Occupational bladder cancer in a 4,4'-methylenebis(2-chloroaniline) (MBOCA)-exposed worker.
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 by-products and arsenic in drinking water, ionizing radiation, bladder infection, high consumption of phenacetin-containing analgesics, 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 and 2-naphthylamine as bladder carcinogens (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 (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 (ATSDR) 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 in humans (Hosein and Van Roosmalen 1978). Intermediate and chronic exposure to MBOCA may lead to tumors of the urinary bladder (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 cell tumor in one worker, and low-grade papillary transitional cell 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 has determined that MBOCA may reasonably be anticipated to be a carcinogen (ATSDR 1994). IARC has determined that MBOCA is probably carcinogenic to humans (category 2A; IARC 1993). The U.S. Environmental Protection Agency has determined that MBOCA is a probable human carcinogen (category 2A; ATSDR 1994). In the Report on Carcinogens, Eleventh Edition [National Toxicology Program (NTP) 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). 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 with ileal conduit combined with radiotherapy was performed because the bladder tissue showed lymphovascular permeation with lymph node metastasis. The worker is still on medical leave because of disease.
Occupational history. The manufacturing of MBOCA includes the reaction, neutralization, washing, purification, and packing processes. Briefly, o-chloroaniline is reacted with 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), Council of Labor Affairs (IOSH 2003a). The U.S. Occupational Safety and Health Administration's (OSHA) 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) 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 (NIOSH) 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 (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 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 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).
ATSDR. 1994. Toxicological Profile for 4,4'-Methylenebis(2chloroaniline) (MBOCA). Atlanta, GA:Agency for Toxic Substances and Disease Registry. Available: http://www. atsdr.cdc.gov/toxprofiles/tp45.html [accessed 31 March 2005].
Case RA, Hosker ME, McDonald DB, Pearson JT. 1954. Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. Part I. The role of aniline, benzidine, alpha-naphthylamine, and beta-naphthylamine. Br J Ind Med 11:75-104.
Chin B, Tobes MC, Han SS. 1983. Absorption of 4,4'-methylenebis(2-chloroaniline) by human skin. Environ Res 32:167-178.
Clapp DE, Piacitelli GM, Zaebst DD, Ward E. 1991. Assessing exposure to 4,4'-methylenebis(2-chloroaniline) (MBOCA) in the workplace. Appl Occup Environ Hyg 6:125-130.
Cocker J, Boobis AR, Davis DS. 1988. Determination of the n-acetyl metabolites of 4,4'-methylene dianiline and 4,4'-methylene-bis(2-chloroaniline) in urine. Biomed Environ Mass Spectrom 17:161-167.
Cocker J, Boobis AR, Wilson HK, Gompertz D. 1990. Evidence that a beta-n-glucuronide of 4,4'-methylene-bis(2-chloroaniline) (MBOCA) is a major urinary metabolite in man: implications for biological monitoring. Br J Ind Med 47:154-161.
Ducos P, Maire C, Gauidin R. 1985. Assessment of occupational exposure to 4,4'-methylenebis(2-chloroaniline) (MOCA) by a new sensitive method for biological monitoring. Int Arch Occup Environ Health 55:159-522.
Engel LS, Taioli E, Pfeiffer R, Garcia-Closas M, Marcus PM, Lan Q, et al. 2002. Pooled analysis and meta-analysis of glutathione S-transferase M1 and bladder cancer: a HuGE review. Am J Epidemiol 156:95-109.
Goroll AH, May LA, Mulley AG, eds. 2000. Chapter 28: Screening for cancers of the lower urinary tract. In: Primary Care Medicine. 4th ed. Philadelphia:Lippincott, Williams & Wilkins.
Hosein HR, Van Roosmalen PB. 1978. Acute exposure to methylene-bis-ortho chloroaniline (MOCA). Am Ind Hyg Assoc J 39:496-497.
IARC. 1987. Overall Evaluations of Carcinogenicity. An Updating of IARC Monographs Volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum(suppl 7):1-440.
IARC. 1993. Occupational Exposure of Hairdressers and Barbers and Personal Use of Hair Colourants: Some Hair Dyes, Cosmetic Colourants, Industrial Dyestuffs, and Aromatic Amines. IARC Monogr Eval Carcinog Risks Hum 57:1-428.
Ichikawa Y, Yoshida M, Okayama A, Hara I, Morimoto K. 1990. Biological monitoring for workers exposed to 4,4'-methylenebis(2-chloroaniline). Am Ind Hyg Assoc J 51:5-7.
IOSH. 2003a. 4,4'-Methylene bis(ortho-chloroaniline) Sampling Method Establishment and Preliminary Study of Occupational Exposure Assessment at Curing Agent Manufacturing Plant. IOSH 92-A317. Taiwan:Institute of Occupational Safety and Health.
IOSH. 2003b. Development of Biological Monitoring of Occupational Exposure to 4,4'-Methylene Bis(orthochioroaniline). IOSH 92-A303. Taiwan:Institute of Occupational Safety and Health.
Keeslar FL. 1986. The removal and control of methylene-bis orthochloroaniline in residential and industrial areas of Adrian, Michigan. In: Proceedings of the 1986 Conference on Hazardous Material. Spills, Preparedness, Prevention Control, and Cleanup of Releases, St. Louis, MO, 5-8 May 1986 (Ludwigson J, ed). Rockville, MD:Government Institute Inc., 93-97.
Kommineni C, Groth DH, Frockt IJ, Voelker RW, Stanovick RP. 1979. Determination of the tumorigenic potential of methylene-bis-orthochloroaniline. J Environ Pathol Toxicol 2:149-171.
NIOSH. 1986. Industrial Hygiene Survey Report, Parkway Products, Inc., Cincinnati, OH. Contract IWS-144.13. Document PB87-222360. Cincinnati, OH:National Institute for Occupational Safety and Health.
NIOSH. 1994. MBOCA in urine. In: Manual of Analytical Methods, Method 8302.4th ed. Cincinnati, OH:National Institute for Occupational Safety and Health. Available: http://www.cdc.gov/niosh/nmam/pdfs/8302.pdf [accessed 1 April 2005].
NTP. 2005.4,4'-Methylenebis (2-chloroaniline) CAS No. 101-14-4. In: Report on Carcinogens, Eleventh Edition. Research Triangle Part, NC:National Toxicology Program. Available: http://ntp.niehs.nih.govlntplrocleleventh/profiles/ s106mboc.pdf [accessed 8 April 2005].
OSHA. 1981. 4,4'-Methylenebis(O-Chloroaniline (MOCA). Method 24. 2nd ed. Salt Lake City, UT:Occupational Safety and Health Administration. Available: http://www.osha.gov/ dts/sltc/methods/organic/org024/org024.html [accessed 1 April 2005].
Osorio AM, Clapp D, Ward E, Wilson HK, Cocker J. 1990. Biological monitoring of a worker acutely exposed to MBOCA. Am J Ind Med 18:577-589.
Rehn L. 1895. Blasengeschwuste bei Fuchsin-arbeitern. Arch Klin Chir 50:588-600.
Robert A, Duces P, Francin JM. 1999. Biological monitoring of workers exposed to 4,4'-methylene-bis-(2-erthochloroaniline). I. A new and easy determination of "free" and "total" MOCA in urine. Int Arch Occup Environ Health 72:223-237.
Russfield AB, Homburger F, Boger E, Van Dengen CG, Weisburger EK, Weisburger JH. 1975. The carcinogenic effect of 4,4'-methylene-bis-(2-chloroaniline) in mice and rats. Toxicol Appl Pharmacol 31:47-54.
Stula EF, Barnes JR, Sherman H, Reinhardt CF, Zapp JA Jr. 1978. Urinary bladder tumors in dogs from 4,4'-methylene-bis (2chleroaniline) (MOCA). J Environ Pathol Toxicol 1:31-50.
Stula EF, Sherman H, Zapp JA Jr, Clayton JW Jr. 1975. Experimental neoplasia in rats from oral administration of 3,3'-dichlorobenzidine, 4,4'-methylene-bis(2-chloroaniline), and 4,4'-methylene-bis(2-methylaniline). Toxicol Appl Pharmacol 31:159-176.
Taiwan DOH. 2004. Annual Report of Cancer Registry. Teipei, Taiwan:Department of Health.
Wan KC, Dare BR, Street NR. 1989. Biomedical surveillance of workers exposed to 4,4'-methylene-bis-(2-chloroaniline) (MBOCA) in Perth, Western Australia. J R Soc Health 109:159-165.
Ward E, Halperin W, Thun M, Grossman HB, Fink B, Koss L, et al. 1988. Bladder tumors in two young males occupationally exposed to MBOCA. Am J Ind Med 14:267-272.
Ward E, Halperin W, Thun M, Grossman HB, Fink B, Koss L, et al. 1990. Screening workers exposed to 4,4'-methylenebis-(2-chloroaniline) for bladder cancer by cystoscopy. J Occup Med 32:865-868.
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, 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.
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|Title Annotation:||Environmental Medicine / Grand Rounds|
|Publication:||Environmental Health Perspectives|
|Date:||Jun 1, 2005|
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