Occupational bladder cancer in a 4,4'-methylenebis(2-chloroaniline) (MBOCA)-exposed worker.
A 52-year-old male chemical worker was admitted to the hospital with a history of paroxysmal paroxysmal (per´ksiz´ml),
adj recurring in paroxysms. microscopic hematuria microscopic hematuria Microhematuria Hematuria that can only be detected by LM examination of the urine for about 2 years and nocturia with gross hematuria hematuria
Blood in the urine. It usually indicates injury or disease of the kidney or another structure of the urinary system or possibly, in males, the reproductive system. It may result from infection, inflammation, tumours, kidney stones, or other disorders. about five times per night for 2 months. He was a nonsmoker and denied a history of any other bladder carcinogen carcinogen: see cancer.
Agent that can cause cancer. Exposure to one or more carcinogens, including certain chemicals, radiation, and certain viruses, can initiate cancer under conditions not completely understood. exposure except for occasional pesticide application during agricultural work. Intravenous urogram urogram /uro·gram/ (u´ro-gram) a film obtained by urography.
A radiograph of the urinary tract.
a radiograph obtained by urography. imaging showed a mass occupying half of the bladder capacity. Cystoscopy Cystoscopy Definition
Cystoscopy (cystourethroscopy) is a diagnostic procedure that is used to look at the bladder (lower urinary tract), collect urine samples, and examine the prostate gland. revealed a mass over the left dome of the bladder. Cystoscopic biopsy revealed a grade 3 invasive transitional cell carcinoma tran·si·tion·al cell carcinoma
A malignant neoplasm derived from transitional epithelium and occurring primarily in the urinary bladder, ureters, or renal pelvises.
transitional cell carcinoma Bladder cancer, see there with marked necrosis. From 1987 until hospital admission in 2001, the patient had worked in a company that produced the 4,4'-methylenebis(2-chloroaniline) (MBOCA) curing agent. He did not wear any personal protective equipment during work. Ambient air MBOCA levels in the purification process area (0.23-0.41 mg/[m.sup.3]) exceeded the U.S. Occupational Safety and Health Administration's permissible exposure level. Urinary MBOCA levels (267.9-15701.1 [micro]g/g creatinine) far exceeded the California Occupational Safety and Health Administration's reference value of 100 [micro]g/L. This patient worked in the purification process with occupational exposure to MBOCA for 14 years. According to the environmental and biologic monitoring data and latency period latency period
In psychoanalytic theory, the fourth stage of psychosexual development, extending from about age 5 to puberty, when a child apparently represses sexual urges and prefers to associate with members of the same sex. , and excluding other potential bladder carcinogen exposure, this worker was diagnosed as having occupational bladder cancer bladder cancer
Malignant tumour of the bladder. The most significant risk factor associated with bladder cancer is smoking. Exposure to chemicals called arylamines, which are used in the leather, rubber, printing, and textiles industries, is another risk factor. due to high exposure to MBOCA through inhalation or dermal dermal /der·mal/ (der´mal) pertaining to the dermis or to the skin.
der·mal or der·mic
Of or relating to the skin or dermis. absorption in the purification area. This case finding supports that MBOCA is a potential human carcinogen. Safe use of skin-protective equipment and respirators is required to prevent workers from MBOCA exposure. Key words: bladder cancer, MBOCA, transitional cell carcinoma. Environ Health Perspect 113:771-774 (2005). doi:10.1289/ehp.7666 available via http://dx.doi.org/ [Online 25 February 2005]
Incidence and mortality rates of bladder cancer vary about 10-fold worldwide. The highest rates are found in North America and Europe, and the rates are low in many parts of Asia (Engel et al. 2002). In Taiwan, the incidence and mortality rates of bladder cancer (per 100,000) in 2000 were 8.93 and 3.00 for males and 3.87 and 1.36 for females, respectively [Taiwan Department of Health (DOH) 2004]. Transitional cell carcinomas account for about 95% of bladder neoplasms. The remaining 5% consist of squamous cell carcinomas, adenocarcinomas, and others (Engel et al. 2002). Cigarette smoking and occupational exposures are well-documented risk factors for bladder cancer. Other known or suspected risk factors for bladder cancer include race, sex, age, lifestyle, chlorination chlorination Public health Addition of chlorinated compounds to drinking water as disinfectants. Cf Ozonation. by-products and arsenic in drinking water drinking water
supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g. , ionizing radiation i·on·i·zing radiation
High-energy radiation capable of producing ionization in substances through which it passes.
Ionizing radiation , bladder infection bladder infection 1 Cystitis, see there 2 Urinary tract infection, see there , high consumption of phenacetin-containing analgesics Analgesics Definition
Analgesics are medicines that relieve pain.
Analgesics are those drugs that mainly provide pain relief. , and hair dyes (Engel et al. 2002). Several genetic susceptibility factors have been found to be related to bladder cancer (Engel et al. 2002).
Bladder cancer is associated with a number of occupational exposures. The first such association was observed in 1895 (Rehn 1895), and subsequent research among dyestuff workers identified the aromatic amines benzidine benzidine /ben·zi·dine/ (ben´zi-den) a carcinogen and toxin once widely used as a test for occult blood.
n. and 2-naphthylamine as bladder carcinogens Carcinogens
Substances in the environment that cause cancer, presumably by inducing mutations, with prolonged exposure.
Mentioned in: Colon Cancer, Rectal Cancer (Case et al. 1954). Several other aromatic amines and related compounds have also been identified as suspected human bladder carcinogens, including 1-naphthylamine, 4-aminobiphenyl, 4-chloro-o-toluidine, o-toluidine, and 4,4'-methylenedianiline [Engel et al. 2002; International Agency for Research on Cancer The International Agency for Research on Cancer (IARC, or CIRC in its French acronym) is an intergovernmental agency forming part of the World Health Organisation of the United Nations.
Its main offices are in Lyon, France. (IARC) 1987]. Excess risk of bladder cancer has also been observed among rubber workers; painters; truck, bus, and taxi drivers; aluminum workers; and leather workers (Engel et al. 2002). It has been estimated that these occupational exposures are responsible for 18% of bladder cancer cases. As little as 2 years' exposure may be sufficient in increase the risk, but the time between exposure and subsequent cancer may be as long as 45 years (Goroll et al. 2000).
4,4'-Methylenebis (2-chloroaniline) (MBOCA) is used as a curing agent in industries that primarily produce castable polyurethane parts; thus, occupational exposure may occur during the manufacturing processes in these industries [Agency for Toxic Substances and Disease Registry The United States Agency for Toxic Substances and Disease Registry, (ATSDR) is an agency for the U.S. Department of Health and Human Services that is directed by a congressional mandate to perform specific functions concerning the effect on public health of hazardous (ATSDR ATSDR Agency for Toxic Substances & Disease Registry ) 1994]. Workers may inhale MBOCA in small particles in the air or absorb it through the skin during contact with MBOCA dust or vapor. Acute exposure to high levels of MBOCA may cause eye and skin irritation skin irritation,
n reaction to a particular irritant that results in inflammation of the skin and itchiness. in humans (Hosein and Van Roosmalen 1978). Intermediate and chronic exposure to MBOCA may lead to tumors of the urinary bladder urinary bladder
A musculomembranous elastic receptacle in the anterior part of the pelvic cavity serving as the temporary storage place for urine. (ATSDR 1994; Kommineni et al. 1979; Russfield et al. 1975; Stula et al. 1975, 1978). In a U.S. retrospective bladder cancer incidence study, 385 of 532 workers ever exposed to MBOCA from 1968 to 1979 and 20 workers who were first employed in 1980 and 1981 participated in a urine screening test (Ward et al. 1990). Workers were exposed to MBOCA for a median employment period of 3.2 months (between 1968 and 1981). Cystoscopy revealed a papillary papillary /pap·il·lary/ (pap´i-lar?e) pertaining to or resembling a papilla, or nipple.
adj similar to a small, nipple-shaped elevation or projection. cell tumor in one worker, and low-grade papillary transitional cell transitional cell
cells which make up an epithelium, e.g. in the urinary bladder, consisting of several layers of soft cuboidal cells which flatten out when stretched.
transitional cell tumors
1. tumors of the urinary bladder were diagnosed in 2 of the remaining 200 workers examined by cystoscopy (Ward et al. 1990). The U.S. Department of Health and Human Services Noun 1. Department of Health and Human Services - the United States federal department that administers all federal programs dealing with health and welfare; created in 1979
Health and Human Services, HHS has determined that MBOCA may reasonably be anticipated to be a carcinogen (ATSDR 1994). IARC has determined that MBOCA is probably carcinogenic carcinogenic
having a capacity for carcinogenesis. to humans (category 2A; IARC 1993). The U.S. Environmental Protection Agency Environmental Protection Agency (EPA), independent agency of the U.S. government, with headquarters in Washington, D.C. It was established in 1970 to reduce and control air and water pollution, noise pollution, and radiation and to ensure the safe handling and has determined that MBOCA is a probable human carcinogen (category 2A; ATSDR 1994). In the Report on Carcinogens, Eleventh Edition [National Toxicology Program National Toxicology Program Environment A program that conducts toxicologic tests on substances frequently found at the EPA's National Priorities List sites, which have the greatest potential for human exposure (NTP (Network Time Protocol) A TCP/IP protocol used to synchronize the real time clock in computers, network devices and other electronic equipment that is time sensitive. It is also used to maintain the correct time in NTP-based wall and desk clocks. ) 2005], the NTP reported that MBOCA may reasonably be anticipated to be a human carcinogen. In this article we report a sentinel case of transitional cell carcinoma of the urinary bladder diagnosed in an MBOCA-manufacturing factory in Taiwan.
Case report. A 52-year-old male chemical worker was admitted to the hospital with a history of paroxysmal microscopic hematuria for about 2 years and nocturia with gross hematuria about five times per night for 2 months. He was a nonsmoker and denied taking any medication. He did not use hair dye or reside in an area with endemic blackfoot disease (arsenic intoxication arsenic intoxication Arsenic poisoning A toxic trace metal that is a key component of herbicides, insecticides, rodenticides, wood preservatives, and used in manufacturing glass, and paints; the usual fatal dose is 100–200 mg; there are ± 1900 arsenic ). Social alcohol drinking was noted.
Microscopic hematuria was noted in the periodic health examinations for about 2 years, but the patient ignored it. Two months before admission, he developed nocturia about five times per night. Paroxysmal painless hematuria was also noted. Gross hematuria accompanied by lower abdominal distress occurred 2 weeks before admission. His body weight had decreased from 75 kg to 72 kg over the previous 3 months. He visited the hospital, and an intravenous urogram (IVU) showed a mass occupying half of the bladder capacity. Cystoscopy revealed a mass over the left dome area of the bladder. Cystoscopic biopsy specimens revealed a grade 3/3 invasive transitional cell carcinoma with marked necrosis. Radical cystectomy Radical cystectomy
A surgical procedure that is used when the cancer is in more than one area of the bladder. Along with the bladder, the adjoining organs also are removed. with ileal ileal /il·e·al/ (il´e-ahl) pertaining to the ileum.
Of or relating to the ileum.
pertaining to the ileum. conduit combined with radiotherapy was performed because the bladder tissue showed lymphovascular permeation with lymph node lymph node
Small, rounded mass of lymphoid tissue contained in connective tissue. They occur all along lymphatic vessels, with clusters in certain areas (e.g., neck, groin, armpits). metastasis metastasis /me·tas·ta·sis/ (me-tas´tah-sis) pl. metas´tases
1. transfer of disease from one organ or part of the body to another not directly connected with it, due either to transfer of pathogenic microorganisms or to . The worker is still on medical leave because of disease.
Occupational history. The manufacturing of MBOCA includes the reaction, neutralization neutralization, chemical reaction, according to the Arrhenius theory of acids and bases, in which a water solution of acid is mixed with a water solution of base to form a salt and water; this reaction is complete only if the resulting solution has neither acidic nor , washing, purification, and packing processes. Briefly, o-chloroaniline is reacted with sulfuric acid sulfuric acid, chemical compound, H2SO4, colorless, odorless, extremely corrosive, oily liquid. It is sometimes called oil of vitriol. Concentrated Sulfuric Acid
and formaldehyde under the catalyst of stannous chloride for 3-4 hr. The MBOCA products are then neutralized with an alkali, sodium hydroxide, at a high temperature. After washing and purification, the solid MBOCA is cut into pellets. Although most of the processes are done in closed systems and are automatic, leakage of products from pipes and tanks has been reported. The work schedule in the factory where our patient worked has three 8-hr shifts, and three or four workers in each shift are assigned to each manufacturing line.
The patient was a farmer until he began working at this factory. He worked in the purification area of this MBOCA-producing company for 14 years (1987-2001), and he did not wear any personal protective equipment during work. He denied working for any chemical company other than his present company. He occasionally applied pesticides during agricultural work.
Environmental monitoring data. An area sampling program to monitor MBOCA levels in the work environment of this MBOCA manufacturing factory was initiated by the Taiwan Institute of Occupational Safety and Health (IOSH IOSH Institution of Occupational Safety and Health (UK) ), Council of Labor Affairs (IOSH 2003a). The U.S. Occupational Safety and Health Administration's (OSHA OSHA
Occupational Safety and Health Administration, a branch of the US Department of Labor responsible for establishing and enforcing safety and health standards in the workplace. ) Analytic Method 24 was adopted in this study (OSHA 1981). Briefly, an impinger filled with 0.1N HCl was used for sampling. The sampling rate was 1 L/min. The sampling time was > 6 hr or > 100 L air. The solution was then analyzed with high-performance liquid chromatography (HPLC HPLC high-performance liquid chromatography.
high performance liquid chromatography.
HPLC High-performance liquid chromatography Lab instrumentation A highly sensitive analytic method in which analytes are placed ) with a 254 nm ultraviolet (UV) detector. The detection limit was 0.056 [micro]g/mL. A quality assurance and quality control program was implemented during the sampling and analysis procedures. All quality tests were shown to be adequate (IOSH 2003a).
Two consecutive days' air samples were collected in the MBOCA-manufacturing factory, in the areas where the reaction, neutralization, washing, purification, and cutting/packing processes took place. The concentration of MBOCA was highest in the purification area (0.23-0.41 mg/[m.sup.3], n = 2), followed by the washing area (< 0.02-0.08 mg/[m.sup.3], n = 7) and the neutralization area (< 0.05-0.06 mg/[m.sup.3], n = 2) (IOSH 2003a). The concentrations of MBOCA were within OSHA permissible exposure level (0.22 mg/[m.sup.3]) except for the purification area, where levels exceeded permissible levels.
Biological monitoring data. In addition to environmental monitoring, the Taiwan IOSH also collected workers' urine to monitor MBOCA concentrations. The U.S. National Institute for Occupational Safety and Health National Institute for Occupational Safety and Health,
n.pr an institute of the Centers for Disease Control and Prevention that is responsible for assuring safe and healthful working conditions and for developing standards of safety and health. (NIOSH NIOSH National Institute for Occupational Safety & Health, see there
NIOSH Recommendations for Safety & Health Standards
Agent NIOSH REL*/OSHA PEL† Health effects ) analytic method 8302 (NIOSH 1994) and the method used by Robert et al. (1999) were adopted in this study. Briefly, sulfamic acid (10 g/L) was used as urine preservative, and urine was neutralized by sodium hydroxide (0.05 g/mL). After cleaning with the Extrelut NT3 column (Merck, Darmstadt, Germany) and evaporating with methanol, the concentrated urine was analyzed by HPLC with a 254 nm UV detector. The limit of detection was 9.54 [micro]g/L.
Urine from 10 workers in this MBOCA-manufacturing company was analyzed. The total urine MBOCA concentrations ranged from 267.9 to 15701.1 [micro]g/g creatinine, with a mean of 5,544 [micro]g/g creatinine (IOSH 2003b). All the urine MBOCA concentrations far exceeded the California Occupational Safety and Health Administration The California Occupational Safety and Health Administration (Cal/OSHA) enforces the U.S. state of California's occupational and public safety laws and provides information and consultative assistance to employers, workers, and the public regarding workplace safety and health (Cal-OSHA) reference value of 100 [micro]g/L (Robert et al. 1999).
Although the production of MBOCA in the United States ceased in 1982, MBOCA is still manufactured in other countries. It is also widely used, primarily in industries producing castable polyurethane elastomers (ATSDR 1994). Therefore, the health impact of MBOCA is still of concern in occupational settings in many countries. In this article we report the first known case of MBOCA-related occupational bladder cancer in Taiwan, which led to the establishment of recommended exposure levels of MBOCA in the workplace. This case report supports the conclusion that MBOCA is a potential human carcinogen.
Environmental monitoring of MBOCA levels in ambient air performed in the present study showed that the concentration was high in the purification process area (0.23-0.41 mg/[m.sup.3]) and exceeded the OSHA permissible exposure level (0.22 mg/[m.sup.3]) and NIOSH's recommended exposure level of MBOCA (3 mg/[m.sup.3] as a 10-hr time-weighted average) (Ward et al. 1990). The production quantity of MBOCA at this patient's plant was about 1,500 tons/year, which was much higher than the 184-580 tons/year reported by Ward et al. (1990). The air levels of MBOCA in this plant were also higher than those in a polyurethane elastomer elastomer (ĭlăs`təmər), substance having to some extent the elastic properties of natural rubber. The term is sometimes used technically to distinguish synthetic rubbers and rubberlike plastics from natural rubber. factory using MBOCA as a curing agent (Clapp et al. 1991). No airborne MBOCA was detected in another polyurethane elastomer factory (Clapp et al. 1991). In another study, personal sampling of the breathing zone of workers for 6-7 hr every other day found levels ranging from 0.002 to 0.0089 mg/[m.sup.3] (Ichikawa et al. 1990).
In addition to exposure to high air concentrations of MBOCA, workers in the patient's plant also showed high levels of MBOCA in urine. The urine MBOCA concentrations ranged from 267.9 to 15701.1 [micro]g/g creatinine with a mean of 5,544 [micro]g/g creatinine. The urine MBOCA concentrations of all 10 workers far exceeded the Cal-OSHA reference value of 100 [micro]g/L (Robert et al. 1999). Urine samples obtained by Ward et al. (1990) from plant workers several months after production ceased also showed detectable MBOCA levels that ranged as high as 50,000 [micro]g/L. Osorio et al. (1990) reported a urine MBOCA level of 1,700 [micro]g/L 4 hr postexposure in a worker who was accidentally sprayed with molten MBOCA, but no acute symptoms or other laboratory abnormalities were observed. The urine MBOCA levels in the MBOCA-manufacturing factory workers were much higher than in workers at a polyurethane elastomer factory using MBOCA as a curing agent. Clapp et al. (1991) reported concentrations for mixers in the polyurethane elastomer factory ranging from 5 [micro]g/L to > 100 [micro]g/L urine (average of 61.9 [micro]g/L), whereas concentrations for molders were considerably lower (nondetectable to 50 [micro]g/L urine; average of 14.8 [micro]g/L). Workers in a plant that used MBOCA had urine concentrations of MBOCA ranging from 13 to 458 [micro]g/L (mean 145 [micro]g/L; Keeslar 1986). Another study of 150 workers with industrial exposure to MBOCA in 19 factories showed that, at the end of the work shift, excretion levels of MBOCA ranged from < 0.5 [micro]g/L to 1,600 [micro]g/L, with the highest average urine concentrations (600 [micro]g/L) in workers directly involved in MBOCA manufacture or use (Ducos et al. 1985). In a NIOSH study of urine samples from mixers and molders in a polyurethane elastomer factory (NIOSH 1986), the average urine MBOCA level during the week was approximately 30 [micro]g/L for a mixer over a 5-day work week; the level dropped to 8.9 [micro]g/L over the weekend. However, in Australia, monitoring of workers at seven facilities that used MBOCA in the manufacture of polyurethane polymers showed that the average MBOCA levels in the urine of the workers dropped from 29,600 to 10,400 [micro]g/L within 8-9 months after the implementation of an exposure prevention program (Wan et al. 1989).
The bladder cancer patient reported here worked in the purification process with high exposure to MBOCA for 14 years. He did not wear any personal protective equipment during work. Workers may inhale small particles of MBOCA in the air or absorb the agent through the skin if they come into contact with MBOCA dust or vapor (Chin et al. 1983; Cocker et al. 1988, 1990; Ichikawa et al. 1990; NIOSH 1986). According to the environmental monitoring data for the patient's factory, he may have been exposed to high concentrations of MBOCA through inhalation or dermal absorption.
Limited epidemiologic studies have examined the incidence of cancer in workers exposed to MBOCA, and three cases of bladder cancer have been reported to be associated with MBOCA exposure. Ward et al. (1990) screened 385 MBOCA-exposed workers and revealed a papillary tumor in one worker after cystoscopy; two low-grade papillary transitional cell carcinomas of the urinary bladder were diagnosed in two of the remaining 200 workers examined by cystoscopy. Two of the men with bladder cancer in Ward et al.'s study (Ward et al. 1988) were younger than 30 years of age. The interval between the time of first exposure and the initiation in that study averaged 11.5 years. The latency period in our case was 14 years, which was compatible with that reported by Ward et al. (1988). The present study adds evidence to the potential carcinogenicity carcinogenicity /car·ci·no·ge·nic·i·ty/ (kahr?si-no-je-nis´i-te) the ability or tendency to produce cancer.
the ability or tendency to produce cancer. of MBOCA. Human epidemiologic findings are supported by results obtained in dogs (Stula et al. 1978). Results in other animal species also support the conclusion that MBOCA is a potential carcinogen (ATSDR 1994). In addition to the bladder, other target organs include the lung, liver, breast, and Zymbal's gland in rats (Kommineni et al. 1979; Russfield et al. 1975; Stula et al. 1975) and the lung, liver, and vascular system in mice (Russfield et al. 1975). No adequate epidemiologic studies of MBOCA had been conducted. The present case supports the conclusions from other studies that MBOCA is potentially carcinogenic to humans as well as animals, but it does not substitute for the gap between epidemiologic evidence and animal studies.
This patient was a nonsmoker. Because no other potential risk factors of bladder cancer could be found, occupation-related cancer was strongly suspected. This case finding supports the conclusion that MBOCA is a potential human carcinogen. In most cases, dermal absorption is the most important occupational exposure pathway. Workplace monitoring by air sampling has been reported to be useless because contamination may occur in the absence of observable air levels (Clapp et al. 1991). Biological monitoring of urine MBOCA concentration is a useful method to assess percutaneous MBOCA absorption. Because MBOCA is a potential human carcinogen, it is important to reduce exposure primarily through engineering ventilation controls. However, safe use of skin protective equipment and respirators is required to prevent MBOCA exposure. In addition, appropriate clearance of spills, work training, air monitoring, and periodic health examinations are recommended (ATSDR 1994; Clapp et al. 1991).
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1. Of or relating to biomedicine.
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Perth is the capital of the Australian state of Western Australia. . J R Soc Health 109:159-165.
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Chiu-Shong Liu, (1) Saou-Hsing Liou, (2,3) Ching-Hui Loh, (4) Yi-Chun Yu, (5) Shi-Nian Uang, (5) Tung-Sheng Shih, (5) and Hong-I Chen (6)
(1) Department of Family Medicine, China Medical University, Taichung, Taiwan, Republic of China; (2) Department of Public Health, National Defense Medical Center, Nei-Hu, Taipei, Taiwan, Republic of China; (3) Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Kaohsiung, Taiwan, Republic of China; (4) Department of Family Medicine and Internal Medicine, Tri-Service General Hospital The Tri-Service General Hospital (Chinese: 三軍總醫院; Pinyin: Sānjūn Zǒngyīyuàn; abbreviation TSGH) is a medical center in Taipei, Republic of China. , National Defense Medical Center, Nei-Hu, Taipei, Taiwan, Republic of China; (5) Institute of Occupational Safety and Health, Council of Labor Affairs, Shi-Jr, Taipei, Taiwan, Republic of China; (6) Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Nei-Hu, Taipei, Taiwan, Republic of China
Address correspondence to H.-I. Chen, Division of Urology, Department of Surgery, Tri-Service General Hospital, 325 Chen-Kung Rd., Section 2, Nei-Hu, Taipei, 114 Taiwan ROC. Telephone: 886-2-87923100. Fax: 886-2-87924814. E-mail:hong_i@ ndmctsgh.edu.tw
This study was supported in part by the Taiwan National Health Research Institutes (NHRI-92A1-EOPP12-1).
The authors declare they have no competing financial interests.
Received 18 October 2004; accepted 24 February 2005.