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Abstract Sufficiently high and prolonged inhalation exposures to some respirable elongated mineral particles (REMPs), notably including amphibole asbestos fibers, can increase risk of inflammation-mediated diseases including malignant mesothelioma, pleural diseases, fibrosis, and lung cancer. Chronic inflammation involves ongoing activation of the NLRP3 inflammasome, which enables immune cells to produce potent proinflammatory cytokines IL-1β and IL-18. Reactive oxygen species (ROS) (in particular, mitochondrial ROS) contribute to NRLP3 activation via a well-elucidated mechanism involving oxidation of reduced thioredoxin and association of thioredoxin-interacting protein with NLRP3. Lysosomal destabilization, efflux of cytosolic potassium ions and influx of calcium ions, signals from damaged mitochondria, both translational and post-translational controls, and prion-like polymerization have increasingly clear roles in regulating NLRP3 activation. As the molecular biology of inflammation-mediated responses to REMP exposure becomes clearer, a practical question looms: What do these mechanisms imply for the shape of the dose-response function relating exposure concentrations and durations for EMPs to risk of pathological responses? Dose-response thresholds or threshold-like nonlinearities can arise from (a) Cooperativity in assembly of supramolecular signaling complexes; (b) Positive feedback loops and bistability in regulatory networks; (c) Overwhelming of defensive barriers maintaining homeostasis; and (d) Damage thresholds, as in lysosome destabilization-induced activation of NLRP3. Each of these mechanisms holds for NLRP3 activation in response to stimuli such as REMP exposures. It is therefore timely to consider the implications of these advances in biological understanding for human health risk assessment with dose-response thresholds. [ABSTRACT FROM AUTHOR]

Hormesis is a dose-response phenomenon that, when applied to nanomaterial-biological interactions, refers to growth stimulation at low doses and growth inhibition at high doses. MUDENG (Mu-2-related death-inducing gene, MuD) is involved in cell death signaling. Astrocytes, the major glial cell type in the central nervous system, are a major source of brain tumors. In this study, we investigated whether silver nanoparticles (AgNPs) induce hormesis in astroglioma cells and the possible involvement of MuD in AgNP-induced hormesis. AgNPs exhibited cytotoxic effects on cell proliferation in a dose-dependent manner and increased MuD expression was observed during AgNP-induced astroglioma hormesis. Studies using MuD -knockout cells and MuD siRNA transfection showed that MuD might influence cell viability upon AgNP treatment. In addition, apoptotic cell population and production of reactive oxygen species in the absence of MuD were significantly increased. The phosphorylation of two mitogen-activated protein kinases, p38 and extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinases (JNK), was observed upon AgNP stimulation. In summary, AgNPs at low doses induced hormesis of human astroglioma cells, and MuD and p38/ERK mediators are involved in AgNP-induced astroglioma hormesis, resulting in beneficial effects from the cellular point of view. [ABSTRACT FROM AUTHOR]

Risk assessment of chemical hazards is typically based on single critical health effects. This work aims to expand the current approach by characterizing the dose-related sequence of the development of multiple (lower- to higher-order) toxicological health effects caused by a chemical. To this end a “reference point profile” is defined as the relation between benchmark doses for considered health effects, and a standardized severity score determined for these effects. For a given dose of a chemical or mixture the probability for exceeding the reference point profile, thereby provoking lower- to higher-order effects, can be assessed. The overall impact at the same dose can also be derived by integrating contributions across all health effects following severity-weighting. In its generalized form the new impact metric relates to the probability of response for the most severe health effects. Reference points (points of departure) corresponding to defined levels of response can also be estimated. The proposed concept, which is evaluated for dioxin-like chemicals, provides an alternative for characterizing the low-dose region below the reference point for a severe effect like cancer. The shape and variability of the reference point profile add new dimensions to risk assessment, which for example extends the characterization of chemical potency, and the concept of acceptable effect sizes for individual health effects. Based on the present data the method shows high stability at low doses/responses, and is also robust to differences in severity categorization of effects. In conclusion, the novel method proposed enables risk-based integration of multiple dose-related health effects. It provides a first step towards a more comprehensive characterization of chemical toxicity, and suggests a potential for improved low-dose risk assessment. [ABSTRACT FROM AUTHOR]

Black carbon (BC) is a fraction of airborne PM2.5 emitted by combustion, causing deleterious effects on human health. Due to its abundance in cities, assessing personal exposure to BC is of utmost importance. Personal exposure and dose of six couples with different working routines were determined for 48 h based on 1-min mobile BC measurements and on ambient concentrations monitored simultaneously at home (outdoor) and at a suburban site. Although couples spent on average ~ 10 h together at home, the routine of each individual in other microenvironments led to 3-55% discrepancies in exposure between partners. The location of the residences and background concentrations accounted for the differences in inter-couple exposure. The overall average exposure and dose by gender were not statistically different. The personal exposure and dose calculated with datasets from fixed sites were lower than the calculations using data from mobile measurements, with the largest divergences (between four and nine times) in the transport category. Even though the individuals spent only 7% of the time commuting, this activity contributed to between 17 and 20% of the integrated exposure and inhaled dose, respectively. On average, exposure was highest on bus trips, while pedestrians and bus passengers had lower doses. Open windows elevated the in-car exposure and dose four times compared to settings with closed windows. [ABSTRACT FROM AUTHOR]

Although crime prevention tactics are designed to reduce offending, some studies have revealed instances where reported crime actually increases after introducing lower intensity interventions. An analogous trend--characterized by low-dose stimulation and high-dose inhibition--called hormesis has already been observed in the natural sciences. We argue that this phenomenon is theoretically applicable to crime prevention. Findings suggest that researchers should test varying intensities of interventions to avoid rejecting ones that would be otherwise effective at higher levels. Research using dose-response techniques and simulation models should be explored to determine whether a weak intervention backfire effect occurred or is possible. Knowledge of such information could lead to more effective crime prevention strategies and better specified analytic models for evaluation. [ABSTRACT FROM AUTHOR]

To investigate the genotoxic characteristics of typical toxicants in particle phase of cigarette smoke, including B[a]P, nicotine, tar, NNN and NNK. The in vitro γH2AX assay was used to detect the DNA double-strand breaks (DSBs) in A549 cells using high content screening (HCS). The results showed all toxicants had a dose/time-dependent effects on induction of γH2AX except for NNN and NNK. Based on dose-response of γH2AX and Hill model, the ability to induce DSBs was evaluated: NNN-acetate > B[a]P > NNK-acetate > tar > nicotine. Based on time-course of γH2AX and two-component model, the complex DNA damage was the main subtypes of DNA damage induced by these toxicants. Overall, all toxicants were genotoxic in A549 cells in a dose- or time- dependent manner except for NNN and NNK based on the γH2AX HCS assay. NNN-acetate had more potential to induce DSBs, which was followed by B[a]P, NNK-acetate, tar and nicotine. [ABSTRACT FROM AUTHOR]

Copyright of Julius-Kühn-Archiv is the property of Julius Kuehn Institut and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Julius-Kühn-Archiv is the property of Julius Kuehn Institut and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The application of chemical-specific toxicokinetic or toxicodynamic data to address interspecies differences and human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared with the use of traditional default or categorically-based uncertainty factors. The present review summarizes the state-of-the-science since the introduction of the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) guidance on chemical-specific adjustment factors (CSAF) in 2005 and the availability of recent applicable guidance including the WHO/IPCS guidance on physiologically-based pharmacokinetic (PBPK) modeling in 2010 as well as the U.S. EPA guidance on data-derived extrapolation factors in 2014. A summary of lessons learned from an analysis of more than 100 case studies from global regulators or published literature illustrates the utility and evolution of CSAF in regulatory decisions. Challenges in CSAF development related to the adequacy of, or confidence in, the supporting data, including verification or validation of PBPK models. The analysis also identified issues related to adequacy of CSAF documentation, such as inconsistent terminology and often limited and/or inconsistent reporting, of both supporting data and/or risk assessment context. Based on this analysis, recommendations for standardized terminology, documentation and relevant interdisciplinary research and engagement are included to facilitate the continuing evolution of CSAF development and guidance. [ABSTRACT FROM AUTHOR]

Hormesis has aroused much attention during the past two decades and may have great implications on many fields, including toxicology and risk assessment. However, the observation of hormesis remains challenged under laboratory conditions. To determine favorable conditions under which to observe hormesis, we investigated the hormetic responses of Escherichia coli (E. coli) upon exposure of different concentrations of sulfonamides and erythromycin at different time points and in different culture media: Luria-Bertani (LB) broth and Mueller Hinton (MH) broth. Our results reveal that the antibiotics, both individually and combined, produce hormetic effects on E. coli growth in MH broth at the stationary phase, with the maximum stimulatory response increasing with time. However, in LB broth, the hormetic response was not observed, which can be explained by an analogous “wood barrel theory”. Our study suggests that the culture medium and time should be taken into consideration in hormetic studies, and compound mixtures should also receive more attention for their potential to induce hormesis. [ABSTRACT FROM AUTHOR]

Toxicity outcomes derived in vitro do not always reflect in vivo toxicity values, which was previously observed for a series of phenols tested in the embryonic stem cell test (EST). Translation of in vitro data to the in vivo situation is therefore an important, but still limiting step for the use of in vitro toxicity outcomes in the safety assessment of chemicals. The aim of the present study was to translate in vitro embryotoxicity data for a series of phenols to in vivo developmental toxic potency values for the rat by physiologically based kinetic (PBK) modelling-based reverse dosimetry. To this purpose, PBK models were developed for each of the phenols. The models were parameterised with in vitro-derived values defining metabolism and transport of the compounds across the intestinal and placental barrier and with in silico predictions and data from the literature. Using PBK-based reverse dosimetry, in vitro concentration-response curves from the EST were translated into in vivo dose-response curves from which points of departure (PoDs) were derived. The predicted PoDs differed less than 3.6-fold from PoDs derived from in vivo toxicity data for the phenols available in the literature. Moreover, the in vitro PBK-based reverse dosimetry approach could overcome the large disparity that was observed previously between the in vitro and the in vivo relative potency of the series of phenols. In conclusion, this study shows another proof-of-principle that the in vitro PBK approach is a promising strategy for non-animal-based safety assessment of chemicals. [ABSTRACT FROM AUTHOR]

There is increasing interest in the use of quantitative transcriptomic data to determine benchmark dose (BMD) and estimate a point of departure (POD) for human health risk assessment. Although studies have shown that transcriptional PODs correlate with those derived from apical endpoint changes, there is no consensus on the process used to derive a transcriptional POD. Specifically, the subsets of informative genes that produce BMDs that best approximate the doses at which adverse apical effects occur have not been defined. To determine the best way to select predictive groups of genes, we used published microarray data from dose-response studies on six chemicals in rats exposed orally for 5, 14, 28, and 90 days. We evaluated eight approaches for selecting genes for POD derivation and three previously proposed approaches (the lowest pathway BMD, and the mean and median BMD of all genes). The relationship between transcriptional BMDs derived using these 11 approaches and PODs derived from apical data that might be used in chemical risk assessment was examined. Transcriptional BMD values for all 11 approaches were remarkably aligned with corresponding apical PODs, with the vast majority of toxicogenomics PODs being within tenfold of those derived from apical endpoints. We identified at least four approaches that produce BMDs that are effective estimates of apical PODs across multiple sampling time points. Our results support that a variety of approaches can be used to derive reproducible transcriptional PODs that are consistent with PODs produced from traditional methods for chemical risk assessment. [ABSTRACT FROM AUTHOR]

The study goal was to develop a sediment polychlorinated biphenyl (PCB) dose-response model based on benthic invertebrate effects to PCBs. The authors used an equilibrium partitioning (EqP) approach to generate predicted PCB sediment effect concentrations (largely Aroclor 1254) associated with a gradient of toxic effects in benthic organisms from effects observed in aquatic toxicity studies. The present study differs from all other EqP collective sediment investigations in that the authors examined a common dose-response gradient of effects for PCBs rather than a single, protective value. The authors reviewed the chronic aquatic toxicity literature to identify measured aqueous PCB concentrations and associated benthic invertebrate effects. The authors control-normalized the aquatic toxic effect data and expressed results from various studies as a common metric, percent injury. Then, they calculated organic carbon-normalized sediment PCB concentrations (mg/kg organic carbon) from the aqueous PCB toxicity data set using EqP theory based on the US Environmental Protection Agency's (EPIWEB 4.1) derivation of the water-organic carbon partition coefficient ( KOC). Lastly, the authors constructed a nonlinear dose-response numerical model for these synoptic sediment PCB concentrations and biological effects: Y = 100/1 + 10([logEC50-log X] × [Hill slope]) (EC50 = median effective concentration). These models were used to generate 'look-up' tables reporting percent injury in benthic biota for a range of Aroclor-specific sediment concentrations. For example, the model using the EPIWEB KOC estimate predicts mean benthic injury of 23.3%, 46.0%, 70.6%, 87.1%, and 95% for hypothetical sediment concentrations of 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, and 16 mg/kg dry weight of Aroclor 1254, respectively (at 1% organic carbon). The authors recommend the model presented for screening but suggest, when possible, determining a site-specific KOC that, along with the tables and equations, allows users to create their own protective dose-response sediment concentration. Environ Toxicol Chem 2017;36:1311-1329. © 2016 SETAC [ABSTRACT FROM AUTHOR]

Toxicokinetics-toxicodynamic (TKTD) models have emerged as a powerful means to describe survival as a function of time and concentration in ecotoxicology. They are especially powerful to extrapolate survival observed under constant exposure conditions to survival predicted under realistic fluctuating exposure conditions. But despite their obvious benefits, these models have not yet been adopted as a standard to analyze data of survival toxicity tests. Instead simple dose-response models are still often used although they only exploit data observed at the end of the experiment. We believe a reason precluding a wider adoption of TKTD models is that available software still requires strong expertise in model fitting. In this work, we propose a fully automated fitting procedure that extracts prior knowledge on parameters of the model from the design of the toxicity test (tested concentrations and observation times). We evaluated our procedure on three experimental and 300 simulated data sets and showed that it provides robust fits of the model, both in the frequentist and the Bayesian framework, with a better robustness of the Bayesian approach for the sparsest data sets. [ABSTRACT FROM AUTHOR]

Prochloraz is an imidazole fungicide, and its regulatory toxicological data package has been primarily generated in the 1990s. More recently, studies have been published demonstrating an interaction with hormone receptors/steroidogenesis and effects with an endocrine mode of action. In the present study, prochloraz has been investigated in a comprehensive in vivo study including relevant elements of current regulatory reproduction toxicity studies and additional mechanistic parameters. Prochloraz was administered per gavage in oil from GD 6 to PND 83 to pregnant and lactating Wistar rats and their respective offspring, at doses of 0.01 mg/kg bw/day (acceptable daily intake of prochloraz), 5 mg/kg bw/day [expected no-observed-effect-level (NOEL)] and 30 mg/kg bw/day. At 30 mg/kg bw/day maternal and offspring effects (decreased viability, lower number of live offspring) were seen including a delayed entry into male puberty (+1 day) accompanied by lower male offspring body weights, increased anogenital distance/index in females and transiently retained nipples in males at PND 12 (not seen at PND 20). The only finding at the 'expected NOEL' was increased incidences of transiently retained nipples in males which are not considered adverse. No effects were seen in the low-dose group. There was no evidence for a non-monotonic dose-response curve or effects at low levels. [ABSTRACT FROM AUTHOR]

In this report, we investigated the cytotoxicity of two types of quantum dots(QDs) (carbon quantum dots(CQDs): N, S doped CQDs, N doped CQDs, no doped CQDs; metal QDs(MQDs): CdTe QDs, CdS QDs, CuInS 2 /ZnS QDs) on Chlorella pyrenoidosa(C. Pyrenoidosa) at different concentrations. We compared the toxicity of different QDs on C. Pyrenoidosa through determination of the algal growth inhibition, acute toxicity tests (EC 50 ), Chlorophyll a(Chla) contents, protein contents, the activity of enzymatic and metabolites contents. When C. Pyrenoidosa was treated by various concentrations of QDs, the Chla contents were consistent to the number of algae cells, showing a good dose-response relationship. At the 96 h, the EC 50 of N, S doped CQDs, N doped CQDs, no doped CQDs and CdTe QDs, CdS QDs, CuInS 2 /ZnS QDs were 38.56, 185.83, 232.47, 0.015, 4.88, 459.5 mg/l, respectively. The toxicity order of them was: CuInS 2 /ZnS QDs

We present the case histories, autopsy findings and toxicology findings of two fatal intoxications involving the designer drug, butyryl fentanyl. The quantitative analysis of butyryl fentanyl in postmortem fluids and tissues was performed by an ultrahigh-performance liquid chromatography tandem mass spectrometry method. In the first case, butyryl fentanyl was the only drug detected with concentrations of 99 ng/mL in peripheral blood, 220 ng/mL in heart blood, 32 ng/mL in vitreous humor, 590 ng/mL in gastric contents, 93 ng/g in brain, 41 ng/g in liver, 260 ng/mL in bile and 64 ng/mL in urine. The cause of death was ruled fatal intoxication by butyryl fentanyl. In the second case, butyryl fentanyl was detected along with acetyl fentanyl, alprazolam and ethanol. The butyryl fentanyl concentrations were 3.7 ng/mL in peripheral blood, 9.2 ng/mL in heart blood, 9.8 ng/mL in vitreous humor, 4,000 ng/mL in gastric contents, 63 ng/g in brain, 39 ng/g in liver, 49 ng/mL in bile and 2 ng/mL in urine. The acetyl fentanyl concentrations were 21 ng/mL in peripheral blood, 95 ng/mL in heart blood, 68 ng/mL in vitreous humor, 28,000 ng/mL in gastric contents, 200 ng/g in brain, 160 ng/g in liver, 330 ng/mL in bile and 8 ng/mL in urine. In addition, the alprazolam concentration was 40 ng/mL and the ethanol concentration was 0.11 g/dL, both measured in peripheral blood. The cause of death in the second case was ruled a mixed drug intoxication. In both cases, the manner of death was accident. [ABSTRACT FROM AUTHOR]

Fentanyl induces pharmacological effects and abuse liability comparable to other prescription opioids and heroin. A surge in fentanyl-related fatalities has been periodically reported throughout the USA. The University of Florida Forensic Toxicology Laboratory observed a significant increase in fentanyl-related deaths starting in mid-2014. The present report evaluated toxicological findings, demographics of the decedents and circumstances of death in the postmortem cases that were submitted to the laboratory for toxicological analysis from July 2014 to January 2015 and that were tested for fentanyl in biological specimens. The cases originated from 6 of the 24 Florida Medical Examiner Districts, with the majority from District 12 (Desoto, Manatee and Sarasota counties). The specimens were analyzed for fentanyl by gas chromatography-mass spectrometry; the limit of detection (LOD) was 0.62 ng/mL and the limit of quantification (LOQ) was 2.5 ng/mL. During the 7-month period, the laboratory tested 143 postmortem cases for fentanyl and 50% had quantifiable fentanyl in postmortem blood. Fentanyl concentrations ranged from 2.5 to 68 ng/mL (n = 66; median: 9.8 ng/mL); six cases were positive for fentanyl >LOD but

The mean primary diameter ( d) of nanoparticles (NPs) is commonly used as the best basis to assess the dose metric for expressing the toxicity of spherical NPs. However, d bears no relevance for nonspherical NPs. In the present study, the mean surface area to volume ratio, applicable to both spherical and nonspherical NPs, was used to replace d given the aim of obtaining the best dose metric (volume, surface area, or number) of differently shaped metallic NPs in vivo (9 organisms) and in vitro (6 mammalian cell lines). The slope of the curves obtained by relating the total particle number of NPs at various effect concentrations to the mean surface area to volume ratio was subsequently used to deduce the best dose metric. For the majority of the organisms studied, it was found that NP volume is the most appropriate dose metric, independent of the composition of the NPs tested. For 3 organisms exposed to Ag NPs, however, surface area was found to be the best dose metric. It is therefore concluded that the optimum dose metric depends on organism and NP properties. Environ Toxicol Chem 2016;35:2466-2473. © 2016 SETAC [ABSTRACT FROM AUTHOR]

Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn’s disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/d. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days (n = 10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical, and continuous end points, including posture, in cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of the brain, kidney, liver, adrenal gland, testes, stomach, small and large intestines, duodenum, pancreas, heart, lungs, spleen, thymus, and rib found no significant differences between the groups. Plasma enzymes associated with liver function were transiently elevated 2 to 4 days after the 500 mg/kg single dose but returned to normal values by 8 days and were not observed at any time in rats given 80 mg/kg/d for 14 days. One hour after oral administration of a single dose of 80 mg/kg, BT-11 had a maximal concentration of 21 ng/mL; the half-life was 3 hours. These experimental results demonstrated that BT-11 is well tolerated in rats, and, with further testing, may hold promise as an orally active therapeutic for CD. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox), one of the most used chemotherapeutic agents, is known to generate oxidative stress and block DNA synthesis, which result in severe dose-limiting toxicity. A strategy to protect against Dox toxic effects could be to use dietary antioxidants of which fruits and vegetable are a rich source. In this context, strawberry consumption is associated with the maintenance of good health and the prevention of several diseases, thanks to the antioxidant capacities of its bioactive compounds. The aim of the present study was to evaluate the protective effects of strawberry consumption against oxidative stress induced by Dox in rats. Animals were fed with strawberry enriched diet (15% of the total calories) for two months and Dox (10 mg/kg; i.p.) was injected at the end of the experimental period. Strawberry consumption significantly inhibited ROS production and oxidative damage biomarkers accumulation in plasma and liver tissue and alleviated histopathological changes in rat livers treated with Dox. The reduction of antioxidant enzyme activities was significantly mitigated after strawberry consumption. In addition, strawberry enriched diet ameliorated liver mitochondrial antioxidant levels and functionality. In conclusion, strawberry intake protects against Dox-induced toxicity, at plasma, liver and mitochondrial levels thanks to its high contents of bioactive compounds. [ABSTRACT FROM AUTHOR]

Hormesis is a biphasic dose response with specific quantitative features for the amplitude and width of the stimulation. It is highly generalizable and independent of biological model, endpoint, inducing agent, level of biological organization and mechanism. Hormesis may be induced via a direct stimulation or by overcompensation to a disruption of homeostasis. The induction of hormesis by low-level stressor agents not only rapidly upregulates adaptive processes to repair damage but also protects the adapted system from damage due to a subsequent challenging dose (toxic) within a definable temporal window. The striking consistency of the amplitude of hormetic response suggests that hormesis provides a quantitative description of biological plasticity. Knowledge of hormesis has particular potential biomedical significance with respect to slowing or retarding both normal aging processes and the progression of severe neurological diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To characterize the signalment, dose response, and clinical signs of diph enhydramine toxicosis in dogs. DESIGN: Retrospective case series. ANIMALS: 621 dogs with diphenhydramine exposure. PROCEDURES: The electronic medical record database for an animal poison control center was reviewed from January 2008 through December 2013 to identify dogs that had ingested or been injected with diphenhydramine. Information extracted from the records and evaluated included the signalment, clinical signs observed, and estimated exposure dose of diphenhydramine. Clinical signs were categorized as none, mild, moderate, and severe. RESULTS: The mean ± SEM age of dogs was 3.6 ± 0.1 years (range, 0.1 to 16 years). Diphenhydramine exposure was by ingestion for 581 (93.6%) dogs and injection for 40 (6.4%) dogs. Only 146 (23.5%) dogs developed > I clinical signs of toxicosis, the most common of which were associated with the nervous (lethargy, hyperactivity, agitation, hyperthermia, ataxia, tremors, and fasciculations) or cardiovascular (tachycardia) systems, and 3 dogs died. Although the presence and extent of clinical signs varied greatly among dogs, the exposure dose of diphenhydramine was positively associated with the severity of clinical signs in a dose-dependent manner regardless of the route of exposure (ingestion or in jection). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that dogs exposed to diphenhydramine developed clinical signs of toxicos is fairly infrequently, and those clinical signs were generally mild and primarily affected the neurologic and cardiovascular systems. Supportive treatment for diphenhydramine toxicos is should be administered on the basis of the clinical signs observed. [ABSTRACT FROM AUTHOR]

To further define the utility of the Ishikawa cells as a reliable in vitro model to determine the potential estrogenic activity of chemicals of interest, transcriptional changes induced by genistein (GES) in Ishikawa cells at various doses (10pM, 1nM, 100nM, and 10µM) and time points (8, 24, and 48h) were identified using a comprehensive microarray approach. Trend analysis indicated that the expression of 5342 unique genes was modified by GES in a dose- and time-dependent manner (P=0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest dose of GES evaluated (10µM). The GES' estrogenic activity was identified by comparing the Ishikawa cells' response to GES versus 17 α-ethynyl estradiol (EE, at equipotent doses, ie, 10µM vs 1µM, respectively) and was defined by changes in the expression of 284 unique genes elicited by GES and EE in the same direction, although the magnitude of the change for some genes was different. Further, comparing the response of the Ishikawa cells exposed to high doses of GES and EE versus the response of the juvenile rat uterus exposed to EE, we identified 66 unique genes which were up- or down regulated in a similar manner in vivo as well as in vitro. Genistein elicits changes in multiple molecular pathways affecting various biological processes particularly associated with cell organization and biogenesis, regulation of translation, cell proliferation, and intracellular transport; processes also affected by estrogen exposure in the uterus of the rat. These results indicate that Ishikawa cells are capable of generating a biologically relevant estrogenic response and offer an in vitro model to assess this mode of action. [ABSTRACT FROM AUTHOR]

In the pharmaceutical industry, genotoxic drug substances are developed for life-threatening indications such as cancer. Healthy employees handle these substances during research, development, and manufacturing; therefore, safe handling of genotoxic substances is essential. When an adequate preclinical dataset is available, a risk-based decision related to exposure controls for manufacturing is made following a determination of safe health-based limits, such as an occupational exposure limit (OEL). OELs are calculated for substances based on a threshold dose-response once a threshold is identified. In this review, we present examples of genotoxic mechanisms where thresholds can be demonstrated and OELs can be calculated, including a holistic toxicity assessment. We also propose a novel approach for inhalation Threshold of Toxicological Concern (TTC) limit for genotoxic substances in cases where the database is not adequate to determine a threshold. [ABSTRACT FROM AUTHOR]

Certain arsenic and selenium compounds show a remarkable mutual cancelation of toxicities, where a lethal dose of one can be voided by an equimolar and otherwise lethal dose of the other. It is now well established that the molecular basis of this antagonism is the formation and biliary excretion of seleno bis -(S-glutathionyl) arsinium anion [(GS) 2 AsSe] − . Previous work has definitively demonstrated the presence of [(GS) 2 AsSe] − in rabbit bile, but only in the presence of other arsenic and selenium species. Rabbits have a gall bladder, which concentrates bile and lowers its pH; it seems likely that this may be responsible for the breakdown of biliary [(GS) 2 AsSe] − . Since rats have no gall bladder, the bile proceeds directly through the bile duct from the hepatobiliary tree. In the present work we have shown that the primary product of biliary co-excretion of arsenic and selenium in rats is [(GS) 2 AsSe] − , with essentially 100% of the arsenic and selenium present as this species. The chemical plausibility of the X-ray absorption spectroscopy-derived structural conclusions of this novel arsenic and selenium co-excretion product is supported by density functional theory calculations. These results establish the biomolecular basis to further explore the use of selenium dietary supplements as a possible palliative for chronic low-level arsenic poisoning of human populations. [ABSTRACT FROM AUTHOR]

Non-cancer risk assessment traditionally assumes a threshold of effect, below which there is a negligible risk of an adverse effect. The Agency for Toxic Substances and Disease Registry derives health-based guidance values known as Minimal Risk Levels (MRLs) as estimates of the toxicity threshold for non-carcinogens. Although the definition of an MRL, as well as EPA reference dose values (RfD and RfC), is a level that corresponds to 'negligible risk,' they represent daily exposure doses or concentrations, not risks. We present a new approach to calculate the risk at exposure to specific doses for chemical mixtures, the assumption in this approach is to assign de minimis risk at the MRL. The assigned risk enables the estimation of parameters in an exponential model, providing a complete dose-response curve for each compound from the chosen point of departure to zero. We estimated parameters for 27 chemicals. The value of k, which determines the shape of the dose-response curve, was moderately insensitive to the choice of the risk at the MRL. The approach presented here allows for the calculation of a risk from a single substance or the combined risk from multiple chemical exposures in a community. The methodology is applicable from point of departure data derived from quantal data, such as data from benchmark dose analyses or from data that can be transformed into probabilities, such as lowest-observed-adverse-effect level. The individual risks are used to calculate risk ratios that can facilitate comparison and cost-benefit analyses of environmental contamination control strategies. [ABSTRACT FROM AUTHOR]

Intensive risk assessment is required before the approval of food additives. During this process, based on the toxicological principle of 'the dose makes the poison,ˮ maximum usage doses are assessed. However, most consumers are not aware of these efforts to ensure the safety of food additives and are therefore sceptical, even though food additives bring certain benefits to consumers. This study investigated the effect of a short video, which explains the scientific risk assessment and regulation of food additives, on consumers' perceptions and acceptance of food additives. The primary goal of this study was to inform consumers and enable them to construct their own risk-benefit assessment and make informed decisions about food additives. The secondary goal was to investigate whether people have different perceptions of food additives of artificial (i.e., aspartame) or natural origin (i.e., steviolglycoside). To attain these research goals, an online experiment was conducted on 185 Swiss consumers. Participants were randomly assigned to either the experimental group, which was shown a video about the scientific risk assessment of food additives, or the control group, which was shown a video about a topic irrelevant to the study. After watching the video, the respondents knew significantly more, expressed more positive thoughts and feelings, had less risk perception, and more acceptance than prior to watching the video. Thus, it appears that informing consumers about complex food safety topics, such as the scientific risk assessment of food additives, is possible, and using a carefully developed information video is a successful strategy for informing consumers. [ABSTRACT FROM AUTHOR]

Objective: This study investigates the correlation between dose-volume histogram derived from three bowel contouring methods and late toxicity in patients undergoing post-operative radiation therapy (PORT) for cervical cancer. Methods: From June 2010 to May 2013, 103 patients undergoing PORT were included. Three different contouring methods were used: (a) individual small bowel (SB) and large bowel (LB) loops, (b) total bowel (TB; including SB and LB) and (c) peritoneal cavity (PC). The volume of SB, LB, TB and PC receiving 15, 30 and 40 Gy was calculated. Acute and late bowel toxicities were scored using Common Terminology Criteria for Adverse events v. 3.0. Receiver operating characteristic curve identified thresholds predicting late toxicity with the highest specificity. All data were dichotomized across these thresholds. Univariate and multivariate analyses were performed using SPSS® v. 20 (IBM Corporation, Armonk, NY; formerly SPSS Inc., Chicago, IL). Results: On univariate analysis, V30 PC ≥ 900 cm³ (p = 0.01), V40 PC ≥ 750 cm³ (p = 0.03) and V40 TB ≥ 280 cm³ (p = 0.03) and use of concurrent chemotherapy (p = 0.03) predicted grade ≥II acute toxicity. On multivariate analysis, use of concurrent chemotherapy [odds ratio (OR) 3.5, 95% confidence interval (CI) 1.1-11.1, p = 0.03] and V30 PC ≥ 900 cm³ (OR 2.3, 95% CI 1-5.5, p = 0.05) predicted acute grade ≥II toxicity. On univariate analysis for late toxicity, SB (V30 ≥ 190 cm³, p = 0.009; V40 ≥ 150 cm³, p = 0.03), LB (V15 ≥ 250 cm³, p = 0.04), V40 PC (V40 ≥ 750 cm³, p = 0.001) and presence of acute grade ≥III toxicity (p = 0.006), treatment technique (three-dimensional conformal radiation or intensity modulated radiotherapy, p = 0.02) predicted more than or equal to grade ll late bowel toxicity. On multivariate analysis, only body mass index ≥25 kg m-2 (OR 7.3, 95% CI 1.6-31.6, p = 0.008) and presence of acute grade III toxicity predicted toxicity (OR 5.1, 95% CI 1.4-18.1, p = 0.007). Conclusion: V30 PC ≥ 900 cm³ and use of concurrent chemotherapy independently predicts acute toxicity. Presence of acute grade ≥III toxicity independently predicts late toxicity. Minimizing dose to PC subvolumes can therefore reduce both acute and late toxicities. Advances in knowledge: Study establishes PC thresholds that can minimize both acute and late bowel toxicities. [ABSTRACT FROM AUTHOR]

Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2-year bioassay for TBBPA. The objective of the present study was to develop a cancer-based and a non-cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2-year and 13-week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg−1 day−1 based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg−1 day−1 based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E−7 to 3.9 E−6 mg kg−1 day−1 based on age-adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E −7 to 8.4 E−5 mg kg−1 day−1. Resulting margin of exposure (MOE) values were > 800 000 for non-cancer endpoints and > 32 000 000 for cancer-based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA. Copyright © 2015. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

To investigate the usefulness of follicular fluid ( FF) in relation to blood plasma and bile as indicators of exposure of dairy cows to ZEN, DON and their metabolites, a dose-response study was performed with 30 dairy cows. The cows, 10 in each group (named CON; FUS-50, FUS-100), received a diet with three different concentrations of Fusarium toxin-contaminated maize. Thereby, the following dietary concentration were reached: CON (0.02 mg ZEN and 0.07 mg DON, per kg dry matter, DM), FUS-50 (0.33 mg ZEN and 2.62 mg DON, per kg DM) and FUS-100 (0.66 mg ZEN and 5.24 mg DON, per kg DM). ZEN, DON and de-epoxy- DON (de- DON) were detected in FF. Based on the linear regression between toxin concentration in plasma and FF, it seems that about 50 % (m = 0.5) of ZEN present in plasma is present in FF while an increase of 1 ng/ml DON or de- DON in plasma is paralleled by an increase of 1.5 ng/ml DON or 1.1 ng/ml de- DON in FF. ZEN, DON and their metabolites, except zearalenone ( ZAN), were also detected in bile. Contrary to DON and de- DON, ZEN and its metabolites were accumulated in bile so that the concentration of ZEN and metabolites was much higher than for DON and de- DON. The main compound was β-zearalenol ( β- ZEL). The biliary ZEN, α-zearalenol ( α- ZEL) and β- ZEL concentration correlated linearly with each other with an uncertainty of <15 % ( r2 ≥ 0.86), whereas the ratio between ZEN: α- ZEL: β- ZEL was about 1.5:1:11. With the help of established linear relationship between toxin intake and toxin concentration, bile could be used as diagnostic indicator to assess the exposure of cows. [ABSTRACT FROM AUTHOR]

Endocrine-disrupting chemicals (EDC) are defined as environmental compounds that produce adverse health manifestations in mammals by disrupting the endocrine system. Benzophenone-1 (2,4-dihydroxybenzophenone, BP1) and nonylphenol (NP), which are discharged from numerous industrial products, are known EDC. The aim of this study was to examine the effects of BP1 and NP on proliferation and metastasis of MCF-7 human breast cancer cells expressing estrogen receptors (ER). Treatment with BP1 (10−5-10−7M) and NP (10−6-10−7M) promoted proliferation of MCF-7 cells similar to the positive control 17 -beta-estradiol (E2). When ICI 182,780, an ER antagonist, was co-incubated with E2, BP1, or NP, proliferation of MCF-7 cells returned to the level of a control. Addition of BP1 or NP markedly induced migration of MCF-7 cells similar to E2. To elucidate the underlying molecular mechanisms produced by these EDC, alterations in transcriptional and translational levels of proliferation and metastasis-related markers, including cyclin D1, p21, and cathepsin D, were determined. Data showed increase in expression of cyclin D1 and cathepsin D and decrease in p21 at both transcriptional and translational levels. However, BP1- or NP-induced alterations of these genes were blocked by ICI 182,780, suggesting that changes in expression of these genes may be regulated by an ERα-dependent pathway. In conclusion, BP1 and NP may accelerate growth of MCF-7 breast cancer cells by regulating cell cycle-related genes and promote cancer metastasis through amplification of cathepsin D. [ABSTRACT FROM PUBLISHER]

Background: Corticosteroids are a common, short-term, local antiinflammatory and analgesic for treating patients with musculoskeletal disorders. Studies have shown the deleterious effects of corticosteroids on chondrocytes, suggesting a potentiation of degenerative joint disease. Mesenchymal stem cells (MSCs) are the direct progenitors of chondrocytes and other musculoskeletal tissue. Additionally, they serve an important antiinflammatory role, which can combat the chronic inflammatory state that mediates degenerative joint disease. Little is known about how corticosteroids interact with this regenerative and reparative cell population. Questions/purposes: We asked: (1) Are corticosteroids cytotoxic to MSCs in a dose-response fashion? (2) Is there a differential effect in the level of cytotoxicity to MSCs between commercially available corticosteroid preparations? Methods: Human MSCs were isolated and cultured from periarticular adipose tissue obtained from 20 patients undergoing primary THA. MSCs were exposed for 60 minutes to one of four commonly used corticosteroid preparations: betamethasone sodium phosphate-betamethasone acetate (6 mg/mL), dexamethasone sodium phosphate (4 mg/mL), methylprednisolone (40 mg/mL), or triamcinolone acetonide (40 mg/mL). Among the four preparations (treatment groups), cells were exposed to increasing concentrations of drugs according to the following titrations of the commercially available preparation: 0.0 (control solution of 1X phosphate buffered saline), 3.125, 6.25, 12.5, 25, 50, 75, and 100 % (undiluted commercial product). Cells were allowed to recover in standard culture media for 24 hours. After the recovery period, cell viability was measured using -(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) tetrazolium dye-based cellular viability assay and live-dead cell fluorescent staining. For the MTS assay, measurements were quantified in units of optical density (OD). ANOVA was performed at every experimental steroid concentration. When this global test was statistically significant, all pairwise comparisons were performed at that concentration with p values adjusted by the Tukey method to guard against Type I error. Results: Exposure to corticosteroids decreased MSC viability in a curvilinear dose-response pattern. For betamethasone, the mean MTS OD at 0% steroid concentration was 1.03 (SD, 0.12) and decreased to 0.00 (SD, 0.00) at 25% steroid concentration. For dexamethasone, the mean MTS OD at 0% steroid concentration was 1.00 (SD, 0.07) and decreased to 0.00 (SD, 0.01) at 100% steroid concentration. For methylprednisolone, the mean MTS OD at 0% steroid concentration was 1.03 (SD, 0.09) and decreased to 0.00 (SD, 0.00) at 100% steroid concentration. For triamcinolone, the mean MTS OD at 0% steroid concentration was 1.02 (SD, 0.09) and decreased to 0.00 (SD, 0.00) at 75% steroid concentration. There were large differences among commercially available preparations, and these differences were present at every concentration. In general, dexamethasone was most gentle on MSCs (average OD by steroid concentration: 0% = 1.00; 3.125% = 0.86; 6.25% = 0.74; 12.5% = 0.53; 25% = 0.30; 50% = 0.20; 75% = 0.09; 100% = 0.00, triamcinolone and methylprednisolone were intermediate (triamcinolone average OD by steroid concentration: 0% = 1.02; 3.125% = 0.82; 6.25% = 0.64; 12.5% = 0.45; 25% = 0.18; 50% = 0.03; 75% = 0.00; 100% = 0.00; methylprednisolone average OD by steroid concentration: 0% = 1.03; 3.125% = 0.74; 6.25% = 0.54; 12.5% = 0.31; 25% = 0.12; 50% = 0.01; 75% = 0.00; 100% = 0.00), and betamethasone was most toxic (average OD by steroid concentration: 0% = 1.03; 3.125% = 0.74; 6.25% = 0.27; 12.5% = 0.02; 25% = 0.00; 50% = 0.00; 75% = 0.00; 100% = 0.00). ANOVA testing showed p values less than 0.0001 at every tested concentration (with the exception of the 0% control solution; p = 0.204) with subsequent pairwise comparisons supporting the relationships described above. The outcomes were maintained after stratifying by age, sex, or indication for THA (osteoarthritis versus avascular necrosis). Conclusions: Commonly used intraarticular corticosteroids had a dose-dependent, profound, and differential effect on MSCs in this in vitro model, with betamethasone being the most toxic. Further studies are needed to assess if the in vitro effects of these agents translate into similar in vivo outcomes. Clinical Relevance: Corticosteroids frequently are used by physicians to reduce inflammation in patients with musculoskeletal disorders, but these agents may hinder MSCs' innate regenerative capacity in exchange for temporary analgesia. Our study suggests that choosing dexamethasone may result in less harmful effects when compared with other injectable steroids. [ABSTRACT FROM AUTHOR]

Cyproterone acetate (CPA), a synthetic hormonal drug, induces rat liver tumors in a sex-specific manner, with five-fold higher doses needed to induce liver tumors in male rats compared to females. In order to evaluate the potential of the in vivo alkaline Comet assay to predict the sex-specific carcinogenicity of CPA, CPA-induced direct DNA damage (DNA strand breaks and alkali-labile sites) were evaluated in the livers of both male and female F344 rats. In addition, secondary oxidative DNA damage was measured concurrently utilizing the human 8-oxoguanine-DNA-N-glycosylase (hOGG1) and EndonucleaseIII (EndoIII)-modified in vivo alkaline Comet assays and the reticulocyte micronucleus (MN) frequency was analyzed in peripheral blood. Groups of 5 seven-week-old male and female F344 rats received olive oil or 10, 25, 50 or 100 mg/kg bw CPA in olive oil by gavage at 0, 24, and 45 h and were sacrificed at 48 h. CPA-induced direct DNA damage in rat liver showed the same sex-specific pattern as its hepatotumorigenicity: a five-fold-higher dose of CPA was needed to induce a statistically significant increase in direct DNA damage in livers of males compared to females. However, peripheral blood MN frequency was weak in both sexes and CPA-induced oxidative DNA damage was generally greater in male than female rat livers. Taken together, our results demonstrate concordance in the sex-specificity of CPA in the in vivo alkaline Comet assay and cancer bioassay, while the induction of oxidative DNA damage by CPA was not directly correlated with its tumorigenicity. [ABSTRACT FROM AUTHOR]

Embryonic exposures to the components of petroleum, including polycyclic aromatic hydrocarbons (PAHs), cause a characteristic suite of developmental defects and cardiotoxicity in a variety of fish species. We exposed zebrafish embryos to reference sediment mixed with laboratory weathered South Louisiana crude oil and to sediment collected from an oiled site in Barataria Bay, Louisiana in December 2010. Laboratory oiled sediment exposures caused a reproducible set of developmental malformations in zebrafish embryos including yolk sac and pericardial edema, craniofacial and spinal defects, and tissue degeneration. Dose–response studies with spiked sediment showed that total polycyclic aromatic hydrocarbons (tPAH) concentrations of 27 mg tPAH/kg (dry weight normalized to 1 percent organic carbon [1 percent OC]) caused a significant increase in defects, and concentrations above 78 mg tPAH/kg 1 percent OC caused nearly complete embryo mortality. No toxicity was observed in Barataria sediment with 2 mg tPAH/kg 1 percent OC. Laboratory aging of spiked sediment at 4 °C resulted in a nearly 10-fold decrease in sensitivity over a 40-day period. This study demonstrates oiled sediment as an exposure pathway to fish with dose-dependent effects on embryogenesis that are consistent with PAH mechanisms of developmental toxicity. The results have implications for effects on estuarine fish from oiled coastal areas during the Deepwater Horizon spill. [ABSTRACT FROM AUTHOR]

Until recently, primary central nervous system lymphoma ( PCNSL) was associated with a uniformly dismal prognosis. It is now reasonable to anticipate long-term survival and possibly cure for a significant proportion of patients diagnosed with PCNSL. Accumulated data generated over the past 10 years has provided evidence that long-term progression-free survival ( PFS) can reproducibly be attained in a significant fraction of PCNSL patients that receive dose-intensive chemotherapy consolidation, without whole brain radiotherapy. One consolidative regimen that has reproducibly demonstrated promise is the combination of infusional etoposide plus high-dose cytarabine ( EA), administered in first complete remission after methotrexate, temozolomide and rituximab-based induction. Given evolving principles of management and the mounting evidence for reproducible improvements in survival rates in prospective clinical series, our goal in this review is to highlight and update principles in diagnosis, staging and management as well as to review data regarding the pathogenesis of central nervous system lymphomas, information that is likely to constitute a basis for the implementation of novel therapies that are requisite for further progress in this unique phenotype of non-Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

Everolimus, an oral mammalian target of rapamycin ( mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM. [ABSTRACT FROM AUTHOR]

High-dose methotrexate ( HD- MTX) plays an important role in the consolidation therapy of acute lymphoblastic leukaemia ( ALL) in many treatment regimens worldwide. However, there is a large interpatient variability in the pharmacokinetics and toxicity of the drug. We investigated the influence of single nucleotide polymorphisms ( SNPs) in genes of the folate metabolic pathway, transporter molecules and transcription proteins on the pharmacokinetics and toxicity of MTX and 7-hydroxy-methotrexate (7- OH- MTX). 63 SNPs of 14 genes were genotyped and a total of 463 HD- MTX courses (administered according to the ALL- BFM 95 and ALL IC- BFM 2002 protocols) were analysed. Haematological, hepatic and renal toxicities, estimated by routine laboratory parameters were evaluated. Random forest and regression trees were used for variable selection and model building. Linear mixed models were established to prove the significance of the selected variables. SNPs (rs4948502, rs4948496, rs4948487) of the ARID5 B gene were associated with the serum levels of MTX ( P < 0·02), serum levels and area under the curve of 7- OH- MTX ( P < 0·02) and with hypoproteinaemia ( P = 0·004). SLCO1B1 rs4149056 also showed a significant association with serum MTX levels ( P < 0·001). Our findings confirm the association of novel genetic variations in folate-related and ARID5B genes with the serum MTX levels and acute toxicity. [ABSTRACT FROM AUTHOR]

A significant challenge in toxicology is the 'too many chemicals' problem. Human beings and environmental species are exposed to tens of thousands of chemicals, only a small percentage of which have been tested thoroughly using standard in vivo test methods. This study reviews several approaches that are being developed to deal with this problem by the U.S. Environmental Protection Agency, under the umbrella of the ToxCast programme (). The overall approach is broken into seven tasks: (i) identifying biological pathways that, when perturbed, can lead to toxicity; (ii) developing high-throughput in vitro assays to test chemical perturbations of these pathways; (iii) identifying the universe of chemicals with likely human or ecological exposure; (iv) testing as many of these chemicals as possible in the relevant in vitro assays; (v) developing hazard models that take the results of these tests and identify chemicals as being potential toxicants; (vi) generating toxicokinetics data on these chemicals to predict the doses at which these hazard pathways would be activated; and (vii) developing exposure models to identify chemicals for which these hazardous dose levels could be achieved. This overall strategy is described and briefly illustrated with recent examples from the ToxCast programme. [ABSTRACT FROM AUTHOR]

Toxicity testing typically involves studying adverse health outcomes in animals subjected to high doses of toxicants with subsequent extrapolation to expected human responses at lower doses. The low-throughput of current toxicity testing approaches (which are largely the same for industrial chemicals, pesticides and drugs) has led to a backlog of more than 80,000 chemicals to which human beings are potentially exposed whose potential toxicity remains largely unknown. Employing new testing strategies that employ the use of predictive, high-throughput cell-based assays (of human origin) to evaluate perturbations in key pathways, referred as pathways of toxicity, and to conduct targeted testing against those pathways, we can begin to greatly accelerate our ability to test the vast 'storehouses' of chemical compounds using a rational, risk-based approach to chemical prioritization and provide test results that are more predictive of human toxicity than current methods. The NIH Transformative Research Grant project Mapping the Human Toxome by Systems Toxicology aims at developing the tools for pathway mapping, annotation and validation as well as the respective knowledge base to share this information. [ABSTRACT FROM AUTHOR]

Highlights: [•] Continuous data were generated by simulations and evaluated with BMD modeling. [•] Falsely high BMDLs were found to be more frequent than expected. [•] The phenomenon was related to the selection of a non-sigmoid exponential model. [•] Falsely high BMDLs cause’s underestimates of the risk associated with exposure. [Copyright &y& Elsevier]

Reproduction data collected through standard bioassays are Offspring per Individual-day classically analyzed by regression in order to fit exposure-response curves and estimate ECx values (x% effective concentration). But regression is often misused on such data, ignoring statistical issues related to (i) the special nature of reproduction data (count data), (ii) a potential interreplicate variability, and (iii) a possible concomitant mortality. This paper offers new insights in dealing with those issues. Concerning mortality, particular attention was paid not to waste any valuable data-by dropping all the replicates with mortality-or to bias ECx values. For that purpose we defined a new covariate summing the observation periods during which each individual contributes to the reproduction process. This covariate was then used to quantify reproduction-for each replicate at each concentration-as a number of offspring per individual-day. We formulated three exposure-response models differing by their stochastic part. Those models were fitted to four data sets and compared using a Bayesian framework. The individual-day unit proved to be a suitable approach to use all the available data and prevent bias in the estimation of ECx values. Furthermore, a nonclassical negative-binomial model was shown to correctly describe the inter-replicate variability observed in the studied data sets. [ABSTRACT FROM AUTHOR]

Highlights: [•] We manufacture a new cellulose nanocrystal (CNC) in different sizes. [•] Successive strong acid treatment is used in order to obtain the CNCs. [•] The CNCs did not reveal much cytotoxicity at various concentrations up to 250μg/mL. [Copyright &y& Elsevier]

N, N, N′, N′-tetramethylethylenediamine (TEMED) is extensively used for initiating polymerization of acrylamide and bisacrylamide gel for electrophoresis and for inorganic complex structure formation. The present study evaluates the toxicological effect of TEMED on structures of rat brain acetylcholinesterase (AChE) activity. In vitro study showed that the Ki values for striatum, cortex, cerebellum and hypothalamus were found to be 1.24, 1.4, 1.45 and 1.47 mM. Kinetics studies indicated that TEMED caused mixed type of inhibition that is a combination of competitive and noncompetitive inhibition in striatum, cortex, hypothalamus and cerebellum. The result showed that km increased and Vmax decreased with increase in TEMED concentration. The IC50 values calculated for striatum, cortex, cerebellum and hypothalamus were found to be as 0.92, 0.92, 1.44 and 1.42 mM. The present study indicates that TEMED is a toxicant for brain via inhibition of AChE. Therefore, proper precaution should be made during its handling. [ABSTRACT FROM PUBLISHER]

Lead (Pb) is a common heavy metal in the natural environment, but its concentration has been increasing alongside widespread industrial and agricultural development in China. The dark-spotted frog Pelophylax (formerly Rana) nigromaculata (Anura: Ranidae) is distributed across East Asia and inhabits anthropogenic habitats such as farmland. Here, P. nigromaculata tadpoles (Gosner stage 19–46) were exposed to Pb at different concentrations (0, 40, 80, 160, 320, 640 and 1280µg/L) and Pb-induced survival, metamorphosis time, development, malformations, mobility and gonad structure were monitored. The results showed that above the threshold concentration of Pb, adverse effects were obvious. As the concentration of Pb increased, the adverse effects on different traits followed different patterns: the effects on hindlimb length, survival rate, metamorphosis rate, total malformation rate, swimming speed and jumping speed largely exhibited a linear pattern; the effects on snout–vent length, body mass and forelimb length largely exhibited a bimodal pattern. Sex ratio and gonadal histology were not affected by Pb, suggesting that Pb is not strongly estrogenic in P. nigromaculata. [Copyright &y& Elsevier]

An adverse drug reaction (ADR) is a serious concern for practicing veterinarians and other health professionals, and refers to an unintended, undesired and unexpected response to a drug that negatively affects the patient's health. It may be iatrogenic or genetically induced, and may result in death of the affected animal. The ADRs are often complicated and unexpected due to myriad clinical symptoms and multiple mechanisms of drug-host interaction. Toxicity due to commonly used drugs is not uncommon when they are used injudiciously or for a prolonged period. Licosamides, exclusively prescribed against anaerobic pyoderma, often ends with diarrhoea and vomiting in canines. Treatment with Penicillin and β-lactam antibiotics induces onset of pemphigious vulgare, drug allergy or hypersensitivity. Chloroamphenicol and aminoglycosides causes Gray's baby syndrome and ototoxicity in puppies, respectively. Aminoglycosides are very often associated with nephrotoxicity, ototoxicity and neuromuscular blockage. Injudicious use of fluroquinones induces the onset of arthropathy in pups at the weight bearing joints. The most effective therapeutic measure in managing ADR is to treat the causative mediators, followed by supportive and symptomatic treatment. So, in this prospective review, we attempt to bring forth the commonly occurring adverse drug reactions, their classification, underlying mechanism, epidemiology, treatment and management as gleaned from the literature available till date and the different clinical cases observed by the authors. [ABSTRACT FROM AUTHOR]

A re-analysis of a large number of historical dose-response data for continuous endpoints indicates that an exponential or a Hill model with four parameters adequately describes toxicological dose-responses. No exceptions were found for the datasets considered, which related to a wide variety of endpoints and to both in vivo and in vitro studies of various types. For a given endpoint/study type dose-response shapes were found to be homogenous among chemicals in the in vitro studies considered, while a mild among-chemical variation in the steepness parameter seemed to be present in the in vivo studies. Our findings have various practical consequences. For continuous endpoints, model selection in the BMD approach is not a crucial issue. The often applied approach of using constraints on the model parameters to prevent 'infinite' slopes at dose zero in fitting a model is not in line with our findings, and appears to be unjustified. Instead, more realistic ranges of parameter values could be derived from re-analyses of large numbers of historical dose-response datasets in the same endpoint and study type, which could be used as parameter constraints in future individual datasets. This approach will be particularly useful for weak datasets (e.g. few doses, much scatter). In addition, this approach may open the way to use fewer animals in future studies. In the discussion, we argue that distinctions between linear, sub/supralinear or thresholded dose-response shapes, based on visual inspection of plots, are not biologically meaningful nor useful for risk assessment. [ABSTRACT FROM AUTHOR]

Context: A detailed evaluation of the correlation and linearity of industrial hygiene retrospective exposure assessment (REA) for cumulative asbestos exposure with asbestos lung burden analysis (LBA) has not been previously performed, but both methods are utilized for case-control and cohort studies and other applications such as setting occupational exposure limits. Objective: (a) To correlate REA with asbestos LBA for a large number of cases from varied industries and exposure scenarios; (b) to evaluate the linearity, precision, and applicability of both industrial hygiene exposure reconstruction and LBA; and (c) to demonstrate validation methods for REA. Methods: A panel of four experienced industrial hygiene raters independently estimated the cumulative asbestos exposure for 363 cases with limited exposure details in which asbestos LBA had been independently determined. LBA for asbestos bodies was performed by a pathologist by both light microscopy and scanning electron microscopy (SEM) and free asbestos fibers by SEM. Precision, reliability, correlation and linearity were evaluated via intraclass correlation, regression analysis and analysis of covariance. Plaintiff's answers to interrogatories, work history sheets, work summaries or plaintiff's discovery depositions that were obtained in court cases involving asbestos were utilized by the pathologist to provide a summarized brief asbestos exposure and work history for each of the 363 cases. Results: Linear relationships between REA and LBA were found when adjustment was made for asbestos fiber-type exposure differences. Significant correlation between REA and LBA was found with amphibole asbestos lung burden and mixed fiber-types, but not with chrysotile. The intraclass correlation coefficients (ICC) for the precision of the industrial hygiene rater cumulative asbestos exposure estimates and the precision of repeated laboratory analysis were found to be in the excellent range. The ICC estimates were performed independent of specific asbestos fiber-type. Conclusions: Both REA and pathology assessment are reliable and complementary predictive methods to characterize asbestos exposures. Correlation analysis between the two methods effectively validates both REA methodology and LBA procedures within the determined precision, particularly for cumulative amphibole asbestos exposures since chrysotile fibers, for the most part, are not retained in the lung for an extended period of time. [ABSTRACT FROM AUTHOR]

In the fields of endocrinology and toxicology, there are ongoing debates about whether endocrine disrupting chemicals (EDCs) produce non-monotonic dose responses. This type of response is typically characterized by a U- or inverted U-shaped relationship between dose and effect. In a recent report, a US EPA panel concluded that nonmonotonicity is observed for EDCs, but that these responses are not expected in vivo, and are not typically observed in apical endpoints, i.e. endpoints that are indicators of adverse effects. Here, we have analyzed the shapes of the dose response curves in an EPA report analyzing the effectiveness of the Endocrine Disruptor Screening Program (EDSP) Tier 1 assays. This report included the results of 11 guideline assays for each of 4 chemicals. We found indications of nonmonotonic dose response curves (iNMDRCs) for 3 of the 4 coded chemicals. In total, 27% of assays with dose response data included at least one iNMDRC. When the endpoints from the 4 test chemicals with dose response data were considered together, 9% were consistent with non-monotonicity. Collectively, these results indicate that nonmonotonic responses occur in guideline endpoints including the kinds of adverse outcomes that regulatory agencies use in chemical safety assessments such as circulating hormone concentrations and organ weights. These results should inform discussions about whether NMDRCs are 'real' and occur frequently enough to be important. Because risk assessments typically involve high dose testing, limited dose groups (often only 3) and extrapolation to lower doses that are not expected to have adverse effects, the presence of NMDRCs challenges this status quo. [ABSTRACT FROM AUTHOR]