotinoid insecticides.
Abstract: Calypso (thiacloprid), Poncho (clothianidin), Gaucho (imidacloprid), and Jade (imidacloprid) are commercial neonicotinoid insecticides, a new class of agrochemicals in Mexico. However, genotoxic and cytotoxic studies have not been performed. In the present study, human peripheral blood lymphocytes (PBL) were exposed in vitro to different concentrations of the four insecticides. The genotoxic and cytotoxic effects were evaluated using the alkaline comet and trypan blue dye exclusion assays. DNA damage was evaluated using two genotoxicity parameters: tail length and comet frequency. Exposure to 9.5×10-6 to 5.7×10-5 M Jade; 2.8×10-4 to 1.7×10-3 M Gaucho; 0.6×10-1 to 1.4×10-1 M Calypso; 1.2×10-1 to 9.5×10-1 M Poncho for 2 h induced a significant increase DNA damage with a concentration-dependent relationship. Jade was the most genotoxic of the four insecticides studied. Cytotoxicity was observed in cells exposed to 18×10-3 M Jade, 2.0×10-3 M Gaucho, 2.0×10-1 M Calypso, 1.07 M Poncho, and cell death occurred at 30×10-3 M Jade, 3.3×10-3 M Gaucho, 2.8×10-1 M Calypso, and 1.42 M Poncho. This study provides the first report of genotoxic and cytotoxic effects in PBL following in vitro exposure to commercial neonicotinoid insecticides.
88 citations
TL;DR: A primary pathogenic role for oxidative stress in the early initiating stages of ALD that precedes the involvement of the ER stress response is indicated.
Abstract: Alcoholic liver disease (ALD) is a primary cause of morbidity and mortality in the United States and constitutes a significant socioeconomic burden. Previous work has implicated oxidative stress and endoplasmic reticulum (ER) stress in the etiology of ALD; however, the complex and interrelated nature of these cellular responses presently confounds our understanding of ethanol-induced hepatopathy. In this paper, we assessed the pathological contribution of oxidative stress and ER stress in a time-course mouse model of early-stage ALD. Ethanol-treated mice exhibited significant hepatic panlobular steatosis and elevated plasma ALT values compared to isocaloric controls. Oxidative stress was observed in the ethanol-treated animals through a significant increase in hepatic TBARS and immunohistochemical staining of 4-HNE-modified proteins. Hepatic glutathione (GSH) levels were significantly decreased as a consequence of decreased CBS activity, increased GSH utilization, and increased protein glutathionylation. At the same time, immunoblot analysis of the PERK, IRE1α, ATF6, and SREBP pathways reveals no significant role for these UPR pathways in the etiology of hepatic steatosis associated with early-stage ALD. Collectively, our results indicate a primary pathogenic role for oxidative stress in the early initiating stages of ALD that precedes the involvement of the ER stress response.
85 citations
TL;DR: Results of population-based studies suggest that complete methylation of inorganic As to DMA is associated with reduced risk for As-induced health outcomes, and that nutrients involved in one-carbon metabolism, such as folate, can facilitate As methylation and elimination.
Abstract: Exposure to arsenic (As) through drinking water is a substantial problem worldwide. The methylation of As, a reactive metalloid, generates monomethyl- (MMA) and dimethyl-arsenical (DMA) species. The biochemical pathway that catalyzes these reactions, one-carbon metabolism, is regulated by folate and other micronutrients. Arsenic methylation exerts a critical influence on both its urinary elimination and chemical reactivity. Mice having the As methyltransferase null genotype show reduced urinary As excretion, increased As retention, and severe systemic toxicity. The most toxic As metabolite in vitro is MMAIII, an intermediate in the generation of DMAV, a much less toxic metabolite. These findings have raised the question of whether As methylation is a detoxification or bioactivation pathway. Results of population-based studies suggest that complete methylation of inorganic As to DMA is associated with reduced risk for As-induced health outcomes, and that nutrients involved in one-carbon metabolism, such as folate, can facilitate As methylation and elimination.
85 citations
TL;DR: An alternative approach now being explored is to utilize C-CPE, which corresponds approximately to receptor binding domain I, to enhance paracellular permeability and delivery of chemotherapeutic agents against cancer cells.
Abstract: Clostridium perfringens enterotoxin (CPE) causes the symptoms associated with several common gastrointestinal diseases. CPE is a 35 kDa polypeptide consisting of three structured domains, that is, C-terminal domain I (responsible for receptor binding), domain II (responsible for oligomerization and membrane insertion), and domain III (which may participate in physical changes when the CPE protein inserts into membranes). Native CPE binds to claudin receptors, which are components of the tight junction. The bound toxin then assembles into a hexameric prepore on the membrane surface, prior to the insertion of this oligomer into membranes to form an active pore. The toxin is especially lethal for cells expressing large amounts of claudin-3 or -4, which includes many cancer cells. Initial studies suggest that native CPE has potential usefulness for treating several cancers where claudin CPE receptors are overexpressed. However, some challenges with immunogenicity, toxicity, and (possibly) the development of resistance may need to be overcome. An alternative approach now being explored is to utilize C-CPE, which corresponds approximately to receptor binding domain I, to enhance paracellular permeability and delivery of chemotherapeutic agents against cancer cells. Alternatively, C-CPE fusion proteins may prove superior to use of native CPE for cancer treatment. Finally, C-CPE may have application for other medical treatments, including vaccination or increasing drug absorption. The coming years should witness increasing exploitation of this otherwise formidable toxin.
65 citations
TL;DR: A novel finding related to cell-signaling events modulated by APP and PS1 in the development of neurodegeneration is discussed, supported by the presence of a complex network of proteins clearly involved in the regulation of signal transduction mechanisms that interact with both APP andPS1.
Abstract: Alzheimer disease (AD) is a heterogeneous neurodegenerative disorder characterized by (1) progressive loss of synapses and neurons, (2) intracellular neurofibrillary tangles, composed of hyperphosphorylated Tau protein, and (3) amyloid plaques. Genetically, AD is linked to mutations in few proteins amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2). The molecular mechanisms underlying neurodegeneration in AD as well as the physiological function of APP are not yet known. A recent theory has proposed that APP and PS1 modulate intracellular signals to induce cell-cycle abnormalities responsible for neuronal death and possibly amyloid deposition. This hypothesis is supported by the presence of a complex network of proteins, clearly involved in the regulation of signal transduction mechanisms that interact with both APP and PS1. In this review we discuss the significance of novel finding related to cell-signaling events modulated by APP and PS1 in the development of neurodegeneration.
64 citations
TL;DR: Some of the neuronal pathophysiological conditions that could be caused by dysregulated microRNAs are discussed and their impact on neuronal activities is discussed.
Abstract: MicroRNAs are gaining importance as regulators of gene expression with the capability to fine-tune and modulate cellular events. The complex network with their selective targets (mRNAs/genes) pave way for regulation of many physiological processes. Dysregulation of normal neuronal activities could result in accumulation of substances that are detrimental to neuronal functions and subsequently result in neurotoxicity. Neurotoxicity-mediated pathophysiological conditions could then manifest as diseases or disabilities like Parkinson's and Alzheimer's which have debilitating implications. Such toxicity can be a result of individuals predisposed due to genetic inheritance or from other sources such as brain tumours. Neurotoxicity can also be brought about by external agents like drugs and alcohol as well as brain injury with miRNAs playing a pivotal role in diseases. It is therefore vital to understand the expression of these microRNAs and their impact on neuronal activities. In this paper, we discuss some of the neuronal pathophysiological conditions that could be caused by dysregulated microRNAs.
51 citations
TL;DR: The role of the excitotoxic influx and accumulation of zinc, the mechanisms responsible for its cytotoxicity, and a number of disorders of the central nervous system that have been linked to these neuronal ion channels and zinc toxicity are discussed.
Abstract: Ionotropic glutamate receptors, such as NMDA, AMPA and kainate receptors, are ligand-gated ion channels that mediate much of the excitatory neurotransmission in the brain Not only do these receptors bind glutamate, but they are also regulated by and facilitate the postsynaptic uptake of the trace metal zinc This paper discusses the role of the excitotoxic influx and accumulation of zinc, the mechanisms responsible for its cytotoxicity, and a number of disorders of the central nervous system that have been linked to these neuronal ion channels and zinc toxicity including ischemic brain injury, traumatic brain injury, and epilepsy
TL;DR: This special issue contains papers that can provide the basis for future modeling efforts and provide bridges to emerging toxicology paradigms and issues addressed include increased understanding of human variability of pharmacokinetics and pharmacodynamics in the population.
Abstract: Physiologically based Pharmacokinetic (PBPK) models are used for predictions of internal or target dose from environmental and pharmacologic chemical exposures. Their use in human risk assessment is dependent on the nature of databases (animal or human) used to develop and test them, and includes extrapolations across species, experimental paradigms, and determination of variability of response within human populations. Integration of state-of-the science PBPK modeling with emerging computational toxicology models is critical for extrapolation between in vitro exposures, in vivo physiologic exposure, whole organism responses, and long-term health outcomes. This special issue contains papers that can provide the basis for future modeling efforts and provide bridges to emerging toxicology paradigms. In this overview paper, we present an overview of the field and introduction for these papers that includes discussions of model development, best practices, risk-assessment applications of PBPK models, and limitations and bridges of modeling approaches for future applications. Specifically, issues addressed include: (a) increased understanding of human variability of pharmacokinetics and pharmacodynamics in the population, (b) exploration of mode of action hypotheses (MOA), (c) application of biological modeling in the risk assessment of individual chemicals and chemical mixtures, and (d) identification and discussion of uncertainties in the modeling process.
TL;DR: The role as a preparation in the development of toxinological studies in the following electrophysiological methods of Periplaneta americana cockroach is presented.
Abstract: Nervous system of Periplaneta americana cockroach is used in a wide range of pharmacological studies, including electrophysiological techniques. This paper presents its role as a preparation in the development of toxinological studies in the following electrophysiological methods: double-oil-gap technique on isolated giant axon, patch-clamp on DUM (dorsal unpaired median) neurons, microelectrode technique in situ conditions on axon in connective and DUM neurons in ganglion, and single-fiber oil-gap technique on last abdominal ganglion synapse. At the end the application of cockroach synaptosomal preparation is mentioned.
TL;DR: BTX therapy has high cost and transient effect, but its benefits outweigh these disadvantages, and future studies must clarify if this agent alone or adjunctive to other rehabilitative procedures works best on functional outcome.
Abstract: The botulinum toxins (BTX), type A and type B by blocking vesicle acetylcholine release at neuro-muscular and neuro-secretory junctions can result efficacious therapeutic agents for the treatment of numerous disorders in patients requiring neuro-rehabilitative intervention. Its use for the reduction of focal spasticity following stroke, brain injury, and cerebral palsy is provided. Although the reduction of spasticity is widely demonstrated with BTX type A injection, its impact on the improvement of dexterity and functional outcome remains controversial. The use of BTX for the rehabilitation of children with obstetrical brachial plexus palsy and in treating sialorrhea which can complicate the course of some severe neurological diseases such as amyotrophic lateral sclerosis and Parkinson's disease is also addressed. Adverse events and neutralizing antibodies formation after repeated BTX injections can occur. Since impaired neurological persons can have complex disabling feature, BTX treatment should be viewed as adjunct measure to other rehabilitative strategies that are based on the individual's residual ability and competence and targeted to achieve the best functional recovery. BTX therapy has high cost and transient effect, but its benefits outweigh these disadvantages. Future studies must clarify if this agent alone or adjunctive to other rehabilitative procedures works best on functional outcome.
TL;DR: This work investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene to evaluate the ability of the computational framework to predict known inhalation exposures.
Abstract: There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or reverse dosimetry is the retrospective interpretation of external exposure consistent with biomonitoring data. We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene. We used exhaled breath and venous blood m-xylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures. We also investigated the importance of model structure and dimensionality with respect to its ability to reconstruct exposure.
TL;DR: The “human PBPK model toolkit” is one such project; while not necessarily state of the art, this toolkit is sufficiently accurate for screening purposes.
Abstract: Post-exposure risk assessment of chemical and environmental stressors is a public health challenge Linking exposure to health outcomes is a 4-step process: exposure assessment, hazard identification, dose response assessment, and risk characterization This process is increasingly adopting “in silico” tools such as physiologically based pharmacokinetic (PBPK) models to fine-tune exposure assessments and determine internal doses in target organs/tissues Many excellent PBPK models have been developed But most, because of their scientific sophistication, have found limited field application—health assessors rarely use them Over the years, government agencies, stakeholders/partners, and the scientific community have attempted to use these models or their underlying principles in combination with other practical procedures During the past two decades, through cooperative agreements and contracts at several research and higher education institutions, ATSDR funded translational research has encouraged the use of various types of models Such collaborative efforts have led to the development and use of transparent and user-friendly models The “human PBPK model toolkit” is one such project While not necessarily state of the art, this toolkit is sufficiently accurate for screening purposes Highlighted in this paper are some selected examples of environmental and occupational exposure assessments of chemicals and their mixtures
TL;DR: Investigating the toxicology of Thimerosal in normal human astrocytes, paying particular attention to mitochondrial function and the generation of specific oxidants finds that ethylmercury not only inhibits mitochondrial respiration leading to a drop in the steady state membrane potential, but also concurrent with these phenomena increases the formation of superoxide, hydrogen peroxide, and Fenton/Haber-Weiss generated hydroxyl radical.
Abstract: Thimerosal generates ethylmercury in aqueous solution and is widely used as preservative. We have investigated the toxicology of Thimerosal in normal human astrocytes, paying particular attention to mitochondrial function and the generation of specific oxidants. We find that ethylmercury not only inhibits mitochondrial respiration leading to a drop in the steady state membrane potential, but also concurrent with these phenomena increases the formation of superoxide, hydrogen peroxide, and Fenton/Haber-Weiss generated hydroxyl radical. These oxidants increase the levels of cellular aldehyde/ketones. Additionally, we find a five-fold increase in the levels of oxidant damaged mitochondrial DNA bases and increases in the levels of mtDNA nicks and blunt-ended breaks. Highly damaged mitochondria are characterized by having very low membrane potentials, increased superoxide/hydrogen peroxide production, and extensively damaged mtDNA and proteins. These mitochondria appear to have undergone a permeability transition, an observation supported by the five-fold increase in Caspase-3 activity observed after Thimerosal treatment.
TL;DR: This paper summarizes the work on the isolation and characterization of several structurally distinct families of scorpion toxin peptides exhibiting different K+ channel blocking functions and the venom from the Moroccan scorpion AndroctonusMauretanicus provided several high-affinity blockers selective for diverse K+ channels.
Abstract: K + channels selectively transport K + ions across cell membranes and play a key role in regulating the physiology of excitable and nonexcitable cells. Their activation allows the cell to repolarize after action potential firing and reduces excitability, whereas channel inhibition increases excitability. In eukaryotes, the pharmacology and pore topology of several structural classes of K + channels have been well characterized in the past two decades. This information has come about through the extensive use of scorpion toxins. We have participated in the isolation and in the characterization of several structurally distinct families of scorpion toxin peptides exhibiting different K + channel blocking functions. In particular, the venom from the Moroccan scorpion Androctonus mauretanicus mauretanicus provided several high-affinity blockers selective for diverse K + channels ( S K C a , K v 4.x, and K v 1.x K + channel families). In this paper, we summarize our work on these toxin/channel interactions.
TL;DR: It has been identified that application of cosmetics on abraded skin under sunny condition worsens the irritation and those users who have abrading skin are advised not to apply those cosmetics on continuous basis specifically under sun exposure.
Abstract: Background. Rabbit skin model was used to test skin irritation of the most commonly used cosmetic products in Jimma town, southwestern Ethiopia. The most commonly used cosmetics were Dove, Glysolid, College, Top Society, Fair and Lovely, Nivea, Lux, Magic fruit world, Solea, Body talk, Kris, Holly, Victoria, and Sweet Heart. Methods. Intact and abraded rabbit skins were tested for erythema and edema under shade and under sun exposure. Draize Primary Irritation Index (PII) was used to calculate skin irritation of each cosmetic. Cosmetic ingredients were analyzed from the labels. Results and Discussion. Only Dove cream caused no skin irritation except for an abraded skin under sun exposure for five consecutive days. It has been identified that application of cosmetics on abraded skin under sunny condition worsens the irritation. Cosmetic labels revealed that most ingredients used in all products were those restricted chemicals due to their adverse health effects. Conclusion. This study has concluded that use of cosmetics under sunshine and also on abraded skin increases skin irritation. Hence, those users who have abraded skin are advised not to apply those cosmetics on continuous basis specifically under sun exposure.
TL;DR: An update review of tumour microenvironment as well as summary of the progresses and current status of Clostridial spore-based cancer therapies are provided.
Abstract: Solid tumour accounts for 90% of all cancers. The current treatment approach for most solid tumours is surgery, however it is limited to early stage tumours. Other treatment options such as chemotherapy and radiotherapy are non-selective, thus causing damage to both healthy and cancerous tissue. Past research has focused on understanding tumour cells themselves, and conventional wisdom has aimed at targeting these cells directly. Recent research has shifted towards understanding the tumour microenvironment and it's differences from that of healthy cells/tissues in the body and then to exploit these differences for treatmeat of the tumour. One such approach is utilizing anaerobic bacteria. Several strains of bacteria have been shown to selectively colonize in solid tumours, making them valuable tools for selective tumour targeting and destruction. Amongst them, the anaerobic Clostridium has shown great potential in penetration and colonization of the hypoxic and necrotic areas of the tumour microenvironment, causing significant oncolysis as well as enabling the delivery of therapeutics directly to the tumour in situ. Various strategies utilizing Clostridium are currently being investigated, and represent a novel area of emerging cancer therapy. This review provides an update review of tumour microenvironment as well as summary of the progresses and current status of Clostridial spore-based cancer therapies.
TL;DR: The relationship between arsenic exposure and hypertension is still inconclusive and needs further validation through prospective cohort studies and the only major weaknesses of this study were heterogeneity across studies and small sample size.
Abstract: Background. There is inconclusive evidence from cross-sectional and cohort studies that arsenic exposure is a risk factor involved in the development of hypertension. Methods. A database search, using several keywords, was conducted to identify relevant studies. Separate odds ratio estimates for arsenic exposure with concentration only and arsenic exposure with duration, including biomarker, were extracted from studies that met all inclusion criteria. The extracted odds ratios (OR) comparing the highest exposure categories with the lowest in each study were pooled using the random effects methods of meta-analysis. Heterogeneity of odds ratios in the included studies were analyzed using I2 statistics. Results. Eight studies were analyzed. Using the exposure as arsenic concentration in the drinking water, the OR estimate was 1.9 (95% CI: 1.2–3.0), with the I2 = 92%, while using the exposure as concentration and duration, the OR estimate was 1.4 (95% CI: 0.95–2.0) with the I2 = 80%. Meta-regression was done and the quality of exposure measurement was found to be significantly associated with the effect measure. For a one unit increase in the score from exposure assessment, the odds ratio decreased by 6%. No publication bias was evident. The only major weaknesses of this study were heterogeneity across studies and small sample size. Conclusions. The study findings provide limited evidence for a relationship between arsenic and hypertension. In summary, the relationship between arsenic exposure and hypertension is still inconclusive and needs further validation through prospective cohort studies.
TL;DR: Water samples were collected during 3 years (2004–2007) at three sampling sites in the Rio de la Plata estuary to identify the factors promoting cyanobacteria growth and to describe the observed fluctuating patterns of Microcystis aeruginosa, total coliforms, and microcystin-LR.
Abstract: Water samples were collected during 3 years (2004–2007) at three sampling sites in the Rio de la Plata estuary. Thirteen biological, physical, and chemical parameters were determined on the water samples. The presence of microcystin-LR in the reservoir samples, and also in domestic water samples, was confirmed and quantified. Microcystin-LR concentration ranged between 0.02 and 8.6 μg.L−1. Principal components analysis was used to identify the factors promoting cyanobacteria growth. The proliferation of cyanobacteria was accompanied by the presence of high total and fecal coliforms bacteria (>1500 MNP/100 mL), temperature ≥25∘C, and total phosphorus content ≥1.24 mg·L−1. The observed fluctuating patterns of Microcystis aeruginosa, total coliforms, and Microcystin-LR were also described by probabilistic models based on the log-normal and extreme value distributions. The sampling sites were compared in terms of the distribution parameters and the probability of observing high concentrations for Microcystis aeruginosa, total coliforms, and microcystin-LR concentration.
TL;DR: A review of a number of recent reports of interactions of quantum dots (QDs) with aquatic environments and aquatic organisms is provided, focused on providing a summary of recent work investigating the impacts ofquantum dots on aquatic organisms.
Abstract: Because of their unique physical, optical, and mechanical properties, nanomaterials hold great promise in improving on a wide variety of current technologies. Consequently, their use in research and consumer products is increasing rapidly, and contamination of the environment with various nanomaterials seems inevitable. Because surface waters receive pollutants and contaminants from many sources including nanoparticles and act as reservoirs and conduits for many environmental contaminants, understanding the potential impacts of nanoparticles on the organisms within these environments is critical to evaluating their potential toxicity. While there is much to be learned about interactions between nanomaterials and aquatic systems, there have been a number of recent reports of interactions of quantum dots (QDs) with aquatic environments and aquatic organisms. This review is focused on providing a summary of recent work investigating the impacts of quantum dots on aquatic organisms.
TL;DR: In three case studies of physiologically based toxicokinetic (PBTK) modelling in regulatory risk assessment, PBTK modeling helped to identify liver peak concentration as the metric for liver toxicity after dermal exposure of twice the TDI.
Abstract: In this contribution we present three case studies of physiologically based toxicokinetic (PBTK) modelling in regulatory risk assessment. (1) Age-dependent lower enzyme expression in the newborn leads to bisphenol A (BPA) blood levels which are near the levels of the tolerated daily intake (TDI) at the oral exposure as calculated by EFSA. (2) Dermal exposure of BPA by receipts, car park tickets, and so forth, contribute to the exposure towards BPA. However, at the present levels of dermal exposure there is no risk for the adult. (3) Dermal exposure towards coumarin via cosmetic products leads to external exposures of two-fold the TDI. PBTK modeling helped to identify liver peak concentration as the metric for liver toxicity. After dermal exposure of twice the TDI, the liver peak concentration was lower than that present after oral exposure with the TDI dose. In the presented cases, PBTK modeling was useful to reach scientifically sound regulatory decisions.
TL;DR: It is indicated that polymorphisms of GSTP1 combined with GSTT1 and/or GSTM1 deletion are likely to influence on individual susceptibility to cadmium toxicity.
Abstract: The glutathione S-transferases (GSTs) are involved in biotransformation and detoxification of cadmium (Cd). Genetic polymorphisms in these genes may lead to interindividual variation in Cd susceptibility. The objective of this study was to assess the association of GSTs (GSTT1, GSTM1, and GSTP1 Val105Ile) polymorphisms with blood Cd concentrations in a nonoccupationally exposed population. The 370 blood samples were analyzed for Cd concentration and polymorphisms in GSTs genes. Geometric mean of blood Cd among this population was 0.46±0.02 μg/L (with 95% CI; 0.43–0.49 μg/L). Blood Cd concentrations in subjects carrying GSTP1 Val/Val genotype were significantly higher than those with Ile/Ile and Ile/Val genotypes. No significant differences in blood Cd concentrations among individual with gene deletions of GSTT1 and GSTM1 were observed. GSTP1/GSTT1 and GSTP1/GSTM1 combinations showed significantly associated with increase in blood Cd levels. This study indicated that polymorphisms of GSTP1 combined with GSTT1 and/or GSTM1 deletion are likely to influence on individual susceptibility to cadmium toxicity.
TL;DR: The nematode species Caenorhabditis elegans provides an excellent model for the study of oxidative stress and redox signalling in animals and protein sequences from central redox systems in Homo sapiens, Drosophila melanogaster, and Saccharomyces cerevisiae are used to query Genbank for homologous proteins in C. elegans.
Abstract: Oxidative stress is a toxic state caused by an imbalance between the production and elimination of reactive oxygen species (ROS). ROS cause oxidative damage to cellular components such as proteins, lipids, and nucleic acids. While the role of ROS in cellular damage is frequently all that is noted, ROS are also important in redox signalling. The "Redox Hypothesis" has been proposed to emphasize a dual role of ROS. This hypothesis suggests that the primary effect of changes to the redox state is modified cellular signalling rather than simply oxidative damage. In extreme cases, alteration of redox signalling can contribute to the toxicity of ROS, as well as to ageing and age-related diseases. The nematode species Caenorhabditis elegans provides an excellent model for the study of oxidative stress and redox signalling in animals. We use protein sequences from central redox systems in Homo sapiens, Drosophila melanogaster, and Saccharomyces cerevisiae to query Genbank for homologous proteins in C. elegans. We then use maximum likelihood phylogenetic analysis to compare protein families between C. elegans and the other organisms to facilitate future research into the genetics of redox biology.
TL;DR: Protection offered by trans-resveratrol against ethanol-induced neurotoxicity was only effective for low concentrations of this polyphenol.
Abstract: Aims. 3,5,4′-Trihydroxy-trans-stilbene, a natural polyphenolic compound present in wine and grapes and better known as resveratrol, has free radical scavenging properties and is a potent protector against oxidative stress induced by alcohol metabolism. Today, the mechanism by which ethanol exerts its toxicity is still not well understood, but it is generally considered that free radical generation plays an important role in the appearance of structural and functional alterations in cells. The aim of this study was to evaluate the protective action of resveratrol against ethanol-induced brain cell injury. Methods. Primary cultures of rat astrocytes were exposed to ethanol, with or without a pretreatment with resveratrol. We examined the dose-dependent effects of this resveratrol pretreatment on cytotoxicity and genotoxicity induced by ethanol. Cytotoxicity was assessed using the MTT reduction test. Genotoxicity was evidenced using single cell gel electrophoresis. In addition, DNA staining with fluorescent dyes allowed visualization of nuclear damage using confocal microscopy. Results. Cell pretreatment with low concentrations of trans-resveratrol (0.1–10 μM) slowed down cell death and DNA damage induced by ethanol exposure, while higher concentrations (50–100 μM) enhanced these same effects. No protection by cis-resveratrol was observed. Conclusion. Protection offered by trans-resveratrol against ethanol-induced neurotoxicity was only effective for low concentrations of this polyphenol.
TL;DR: Results show that the ORP values are mainly governed by the type of liquid media employed, with little contributions from the nanoparticles, and the lack of redox potential value contribution from the particles themselves is thought to be due to insufficient interaction of the particles at the Pt electrode of theORP probe.
Abstract: Redox potential has been identified by the Organisation for Economic Co-operation and Development (OECD) as one of the parameters that should be investigated for the testing of manufactured nanomaterials. There is still some ambiguity concerning this parameter, i.e., as to what and how to measure, particularly when in a nanoecotoxicological context. In this study the redox potentials of six nanomaterials (either zinc oxide (ZnO) or cerium oxide (CeO2)) dispersions were measured using an oxidation-reduction potential (ORP) electrode probe. The particles under testing differed in terms of their particle size and dispersion stability in deionised water and in various ecotox media. The ORP values of the various dispersions and how they fluctuate relative to each other are discussed. Results show that the ORP values are mainly governed by the type of liquid media employed, with little contributions from the nanoparticles. Seawater was shown to have reduced the ORP value, which was attributed to an increase in the concentration of reducing agents such as sulphites or the reduction of dissolved oxygen concentration. The lack of redox potential value contribution from the particles themselves is thought to be due to insufficient interaction of the particles at the Pt electrode of the ORP probe.
TL;DR: Analysis of the inter-seasonal variation of the main water quality parameters indicates that a higher protective effect of calcium, magnesium, sodium, sulphate, and chloride is expected during the dry season.
Abstract: In order to determine copper toxicity (LC50) to a local species (Cnesterodon decemmaculatus) in the South American Pilcomayo River water and evaluate a cross-fish-species extrapolation of Biotic Ligand Model, a 96 h acute copper toxicity test was performed. The dissolved copper concentrations tested were 0.05, 0.19, 0.39, 0.61, 0.73, 1.01, and 1.42 mg Cu L-1. The 96 h Cu LC50 calculated was 0.655 mg L-1 (0.823-0.488). 96-h Cu LC50 predicted by BLM for Pimephales promelas was 0.722 mg L-1. Analysis of the inter-seasonal variation of the main water quality parameters indicates that a higher protective effect of calcium, magnesium, sodium, sulphate, and chloride is expected during the dry season. The very high load of total suspended solids in this river might be a key factor in determining copper distribution between solid and solution phases. A cross-fish-species extrapolation of copper BLM is valid within the water quality parameters and experimental conditions of this toxicity test.
TL;DR: Novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronicManganese inhalation are presented to guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers.
Abstract: Recently, a variety of physiologically based pharmacokinetic (PBPK) models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans) and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers.