Toxicity of mixtures of zinc oxide and graphene oxide nanoparticles to aquatic organisms of different trophic level: particles outperform dissolved ions

Concomitant releases of various engineered nanoparticles (NPs) into the environment have resulted in concerns regarding their combined toxicity to aquatic organisms. It is however, still elusive to distinguish the contribution to toxicity of components in NP mixtures. In the present study, we quantitatively evaluated the relative contribution of NPs in their particulate form (NP_(particle)) and of dissolved ions released from NPs (NP_(ion)) to the combined toxicity of binary mixtures of ZnO NPs and graphene oxide nanoplatelets (GO NPs) to three aquatic organisms of different trophic levels, including an alga species (Scenedesmus obliquus), a cladoceran species (Daphnia magna), and a freshwater fish larva (Danio rerio). Our results revealed that the effects of ZnO NPs and GO NPs were additive to S. obliquus and D. magna but antagonistic to D. rerio. The relative contribution to toxicity (RCT) of the mixture components to S. obliquus decreased in the order of RCT_{GO NP(particle)} >?RCT_{ZnO NP(particle)}?>?RCT_{ZnO NP(ion)}, while the RCT of the mixture components to D. magna and D. rerio decreased in the order of RCT_{ZnO NP(particle)}?>?RCT_{GO NP(particle)}?>?RCT_{ZnO NP(ion)}. This finding also implies that the suspended particles rather than the dissolved Zn-ions dictated the combined toxicity of binary mixtures of ZnO NPs and GO NPs to the aquatic organisms of different trophic level. The alleviation of the contribution to toxicity of the ionic form of ZnO NPs was caused by the adsorption of the dissolved ions on GO NPs. Furthermore, the ZnO NP_(particle) and GO NP_(particle) displayed a different contribution to the observed mixture toxicity, dependent on the trophic level of the aquatic organisms tested. The difference of the contributions between the two particulate forms was mainly associated with differences in the intracellular accumulation of reactive oxygen species. Our findings highlight the important role of particles in the ecological impact of multi-nanomaterial systems.     

Prediction of chemical toxicity to aquatic organisms: ECOSAR vs. Microtox® Assay

This study was designed to compare the toxicities of various chemical explosives and related compounds to aquatic organisms as predicted by a luminescent bacterium assay (Microtox® assay) and by the computer program ECOSAR. Toxicities were rated “very toxic,” “toxic,” or “less toxic” using the same criteria as the published bacterium assay. The two methods agree for most of the 24 compounds studied, and the disagreements are about equally divided as to which method predicts the greater toxicity. Experimental toxicity data were available for 12 of the 24 compounds. With these data, ECOSAR made eight predictions that coincided with the experimental toxicity class, while the luminescent bacterium assay predicted seven. For 17 of 21 experimental LC₅₀ values, ECOSAR predicted log LC₅₀ within one log unit. Published 1998 John Wiley & Sons, Inc. Environ Toxicol Water Qual 13: 211–216, 1998     

中药新药一般毒理试验及评价

根据多年研究实践,针对新药一般毒理试验及临床前安全性评价进行探讨,提出新药一般毒理试验需在12个环节中予以重视和加强管理。     

Toxicity of elemental sulfur in sediments

Elemental sulfur occurs naturally in marine and limnic sediments. Elemental sulfur, brought in solution in aqueous media by using organic solvents such as methanol as carrier solvent, was toxic in a bacterial luminescence test, known as the Microtox test. Previously, it has been shown that the toxicity in the luminescence test of whole sediments also was correlated to i.a. elemental sulfur using multivariate statistical analysis. Organic solvent extracts of sediments obtained in receiving waters of effluents from a pulp and paper mill was toxic in the luminescence test, and using a toxicity evaluation procedure, the toxic substance was identified as octameric cyclic sulfur, S₈. The substance dominated the toxicity in extracts of both a contaminated sediment and a sediment from a control area. Since the toxicity in the Microtox test of aqueous solutions of S₈ decreased upon storage, a conversion process of the toxic form was indicated. Acute toxicity of S₈ was not limited to the luminescent bacteria in the Microtox test, but was observed in tests with fish larvae if tested with the transient form of elemental sulfur. Tests of acute toxicity with zebra fish and perch larvae were responsive to elemental sulfur. Probably, the toxic form of elemental sulfur is the single cyclic octamer, that due to low aqueous solubility, binding to particulate sediment material or aggregation is converted into a nontoxic form. Acute toxic effects may occur in sulfur containing sediments of varying redox potentials or where elemental sulfur deposits are turbated. © 1998 John Wiley & Sons, Inc. Environ Toxicol Water Qual 13: 217–224, 1998     

Multispecies toxicity test for silver nanoparticles to derive hazardous concentration based on species sensitivity distribution for the protection of aquatic ecosystems

With increasing concerns about the release of silver nanoparticles (AgNPs) into the environment and the risks they pose to ecological and human health, a number of studies of AgNP toxicity to aquatic organisms have been conducted. USEPA and EU JRC have published risk assessment reports for AgNPs. However, most previous studies have focused on the adverse effects of AgNPs on individual species. Hazardous concentration (HC) of AgNPs for protection of aquatic ecosystems that are based on species sensitivity distributions (SSDs) have not yet been derived because sufficient data have not been available. In this study, we conducted multispecies toxicity tests, including acute assays using eight species from five different taxonomic groups (bacteria, algae, flagellates, crustaceans and fish) and chronic assays using six species from four different taxonomic groups (algae, flagellates, crustaceans and fish). Using the results of these assays, we used a SSD approach to derive an AgNP aquatic HC₅ (Hazard concentrations at the 5% species) of 0.614?μg/L. To our knowledge, this is the first report of a proposed HC of AgNPs for the protection of aquatic ecosystems that is based on SSDs and uses chronic toxicity data.     

Toxicity of nitrite to three species of freshwater invertebrates

Nitrite is a compound with a high toxicity to aquatic animals. Several anthropogenic pollution sources are increasing the concentrations of this component of the nitrogen cycle. Despite this toxicity, there is little available literature on its effects on freshwater invertebrates. Laboratory bioassays were performed to obtain data on the lethal effects of nitrite to three species of freshwater invertebrates: the planarian Polycelis felina and the amphipods Echinogammarus echinosetosus and Eulimnogammarus toletanus. The LC(50), LC(10), and LC(0.01) values (mg/L NO(2)--N) at 24, 48, 72, and 96 h were calculated for each species. E. toletanus and E. echinosetosus were the most sensitive species, with 96 h LC(50) values of 2.09 and 2.59 mg/L NO(2)--N, respectively. In contrast, the planarian P. felina showed a higher tolerance to nitrite, with a 96 h LC(50) value of 60.0 mg/L NO(2)--N. The obtained results were compared with the reported nitrite data for other freshwater invertebrates. This study may contribute to a more appropriate assessment of the ecological risk of this compound in freshwater ecosystems.     

复方敏维糖浆的急性毒性和长期毒性研究

摘 要 目的：为复方敏维糖浆的临床安全使用提供实验依据。方法: 急性毒性实验以小鼠为实验对象,以改良寇氏法计算半数致死量(LD₅₀)。长期毒性实验中给予大鼠高、中、低剂量（650,195 ,65 mg·kg^-1）的复方敏维糖浆,连续给药4周,停药2周后观察其一般状况、体质量、摄食量,测定血液学、血液生化学指标,解剖后裸眼观察主要靶器官( 心、肺、肾、肝) 变化。结果: 急性毒性实验中复方敏维糖浆小鼠的LD₅₀为5 581.8 mg·kg^-1。长期毒性实验中高剂量组大鼠血清谷草转氨酶（AST）、谷丙转氨酶（ALT）、总胆固醇（CHOL）均有一定程度升高,且大鼠自发活动减少、有困倦现象,摄食量和体质量均有一定下降。 结论:复方敏维糖浆小鼠的LD₅₀为5 581.8 mg·kg^-1,急性毒性反应与神经系统有关,未见脏器有明显损伤。长期使用高剂量复方敏维糖浆(650 mg·kg^-1) 可引起大鼠AST、ALT、CHOL升高。     

多组分、多靶点中药整体药代动力学研究的思考与探索

中药药代动力学研究是中药现代化研究链上一个不可分割的重要组成部分,在创新中药及现代复方中药研发中发挥着重要作用,但目前尚缺乏符合中药自身特征的药代动力学研究与评价技术体系,对于中药药代动力学学科关键科学问题的认识不够清晰。本文扼要概述了本课题组近年来在中药多组分整合药代动力学、体内外物质组分析、基于机制的方剂组分配伍规律研究及中药有效成分药代动力学研究进展,并试从面向中药现代化研究实际需求的角度,分析和讨论了中药药代动力学学科的关键科学问题,以期能够起到“抛砖引玉”的作用,共同促进我国中药药代动力学研究水平的提高。     

Joint effects of a mixture of 14 chemicals on mortality and inhibition of reproduction of Daphnia magna

The toxicity to Daphnia magna of a mixture of 14 aquatic pollutants with several chemical structures and probable modes of action was determined. The joint effect of this mixture on acute mortality was compared with the effects on inhibition of reproduction. The joint toxicity in the reproduction test was lower in comparison with the mortality test. This study supports the idea that the potential for addition is reduced when more specific sublethal toxicity criteria are studied. Although the joint toxicity at sublethal level is lower than at lethal level, the toxicity of the mixtures remains much higher than that of the individual chemicals and is still near concentration addition.     

基于毒性通路扰动的药物安全性评价新策略

安全性是决定创新药物研发成败的关键因素。传统的药物毒性测试与安全性预测面临严峻挑战。基于毒性通路扰动的毒性测试策略已成为药物安全性评价的重要发展方向。本文针对传统毒性测试方法存在的问题,简要介绍了毒性通路的内涵及其毒理学意义,重点阐述了基于毒性通路扰动的安全性评价新策略的提出及其发展,并以药物线粒体毒性预测为例,介绍了毒性测试新策略的原理及应用,为药物安全性评价的发展提供新的思路。     

Toxicity of ammonia to three marine fish and three marine invertebrates

Laboratory toxicity tests were performed to obtain more data on the toxicity of ammonia to saltwater organisms. The standards for in-stream ammonia limits in marine environments presently are based on toxicity tests involving both freshwater and saltwater organisms. Acute tests (48 and 96 h) were performed at 20 degrees C, and chronic tests (7 days) were performed at 25 degrees C. Synthetic seawater and natural seawater from the Chesapeake Bay were used and compared. Included among the organisms tested were sheepshead minnow (14 days old), summer flounder (2 months old), Atlantic silverside (14 days old), mysid shrimp (less than 2 days old), ghost shrimp (10 days old), and quahog clam (9 months old). Based on these results, it seems the chronic criterion for ammonia in marine environments could be increased from 0.035 to 0.081 mg/L un-ionized ammonia, which would, of course, increase the chronic limit for total ammonia under typical saltwater conditions by a factor of 2.31. No difference was observed in the toxicity of ammonia in natural water compared to synthetic water for both the summer flounder and Atlantic silverside. Furthermore, the Atlantic silverside became more sensitive to ammonia as the salinity was increased from 14 to 22 ppt, but exhibited no change in toxicity response from 22 to 30 ppt.     

新橙皮苷对大鼠胚胎-胎仔发育的毒性研究

目的 评价新橙皮苷对大鼠胚胎-胎仔发育的毒性。方法 妊娠大鼠根据妊娠第0天（gestation day 0,GD0）和体质量采用分层随机法分成5组：对照（0.5%羧甲基纤维素钠）组,环磷酰胺（12 mg·kg^-1）组,新橙皮苷低、中、高（0.45,0.9,1.8 g·kg^-1）3个剂量组。妊娠鼠于GD6开始给药至GD15。实验期间,每周至少测定2次体质量和1次摄食量。GD20处死妊娠鼠,对黄体、着床腺、胎仔、胎盘等情况进行检查。结果 试验期间,各组动物临床症状观察均未见明显异常。与对照组相比,新橙皮苷各剂量组动物体质量未见明显改变,环磷酰胺组动物增重减缓;新橙皮苷各剂量组黄体、着床、活胎、吸收胎、死胎计数均未见明显改变,环磷酰胺组子宫重量下降;新橙皮苷高剂量组胎仔身长降低,环磷酰胺组身长、尾长、重量及胎盘重均降低;新橙皮苷各剂量组胎仔外观检查未见给药相关改变,环磷酰胺组主要可见全身浮肿、头、耳、面、肢、指趾等改变。胎仔内脏检查中,新橙皮苷各剂量组分别可见1例脑室改变,中、高剂量组分别可见2例和1例食管扩张;环磷酰胺组可见腭、脑室、食管、睾丸附睾等改变。骨骼检查中,新橙皮苷可延缓顶骨、胸骨的骨化,可能影响下颌骨、颈椎、腰椎、耻骨、枕骨和肋骨的骨化。环磷酰胺12 mg·kg^-1对颅骨、脊椎骨、肋骨、胸骨、掌骨等的骨化均有所影响。结论 新橙皮苷给药后,对母体未产生明显毒性反应,未观察到临床不良反应的剂量水平（NOAEL）为1.8 g·kg^-1;对胚胎-胎仔的发育毒性主要表现为延缓骨骼如顶骨、胸骨等的骨化外,还可能影响脑部和食管的发育,NOAEL<0.45 g·kg^-1。     

Reproductive and Developmental Toxicity Screening Study of 4-Aminophenol in Rats

Twelve male and female rats per group were given 4-aminophenol (PAP) by gavage at 0, 20, 100, or 500 mg/kg/day. Males were dosed for a total of 49 days, beginning 14 days before mating. Females were dosed for a total of 40–60 days, from 14 days before mating to Day 3 of lactation throughout the mating and gestation periods. Four males and 2 females died at 500 mg/kg/day, and all surviving males and females showed brown urine at 100 mg/kg/day and above. Body-weight gain was lower in males and females at 500 mg/kg/day, and food consumption was decreased in males at 500 mg/kg/day and in females at 100 and 500 mg/kg/day. Absolute and relative weights of the testes and epididymides were decreased at 500 mg/kg/day. Histopathological examinations revealed decreased spermatocyte and spermatid levels in the testis, debris of germ cell in the epididymis lumen, basophilic tubules in the kidney, and deposits of hemosiderin in the red pulp and extramedullary hematopoiesis in the spleen in males at 500 mg/kg/day. Longer gestation period, decreased delivery index, and lower body weight of pups on postnatal day (PND) 0 and increased number of stillborns at 500 mg/kg/day were also observed. At this dose, the viability of pups on PND 4 was decreased markedly. No adverse effects on reproduction or development were detected at 20 and 100 mg/kg/day. These findings indicate that PAP is general and reproductive/developmental toxic, but is unlikely to be teratogenic, in rats.     

Toxicity of perfluorooctane sulfonate and perfluorooctanoic acid to plants and aquatic invertebrates

Acute toxicities of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were tested on four freshwater species and three plant species. PFOS was more toxic than PFOA for all species tested in this study. Similar time-response patterns of PFOS and PFOA toxicity were observed for each tested species. Values of the 48-h LC(50) of PFOS for all test species ranged from 27 to 233 mg/L and values of the 96-h LC(50) for three of the species ranged from 10 to 178 mg/L. Values of the 48-h LC(50) of PFOA for all test species ranged from 181 to 732 mg/L and values of the 96-h LC(50) for three of the species ranged from 337 to 672 mg/L. The most sensitive freshwater species to PFOS was green neon shrimp (Neocaridina denticulate) with a 96-h LC(50) of 10 mg/L. Of the aquatic organisms tested, the aquatic snail (Physa acuta) always has the highest resistance to PFOS or PFOA toxicity over each exposure period. Both PFOS and PFOA had no obvious adverse effect on seed germination for all three plant species. Five-day EC(50) of root elongation was more sensitive to LC(50) of seed germination in this study. Based on EC(10), EC(50), and NOECs, the 5-day root elongation sensitivity of test plants to both PFOS and PFOA was in the order of lettuce (Lactuca sativa) > pakchoi (Brassica rapa chinensis) > cucumber (Cucumis sativus). Based on the results of this study and other published literature, it is suggested that current PFOS and PFOA levels in freshwater may have no acute harmful ecological impact on the aquatic environment. However, more research on the long-term ecological effects of PFOS and PFOA on aquatic fauna are needed to provide important information to adequately assess ecological risk of PFOS and PFOA.     

魔芋止血剂的止血作用及局部用药的安全性评价

目的考察魔芋止血剂局部用药的有效性和安全性。方法通过对小鼠的断尾出血、家兔股动脉出血及家兔肝、脾出血的止血试验,评价魔芋止血剂的止血效果。通过对健康家兔进行皮肤刺激性试验,对豚鼠进行皮肤过敏反应试验及对大鼠进行经皮渗透毒性试验,评价魔芋止血剂局部用药的安全性。结果魔芋止血剂对小鼠的断尾出血、家兔股动脉出血及家兔肝、脾出血均有明显的止血效果。对大鼠、家兔完整皮肤和破损皮肤无刺激性;不引起豚鼠过敏反应;对大鼠无经皮毒性反应,不影响伤口会愈合。结论魔芋止血剂具有明显的止血效果,皮肤局部用药对实验动物安全性良好。     

Comparison of acute to chronic ratios between silver and gold nanoparticles,using Ceriodaphnia dubia

As integration of nanoparticles (NPs) into products becomes more common, the need to address the paucity of chronic hazard information for aquatic environments required to determine risk potential increases. This study generated acute and chronic toxicity reference values for Ceriodaphnia dubia exposed to 20 and 100?nm silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) to generate and evaluate potential differences in acute-to-chronic ratios (ACR) using two different feeding methods. A modified feeding procedure was employed alongside the standard procedures to investigate the influence of food on organism exposure. An 8-h period before food was added allowed direct organism exposure to NP dispersions (and associated ions) without food-to-NP interactions. The AgNPs [chronic lethal median concentrations (LC50) between 18.7 and 31.9?µg/L] were substantially more toxic than AuNPs (LC50?=?21 507 to >26 384?µg/L). The modified chronic testing method resulted in greater sensitivity in AgNPs exposures. However, the modified feeding ration had less of an effect in exposures to the larger (100?nm) AgNPs compared to smaller particles (20?nm). The ACRs for AgNPs using the standard feeding ration were 1.6 and 3.5 for 20?nm and 100?nm, respectively. The ACRs for AgNPs using the modified feeding ration were 3.4 and 7.6 for 20?nm and 100?nm NPs, respectively. This supports that the addition of the standard feeding ration decreases C. dubia chronic sensitivity to AgNPs, although it must also be recognized organisms may be sensitized due to less access to food. The ACRs for 20?nm and 100?nm AuNPs (standard ration only) were 4.0 and 3.0, respectively. It is important to also consider that dissolved Ag⁺ ions are more toxic than AgNPs, based on both acute toxicity values in the cited literature and chronic toxicity thresholds generated in this study that support existing thresholds that Ag⁺ are likely protective of AgNPs effects.     

氯霉素对着床前大鼠胚泡的遗传毒性

为评价氯霉素对着床前胚泡的遗传毒性作用,Wistar大鼠在妊娠d3ip氯霉素65mg／kg,165mg／kg,330mg／kg。孕鼠于妊娠d4处死取胚泡,观察微核率,具微核胚泡率及有关丝分裂指数等。结果表明氛霉素各剂量组的微孩率呈剂量依赖性增加,与对照组相比较均有极显著差异;具微核胚烟率与对照组相比无显著差异,但呈一定量效相关性;ip氯霉素330mg/kg时．平均细胞数显著减少,有丝分裂指数与对照相比较无显著差异。提示氯霉素对整体大鼠着床有胚胞具遗传毒性。     

Toxicity of 2-methyl-4-chlorophenoxy acetic acid alone and in combination with cyhalofop-butyl to Cyprinus carpio embryos

Herbicides may pose considerable danger to non-target aquatic organisms and further threaten human health. The present investigation was aimed to assess the effects of 2-methyl-4-chlorophenoxy acetic acid (MCPA-Na) on Cyprinus carpio embryos. Embryos were exposed to six concentrations of MCPA-Na (0, 52, 54, 56, 58 and 60 mg/L) for 96 h. A series of symptoms were observed in developmental embryos during MCPA-Na exposure, including increased death, hatching inhibited and morphological deformities. Further, MCPA-Na exposure leading to a series of morphological changes (pericardial edema, tail deformation, and spine deformation) in embryos, which were consistent with modifications in the associated genes. In this work, we also investigated the joint toxicity of herbicides (MCPA-Na and cyhalofop-butyl) commonly used in paddy fields on carp embryos, using the 96 h-LC₅₀ of herbicides (59.784 mg/L MCPA-Na and 1.472 mg/L cyhalofop-butyl) and confirmed that a synergistic effect existing in the binary mixtures.