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Journal of Occupational & Environmental Medicine:
doi: 10.1097/JOM.0b013e3182611a49
Original Articles

A Panel Study for Cardiopulmonary Effects Produced by Occupational Exposure to Inhalable Titanium Dioxide

Zhen, Sen MM; Qian, Qin MM; Jia, Guang PhD; Zhang, Ji MM; Chen, Chunying PhD; Wei, Yongjie PhD

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Author Information

From the Department of Occupational and Environmental Health Sciences, School of Public Health (Mr Zhen, Ms Qian, and Dr Jia) and Department of Environmental Sciences (Dr Wei), Peking University, Beijing,; Centers for Disease Control and Prevention, (Mr Zhen), Changzhou City, Jiangsu Province; Center for Disease Control and Prevention, (Mr Zhang), Jinan City, Shandong Province and National Center for Nanoscience and Technology (Dr Chen), Beijing, People's Republic of China.

Address correspondence to: Guang Jia, PhD, Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100191, People's Republic of China (

This study was supported by the project of National Natural Science Foundation of China (grant 30771787).

The authors declare no conflict of interest.

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Objectives: To investigate titanium dioxide (TiO2) exposure level in the finished product workshop, and its short-term cardiopulmonary effects, based on exposure assessment.

Methods: Seven workers were recruited into the panel. Personal TiO2 exposure information, cardiopulmonary function, and the particle size distribution data were collected during working days. Linear mixed effect model was used to examine the association between TiO2 exposure and cardiopulmonary function changes.

Results: The weight percentage of TiO2 particles more than 10 μm, 1 to 10 μm, and less than 1 μm in the total dust was 14.5%, 69.5%, and 16%, respectively. Linear mixed effect model analysis showed that 1 mg/m3 increase in daily personal TiO2 exposure was associated with the decline in maximum voluntary ventilation, peak expiratory flow, maximum mid-expiratory flow, and 75% of maximum expiratory flow.

Conclusion: The study provided new evidence for health effects of occupational inhalable TiO2 exposure, which suggests setting up new occupational exposure standards for fine TiO2.

Titanium dioxide (TiO2) is a noncombustible, white, fine crystal powder used widely as an important commercial chemical product, especially in surface coating, food, cosmetic, and air cleaning materials. Titanium dioxide has two crystal forms: rutile and anatase, with different bioactivity; studies have demonstrated that the bioactivity of rutile form is two magnitudes higher than that of anatase.13 As consumption grows, the chance of population exposure to fine or ultrafine TiO2 increases. Occupational exposure to TiO2 occurs during its production, transport, use, and waste disposal. The occupational permissible concentration-time weighted average for TiO2 total dust (CAS 13463-67-7)4 is 8 mg/m3, whereas the occupational exposure limits for TiO2 fine or ultrafine dust is uncertain. In 2011, the National Institute for Occupational Safety and Health conducted a systematic review of TiO2 health effects from epidemiologic, animal, and in vitro studies and finished a quantitative risk assessment; it recommended exposure limits of 2.4 mg/m3 for fine TiO2 and 0.3 mg/m3 for ultrafine (including engineered nanoscale) TiO2, as time-weighted average concentrations for up to 10 hours per day during a 40-hour work week.5

So far, the existing occupational epidemiologic studies to explore the potential health effects of TiO2 were focused on pulmonary diseases, especially on lung cancer. Studies about occupational exposed workers showed no association between TiO2 exposure and increased risk of lung cancer69; however, the effect of TiO2 on cardiopulmonary function was reported rarely. On the basis of epidemiologic and experimental data, Liao et al10 assessed inhalation risk on workers from TiO2 production factories using a Hill Model, the results of which demonstrated that surface treatment workers and packers in EU/US factories had different polymorphonuclear leukocytes counts, and were unlikely to pose substantial lung cancer risks. The risk of inhalable TiO2 on the pulmonary function was not assessed.

Studies about health effects of ambient particles have shown that daily particle exposure could result in declined lung function in susceptible population,1113 especially for fine particles. It was reported that black carbon was associated with decline in forced vital capacity (FVC), forced expiratory volume in the first second of exhalation (FEV1.0), and maximum mid-expiratory flow (MMEF) at the annual exposure level of 0.62 ± 0.2 μg/m3 among urban women.14 Also, in occupational population, a dose–response relationship between cumulative wood dust exposure and percent annual decrease in FEV1.0 was suggested for female workers15 at the median level of 3.75 mg·year/m3 for cumulative wood dust exposure, as for talc workers.16 As we know, TiO2, black carbon, and talc are defined as poorly soluble, low toxicity dust,17 and they have similar properties. Referring to the results of research on the health effects of black carbon and talc, combined with the role of particle size on the health effects, we determined to explore the cardiopulmonary effects of short-term occupational TiO2 exposure on the basis of particles size distribution assessment in the workshop by a panel study.

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Study Design and Population

Panel study has been described in many researches of environmental and occupational epidemiology.18,19 It is particularly useful for understanding changes at the individual level, taking unobserved heterogeneity across individuals and over time into account. On the basis of particle size distribution in workshop, we carried out a short-term study (June 19, 2009, to July 18, 2009) for the effects of TiO2 on cardiopulmonary function among occupationally exposed workers. Seven male workers were selected randomly from the employees who worked at finished product workshop at least 3 years. Exclusion criteria were the presence of chronic respiratory and heart diseases, liver and kidney diseases, or family history of hypertension and other cardiopulmonary diseases. For each participant, we collected the basic information such as age, height, weight, duration of employment, smoking status, and so forth. Smokers were required to minimize the number of cigarettes consumed during the working time to control the effect of smoking on cardiopulmonary function. All research was approved by Biomedical Ethics Committee of Peking University, and written informed consent was obtained from all subjects.

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Exposure Assessment
Particle Size Distribution

Subjects' workspaces were concentrated in the area between bagging and handling position, where the concentration of TiO2 is relatively high compared with other sites. For this reason, stationary particle measurements were carried out beside the bagging area, next to the handling position. The workers took turns on 8-hour tasks according to three work shifts including morning shift (8 AM to 4 PM), middle shift (4 PM to 12 AM), and night shift (12 AM to 8 AM). Nine days were randomly selected in study period (29 days), with 3 days for each shift to measure particle size distribution by Moudi impactor (Model 125B Nanomoudi, MSP Corporation, Shoreview, MN). At 13 impactor stages, particles were collected onto aluminum foils, the first-stage collected particles greater than 10 μm, and the following stages greater than 5.600, 3.200, 1.800, 1.000, 0.560, 0.320, 0.180, 0.100, 0.056, 0.032, 0.018, and 0.010 μm, respectively. The Teflon membrane (Φ47 mm, Whatman, GE Corporation, Britain) was set at the bottom to collect the remains. The Moudi was run at 10 L/min. Meanwhile, it rotated to make sure particles collected spread out to a large area on the filters. Collected particles were weighted in dry–wet balanced analysis room. The Moudi ran 8 hours consecutively to collect particles in workshop, and the weight percentage of particles collected on each stage was calculated. The percentage of TiO2 in the total dust was more than 98% (m/m), and that of water-soluble substances was less than 0.5%.

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Personal Exposure Assessment

Personal exposure to the TiO2 was measured by personal sampling pump (SIDEPAK, Model Sp330, TSI Corporation, Las Vegas, NV). The subjects wore the sampler while working and the sampling inlet was fixed beside the shoulder, near the subjects' breathing zone. All the subjects wore filtered respirators while working. The sampler was run at 1 L/min for 8 consecutive hours. The particles were collected onto the mixed cellulose ester filters (Φ37 mm, Pall Corporation, Washington, NY) for weighting.

All flters and aluminum foils were maintained for at least 24 hours in the room with 20 ± 1°C and 40 ± 3% of hygrometry, they were weighed before and after sampling using electronic microbalance (Mettler Toledo, 10 μg sensitivity, Zurich, Switzerland) to determine the mass of collected particles. The concentrations of TiO2 particulates were calculated considering sampling time and flow rate.

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Measurement of Pulmonary Function

Pulmonary function testing was performed by professional physicians using Quark PFT-2 spirometry (COSMED Corporation, Rome, Italy) in the workers' restroom. The measures of pulmonary functions included FVC, FEV1.0, MMEF, MEF25%, MEF50%, MEF75%, peak expiratory flow(PEF), maximum voluntary ventilation (MVV), and FEV1.0/FVC ratio. The subjects took a standing position and performed according to the physician's instructions, which referred to the American Thoracic Society standards for lung function testing reproducibility. All the tests were performed 30 minutes before or after working. The parameters were converted to body temperature and pressure saturated with water standard units. If the predicted FVC, FEV1.0, or MVV were lower than 80%, the subject performed the testing after a short rest. The differences of pulmonary function parameters (including MVV, FEV1.0, FVC, MMEF, MEF25%, MEF50%, MEF75%, PEF) between before and after working were analyzed with TiO2 concentrations.

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Blood Pressure Measures

Blood pressure (BP) measurements were collected in a relatively quiet room for two times, before and after working. Before measurement, all the subjects rested for at least 10 minutes. The measures included systolic BP (SBP) diastolic BP (DBP) heart rate, collected by a fixed physician with mercury sphygmomanometer. Blood pressure measurements were taken two times for each subject with 10 minutes' interval; the average of the two measurements was used for statistical analysis.

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Meteorology Data

Meanwhile, digital Thermo-Hygrometer (AZ8703, AZ instrument Corporation, Taiwan, China) was used to monitor the temperature and relative humidity in the sampling and activity area. Each site was measured three to five times. Daily average temperature and relative humidity were calculated as covariate variables for statistical analysis.

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Data Analysis

The data in this study were multilevel; data such as pulmonary function were measured for each subject, and for every working day. Other data such as occupational history and body mass index (BMI) were fixed or not changed in short time. Our analysis took these variables into account.

As the repeated measure data, we used linear mixed effects models to determine the effects of TiO2 on the subjects' cardiopulmonary function. The mixed model generalizes the standard linear model as follows20,21:

Equation (Uncited)
Equation (Uncited)
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In the expression, i represents the subject code, j represents the number of measurements, Yij represents the differences of pulmonary function (FVC, FEV1.0, MMEF, PEF, MVV etc.) between pre-and post-work, Xi denotes a fixed variable (titanium dioxide concentration, sex, age, work shift, employment duration, BMI, air temperature and relative humidity), and β indicates the fixed effects parameters to be estimated, Zij denotes a random effects variable with Yij as random effects parameters, eij is an error term with a multivariate normal distribution. According to the Akaike Information Criterion, we chose an autoregressive covariance matrix as the working covariance structure. Data were analyzed using the statistical package SAS (version 9.1, SAS Institute Inc, Cary, NC) and Excel (version 2003, Microsoft Co, Redmond, WA).

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Subjects' Characteristics

The study included 7 workers and lasted 29 days. The basic description of the study subjects is shown in Table 1. All 7 workers were male, there were 4 smokers, the average age was 36.57 (range, 29 to 48), and the average employment duration as a TiO2 worker was 8.64 years (range, 3 to 23). In the study period, 84 measurements (65%) were collected during the morning shift. All the subjects were in good condition without any chronic cardiovascular or pulmonary diseases.

Table 1
Table 1
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Meteorology and Titanium Dioxide Data

Table 2 shows the meteorologic and personal exposure data during the study period (29 days), and the mean concentration of daily personal TiO2 exposure was 1.194 mg/m3 (range, 0.319 to 6.258 mg/m3). The mean temperature and relative humidity in the sampling sites were 29.95°C and 44.31%, respectively. The meteorologic data of 9 days for stationary particle measurements was 30.03°C and 45.93%, respectively. The meteorologic conditions in the stationary days were similar to those in whole study period.

Table 2
Table 2
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Titanium Dioxide Particulates' Size Distribution

Table 3 shows the results of Model 125B Nanomoudi in 9 days. To investigate particles' size distribution, the TiO2 on each stage was expressed as weight percentage in all particles collected. The mean weight of TiO2 particulate in 14 stages ranged from −0.006 to 0.936 mg, with the weight percentages in total dust ranging from −0.1% to 21.1%. Compared with the sampling results in other 8 days, the weight of TiO2 collected on the first stage on the second day was obviously large (4.865 mg), and the mean weight percentages of the first stages particles in total dust declined to 14.5% when excluded the second day.

Table 3
Table 3
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Figure 1 shows the size distribution according to the weight percentages during the sampling time. Figure 1 shows the data for 9 days, whereas Figure 2 shows the data for 8 days excluding the second day, in which the trend of the lines was consistent except the first stage. Considering the data of the second day may be magnified by an unexpected event, we calculated the particles' size distribution excluding the results of the second day.

Figure 1
Figure 1
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Figure 2
Figure 2
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Considering the health effects of particles with different sizes, and the cutoffs in the cascade impactor, we divided the total dust into three parts by sizes: PM>10, PM1–10, and PM<1. The weight percentage of each part in the total dust was calculated in Table 3. The percentage of particulates for size greater than 10 μm, 1 to 10 μm, and less than 1 μm were 14.5%, 69.6%, and 12.3%, respectively. According to the definition in occupational health,22 inhalable dust refers to those particles with aerodynamic diameter smaller than 15 μm, whereas the respirable dust with aerodynamic diameter smaller than 5 μm and the inhalable TiO2 particles were dominant in this workshop.

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Summaries of Cardiopulmonary Function Data

The physical results showed most of the postwork pulmonary function parameters declined compared with those before work. The prework mean levels of FVC, FEV1.0, PEF, MVV, and MMEF were 4.57, 3.70, 6.53, 144.02, and 3.67 L/s, respectively, whereas these changed to 4.54, 3.67, 6.45, 144.05, and 3.64 L/s after work. The postwork BP increased slightly for SBP and DBP from 131.1 and 75.5 to 131.6 and 76.6, respectively.

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Results of Regression Analysis

A mixed effect model analysis for cardiopulmonary function was shown in Table 4. The differences between post- and preshift parameter values were taken as the dependent variable. Adjusted with age, work shift, employment duration, BMI, and smoking status, the model showed a negative association between pulmonary function and personal total TiO2 particulates exposure. For each 1 mg/m3 increase in TiO2 particulates level, MVV, PEF, MMEF, MEF50%, and MEF75% declined 3.767 (P = 0.01), 0.331 (P = 0.040), 0.131 (P = 0.049), 0.151 (P = 0.045), and 0.244 (P = 0.044), respectively. No such association was found in FVC, FEV1.0, FEV1.0/FVC, nor MEF25%. An increase of 1 mg/m3 total TiO2 particulate concentration was associated with 1.86 mm Hg increase in postwork SBP (P = 0.024), although DBP and heart rate showed an increase tendency without statistical significances.

Table 4
Table 4
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The study was conducted in a finished product workshop of a TiO2 plant. The seven subjects were the workers occupationally exposed to TiO2 particles. The health effect of TiO2 on the occupational population has been studied recently,69 especially on the risk of lung cancer, whereas the effect on the pulmonary function such as ventilation function has rarely been noticed. As far as we know, this study was the first research on the effect of short-term exposure on pulmonary function parameters.

A major strength in our research is that we studied the effect of TiO2 short-term occupational exposure on the basis of particles' size distribution in the workshop. Titanium dioxide particles were dominant in the total dust of the environmental particles. Particles' size distribution in the workshop was assessed by multistage impactor first. The sampling results showed that the inhalable TiO2 was dominant in the total dust. Titanium dioxide particles' size distribution analysis showed that the weight of particles for size between 0.1 and 1 μm were about 10% of the total dust. As the weight of PM1 (particles with diameter smaller than 1 μm) was very slight, the number counts of PM1 were much numerous at this level, which was similar to the findings in an iron foundry.23 Fang et al24 showed that in a traffic-sampling site, the average cumulative fractions of PM0.1, PM2.5, and PM10 were 16.9, 68.9, 94.4%, respectively, whereas the percentages in this study were about 16.0%, 41.1%, and 85.5%, respectively. The research results were consistent to some extent.

As we know, the size of the particles resulted in various deposition regions of the respiratory tract25; according to the International Commission on Radiological Protection model, particles' deposition during sleeping time is significantly different with that during heavy exercise. During exercise, particles in the ultrafine size range (<0.1 μm) are deposited in the alveoli and tracheobronchial regions dominantly, especially the particles in the range of 10 to 100 nm. For fine particles, alveolar deposition is maximal at about 0.3 μm aerodynamic diameters. Combined with the particle size distribution in this study, we deduced that the TiO2 particles were mostly deposited in alveolar and bronchial regions, and part of the large particles probably in the extrathoracic (nasal, pharyngeal, laryngeal regions) regions. The health effects of TiO2 mainly affected the function of small airways.

Maximum mid-expiratory flow, MEF50%, and MEF75% are sensitive parameters representative of the small airway function. The linear mixed effects model, adjusted with age, work shift, duration of employment, and BMI, showed that changes of postwork pulmonary function were associated with personal TiO2 exposure. Values of MMEF, MEF50%, and MEF75% declined 0.131 (P = 0.049), 0.151 (P = 0.045), and 0.244 L/s (P = 0.044) with each 1 mg/m3 increase in TiO2 exposure concentration, respectively. Small airways were the bronchioles, terminal bronchioles and alveoli ducts with diameter smaller than 2 mm. As the ciliated epithelial cells and secreting gland inside the small airways are fewer, cross-section areas are large with less airflow resistance; the particles were probably deposited in these regions and impacted the small airways functions.26 Taking the TiO2 size distribution into account, we believed that the declined pulmonary function was related to particles' deposition in small airways. The fine or ultrafine TiO2 particles deposited in airways can induce aberration of the pulmonary surfactant ultrastructure and function, and increase the surface tension and the retraction resistance of the lung.27 For example, it has been demonstrated that pulmonary surfactant dysfunction was found in some pulmonary diseases.28

As the subjects took up physical activities, the TiO2 health effects could be deduced from the pulmonary function changes produced by the exercise activities. It has been suggested that particle exposure during physical exercise could decrease the human pulmonary diffusing capacity for carbon monoxide,29,30 and increase the particles' deposition 4.5-fold during exercise over rest.31 High fine particulates exposure was correlated with the decreased MMEF.29 Zhang et al 32 obtained the similar results.

In this study, no statistical significance was found between FVC, FEV1.0, FEV1.0/FVC, and personal titanium dioxide exposure. As the participants were all healthy subjects, the basic levels of FVC, FEV1.0, and FEV1.0/FVC were in the normal range, and they possibly had not been changed in the short-term observation; Wild P et al16 showed FVC, FEV1.0 of the talc workers only decreased by 7.71, 6.11 mL per year·mg/m3. Meanwhile, application of the suitable protective equipments could prevent the large particulates from depositing in the extrathoracic regions and affecting the function of the airways.

Also, our data showed that personal TiO2 exposure increased the postwork SBP. Recently, much research has focused on the effect of particulates on the BP, and some conclusions were obtained from different researchers.3335 In this study, 1 mg/m3 increase in TiO2 daily exposure was associated with 1.86 mm Hg (P = 0.024) higher postwork SBP, adjusted for age, BMI, work shift, smoking status, temperature, and humidity. The TiO2 particles' concentration in the finished product workshop was higher than its surroundings, whereas the concentrations of the gaseous pollutants such as sulfur dioxide were lower; it had been demonstrated that gaseous pollutants mostly affected the aorta endothelium function, whereas particle pollutants aggravated small arterial hyperemia,36 and increased the bloodstream in the circulation system, which brought about the BP changes.

Considering the numerous fine or ultrafine TiO2 particles in the workshop, they may cause pulmonary and systemic inflammation after inhalation into the lung, which could indirectly impact the cardiovascular system. The inhaled TiO2 can stimulate the production of proinflammatory factors in the endothelium cells; meanwhile, small particles can transport into the bloodstream, which could affect vascular permeability and bloodstream.37,38 It had been demonstrated that TiO2 particles exposure could damage the endothelium-dependent dilation in the systemic microcirculation.39

In this study, the potential confounders were collected and controlled in the mixed effect model; nevertheless, some limitations still existed. Only 9 days were selected to measure particles' size distribution instead of the whole study period, as the size distribution was daily changed. The weight percentages for particles below 100 nm have some negative values, which suggest that the random noise or the sensitivity of electronic microbalance is out of the weighting requirements. For the second day, the weight percentage of particles in the first stage was obviously an outlier while the machine ran correctly. According to the survey records, we excluded the second day's sampling results. All of those can be improved in our future research.

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In conclusion, we demonstrated significant association between inhalable TiO2 exposure and declines in pulmonary function, as well as increase in BP, especially in small airways functions and SBP in healthy workers at the end of shift. Our data provides new evidence for health effects of short-term occupational inhalable TiO2 exposure, suggesting a demand for setting up new occupational exposure standards on fine or ultrafine TiO2 in workshop. Also, the exposure assessment data suggested the employers should improve the work environment and employees' personal protective equipments, especially reducing TiO2 concentration and using effective respirators, such as N95 respirator.

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The authors thank the doctors of Centers for Disease Control and Prevention of Jinan City, and the subjects in titanium dioxide factory for their support.

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