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1. Metal Toxicity Research Program
A. Interaction of arsenic and cigarette smoke in lung cancer development
To investigate the expression profile of inflammatory related cytokines induced by ETS and arsenic exposure in mouse lung and bronchiole-alveolar lavage fluid, we found all parameters for pulmonary function test showed no difference among all four groups. This result suggested that this four-week exposure of ETS/arsenic may not long enough to influence pulmonary functions. In bronchiole-alveolar lavage fluids (BALF), total cell number showed no difference among four groups, as well as BALF macrophages. However, the numbers of dead epithelial cells were increased in arsenic alone and ETS-arsenic co-exposed groups. It may suggest that the exposure of arsenic on mice leaded to pulmonary epithelial cell injury. Moreover, alveolar enlargement was observed on ETS and arsenic exposed mice. This alveolar enlargement was further confirmed as emphysematous lesions by EVG stain. The mean length intercept (MLI) indicated that only co-exposure of ETS and arsenic significantly increased the size of alveolar space.

B. Impact of nickel on female lung cancer
We examine whether nickel may induce IL-10 and PD-L1 expressions to suppress T-cell immunity, and then to cause HPV persistent infection. A549 cells were enrolled to treat with NiCl2 in time- and dose- course experiments. In the time-dependent experiment, the highest PD-L1 mRNA expression level induced by 2.5 μM NiCl2 was at 2 hr treatment. Moreover, PD-L1 mRNA expressions induced by NiCl2 were in dose-dependent manner. However, IL-10 mRNA expressions were slightly induced by NiCl2. Therefore, we will investigate the role of PD-L1 induced by Ni exposure on HPV-associated lung tumorigenesis.

C. Arsenic and nano-ZnO impact on cardiovascular diseases
This study investigated inflammatory effects of zinc oxide (ZnO) particles on vascular endothelial cells. The effects of 50-nm and 100-nm ZnO particles on human umbilical vein endothelial cells (HUVECs) were characterized by assaying cytotoxicity, cell proliferation, and glutathione levels. Treatments with ZnO concentrations ≤45 μg/ml were performed to determine the expression of intercellular adhesion molecule-1 (ICAM-1) protein, an indicator of vascular endothelium inflammation, revealing that ZnO particles induced a dose-dependent increase in ICAM-1 expression and marked increases in NF-κB reporter activity. Overexpression of IκBα completely inhibited ZnO-induced ICAM-1 expression, suggesting NF-κB plays a pivotal role in regulation of ZnO-induced inflammation in HUVECs. Additionally, TNF-α, a typical inflammatory cytokine, induced ICAM-1 expression in an NF-κB-dependent manner, and ZnO synergistically enhanced TNF-α-induced ICAM-1 expression. This study reveals an important role for ZnO in modulating inflammatory responses of vascular endothelial cells via NF-κB signaling, which could have important implications for treatments of vascular disease.

D. Blood heavy metal concentrations and health effect among Taiwan female immigrants
This study has recruited 496 immigrants and 191 natives to assess the difference of blood metal levels, oxidative stress, gene polymorphism, and demography characteristics. We found that blood lead, mercury and cadmium in immigrants were significant higher than those in natives. There were no statistically significant differences in these genotypes between the two groups. Therefore, the genetic variations in our study populations were similar and could not affect blood metal levels in the comparison. The gene variant in XRCC1(rs25487) and HFE (rs1799945) has elevated risk of oxidative stress, regardless among immigrant or native groups.

2. Environmental Hormone Research Program
In order to study the developmental effect associated with phthalate, we utilized our birth cohort to first determine the phthalate internal doses in children aged 0, 2–3, and 5–6 years. We found that the concentration of most of individual phthalate metabolite in children at 8-9 years is lower than those at 5-6 years. The exposure levels of low-molecular phthalate metabolites (MMP, MEP, MnBP) were higher in girl than in boys, whereas those of high-molecular phthalate metabolites (MBzP, MEHP, 5OH-MEHP, 5oxo-MEHP) were higher in boys than in girls (but did not reach statistical significant). It is possibly that the exposure sources of phthalates in boys and girls are different by their daily contact, such as toys or other stuff, habits and activities as they growing up.
Leptin and creatinine adjusted urinary concentrations of MMP and mono-isobutyl phthalate (MiBP) in girls were correlated. For boys, leptin and creatinine adjusted urinary concentrations of MiBP and sum of DEHP metabolites were correlated. Adiponectin and creatinine adjusted urinary concentrations of MMP were correlated in both genders, but adiponectin and creatinine adjusted urinary concentrations of 2-ethyl-5-hydroxyhexyl phthalate was found only in boys. We did not find significant increasing risk of hs-CRP for high phthalate exposure using logistic regression.
In girls, there is a significantly positive correlation between MnBP (marginal), MBzP, 5OH-MEHP, 5oxo-MEHP, sum MEHP and total IgE. It is indicated that the immune response of girls may be more susceptible as exposed to multiple sources of phthalates.

3. Occupational Medicine Research Program
(1)In order to investigate the potential cardiovascular effects of DE exposure, repeated measurements of inflammation, thrombosis, myocardial infarction and heart failure markers during four-week follow-up period was performed for garage maintenance workers and bus drivers. The increment of 2-naphthol (2-NP), cardiovascular markers of high sensitive C-reactive protein (hs-CRP), homocystein (Hcy) and myoglobin (Myg) were found during the four-week follow-up period among garage maintenance workers. Generalized estimating equations (GEEs) models were further applied to correlate repeated measurements of myoglobin level with DE exposure, adjusted for age, BMI, betel chewing, alcohol consumption confounding factors. Our results showed that a significant association between DE exposure and myoglobin (p=0.05). However, the association between DE exposure and D-dimer was marginally significant (p=0.083) after adjusting for confounding factors. These findings suggest that exposure to DE may lead to increased risk of cardiovascular diseases or myocardial infarction.
(2)We conducted a heat acclimation and heat exposure study on naval vessel. We recruited 195 individuals with 96 heat exposure and 99 controls. WBGT (Wet Bulb Globe Temperature) and CNE (Cumulative Noise Exposure) were estimated for each working environment, and each case can be matched one environmental test data for his working place and working time. Using ELISA, we test the plasma HSP70 before and after sailing for 195 individuals. After adjusting for baseline HSP70, cumulative noise exposure and smoking amount, we found HSP70 in heat exposure group was statistically significant higher than non-exposure group (P=0.014). Other oxidative stress biomarkers, such as urine 8-OHdG and urine N7-MeG, were not statistically significant between these two groups. HSP70 might be the biomarker of heat acclimation.
(3)For individual case of suspected occupational cancer, we have established an investigation model by co-operation with industrial hygienists to conduct environmental exposure assessment, for determining the contribution from occupational exposure. We have conducted 9 field walkthrough surveys at the workplaces during the period from July 2008 to November 2010 and have written certificates for 8 cases of malignant mesothelioma due to occupational asbestos exposure, one case of nasopharyngeal carcinoma related to exposure to Chromium and Nickel in welding, one case of lung adenocarcinoma related to exposure to Chromium from the electroplating process, and one case of lung cancer related to exposure to painting which probably contained Chromium pigment.
(4)We evaluated the impact of malignant mesothelioma (MM) in Taiwan based on the 27-year review of the national cancer registry.  We found increasing trend of incidence of MM in Taiwan and the substantial impact in terms of 14.2 expected years of life lost (EYLL) due to the occurrence of a case of malignant mesothelioma.  These findings can highlight the significant burden of asbestos-related malignancy, which may promote policy-making process for prevention of asbestos-related health risks.
(5) In order to establish and identify the health markers on workers dealing with nanomaterials in manufacturing facilities, we cooperated with Institute of Occupational Safety and Health (IOSH) to establish nanoparticles-exposed cohort and investigate the potential health biomarkers from the longitudinal and cross-sectional design. We recruited 135 nanoparticle-exposed workers and 56 administrative workers in the same plant from 13 plants in Taiwan. Questionnaire was used to collect personal data and potential confounders. Control Banding from Nanotool Risk Level Matrix was adopted to categorize the risk level. The biomarkers investigated include: 1. pulmonary inflammation markers, 2. cardiovascular disease markers, 3. genotoxicity comet assay, 4. the activation of inflammation-related transcription factors by luciferase reporter assays, 5. activities and polymorphism of antioxidant enzymes.
Carbon nanotube (CNT), nano-silicon oxide (SiO2) and nano-titanium oxide (TiO2) were the three most encountered substance among the exposed workers. Cross-sectional study showed that Clara cell protein (CC16) and high-sensitive CRP (hsCRP) were significantly increased in risk level (RL) 2 & RL3 and doses-dependent. Low frequency (LH) in heart rate variability (HRV) and vascular cell adhesion molecule (VCAM) were also marginally significantly increased in RL3, but not doses-dependent. No difference in symptoms, cytokines, 8OhdG, fibrinogens, time domain in HRV, micronucleus, antioxidant enzymes activities, and lung function. Longitudinal follow-up with repeated measurements in an interval of 6 months also showed that the levels of CC16 and VCAM decreased with parallel to decreasing exposure levels. In conclusions, biomarkers of small airway damage (CC16) and lung inflammation (hsCRP) can be served as health effect markers of nanoparticles exposure. Biomarkers of injuries to endothelium (VCAM) and sympathetic activation (LH in HRV) may also be served as health effect markers of nanoparticles exposure.

(6)Herniated intervertebral disc (HIVD) has been listed as a compensable occupational disease in Taiwan. A hospital-based case-control study was constructed to examine the gene-work exposure interaction in causing HIVD. A total of 83 cases and 83 controls were entered for the final analysis of case-control study. In the meantime, we recruited fruit wholesaling workers highly exposed to weight-lifting to determine the roles of genetic susceptibility. A total of 221 fruit market workers participated in the cross-sectional study. Every participant was assessed with questionnaire, MRI and BMD assessment, blood testing and genomic analysis, and photographs were taken for simulated working posture and lumbar load estimation by 3d-SSPP. In conclusion, relationship between cumulative work lifting load and the risk of disc diseases was found in the hospital-based case-control study and the cross-sectional study among fruit workers. THBS2 genotype might be a susceptible marker among highly exposed people. A clearer picture of dose-response relationship between lift load and HIVD, as well as genetic susceptibility can be elucidated with the proposed number of study subjects in the near future.

4. Surveillance of Human internal dose of important pollutants in Taiwan
We selected 1955 subjects (997 in 1993-1996, 870 in 2005-2008 years from the project “Nutrition and Health Survey in Taiwan” (NAHSIT) which carried by Prof. Wen-Han Pan, Academia Sinica and now in NHRI, and 88 subjects for 0-6 years from our division project in Taichung area) by stratified random sampling. We measured important, ubiquitous, and industrial-related metals, including urinary lead (Pb), cadmium (Cd), copper (Cu), cobalt (Co), gallilum (Ga), indium (In), thallium (T1), arsenic (As),  and chromium (Cr),and RBC mercury (Hg). Comparing the metal concentrations in the present study with threshold values, we found some subjects have exceeded the threshold levels. The percentages of exceeding threshold was highest for Cd (>1 μg/L:29%), followed by As (>100 μg/L:22% - >50 μg/L:33%), Co (>2 μg/L:17%), and RBC Hg (>20 μg/L:6% based on the formula obtained from our previous study). However, the data of arsenic was based on 51 individuals from Taipei, Taoyuan, and Hsinchu counties, it may be biased due to small sample size. In conclusion, the important metal pollutants in Taiwan were cadmium, arsenic, cobalt and mercury.

5. The impact of environmental pollution on health inequality
Health inequity was an important issue in the Taiwan among long-term employees. The incidence of most major diseases, i.e. cancers, cardiovascular diseases, pulmonary diseases, skin diseases, diseases of the digestive system, and diseases of the genitourinary system, in the heavy industry district workers were significantly lower than those in business district workers. However, heavy industry district workers had significantly higher incidence for contagious, vigorous, stress-related disorders and reproductive hazards, such as infectious and parasitic diseases, Endocrine, nutritional and metabolic diseases and immunity disorders, Mental disorders, Diseases of the nervous system (except meningitis), Diseases of the musculoskeletal system and connective tissue, and Congenital anomalies than in business district workers. Heavy industry district workers had also higher incidence of malignant neoplasm of female genitourinary organs, ischaemic heart disease, and fractures and Intracranial and internal injuries.
For the single pollutant model, MI admissions were significantly associated with presence of all pollutants except PM10 and SO2 on warm days (> 250 C). Statistically significant positive associations were observed for all pollutants on cool days (< 250 C). On warm days, CO and O3 remained statistically significant in all the two-pollutant models. NO2 remained significant after PM10 or SO2 were included in the model. No associations were found with PM10 or SO2 levels in the two pollutant models. On cool days, NO2 remained statistically significant in all the two-pollutant models. PM10 remained significant after the inclusion of SO2, CO, or O3. CO remained significant after the inclusion of PM10, SO2, or O3. SO2 remained significant after NO2 or O3 was included in the model.



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