Significant Dose-effect Relationships Research Articles

Hand-Arm-Vibrationsdosis und arbeitstechnische Voraussetzungen für die Berufskrankheit Nr. 2103 – Eine epidemiologische Fall-Kontroll-Studie

Hand-arm vibration dose and work-related requirements for occupational disease no. 2103 – An epidemiological case-control study Background: An epidemiological case-control study of dose-effect relationships between hand-arm vibration exposure and musculoskeletal disorders of occupational disease no. 2103 (BK 2103) was carried out in order to provide evidence-based recommendations for the recognition of BK 2103. Methods: Male cases and controls were recruited and standardised personal interviews were conducted between 1 January 2010 and 30 November 2021. In addition to leisure activities and comorbidities, work histories regarding the use of hand-operated and hand-held technical tools that can induce hand-arm vibrations were recorded in detail. To quantify the individual vibration exposure, a database of industrial hygiene measurements of vibration values of over 700 technical power tools was established (vibration register). The vibration measurements recorded in the database allows quantification of the daily dose and lifetime dose of the vibration exposure. The dose-effect relationships between hand-arm vibration exposure and musculoskeletal disorders as defined by BK 2103 were quantified for the various dose models using conditional logistic regression analyses. Results: In total, 209 cases and 614 controls were recruited. Compared to controls, cases suffered more frequently from gout, arm fractures, hip osteoarthritis, knee osteoarthritis, spinal osteoarthritis and trauma injuries or inflammatory conditions of the finger, elbow and shoulder joints. After adjusting for relevant confounders, the study analyses demonstrate consistent and statistically significant dose-effect relationships between hand-arm vibration exposure and musculoskeletal disorders as defined by BK 2103. A vibration dose of Dhv = 142.331 m2/s4 x day or Dhw = 38.724 m2/s4 x day is associated with a doubling of the risk of musculoskeletal disorders of the upper extremities as defined by BK 2103. Conclusions: These dose values serve as a guide and could also be applied in an assessment of the work-related requirements for the recognition of BK 2103. Sensitivity analyses indicate that an exposure duration with a defined threshold daily dose is not suitable for guiding the recognition of BK 2103. Keywords: hand-arm vibration – musculoskeletal disorders – dose-effect relationship – epidemiology – risk-doubling dose

Dose-effect relationship of linear accelerator based stereotactic radiotherapy for brain metastases

ObjectiveThe purpose of this study is to reveal the dose-effect relationship of linear accelerator (LINAC)-based stereotactic radiotherapy (SRT) in patients with brain metastases (BM).Materials and methodsThe PubMed, Cochrane, and Web of Science databases were used to identify studies that reported local tumour control after LINAC-based SRT in patients with BMs. Studies of other approaches that could affect local tumour control, such as whole brain radiotherapy, targeted therapy, and immunotherapy, were excluded from the dose-effect relationship analysis. Data extracted included patient and treatment characteristics and tumour local control. Probit model in XLSTAT 2016 was used for regression analysis, and P < 0.05 was set as the statistically significant level.ResultsAfter literature screening, 19 eligible studies involving 1523 patients were included in the probit model regression analysis. There was no significant dose-effect relationship between nominal BED10 and peripheral BED10 versus 12-month local control probability. There were significant dose effect relationships between the centre BED10 and the average BED10 versus the 12-month local control probability, with P values of 0.015 and 0.011, respectively. According to the model, the central BED10 and the average BED10 corresponding to probabilities of 90% 12-month local control were 109.2 GyBED10 (95% confidence interval (CI): 88.7–245.9 GyBED10) and 87.8 GyBED10 (95% CI: 74.3–161.5 GyBED10), respectively. A 12-month local control rate of 86.9% (95% CI: 81.7–89.7%) and 85.5% (95% CI: 81.2–89.2%) can be expected at a centre BED10 of 80 Gy and an average BED10 of 60 Gy, respectively.ConclusionFor patients with BM treated with LINAC-based SRT, more attention should be given to the central and average doses of PTV. A clear definition of the dose prescription should be established to ensure the effectiveness and comparability of treatment.

Dose–effect relationship of stereotactic body radiotherapy in non-small cell lung cancer patients

ObjectiveTo establish the dose effect relationship between the dose parameters of stereotactic body radiation therapy (SBRT) for early non-small cell lung cancer (NSCLC) and the local tumor control rate.Materials and methodsA comprehensive literature search was conducted using PubMed, the Web of Science and the Cochrane databases to determine the articles treated with SBRT in early-stage NSCLC. Original studies with complete prescription dose information, tumor local control rate and other important parameters were screened and reported. Probit model in XLSTAT 2016 was used for regression analysis, and P < 0.05 was set as a statistically significant level.ResultsAfter literature screening, 22 eligible studies were included in probit model regression analysis, involving 1861 patients. There is no significant dose effect relationship between nominal BED10 and peripheral BED10 versus 3 years local control probability. There were significant dose effect relationships between the center BED10 and the average BED10 versus the 3 years local control probability, with P values are 0.001 and < 0.0001, respectively. According to the results of this model, the 3 years local control rate of 90.5% (87.5–92.1%) and 89.5% (86.7–91.0%) can be expected at the center BED10 of 180 Gy or the average BED10 of 140 Gy, prospectively.ConclusionsFor NSCLC treated with SBRT, more attention should be paid to the central dose and average dose of PTV. A set of clear definition in the dose prescription should be established to ensure the effectiveness and comparability of treatment.

Evaluation of single and joint toxicity of perfluorooctanoic acid and arsenite to earthworm (Eisenia fetida): A multi-biomarker approach

Perfluorooctanoic acid (PFOA) and arsenic are ubiquitous environmental contaminants and could co-exist in soil. However, data on their possible combined toxic effects on terrestrial organisms are still lacking. In this study, we exposed earthworm Eisenia fetida to artificial soil spiked with different sub-lethal levels of PFOA, arsenite (As(III)) or their mixture for 28 days. The bioaccumulation and multi-biomarker responses in the earthworms were measured. Results showed that the co-existence of PFOA and As(III) in soil enhanced the bioaccumulation of arsenic while reduced the bioaccumulation of PFOA. Most selected biomarkers exhibited significant responses at higher exposure levels and indicated oxidative damages. Biomarker Response Index (BRI) was used to integrate the multi-biomarker responses and the results showed significant dose-effect relationships between biological health status and exposure levels. Moreover, variation analysis of multi-biomarkers and BRI proved that As(III) exhibited more toxicity than PFOA to the earthworms. Based on BRI results, Effect Addition Index (EAI) was calculated to evaluate the joint effects of the two toxicants. According to EAI, the joint toxicity of PFOA and As(III) was related to exposure concentration, changing from synergism to slight antagonism with the increase of exposure level. These results provide valuable toxicological information for the risk assessment of co-exposure to PFOA and arsenic in the soil environment. Moreover, this study proved that BRI is an effective tool to integrate multi-biomarker responses, and its combination with EAI provides a useful combined approach to evaluate the joint effects of mixed contamination systems.

Dose-Effects Models for Space Radiobiology: An Overview on Dose-Effect Relationships.

Space radiobiology is an interdisciplinary science that examines the biological effects of ionizing radiation on humans involved in aerospace missions. The dose-effect models are one of the relevant topics of space radiobiology. Their knowledge is crucial for optimizing radioprotection strategies (e.g., spaceship and lunar space station-shielding and lunar/Mars village design), the risk assessment of the health hazard related to human space exploration, and reducing damages induced to astronauts from galactic cosmic radiation. Dose-effect relationships describe the observed damages to normal tissues or cancer induction during and after space flights. They are developed for the various dose ranges and radiation qualities characterizing the actual and the forecast space missions [International Space Station (ISS) and solar system exploration]. Based on a Pubmed search including 53 papers reporting the collected dose-effect relationships after space missions or in ground simulations, 7 significant dose-effect relationships (e.g., eye flashes, cataract, central nervous systems, cardiovascular disease, cancer, chromosomal aberrations, and biomarkers) have been identified. For each considered effect, the absorbed dose thresholds and the uncertainties/limitations of the developed relationships are summarized and discussed. The current knowledge on this topic can benefit from further in vitro and in vivo radiobiological studies, an accurate characterization of the quality of space radiation, and the numerous experimental dose-effects data derived from the experience in the clinical use of ionizing radiation for diagnostic or treatments with doses similar to those foreseen for the future space missions. The growing number of pooled studies could improve the prediction ability of dose-effect relationships for space exposure and reduce their uncertainty level. Novel research in the field is of paramount importance to reduce damages to astronauts from cosmic radiation before Beyond Low Earth Orbit exploration in the next future. The study aims at providing an overview of the published dose-effect relationships and illustrates novel perspectives to inspire future research.

Mental Health Risks after Repeated Exposure to Multiple Stressful Events during Ongoing Social Unrest and Pandemic in Hong Kong: The Role of Rumination: Risques pour la santé mentale après une exposition répétée à de multiples événements stressants d'agitation sociale durable et de pandémie à Hong Kong: le rôle de la rumination.

The co-occurrence of different classes of population-level stressors, such as social unrest and public health crises, is common in contemporary societies. Yet, few studies explored their combined mental health impact. The aim of this study was to examine the impact of repeated exposure to social unrest-related traumatic events (TEs), coronavirus disease 2019 (COVID-19) pandemic-related events (PEs), and stressful life events (SLEs) on post-traumatic stress disorder (PTSD) and depressive symptoms, and the potential mediating role of event-based rumination (rumination of TEs-related anger, injustice, guilt, and insecurity) between TEs and PTSD symptoms. Community members in Hong Kong who had utilized a screening tool for PTSD and depressive symptoms were invited to complete a survey on exposure to stressful events and event-based rumination. A total of 10,110 individuals completed the survey. Hierarchical regression analysis showed that rumination, TEs, and SLEs were among the significant predictors for PTSD symptoms (all P < 0.001), accounting for 32% of the variance. For depression, rumination, SLEs, and PEs were among the significant predictors (all P < 0.001), explaining 24.9% of the variance. Two-way analysis of variance of different recent and prior TEs showed significant dose-effect relationships. The effect of recent TEs on PTSD symptoms was potentiated by prior TEs (P = 0.005). COVID-19 PEs and prior TEs additively contributed to PTSD symptoms, with no significant interaction (P = 0.94). Meanwhile, recent TEs were also potentiated by SLEs (P = 0.002). The effects of TEs on PTSD symptoms were mediated by rumination (β = 0.38, standard error = 0.01, 95% confidence interval: 0.36 to 0.41), with 40.4% of the total effect explained. All 4 rumination subtypes were significant mediators. Prior and ongoing TEs, PEs, and SLEs cumulatively exacerbated PTSD and depressive symptoms. The role of event-based rumination and their interventions should be prioritized for future research.

Inhibitory effect of sugarcane (Saccharum officinarum L.) molasses extract on the formation of heterocyclic amines in deep-fried chicken wings

Sugarcane (Saccharum officinarum L.) molasses, rich in phenolic compounds, is an undervalued coproduct during sugar production. However, limited attention was paid to the inhibitory effect of sugarcane molasses extract (SME) on hazardous compound formation during meat processing. In this study, SME with high antioxidant activity was extracted and purified by many steps. Chicken wings were deep-fried for 2.5 min and 5 min after being painted maltose-water solution (1:1, v:v) with different SME concentration (0.2, 0.5, 1.0, 1.5 and 2.0 mg/L). The heterocyclic amines (HCAs) levels in deep-fried chicken wings were measured. Total HCAs levels in deep-fried 2.5 min samples were 4.51–8.04 ng/g, with the inhibition rates ranged 32.5–43.9% comparing with control. Likewise, total HCAs contents in samples after 5 min deep-frying were 26.2–37.4 ng/g, and the inhibition rates were 18.5–29.9%. In addition, the inhibitory effect of SME on HCAs formation followed significant dose-effect relationships, by correlation analysis between SME antioxidant activities and HCAs contents. But the weak correlations between SME antioxidant activities and relative total free radical contents demonstrated that the inhibition mechanism of SME was more complex than scavenge free radicals. It may be attributed to SME inhibit the HCAs synthesis via both free radical pathway and Maillard reaction pathway.

Ecological risk of combined pollution on soil ecosystem functions: Insight from the functional sensitivity and stability

Assessing the ecological risk of combined pollution, especially from a holistic perspective with the consideration of the overarching functions of soil ecosystem, is crucial and beneficial to the improvement of ecological risk assessment (ERA) framework. In this study, four soils with similar physicochemical properties but contrasting heavy metals contamination levels were selected to explore changes in the integrated functional sensitivity (MSI), resistance (MRS) and resilience (MRL) of soil microbial communities subjected to herbicide siduron, based on which the ecological risk of the accumulation of siduron in the four studied soils were evaluated. The results suggested that the microbial biomass carbon, activity of denitrification enzyme and nitrogenase were indicative of MSI and MRS, and the same three parameters plus soil basal respiration were indicative of MRL. Significant dose-effect relationships between siduron residues in soils and MSI, MRS and MRL under combined pollution were observed. Heavy metal polluted soils showed higher sensitivity and lower resistance to the additional disturbance of herbicide siduron due to the lower microbial biomass, while the resilience of heavy metal polluted soils was much higher due to the pre-adaption to the chemical stresses. The quantifiable indicator microbial functional stability was incorporated in the framework of ERA and the results showed that the accumulation of siduron in the studied soils could exhibit potential harm to the integrated functional stability of soil microbial community. Thus, this work provides insights into the application of integrated function of soil microbial community into the framework of ERA.

不同藻密度下布洛芬浓度对萼花臂尾轮虫生命表统计学参数的影响

PDF HTML阅读 XML下载 导出引用 引用提醒 不同藻密度下布洛芬浓度对萼花臂尾轮虫生命表统计学参数的影响 DOI: 10.5846/stxb201707261350 作者: 作者单位: 安徽师范大学生命科学学院,安徽师范大学生命科学学院,安徽师范大学生命科学学院,安徽师范大学生命科学学院,安徽师范大学生命科学学院 作者简介: 通讯作者: 中图分类号: 基金项目: 国家自然科学基金（31470015）；安徽省高校生物环境与生态安全省级重点实验室专项基金（2004sys003） Effects of varying ibuprofen concentrations on life table demography of Brachionus calyciflorus under different Scenedesmus obliquus densities Author: Affiliation: Center of Cooperative Innovation for Recovery and Reconstruction of Degraded Ecosystem in Wanjiang City Belt,Provincial Key Laboratory of Conservation and Utilization of important Biotic Resources in Anhui Province,Biotic Environment and Ecological Safety,College of Life Sciences,Anhui Normal University,Center of Cooperative Innovation for Recovery and Reconstruction of Degraded Ecosystem in Wanjiang City Belt,Provincial Key Laboratory of Conservation and Utilization of important Biotic Resources in Anhui Province,Biotic Environment and Ecological Safety,College of Life Sciences,Anhui Normal University,Center of Cooperative Innovation for Recovery and Reconstruction of Degraded Ecosystem in Wanjiang City Belt,Provincial Key Laboratory of Conservation and Utilization of important Biotic Resources in Anhui Province,Biotic Environment and Ecological Safety,College of Life Sciences,Anhui Normal University,Center of Cooperative Innovation for Recovery and Reconstruction of Degraded Ecosystem in Wanjiang City Belt,Provincial Key Laboratory of Conservation and Utilization of important Biotic Resources in Anhui Province,Biotic Environment and Ecological Safety,College of Life Sciences,Anhui Normal University,Center of Cooperative Innovation for Recovery and Reconstruction of Degraded Ecosystem in Wanjiang City Belt,Provincial Key Laboratory of Conservation and Utilization of important Biotic Resources in Anhui Province,Biotic Environment and Ecological Safety,College of Life Sciences,Anhui Normal University Fund Project: 摘要 | 图/表 | 访问统计 | 参考文献 | 相似文献 | 引证文献 | 资源附件 | 文章评论 摘要:在不同斜生栅藻（Scenedesmus obliquus）密度（1.0×106、2.0×106个细胞/mL和4.0×106个细胞/mL）下，研究了不同浓度的（0、1、10、100、1000 μg/L和5000 μg/L）布洛芬对萼花臂尾轮虫（Brachionus calyciflorus）生命表统计学参数的影响。结果表明，与各藻密度下的对照组相比，当藻密度为1.0×106个细胞/mL时，100-5000 μg/L布洛芬处理组中轮虫的生命期望和平均寿命显著缩短，100 μg/L布洛芬处理组中轮虫的世代时间显著缩短，1.0 μg/L布洛芬处理组中轮虫的净生殖率显著提高，10-5000 μg/L布洛芬处理组中轮虫的后代混交率显著提高。当藻密度为2.0×106个细胞/mL时，10-5000 μg/L布洛芬处理组中轮虫的生命期望和平均寿命显著缩短，1000 μg/L和5000 μg/L布洛芬处理组中轮虫的世代时间显著缩短，1、10、1000 μg/L和5000 μg/L布洛芬处理组中轮虫的种群内禀增长率显著提高，1 μg/L和1000 μg/L布洛芬处理组中轮虫的后代混交率显著提高。当藻密度为4.0×106个细胞/mL时，10-5000 μg/L布洛芬处理组中轮虫的生命期望、平均寿命和世代时间显著缩短。藻密度对轮虫的世代时间、净生殖率和种群内禀增长率有显著性影响（P < 0.05），布洛芬浓度对轮虫的生命期望、平均寿命、世代时间、净生殖率和种群内禀增长率有显著性影响（P < 0.05），藻密度和布洛芬浓度的交互作用对轮虫的生命期望、平均寿命和后代混交率有显著性影响（P < 0.05）。在实验设置的布洛芬浓度范围内，2.0×106个细胞/mL藻密度下，轮虫的生命期望、平均寿命和世代时间与布洛芬浓度之间均具有显著的剂量-效应关系（P < 0.05）；4.0×106个细胞/mL藻密度下，轮虫的生命期望、平均寿命和净生殖率与布洛芬浓度之间均具有显著的剂量-效应关系（P < 0.05）。 Abstract:The levels of emerging chemicals have increased dramatically during the last two decades, posing problems for human and environmental health. The lack of a rigorous control of pharmaceutical discharges into natural water bodies is a concern for limnologists and ecotoxicologists because of the possible harmful effects of these chemicals on non-target organisms. The present study was performed to assess the chronic toxicity of a pollutant to an aquatic organism under different food densities and to screen out sensitive endpoints for monitoring ibuprofen pollution with rotifers as test animals. In particular, we studied the effects of varying ibuprofen concentrations (0, 1, 10, 100, 1000, and 5000 μg/L) on the life table demographic parameters, including life expectancy at hatching, average lifespan, generation time, net reproductive rate, intrinsic rate of population increase, and proportion of the sexual offspring of Brachionus calyciflorus fed on different densities (1.0×106, 2.0×106, and 4.0×106 cells/mL) of Scenedesmus obliquus. The results showed that compared to the controls, 100-5000 μg/L of ibuprofen significantly decreased the life expectancy at hatching and average lifespan, 100 μg/L of ibuprofen decreased the generation time, but 1.0 μg/L of ibuprofen increased the net reproductive rate, and 10-5000 μg/L of ibuprofen increased the proportion of sexual offspring of B. calyciflorus under the algal density of 1.0×106 cells/mL. When S. obliquus density was 2.0×106 cells/mL, 10-5000 μg/L of ibuprofen decreased the life expectancy at hatching and average lifespan, 1000 and 5000 μg/L of ibuprofen decreased the generation time, but 1, 10, 1000, and 5000 μg/L of ibuprofen increased the intrinsic rate of population increase, and 1 and 1000 μg/L of ibuprofen increased the proportion of sexual offspring. When S. obliquus density was 4.0×106 cells/mL, 100-5000 μg/L of ibuprofen decreased the life expectancy at hatching, average lifespan, and generation time. The S. obliquus density had significant effects on the generation time, net reproductive rate, and intrinsic rate of population increase (P < 0.05). The ibuprofen concentration had significant effects on the life expectancy at hatching, average lifespan, generation time, net reproductive rate, and intrinsic rate of population increase (P < 0.05). The interaction between S. obliquus density and ibuprofen concentration had significant effects on the life expectancy at hatching, average lifespan, and proportion of sexual offspring (P < 0.05). When the S. obliquus density of 2.0×106 cells/mL was used in association with the range of tested ibuprofen concentrations, significant dose-effect relationships were observed between the ibuprofen concentrations and life expectancy at hatching, average lifespan, and generation time, and these relationships could be described as y=2.419×10-6x2-0.015x + 79.818, y=2.419×10-6x2-0.015x + 67.818, and y=1.229×10-6x2-0.007x + 57.941, respectively. When the S. obliquus density was 4.0×106 cells/mL, significant dose-effect relationships were observed between the ibuprofen concentrations and life expectancy at hatching, average lifespan, and net reproductive rate, and these relationships could be described as y=2.483×10-7x2-0.005x + 77.624, y=2.483×10-7x2-0.005x + 65.624, and y=- 5.434×10-7x2 + 0.002x + 14.530, respectively. 参考文献 相似文献 引证文献

Longitudinal analysis of impulse control disorders in Parkinson disease.

To investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD). We used data from a multicenter longitudinal cohort of consecutive patients with PD with ≤5 years' disease duration at baseline followed up annually up to 5 years. ICDs were evaluated during face-to-face semistructured interviews with movement disorder specialists. Generalized estimating equations and Poisson models with robust variance were used to study the association between several time-dependent definitions of dopamine agonist (DA) use, taking dose and duration of treatment into account, and ICDs at each visit. Other antiparkinsonian drugs were also examined. Among 411 patients (40.6% women, mean age 62.3 years, average follow-up 3.3 years, SD 1.7 years), 356 (86.6%) took a DA at least once since disease onset. In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 46.1% (95% confidence interval [CI] 37.4-55.7, DA ever users 51.5% [95% CI 41.8-62.1], DA never users 12.4% [95% CI 4.8-30.0]). ICD prevalence increased from 19.7% at baseline to 32.8% after 5 years. ICDs were associated with ever DA use (prevalence ratio 4.23, 95% CI 1.78-10.09). Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships. Similar analyses for levodopa were not in favor of a strong association. ICDs progressively resolved after DA discontinuation. In this longitudinal study of patients with PD characterized by a high prevalence of DA treatment, the 5-year cumulative incidence of ICDs was ≈46%. ICDs were strongly associated with DA use with a dose-effect relationship; both increasing duration and dose were associated with ICDs. ICDs progressively resolved after DA discontinuation. NCT01564992.

Interstitial lung disorders in the indium workers of Korea: An update study for the relationship with biological exposure indices

Korea is one of the highest indium-consuming countries worldwide. The present study aims to determine the relationship between interstitial lung disorders and indium exposure in Korea. In 50 indium workers from seven plants, the effect of serum indium on the lungs was determined using laboratory tests, spirometry, and high-resolution computed tomography (HRCT). Higher serum indium and Krebs von den Lungen-6 (KL-6) levels were associated with HRCT-detected interstitial lung changes. Workers with high serum indium levels (≥3 µg/L) had longer exposure durations and a higher prevalence of HRCT-detected interstitial lung changes. KL-6 and surfactant protein-D (SP-D) levels were significantly higher in the highest serum indium quartile than the lowest quartile. Significant dose-effect relationships existed between serum indium levels and KL-6, SP-D levels and the prevalence of HRCT-detected interstitial lung changes. Workforce medical surveillance should be established to prevent indium-induced interstitial lung disease in Korea.

Multiple cytotoxic and genotoxic effects induced in vitro by differently shaped copper oxide nanomaterials

In nanotoxicology, the capacity of nanoparticles of the same composition but different shape to induce cytotoxicity and genotoxicity is largely unknown. A series of cytotoxic and genotoxic responses following in vitro exposure to differently shaped CuO nanoparticles (CuO NPs, mass concentrations from 0.1 to 100 μg/ml) were assessed in murine macrophages RAW 264.7 and in peripheral whole blood from healthy volunteers. Cytotoxicity, cytostasis and genotoxicity were evaluated by the colorimetric assay of formazan reduction [3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT)] and by the cytokinesis-block micronucleus cytome (CBMN Cyt) assay. The comet assay was applied for detecting DNA strand breaks and information on oxidative damage to DNA (oxidised purines and pyrimidines). The MTT assay revealed a decrease in cell viability in RAW 264.7 cells and peripheral blood lymphocytes (PBL) with significant dose-effect relationships for the different CuO NP shapes. The comet assay revealed a dose-dependent increase in primary DNA damage, and a significant increase in oxidative damage to DNA was also detectable, as well as increased frequency of micronuclei in binucleated cells, often in a dose-related manner. Proliferative activity, cytotoxicity and apoptotic markers showed a significant trend in the two cell types. Finally, we have differentiated clastogenic events from aneugenic events by fluorescence in situ hybridisation with human and murine pancentromeric probes, revealing for the first time characteristic aneugenic responses related to the shape of CuO NPs and cell type. Independently of size and shape, all CuO NPs revealed a clear-cut cytotoxic and genotoxic potential; this suggests that CuO NPs are good candidates for positive controls in nanotoxicology.

Dose-Effect Relationships for Adverse Events After Cranial Radiation Therapy in Long-term Childhood Cancer Survivors

To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships. The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD(2)). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 years after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD(2) in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy. There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD(2), we found significant dose-effect relationships for these and other AEs. Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD(2) instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.

Pharmacokinetics and Pharmacodynamics of Oral Artesunate Monotherapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

Artemisinin-resistant malaria along the Thailand-Cambodian border is an important public health concern, yet mechanisms of drug action and their contributions to the development of resistance are poorly understood. The pharmacokinetics and pharmacodynamics of oral artesunate monotherapy were explored in a dose-ranging trial in an area of emerging artesunate resistance in western Cambodia. We enrolled 143 evaluable subjects with uncomplicated Plasmodium falciparum malaria in an open label study of directly observed artesunate monotherapy at 3 dose levels (2, 4, and 6 mg/kg of body weight/day) for 7 days at Tasanh Health Center, Tasanh, Cambodia. Clinical outcomes were similar among the 3 groups. Wide variability in artesunate and dihydroartemisinin concentrations in plasma was observed. No significant dose-effect or concentration-effect relationships between pharmacokinetic (PK) and parasite clearance parameters were observed, though baseline parasitemia was modestly correlated with increased parasite clearance times. The overall parasite clearance times were prolonged compared with the clearance times in a previous study at this site in 2006 to 2007, but this did not persist when the evaluation was limited to subjects with a comparable artesunate dose (4 mg/kg/day) and baseline parasitemia from the two studies. Reduced plasma drug levels with higher presentation parasitemias, previously hypothesized to result from partitioning into infected red blood cells, was not observed in this population with uncomplicated malaria. Neither in vitro parasite susceptibility nor plasma drug concentrations appeared to have a direct relationship with the pharmacodynamic (PD) effects of oral artesunate on malaria parasites. While direct concentration-effect relationships were not found, it remains possible that a population PK modeling approach that allows modeling of greater dose separation might discern more-subtle relationships.

Cancer mortality among two different populations of French nuclear workers

The aim of this paper is to study the effect of external photon radiation on the mortality of two populations of French nuclear workers: workers exposed only to external photon radiation and workers potentially exposed also to internal contamination or to neutrons. External photon radiation has been measured through individual dosimeters. Potential exposure to internal contamination or to neutrons has been assessed by experts on the basis of quantitative measurements or of worksite and type of activity. The mortality observed in each population was compared with that expected from national mortality statistics, by computing standardized mortality ratios. Dose-effect relationships were analyzed through trend tests and log-linear Poisson regressions. 14,796 workers were exposed only to external photon radiation; 14,408 workers were also potentially exposed to internal radiation or to neutrons. Between 1968 and 1994, the number of deaths is respectively, 645 and 1,197. The mean external photon dose was respectively, 3.7 and 12.9mSv. Similar Healthy Worker Effects were observed in the two populations (SMR=0.59). SMR of 2.41 90% CI [1.39-3.90] was observed for malignant melanoma among workers of the second population. Significant dose-effect relationships were observed: among workers exposed only to external photon radiation for leukemia except CLL and in the other population, for cancers and other diseases related to tobacco or alcohol consumption. Results differed between the two populations. The increase in leukemia risk with dose in the first population will have to be confirmed with extended follow-up. In the other population, results may have been confounded by alpha-emitters inhalation, tobacco, or alcohol consumption.

Effects of Deoxynivalenol on Cell Cycle and Apoptosis of Human Gastric Carcinoma Cell Line HGC-27 in vitro

Objective To explore the putative effect of deoxynivalenol on cell cycle and apoptosis of human gastric carcinoma cell line HGC-27 in vitro.Methods HGC-27 cells were treated with DON at different concentrations(50、100、1 000、2 000μg/L) for 12,24 and 48 hours,and then cells were harvested for analysis of apoptosis,cell cycle distribution and expression of Bax,Bcl-2 and Caspase-3 with flow cytometric(FCM) and Western Blot methods.Results At relatively higher concentrations(1 000 and 2 000 g/L),DON could affect cell cycle distribution in a time dependent manner.DON treatment for 12 h,the percentages of cells in G0/G1 phases was significantly decreased and that in S phase increased.As the treatment time lasted for 24 h and 48 h,the percentages of cells in G0/G1 phases were significantly increased while that in S phase decreased(P0.05).No significant effects on G2/M phase could be found.The apoptosis rates in all DON treated groups for 12 h,24 h and 48 h were all higher than that in control.Though statistical significance in the difference of apoptosis rate between control and the DON treated groups was not found 12 h after DON treatment but it could be seen 24 and 48 h after DON treatment(P0.05).Significant dose-effect relationships were found between DON concentrations and the apoptosis rates.Western Blot analysis showed bax and caspase-3 expression was up-regulated and bcl-2 expression was down-regulated in DON treated HGC-27 cells in vitro.Conclusion DON could significantly affect the cell cycle distribution of HGC-27 cells in vitro and the effects of DON on cell cycle varied as the concentratrion and treatment time of DON changed.DON treatment could induce apoptosis of HGC-27 cell possibly by up-regulating bax and caspase-3 expression and down-regulating bcl-2 expression.

Impact of cognitive reserve on the relationship of lead exposure and neurobehavioral performance

Cognitive reserve (CR)--a construct studied in many neurologic disorders--refers to the maintenance of cognitive performance in spite of ongoing underlying brain pathology. We hypothesized that a dose-effect relationship would exist between chronic occupational lead exposure and cognitive effects in workers with low CR but not in workers with high CR and identical lead exposure, and that level of CR would not influence the relationship between lead exposure and motor performance. We stratified currently employed lead smelter workers by Wide Range Achievement Test-R for reading (WRAT), a recognized measure of CR, into loCR and hiCR groups. From these two groups we matched 56 pairs on working lifetime weighted blood lead (TWA). We performed a factor analysis on 14 neuropsychological outcome variables. Within each CR group regression analyses after adjusting for age, alcohol use, and depression scale score tested for dose-effect relationships between TWA and outcome variables. Both CR groups had comparable age, years employed, alcohol use, and current blood lead levels. Factor analysis provided three factors and five tests used in the regression analyses. Significant dose-effect relationships between TWA and cognitive tests present only in the loCR group included Attention Factor and Digit Symbol. Both CR groups demonstrated significant dose-effect relationships on the Motor Factor. This study found that cognitive reserve protects against the effect of chronic lead exposure on select measures of cognitive performance but not on motor performance.

Low bone density and renal dysfunction following environmental cadmium exposure in China.

This paper presents the main findings of a study on health effects of environmental cadmium pollution in China, performed in 1998, i.e. approximately 25 years after the first warnings of such effects were published in Ambio. Forearm bone mineral density (BMD) and renal dysfunction were assessed in population groups exposed to cadmium via rice. Decreased BMD was found in postmenopausal women with elevated urinary cadmium (CdU) or cadmium in blood (CdB) and among men with elevated CdB. Also, clear and statistically significant dose-effect and dose-response relationships were found between CdB or CdU and renal dysfunction (increased excretion of retinol-binding protein). This is the first report of bone effects among Cd-exposed population groups in Asia outside Japan. The report is also of interest since it demonstrates that bone effects, a comparatively severe adverse health effect of Cd, in combination with renal dysfunction, still occurs in environmentally exposed population groups in Asia. Recent reports on bone effects in Cd-exposed population groups in Europe are discussed.

Chromosome aberration assays for the study of cyclophosphamide and Bacillus thuringiensis in Oxya chinensis (Orthoptera: Acrididae)

Chromosome aberrations induced by an anti-neoplastic drug, cyclophosphamide (CP) and a bioinsecticide, Bacillus thuringiensis (B.t.) were examined using grasshoppers as an animal model, with injection as the route of exposure. Oxya chinensis (Thunberg), having a small number ( 2n♂=23) of large-sized chromosomes in males, was used for this purpose. The fifth instar nymphs were treated with various concentrations of CP (2, 5 and 10 mg/ml) and B.t. (0.55, 1.83 and 5.50 IU/ml) by injection into the abdomen, using physiological saline and distilled water as negative controls, respectively. The chromosomal preparations were made from the spermatogonia of the specimen testis at different intervals after dosing (24 and 48 h). The effect of the high dose of CP (10 mg/ml) in O. chinensis was also analyzed at the 42-h time point. The chromosome aberrations observed were mainly chromatid and chromosome breaks. CP induced a dose- and time-dependents increase in the number of chromosome aberrations (CAs) per cell and in the percentage of aberrant cells. The strongest effect was seen when grasshoppers were injected with the highest dose and cells were analyzed at the 48-h time point. The results show that CP induced a significant increase in the frequency of CAs in testicular cells of O. chinensis with the three doses employed, compared to the negative control. Our results suggest that there exists in the grasshopper an enzyme system analogous to liver-S9 fraction, and that CP may be used as a positive control in genotoxicity test in this species. In addition, the evaluation of the chromosome aberrations induced by B.t. in the grasshoppers’ testicular cells showed that B.t. may induce chromosome aberrations, mainly chromatid and chromosome breaks, in spermatogonia. By statistical analysis, B.t. showed significant dose–effect relationships and it may be mutagenic in this species. Recent research has focused on the development of biological insecticides to protect cereal crops against damage by insect species, such as beetles and grasshoppers. The present studies may contribute to our knowledge of entomological genotoxicity in grasshoppers and provide reference for the research on the mechanism of B.t. toxicity.

Impact of prenatal methylmercury exposure on child neurodevelopment in the Faroe Islands

Recent interest concerning methylmercury that accumulates in the aquatic food chain appears to be directed not to the adverse effects of high-dose exposure in humans, but to the critical concentration at which methylmercury may affect the progeny of the exposed population. In epidemiological studies, however, uncertainties and limitations in estimating exposure make it difficult to quantify dose-response associations and can thereby lead to inaccuracies when deriving such concentrations. In this respect, benchmark dose calculation for quantitative outcomes may shed new light on the epidemiological procedure for estimating the critical concentration. After the epidemic outbreaks of methylmercury poisoning in Japan and Iraq, large-scale follow-up studies were carried out in the Faroe Islands, Seychelles and New Zealand, to clarify the effects of prenatal methylmercury exposure on child neurodevelopment in the latter half of the 1980s. This article presents an overview of the outcomes obtained from the Faroe Islands Prospective Study, as well as a brief interpretation of the benchmark dose calculation. Although the Faroe and Seychelles Islands studies did not seem to differ greatly in the study setting, such as the exposure level and sample size, the former study observed some significant dose-effect relationships between methylmercury concentrations at birth and neurobehavioral end-points, but the latter failed to find any significant associations except in one test. The discrepancy between the two conclusions is also discussed.