Novel insights into the risk assessment of the nanomaterial synthetic amorphous silica,additive E551, in food

Abstract

This study presents novel insights in the risk assessment of synthetic amorphous silica (SAS) in food. SAS is a nanostructured material consisting of aggregates and agglomerates of primary particles in the nanorange (<100?nm). Depending on the production process, SAS exists in four main forms, and each form comprises various types with different physicochemical characteristics. SAS is widely used in foods as additive E551. The novel insights from other studies relate to low gastrointestinal absorption of SAS that decreases with increasing dose, and the potential for accumulation in tissues with daily consumption. To accommodate these insights, we focused our risk assessment on internal exposure in the target organ (liver). Based on blood and tissue concentrations in time of two different SAS types that were orally and intravenously administered, a kinetic model is developed to estimate the silicon concentration in liver in (1) humans for average-to-worst-case dietary exposure at steady state and (2) rats and mice in key toxicity studies. The estimated liver concentration in humans is at a similar level as the measured or estimated liver concentrations in animal studies in which adverse effects were found. Hence, this assessment suggests that SAS in food may pose a health risk. Yet, for this risk assessment, we had to make assumptions and deal with several sources of uncertainty that make it difficult to draw firm conclusions. Recommendations to fill in the remaining data gaps are discussed. More insight in the health risk of SAS in food is warranted considering the wide applications and these findings.     

疫苗生产中基于风险评估的清洗剂变更

目的 在白喉-破伤风-无细胞百日咳疫苗生产车间玻璃瓶清洗剂的变更中,引入质量风险管理,对新清洗剂进行风险分析与评估,以确保更换清洗剂对产品质量无影响。方法 运用风险评估工具对新清洗剂进行相应风险评估,根据风险级别制定风险控制措施,对新清洗剂进行验证,确认其清洗效果以及对产品的影响。结果 清洗后玻璃瓶淋洗水中细菌内毒素含量≤0.25内毒素单位/ml、总好氧微生物计数≤100菌落形成单位/ml、总霉菌酵母菌计数≤10菌落形成单位/ml、总有机碳≤1.5 μg/cm2（淋洗水和擦拭取样）、电导率≤1.3 µS/cm,结果均符合要求。结论 在变更控制中运用质量风险管理,指导变更控制措施的制定和变更内容的实施,保证了新清洗剂的风险可接受且产品质量不受变更影响。     

Nano-TiO2 – feasibility and challenges for human health risk assessment based on open literature

Abstract

This study aims at investigating feasibility and challenges associated with conducting a human health risk assessment for nano-titanium-dioxide (nano-TiO₂) based on the open literature by following an approach similar to a classical regulatory risk assessment. Gaps in the available data set, both in relation to exposures and hazard, do not allow reaching any definite conclusions that could be used for regulatory decision-making. Results show that repeated inhalation in the workplace and possibly consumer inhalation may cause risks. Also short-term inhalation following spray applications may cause risks. Main future work should focus on generating occupational and consumer inhalation exposure data, as well as toxicity data on absorption following inhalation, repeated dermal contact, and contact with damaged skin. Also relevant seems further information on possible neurotoxicity and genotoxicity/carcinogenicity, as well as establishing a No Observed Adverse Effect Level (NOAEL) for acute inhalation of nano-TiO₂.     

An in vivo study of nanorod,nanosphere, and nanowire forms of titanium dioxide using Drosophila melanogaster: toxicity,cellular uptake,oxidative stress,and DNA damage

ABSTRACT

The biological impact of nanomaterials (NMs) is determined by several factors such as size and shape, which need to be taken into consideration in any type of analysis. While investigators often prefer to conduct in vitro studies for detection of any possible adverse effects of NMs, in vivo approaches yield more relevant data for risk assessment. For this reason, Drosophila melanogaster was selected as a suitable in vivo model to characterize the potential risks associated with exposure nanorods (NRs), nanospheres (NSs), nanowires (NWs) forms of titanium dioxide (TiO₂), and their microparticulated (or bulk) form, as TiO₂. Third instar larvae (72 hr old larvae) were fed with TiO₂ (NRs, NSs, or NWs) and TiO₂ at concentrations ranging from 0.01 to 10 mM. Viability (toxicity), internalization (cellular uptake), intracellular reactive oxygen species (ROS) production, and genotoxicity (Comet assay) were the end-points evaluated in hemocyte D. melanogaster larvae. Significant intracellular oxidative stress and genotoxicity were noted at the highest exposure concentration (10 mM) of TiO₂ (NRs, NSs, or NWs), as determined by the Comet assay and ROS analysis, respectively. A concentration–effect relationship was observed in hemocytes exposed to the NMs. Data demonstrated that selected forms of TiO₂.-induced genotoxicity in D. melanogaster larvae hemocytes indicating this organism is susceptible for use as a model to examine in vivo NMs-mediated effects.     

某350MW级燃煤电厂化学毒物职业危害风险评估

目的 对皖北某350 MW级燃煤电厂的化学毒物进行职业危害风险评估,为350 MW级燃煤电厂职业危害关键控制点的风险管理提供技术依据。方法 调查某350 MW级燃煤电厂的职业卫生现状及主要化学危害因素种类,采用风险矩阵分析法对某350 MW级燃煤电厂的化学毒物职业危害风险进行评估,风险水平根据健康危害等级(HR)和暴露等级(ER)进行计算。结果 皖北某350 MW级燃煤电厂化学毒物中的氨、盐酸、二氧化氮、一氧化碳、硫化氢为中等风险水平,氢氧化钠、二氧化硫、臭氧、硫酸为低风险水平。结论 皖北某350 MW级燃煤电厂化学毒物职业危害风险为可接受水平,今后化学毒物危害风险控制重点应加强安全防护措施,防止氨泄漏、盐酸挥发和二氧化氮、一氧化碳逸散引发急性职业中毒以及脱硫废水处理中的硫化氢中毒。     

质量风险管理在注射剂和滴眼剂质量控制中的应用

目的：查找注射剂和滴眼剂生产的关键控制点，制定预防措施，为注射剂和滴眼剂提供良好的质控保障。方法：调研两家医药企业，采用危害分析和关键控制点法、失败模式影响分析等风险管理工具，查找生产过程的风险点，开展风险评估和风险控制，制定预防措施。结果：对风险系数处于高风险和中等风险水平的风险源采取控制措施后，各风险点的风险等级有所降低。结论：注射剂和滴眼剂原辅包须与制剂的生产环境相匹配，生产监测的全面化与规范化有待提升。     

Material-specific properties applied to an environmental risk assessment of engineered nanomaterials – implications on grouping and read-across concepts

Abstract

Engineered nanomaterials (ENMs) are intentionally designed in different nano-forms of the same parent material in order to meet application requirements. Different grouping and read-across concepts are proposed to streamline risk assessments by pooling nano-forms in one category. Environmental grouping concepts still are in their infancy and mainly focus on grouping by hazard categories. Complete risk assessments require data on environmental release and exposure not only for ENMs but also for their nano-forms. The key requirement is to identify and to distinguish the production volumes of the ENMs regarding nano-form-specific applications. The aim of our work was to evaluate whether such a grouping is possible with the available data and which influence it has on the environmental risk assessment of ENMs. A functionality-driven approach was applied to match the material-specific property (i.e. crystal form/morphology) with the functions employed in the applications. We demonstrate that for nano-TiO₂, carbon nanotubes (CNTs), and nano-Al₂O₃ the total production volume can be allocated to specific nano-forms based on their functionalities. The differentiated assessments result in a variation of the predicted environmental concentrations for anatase vs. rutile nano-TiO₂, single-wall vs. multi-wall CNTs and α- vs. γ-nano-Al₂O₃ by a factor of 2 to 13. Additionally, the nano-form-specific predicted no-effect concentrations for these ENMs were derived. The risk quotients for all nano-forms indicated no immediate risk in freshwaters. Our results suggest that grouping and read-across concepts should include both a nano-form release potential for estimating the environmental exposure and separately consider the nano-forms in environmental risk assessments.     

基于生物可给性和靶器官毒性剂量法的乌梢蛇中铅和砷联合暴露评估

目的 通过考察乌梢蛇Zaocys dhumnades（Cantor）中铅（Pb）和砷（As）的生物可给性,并探索靶器官毒性剂量（TTD）法在评估中药中重金属联合暴露风险中的应用,为限量标准的制定提供参考。方法 通过胃-肠两步模拟消化（in vitro PBET）联合电感耦合等离子体质谱（ICP-MS）法对乌梢蛇中Pb和As的生物可给性进行考察,根据其生物可给性计算其日暴露量。采用危害指数（HI）法对于Pb和As联合暴露产生的健康风险进行初步筛查;进一步针对不同毒理学终点,采用TTD法对Pb和As的累积风险进行更加精确的评估。结果 8批乌梢蛇中Pb和As的合格率为100%。HI法的初步评估结果表明,所有批次乌梢蛇中Pb和As的HI值均＜1。TTD法评估结果表明,作用终点心血管系统、神经系统、肾脏、血液和睾丸,所有批次乌梢蛇的HI值均＜1,健康风险可接受。结论 基于生物可给性,探索乌梢蛇中Pb和As的累积风险评估方法,为中药外源性有害残留物风险评估的方法开发提供新的思路,为制定更加科学的限量标准提供技术支撑。     

Probabilistic risk assessment of emerging materials: case study of titanium dioxide nanoparticles

The development and use of emerging technologies such as nanomaterials can provide both benefits and risks to society. Emerging materials may promise to bring many technological advantages but may not be well characterized in terms of their production volumes, magnitude of emissions, behaviour in the environment and effects on living organisms. This uncertainty can present challenges to scientists developing these materials and persons responsible for defining and measuring their adverse impacts. Human health risk assessment is a method of identifying the intrinsic hazard of and quantifying the dose–response relationship and exposure to a chemical, to finally determine the estimation of risk. Commonly applied deterministic approaches may not sufficiently estimate and communicate the likelihood of risks from emerging technologies whose uncertainty is large. Probabilistic approaches allow for parameters in the risk assessment process to be defined by distributions instead of single deterministic values whose uncertainty could undermine the value of the assessment. A probabilistic approach was applied to the dose–response and exposure assessment of a case study involving the production of nanoparticles of titanium dioxide in seven different exposure scenarios. Only one exposure scenario showed a statistically significant level of risk. In the latter case, this involved dumping high volumes of nano-TiO₂ powders into an open vessel with no personal protection equipment. The probabilistic approach not only provided the likelihood of but also the major contributing factors to the estimated risk (e.g. emission potential).     

A systematic review of occupational exposure to synthetic vitreous fibers and mesothelioma

Objective We investigated whether available epidemiological and toxicological data suggest an increased risk of mesothelioma among workers exposed to synthetic vitreous fibers (SVF). Methods We conducted a systematic review of epidemiological studies on the risk of mesothelioma among workers exposed to SVF, and toxicological studies on SVF and mesothelioma. Results Seven cohort studies were conducted among workers employed in production of rock/slag wool, glass wool, or continuous glass filament in the United States, Canada, and Europe. Of the six deaths from mesothelioma identified in these studies, three had exposure to asbestos. A review of death certificates in a study of rock wool production workers identified one additional probable death. A formal comparison with expected deaths is not feasible. Four community-based case–control studies were identified, of which three reported an increased risk among SVF-exposed workers. The number of cases not exposed to asbestos was less, and residual confounding from asbestos exposure misclassification may explain the association in these studies. The toxicology review of SVF suggested that they present a low hazard mostly due to their low biopersistence, typically with a half-life in rat studies of tens of days compared to amphibole asbestos which has a half-life of 400–500 days. Conclusions The combined evidence from epidemiology and toxicology provide little evidence that exposure to SVF increases the risk of mesothelioma.     

Preexposure to Amorphous Silica Particles Attenuates but also Enhances Allergic Reactions in Trimellitic Anhydride-Sensitized Brown Norway Rats

Irritant-induced inflammation of the airways may aggravate respiratory allergy induced by chemical respiratory allergens. Therefore, the effect of airway irritation by synthetic amorphous silica (SAS) on respiratory allergy to trimellitic anhydride (TMA) was studied. Brown Norway (BN) rats were topically sensitized on day 0 and on day 7, subsequently exposed for 6 h/day for 6 days to 27 mg/m³ SAS, and challenged by inhalation to a minimally irritating concentration of 12 mg/m³ TMA, 24 h after the last SAS exposure. An additional group was exposed to SAS before a second challenge to TMA. Control groups were treated with vehicle, and/or did not receive SAS exposure. Breathing parameters, cellular and biochemical changes in bronchoalveolar lavage (BAL) fluid, and histopathological airway changes 24 h after challenge were the main parameters studied. Exposure to SAS alone resulted in transient changes in breathing parameters during exposure, and in nasal and alveolar inflammation with neutrophils and macrophages. Exposure to SAS before a single TMA challenge resulted in a slightly irregular breathing pattern during TMA challenge. SAS also diminished the effect of TMA on tidal volume, laryngeal ulceration, laryngeal inflammation, and the number of BAL (lung) eosinophils in most animals, but aggravated laryngeal squamous metaplasia and inflammation in a single animal. The pulmonary eosinophilic infiltrate and edema induced by a second TMA challenge was diminished by the preceding SAS exposure, but the number of lymphocytes in BAL was increased. Thus, a respiratory particulate irritant like SAS can reduce as well as aggravate certain aspects of TMA-induced respiratory allergy.     

Organ burden and pulmonary toxicity of nano-sized copper (II) oxide particles after short-term inhalation exposure

Introduction: Increased use of nanomaterials has raised concerns about the potential for undesirable human health and environmental effects. Releases into the air may occur and, therefore, the inhalation route is of specific interest. Here we tested copper oxide nanoparticles (CuO NPs) after repeated inhalation as hazard data for this material and exposure route is currently lacking for risk assessment.

Methods: Rats were exposed nose-only to a single exposure concentration and by varying the exposure time, different dose levels were obtained (C?×?T protocol). The dose is expressed as 6?h-concentration equivalents of 0, 0.6, 2.4, 3.3, 6.3, and 13.2?mg/m³ CuO NPs, with a primary particle size of 10 9.2–14?nm and an MMAD of 1.5?μm.

Results: Twenty-four hours after a 5-d exposure, dose-dependent lung inflammation and cytotoxicity were observed. Histopathological examinations indicated alveolitis, bronchiolitis, vacuolation of the respiratory epithelium, and emphysema in the lung starting at 2.4?mg/m³. After a recovery period of 22 d, limited inflammation was still observed, but only at the highest dose of 13.2?mg/m³. The olfactory epithelium in the nose degenerated 24?h after exposure to 6.3 and 13.2?mg/m³, but this was restored after 22 d. No histopathological changes were detected in the brain, olfactory bulb, spleen, kidney and liver.

Conclusion: A 5-d, 6-h/day exposure equivalent to an aerosol of agglomerated CuO NPs resulted in a dose-dependent toxicity in rats, which almost completely resolved during a 3-week post-exposure period.     

Carcinogenicity of the insulation wools: reassessment of the IARC evaluation

In assessing the health evidence concerning man-made mineral fibers, the chemical composition, surface activity, durability, and size of fibers have to be taken into account. Special-purpose fine glass fibers need to be separated from the insulation wools (glass, rock, and slag wool). The epidemiological evidence is sufficient to conclude that there has been no mesothelioma risk to workers producing or using glass wool, rock wool, or slag wool. The epidemiological studies have been large and powerful, and they show no evidence of a cause-effect relationship between lung cancer and exposure to glass wool, rock wool, or slag wool fibers. There is some evidence of a small cancer hazard attached to the manufacturing process in slag wool plants 20 to 50 years ago, when asbestos was used in some products and other carcinogenic substances were present. However, this hazard is not associated with any index of exposure to slag wool itself. Animal inhalation studies of ordinary insulation wools also show that there is no evidence of hazard associated with exposure to these relatively coarse, soluble fibers. The evidence of carcinogenicity is limited to experiments with special-purpose fine durable glass fibers or experimental fibers, and only when these fibers are injected directly into the pleural or peritoneal cavity. Multiple chronic inhalation studies of these same special-purpose fine glass fibers have not produced evidence of carcinogenicity. It is suggested that the present IARC evaluation of the carcinogenic risk of insulation wools should be revised to Category 3: not classifiable as to carcinogenicity to humans.     

Piperacillin/tazobactam and risk of acute kidney injury in adults hospitalized with infection without vancomycin: a multi-centre real-world data analysis

BackgroundThere is uncertainty about whether piperacillin/tazobactam (PT) increases the risk of acute kidney injury (AKI) in patients without concomitant use of vancomycin. This study compared the risk of hospital-acquired AKI (HA-AKI) among adults treated with PT or antipseudomonal β-lactams (meropenem, ceftazidime) without concomitant use of vancomycin.MethodsThis real-world study analysed the data from China Renal Data System and assessed the risk of HA-AKI in adults hospitalized with infection after exposure to PT, meropenem or ceftazidime in the absence of concomitant vancomycin. The primary outcome was any stage of HA-AKI according to the Kidney Disease Improving Global Outcomes guidelines. A multi-variable Cox regression model and different propensity score (PS) matching models were used.ResultsAmong the 29,441 adults [mean (standard deviation) age 62.44 (16.84) years; 17,980 females (61.1%)] included in this study, 14,721 (50%) used PT, 9081 (31%) used meropenem and 5639 (19%) used ceftazidime. During a median follow-up period of 8 days, 2601 (8.8%) develped HA-AKI. The use of PT was not associated with significantly higher risk of HA-AKI compared with meropenem [adjusted hazard ratio (aHR) 1.07, 95% confidence interval (CI) 0.97–1.19], ceftazidime (aHR 1.09, 95% CI 0.92–1.30) or both agents (aHR 1.07, 95% CI 0.97–1.17) after adjusting for confounders. Results were consistent in stratified analyses, PS matching using logistic regression or random forest methods to generate a PS, and in an analysis restricting outcomes to AKI stage 2–3.ConclusionsWithout concomitant use of vancomycin, the risk of AKI following PT therapy is comparable with that of meropenem or ceftazidime among adults hospitalized with infection.     

前列地尔脂微球注射液临床超说明书用药干预分析

目的 调查第二军医大学附属长海医院前列地尔脂微球注射液的应用情况,分析其临床应用合理性,评价医院行政干预在促进临床合理用药中的作用。方法 以2016年7月28日医院行政干预为界限,对2016年7月和8月共计1 351例使用本品的患者,统计其所在科室、临床诊断、前列地尔的用法用量。结果 本品在医院各科室广泛应用,65.41%的病例出现了超适应证用药的情况,99.85%的病例存在超说明书用法用量的情况,0.39%的病例出现了禁忌证用药的情况,医院行政干预前后结果近乎一致。结论 超说明书应用本品的情况在临床广泛存在,应当引起临床重视,仅实施行政干预的效果较差。     

Pulmonary and cardiovascular responses of rats to inhalation of a commercial antimicrobial spray containing titanium dioxide nanoparticles

Our laboratory has previously demonstrated that application of an antimicrobial spray product containing titanium dioxide (TiO₂) generates an aerosol of titanium dioxide in the breathing zone of the applicator. The present report describes the design of an automated spray system and the characterization of the aerosol delivered to a whole body inhalation chamber. This system produced stable airborne levels of TiO₂ particles with a median count size diameter of 110 nm. Rats were exposed to 314 mg/m³ min (low dose), 826 mg/m³ min (medium dose), and 3638 mg/m³ min (high dose) of TiO₂ under the following conditions: 2.62 mg/m³ for 2 h, 1.72 mg/m³ 4 h/day for 2 days, and 3.79 mg/m³ 4 h/day for 4 days, respectively. Pulmonary (breathing rate, specific airway resistance, inflammation, and lung damage) and cardiovascular (the responsiveness of the tail artery to constrictor or dilatory agents) endpoints were monitored 24 h post-exposure. No significant pulmonary or cardiovascular changes were noted at low and middle dose levels. However, the high dose caused significant increases in breathing rate, pulmonary inflammation, and lung cell injury. Results suggest that occasional consumer use of this antimicrobial spray product should not be a hazard. However, extended exposure of workers routinely applying this product to surfaces should be avoided. During application, care should be taken to minimize exposure by working under well ventilated conditions and by employing respiratory protection as needed. It would be prudent to avoid exposure to children or those with pre-existing respiratory disease.     

Current Advances,Research Needs and Gaps in Mycotoxins Biomonitoring under the HBM4EU—Lessons Learned and Future Trends

Mycotoxins are natural metabolites produced by fungi that contaminate food and feed worldwide. They can pose a threat to human and animal health, mainly causing chronic effects, e.g., immunotoxic and carcinogenic. Due to climate change, an increase in European population exposure to mycotoxins is expected to occur, raising public health concerns. This urges us to assess the current human exposure to mycotoxins in Europe to allow monitoring exposure and prevent future health impacts. The mycotoxins deoxynivalenol (DON) and fumonisin B₁ (FB₁) were considered as priority substances to be studied within the European Human Biomonitoring Initiative (HBM4EU) to generate knowledge on internal exposure and their potential health impacts. Several policy questions were addressed concerning hazard characterization, exposure and risk assessment. The present article presents the current advances attained under the HBM4EU, research needs and gaps. Overall, the knowledge on the European population risk from exposure to DON was improved by using new harmonised data and a newly derived reference value. In addition, mechanistic information on FB₁ was, for the first time, organized into an adverse outcome pathway for a congenital anomaly. It is expected that this knowledge will support policy making and contribute to driving new Human Biomonitoring (HBM) studies on mycotoxin exposure in Europe.     

Magnesium oxide use and reduced risk of dementia: a retrospective,nationwide cohort study in Taiwan

Objective: Dietary magnesium may be associated with a lower risk of dementia; however, the impact of magnesium oxide (MgO), a common laxative, on dementia has yet to be elucidated. This study aimed to investigate the association between the usage of MgO and the risk of developing dementia.

Methods: We used a dataset from the National Health Research Institute Database (NHRID) of Taiwan containing one million randomly sampled subjects to identify patients aged ≥50 years with no history of MgO usage. A total of 1547 patients who had used MgO were enrolled, along with 4641 controls who had not used the MgO propensity score matched by age, gender and comorbidity, at a ratio of 1:3. After adjusting for confounding risk factors, a Cox proportional hazards model was used to compare the risk of developing dementia during a 10 year follow-up period.

Results: Of the enrolled patients, 44 (2.84%) developed dementia, when compared to 199 (4.28%) in the control group. The Cox proportional hazards regression analysis revealed that the patients who had used MgO were less likely to develop dementia with a crude hazard ratio of 0.617 (95% CI, 0.445–0.856, p?=?.004). After adjusting for age, gender, comorbidity, geographical area and urbanization level of residence, and monthly income, the adjusted hazard ratio was 0.517 (95% CI, 0.412–0.793, p?=?.001).

Conclusions: The patients who used MgO had a decreased risk of developing dementia. Further studies on the effects of MgO in reducing the risk of dementia are therefore warranted.     

全国10种中药材品种中亚硫酸盐残留量的初步风险评估

目的：统计全国市场上10种常用中药材及饮片品种的亚硫酸盐残留量，初步评估摄入的健康风险，对目前《中国药典》限量值提出建议标准。方法：在全国范围内，统计2013-2017年10种药材及饮片的二氧化硫残留量值，结合《中国药典》2015年版对服用剂量的规定，采用点评估的方法初步评估二氧化硫的暴露风险。结果：按各品种二氧化硫残留量平均值、中位值以及限量值计算，人群服用这10种药材及饮片二氧化硫暴露值低于国际食品法典食品添加剂专家委员会（JFCFA）规定的二氧化硫每日允许摄入量上限（0.7 mg·kg^-1体重），风险系数HI小于1，风险可接受；但部分品种二氧化硫残留量最大值计算的HI大于1，具有一定的风险。结论：从整体水平看，人群单一摄入10种中药材及饮片暴露二氧化硫的健康风险较低；但对于二氧化硫残留量超标的样品，会有一定的健康风险。《中国药典》2015年版规定的二氧化硫残留限量标准基本合理，可以达到控制风险的目的。但本次评估仅局限于单一药材的摄入暴露，未计算累积暴露风险，因此，建议在产业技术不断进步的基础上，逐渐严格限量标准值，以降低安全风险。