1,4-二氯苯暴露及健康危害評估研究

Exposure and health assessment of 1,4-dichlorobenzene

蕭寶桂(Pao-Kuei Hsiao)

指導教授 ： 林宜長 ； 陳家揚

國立臺灣大學/公共衛生學院/環境衛生研究所/博士(2009年)

https://doi.org/10.6342/NTU.2009.01933

摘要

1,4-二氯苯（1,4-Dichlorobenzene, 1,4-DCB）又稱對二氯苯（p-Dichlorobenzene），其蒸氣壓高（1.28 mmHg）故易昇華。1,4-二氯苯除用在驅除蟲類、蛾類等病媒，也常被放置在廁所作為除臭劑。1,4-二氯苯主要是透過呼吸道，以吸入方式進入人體，其吸入的細微粉粒及晶體均可能造成健康危害。根據文獻顯示，高濃度的1,4-二氯苯暴露所造成的健康危害包括皮膚及黏膜的刺激、上呼吸道及眼睛的不適、影響肝腎功能、造成肺部的傷害以及呼吸系統的刺激等。因此本研究之目的在透過暴露評估，內在劑量評估及健康檢查結果瞭解人體暴露1,4-二氯苯後所造成的健康影響。
1,4-二氯苯的內在暴露劑量調查可經由分析尿液中的1,4-二氯苯原體，自由態2,5-二氯酚，及2,5-二氯酚共軛結合物（硫酸，葡萄糖苷酸）的濃度得知。為進行尿中代謝物的分析，本研究建立UPLC/MS/MS同步分析方法配合固相萃取方法分析尿液中2,5-二氯酚，2,5-二氯水合醌，及2,5-二氯酚共軛結合物（硫酸及葡萄糖苷酸）的濃度。由於2,5-二氯酚共軛結合物無市售標準品可供使用，因此本研究分別合成2,5-二氯酚葡萄糖苷酸與2,5-二氯酚硫酸共軛結合物，經鑑定後隨即建立尿液同步分析方法。經方法驗證及實際樣本分析後，確定本方法為一可靠且快速的分析方法，並將其實際應用於暴露調查之尿液分析。
本研究針對製造以1,4-DCB為主要成分的驅蟲劑工廠進行暴露調查，研究期間共完成三間工廠採樣， A、C廠在北台灣，B廠在南台灣，至於1,4-DCB的用量以C廠最大，B廠最小。勞工暴露調查項目包括個人空氣樣本採樣，尿液檢體收集，問卷調查以及血液常規檢測。經由尿液樣本的結果顯示，自由態2,5-二氯酚及2,5-二氯酚硫酸共軛化合物平均濃度較低（70 ~ 1050 ng/mL）， 2,5-二氯酚葡萄糖苷酸共軛化合物平均濃度最高（20 ~ 350 mg/L），顯示暴露後的尿中代謝物以2,5-二氯酚葡萄糖苷酸共軛化合物為主。
空氣採樣的結果，本研究使用3M 3500被動式採樣器進行個人空氣採樣，採樣時間分別為工作8小時及非工作16小時，分析儀器為氣相層析儀搭配火焰離子偵測器。結果得知工作時的個人空氣時量濃度為C廠>A廠>B廠（最高9.15 ± 6.37 ppm，最低1.19 ± 0.84 ppm）。非工作時的個人空氣濃度也是C廠>A廠>B廠（最高0.84 ± 0.68 ppm，最低0.08 ± 0.04 ppm）。
將空氣濃度，尿中代謝物濃度與問卷資料及健檢資料進行統計分析，得知現場作業員工空氣濃度值顯著高於非現場作業員工；若以工作型態區分，原料操作者濃度顯著高於半成品收集、包裝者，而行政文書類者濃度最低（p < 0.05）；暴露組非工作時空氣濃度顯著高於對照組（p < 0.05）；家中使用含1,4-DCB類驅蟲劑之空氣濃度顯著高於未使用者（p < 0.05）。空氣濃度愈高者，尿中2,5-DCPG及2,5-DCP濃度愈高（p < 0.01）。在健檢方面，暴露空氣濃度及尿中代謝物濃度愈高者，白血球數量，血中尿素氮濃度及血中尿素氮濃度/肌苷酸比值有顯著較高的趨勢（p < 0.05）。
本研究成功建立UPLC/MS/MS同步分析尿中代謝物方法並將其實際應用於樣本分析中。空氣採樣結果顯示24小時全日採樣更接近實際暴露情形。暴露1,4-DCB的空氣濃度與尿中代謝物濃度與白血球數量、血中尿素氮濃度，血中尿素氮濃度/肌苷酸比值增加有顯著相關，但檢查數值仍在正常範圍內。本研究完成探討暴露1,4-DCB後空氣濃度，尿中代謝物濃度及健康效應間的相關探討。

關鍵字

1,4-二氯苯 ； 化學合成 ； 暴露評估 ； 健康效應

並列摘要

1,4-Dichlorobenzene (1,4-DCB) is widely used as a deodorizer because of it’s volatility (vapor pressure is 1.08 mg/m3 at 25℃). It is also used as a moth repellent and toilet deodorizer. Many studies have showed that human exposed to 1,4-DCB mainly by inhalation. Human inhale high 1,4-DCB concentration may cause eye and upper respiratory tract irritation, abnormal liver/kidney function and lung disorders. In this study, we conduct an exposure assessment to clarify the relationship between 1,4-DCB exposure profile and the related health effects.
The human internal dose can be analyzed by the concentrations of 1,4-DCB, 2,5-dichlorophenol (2,5-DCP), 2,5-dichlorophenol glucuronide (2,5-DCPG), and 2,5-dichlorophenol sulphate (2,5-DCPS) in urine. However, chemical standards of 2,5-DCPG and 2,5-DCPS are not commercially available, therefore, 2,5-DCPG and 2,5-DCPS were synthesized in our study. In the present study, we developed a method to analyze urinary 2,5-dichlorophenol (2,5-DCP), 2,5-dichlorohydroquinone, 2,5-DCPS, and 2,5-DCPG simultaneously by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC/MS/MS). Our method has been successfully used to detect urinary metabolites of 1,4-DCB with high throughput and represented a good sensitivity.
After analysis method was established, we conducted an assessment of human 1,4-DCB exposure in three major moth repellent product plants, plant A and C are in northern Taiwan as well as plant B is in southern Taiwan. Plant C has the highest output of 1,4-DCB repellent product, and plant B has the smallest one. In our evaluated plants, samples of workers’ personal air and urine were simultaneously collected; in addition, we also collected workers’ questionnaire and biochemical test results. Our data has demonstrated the concentration of free form 2,5-DCP/2,5-DCPS in urine was generally lower (70 ~ 1050 ng/mL) than 2,5-DCPG (20 ~ 350 mg/L). Therefore, 2,5-DCPG was found to be the major metabolite after human exposed to 1,4-DCB.
For air sampling, we used 3M 3500 passive sampler to evaluate repellent workers’ exposure profile. The sampling time included 8 hours daytime, and 16 hours overnight. After sampling, the air samples were analyzed by Gas Chromatography Flame Ionization Detector (GC-FID). Our results demonstrated that the highest air concentration (9.15 ± 6.37 ppm in daytime and 0.84 ± 0.68 ppm in over night) wad found in plant C, and plant B had the lowest concentration (1.19 ± 0.84 ppm in daytime and 0.08 ± 0.04 ppm in over night ).
From the statistical results, the 1,4-DCB concentration in air was significantly higher in on-site workers than in non-on-site workers (p < 0.05). Moreover, the air concentration was also found to be higher in raw material operator than in semi-finished product collector (p < 0.05). The air concentration was higher in who has the habit of using mothball contained 1,4-DCB in home (p < 0.05). Once the worker has the higher air concentration of 1,4-DCB, their metabolite concentration in urine was also found to be higher (p < 0.05). In health effect, the biochemical indices such as white blood cell count (WBC), blood urea nitrogen (BUN) level and BUN/creatinine ratio are positively correlated with the air concentration and urinary metabolite concentration (p < 0.05).
This study employed solid-phase extraction (SPE) to extract 1,4-DCB metabolites from urine and the metabolites were then subsequent to analysis by UPLC/MS/MS coupled with negative electrospray ionization. This method has successfully measured urinary metabolites of 1,4-DCB with high throughput and represented a good sensitivity. We found the major metabolite of 2,5-DCP in urine is 2,5-DCPG. From air sampling results, the 24 hours sampling data is much closer to the real exposure situation than 8 hours sampling. The concentration of 1,4-DCB in air and major metabolite in urine are positively correlated with WBC count, BUN concentration and BUN/creatinine ratio, but these indices is still in the normal range.

並列關鍵字

1,4-dichlorobenzene ； synthesis ； exposure assessment ； health effect

參考文獻

58.李茂榮, 陳崇宇, 李祖光, 固相微萃取技術於微量分析之應用. Chemistry, 2005. 63(3): p. 14.

70.陳家揚, 液相層析/質譜儀的基質效應與因應之道. Chemistry （化學）, 2007. 65(2): p. 151-155.

2.Azouz, W.M., D.V. Parke, and R.T. Williams, Studies in Detoxication. The Metabolism of Halogenobenzenes - ortho-dichlorobenzenes and para-dichlorobenzenes. Biochemical Journal, 1955. 59(3): p. 410-415.

3.ATSDR, Toxicological Profile for 1,4-Dichlorobenzene. 1998, ATSDR.

4.Hill, R.H., et al., p-Dichlorobenzene exposure among 1,000 adults in the united-states. Archives of Environmental Health, 1995. 50(4): p. 277-280.