4,4’-Methylenebis(2-chloroaniline) (MBOCA) May Be Highly Toxic and a Carcinogen Based on an Experimental Study with Mice
Author(s)
Hong-I Chen,
Tzong-Cherng Chi,
Shun-Yao Ko,
Yi-Chiang Hsu,
I-Hsuan Lin,
Ann Chen,
Saou-Hsing Liou,
Chien-Feng Li
Affiliation(s)
Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan. Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan. Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan. Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan. Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
ABSTRACT
4,4’-Methylenebis(2-chloroaniline) (MBOCA) is a probable human carcinogen. Few studies have been performed regarding the genotoxicity of MBCOA, and the MBOCA metabolic pathway is not fully understood. We treated four-week-old ICR male mice weighing 25 - 30 g with MBOCA and observed the effects of MBOCA on the internal organs. It can be concluded that MBOCA is a carcinogen and also affects gene regulation. Oral or topical administration of 50 mg/kg, 100 mg/kg or 200 mg/kg MBOCA resulted in 56% - 81% of mice showing unusual inflammation, degeneration, and dysplasia in kidney, liver, stomach, intestine and urinary bladder based on histology. Furthermore, we investigated the association between oxidative DNA damage and MBOCA exposure by measuring plasma level of 8-hydroxydeoxyguanosine (8-OHdG). The results showed that the MBOCA-treated mice had significantly higher 8-OHdG levels than the control mice. This study confirms that MBOCA is potentially carcinogenic and highly toxic to both animals and humans.
4,4’-Methylenebis(2-chloroaniline) (MBOCA) is a probable human carcinogen. Few studies have been performed regarding the genotoxicity of MBCOA, and the MBOCA metabolic pathway is not fully understood. We treated four-week-old ICR male mice weighing 25 - 30 g with MBOCA and observed the effects of MBOCA on the internal organs. It can be concluded that MBOCA is a carcinogen and also affects gene regulation. Oral or topical administration of 50 mg/kg, 100 mg/kg or 200 mg/kg MBOCA resulted in 56% - 81% of mice showing unusual inflammation, degeneration, and dysplasia in kidney, liver, stomach, intestine and urinary bladder based on histology. Furthermore, we investigated the association between oxidative DNA damage and MBOCA exposure by measuring plasma level of 8-hydroxydeoxyguanosine (8-OHdG). The results showed that the MBOCA-treated mice had significantly higher 8-OHdG levels than the control mice. This study confirms that MBOCA is potentially carcinogenic and highly toxic to both animals and humans.
KEYWORDS
4, 4’-Methylenebis(2-chloroaniline), MBOCA, Transitional Cell Carcinoma of Bladder, Oxidative DNA Damage, 8-Hydroxydeoxyguanosine (8-OHdG)
4, 4’-Methylenebis(2-chloroaniline), MBOCA, Transitional Cell Carcinoma of Bladder, Oxidative DNA Damage, 8-Hydroxydeoxyguanosine (8-OHdG)
Cite this paper
Chen, H. , Chi, T. , Ko, S. , Hsu, Y. , Lin, I. , Chen, A. , Liou, S. and Li, C. (2014) 4,4’-Methylenebis(2-chloroaniline) (MBOCA) May Be Highly Toxic and a Carcinogen Based on an Experimental Study with Mice. Advances in Biological Chemistry, 4, 203-213. doi: 10.4236/abc.2014.43025.
Chen, H. , Chi, T. , Ko, S. , Hsu, Y. , Lin, I. , Chen, A. , Liou, S. and Li, C. (2014) 4,4’-Methylenebis(2-chloroaniline) (MBOCA) May Be Highly Toxic and a Carcinogen Based on an Experimental Study with Mice. Advances in Biological Chemistry, 4, 203-213. doi: 10.4236/abc.2014.43025.
References
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http://dx.doi.org/10.1080/0002889718506543 [2] Homburger, A.B.F., Boger, E., Van Dongen, C.G., Weisburger, E.K. and Weisburger, J.H. (1975) The Carcinogenic Effect of 4,4’-Methylene-bis-(2-chloroaniline) in Mice and Rats. Toxicology and Applied Pharmacology, 31, 47-54.
http://dx.doi.org/10.1016/0041-008X(75)90050-2 [3] Hosein, H.R. and Van Roosmalen, P.B. (1978) Acute Exposure to Methylene-bis-ortho Chloroaniline (MOCA). American Industrial Hygiene Association Journal, 39, 496-497.
http://dx.doi.org/10.1080/0002889778507795 [4] Rehn, L. (1895) Blasengeschwülste bei Fuch-sin-arbeitern. Langenbecks Archiv für klinische Chirurgie, 50, 588-600. [5] IARC (1974) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man: Some Aromatic Amines, Hydrazine and Related Substances, n-Nitroso Compounds and Miscellaneous Alkylating Agents. International Agency for Research on Cancer, Lyon, 65-71. [6] ATSDR (1994) Toxicological Profile for 4,4’-Methylenebis(2-chloroaniline) (MBOCA). The US Agency for Toxic Substances and Disease Registry, Available: tp45.pdf. [7] NTP (2002) Notice of Availability of 10th Report on Carcinogens. National Toxicology Program, 67, 77283-77285. [8] ATSDR (2000) Toxicological Profile for 4,4’-Methylenebis (2-Chloroaniline) (MBOCA). The US Agency for Toxic Substances and Disease Registry, Available: tp17.pdf. [9] IARC (1987) Overall Evaluations of Carcinogenicity. An updating of IARC Monographs. International Agency for Research on Cancer, Lyon. [10] Liu, C.S., Liou, S.H., Loh, C.H., Yu, Y.C., Uang, S.N., Shih, T.S. and Chen H.I. (2005) Occupational Bladder Cancer in a 4,4’-Methylenebis (2-Chloroaniline) (MBOCA)-Exposed Worker. Environmental Health Perspectives, 113, 771-774.
http://dx.doi.org/10.1289/ehp.7666 [11] Stula, E.F., Sherman, H., Zapp Jr., J.A. and Clayton Jr., J.W. (1975) Experimental Neoplasia in Rats from Oral Administration of 3,3’-Dichlorobenzidine, 4,4’-Methylene-bis-(2-chloroaniline), and 4,4’-Methylene-bis(2methylaniline). Toxicology and Applied Pharmacology, 31, 159-176.
http://dx.doi.org/10.1016/0041-008X(75)90064-2 [12] Schirmacher, P., Peters, M., Ciliberto, G., Blessing, M., Lotz, J., Büschenfelde, K.H.M. and Stefan Rose-John, S. (1998) Hepatocellular Hyperplasia, Plasmacytoma Formation, and Extramedullary Hematopoiesis in Interleukin (IL)- 6/Soluble IL-6 Receptor Double-Transgenic Mice. The American Journal of Pathology, 153, 639-648.
http://dx.doi.org/10.1016/S0002-9440(10)65605-2 [13] Xie, R., Chung, J.Y., Ylaya, K., Williams, R.L., Guerrero, N., Nakatsuka, N., Badie, C. and Hewitt, S.M. (2011) Factors Influencing the Degradation of Archival Formalin-Fixed Paraffin-Embedded Tissue Sections. Journal of Histochemistry & Cytochemistry, 59, 356-365.
http://dx.doi.org/10.1369/0022155411398488 [14] Yang, S.M., Ka, S.M., Hua, K.F., Wu, T.H., Chuang, Y.P., Lin, Y.W., Yang, F.L., Wu, S.H., Yang, S.S., Lin, S.H., Chang, J.M. and Chen, A. (2013) Antroquinonol Mitigates an Accelerated and Progressive IgA Nephropathy Model in Mice by Activating the Nrf2 Pathway and Inhibiting T Cells and NLRP3 Inflammasome. Free Radical Biology and Medicine, 6, 285-297.
http://dx.doi.org/10.1016/j.freeradbiomed.2013.03.024 [15] Chen, H.I., Liou, S.H., Loh, C.H., Uang, S.N., Yu, Y.C. and Shih, T.S. (2005) Bladder Cancer Screening and Monitoring of 4,4-Methylenebis(2-chloroaniline) Exposure among Worker in Taiwan. Urology, 66, 305-310.
http://dx.doi.org/10.1016/j.urology.2005.02.031 [16] Ward, E., Halperin, W., Thun, M., Grossman, H.B., Fink, B., Koss, L., Osorio, A.M. and Schulte, P. (1990) Screening Workers Exposed to 4,4’-Methylenebis (2-Chloroaniline) for Bladder Cancer by Cystoscopy. Journal of Occupational and Environmental Medicine, 32, 865-868.
http://dx.doi.org/10.1097/00043764-199009000-00020 [17] IARC (2012) IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans: A Review of Human Carcinogens: Chemical Agents and Related Occupations. International Agency for Research on Cancer, Lyon, Vol. 100F, 73-82. [18] Dost, A., Straughan, J.K. and Sorahan, T. (2009) Cancer Incidence and Exposure to 4, 4’-Methylene-bis-ortho-chloroaniline (MbOCA). Occupational Medicine, 59, 402-405.
http://dx.doi.org/10.1097/00043764-199009000-00020 [19] Stula, E.F., Barnes, J.R., Sherman, H., Reinhardt, C.F. and Zapp Jr., J.A. (1978) Urinary Bladder Tumors in Dogs from 4,4’-Methylene-bis-(2-Chloroaniline) (MOCA). Journal of Environmental Pathology, Toxicology and Oncology, 1, 31-50.
http://dx.doi.org/10.1016/0378-4274(83)90037-1 [20] Tobes, M.C., Brown, L.E., Chin, B. (1983) Kinetics of Tissue Distribution and Elimination of 4,4’Methylenebis-(2-chloroaniline) in Rats. Toxicology Letters, 17, 69-76.
http://dx.doi.org/10.1016/0378-4274(83)90037-1 [21] Farmer, P.B., Rickard, J. and Robertson, S. (1981) The Metabolism and Distribution of 4,4’-Methylenebis(2-chloroaniline) (MBOCA) in Rats. Journal of Applied Toxicology, 1, 317-322.
http://dx.doi.org/10.1002/jat.2550010610 [22] NTP (2011) Notice of Availability of 12th Report on Carcinogens. National Toxicology Program, 262-264. [23] Kommineni, C., Groth, D.H., Frockt, I.J., Voelker, R.W. and Stanovick, R.P. (1979) Determination of the Tumorigenic Potential of Methylene-bis-orthochloroaniline. Journal of Environmental Pathology, Toxicology and Oncology, 2, 149-171. [24] Grundmann, E. and Steinhoff , D. (1970) Liver and Lung Tumors following 3,3’-Dichloro-4,4’-Diaminodiphenyl-methane in Rats. Zeitschrift für Krebsforschung, 74, 28-39.
http://dx.doi.org/10.1007/BF00524677 [25] Nesnow, S., Triplett, L.L. and Slaga, T.J. (1985) Studies on the Tumor Initiating, Tumor Promoting, and Tumor Co-Initiating Properties of Respiratory Carcinogens. Carcinogenesis: A Comprehensive Survey, 8, 257-277. [26] Steinhoff, D. and Grundmann, E. (1971) Cancerogenic Effect of 3,3’-dichlor-4,4’-Diaminodiphenylmethane in Rats. Naturwissenschaften, 58, 578. ( in German)
http://dx.doi.org/10.1007/BF00598744 [27] Rozinova, E., Khalil, M. and Bonin, A.M. (1998) MOCA and Some Proposed Substitutes (Cyanacure, Conacure, Polacure 740M and Ethacure 300) as Two-Stage Skin Carcinogens in HRA/Skh Hairless Mice. Mutation Research, 398, 111-121.
http://dx.doi.org/10.1016/S0027-5107(97)00247-9 [28] Kugler-Steigmeier, M.E., Friederich, U., Graf, U., Lutz, W.K., Maier, P. and Schlatter, C. (1989) Genotoxicity of Aniline Derivatives in Various Short-Term Tests. Mutation Research, 211, 279-289.
http://dx.doi.org/10.1016/0027-5107(89)90011-0 [29] Pilger, A. and Rüdiger, H.W. (2006) 8-Hydroxy-2’-Deoxyguanosine as a Marker of Oxidative Damage Related to Occupational and Environmental Exposure. International Archives of Occupational and Environmental Health, 80, 1-15.
http://dx.doi.org/10.1007/s00420-006-0106-7
[1] Linch, A.L., O’Connor, G.B., Barnes, J.R., Killian Jr., A.S. and Neeld Jr., W.E. (1971) Methylene-bis-ortho-chloro-aniline (MOCA): Evaluation of Hazards and Exposure Control. American Industrial Hygiene Association Journal, 32, 802-819.
http://dx.doi.org/10.1080/0002889718506543 [2] Homburger, A.B.F., Boger, E., Van Dongen, C.G., Weisburger, E.K. and Weisburger, J.H. (1975) The Carcinogenic Effect of 4,4’-Methylene-bis-(2-chloroaniline) in Mice and Rats. Toxicology and Applied Pharmacology, 31, 47-54.
http://dx.doi.org/10.1016/0041-008X(75)90050-2 [3] Hosein, H.R. and Van Roosmalen, P.B. (1978) Acute Exposure to Methylene-bis-ortho Chloroaniline (MOCA). American Industrial Hygiene Association Journal, 39, 496-497.
http://dx.doi.org/10.1080/0002889778507795 [4] Rehn, L. (1895) Blasengeschwülste bei Fuch-sin-arbeitern. Langenbecks Archiv für klinische Chirurgie, 50, 588-600. [5] IARC (1974) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man: Some Aromatic Amines, Hydrazine and Related Substances, n-Nitroso Compounds and Miscellaneous Alkylating Agents. International Agency for Research on Cancer, Lyon, 65-71. [6] ATSDR (1994) Toxicological Profile for 4,4’-Methylenebis(2-chloroaniline) (MBOCA). The US Agency for Toxic Substances and Disease Registry, Available: tp45.pdf. [7] NTP (2002) Notice of Availability of 10th Report on Carcinogens. National Toxicology Program, 67, 77283-77285. [8] ATSDR (2000) Toxicological Profile for 4,4’-Methylenebis (2-Chloroaniline) (MBOCA). The US Agency for Toxic Substances and Disease Registry, Available: tp17.pdf. [9] IARC (1987) Overall Evaluations of Carcinogenicity. An updating of IARC Monographs. International Agency for Research on Cancer, Lyon. [10] Liu, C.S., Liou, S.H., Loh, C.H., Yu, Y.C., Uang, S.N., Shih, T.S. and Chen H.I. (2005) Occupational Bladder Cancer in a 4,4’-Methylenebis (2-Chloroaniline) (MBOCA)-Exposed Worker. Environmental Health Perspectives, 113, 771-774.
http://dx.doi.org/10.1289/ehp.7666 [11] Stula, E.F., Sherman, H., Zapp Jr., J.A. and Clayton Jr., J.W. (1975) Experimental Neoplasia in Rats from Oral Administration of 3,3’-Dichlorobenzidine, 4,4’-Methylene-bis-(2-chloroaniline), and 4,4’-Methylene-bis(2methylaniline). Toxicology and Applied Pharmacology, 31, 159-176.
http://dx.doi.org/10.1016/0041-008X(75)90064-2 [12] Schirmacher, P., Peters, M., Ciliberto, G., Blessing, M., Lotz, J., Büschenfelde, K.H.M. and Stefan Rose-John, S. (1998) Hepatocellular Hyperplasia, Plasmacytoma Formation, and Extramedullary Hematopoiesis in Interleukin (IL)- 6/Soluble IL-6 Receptor Double-Transgenic Mice. The American Journal of Pathology, 153, 639-648.
http://dx.doi.org/10.1016/S0002-9440(10)65605-2 [13] Xie, R., Chung, J.Y., Ylaya, K., Williams, R.L., Guerrero, N., Nakatsuka, N., Badie, C. and Hewitt, S.M. (2011) Factors Influencing the Degradation of Archival Formalin-Fixed Paraffin-Embedded Tissue Sections. Journal of Histochemistry & Cytochemistry, 59, 356-365.
http://dx.doi.org/10.1369/0022155411398488 [14] Yang, S.M., Ka, S.M., Hua, K.F., Wu, T.H., Chuang, Y.P., Lin, Y.W., Yang, F.L., Wu, S.H., Yang, S.S., Lin, S.H., Chang, J.M. and Chen, A. (2013) Antroquinonol Mitigates an Accelerated and Progressive IgA Nephropathy Model in Mice by Activating the Nrf2 Pathway and Inhibiting T Cells and NLRP3 Inflammasome. Free Radical Biology and Medicine, 6, 285-297.
http://dx.doi.org/10.1016/j.freeradbiomed.2013.03.024 [15] Chen, H.I., Liou, S.H., Loh, C.H., Uang, S.N., Yu, Y.C. and Shih, T.S. (2005) Bladder Cancer Screening and Monitoring of 4,4-Methylenebis(2-chloroaniline) Exposure among Worker in Taiwan. Urology, 66, 305-310.
http://dx.doi.org/10.1016/j.urology.2005.02.031 [16] Ward, E., Halperin, W., Thun, M., Grossman, H.B., Fink, B., Koss, L., Osorio, A.M. and Schulte, P. (1990) Screening Workers Exposed to 4,4’-Methylenebis (2-Chloroaniline) for Bladder Cancer by Cystoscopy. Journal of Occupational and Environmental Medicine, 32, 865-868.
http://dx.doi.org/10.1097/00043764-199009000-00020 [17] IARC (2012) IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans: A Review of Human Carcinogens: Chemical Agents and Related Occupations. International Agency for Research on Cancer, Lyon, Vol. 100F, 73-82. [18] Dost, A., Straughan, J.K. and Sorahan, T. (2009) Cancer Incidence and Exposure to 4, 4’-Methylene-bis-ortho-chloroaniline (MbOCA). Occupational Medicine, 59, 402-405.
http://dx.doi.org/10.1097/00043764-199009000-00020 [19] Stula, E.F., Barnes, J.R., Sherman, H., Reinhardt, C.F. and Zapp Jr., J.A. (1978) Urinary Bladder Tumors in Dogs from 4,4’-Methylene-bis-(2-Chloroaniline) (MOCA). Journal of Environmental Pathology, Toxicology and Oncology, 1, 31-50.
http://dx.doi.org/10.1016/0378-4274(83)90037-1 [20] Tobes, M.C., Brown, L.E., Chin, B. (1983) Kinetics of Tissue Distribution and Elimination of 4,4’Methylenebis-(2-chloroaniline) in Rats. Toxicology Letters, 17, 69-76.
http://dx.doi.org/10.1016/0378-4274(83)90037-1 [21] Farmer, P.B., Rickard, J. and Robertson, S. (1981) The Metabolism and Distribution of 4,4’-Methylenebis(2-chloroaniline) (MBOCA) in Rats. Journal of Applied Toxicology, 1, 317-322.
http://dx.doi.org/10.1002/jat.2550010610 [22] NTP (2011) Notice of Availability of 12th Report on Carcinogens. National Toxicology Program, 262-264. [23] Kommineni, C., Groth, D.H., Frockt, I.J., Voelker, R.W. and Stanovick, R.P. (1979) Determination of the Tumorigenic Potential of Methylene-bis-orthochloroaniline. Journal of Environmental Pathology, Toxicology and Oncology, 2, 149-171. [24] Grundmann, E. and Steinhoff , D. (1970) Liver and Lung Tumors following 3,3’-Dichloro-4,4’-Diaminodiphenyl-methane in Rats. Zeitschrift für Krebsforschung, 74, 28-39.
http://dx.doi.org/10.1007/BF00524677 [25] Nesnow, S., Triplett, L.L. and Slaga, T.J. (1985) Studies on the Tumor Initiating, Tumor Promoting, and Tumor Co-Initiating Properties of Respiratory Carcinogens. Carcinogenesis: A Comprehensive Survey, 8, 257-277. [26] Steinhoff, D. and Grundmann, E. (1971) Cancerogenic Effect of 3,3’-dichlor-4,4’-Diaminodiphenylmethane in Rats. Naturwissenschaften, 58, 578. ( in German)
http://dx.doi.org/10.1007/BF00598744 [27] Rozinova, E., Khalil, M. and Bonin, A.M. (1998) MOCA and Some Proposed Substitutes (Cyanacure, Conacure, Polacure 740M and Ethacure 300) as Two-Stage Skin Carcinogens in HRA/Skh Hairless Mice. Mutation Research, 398, 111-121.
http://dx.doi.org/10.1016/S0027-5107(97)00247-9 [28] Kugler-Steigmeier, M.E., Friederich, U., Graf, U., Lutz, W.K., Maier, P. and Schlatter, C. (1989) Genotoxicity of Aniline Derivatives in Various Short-Term Tests. Mutation Research, 211, 279-289.
http://dx.doi.org/10.1016/0027-5107(89)90011-0 [29] Pilger, A. and Rüdiger, H.W. (2006) 8-Hydroxy-2’-Deoxyguanosine as a Marker of Oxidative Damage Related to Occupational and Environmental Exposure. International Archives of Occupational and Environmental Health, 80, 1-15.
http://dx.doi.org/10.1007/s00420-006-0106-7