1,3-丁二烯、丙烯腈、苯乙烯是合成塑膠的主要原料，其最主要的產品為ABS樹脂。其中，1,3-丁二烯已被國際癌症研究署(International Agency for Research on Cancer，IARC)歸類為確定人類致癌物(Group 1)，丙烯腈和苯乙烯則被歸類為疑似人類致癌物(Group 2B)。1,3-丁二烯的主要代謝產物為DHBMA(1,2-dihydroxybutyl mercapturic acid)與MHBMA (monohydroxy -3-butenyl mercapturic acid)，丙烯腈的代謝產物為CEMA (1-cyano-2-hydroxyethyl) cysteine)。過去研究指出1,3-丁二烯、丙烯腈、苯乙烯三者共同暴露之工人，其職業性肝病以及毒物相關之脂性肝炎(Toxicant- Associated Steatohepatitis, TASH)發生率都伴隨提高，亦有研究指出，TASH會造成胰島素阻抗，但該研究並未實際偵測勞工暴露情形，因此無法判斷暴露與健康效應的相關性。由於1,3-丁二烯、丙烯腈與苯乙烯均為製造ABS的單體，三者在工業製程上常有共同使用的情形，因此作業勞工可能有同時暴露於多種物質的情形。我國為ABS輸出量最多的國家，但過去研究多為探討單一化合物與健康的情形，鮮少探討共同暴露與健康效應的研究，因此，共同暴露是否會造成勞工的健康危害，目前尚無定論。本研究之目的為建立1,3-丁二烯、丙烯腈及苯乙烯製造及使用作業勞工之暴露實態，並進一步探討三者共暴露與健康效應之關係，最後利用尿中代謝物DHBMA、MHBMA與CEMA瞭解勞工暴露實態並與空氣濃度進行相關性比較，以建立生物偵測指標。本研究共進行4家ABS運作工廠之勞工個人空氣與尿液採樣，及其個人空氣、尿液與血液生化之分析，有效樣本共102位。各分析項目如下：(1)以氣相層析-火焰離子偵測器分析勞工個人空氣樣本中1,3-丁二烯、丙烯腈與苯乙烯濃度；(2)分析個人血液樣本中肝功能指標與脂肪代謝指標；(3)以液相層析-串聯式質譜儀建立個人尿液樣本1,3-丁二烯與丙烯腈代謝物濃度分析方法。研究結果顯示，作業勞工個人空氣樣本中1,3-丁二烯、丙烯腈與苯乙烯之幾何平均濃度分別為0.018 ppm (ND- 2.155 ppm)、0.051 ppm (ND- 6.891 ppm)與0.032 ppm (ND- 1.548 ppm)，其中有三名勞工丙烯腈濃度高於法定規範容許濃度(2 ppm)。本研究將勞工1,3-丁二烯、丙烯腈與苯乙烯的暴露濃度除以各自之PEL後相加，作為共同暴露指標，進一步排除飲酒後區分為高/低共同暴露組後發現高共同暴露組勞工，在胰島素(p=0.018)、瘦體素(p=0.019)與胰島素阻抗指標HOMA-IR (p=0.045)三項均顯著高於低共同暴露組勞工，顯示在1,3-丁二烯、丙烯腈與苯乙烯的共同暴露下，可能造成代謝異常，甚至有增加胰島素阻抗之情形。尿中代謝物分析方法建置部分，測試結果發現，層析管柱選用Agilent ZORBOX Eclipse XDB-C18 (2.1×150 mm, 3 μm)，搭配移動相為0.1%醋酸水溶液與甲醇，可得到最佳的層析效果。生物指標部分，102名勞工的尿液樣本中，上班前尿液中DHBMA濃度中位數為270.26 μg/g-cre (96.79-1347.06 μg/g-cre)，MHBMA濃度中位數為53.33 μg/g-cre (3.04-1381.71 μg/g-cre) ，CEMA濃度中位數為95.69 μg/g-cre (2.82-5240.89 ng/g-cre)。下班尿液之DHBMA濃度中位數為305 μg/g-cre (87.28-869.27 ng/g-cre)，MHBMA濃度中位數為82.17 μg/g-cre(11.76-402.76 μg/g-cre)，CEMA的濃度中位數為270.02 μg/g-cre (2.86-45646.49 μg/g-cre)。利用線性回歸模型觀察尿中代謝物濃度與空氣中丙烯腈濃度之相關性，結果顯示校正抽菸、飲酒與呼吸防護具配戴後，上班前（P＝0.001）與下班前（P＝0.048）尿中CEMA與空氣中丙烯腈濃度均達到統計上顯著相關，顯示CEMA適合作為丙烯腈職業暴露的生物指標。但在尿液中、DHBMA與MHBMA和空氣中1,3-丁二烯濃度均未達統計上顯著相關，可能原因為目前1,3-丁二烯濃度已有良好的控制，使勞工暴露濃度降低，因而無法代謝出足量的代謝物，造成尿中代謝物濃度偏低無法與空氣濃度呈現相關性。由於尿中CEMA與丙烯腈濃度呈現良好相關性，本研究利用尿中CEMA回推空氣中丙烯腈濃度，結果顯示以下班前尿液中CEMA回推的丙烯腈濃度範圍為0.1- 1198.39 μg/m3，排除吸菸勞工後將下班前尿液回推濃度與空氣濃度進行Spearman相關分析，其相關係數r=0.605（P<0.001），另比較防護具配戴習慣與回推濃度的關係，結果指出配戴呼吸防護具的勞工回推丙烯腈濃度與未配戴勞工並無顯著差異，顯示個人呼吸防護具可將丙烯腈濃度有效降低，其平均防護效率約為93%。最後依據勞工個人空氣中1,3-丁二烯、丙烯腈與苯乙烯濃度來計算勞工個人健康風險，數據分析結果顯示，有8名勞工之1,3-丁二烯非致癌風險大於1，其致癌風險亦有8名勞工大於可接受風險10-3；有27名勞工之丙烯睛暴露的非致癌風險大於1，更有31位勞工之丙烯腈致癌風險大於可接受風險10-3。但依據以尿中CEMA回推之個人空氣丙烯腈濃度計算之致癌與非致癌風險，只有5名勞工致癌風險大於可接受風險10-3，3名勞工非致癌風險大於可接受風險，顯示個人呼吸防護具可有效降低勞工個人風險。雖然勞工1,3-丁二烯暴露濃度均小於法定規範，但仍有部分勞工致癌與非致癌風險較高，與其他國家相比，建議1,3-丁二烯法定規範濃度可降至2 ppm。另外，以尿中代謝物回推丙烯腈濃度計算之致癌風險指出，雖然大部分勞工致癌風險都在容許範圍內，但仍有少部分勞工致癌風險高於可接受風險，其原因可能為呼吸防護具使用不當，或是當日進行暴露濃度較高的作業，如清槽等短時間內暴露較高濃度的作業所致。

Health risk assessment of multiple exposure to 1, 3-butadiene, acrylonitrile, and styrene for manufacturing and operating workers
Meng-Yu Wu
Ching-Chang Lee
Department of Environmental and Occupational Health,
Medical College, National Cheng Kung University

SUMMARY

The objectives of present research are to assess the exposure profile of 1,3-butadiene, acrylonitrile, and styrene for ABS manufacturing workers, and to explore the association between 1,3-butadiene, acrylonitrile, and styrene concurrent exposure with health outcomes. A analytical method was established to simultaneously analyze the urinary metabolites of 1,3-butadiene and acrylonitrile (DHBMA, MHBMA and CEMA), and then, the association between urinary metabolites concentrations with airborne 1,3-butadiene and acrylonitrile were examined to setup the exposure biomarker of 1,3-butadiene and acrylonitrile. In present research, the geometric mean of personal exposure concentrations of 1,3-butadiene, acrylonitrile, and styrene are 0.018 ppm, 0.051 ppm, and 0.032 ppm respectively. To evaluate the health outcomes of concurrent exposure to 1,3-butadiene, acrylonitrile, and styrene, the individual personal exposure level was divided individual permissible exposure level, then summate as concurrent exposure index (CEI). After excluded the worker who had alcohol drinking habit and grouped all the worker to high and low concurrent exposure group, the insulin (p=0.018)、leptin (p=0.019) and HOMA-IR (p=0.045) in high concurrent exposure group are significant higher than low concurrent exposure group. The urinary metabolites of 1,3-butadiene and acrylonitrile were analyzed by HPLC-MS/MS with Agilent ZORBOX Eclipse XDB-C18. After excluded smokers, the significant correlation between CEMA and airborne acrylonitrile was found. The results indicate that CEMA is good biomarker to represent the internal exposure to acrylonitrile. Only five workers’ lifetime carcinogen risk were higher than acceptable risk (10-3) which was calculated by back estimation of urinary CEMA.

Key words: 1,3-butadiene, acrylonitrile, styrene, urinary metabolits, biological monitoring, concurrent exposure

INTRODUCTION

1, 3-butadiene, acrylonitrile, and styrene are monomers for polymerization of rubber, especially for ABS rubber (Acrylonitrile-Butadiene-Styrene rubber). Butadiene had been classified as group 1 (carcinogenic to humans) and acrylonitrile and styrene had been classifiedas group 2B (possibly carcinogenic to humans) by International Agency for Research on Cancer (IARC). The major metabolites of 1,3-butadiene and acrylonitrile are DHBMA(1,2-dihydroxybutyl mercapturic acid), MHBMA (monohydroxy -3-butenyl mercapturic acid) and CEMA ((1-cyano-2-hydroxyethyl) cysteine) respectively. A 1,3-butadiene exposure study for workers in ABS factory reported that the high-exposure workers had lower glucose (GLU) and higher trigriceride (TG) which suggested that abnormal metabolism of glucose and lipid may resulted from high exposure to butadiene. The increasing incidence of Toxicant-Associated Steatohepatitis (TASH) was found in the workers who concurrent exposure to 1,3-butadiene, acrylonitrile, and styrene and may cause insulin resistant. 1,3-butadiene, acrylonitrile and styrene are operated together frequently, but little is known regarding the concurrent exposure to 1,3-butadiene, acrylonitrile, and styrene. Therefore, the objectives in this research are (1) to recognize the exposure profile for 1,3-butadiene, acrylonitrile, and styrene manufacturing and operating workers, (2) to explore the association between 1,3-butadiene, acrylonitrile, and styrene concurrent exposure and health outcomes, (3) to establish a method to simultaneously analyze the urinary metabolites of 1,3-butadiene and acrylonitrile, (4) to examine the representation of urinary metabolites for airborne 1,3-butadiene and acrylonitrile exposure, (5) to assess the health risk of 1,3-butadiene, acrylonitrile, and styrene exposure for manufacturing and operating workers.

MTERIALS AND METHODS

102 workers in four ABS manufacturing and operating plants were recruited in this study. Airborne, blood and urine sample of those workers were collected after signing informed consent, and questionnaire was used to investigate workers’ life style, occupational history and disease history. Airborne sample was collected by charcoal adsorbent coated with 4-tert-butylcatechol (TBC), and the concentrations of 1,3-butadiene, acrylonitrile and styrene were analyzed by GC-FID. 30 mL Blood samples were collected from each worker as well as liver function tests and adipokines were examined. To evaluate the health outcomes of concurrent exposure to 1,3-butadiene, acrylonitrile, and styrene, the individual personal exposure level was divided individual permissible exposure level, then summate as concurrent exposure index (CEI).. A analytical method was established to simultaneously analyze the urinary metabolites of 1,3-butadiene and acrylonitrile (DHBMA, MHBMA and CEMA), and the representation of urinary metabolites for airborne 1,3-butadiene and acrylonitrile exposure were examined. Lifetime carcinogenic and non-carcinogenic risk was assessed by airborne concentration and back estimated concentration of urinary metabolites respectively.

RESULTS AND DISCUSSIONS

In our results, the geometric mean of personal exposure concentrations of 1,3-butadiene, acrylonitrile, and styrene are 39.94 μg/m3 (0.018 ppm), 109.59 μg/m3 (0.051 ppm),snd 137.94 μg/m3 (0.032 ppm), all lower than permissible exposure level (PEL), but, 3 workers’ acrylonitrile exposure concentrations are higher than PEL. To divide the workers to high- and low- exposure groups by job title, and compare the demographic data, airborne exposure levels of 1,3-butadiene, acrylonitrile, and styrene and blood biochemical index in these two groups. We found that the airborne exposure levels of 1,3-butadiene, acrylonitrile, and styrene n high exposure group were significant higher than low exposure group (1,3-butadiene：p=0.003, acrylonitrile：p=0.000, styrene: p=0.000) (table 1), and the habit of wearing personal respiratory protector between the two group are significantly difference (p=0.000).
After excluded the alcohol drinking worker and grouped all the worker to high and low concurrent exposure group, the insulin (p=0.018), leptin (p=0.019) and HOMA-IR (p=0.045) in high concurrent exposure group are significant higher than low concurrent exposure group (table 2), it means concurrent exposure may cause metabolic abnormalities, even insulin resistant.

Table 1. Airborne levels of 1,3-butadiene, acrylonitrile and styrene
Item Unit High exposure group (n=72) Low exposure group (n=30) P-valueb
1,3-butadiene μg/m3 ND
(ND-4751.01) a ND
(ND- 474.18) 0.003*
Acrylonitrile μg/m3 106.01
(ND- 14906.96) ND
(ND- 1002.59) 0.000*
Styrene μg/m3 218.21
(ND- 6570.75) ND
(ND- 506.95) 0.000*
a median(range)
b Non-normal distribution，analysis by Wilcoxon rank sum test
* p<0.05

Table 2. Concurrent exposure Assessment (exclude alcohol drinking)
CEI High CEI group (n=28) Low CEI group (n=51) P-value
Insulin μU/mL 8.0 (3.3)a 7.5 (6.0) 0.018*
Leptin μg/mL 8.5 (5.2) 5.9 (3.3) 0.019*
HOMA-IR 1.8(0.8) 1.8 (1.5) 0.045*
aMean(SD)

The median (range) of urinary metabolites concentrations of DHBMA, MHBMA and CEMA at pre-shift are 270.26 (96.79-1347.06), 53.33 (3.04-1381.71) and 95.69 (2.82-5240.89) μg/g-cre, and at post-shift are 305 (87.28-869.27), 82.17 (11.76-402.76) and 270.02 (2.86-45646.49) μg/g-cre, respectively. After excluded smokers, the significant correlation between CEMA and airborne acrylonitrile was found (table 3); it means that CEMA is good biomarker for exposure to acrylonitrile. We developed a formula which was used to back estimate acrylonitrile exposure by urinary CEMA, and the result showed that personal protect equipment could efficiently decreased the exposure concentration of acrylonitrile.

Table 3. Correlation between concentration of urinary metabolites with airborne levels of 1,3-butadiene and acrylonitrile (adjust smoking, PPE wearing and drinking)
DHBMA MHBMA CEMA
N=102 Pre-shift Post-shift Pre-shift Post-shift Pre-shift Post-shift
1,3-butadiene β= 0.88
p= 0.381 β= 1.791
p= 0.076 β= -0.381
p= 0.704 β= -0.203
p= 0.840 - -
Acrylonitrile - - - - β= 4.051
p= 0.001 β= 2.005
p= 0.048

Only five workers’ lifetime carcinogen risk were higher than acceptable risk (10-3) which was calculated by back estimation of urinary CEMA.

CONCLUSIONS

This study is the first study that explored the association between 1,3-butadiene, acrylonitrile, and styrene exposure profile and health outcomes. We found that the airborne exposure levels of 1,3-butadiene, acrylonitrile, and styrene in high exposure group were significant higher than low exposure group (p<0.005) by job title. Furthermore, we excluded the alcohol drinking worker and grouped all the worker to high and low concurrent exposure group and found the insulin (p=0.018)、leptin (p=0.019) and HOMA-IR (p=0.045) in high concurrent exposure group are significant higher than low concurrent exposure group. After excluded smokers, the significant correlation between CEMA and airborne acrylonitrile was found; it means that CEMA is good biomarker for exposure to acrylonitrile. According to the present study, 99% of 1,3-butadiene personal exposure levels was lower than 1.25 ppm, we suggested to modified the PEL of 1,3-butadiene from 5 ppm to 2 ppm. In present research, we found that the personal protect equipment could efficiently decreased the exposure concentration of acrylonitrile.

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