Characterization of Occupational Plasticizer Exposure and Its Associations With Thyroid and Sex Hormones Among Male Automotive Workers = 근로자의 인체 내 프탈레이트 노출 농도와 내분비계 건강영향 연구

다국어 초록 (Multilingual Abstract)

Phthalate acid esters (PAEs) are a widely used class of plasticizers added to polymeric materials to enhance flexibility, softness, and durability. Several PAEs are classified as suspected endocrine- disrupting chemicals (EDCs) in humans, having demonstrated reproductive and developmental toxicity in experimental animal models. Driven by stricter regulations and health concerns, the industry is shifting towards non-phthalate alternative plasticizers (non-PAEs). Major APs include di(2-ethylhexyl) terephthalate (DEHTP), the non- aromatic and non-planar 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), and adipate-based plasticizers such as di(2-ethylhexyl) adipate (DEHA). These alternatives are now high-production-volume chemicals and undergoing regulatory evaluation under programs such as EU REACH and OECD HPVC (high-production-volume substances). However, the safety profile of these alternatives is not fully established ("regrettable substitution"). Emerging research suggests that APs may exhibit endocrine-disrupting properties. In the automotive industry, specifically, PAEs are essential additives in polyvinyl chloride (PVC) components such as wire harnesses, seat coverings, and interior trims. A critical characteristic of PAEs is that they are physically mixed into the polymer matrix rather than chemically bonded. Consequently, they are prone to gradual release into the surrounding environments through volatilization, abrasion, or leaching. This migration is often accelerated under high-temperature conditions, which are common in both the manufacturing processes of automobile parts and the vehicular environment itself. However, research on plasticizer exposure and its endocrine effects among workers remains limited. This study provides a detailed assessment of plasticizer exposure among male workers in the automobile parts manufacturing industry and comprehensively examines the associations between occupational plasticizer exposure and thyroid and sex hormone levels. It is the first study to apply clustering analysis to urinary plasticizer exposure patterns in this occupational group and to evaluate the associated health risks, including potential antiandrogenic effects. More broadly, it represents the first comprehensive evaluation of multiple plasticizer exposures in relation to both thyroid and reproductive hormone profiles, offering foundational data for research on occupational endocrine-disrupting chemicals. Chapter 1 provides an overview of the study background and outlines the research objectives. In Chapter 2, a systematic literature review was conducted to evaluate occupational exposure to plasticizers (phthalates and alternative plasticizers) in workplace air and dust. Data from 21 workplace studies were harmonized according to matrix, concentration range, sampling method, study design, industry/sector, location, and key methodological factors. The present study recruited 490 male workers from five automobile parts manufacturing plants between August and December 2023. From each participant, prior to workweek and end of workweek urine samples (one each), a single blood sample, and a questionnaire on plasticizer exposure sources were collected. Thirty-three metabolites of 18 parent plasticizers in urine were quantified using UHPLC–MS/MS. Serum concentrations of five thyroid hormones and six sex hormones were measured using immunoassay kits. To characterize workers’ plasticizer exposure profiles, k-means clustering analysis was performed. Associations between plasticizer exposure and thyroid and sex hormone levels were assessed using generalized linear regression models, while mixed-exposure effects were evaluated using G-computation. Nonlinear exposure–response relationships were examined using restricted cubic splines (RCS) and Bayesian Kernel Machine Regression (BKMR). These methods and findings are presented in chapter 3. In chapter 4, we characterized plasticizer exposure by incorporating job-specific differences as well as pre- and post-shift variations. Clustering analysis identified distinct and heterogeneous exposure groups shaped by work processes and workplace characteristics. We further identified potential occupational sources of exposure and found that the use of personal protective equipment was associated with reduced urinary metabolite levels. Risk assessment suggested a potential for antiandrogenic effects in specific exposure profiles, underscoring the need for monitoring endocrine-related outcomes in occupational settings. These findings support the importance of strengthened exposure management and regulatory measures to protect workers’ health in industries using plasticizers. In chapter 5, several plasticizer metabolites showed significant associations with thyroid hormone levels, with overall patterns of decreased TSH and increased T4 and T3. Mixture analyses using G- computation demonstrated consistent positive associations with total T3 and total T4. Nonlinear and cumulative mixture effects, identified using restricted cubic splines (RCS) and Bayesian Kernel Machine Regression (BKMR), highlighted the complex thyroid responses to plasticizer mixtures. In chapter 6, plasticizer exposure was associated with increased estradiol, an elevated total testosterone/LH ratio, and reduced LH. Mixture analyses, including BKMR, revealed consistent cumulative effects on estradiol and the testosterone/LH ratio, suggesting that plasticizer mixtures may influence male reproductive endocrine function. Chapter 7 presents the overall summary and conclusions. Taken together, the findings indicate that real-world occupational exposure to plasticizers may lead to measurable alterations in thyroid and reproductive endocrine function. The consistent nonlinear and mixture effects highlight the importance of evaluating plasticizers as combined exposures rather than in isolation. This work is among the first to systematically characterize occupational plasticizer exposure and associated endocrine effects in Korean manufacturing workers. The results underscore the need for (i) strengthened workplace exposure management and regulatory oversight, (ii) effective PPE use and exposure-reduction strategies, and (iii) long-term studies to evaluate potential health consequences.

목차 (Table of Contents)

• Chapter 1. Introduction 1
• 1.1. Plasticizers in industrial manufacturing: classification and uses of phthalates 2
• 1.2. Endocrine-disrupting effects of phthalates 3
• 1.3. Occupational exposure and health risks and regulatory measures 5
• 1.4. Emerging alternative plasticizers and potential toxicity concerns 8
• 1.5. Study objectives 9
• References 11
• Chapter 2. Occupational Plasticizer Exposure: A Systematic Review of Environmental Monitoring and Methodological Gaps 14
• 2.1. Introduction 15
• 2.2. Methods 17
• 2.3. General characteristics of the studies 20
• 2.4. Active air sampling studies 22
• 2.4.1. Sampling and analytical methods 23
• 2.4.2. Exposure levels by work setting 24
• 2.4.3. Composition profiles and dominant plasticizers by industry type 30
• 2.5. Passive air sampling studies 42
• 2.5.1. Sampling and analytical methods 42
• 2.5.2. Exposure levels by occupational setting 43
• 2.5.3. Composition profiles and variability by sampling method and placement 44
• 2.6. Settled dust monitoring 48
• 2.6.1. Sampling and analytical methods 48
• 2.6.2. Dust contamination by work setting 49
• 2.6.3. Composition of plasticizers in dust 51
• 2.7. Methodological limitations in study design and reporting 56
• 2.8. Conclusions 58
• References 59
• Chapter 3. Study Population and Methods 62
• 3.1. Sampling sites and conditions 63
• 3.2. Study population 66
• 3.3. Sample collection 67
• 3.4. Measurement of plasticizer metabolites in urine 67
• 3.5. Measurement of thyroid hormones, sex hormones and clinical variables 69
• 3.6. Questionnaire variables 70
• 3.7. Statistical analysis 71
• 3.8. Risk assessment 75
• References 81
• Chapter 4. Distribution of Urinary Plasticizers and Risk Assessment among Male Workers in Automobile Parts Industries 82
• 4.1. Characteristics of the study population 83
• 4.2. Distribution of plasticizers in urine 85
• 4.2.1. Concentration of urinary plasticizers 85
• 4.2.2. Concentration of plasticizers by different factories and job roles 87
• 4.2.3. Pre-workweek vs. Post-workweek 95
• 4.3. Clustering analysis 96
• 4.4. Factors influencing exposure among automobile parts workers 101
• 4.5. Human exposure and health risk assessment 105
• 4.6. Discussion 108
• 4.6.1. Comparison of urinary plasticizer levels among workers 109
• 4.6.2. Concentration of plasticizers by different working conditions 111
• 4.6.3. Clustering analysis 112
• 4.6.4. Factors influencing exposure among automobile parts workers 114
• 4.6.5. Exposure assessment through estimated daily intake 116
• 4.6.6. Strength and limitations 117
• 4.7. Conclusions 118
• References 119
• Chapter 5. Association Between Urinary Metabolites of Plasticizers and Thyroid Hormones 122
• 5.1. Characteristics of the study population and distribution of serum thyroid hormones and urinary plasticizers 123
• 5.1.1. Characteristics of the study population 123
• 5.1.2. Distribution of thyroid measurements and urinary metabolites of plasticizers 125
• 5.2. Association of urinary plasticizer metabolites with serum thyroid hormones 127
• 5.3. Quantile-based g-computation estimates of the joint effects of plasticizer mixtures on thyroid hormones 129
• 5.4. Dose-response relationship of urinary plasticizer metabolites with thyroid hormones 131
• 5.4.1. Dose-response association of plasticizers with thyroid hormones (RCS analyses) 131
• 5.4.2. The joint effect of mixed plasticizers on thyroid hormones (BKMR) 138
• 5.5. Discussion 147
• 5.5.1. Association between urinary plasticizers and thyroid hormones 147
• 5.5.2. Non-monotonic relationship between plasticizer exposure and thyroid hormones 150
• 5.5.3. Strength and limitations 151
• 5.6. Conclusions 152
• References 153
• Chapter 6. Association Between Urinary Metabolites of Plasticizers and Sex Hormones 155
• 6.1. Characteristics of the study population and distribution of serum sex hormones and urinary plasticizers 156
• 6.2. Association of urinary plasticizer metabolites with serum sex hormones 157
• 6.3. Quantile-based g-computation estimates of the joint effects of plasticizer mixtures on sex hormones 160
• 6.4. Dose-response relationship of urinary plasticizer metabolites with sex hormones 163
• 6.4.1. Dose-response association of plasticizers with sex hormones (RCS analyses) 163
• 6.4.2. The joint effect of mixed plasticizers on sex hormones (BKMR) 174
• 6.5. Age-stratified associations between urinary plasticizer metabolites and sex hormones 189
• 6.6. Discussion 194
• 6.6.1. Association between urinary plasticizer exposure and sex hormones 194
• 6.6.2. Non-monotonic relationship between plasticizer exposure and sex hormones 197
• 6.6.3. Age-stratified association between plasticizer exposure and sex hormones 197
• 6.6.4. Strength and limitations 198
• 6.7. Conclusions 199
• References 200
• Chapter 7. Summary and Conclusions 201
• Korean Abstract 203
• Appendices, Index 206