目前二甲基甲醯胺(DMF)職業暴露所建議的生物指標為尿中(U-)的代謝物N-methylformamide（NMF）及N-acetyl-S-（N-methylcarbamoyl）cysteine （AMCC），而尿中的DMF原形物與空氣中的DMF亦有良好的相關性。唾液樣本有收集方便，隱私困擾較低並可藉由量測唾液中化學物質的含量來推估血液中的含量等優點。因此本研究目的為：(1) 藉由評估唾液生物指標(S-)與空氣DMF暴露濃度和尿中DMF生物指標之相關性，探討唾液DMF、NMF與AMCC濃度值作為DMF職業暴露生物指標之可行性；(2) 探討在連續五個工作天之暴露下，DMF生物指標是否有累積之情形；(3) 探討唾液生物指標和肝功能指數之相關性；(4) 探討唾液生物指標之動力學特性。本研究選取台灣中部某合成皮工廠，藉由兩階段現場之測定方式，第一階段針對所有可能暴露DMF之74位員工進行採樣，進行一天空氣、尿液、唾液樣本、健檢資料之收集及問卷調查，再從中選出20位高暴露勞工進行第二階段採樣。第二階段分為兩部分：(1) 探討累積之部分：進行一週連續工作五天 ( W1~W5 )包括空氣之DMF環境測定與收集包括五天上班前(-pre)後(-post)之尿液及唾液樣本。(2) 探討動力學之部分：兩個工作天 ( W5、W6 ) 之空氣樣本及兩天之上班前後之尿液及唾液樣本，並且收集最後一個工作天( W6 )下班後連續36小時之尿液及唾液樣本。本研究結果發現經由ANOVA及correlation matrix統計分析，連續五個工作天之空氣中DMF濃度在不同人與在不同工作天皆相當穩定。而利用簡單線性廻歸模式及複迴歸模式發現尿中的NMF、AMCC及唾液中的NMF會隨著工作天數增加而顯著有上升的趨勢(p<0.05)，而推論DMF職業暴露勞工連續一週工作後，體內DMF生物指標會有累積。在S-DMF方面，空氣DMF暴露濃度和S-DMF相關性並不一致，並不建議作為DMF暴露濃度之生物指標；而空氣DMF暴露濃度和S-NMF相關性良好，但空氣DMF暴露濃度和S-AMCC相關性較差，所以S-NMF可以作為當天空氣DMF暴露濃度之良好指標，但S-AMCC似乎不適合做為當天空氣DMF暴露濃度之良好指標。而以一階動力學(first-order kinetics)推估唾液中NMF之平均半衰期( 16.5 h )明顯較尿液的NMF( 9.1 h )為長，顯示S-NMF是屬於較長半衰期的生物指標，也說明S-NMF-pre和前一天的空氣DMF濃度有良好的相關性及S-NMF-pre會隨著工作天數增加而有逐日累積的原因。另外可以發現S-NMF-post除了和外在暴露有很好的相關性外，且和U-NMF-post有良好的相關性，所以可以判斷S-NMF-post適合作為職業暴露二甲基甲醯胺的生物指標。另外以卡方檢定及多變項邏輯式迴歸模式探討肝功能異常是否和生物指標之代謝比值( Metabolic index, MI )高低不同有相關。結果發現GPT異常與否和唾液中NMF代謝比值高低有統計顯著相關，此代謝比值亦會受CYP2E1之基因多型性( Dra1 )影響：Dra1呈現wild-type homozygous者體內S-NMF濃度值顯著高於mutant type者，即wild-type homozygous的代謝活性較高，使得產生較多之S-NMF。另外發現肝功能不正常者，其下班後連續36小時之S-NMF之半衰期、滯留時間(Mean residence time, MRT)較長，體內之總暴露負荷劑量( Total body burden of exposure )皆較高，所以唾液中NMF之總暴露劑量與肝功能不正常息息相關。本研究結論及建議為 (1) S-NMF可作為當天及前一天DMF暴露之生物指標，且與U-NMF有良好之相關性。在往後的DMF職業暴露之研究，可以建議以唾液中NMF作為另一項DMF職業暴露之生物指標。另一方面，由於AMCC是屬於conjugated form，所以不容易通過血管內質網細胞膜，導致唾液中AMCC的含量較低甚至低於偵測下限，因此並不適合作為DMF職業暴露的生物指標。(2) 証實DMF工作在連續五個工作天暴露下， DMF體內之內在劑量會產生累積之情形，因此DMF暴露員工應密切觀察所造成可能之健康效應。(3) 鑑於唾液中有害物可反應血液中化學物質濃度值，唾液中NMF產生濃度較高者可能會導致肝危害之情形，因此本研究推論S-NMF亦可以作為評估DMF所造成之健康效應。 (4) 勞工之CYP2E1之基因型屬Dra1為wild-type homozygous者，可能應避免長時間暴露於高濃度DMF，減少可能之健康危害。(5) 在S-NMF之動力學方面，整體而言，終止暴露後之S-NMF動力學行為較符合first-order kinetic。

The current recommended biological exposure indices of N,N-dimethylformamide (DMF) exposure are urinary N-methylformamide (NMF) and N-acetyl-S- (N-methylcarbamoyl) cysteine (AMCC). Several studies showed excellent linear relationship between air DMF concentrations and urinary DMF. Due to the privacy concern and uncontrollable timing issue in urine sample collection, there is a need to seek for other biological specimen like saliva to accommodate the needs of biological monitoring in field study. The purposes of study are: (1) To explore the relations of the salivary biomarkers to airborne DMF concentrations and to explore the feasibility of salivary biomarkers to reflect DMF exposure. (2) To determine whether there is an accumulation of DMF biomarkers throughout five consecutive workdays. (3) To explore the relations of the liver function indices to salivary biomarker levels. (4) To explore kinetic characteristics in salivary biomarkers. Seventy-four subjects occupationally exposed to DMF have been monitored for their airborne DMF exposure and urinary and salivary biomarker levels in the first stage. Twenty subjects were further enrolled in the second stage based on the environmental monitoring results from the first stage. Airborne DMF monitoring throughout their whole work shift and biological monitoring of the concentrations of NMF and AMCC both in urine and saliva were conducted on the individual basis for five consecutive days. Moreover, 36-hour series of samples of saliva and urine were collected since the termination of the exposure on the last weekday to determine their kinetic parameters. We found that airborne DMF concentrations were constant within individual and stable across the working weekdays. Accumulation could take place in U-NMF, U-AMCC and S-NMF throughout a five-day consecutive workdays’ exposure. S-NMF at post shift revealed satisfactory associations with both airborne DMF exposure on the same day and the preceding day by simple linear regression. It could be due to the half-life of S-NMF was estimated as 16.5 hrs, longer than that of U-NMF of 9.1 hrs. DMF and AMCC in salivary, however, was found poor associations with either airborne DMF or any biomarkers in urine. S-NMF was not only a satisfactory predictor of airborne DMF but also revealed satisfactory association with U-NMF. Therefore, S-NMF could be an alternative predictor of airborne DMF exposure. The metabolic index of salivary NMF to DMF was significantly associated with liver function parameters examined by the tests of Chi-square and multiple logistic regression. The metabolic index revealed a significant association with genotype of CYP2E1. The workers with higher abnormality in liver function index were found with higher metabolic index (MI). The estimates of half-life, area under curve (AUC), and mean residence time (MRT) in abnormal case were larger than those in normal groups, possibly, resulting from the increase total body burden of DMF exposure and sequently causing liver abnormality. We concluded that (1) NMF in saliva (S-NMF) could be considered as an appropriate exposure biomarker of daily and proceeding-day exposure to DMF. In view of the convenience in sample collection, satisfactory association with DMF exposure, salivary NMF could be considered as an ideal indicator for both biomarkers in exposure. S-AMCC is not an ideal biomarker of DMF exposure. Possibly owing to that AMCC is a conjugated form and hardly penetrate through blood vessel endothelium membrane. (2) Accumulation could be observed in U-NMF, U-AMCC and S-NMF for those workers occupationally exposed to DMF during five-day cycles. All DMF-exposed employees should be intensively monitored on their health effects. (3) AMCC could be a metabolic detoxicification product and NMF greater toxicity than DMF. NMF could be more related to the hepatotoxicity than external exposure levels of DMF. Salivary NMF could be considered as an ideal indicator for health effect. (4) DMF exposed employees with wild-type of Dra1 were recommended avoiding working at prolonged DMF exposure and higher DMF levels. (5) First-order kinetic pattern was conducted for excretive S-NMF.

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行政院勞工委員會勞工安全衛生研究所，有機溶劑中毒預防規則，第三條第一款，民國92年
財團法人工業技術研究院工業安全衛生技術發展中心，物質安全資料表，序號260，民國89年
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