Results of a Series of Epidemiological Investigations on Health Effects in Toner-Manufacturing Workers

Abstract

A cohort study spanning ten years was conducted to assess the health effects on toner manufacturing workers. A survey consisting of questions investigating subjective respiratory symptoms, current medical history, disease occurrence, dust exposure concentrations at the workplace, respiratory function tests, biochemical and immunological items in blood and urine, and a chest radiograph or chest computed tomography survey was conducted. The results of these surveys have been published in academic journals, and none of the surveys showed any findings suggesting significant health problems in the toner-worker group compared to the non-toner-worker group. The results suggest that the health risks associated with toner handling are not high when the work environment at the toner handling site is well controlled.

1. Introduction

Adverse health effects can occur in occupational engagements in various industries, and there have been several reports on the contamination of work environments by long-term exposure to chemicals such as heavy metals and organic solvents [1,2]. Dust has long caused serious health problems at workplaces such as coal mines, tunnel construction, arc welding, metal grinding, foundries, and quarries.

A toner particle is a particulate material sized 5–10 μm in diameter and used in photocopiers and laser printers to form printed images and text on paper. The toner particle is not nano-sized, and industrial nanomaterials are used as the constituent components. Industrial nano-substances include coloring agents such as carbon black (dispersed in the resin, which is the main component of toner), with nano-titanium dioxide and nano-amorphous silica as external additives.

Since the first reported case of siderosilicosis due to toner exposure in 1994, there have been additional case reports of sarcoidosis, allergic rhinitis, and asthma associated with toner exposure [3,4,5,6,7]. These reports raised concerns about the health effects associated with toner exposure and copier and printer use. A recent study found that many studies have shown that the use of laser printing devices (LPDs), such as printers and copiers, contributes to the emission of particles into the indoor environment and may increase indoor air pollution [8,9,10]. However, despite more than 20 years of mixed results on this issue, the substantial relationship between the physico-chemical properties of LPD-emitting particles and the possible health effects of particle exposure in workplaces is still being debated. However, from the industrial hygiene standpoint, toner particles’ production method has changed since the 1990s, and the working environment has also changed. Therefore, the potential health effects of PM emitted from office equipment in laser printer users must be evaluated separately.

Our department has conducted studies on the health effects of toner handling workers and published several papers [11,12,13,14,15,16,17,18,19,20,21]. This paper presents the 10-year cohort of papers we have submitted and published to date and outlines the health effects of toner p article exposure among toner handling workers.

2. Materials and Methods

2.1. Research Design

The survey research was conducted independently at six business establishments. Each establishment’s survey method used the same items and procedures as much as possible. The findings of five of the six companies surveyed were published in an English academic paper [11,12,13,14,15].

Table 1. Number of participants and follow-up rates for five papers.

Authors	Published Years	Follow-up Years	Number of Workers Surveyed (At Entry)	Number of Workers Surveyed (Analysed)		10 Years Follow-up Rate(%)	Survey Items Analyzed in the Paper
				Toner-Handling Workers	Non-Toner-Handling Workers
Ikegami et al. [15]	2016	2004 to 2013	112	2004: 53, 2004 to 2008: 32 2013: 13	2004: 59, 2004 to 2008: 45 2013: 24	37/112 (33.0)	Qustionnaire, Blood test, Chest X-ray
Kitamura et al. [13]	2019	2004 to 2013	296	155	136	673/752 (89.5)	Qustionnaire, Blood test, Urne test, Spirometry, Chest X-ray
Hasegawa et al. [14]	2018	2004 to 2013	752	523	150	673/752 (89.5)	Qustionnaire, Blood test, Urne test, Spirometry, Chest X-ray
Yanagi et al. [11]	2021	2006 to 2015	90	38	27	65/90 (72.2)	Qustionnaire, Blood test, Urne test, Spirometry, Chest X-ray, Chest CT
Terunuma et al. [12,22]	2019	2004 to 2013	1504	887	581	1468/1504 (97.6)	Questionnaire
	2020						Blood test, Urne test, Spirometry, Chest X-ray
		total	2754	1616	918	2534/2754 (92.0)

shows the survey period profile and items at each toner-manufacturing company. The total number of participants was 2754 at the start and 2534 at the end of the survey, with a follow-up rate of 92.0%. Among them, the research study of Ikegami Paper 1 includes a small number of women, but all the other papers include male data.

2.2. Overview of the Research Protocol

2.2.1. Participants

The participants were workers at toner manufacturing plants who were 50 years old or younger at the start of the survey and engaged in toner manufacturing, development, maintenance, and recycling work as well as non-toner-handling workers as a control group. To control for potential biases arising from differences in lifestyle and nutritional status due to socio-economic factors, differences in non-occupational exposure to air pollution due to living conditions and environmental factors, and differences in occupational exposure to air pollution other than toner, subjects in the non-toner-handling group were recruited from among male workers of a similar age working at the same business sites as those of the toner-handling group. Selection was made with consideration to avoiding differences in factors that could be confounding factors as much as possible. We obtained written informed consent from each participant.

2.2.2. Questionnaire

At the annual survey, a self-administered questionnaire collected information on participants’ occupational history, history of illness, current illness, respiratory symptoms, and diseases using the Japanese translation of the standardized self-administered questionnaire by the American Thoracic Society (ATS-DLD-78A) [23].

2.2.3. Work Environment Evaluation of the Exposure Status of Toner

In some studies, the exposure level of workers was estimated based on the work environment survey, conducted annually. In other studies, the annual exposure concentration was estimated by wearing a personal exposure concentration monitor at the time of work. Personal exposure measurements by light scattering were performed on randomly selected workers at each measurement site. The standard value of 3.0 mg/m³ (threshold limit value) for the time-weighted average of 8 h (8 h-TWA) for “Particles (insoluble or poorly soluble) not otherwise specified” by the American Conference of Government Industrial Hygienists (ACGIH) [24] (threshold limit value–time-weighted average; TLV-TWA) was adopted as the exposure limit standard for evaluating the measurement results.

2.2.4. Biomarker Analyses

Blood leukocyte count, C-reactive protein (CRP or high-sensitivity CRP), interleukin 6 (IL-6), interferon-gamma (IFN-γ), lung C-reactive sugar chain antigen KL-6 (KL-6), pulmonary surfactant protein D (SP-D) as an index showing fibrosis, immunoglobulin E (IgE) as an index related to allergies, and urinary urine as an evaluation of oxidative stress 8- Hydroxy-deoxyguanosine (8-OHdG in urine) were measured. White blood cell count, CRP, and 8-OHdG were measured annually, and other items were measured every other year. To maintain accuracy and precision throughout the whole survey, we requested the OHG Institute Co., Ltd. (Kitakyushu, Japan) to perform the analysis of 8-OHdG and SRL Inc. (Tokyo, Japan) to analyze other biomarkers.

2.2.5. Pulmonary Function Test

A yearly respiratory function test was performed on the participants. Pulmonary function tests were measured using an electronic spirometer, according to the measurement manual presented by the American Thoracic Society (ATS) [25]. As the degree of habituation and proficiency affects the results, three measurements were performed. Forced vital capacity (FVC), forced expiratory flow in one second (FEV1%), and peak flow (PEF) values were obtained in some surveys indicated by the Japanese Respiratory Society [26].

2.2.6. Chest Radiography and CT Examination

The images were taken annually per the standard method stipulated in the Dust and Lung Act as an internationally comparable imaging condition [27,28]. The radiographs were interpreted based on the ILO International Pneumoconiosis Classification [29], and the doctor performed a double interpretation. The image interpretation was performed in pairs by a doctor at the University of Occupational and Environmental Health. In addition, chest CT scans were performed in some studies. In certain studies, chest CT examinations were performed at baseline, 5th, and 10th years, and the report compared the results at baseline and year 10.

2.2.7. Statistical Analysis

In each of the papers, various statistical analysis methods were used depending on the data, due to the different deviation and distribution of the data obtained. In the Ikegami paper [15], analyses were conducted using mixed models and repeated measures analysis of variance (ANOVA), Bonferroni multiple comparison method, Mann–Whitney U test, Student’s t test, and Fisher’s exact test. In the Kitamura paper [13], one-way ANOVA, Tukey’s honestly significant difference (HSD) test, Welch test, Games Howell test, Pearson’s chi-square test, and multiple regression analysis analyses were conducted. In the Hasegawa paper [14], two-way analysis of variance (ANOVA) and post hoc Tukey test, Mann–Whitney U test, multiple regression analysis, and Pearson’s chi-square test were conducted. In the Yanagi paper [11], normality was assessed with the Shapiro–Wilk test, Mann–Whitney U test, and Student’s t test. Changes in respiratory function over time due to toner exposure were estimated by stepwise multiple regression analysis. In the Terunuma paper [12,22], chi-square and Fisher’s exact tests, simple t-test and Welch’s t-test for quantitative variables, logistic regression analysis with generalized estimating equations (GEE), two-way repeated measures analysis of variance (ANOVA), and linear mixed models (LMM) were used. In all analyses, the significance level was less than 0.05. IBM SPSS Statistics for Windows 22.0 J, 23.0 J, 24 (IBM Corp., Armonk, NY, USA) was used as the statistical analysis software.

3. Results

3.1. The Assessment of Health Disorders (Symptoms) by Questionnaire

Respiratory symptoms, respiratory diseases, and statistical analysis observed in five papers were shown in

Table 2. Respiratory symptoms, respiratory diseases, and statistical analysis observed in five papers.

Authors	Observed symptoms by Questionnaire	Observed Respiratory Diseases	Statistics
Ikegami et al. [15]	Persistent cough, persistent phlegm, persistent cough and phlegm	chronic brochitis (in toner-handling group)brochiectasis, other respiratory diseases (in non-toner handling group)	No significant differences were found between toner-exposed group and never toner-handling group for the other items. Fisher’s exact test was performed for annual comparisons of prevalence rates of each respiratory symptom between the toner– handling and non– toner –handling groups.
Kitamura et al. [13]	chronic phlegm, chronic wheezing and breathlessness,	N/A	Logistic regression analyses using generalized estimating equations (GEE) were conducted. There were no estimated statistically significant effects of the dust exposure levels and the cumulative toner-handling years till 2013 adjusting for age and smoking status.
Hasegawa et al. [14]	persistent phlegm	lung cancer (1 case in toner-handling group), brochial asthma (15 cases in toner-handling group, 4 cases in non-toner handling group)	No significant differences were found between toner-exposed group and never toner-handling group for the other items.
Yanagi et al. [11]	N/A	N/A
Terunuma et al.	Chronic cough, chronic phlegm, chronic cough and phlegm, wheezing without an asthmatic response, and shortness of breath.	asthma, allergic rhinitis, allegic dermatitis, pneumonia, sinusitis	They adjusted for the effects of potential con-founders in four models with additional variables (Model 1 to Model 4).Models 1 through 3 show the estimated effect of toner exposure on the annual change in each respiratory subjective symptom as a quotient of the odds ratio of annual change in the toner-handling group divided by the odds ratio in the non-toner-handling group. No significant effect of toner exposure was found for any of the five symptoms. The highest goodness-of-fit was demonstrated for four of the symptoms in Model 3. Model 2 showed the highest goodness of fit with only wheezing without an asthmatic response. When GEE analyses were performed separately for each level of toner exposure, they showed that toner-handling work was not associated with exacerbation of these outcomes.

. The questionnaire focused on the development of respiratory symptoms over 10 years. Of the papers describing the results of questionnaires, the Ikegami paper [15], Hasegawa paper [14], and Kitamura paper [13] reported “persistent cough’’, “persistent phlegm’’, “persistent cough’’, “persistent cough and phlegm”, and “wheezing and shortness of breath without asthma reaction” as major respiratory symptoms related to toner exposure. Significant differences were observed at intermittent points during the observation period between the toner-handling-worker and the non-toner-handling-worker groups. However, there were no significant differences in the expression of these symptoms in the entire observation period’s analysis. No statistically significant effects were estimated after adjusting for age or smoking status. However, regarding the effect of smoking on the onset of these symptoms, the Kitamura paper [13] found a statistically significant relationship. The questionnaire survey of respiratory symptoms found that the effect of smoking was more pronounced than that of toner-handling work. Therefore, smokers are also suggested to be at high risk.

In the Terunuma paper [28], a more detailed statistical analysis was performed. A logistic regression analysis using the generalized estimating equation (GEE), with each participant as the subject variable and the survey year as the within-subject variable, was adopted for the longitudinal data. They also adjusted for the effects of potential con-founders in the following four models with additional variables:

• Model 1. Without Adjusting for Confounding Factors,
• Model 2. Adjusted for Baseline Age and Body Mass Index (BMI),
• Model 3. With Further Data Adjustment for Smoking, Asthma, Allergic Rhinitis, Allergic Dermatitis, Pneumonia, Sinusitis, Dust Other than Toner Work, and Organic Solvent Work (Taking the BMI as a Confounder),
• Model 4. Adjusted for the Combination of Confounding Factors of the Model with the Highest Goodness of Fit.

Models 1 through 3 show the estimated effect of toner exposure on the annual change in each respiratory subjective symptom as a quotient of the odds ratio of annual change in the toner-handling group divided by the odds ratio in the non-toner-handling group.

No significant effect of toner exposure was found for any of the five symptoms: chronic cough, chronic phlegm, chronic cough and phlegm, wheezing without an asthmatic response, and shortness of breath, with or without adjustment for confounding factors. The highest goodness-of-fit was demonstrated for four of the symptoms in Model 3.

Model 2 showed the highest goodness of fit, with only wheezing and without an asthmatic response. When GEE analyses were performed separately for each level of toner exposure, the odds ratios for annual change in wheezing without asthma response were 0.70 (95% CI: 0.53–0.93) for the high toner exposure group, 1.0 (95% CI: 0.93–1.10) for the low toner exposure group, and 0.96 (95 (95% CI: 0.87–1.05) in the non-toner group.

Thus, a GEE analysis that adjusted for confounding factors and accounted for the correlation of within-subject data showed that toner-handling work was not associated with exacerbating the assessed outcomes. This study suggests that toner-handling work had a minor adverse effect on human health in a work environment with sufficiently controlled ventilation.

3.2. Work Environment Evaluation

Exposure concentrations in the work environment in five papers are shown in

Table 3. Exposure concentrations in the work environment in five papers.

Authors	Published Year	Journal	Overall Average Personal Toner Exposure
Ikegami et al. [15]	2016	Industrial Health	TWA 8h <0.24 (mg/m3): R&D of toner or machine development group <0.08 (mg/m3): production and maintenance group
Kitamura et al. [13]	2019	J UOEH	Mean dust concentration <0.215(mg/m3) in toner manufacturing group <0.575(mg/m3) in R&D of toner group <0.323(mg/m3) in engineering group
Hasegawa et al. [14]	2018	Int J Occup Med and Env Health	TWA 8h <0.30 (mg/m3) in customer service group, toner manufacturing group, and toner development group
Yanagi et al. [11]	2021	J UOEH	arithmetical mean <0.054(mg/m3) in Laser printer quality assurance group, and laser printer mechanism group
Terunuma et al. [12,22]	2019	Atmosphere	A total of 0.989 (0.786) mg/m3 for toner and copy machine recycling, 0.203 (0.441) mg/m3 for toner manufacturing, 0.034 (0.030) mg/m3 for tonerdevelopment, 0.019 (0.063) mg/m3 for toner and copy machine development, and 0.020 (0.060) mg/m3 for customer service.
	2020	BMC Pulmonary Medicine

. Dust concentration measurements in toner handling workplaces were evaluated through individual exposure measurements and workplace dust concentration measurements. As mentioned in the Terunuma paper [12,22], there were differences in individual exposure concentrations among work categories by toner operation, with significantly higher concentrations in the machine recycling and toner manufacturing work categories than in the other work categories. This trend is similar to that observed in the Kitamura paper [13], where results of individual exposure measurements showed that the average dust concentration over the 10-year observation period ranged from 0.109 to 0.215 mg/m³ for toner manufacturing, 0.038 to 0.575 mg/m³ for toner research and development, and 0.044 to 0.323 mg/m³ for engineering. This is also similar to the Ikegami paper [15] (by work category, “production and maintenance”) which found a tendency for the average TWA8 h to be higher than that of “research and development”. However, each of the papers’ reports calculated 8-h weighted average concentrations of personal dust exposure and compared them to the ACGIH definition of allowable concentrations of 3.0 mg/m³ for “non-water soluble or insoluble substances that cannot be classified”. Still, no circumstances were found where the work was performed above this standard over the 10-year observation period. In addition, occupational health measures such as wearing protective equipment and installing local exhaust ventilation systems were implemented in almost all workplaces.

3.3. Biomarker Analyses

The Ikegami paper [15] evaluated the effects of each biomarker (except CRP) between toner-treated and non-toner-treated groups at the three survey points in 2004, 2008, and 2013. No significant differences were found and no interaction effects between biomarkers and each dependent variable were detected. No statistically significant differences were found between the toner-handling and non-toner-handling groups over the 10-year observation period for CRP. In the Hasegawa paper [14], in analyzing the interaction between working with toner and smoking over a 10-year observation period, some years showed significant differences in SP-D concentrations between the toner-handling and non-handling groups in two-way ANOVA, but not in multiple comparisons. A similar trend was also observed in the blood IgE concentration item between the toner-handling and toner-non-handling groups in years in which concentrations were significantly higher in the toner-handling group than in the past smoker or nonsmoker groups. Statistically significant differences were detected for several biomarkers, but all values were very low and varied within the test reference range. In the Kitamura paper [13], among the biological markers measured, IL-4, IL-8, and IFN-γ were excluded from the analysis. Most parameters showed no significant difference between the toner-handling group and the non-handling group during the ten years of investigation. The Yanagi paper [11] showed no statistically significant differences between groups for CRP, IgE, SP-D, and 8-OHdG/Cre throughout the 10-year observation period. However, KL-6 was significantly higher in the toner non-treatment group than in the toner treatment group. In the Terunuma paper [12], measurement of four cytokines (IL-4, IL-6, IL-8, and IFN-γ) was discontinued by 2008 (fifth follow-up) and excluded from the longitudinal analysis. IL-4 and IL-8 showed no significant differences between the toner-handling and non-toner-handling groups in any year up to the fifth year of the study. For IL-6 and IFN-γ, significant differences were observed between the two groups in some years, but these differences were not consistent and did not exceed reference values. Therefore, they concluded that these parameters, such as cytokines, were not clinically significant.

3.4. Pulmonary Function Test

Pulmonary function tests were performed annually using a spirometry measuring unit that meets the criteria set by the American Thoracic Society. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and percentile forced expiratory volume in 1 s (FEV1%) were analyzed. In the Ikegami paper [15], the multiple comparisons analysis showed that %VC and FEV1% analysis was adjusted for smoking with a statistical model. Still, there was no respiratory effect due to toner exposure, regardless of smoking status. In the Hasegawa paper [14], individual annual changes were determined from the measured values of FVC, FEV1, and FEV1% for each participant over 10 years to determine a standard curve. The slope was calculated as the annual change (l/year or %/year). As a result, no significant difference was observed in any items when the changes in FVC, FEV1, and FEV1% were analyzed for the toner handling and non-toner-handling groups. Since pulmonary function tests are affected by smoking, no significant differences were observed when participants were analyzed by smoking status (current or former smokers and non-smokers). They also evaluated the relationship between long-term occupational toner handling history and changes in respiratory function. However, no correlation was found for any variable, including long-term occupational toner handling history. The analysis did not find variables influencing annual respiratory function changes in the Kitamura paper [13]. Annual changes in lung function indices such as vital capacity (VC), forced vital capacity (FVC), and FEV1.0 were used to assess the effects of toner exposure. Multiple regression analysis was performed using the annual change in pulmonary function index as the dependent variable, and the estimated average dust concentration over 10 years and cumulative toner handling years up to 2013 as the independent variables adjusted for age and smoking status in 2004. No significant effect was observed in the estimated average dust concentration and cumulative toner age. The Yanagi paper [11] found no statistically significant difference between baseline and 10-year toner-handling and non-toner-handling groups. They also compared the difference in the annual decline in respiratory function between all participants and his 10-year non-smoker, examining changes in respiratory function over time with and without toner exposure. However, no statistically significant difference was observed between the two groups. A similar analysis was conducted on 55 non-smokers (20 non-users of toner, 35 users of toner) during the 10-year survey, but no statistically significant difference was observed between the two groups. In the Terunuma paper [12], the effect of toner exposure on respiratory function was shown as the difference in annual changes in parameters between the toner-handling group (including subgroups) and the toner-non-handling group. No significant difference was observed when comparing the results of respiratory function tests in the toner-handling and non-toner-handling groups at baseline and in the 10th year. In addition, the annual decrease in respiratory function was compared. This was obtained by subtracting the respiratory function test value at the 10th year from the baseline respiratory function test value, dividing it by 9 years, and comparing the respiratory function of the toner-handling group and the non-toner-handling group. The functional change rate was examined. However, no significant difference was observed. Since smoking affects respiratory function, similar comparisons were performed in non-smokers at year 10, controlling for smoking factors. Still, there were no significant differences between the toner-handling and non-toner-handling groups.

3.5. Chest Radiography and CT Examination

In chest radiography findings, no significant results attributed to toner-related work were observed with respect to the development of pneumoconiosis, pulmonary fibrosis, and lung cancer throughout the 10-year observation period. In Kitamura’s paper [13], toner-handling workers, namely toner manufacturing groups, research and development groups, and technology groups, were compared with non-toner-handling groups. Regarding the detection rate of ILO pneumoconiosis classification of 0/1, no significant relative risk was observed in the toner-handling group. In the Terunuma paper [12], which had the largest number of studies, 11,563 chest radiography examinations were performed during the 10-year follow-up period. No significant findings related to toner exposure were observed even when analyzed separately for each engagement of toner exposure. The chest CT examination is discussed in the Yanagi paper [11]. They also found no findings suggesting granulomatous pneumonia or malignancy in baseline and 10-year chest CT results for workers who did not handle and workers who handled toner.

4. Discussion

Since toner particles are powders, the biological effects of toner particles, mainly through inhalation, are problematic in toner-handling workplaces. As toner particles are used in laser printers, the biological effects of emissions from laser printers and copy machines have received considerable attention. Several recent cross-sectional studies have evaluated the relationship between printing work in copy centers and subjective respiratory symptoms [8,10]. All of these studies report that the prevalence of subjective symptoms tends to be higher in copy center workers than in controls [8,9]. However, the biological effects of inhalation of toner particles and the biological effects of substances emitted from laser printers are not identical and should be considered separately. According to the review by Gu et al., the trend in publications on the biological effects of toner, especially substances emitted from laser printers, shows in the literature over time [30]. The review states that the literature can be divided into two main phases: from 2006 to 2011, where the majority of papers focused mainly on the physical and chemical properties of substances emitted from laser printers, and since 2010, where there has been an increase in the number of investigations on the biological effects of substances emitted from laser printers.

In this review, we presented a paper from our laboratory, which conducted a 10-year epidemiological cohort study on the health effects of workers in a workplace engaged in manufacturing toner particles. In our protocol, the toner-handling and non-toner-handling groups were divided into two groups. The incidence of respiratory disease and the occurrence of respiratory symptoms were investigated using a questionnaire. A survey of toner particle exposure in the work environment, a survey of urinary markers in the blood, a respiratory function test, and chest radiography and CT examinations were mainly conducted. As shown in Table 1, the number of entries followed up for 10 years in our laboratory was 2754 in total in the toner-handling and non-toner-handling groups, and the number of entries that could be analyzed was 2534 out of 2754. According to the individual test items, there was no clear evidence of excess health effects due to toner use during the 10-year observation period.

One of the reasons for this is that the dust exposure concentrations for workers engaged in toner use during the 10-year observation period did not exceed the ACGIH acceptable standard of 3.0 mg/m³ during the 10-year observation period. In this regard, although we conducted an analysis including cumulative exposure and past exposure, as well as taking into account high and low concentration exposure for each task, no significant health effects due to toner exposure, including smoking status as a confounding factor, were found. As for respiratory symptoms centering on the upper respiratory tract, it was observed that symptoms such as chronic cough and phlegm tended to occur more frequently in the toner-handling group than in the control group. However, symptoms such as phlegm, cough, and shortness of breath may often happen when the general condition is poor, such as a cold. Therefore, there is room for further investigation as to whether these symptoms are caused by toner particle exposure.

In this study group, chest radiographs and chest CT images were compared. However, no findings suggestive of pneumoconiosis or malignant or active disease were observed in toner-handling workers. Since no effects of toner exposure on the occurrence of pneumoconiosis, respiratory tumors, or allergic diseases were observed throughout the observation period, it can be inferred that the risk of working with toner in a proper work environment and with appropriate work measures may be low compared to the respiratory effects of smoking habits.

A cohort study of health effects in toner workers over 10 years, similar to our laboratory, is reported in Nakadate et al. [31] Their study analyzed 694 participants (477 in the toner worker group) in 1557 entries. As in the present results, they found that under current reasonably controlled work environmental conditions, pulmonary fibrotic changes due to inhalation dust exposure, including powder toner, appear to be relatively rare. The authors conclude that although pulmonary fibrotic changes from inhalation dust exposure, including powder toners, this appears to be relatively rare under current reasonably controlled work environment conditions. There does appear to be a potential for nonspecific time irritation producing subjective symptoms and inflammatory responses.

With regard to changes in respiratory function, we examined whether there were significant differences in each index of respiratory function in the toner-handling relative to the non-toner-handling group over the 10-year observation period. We also attempted to determine whether the respiratory function indices decreased over time with exposure to higher concentrations of toner, based on estimates of dust concentrations in the work environment and individual exposure concentrations. The results showed no significant differences in respiratory function between the toner-free and toner-handling groups over 10 years in either study. Smoking is a well-known factor affecting respiratory function. Therefore, a multifactorial analysis of smoking factors was attempted in each study according to the presence or absence of toner-handling employment and the amount of toner exposure concentration, and a similar comparison was made for nonsmokers at the 10-year mark. Still, no significant differences were found between the non-toner-handling and toner-handling groups. In general, the results from our laboratory did not indicate any risk of the respiratory function being affected by toner handling engagements beyond the effect of smoking on breathing.

In studies with biological markers in blood and urine, WBC counts and CRP levels are increased in association with acute inflammation in the body, including the respiratory tract [32], suggesting that they are useful as markers of airway inflammation [33]. Furthermore, the IgE antibody titer is a versatile marker in allergic diseases, such as bronchial asthma patients. In the present study group, the annual changes in serum and urine biomarkers between toner non-handling and toner handling workers were similar. They did not differ significantly, suggesting that the factor of working with toner does not induce chronic inflammatory or allergic reactions under the kind of work environment investigated in the present study group. The results also suggest that KL-6 and SP-D are known to increase in patients with idiopathic pulmonary fibrosis [34] and are used as biomarkers of interstitial pneumonia in routine medical care and occupational health. In the present study group, no significantly elevated levels were found in toner-handling workers, suggesting that exposure to toner does not induce interstitial pneumonia. With regard to the toxicity of toner particles, the results of rat intratracheal instillation and long-term inhalation exposure tests [35,36] suggest that the carcinogenicity of toner particles is not so apparent and that, as with general dust, the excess amount of inhalation exposure and duration of exposure are involved in lung damage.

Limitations of these studies include several points. The sample sizes in each paper were small, and the 10-year follow-up rates in each paper varied from 33% to 99.3%. In addition, the data on toner exposure prior to the study period were scarce, except for the Hasegawa paper, making it difficult to examine cumulative exposure. In addition, the toner exposure concentrations at each of the workplaces surveyed in this study may be quite low. This may be due to the properly controlled work environment to prevent dust dispersion (use of exhaust ventilation). In addition, because the follow-up investigation was terminated with the occurrence of the endpoint disease, it is possible that other endpoint diseases that occurred after the follow-up investigation were missed. Therefore, the health risk of toner handling operations may have been estimated to be low.

5. Conclusions

After 10 years of observation of toner handling workers under 50, the apparent effects of toner handling work on biomarkers for increased pulmonary fibrosis, decreased respiratory function, and inflammation, allergies, and oxidative stress were not recognized.

This study, which reviewed a series of field studies operated by the same institution, shows that toner handling work is unlikely to adversely affect the operator’s respiratory system in a work environment where dust scattering is well controlled. Authors believe the so-called negative results study was well designed and has important implications for the safe operation of the manufacturing site and to give peace of mind to involved workers. However, an even longer follow-up is necessary to identify the late onset effects, such as malignancy.