Life-history traits of standard and autochthonous cladocerans: II. Acute and chronic effects of acetylsalicylic acid metabolites

Metabolic products are often more toxic than their pharmacological parent compounds. Therefore, the acute and chronic effects of the main metabolites--salicylic acid (SAL), gentisic acid (GEN), and o-hydroxyhippuric acid (HDP)--of acetylsalicylic acid (ASA), the active ingredient in Aspirin and many other pharmaceuticals, were assessed using standard (Daphnia magna) and autochthonous (Daphnia longispina) cladocerans. The sequence of decreasing levels of acute and chronic toxicity of ASA metabolites to daphnids was GEN > SAL > HDP. HDP did not present acute toxicity, but chronic exposures enabled the production of abnormal neonates and, in particular, egg abortion. Thus, reproduction was the end point most susceptible to HDP. On the other hand, SAL and GEN induced changes in the normal patterns of reproduction and growth of both species. In general, D. longispina was more sensitive than was D. magna, although the population growth of the autochthonous species was superior under SAL exposures than that of the standard test species. Although the concentrations that were determined to have a toxic effect were above the levels detected in aquatic environmental samples, exposure to low levels of pharmacologically active substances for a duration longer than the test period may induce changes in nontarget organisms.     

Chronic effects of p-nonylphenol on survival and reproduction of Daphnia galeata: multigenerational life table experiment

The chronic effect of p-nonylphenol on survival and reproduction for two generations of the freshwater cladoceran Daphnia galeata was examined by life table experiments. The effects on survival and reproduction were used as the intrinsic rate of natural increase, r, with the Euler-Lotka equation and were analyzed with a simple mathematical model (a power function). The population-level EC(50), the concentration of a substance that reduces the intrinsic rate of natural increase by 50%, was estimated as 65.2 microg/L for the first generation and 81.5 microg/L for the second generation. No transgenerational effect that reinforces adverse responses in the offspring generation has been detected. From a 48-h immobility test an acute LC(50) was estimated to be 60.8 microg/L. The acute LC(50) is a good indicator of the chronic population-level effects of this chemical to this species.     

Effect of linear alkylbenzene sulfonate on population growth of Daphnia galeata: a life table evaluation

The chronic effect of linear alkylbenzene sulfonate (LAS12) on a daphnid species (Daphnia galeata) was examined by the life table experiment. The estimated responses in the intrinsic rate of population growth r were analyzed with two alternate concentration-response functions, i.e., the power function and the quadratic function. Based on the best-fit power function model with biases corrected by the jackknife procedure, the population-level EC50, which is defined as the concentration of chemicals that reduces the population growth rate (the intrinsic rate of natural increase) by 50%, was estimated as 2.5 mg/L. The 48-h acute immobility test yielded EC50 of 4.6 mg/L. The population-level effect of LAS12 on this test species is considerably more sensitive than the acute lethal effects to neonates.     

Acute and chronic toxic effects of bisphenol a on Chlorella pyrenoidosa and Scenedesmus obliquus

The acute and chronic toxic effects of Bisphenol A (BPA) on Chlorella pyrenoidosa (C. pyrenoidosa) and Scenedesmus obliquus (S. obliquus) were not well understood. The indoor experiments were carried out to observe and analyze the BPA‐induced changes. Results of the observations showed that in acute tests BPA could significantly inhibit the growth of both algae, whereas chronic exposure hardly displayed similar trend. Superoxide dismutase (SOD) and Catalase (CAT) activities of both algae were promoted in all the treatments. Chlorophyll a synthesis of the two algae exhibited similar inhibitory trend in short‐term treatments, and in chronic tests C. pyrenoidosa hardly resulted in visible influence, whereas in contrast, dose‐dependent inhibitory effects of S. obliquus could be clearly observed. The experimental results indicated that the growth and Chlorophyll a syntheses of S.obliquus were more sensitive in response to BPA than that of C. pyrenoidosa, whereas for SOD andCAT activities, C. pyrenoidosa was more susceptible. This research provides a basic understanding of BPA toxicity to aquatic organisms. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 714–722, 2014.     

Acute acetylsalicylic acid poisoning: Treatment with forced alkaline diuresis and diuretics

Summary The effect of acetylsalicylic acid (ASA) in patients with renal insufficiency has been examined. In one investigation (A), in patients with a mean GFR of 23.0 ml/min the acute effects of ASA 750 mg i.v. (lysine-ASA 7.5 ml) and 0.9% NaCl 7.5 ml on renal water and solute output and on the clearance of inulin, creatinine and PAH were compared. In another (B) the effects of simultaneous administration of ASA 750 mg or 0.9% NaCl 7.5 ml i.v. with an infusion of furosemide 250 mg were investigated in six patients (mean GFR 12.9 ml/min) in a cross-over study. In study A there was a significant fall in urinary sodium excretion within the first 15 min after ASA administration, with a maximal decrease to 21% of the control period. Urine flow fell to 35%, osmolal clearance to 41%, inulin clearance to 54% and PAH clearance to 66%, whilst tubular reabsorption of sodium increased. The effect of ASA lasted for 2–6 h. The mean salicylic acid concentration during the first two hours after ASA administration was 60.0 µg/ml, and the mean protein bound salicylic acid (SA) was 70.4%. There was no effect of placebo (0.9% NaCl7.5 ml) on renal function. Pretreatment with ASA 750 mg i.v. attenuated the diuretic effect of furosemide 250 mg, and reduced creatinine clearance significantly within 0–2 h after drug administration.     

Chronic toxicity of Great Lakes sediments to Daphnia magna: elutriate effects on survival, reproduction and population growth

Seventeen Great Lakes sediments ranging in degree of expected toxicity were evaluated using a 21 day sediment elutriate bioassay with Daphnia magna. Sediments differed in their effects on survival, age at first reproduction, the number of broods produced and the total number of young produced per adult. Sediments producing low survivorship (50–60%) also had negative effects on reproduction. However, both positive and negative effects on reproduction were found among sediments producing high survivorship. To integrate all test end-points, a stochastic matrix population model was constructed and parameterized with survival and reproduction data from each sediment. By including estimates of variability in vital rates, the model output provided quantitative estimates of uncertainty in projected population size. Sediment effects on survival and reproduction translated into large differences in projected population growth; mean estimates of projected population size at day 28 of the simulations ranged over two orders of magnitude among the 17 sediments. Reproductive timing (e.g. age at first reproduction), followed by fecundity and survivorship, had the largest effect on population growth. Results of this study also indicate that the presence of suspended sediment in elutriates may confound toxicity evaluations using cladocerans. The concentration of total suspended solids was negatively correlated with age at first reproduction and positively correlated with measures of fecundity and population growth. In order to realize the potential benefits of chronic testing we must develop ecologically relevant ways of interpreting sediment bioassay results and expressing the uncertainty associated with our estimates of ecological risk.     

对氯苯氧异丁酸甲氧基苯丙烯酸酯的小鼠急性毒性和大鼠长期毒性

目的评价对氯苯氧异丁酸甲氧基苯丙烯酸酯(AZ)的安全性。方法 小鼠分别ig给予AZ3000～1001mg.kg-1或ip给予AZ1600～983mg.kg-1,观察14d,测定小鼠的半数致死量(LD50)。大鼠ig给予AZ500,291.7和166.7mg.kg-1(为临床拟用剂量的60倍、35倍和20倍),连续13周,停药2周后,观察大鼠一般状况、体质量增长、血液学、血液生化学和病理组织学等指标的变化。结果小鼠ig及ip给AZ的LD50分别为2053和1254mg.kg-1。大鼠给药13周后,AZ500mg.kg-1组血清转氨酶、尿素氮和肝系数升高(P<0.05),AZ291.7mg.kg-1组血清天冬氨酸转氨酶(AST)和肝系数升高(P<0.05),其他各组各指标与溶媒对照组相比均无显著性差异。病理组织学检查显示,AZ500mg.kg-1有1例肝组织炎细胞浸润,其余组大鼠未见与药物毒性相关的明显病变。停药2周后各异常指标均恢复正常。结论 AZ在规定剂量下使用应有较好的安全性。     

Acute exposure of mice to hydrochloric acid leads to the development of chronic lung injury and pulmonary fibrosis

Objective: Accidental exposure to hydrochloric acid (HCl) is associated with acute lung injury in humans, development of long-term chronic airway obstruction, and fibrosis. However, the mechanisms responsible for the progression to pulmonary fibrosis remain unclear. We utilized a mouse model of progressive lung injury from a single exposure to HCl to investigate the effects of HCl on the lower respiratory tract.

Materials and methods: HCl (0.05–0.3?N) or saline was injected intratracheally into male C57Bl/6J mice. At 1, 4, 10 and 30 days post instillation, bronchoalveolar lavage fluid (BALF) and lung tissues were collected and examined for multiple outcomes.

Results and discussion: We observed an early inflammatory response and a late mild inflammation present even at 30?d post HCl exposure. Mice treated with HCl exhibited higher total leukocyte and protein levels in the BALF compared to the vehicle group. This was characterized by increased number of neutrophils, monocytes, and lymphocytes as well as pro-inflammatory cytokines during the first 4?d of injury. The late inflammatory response exhibited a predominant presence of mononuclear cells, increased permeability to protein, and higher levels of the pro-fibrotic mediator TGFβ. Pro-fibrotic protein biomarkers, phosphorylated ERK, and HSP90, were also overexpressed at 10 and 30?d following HCl exposure. In vivo lung function measurements demonstrated lung dysfunction and chronic lung injury associated with increased lung hydroxyproline content and increased expression of extracellular matrix (ECM) proteins. The acute inflammation and severity of fibrosis increased in HCl-concentration dependent manner.

Conclusions: Our findings suggest that the initial inflammatory response and pro-fibrotic biomarker upregulation may be linked to the progression of pulmonary fibrosis and airway dysfunction and may represent valuable therapeutic targets.     

Comparative study of dissolved and nanoparticulate Ag effects on the life cycle of an estuarine meiobenthic copepod,Amphiascus tenuiremis

Many nanotoxicological studies have assessed the acute toxicity of nanoparticles (NPs) at high exposure concentrations. There is a gap in understanding NP chronic environmental effects at lower exposure concentrations. This study reports life-cycle chronic toxicity of sublethal exposures of polyvinylpyrrolidone-coated silver nanoparticles (PVP-AgNPs) relative to dissolved silver nitrate (AgNO₃) for the estuarine meiobenthic copepod, Amphiascus tenuiremis, over a range of environmentally relevant concentrations, i.e., 20, 30, 45, and 75?µg-Ag?L^?1. A concentration-dependent increase in mortality of larval nauplii and juvenile copepodites was observed. In both treatment types, significantly higher mortality was observed at 45 and 75?µg-Ag?L^?1 than in controls. In AgNO₃ exposures, fecundity declined sharply (1.8–7 fold) from 30 to 75?µg Ag?L^?1. In contrast, fecundity was not affected by PVP-AgNPs exposures. A Leslie matrix population-growth model predicted sharply 60–86% of decline in overall population sizes and individual life-stage numbers from 30–75?µg-Ag L^?1 as dissolved AgNO₃. In contrast, no population growth suppressions were predicted for any PVP-AgNPs exposures. Slower release of dissolved Ag from PVP-AgNPs and/or reduced Ag uptake in the nanoform may explain these sharp contrasts in copepod response.     

Evaluation of submarine atmospheres: effects of carbon monoxide,carbon dioxide and oxygen on general toxicology,neurobehavioral performance,reproduction and development in rats. I. Subacute exposures

Abstract

The inhalation toxicity of submarine contaminants is of concern to ensure the health of men and women aboard submarines during operational deployments. Due to a lack of adequate prior studies, potential general, neurobehavioral, reproductive and developmental toxicity was evaluated in male and female rats exposed to mixtures of three critical submarine atmospheric components: carbon monoxide (CO) and carbon dioxide (CO₂; levels elevated above ambient), and oxygen (O₂; levels decreased below ambient). In a 14-day, 23?h/day, whole-body inhalation study of exposure to clean air (0.4?ppm CO, 0.1% CO₂ and 20.6% O₂), low-dose, mid-dose and high-dose gas mixtures (high dose of 88.4?ppm CO, 2.5% CO₂ and 15.0% O₂), no adverse effects on survival, body weight or histopathology were observed. Reproductive, developmental and neurobehavioral performance were evaluated after a 28-day exposure in similar atmospheres. No adverse effects on estrus phase, mating, gestation or parturition were observed. No developmental or functional deficits were observed in either exposed parents or offspring related to motor activity, exploratory behavior or higher-level cognitive functions (learning and memory). Only minimal effects were discovered in parent-offspring emotionality tests. While statistically significant increases in hematological parameters were observed in the offspring of exposed parents compared to controls, these parameters remained within normal clinical ranges for blood cells and components and were not considered adverse. In summary, subacute exposures to elevated concentrations of the submarine atmosphere gases did not affect the ability of rats to reproduce and did not appear to have any significant adverse health effects.     

Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic, and toxicologic effects.

The tolerability, pharmacodynamic effects, and pharmacokinetics of belimumab (LymphoStat-B) were evaluated in cynomolgus monkeys. Belimumab is a fully human IgG1lambda antibody directed against B-lymphocyte stimulator (BLyS) protein. BLyS is a TNF family member that supports B-lymphocyte maturation and survival and has been implicated in the pathogenesis of autoimmune diseases and B-lymphocyte malignancies. Belimumab was developed to antagonize BLyS activity in autoimmune diseases and B-lymphocyte malignancies, where undesirable effects of B-lymphocyte activity may cause or contribute to disease. Pharmacodynamic effects of belimumab were monitored by immunophenotyping of peripheral blood. Pathology end points, including tissue immunophenotyping, are described after 13 and 26 weeks of treatment and after a 34-week treatment-free (recovery) period. Belimumab was safe and well tolerated in repeat-dose toxicology studies at 5-50 mg/kg for up to 26 weeks. Monkeys exposed to belimumab had significant decreases in peripheral blood B lymphocytes by 13 weeks of exposure, continuing into the recovery period, despite total lymphocyte counts similar to the controls. There were concomitant decreases in spleen and lymph node B-lymphocyte representation after 13 or 26 weeks of treatment with belimumab. Microscopically, monkeys treated with belimumab for 13 or 26 weeks had decreases in the number and size of lymphoid follicles in the white pulp of the spleen. All findings were generally reversible within a 34-week recovery period. These data confirm the specific pharmacologic activity of belimumab in reducing B lymphocytes in the cynomolgus monkey. The favorable safety profile and lack of treatment-related infections also support continued clinical development of belimumab.     

Predicting points of departure for risk assessment based on in vitro cytotoxicity data and physiologically based kinetic (PBK) modeling: The case of kidney toxicity induced by aristolochic acid I

Aristolochic acids are naturally occurring nephrotoxins. This study aims to investigate whether physiologically based kinetic (PBK) model-based reverse dosimetry could convert in vitro concentration-response curves of aristolochic acid I (AAI) to in vivo dose response-curves for nephrotoxicity in rat, mouse and human. To achieve this extrapolation, PBK models were developed for AAI in these different species. Subsequently, concentration-response curves obtained from in vitro cytotoxicity models were translated to in vivo dose–response curves using PBK model-based reverse dosimetry. From the predicted in vivo dose–response curves, points of departure (PODs) for risk assessment could be derived. The PBK models elucidated species differences in the kinetics of AAI with the overall catalytic efficiency for metabolic conversion of AAI to aristolochic acid Ia (AAIa) being 2-fold higher for rat and 64-fold higher for mouse than human. Results show that the predicted PODs generally fall within the range of PODs derived from the available in vivo studies. This study provides proof of principle for a new method to predict a POD for in vivo nephrotoxicity by integrating in vitro toxicity testing with in silico PBK model-based reverse dosimetry.