苯（Benzene）為煤化學工業之副產品，該製程為職業苯暴露之主要來源。過去有研究指出，受苯暴露的職場勞工罹患白血病之風險與空氣中苯暴露濃度呈現正相關，即使在低苯暴露濃度下，亦可發現臨床血液指標異常之現象。然而，勞工自暴露苯到發病的潛伏期從四個月至十年不等，目前尚未有研究針對健康之低苯暴露勞工探討低苯暴露對長期血液指標之變化。苯藉呼吸或皮膚吸收等途徑進入人體後可快速代謝，因此在體內多以代謝物的形式存在並自尿中排出，其中S-phenylmercapturic acid（S-PMA）為具高特異性之苯代謝產物，而另一代謝物對苯二酚（Hydroquinone，HQ）在過去體外試驗中發現其對細胞具有毒性。此二種代謝物在體內主要受CYP2E1（Cytochrome P450 2E1）和GST（Glutathione S-transferase）、NQO1（NAD(P)H:Quinone Oxidoreductase）等具基因多型性之酵素調控。顯示苯代謝酵素的基因多型性將可能影響苯在體內之代謝情形，進而影響個人對苯毒性之易感性。因此本研究目的為：1. 探討苯之尿中代謝物HQ、S-PMA與代謝酵素CYP2E1、GSTs、NQO1基因多型性的關係；2. 探討苯暴露勞工尿中HQ濃度與血液指標的劑量效應關係；3. 探討苯暴露勞工代謝酵素CYP2E1、GSTs、NQO1基因多型性與長期血液指標變化之相關性。研究對象依作業型態分為高低苯暴露組，共84人。使用被動式採樣器與GC-FID分析個人之空氣中苯暴露濃度，並採集血液樣本與上班前後各一次尿液。此外，彙整1990~2006年該廠員工之歷年健檢資料做為長期血液指標變化之評估基本資料。取得之血液樣本，利用限制酶切割片段長度多型性方法（restriction fragment length polymorphism，RFLP）判定CYP2E1- c.-1259C>T, CYP2E1- c.7668T>A及NQO1- c.609C>T基因型，GSTM1及GSTT1基因型則利用聚合酶連鎖反應（polymerase chain reaction，PCR）分析。尿液樣本分別以以高效能液相層析儀結合電灑法串聯式質譜儀 （high performance liquid chromatography- electrospray ionization tandem mass spectrometry, HPLC-ESI-MS/MS）分析尿中苯代謝物S-PMA 之濃度，及以氣相層析質譜儀（Gas Chromatography-Mass Spectrophotometer, GC-MS）測定尿中HQ濃度。
本研究結果顯示：（1）個人苯暴露濃度呈對數常態分佈，中位數＝29.44 ppb，而尿中S-PMA濃度中位數＝0.055 μg/g creatinine皆遠低於法規容許濃度，是為低苯暴露族群；（2）勞工下班前尿中HQ濃度較上班前顯著增加，工作場所中之苯暴露的確會影響體內HQ的產生，然而在此低苯暴露濃度下，未見空氣中苯濃度與尿中HQ濃度成顯著相關（r=0.18，p=0.116）；（3）本研究未發現CYP2E1之基因多型性與尿中S-PMA或HQ有顯著相關；（4）GSTT1之基因多型性與S-PMA濃度無關，而GSTM1無效基因型所代謝之S-PMA則顯著較有效基因型者高；（5）並未發現GST之基因型與尿中HQ濃度有關；（6） NQO1 c.609 C＞T非雙套變異型者，尿中HQ濃度比NQO1 c.609 雙套變異型者為高；（7）單一酵素之基因多型性與單年度血液指標異常無顯著相關；（8）發現具NQO1 c.609 T/T×CYP2E1 c.-1259 C/T（或 T/T）及NQO1 c.609 T/T×CYP2E1 c.7668 T/A（或A/A）基因型者，其紅血球數、平均紅血球容積、平均紅血球血色素異常風險比同時具有NQO1非雙套變異型及CYP2E1野生型者要高6.56～7.61倍；（9）具GSTM1 null type或GSTT1 null type基因型者，白血球異常風險比具GST有效基因型者要高10.5倍；（10）長期血液指標異常與基因多型性分析方面，發現具有CYP2E1 c.-1259 T/C（或T/T）之長期苯暴露勞工其淋巴球數異常的危險性比CYP2E1 c.-1259 C/C者要高7.22倍。（11）NQO1× GSTT1之基因多型性及抽菸習慣分別與歷年白血球數平均值及歷年紅血球數平均值的降低有關。由於本研究僅為一次採樣，且苯暴露濃度甚低，可能因此無法看出苯代謝物在體內長期暴露對血液指標引起之不良影響，建議以職業苯暴露勞工體內實際HQ濃度來進一步探討較為敏感之短期健康危害指標。此外，由研究結果可知，即使是遠低於法規容許濃度5 ppm之作業場所，苯的造血毒性對特定基因型之長期暴露勞工仍有不良影響。因此建議將對苯毒性具高易感受性基因之勞工列管，定期進行健康檢查，並依據健檢結果加強職業苯暴露勞工之健康評估與管理。

Benzene was common by-product in coal chemistry process, and it was one of the major occupational benzene exposure sources. Reports reveal that employees who are exposed to high benzene concentrations could have elevated risk of leukemia, and the complete blood count (CBC) decreases even at low exposure. Moreover, the latency period extended about 4 months to 10 years, but few study have researched the long term hematological parameters among low benzene-exposed healthy workers. After inhalatary and dermal exposure, the remainder of benzene is metabolized in the body and excreted through urine. S-phenylmercapturic acid（S-PMA）is the specific metabolite of benzene, and hydroquinone（HQ）is a benzene-derived toxicity found by in vitro study. These metabolites modulated by enzymes, Cytochrome P450 2E1（CYP2E1）, Glutathione S-transferase（GST）and NAD(P)H:Quinone Oxidoreductase （NQO1）with genetic polymorphisms. Thus, the genetic polymorphism of aforementioned enzymes could affect the metabolic pathway of exposed benzene and human susceptibility of benzene-derived toxicity. The objectives of this study were （1） to study the effects of various genetic polymorphisms on levels of HQ and S-PMA;（2） to investigate the dose-response between the levels of HQ and alteration of hemotological parameters; and （3） to investigate the CBC outcomes over years in relation to individual genotype of CYP2E1, NQO1, GST. Eighty-four workers were recruited based on different benzene-exposed levels in a coal chemistry plant from southern Taiwan. We have analyzed the airborne benzene, the hematological parameters, single nucleotide polymorphisms (SNPs) in CYP2E1- c.-1259C>T, CYP2E1- c.7668T>A, NQO1- c.609C>T, GSTM1, GSTT1, and long term physical examination records since 1990 to 2006 for each participant. Genetic polymorphisms of CYP2E1 and NQO1 were analyzed by restriction fragment length polymorphism（RFLP）, and GSTs were analyzed by polymerase chain reaction（PCR）. The levels of S-PMA and HQ in urine samples were determined by high performance liquid chromatography- electrospray ionization tandem mass spectrometry（HPLC-ESI-MS/MS）and Gas Chromatography-Mass Spectrophotometer（GC-MS）respectively.
We found:（1）personal airborne benzene concentration showed log normal distribution. Medium levels of air-Bz and urinary S-PMA were 29.44 ppb and 0.055 μg/g creatinine, respectively, and those levels far below the current permissible exposure limit and biological exposure index; （2）The level of HQ in workers was increased significantly in the end-shift, and it indicated that the benzene exposure in work place would cause personal urinary HQ rising. However, significant correlation was not found between air benzene and HQ（r=0.18，p=0.116）due to the low benzene concentration; （3）The genotype of CYP2E1- c.-1259C>T, CYP2E1- c.7668T>A might not effect the level of HQ and S-PMA in low benzene-exposed workers; （4）The level of S-PMA might not be effect by the genetic polymorphism of GSTT1, but GSTM1. Our data revealed subjects with GSTM1 null type have more S-PMA in urine than GSTM1 non null type; （5）No significant relationship was found between urinary HQ level and genotype of GSTs in benzene-exposed workers.（6）Urinary HQ level were found significantly higher in individuals with NQO1 c.609 T/T compared to those with NQO1 c.609 C/T（or C/C）; （7）No significant odds ratios in genotypes of CYP2E1, NQO1, GST between all hematological parameters in 2006 physical examination were found.（8）Individuals with NQO1 c.609 T/T×CYP2E1 c.-1259 C/T（or T/T）, NQO1 c.609 T/T×CYP2E1 c.7668 T/A（or A/A） tended to be more susceptible to have abnormal red blood cell counts（RBC）, mean corpuscular volume（MCV）, mean corpuscular hemoglobin（MCH） than NQO1 c.609 C/T（or C/C）×CYP2E1 c.-1259 C/C, NQO1 c.609 C/T（or C/C）×CYP2E1 c.7668 T/T （odds ratio=6.56～7.61）; （9） We also observed a 10.5-fold increased risk among workers with GSTs null type compared to those with GSTs non null type; （10） Long term benzene-exposed workers who carry genotypes of CYP2E1 c.-1259 T/C（or T/T） have significant higher risk of abnormal lymphocytes than those carry CYP2E1 c.-1259 wild type;（11）Subjects with NQO1 c.609 T/T× GSTT1 null genotype and smoked was found decreased long term average WBC and RBC respectively.

Aksoy M. 1989. Hematotoxicity and carcinogenicity of benzene. Environmental
Health Perspectives 82:193-7.
Andreoli C, Rossi S, Leopardi P, Crebelli R. 1999. DNA damage by hydroquinone in
human white blood cells: analysis by alkaline single-cell gel electrophoresis.
Mutation Research 438(1):37-45.
Arand M, Muhlbauer R, Hengstler J, Jager E, Fuchs J, Winkler L, Oesch F. 1996. A
multiplex polymerase chain reaction protocol for the simultaneous analysis
of the glutathione S-transferase GSTM1 and GSTT1 polymorphisms.
Analytical Biochemistry 236(1):184-6.
Asou N. 2003. The role of a Runt domain transcription factor AML1/RUNX1 in
leukemogenesis and its clinical implications.[erratum appears in Crit Rev
Oncol Hematol. 2006 Oct;60(1):87]. Critical Reviews in
Oncology-Hematology 45(2):129-50.
Baselt RC, Franch S. 1980. Plasma and urine concentrations of methapyrilene by
nitrogen-phosphorus gas-liquid chromatography. Journal of
Chromatography A. 183(2):234-8.
Bauer AK, Faiola B, Abernethy DJ, Marchan R, Pluta LJ, Wong VA, Roberts K,
Jaiswal AK, Gonzalez FJ, Butterworth BE and others. 2003. Genetic
susceptibility to benzene-induced toxicity: role of NADPH: quinone
oxidoreductase-1. Cancer Research 63(5):929-35.
Boersma MG, Balvers WG, Boeren S, Vervoort J, Rietjens IM. 1994.
NADPH-cytochrome reductase catalysed redox cycling of 1,
4-benzoquinone; hampered at physiological conditions, initiated at
increased pH values. Biochem Pharmacol 47(11):1949-55.
Bolton JL, Trush MA, Penning TM, Dryhurst G, Monks TJ. 2000. Role of quinones
in toxicology. Chemical Research in Toxicology 13(3):135-60.
Chen Y, Li G, Yin S, Xu J, Ji Z, Xiu X, Liu L, Ma D. 2007. Genetic polymorphisms
involved in toxicant-metabolizing enzymes and the risk of chronic benzene
poisoning in Chinese occupationally exposed populations. Xenobiotica
37(1):103-12.
Chung HW, Kim SY. 2002. Detection of chromosome-specific aneusomy and
translocation by benzene metabolites in human lymphocytes using
fluorescence in situ hybridization with DNA probes for chromosomes 5, 7, 8,
and 21. Journal of Toxicology & Environmental Health Part A 65(5-6):365-72.
Colman R, Coleman A. 2006. Unexpected cause of raised benzene absorption in
coke oven by-product workers. Occupational Medicine 56(4):269-71.
Dean BJ. 1985. Recent findings on the genetic toxicology of benzene, toluene,
xylenes and phenols. Mutation Research 154(3):153-81.Deisinger PJ, Hill TS, English JC. 1996. Human exposure to naturally occurring
hydroquinone. Journal of Toxicology & Environmental Health 47(1):31-46.
do Ceu Silva M, Gaspar J, Duarte Silva I, Leao D, Rueff J. 2003. Mechanisms of
induction of chromosomal aberrations by hydroquinone in V79 cells.
Mutagenesis 18(6):491-6.
Doepker CL, Dumont KW, O'Donoghue J, English JC. 2000. Lack of induction of
micronuclei in human peripheral blood lymphocytes treated with
hydroquinone. Mutagenesis 15(6):479-87.
Ducos P, Gaudin R, Robert A, Francin JM, Maire C. 1990. Improvement in HPLC
analysis of urinary trans,trans-muconic acid, a promising substitute for
phenol in the assessment of benzene exposure. International Archives of
Occupational & Environmental Health 62(7):529-34.
Eastmond DA, Mondrala ST, Hasegawa L. 2005. Topoisomerase II inhibition by
myeloperoxidase-activated hydroquinone: a potential mechanism underlying
the genotoxic and carcinogenic effects of benzene. Chemico-Biological
Interactions 153-154:207-16.
Erexson GL, Wilmer JL, Kligerman AD. 1985. Sister chromatid exchange induction
in human lymphocytes exposed to benzene and its metabolites in vitro.
Cancer Research 45(6):2471-7.
Frantz CE, Chen H, Eastmond DA. 1996. Inhibition of human topoisomerase II in
vitro by bioactive benzene metabolites. Environmental Health Perspectives
104 Suppl 6:1319-23.
Gaedigk A, Tyndale RF, Jurima-Romet M, Sellers EM, Grant DM, Leeder JS. 1998.
NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in
Caucasian, Chinese and Canadian Native Indian and Inuit populations.
Pharmacogenetics 8(4):305-13.
Harada S. 2001. [Classification of alcohol metabolizing enzymes and
polymorphisms--specificity in Japanese]. Nihon Arukoru Yakubutsu Igakkai
Zasshi 36(2):85-106.
Hawthorne SB, Krieger MS, Miller DJ, Mathiason MB. 1989. Collection and
quantitation of methoxylated phenol tracers for atmospheric pollution from
residential wood stoves. Environmental Science & Technology
23(4):470-475.
Hayes RB, Yin SN, Dosemeci M, Li GL, Wacholder S, Travis LB, Li CY, Rothman N,
Hoover RN, Linet MS. 1997. Benzene and the dose-related incidence of
hematologic neoplasms in China. Chinese Academy of Preventive
Medicine--National Cancer Institute Benzene Study Group.[see comment].
Journal of the National Cancer Institute 89(14):1065-71.
Hirvonen A, Husgafvel-Pursiainen K, Anttila S, Karjalainen A, Vainio H. 1993. The
human CYP2E1 gene and lung cancer: DraI and RsaI restriction fragment
length polymorphisms in a Finnish study population. Carcinogenesis.
14(1):85-8.
Hu Y, Chen B, Yin Z, Jia L, Zhou Y, Jin T. 2006. Increased risk of chronic obstructivepulmonary diseases in coke oven workers: interaction between occupational
exposure and smoking. Thorax 61(4):290-5.
Inayat-Hussain SH, Winski SL, Ross D. 2001. Differential involvement of caspases
in hydroquinone-induced apoptosis in human leukemic hl-60 and jurkat cells.
Toxicology & Applied Pharmacology 175(2):95-103.
Johnstone RW, Ruefli AA, Lowe SW. 2002. Apoptosis: a link between cancer
genetics and chemotherapy. Cell 108(2):153-64.
Joseph P, Klein-Szanto AJ, Jaiswal AK. 1998. Hydroquinones cause specific
mutations and lead to cellular transformation and in vivo tumorigenesis.
British Journal of Cancer 78(3):312-20.
Kalf GF. 1987. Recent advances in the metabolism and toxicity of benzene. Crit
Rev Toxicol 18(2):141-59.
Kato S, Shields PG, Caporaso NE, Hoover RN, Trump BF, Sugimura H, Weston A,
Harris CC. 1992. Cytochrome P450IIE1 genetic polymorphisms, racial
variation, and lung cancer risk. Cancer Research 52(23):6712-5.
Ketterer B. 1998. Glutathione S-transferases and prevention of cellular free radical
damage. Free Radical Research 28(6):647-58.
Kim S, Vermeulen R, Waidyanatha S, Johnson BA, Lan Q, Rothman N, Smith MT,
Zhang L, Li G, Shen M and others. 2006. Using urinary biomarkers to
elucidate dose-related patterns of human benzene metabolism.
Carcinogenesis 27(4):772-81.
Kim SY, Choi JK, Cho YH, Chung EJ, Paek D, Chung HW. 2004. Chromosomal
aberrations in workers exposed to low levels of benzene: association with
genetic polymorphisms. Pharmacogenetics 14(7):453-63.
Lan Q, Zhang L, Li G, Vermeulen R, Weinberg RS, Dosemeci M, Rappaport SM,
Shen M, Alter BP, Wu Y and others. 2004. Hematotoxicity in workers
exposed to low levels of benzene.[see comment]. Science
306(5702):1774-6.
Landi L, Fiorentini D, Galli MC, Segura-Aguilar J, Beyer RE. 1997. DT-Diaphorase
maintains the reduced state of ubiquinones in lipid vesicles thereby
promoting their antioxidant function. Free Radical Biology & Medicine
22(1-2):329-35.
Larson RA, LeBeau MM, Vardiman JW, Rowley JD. 1996. Myeloid leukemia after
hematotoxins. Environmental Health Perspectives 104 Suppl 6:1303-7.
Lastowska M, Cotterill S, Bown N, Cullinane C, Variend S, Lunec J, Strachan T,
Pearson ADJ, Jackson MS. 2002. Breakpoint position on 17q identifies the
most aggressive neuroblastoma tumors. Genes, Chromosomes & Cancer
34(4):428-36.
Lindsey RH, Jr., Bromberg KD, Felix CA, Osheroff N. 2004. 1,4-Benzoquinone is a
topoisomerase II poison. Biochemistry 43(23):7563-74.
Lovern MR, Maris ME, Schlosser PM. 1999. Use of a mathematical model of rodent
in vitro benzene metabolism to predict human in vitro metabolism data.
Carcinogenesis 20(8):1511-1520.Lucas D, Ferrara R, Gonzales E, Albores A, Manno M, Berthou F. 2001.
Cytochrome CYP2E1 phenotyping and genotyping in the evaluation of
health risks from exposure to polluted environments. Toxicology Letters
124(1-3):71-81.
Lutz WK. 1986. Quantitative evaluation of DNA binding data for risk estimation and
for classification of direct and indirect carcinogens. Journal of Cancer
Research & Clinical Oncology 112(2):85-91.
Maga JA. 1978. Simple phenol and phenolic compounds in food flavor. CRC
Critical Reviews in Food Science & Nutrition 10(4):323-72.
Marchand A, Mathe C, Imbach JL, Gosselin G. 2000. Synthesis and antiviral
evaluation of unnatural beta-L-enantiomers of 3'-fluoro- and
3'-azido-2',3'-dideoxyguanosine derivatives. Nucleosides, Nucleotides &
Nucleic Acids 19(1-2):205-17.
McDonald TA, Holland NT, Skibola C, Duramad P, Smith MT. 2001. Hypothesis:
phenol and hydroquinone derived mainly from diet and gastrointestinal flora
activity are causal factors in leukemia. Leukemia 15(1):10-20.
Melikian AA, Qu Q, Shore R, Li G, Li H, Jin X, Cohen B, Chen L, Li Y, Yin S and
others. 2002. Personal exposure to different levels of benzene and its
relationships to the urinary metabolites S-phenylmercapturic acid and
trans,trans-muconic acid. Journal of Chromatography B: Analytical
Technologies in the Biomedical & Life Sciences 778(1-2):211-21.
Mendoza-Cantu A, Castorena-Torres F, de Leon MB, Cisneros B, Lopez-Carrillo L,
Rojas-Garcia AE, Aguilar-Salinas A, Manno M, Albores A. 2006.
Occupational Toluene Exposure Induces Cytochrome P450 2E1 mRNA
Expression in Peripheral Lymphocytes. Environmental Health Perspectives
114(4):494-499.
Moran JL, Siegel D, Ross D. 1999. A potential mechanism underlying the increased
susceptibility of individuals with a polymorphism in NAD(P)H:quinone
oxidoreductase 1 (NQO1) to benzene toxicity.[see comment]. Proceedings
of the National Academy of Sciences of the United States of America
96(14):8150-5.
Morgan GJ, Alvares CL. 2005. Benzene and the hemopoietic stem cell.
Chemico-Biological Interactions 153-154:217-22.
Nakakuma H, Kawaguchi T. 2003. Pathogenesis of selective expansion of PNH
clones. International Journal of Hematology 77(2):121-4.
Nomiyama K, Nomiyama H. 1974. Respiratory retention, uptake and excretion of
organic solvents in man. Internationales Archiv fur Arbeitsmedizin
32(1):75-83.
Nomura F, Itoga S, Uchimoto T, Tomonaga T, Nezu M, Shimada H, Ochiai T. 2003.
Transcriptional activity of the tandem repeat polymorphism in the 5'-flanking
region of the human CYP2E1 gene. Alcoholism: Clinical & Experimental
Research 27(8 Suppl):42S-46S.
Ong CN, Kok PW, Ong HY, Shi CY, Lee BL, Phoon WH, Tan KT. 1996. Biomarkersof exposure to low concentrations of benzene: a field assessment.[see
comment]. Occupational & Environmental Medicine 53(5):328-33.
Ong CN, Lee BL, Shi CY, Ong HY, Lee HP. 1994. Elevated levels of
benzene-related compounds in the urine of cigarette smokers. International
Journal of Cancer 59(2):177-80.
Pavanello S, Clonfero E. 2000. [Biomarkers of gentotoxic risk and metabolic
polymorphism]. Medicina del Lavoro 91(5):431-69.
Pemble S, Schroeder KR, Spencer SR, Meyer DJ, Hallier E, Bolt HM, Ketterer B,
Taylor JB. 1994. Human glutathione S-transferase theta (GSTT1): cDNA
cloning and the characterization of a genetic polymorphism. Biochem J
300(Pt 1):271-276.
Peterson LF, Zhang D-E. 2004. The 8;21 translocation in leukemogenesis.
Oncogene 23(24):4255-62.
Piedrafita FJ, Molander RB, Vansant G, Orlova EA, Pfahl M, Reynolds WF. 1996.
An Alu element in the myeloperoxidase promoter contains a composite
SP1-thyroid hormone-retinoic acid response element. Journal of Biological
Chemistry 271(24):14412-20.
Powell H, Kitteringham NR, Pirmohamed M, Smith DA, Park BK. 1998. Expression
of cytochrome P4502E1 in human liver: assessment by mRNA, genotype
and phenotype. Pharmacogenetics 8(5):411-21.
Puccetti E, Ruthardt M. 2004. Acute promyelocytic leukemia: PML/RARalpha and
the leukemic stem cell. Leukemia 18(7):1169-75.
Qu Q, Melikian AA, Li G, Shore R, Chen L, Cohen B, Yin S, Kagan MR, Li H, Meng
M and others. 2000. Validation of biomarkers in humans exposed to
benzene: urine metabolites. American Journal of Industrial Medicine
37(5):522-31.
Qu Q, Shore R, Li G, Su L, Jin X, Melikian AA, Roy N, Chen LC, Wirgin I, Cohen B
and others. 2005. Biomarkers of benzene: urinary metabolites in relation to
individual genotype and personal exposure. Chemico-Biological Interactions
153-154:85-95.
Rangan U, Snyder R. 1997. Scientific update on benzene. Annals of the New York
Academy of Sciences 837:105-13.
Reddy MV, Blackburn GR, Schreiner CA, Mehlman MA, Mackerer CR. 1989. 32P
analysis of DNA adducts in tissues of benzene-treated rats. Environmental
Health Perspectives 82:253-7.
Rinsky RA, Smith AB, Hornung R, Filloon TG, Young RJ, Okun AH, Landrigan PJ.
1987. Benzene and leukemia. An epidemiologic risk assessment. New
England Journal of Medicine 316(17):1044-50.
Rinsky RA, Young RJ, Smith AB. 1981. Leukemia in benzene workers. American
Journal of Industrial Medicine 2(3):217-45.
Ross D. 2000. The role of metabolism and specific metabolites in benzene-induced
toxicity: evidence and issues. Journal of Toxicology & Environmental Health
Part A 61(5-6):357-72.Ross D. 2005. Functions and distribution of NQO1 in human bone marrow:
potential clues to benzene toxicity. Chemico-Biological Interactions
153-154:137-46.
Ross D, Kepa JK, Winski SL, Beall HD, Anwar A, Siegel D. 2000.
NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation,
gene regulation and genetic polymorphisms. Chemico-Biological
Interactions 129(1-2):77-97.
Rossi AM, Guarnieri C, Rovesti S, Gobba F, Ghittori S, Vivoli G, Barale R. 1999.
Genetic polymorphisms influence variability in benzene metabolism in
humans. Pharmacogenetics 9(4):445-51.
Rothman N, Smith MT, Hayes RB, Traver RD, Hoener B, Campleman S, Li GL,
Dosemeci M, Linet M, Zhang L and others. 1997. Benzene poisoning, a risk
factor for hematological malignancy, is associated with the NQO1 609C-->T
mutation and rapid fractional excretion of chlorzoxazone. Cancer Research
57(14):2839-42.
Rund D, Ben-Yehuda D. 2004. Therapy-related leukemia and myelodysplasia:
evolving concepts of pathogenesis and treatment. Hematology 9(3):179-87.
Rushton L, Romaniuk H. 1997. A case-control study to investigate the risk of
leukaemia associated with exposure to benzene in petroleum marketing and
distribution workers in the United Kingdom.[see comment]. Occupational &
Environmental Medicine 54(3):152-66.
Schnatter AR, Armstrong TW, Thompson LS, Nicolich MJ, Katz AM, Huebner WW,
Pearlman ED. 1996a. The relationship between low-level benzene exposure
and leukemia in Canadian petroleum distribution workers. Environmental
Health Perspectives 104 Suppl 6:1375-9.
Schnatter AR, Nicolich MJ, Bird MG. 1996b. Determination of leukemogenic
benzene exposure concentrations: refined analyses of the Pliofilm cohort.
Risk Analysis 16(6):833-40.
Shen J, Wang R, Wang Z, Xing H, Wang L, Wang B, Li M, Hua Z, Wang J, Guo C.
2002. The distributive features of three kinds of metabolic genes
polymorphisms in population of Han nationality in south area of China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2002:302-7.
Sherwood RJ. 1988. Pharmacokinetics of benzene in a human after exposure at
about the permissible limit. Annals of the New York Academy of Sciences
534:635-47.
Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D. 2001. Rapid
polyubiquitination and proteasomal degradation of a mutant form of
NAD(P)H:quinone oxidoreductase 1. Molecular Pharmacology 59(2):263-8.
Siegel D, Bolton EM, Burr JA, Liebler DC, Ross D. 1997. The reduction of
alpha-tocopherolquinone by human NAD(P)H: quinone oxidoreductase: the
role of alpha-tocopherolhydroquinone as a cellular antioxidant. Molecular
Pharmacology 52(2):300-5.
Siegel D, McGuinness SM, Winski SL, Ross D. 1999. Genotype-phenotyperelationships in studies of a polymorphism in NAD(P)H:quinone
oxidoreductase 1.[erratum appears in Pharmacogenetics 1999
Jun;9(3):419]. Pharmacogenetics 9(1):113-21.
Silva MdC, Gaspar J, Duarte Silva I, Faber A, Rueff J. 2004. GSTM1, GSTT1, and
GSTP1 genotypes and the genotoxicity of hydroquinone in human
lymphocytes. Environmental & Molecular Mutagenesis 43(4):258-64.
Snyder R, Hedli CC. 1996. An overview of benzene metabolism. Environmental
Health Perspectives 104 Suppl 6:1165-71.
Sorensen M, Skov H, Autrup H, Hertel O, Loft S. 2003. Urban benzene exposure
and oxidative DNA damage: influence of genetic polymorphisms in
metabolism genes. Science of the Total Environment 309(1-3):69-80.
Stephens EA, Taylor JA, Kaplan N, Yang CH, Hsieh LL, Lucier GW, Bell DA. 1994.
Ethnic variation in the CYP2E1 gene: polymorphism analysis of 695
African-Americans, European-Americans and Taiwanese.
Pharmacogenetics 4(4):185-92.
Stillman WS, Varella-Garcia M, Gruntmeir JJ, Irons RD. 1997. The benzene
metabolite, hydroquinone, induces dose-dependent hypoploidy in a human
cell line. Leukemia 11(9):1540-5.
Strange RC, Spiteri MA, Ramachandran S, Fryer AA. 2001.
Glutathione-S-transferase family of enzymes. Mutation Research
482(1-2):21-6.
Talalay P, Prochaska HJ. 1987. Mechanisms of induction of NAD (P) H: quinone
reductase. Chemica Scripta 27A:61–66.
Traver RD, Horikoshi T, Danenberg KD, Stadlbauer TH, Danenberg PV, Ross D,
Gibson NW. 1992. NAD(P)H:quinone oxidoreductase gene expression in
human colon carcinoma cells: characterization of a mutation which
modulates DT-diaphorase activity and mitomycin sensitivity. Cancer
Research 52(4):797-802.
Tsutsui T, Hayashi N, Maizumi H, Huff J, Barrett JC. 1997a. Benzene-, catechol-,
hydroquinone- and phenol-induced cell transformation, gene mutations,
chromosome aberrations, aneuploidy, sister chromatid exchanges and
unscheduled DNA synthesis in Syrian hamster embryo cells. Mutation
Research 373(1):113-23.
Tsutsui T, Hayashi N, Maizumi H, Huff J, Barrett JC. 1997b. Benzene-, catechol-,
hydroquinone-and phenol-induced cell transformation, gene mutations,
chromosome aberrations, aneuploidy, sister chromatid exchanges and
unscheduled DNA synthesis in Syrian hamster embryo cells. Mutat Res
373(1):113-23.
Vaughan AT, Betti CJ, Villalobos MJ, Premkumar K, Cline E, Jiang Q, Diaz MO.
2005. Surviving apoptosis: a possible mechanism of benzene-induced
leukemia. Chemico-Biological Interactions 153-154:179-85.
Verdina A, Galati R, Falasca G, Ghittori S, Imbriani M, Tomei F, Marcellini L, Zijno A,
Vecchio VD, Crebelli R. 2001. METABOLIC POLYMORPHISMS ANDURINARY BIOMARKERS IN SUBJECTS WITH LOW BENZENE
EXPOSURE. Journal of Toxicology and Environmental Health, Part A
64(8):607-618.
Vian L, Van Hummelen P, Bichet N, Gouy D, Kirsch-Volders M. 1995. Evaluation of
hydroquinone and chloral hydrate on the in vitro micronucleus test on
isolated lymphocytes. Mutation Research 334(1):1-7.
Waidyanatha S, Rothman N, Li G, Smith MT, Yin S, Rappaport SM. 2004. Rapid
determination of six urinary benzene metabolites in occupationally exposed
and unexposed subjects. Analytical Biochemistry 327(2):184-99.
Wan J, Shi J, Hui L, Wu D, Jin X, Zhao N, Huang W, Xia Z, Hu G. 2002. Association
of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1
genes with benzene poisoning. Environmental Health Perspectives
110(12):1213-8.
Waters MD, Stack HF, Brady AL, Lohman PH, Haroun L, Vainio H. 1988. Use of
computerized data listings and activity profiles of genetic and related effects
in the review of 195 compounds. Mutat Res 205(1-4):295-312.
Westoo G. 1964. On the metabolism of sorbic acid in the mouse. Acta Chem.
Scand 18:1373-1378.
Whysner J, Verna L, English JC, Williams GM. 1995. Analysis of studies related to
tumorigenicity induced by hydroquinone. Regulatory Toxicology &
Pharmacology 21(1):158-76.
Yager JW, Eastmond DA, Robertson ML, Paradisin WM, Smith MT. 1990.
Characterization of micronuclei induced in human lymphocytes by benzene
metabolites. Cancer Research 50(2):393-9.
Yin SN, Hayes RB, Linet MS, Li GL, Dosemeci M, Travis LB, Zhang ZN, Li DG,
Chow WH, Wacholder S and others. 1996. An expanded cohort study of
cancer among benzene-exposed workers in China. Benzene Study Group.
Environmental Health Perspectives 104 Suppl 6:1339-41.
Yoshimura K, Hanaoka T, Ohnami S, Ohnami S, Kohno T, Liu Y, Yoshida T,
Sakamoto H, Tsugane S. 2003. Allele frequencies of single nucleotide
polymorphisms (SNPs) in 40 candidate genes for gene-environment studies
on cancer: data from population-based Japanese random samples. Journal
of Human Genetics 48(12):654-8.
Zhang L, Robertson ML, Kolachana P, Davison AJ, Smith MT. 1993. Benzene
metabolite, 1,2,4-benzenetriol, induces micronuclei and oxidative DNA
damage in human lymphocytes and HL60 cells. Environmental & Molecular
Mutagenesis 21(4):339-48.
陳曉雯，基因多型性對職業苯暴露生物偵測之影響，國立成功大學醫學院環境醫學研
究所碩士論文，p.37，2004。
王正宏，「血液學」，藝軒圖書出版社，台北，中華民國，1991。林昇峰，「血液學概論」，合記圖書出版社，台北，中華民國，1992。
陳吉平，「最新毒理學」，藝軒圖書出版社，台北，中華民國，2000。
陳登來、陳碧珍，「血液學」，藝軒圖書出版社，台北，中華民國，2002。