Kuen-Yuh Wu

Chromium (VI) induced oxidative damage to DNA: increase of urinary 8-hydroxydeoxyguanosine concentrations (8-OHdG) among electroplating workers

Aims: To investigate the concentration of urinary 8-hydroxydeoxyguanosine (8-OHdG) among electroplating workers in Taiwan. Methods: Fifty workers were selected from five chromium (Cr) electroplating plants in central Taiwan. The 20 control subjects were office workers with no previous exposure to Cr. Urinary 8-OHdG concentrations were determined using high performance liquid chromatography with electrochemical detection. Results: Urinary 8-OHdG concentrations among Cr workers (1149.5 pmol/kg/day) were higher than those in the control group (730.2 pmol/kg/day). There was a positive correlation between urinary 8-OHdG concentrations and urinary Cr concentration (r = 0.447, p < 0.01), and urinary 8-OHdG correlated positively with airborne Cr concentration (r = 0.285). Using multiple regression analysis, the factors that affected urinary 8-OHdG concentrations were alcohol, the common cold, and high urinary Cr concentration. There was a high correlation of urinary 8-OHdG with both smoking and drinking, but multiple regression analysis showed that smoking was not a significant factor. Age and gender were also non-significant factors. Conclusion: 8-OHdG, which is an indicator of oxidative DNA damage, was a sensitive biomarker for Cr exposure.

Pulmonary toxicity of inhaled nanoscale and fine zinc oxide particles: Mass and surface area as an exposure metric

The total surface area is known to be an effective exposure metric for predicting the lung toxicity of low solubility nanoparticles (NPs). However, if NPs are dissolved quickly enough in the lungs, the mass may be correlated with the toxicity. Recent studies have found that the toxicity of zinc oxide (ZnO) NPs was caused by the release of zinc ions. Thus, we hypothesized that mass could be used as an exposure metric for the toxicity of ZnO NPs. Healthy Sprague-Dawley rats were exposed to a low, moderate, or high dose of 35 and 250 nm ZnO particles or filtered air. Bronchoalveolar lavage fluid was collected to determine lung inflammation, injury and oxidative stress. The lung inflammation induced by ZnO particles according to different concentration metrics, including number, mass and surface area, was compared. The mass concentration was significantly correlated with the percentage of neutrophils (R2 = 0.84), number of neutrophils (R2 = 0.84) and total cells (R2 = 0.73). Similarly, surface area concentration was significantly correlated with the percentage of neutrophils (R2 = 0.94), number of neutrophils (R2 = 0.81) and total cells (R2 = 0.76). There was no correlation between the number and lung inflammation. We found that both mass and surface area were effective as metrics for the toxicity of ZnO NPs, although only surface area was previously indicated to be an effective metric. Our results are also consistent with recent study results that ZnO NPs and released zinc ions may play a role mediating the toxicity of NPs.

Characterization of multiple airborne particulate metals in the surroundings of a municipal waste incinerator in Taiwan

Abstract Heavy metals are one of the concerned pollutants emitted by the municipal waste incineration system (MWIs). The objective of this study was to evaluate the potential impact on local airborne metals from the emissions of an MWI. Aerosol samples were simultaneously collected at eight different sites around the municipal waste incinerator using PS-1 sampler. The concentrations of 16 elements (Mg, Al, Fe, Cu, Zn, Pb, Ti, V, Cr, Mn, Co, Ni, As, Cd, Ba and Hg) were quantified by inductively coupled plasma-mass spectrometry (ICP–MS) and atomic absorption spectrometer (AA). The profiles of the 16 metals in the surroundings of a municipal incinerator in central Taiwan were compared with those of the emission sources. The results showed that the profiles of multiple metals obtained at all sampling sites were similar to those emitted from the MWI stack. These findings suggested that the local airborne metal pollutants might probably derive from the stack emission of the MWI. Using cadmium as an index metal, it was found that the metals like Mg, Ti, V, Cr, Mn, Co, Ni, As, and Hg are highly influenced by the stack emission from the municipal incinerator. Moreover, the ratio of other metals to Cd that were increased with the distance from the incinerator. This might be due to the additional sources contributed to airborne metals following the emission from the incinerator and a difference in particle size of each particle-bound metal.

Dose-response relationships for carcinogens

Biotransformation of chemical carcinogens involves both metabolic activation and detoxication. The molecular dose present on DNA as adducts represents a balance between these two pathways (formation) and DNA repair. All of these are enzymatic processes subject to saturation. When none of the pathways is saturated, linear molecular dosimetry is expected, whereas if metabolic activation is saturated, a supralinear response occurs. If detoxication or DNA repair is saturated, a sublinear response occurs. With chronic exposure, steady-state concentrations of DNA adducts develop and these follow the same patterns. With several alkylating agents, multiple adducts are formed. The extent of formation is chemically defined, but different DNA repair pathways can be involved for different adducts. By understanding the molecular dose and biology of each adduct and comparing these to the dose-response for tumor induction, it may be possible to identify the most appropriate biomarkers for risk assessment. Recently, endogenous DNA adducts identical to those induced by known human carcinogens have been identified. These endogenously formed adducts may play an important role in human carcinogenesis.

Effects of Treatment Intensity in Upper Limb Robot-Assisted Therapy for Chronic Stroke A Pilot Randomized Controlled Trial

Background and Objectives. Robot-assisted therapy (RT) is a current promising intervention in stroke rehabilitation, but more research is warranted for examining its efficacy and the dose–benefit relation. The authors investigated the effects of higher intensity versus lower intensity RT on movements of forearm pronation–supination and wrist flexion–extension relative to conventional rehabilitation (CR) in patients poststroke for a mean of 21 months. Methods. In this pilot study, 18 patients with initial mean Fugl-Meyer Assessment (FMA) of 37 to 44 for the upper extremity were randomized to higher intensity RT, lower intensity RT, or CR intervention for 4 weeks. The dose of the higher intensity RT was twice the number of repetitions in the lower intensity RT. Outcome measures at pretreatment and posttreatment were administered to patients to evaluate beneficial and adverse effects of interventions. Primary outcomes were the FMA and Medical Research Council scale. Results. There were significant differences in motor function (P = .04) and daily performance (P = .03) among the 3 groups. The higher intensity RT group showed better improvement in motor function, muscle strength, performance of daily activities, and bimanual ability than the other 2 groups. The intensive RT intervention did not induce higher levels of an oxidative DNA biomarker. Conclusions. Higher intensity of RT that assists forearm and wrist movements may lead to greater improvement in motor ability and functional performance in stroke patients. A sample size of only 20 to 25 in each arm of a larger randomized controlled trial is needed to confirm the findings for similar subjects.

Emissions of Polychlorinated Dibenzo-p-Dioxins and Dibenzofurans from Stack Gases of Electric Arc Furnaces and Secondary Aluminum Smelters

Abstract This study investigates the emissions of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) from four electric arc furnaces (EAFs) and eight secondary aluminum smelters (secondary ALSs) in Taiwan. The mean PCDD/F International-Toxicity Equivalents (I-TEQ) concentrations in the stack gases of these EAFs and secondary ALSs are 0.28 ng I-TEQ/Nm3 (relative standard deviation [RSD = 100%) and 3.3 ng I-TEQ/Nm3 (RSD = 260%), respectively. The high RSDs, especially for those obtained from secondary ALSs, could be caused by the intrinsic differences in their involved feeding materials, furnace operating conditions, and air pollution control devices. The mean I-TEQ emission factor of PCDD/Fs for EAFs (1.8 μg I-TEQ/tonne-feedstock) is lower than that for secondary ALSs (37 μm g I-TEQ/tonne-feedstock). This result might be because the involved furnace temperatures for secondary ALSs (650–750 °C) are lower than those for EAFs (1600–1700 °C), resulting in the deterioration of the combustion condition, leading to the formation of PCDD/Fs during the industrial process. This study found that the total PCDD/F emissions from EAFs (20 g I-TEQ/yr) and secondary ALSs (18 g I-TEQ/yr) are ∼27, 53, and ∼24, 49 times higher than those from municipal solid waste incinerators (MSWIs; 0.74 g ITEQ/yr) and medical waste incinerators (MWIs; 0.37 g I-TEQ/yr), respectively; while those are 44 and 40% of total PCDD/F emission from sinter plants (45 g I-TEQ/yr), respectively. Considering a more stringent emission limit has been applied to waste incinerators (0.1 ng I-TEQ/Nm3) in Taiwan lately, the results suggest that the control of the emissions from metallurgical processes has become the most important issue for reducing the total PCDD/F emission from industrial sectors to the ambient environment.

DNA adducts: Effects of low exposure to ethylene oxide, vinyl chloride and butadiene

Dose-response relationships of genotoxic agents differ greatly depending on the agent and the endpoint being evaluated. Simple conclusions that genotoxic effects are linear cannot be applied universally. The shape of the molecular dose of DNA adducts varies from linear, to supralinear, to sublinear depending on metabolic activation and detoxication, and repair of individual types of DNA adducts. For mutagenesis and other genotoxicity endpoints, the dose-response reflects the molecular dose of each type of DNA adduct, cell proliferation, as well as endogenous factors that lead to mutagenesis such as the formation and repair of endogenous DNA adducts. These same factors are important when interpreting the shape of dose-response data for carcinogenesis of genotoxic agents, however, tumor background variability adds additional complexity. Endogenously formed DNA adducts may be identical to those formed by chemicals, as in the case of vinyl chloride and ethylene oxide, or they may be those associated with oxidative stress. Data presented in this paper demonstrate that the exogenous number of adducts induced by 5 days of exposure to 10 ppm vinyl chloride is only 2. 2-fold greater than that present as a steady-state amount in unexposed control rats. Similar data are shown for ethylene oxide. Extremely sensitive methods have been developed for measuring the molecular dose of genotoxins. These methods can detect DNA adducts as low as 1 per 10(9) to 10(10). However, in view of the high number of endogenous DNA adducts that are present in all cells, it is unlikely that causal relationships can be attributed to very low numbers of such DNA adducts. Effects of both exogenous and endogenous DNA adducts need to be factored into the interpretation of chemical exposures.

Analysis of perfluorinated chemicals in umbilical cord blood by ultra-high performance liquid chromatography/tandem mass spectrometry

Perfluorinated compounds (PFCs) can cross the placental barrier and enter fetal circulation. This study aimed at developing a fast and sensitive ultra-high performance liquid chromatography/tandem mass spectrometry method for the determination of twelve perfluorinated compounds in cord blood. Samples were processed with protein precipitation using formic acid and methanol, mixed with stable isotope labeled standard, followed by sonication and centrifugation, and were analyzed using a Waters ACQUITY UPLC coupled with a Waters Quattro Premier XE triple-quadrupole mass spectrometer. The instrument was operated in selected reaction monitoring (SRM) with negative electrospray ionization. Using BEH C(18) column (2.1 mm×50 mm, 1.7 μm) with 10-mM N-methylmorpholine/methanol gradient elution provided a fast chromatographic separation (5.5 min) and sharp peaks. Intra- and inter-day calibration bias was less than 7% and intra- and inter-day calibration of relative standard deviations were within 0.02-8.22% for all the analytes and concentrations. The recoveries of PFCs spiked into bovine serum ranged from 85 to 104% with relative standard deviations from 0.02 to 6.37%. The limits of quantitation (LOQs), defined as a signal-to-noise ratio of ten, ranged from 0.15 to 3.1 ng/mL for the twelve PFCs. Perfluorooctanoic acid (PFOA), perfluorooctyl sulfonate (PFOS), perfluoroundecanoic acid (PFUA) and perfluorononanoic acid (PFNA) were detected in up to 68% of umbilical cord plasma (n=444) in Taiwan Birth Panel Study and the health effect of these chemicals on children developmental deserves further investigation.

Dose–Response Relationship of Robot-Assisted Stroke Motor Rehabilitation The Impact of Initial Motor Status

Background and Purpose— The increasing availability of robot-assisted therapy (RT), which provides quantifiable, reproducible, interactive, and intensive practice, holds promise for stroke rehabilitation, but data on its dose–response relation are scanty. This study used 2 different intensities of RT to examine the treatment effects of RT and the effect on outcomes of the severity of initial motor deficits. Methods— Fifty-four patients with stroke were randomized to a 4-week intervention of higher-intensity RT, lower-intensity RT, or control treatment. The primary outcome, the Fugl-Meyer Assessment, was administered at baseline, midterm, and posttreatment. Secondary outcomes included the Medical Research Council scale, the Motor Activity Log, and the physical domains of the Stroke Impact Scale. Results— The higher-intensity RT group showed significantly greater improvements on the Fugl-Meyer Assessment than the lower-intensity RT and control treatment groups at midterm (P=0.003 and P=0.02) and at posttreatment (P=0.04 and P=0.02). Within-group gains on the secondary outcomes were significant, but the differences among the 3 groups did not reach significance. Recovery rates of the higher-intensity RT group were higher than those of the lower-intensity RT group, particularly on the Fugl-Meyer Assessment. Scatterplots with curve fitting showed that patients with moderate motor deficits gained more improvements than those with severe or mild deficits after the higher-intensity RT. Conclusions— This study demonstrated the higher treatment intensity provided by RT was associated with better motor outcome for patients with stroke, which may shape further stroke rehabilitation. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00917605.

Effect of gestational smoke exposure on atopic dermatitis in the offspring

The adverse impact of smoking on respiratory diseases and birth outcomes in children is well‐known. However, the influence of smoke exposure including environmental tobacco smoke (ETS) and maternal smoking during pregnancy on atopic dermatitis (AD) is not clear. The purpose of this study was to evaluate the effect of gestational smoke exposure on the development of AD in the offspring on the basis of the maternal and cord blood cotinine. We recruited 261 mother and newborn pairs in 2004. Cord blood and information on perinatal factors of children were gathered at birth. At 2 yr of age, information about development of AD and environmental exposures were collected. We compared AD with non‐AD children for the concentration of cotinine in cord and maternal blood measured by high performance liquid chromatography–mass spectrometry. Multiple logistic regressions were performed to estimate the relationship of cotinine levels and AD. About 150 mother and child pairs completed the follow‐up study and specimen collection with 38 (25.3%) children developing AD. Two (1.3%) out of 150 mothers smoked during pregnancy, while 38 (25.3%) mothers reported having ETS exposure. Cotinine levels in cord blood and maternal blood were highly correlated (r = 0.71, p < 0.001). The risk of AD was found to increase with maternal and cord blood cotinine levels in a dose–response manner (p for trend = 0.01). Children exposed to high levels (>75th percentile) had a significantly increased risk of AD. Smoke exposure during pregnancy might increase the risk of AD in children. Avoidance of prenatal smoke exposure may be warranted for early prevention.