在職場暴露中，作業勞工的化學物質暴露濃度常受工作性質、工作量、工作廠所通風換氣，以及有無配戴防護具所影響而有很大的變異，導致職業暴露流行病學研究，探討暴露與疾病的相關時，易產生高估或低估的現象。過去針對二甲基甲醯胺（N,N-dimethylformamide, DMF）的相關性研究，皆利用短期(單日或單週)的量測資料，探討DMF暴露勞工之生物指標及健康影響。然而真實職業環境中化學物質的暴露濃度常有極大變異，單日或短期的量測結果並無法有效代表長期暴露以及評估其內在劑量與健康的相關性。本研究主要目的為藉由連續監測DMF作業勞工的10週暴露濃度及尿中生物指標之量測資料，以了解DMF作業勞工長期暴露濃度及尿中各種DMF代謝物濃度及分布情形，以及暴露濃度的變化對尿中生物指標的影響，並藉由探討長期監測之DMF暴露勞工其空氣中濃度與DMF尿中生物指標之相關性來評估短期量測資料之適用性。本研究亦探討混合暴露對DMF暴露勞工尿中代謝物濃度之影響，以及探討尿中DMF代謝物AMCC之累積情形。研究結果顯示，勞工10週空氣中平均暴露濃度GMGSD (n=450) 分別為7.542.21 ppm (DMF)、17.76.42 ppm (MEK)、7.084.90 ppm (TOL)，量測資料中有31%勞工其作業環境空氣中DMF濃度高於PEL (10 ppm)，同時約28% (14/47)混料作業勞工之作業環境空氣中TOL暴露濃度高於PEL(100ppm)，DMF暴露濃度以乾式底部塗佈勞工最高，混料作業勞工最低，MEK暴露濃度以乾式底部塗佈勞工最高，濕式塗佈勞工最低，TOL暴露濃度以混料作業勞工為最高，濕式塗佈為最低，在不同勞工之間及不同工作天之間暴露濃度皆有很大的差異且變化趨勢也不相同。高達70%量測資料尿中DMF代謝物U-DMF皆低於偵測下限，且下班前尿液中U-NMF濃度皆高於上班前，而U-AMCC則是上班前尿液中濃度高於下班前尿液中濃度，濃度變異情形則是隨著代謝物半衰期的增加而有下降的趨勢其中以U-AMCC為最低，但不同勞工及工作天濃度變異依然很高。而下班前U-NMF濃度與空氣中DMF暴露濃度有良好的相關性(r=0.54)，利用TWA-DMF濃度對應下班前U-NMF濃度為19.2mg/L；以各週暴露濃度與當週之下班前尿液中U-NMF濃度進行相關性分析則顯示差異很大(r=0.32-0.73)，然而利用勞工10週平均空氣中暴露濃度與下班後U-NMF平均濃度，相關卻呈現高度相關(r=0.95)，而各週最後一天工作天下班前U-AMCC濃度與當週暴露濃度亦有良好的相關性(r=0.63)。數據顯示混合暴露MEK及TOL會抑制上班前或下班前尿液中U-NMF及U-AMCC濃度，且抑制情形皆不相同，顯示抑制機制並非單一路徑，其中間機制尚需做進一步的探討。尿中AMCC濃度在連續10週暴露下，會有顯著的累積產生，此可作為長期暴露濃度與疾病相關性研究的重要指標之一。整體而言，DMF作業勞工暴露濃度及尿中代謝物濃度皆有很大的變異及變化趨勢，在探討暴露濃度與疾病之間的相關性研究時，建議要以長期的量測資料為依據，如此才可以較為準確的評估勞工實際的暴露情形，甚至於推估到對其健康之影響

In most occupational exposure settings, the variation of the workers exposure to chemicals usually affected by job title, quantity of output, the use of ventilation system,and respirator wearing. It may bias the relationship between the exposure and health outcomes in occupational epidemiology studies. In the past, most N,N-dimethylformamide (DMF) researches applied short-term measurements (one-day or one-week) to represent the exposure levels and to assess the association between biomarker and health outcomes for DMF exposed workers . However, the exposure profiles of workers varied considerably with different occupational exposure settings. One-day or short-term measurements were insufficient to evaluate the relationship between external exposure and internal dose or health risk. The objectives of this study are 1) to evaluate the long-term profiles of external exposure and their relevant biomarkers during 10 weeks for DMF exposed workers; 2) to investigate the intra-individual and inter-individual variability of the measurements from daily air, and urinary biomarkers; 3) to investigate the effects of the different exposure scenario on different biomarkers (U-DMF, U-NMF, and U-AMCC); 4) to evaluate the accumulation of urinary biomarker U-AMCC and the effects of co-exposure of toluene(TOL) and methyl ethyl ketone(MEK) to the metabolism of DMF. We found the geometric mean and geometric standard deviation (GMGSD)) of airborne DMF, MEK, TOL concentrations were 7.542.21 ppm, 17.76.42 ppm, 7.084.90 ppm (n=450), respectively during 10 weeks. The DMF exposure levels in 31% workers were higher than permissible exposure level (10 ppm ), but only the workers in mixing process had higher exposure levels of TOL than permissible exposure level (100 ppm). The highest exposure level of DMF was found in dry Bottom Coating process, and the lowest was found in Mixing process; the highest MEK levels was found in Dry bottom Coating process, but the lowest exposure levels was Wet Coating process, and the highest TOL levels was found in Mixing process, lowest in Dry Coating process, too. Moreover, the individual exposure profiles showed significantly day-by-day variations among workers (inter-individual and intra-individual variability, P<0.05). The U-DMF of 70% samples were lower than the MDL. Furthermore, the concentration of biomarker of NMF in the post-shift urine samples was higher than that of the pre-shift urine samples, but the opposite results showed in the concentration of the biomarker of AMCC. Higher inter-&intra-individual variation was also found in the urinary biomarker and the variation of urinary DMF concentration was decreased with the increase of the half-life of biomarker, the lowest variation was found in U-AMCC. In addition, a significant association was found between daily exposure levels and post-shift urinary U-NMF (r=0.54). Furthermore the post-shift U-NMF corresponded to 8 hour time-weighted average DMF was 19.2 mg/L in ten weeks data. Higher variation was found between exposure levels in the different weeks and post-shift urinary U-NMF (r=0.32-0.73). However, the highest correlation was found between average exposures levels and average post-shift urinary U-NMF of ten weeks (r=0.95).Finally a high association was found between the weekly exposure levels and the post-shift urinary U-AMCC in final work-day during one week (r=0.63). The co-exposure to MEK and TOL showed no coincidence with the biomarkers of U-NMF and U-AMCC in pre-&post-shift urine samples. Further studies were needed to evaluate the mechanism of effects. The results showed that long term occupational DMF exposure might result in significant accumulation of DMF in human body. In conclusion, higher inter-and intra- variability of exposure levels and urinary biomarkers of DMF occupational exposed workers were observed. In further studies, long-term monitoring is needed to assess the relationship between exposure levels and health outcomes.

Anonymous. Reproductive toxicology. N,N-dimethylformamide. Environmental Health Perspectives 105 Suppl 1: 305-307 (1997).
Bartsch H. Studies on biomarkers in cancer etiology and prevention: a summary and challenge of 20 years of interdisciplinary research. Mutat Res;462:255–79 (2000).
Buringh E, Lanting R, Buringh E, Lanting R. Exposure variability in the workplace: its implications for the assessment of compliance.[see comment]. American Industrial Hygiene Association Journal 52(1): 6-13 (1991).
Lareo AC, Perbellini L. 1995. Biological monitoring of workers exposed to N-N-dimethylformamide. II. Dimethylformamide and its metabolites in urine of exposed workers. International Archives of Occupational & Environmental Health 67(1): 47-52.
Chang HY, Shih TS, Cheng CC, Tsai CY, Lai JS, Wang VS, et al. The effects of co-exposure to methyl ethyl ketone on the biological monitoring of occupational exposure to N,N-dimethylformamide. International Archives of Occupational & Environmental Health 76(2): 121-128 (2003).
Chang HY, Shih TS, Guo YL, Tsai CY, Hsu PC, Chang H-Y, et al. Sperm function in workers exposed to N,N-dimethylformamide in the synthetic leather industry. Fertility & Sterility 81(6): 1589-1594 (2004a).
Chang HY, Tsai CY, Lin YQ, Shih TS, Lin YC, Chang H-Y, et al. Urinary biomarkers of occupational N,N-dimethylformamide (DMF) exposure attributed to the dermal exposure. Journal of Exposure Analysis and Environmental Epidemiology 14(3): 214-221 (2004b).
Chang HY, Tsai CY, Lin YQ, Shih TS, Lin WC, Chang HY, et al. Total body burden arising from a week's repeated dermal exposure to N,N-dimethylformamide. Occupational & Environmental Medicine 62(3): 151-156 (2005a).
Chang HY, Yun YD, Yu YC, Shih TS, Lin MS, Kuo HW, et al. The effects of simultaneous exposure to methyl ethyl ketone and toluene on urinary biomarkers of occupational N,N-dimethylformamide exposure. Toxicology Letters 155(3): 385-395 (2005b).
Chivers CP, Chivers CP. Disulfiram effect from inhalation of dimethylformamide. Lancet 1(8059): 331 (1978).
Chieli E, Saviozzi M, Menicagli S, Branca T, Gervasi PG, Chieli E, et al. Hepatotoxicity and P-4502E1-dependent metabolic oxidation of N,N-dimethylformamide in rats and mice. Archives of Toxicology 69(3): 165-170 (1995).
Cox NH, Mustchin CP, Cox NH, Mustchin CP. Prolonged spontaneous and alcohol-induced flushing due to the solvent dimethylformamide. Contact Dermatitis 24(1): 69-70 (1991).
DiVincenzo, G. D., Kaplan, C. J. and Dedinas, J. "Characterization of the metabolites of methyl n-butyl ketone, methyl iso-butyl ketone, and methyl ethyl ketone in guinea pig serum and their clearance." Toxicology & Applied Pharmacology. 36(3): 511-22 (1976).
Ducatman AM, Conwill DE, Crawl J, Ducatman AM, Conwill DE, Crawl J. Germ cell tumors of the testicle among aircraft repairmen. Journal of Urology 136(4): 834-836 (1986).
Droz PO, Berode M, Wu MM. Evauation of concomitant biological and air monitoring results. Apply of Occupational and Environmental Hygiene 6:465–74 (1991).
Fail PA, George JD, Grizzle TB, Heindel JJ, Fail PA, George JD, et al. Formamide and dimethylformamide: reproductive assessment by continuous breeding in mice. Reproductive Toxicology 12(3): 317-332 (1998).
Johnson W, and Yagi K. 2002. CEH Report: Dimethylformamide. Menlo Park, CA, SRI Consulting.
Kafferlein HU, Angerer J, Kafferlein HU, Angerer J. Simultaneous determination of two human urinary metabolites of N,N-dimethylformamide using gas chromatography-thermionic sensitive detection with mass spectrometric confirmation. Journal of Chromatography B, Biomedical Sciences & Applications 734(2): 285-298 (1999).
Kafferlein HU, Angerer J, Kafferlein HU, Angerer J. N-methylcarbamoylated valine of hemoglobin in humans after exposure to N,N-dimethylformamide: evidence for the formation of methyl isocyanate? Chemical Research in Toxicology 14(7): 833-840 (2001).
Kawai, T., Yasugi, T., Mizunuma, K., Watanabe, T., Cai, S. X., Huang, M. Y., Xi, L. Q., Qu, J. B., Yao, B. Z. and Ikeda, M. "Occupational dimethylformamide exposure. 2. Monomethylformamide excretion in urine after occupational dimethylformamide exposure." International Archives of Occupational & Environmental Health 63(7): 455-60 (1992).
Kennedy GL, Jr., Sherman H, Kennedy GL, Jr., Sherman H. Acute and subchronic toxicity of dimethylformamide and dimethylacetamide following various routes of administration. Drug & Chemical Toxicology 9(2): 147-170 (1986).
Kestell P, Threadgill MD, Gescher A, Gledhill AP, Shaw AJ, Farmer PB, et al. An investigation of the relationship between the hepatotoxicity and the metabolism of N-alkylformamides. Journal of Pharmacology & Experimental Therapeutics 240(1): 265-270 (1987).
Kimmerle G, Eben A, Kimmerle G, Eben A. Metabolism studies of N,N-dimethylformamide. II. Studies in persons. Internationales Archiv fur Arbeitsmedizin 34(2): 127-136 (1975a).
Kimmerle G, Eben A, Kimmerle G, Eben A. Metabolism studies of N,N-dimethylformamide. I. Studies in rats and dogs. Internationales Archiv fur Arbeitsmedizin 34(2): 109-126 (1975b).
Kim, H., Wang, R. S., Elovaara, E., Raunio, H., Pelkonen, O., Aoyama, T., Vainio, H. and Nakajima, T. "Cytochrome P450 isozymes responsible for the metabolism of toluene and styrene in human liver microsomes." Xenobiotica. 27(7): 657-65 (1997).
Kromhout H, Heederik D, Kromhout H, Heederik D. Occupational epidemiology in the rubber industry: implications of exposure variability. American Journal of Industrial Medicine 27(2): 171-185 (1995).
Lyle WH, Spence TW, McKinneley WM, Duckers K, Lyle WH, Spence TW, et al. Dimethylformamide and alcohol intolerance. British Journal of Industrial Medicine 36(1): 63-66 (1979).
Leidel, N.A; Busch, K.A.; Crouse, W.E. Exposure Measurement Action Level and Occupational Enviromental Variability. U.S. Department of Health, Education, and Welfare/National Institute for Occupational Safety and Health. HEW (NIOSH) Publish No. 76-131, incinnati, OH (1975).
Lin YS, Kupper LL, Rappaport SM. Air samples versus biomarkers for epidemiology. Occupational & Environmental Medicine 62(11): 750-760. (2005).
Mraz J, Nohova H, Percutaneous absorption of N,N-dimethylformamide in humans. International Archives of Occupational & Environmental Health 64(2): 79-83. (1992a).
Mraz J, Nohova H. Absorption, metabolism and elimination of N,N-dimethylformamide in humans. International Archives of Occupational & Environmental Health 64(2): 85-92. (1992b).
Mraz, J., Jheeta, P., Gescher, A., Hyland, R., Thummel, K. and Threadgill, M. D. "Investigation of the mechanistic basis of N,N-dimethylformamide toxicity. Metabolism of N,N-dimethylformamide and its deuterated isotopomers by cytochrome P450 2E1." Chemical Research in Toxicology. 6(2): 197-207 (1993).
Moorman WJ, Ahlers HW, Chapin RE, Daston GP, Foster PM, Kavlock RJ, et al. Prioritization of NTP reproductive toxicants for field studies. Reproductive Toxicology 14(4): 293-301.
Mutti A. 1999. Biological monitoring in occupational and environmental toxicology. Toxicology letters 108(2-3):77-89 (2000).
Olsen E. Jensen B On the concept of the “normal” day. Quality control of occupational hygiene measurements. Apply of Occupational and Environmental Hygiene 9:245-255.
Olsen E. 1994. Analysis of Exposure Using a Logbook Method. Apply of Occupational and Environmental Hygiene 9:245-255 (1994).
Rappaport SM. Assessment of long-term exposures to toxic substances in air.[see comment]. Annals of Occupational Hygiene 35(1): 61-121 (1991)..
Rappaport SM, Symanski E, Yager JW, et al. The relationship between environmental monitoring and biological markers in exposure assessment. Environ Health Perspect 103(suppl 3):49–53 (1995).
Rappaport SM, Weaver M, Taylor D, Kupper L, Susi P. Application of mixed models to assess exposures monitored by construction workers during hot processes. Annals of Occupational Hygiene 43(7): 457-469 (1999).
Rappaport SM, Kupper LL, Lin YS, Rappaport SM, Kupper LL, Lin YS. On the importance of exposure variability to the doses of volatile organic compounds. Toxicological Sciences 83(2): 224-236 (2005).
Rothman N, Stewart WF, Schulte PA. Incorporating biomarkers into cancer epidemiology: a matrix of biomarker and study design categories. Cancer Epidemiology Biomarkers Prevent. 4:301-311 (1995).
Sabbioni G, Jones CR. Biomonitoring of arylamines and nitroarenes. Biomarkers 7:347–421 (2002).
Shieh DB, Chen CC, Shih TS, Tai HM, Wei YH, Chang HY, et al. Mitochondrial DNA alterations in blood of the humans exposed to N,N-dimethylformamide. Chemico-Biological Interactions 165(3): 211-219 (2007).
Symanski E., Chan W. And Chang CC et al. Mixed-Effects Models for the Evaluation of Long-term Trends in Exposure Levels with an Example from the Nickel Industry. Annals of Occupational Hygiene, Vol. 5, No. 1, pp. 71-81 (2001).
Tielemans E, Kupper LL, Kromhout H, Heederik D, Houba R, Tielemans E, et al. Individual-based and group-based occupational exposure assessment: some equations to evaluate different strategies. Annals of Occupational Hygiene 42(2): 115-119 (1998).
Yang JS, Kim EA, Lee MY, Park IJ, Kang SK, Yang JS, et al. Biological monitoring of occupational exposure to N,N-dimethylformamide--the effects of co-exposure to toluene or dermal exposure. International Archives of Occupational & Environmental Health 73(7): 463-470 (2000).