Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens (2014)

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Appendix E Genotoxicity and Mutagenicity Summary Tables The committee undertook a comprehensive review of scientific peer- reviewed literature on formaldehyde genotoxicity and mutagenicity. The review included studies that were available to the National Toxicology Program at the time the12th Report on Carcinogens was published and new literature published since July 10, 2011 (see the description of the literature search strategy, includ- ing the dates of the search, in Appendix D). The tables in this appendix provide information on the following outcomes: DNA adducts (Table E-1), DNA–DNA cross-links (Table E-2), DNA–protein cross-links (Table E-3), DNA strand breaks (Table E-4), mutations (Table E-5), sister-chromatid exchanges (Table E- 6), micronuclei (Table E-7), and chromosomal aberrations (Table E-8). The evi- dence is organized by cell-free systems; nonmammalian model organisms; mammalian in vitro systems in the rodent, primate, and human; mammalian in vivo systems showing portal-of-entry effects in the rodent, primate, and human; and mammalian in vivo systems showing systemic effects in the rodent, primate, and human. The studies are categorized as either positive (the effect studied was statistically significant for the outcome of interest) or negative (the effect was studied, but no statistically significant change in the outcome of interest was observed). Table 3-9 summarizes the evidence. 207 

208 TABLE E-1 DNA Adducts Positive Studies Negative Studies Cell-free systems Von Hippel and Wong 19711 — Beland et al. 19841 Snyder and Van Houten 19861 Zhong and Que Hee 2004a, 20051 Cheng et al. 20081 Lu et al. 20091 Nonmammalian model organisms — — 1 Mammalian in vitro Rodent Beland et al. 1984 — Human Zhong and Que Hee 2004b1 — Lu et al. 20122 Mammalian in vivo: Rodent Lu et al. 2010a1 — portal-of-entry effects Lu et al. 20112 Primate Moeller et al. 20112 — Human — — Mammalian in vivo: Rodent — Lu et al. 2010a1 systemic effects* Primate — Moeller et al. 20112 2,# Human Bono et al. 2010 — *The committee acknowledges that although most investigators consider the effects on circulating blood mononucleated cells systemic because cells for the analyses were collected from the systemic circulation, it is also plausible that these cells may have been exposed to formaldehyde in the nose through lymphoid tissue in the mucosa. # M1G adduct has been postulated to be the result of secondary DNA damage from formaldehyde-associated oxidative stress. 1 The study was identified from the background document or the substance profile for formaldehyde in the National Toxicology Program 12th Report on Carcinogens (NTP 2010, 2011). 2 The study was identified from the committee’s new literature search (see Appendix D). Source: Committee generated. 

TABLE E-2 DNA–DNA Cross-Links Positive Studies Negative Studies 1 Cell-free systems Chaw et al. 1980 — Huang et al. 19921 Huang and Hopkins 19931 Nonmammalian model organisms — — Mammalian in vitro Rodent — — Human — — Mammalian in vivo: Rodent — — portal-of-entry effects Primate — — Human — — Mammalian in vivo: Rodent — — systemic effects Primate — — Human — — 1 The study was identified from the background document or the substance profile for formaldehyde in the National Toxicology Program 12th Report on Carcinogens (NTP 2010, 2011). Source: Committee generated. 209 

210 TABLE E-3 DNA–Protein Cross-Links Positive Studies Negative Studies Cell-free systems Kuykendall and Bogdanffy 19922 — Lu et al. 20084 Lu et al. 2010b4 Nonmammalian model organisms — — Mammalian in vitro Rodent Ross and Shipley 19801 Casanova et al. 19971 Ross et al. 19811 Swenberg et al. 1983b1 O'Connor and Fox 19871 Cosma et al. 1988a1 Zhitkovich and Costa 19921 Olin et al. 19961 Casanova and Heck 19971 Casanova et al. 19971 Merk and Speit 1998, 19991 Speit et al. 2007a1 Garcia et al. 20091 She et al. 20133 Human Fornace et al. 19821 — Grafström et al. 1984 Saladino et al. 19851 Grafström et al. 19861 Craft et al. 19871 Grafström 19901 Olin et al. 19961 Shaham et al. 1996a1 Costa et al. 19971 Blasiak et al. 20001 Andersson et al. 20031 Emri et al. 20041 

Saito et al. 20051 Liu et al. 20061 Schmid and Speit 20071 Speit et al. 2008b1 Neuss et al. 2010a,b3 Speit et al. 20103 Duan 20113 Zeller et al. 2011a3 Wong et al. 20123 Ren et al. 20133 Mammalian in vivo: Rodent Casanova-Schmitz et al. 1984a1 — portal-of-entry effects Lam et al. 19851 Casanova and Heck 19871 Heck et al. 1986, 19891 Cosma et al. 1988b1 Casanova et al. 1989, 19941 Primate Heck et al. 19891 — Casanova et al. 19911 Human — — Mammalian in vivo: Rodent Ke et al. 20123 Casanova-Schmitz et al. 1984a1 systemic effects Ye et al. 20133 Casanova and Heck 19871 Primate — Heck et al. 19891 Casanova et al. 19911 Human Shaham et al. 1996a, 20031 — Lin et al. 20133 1 The study was identified from the background document or the substance profile for formaldehyde in the National Toxicology Program 12th Report on Carcinogens (NTP 2010, 2011). 2 The study was identified from IARC 2006 or IARC 2012. 3 The study was identified from the committee’s new literature search (see Appendix D). 4 The study was identified through additional ad hoc searches or from the reference list of other studies. 211 Source: Committee generated. 

212 TABLE E-4 DNA Strand Breaks Positive Studies Negative Studies Cell-free systems — — 2 Nonmammalian model organisms Poverenny et al. 1975 — Wilkins and Macleod 19762 Magana-Schwencke et al. 19781 Magana-Schwencke and Ekert 19782 Magana-Schwencke and Moustacchi 19802 Le Curieux et al. 19932 Mammalian in vitro Rodent Ross and Shipley 19801 Ross et al. 19811 O'Connor and Fox 19871 Speit et al. 2007a1 Cosma et al. 1988a1 Demkowicz-Dobrzanski and Castonguay 19921 Kumari et al. 20123 She et al. 20133 Human Fornace et al. 19821 — Grafström et al. 19841 Saladino et al. 19851 Grafström et al. 19861 Snyder and Van Houten 19861 Grafström 19901 Vock et al. 19991 Liu et al. 20061 Mammalian in vivo: Rodent — Neuss et al. 2010c3 portal-of-entry effects Primate — — Human — — 

Mammalian in vivo: Rodent Im et al. 20061 Speit et al. 20091 systemic effects Wang and Liu 20061 Primate — — Human Yu et al. 20051 Zeller et al. 2011b3 Jiang et al. 20061 Aydin et al. 20134 Jiang et al. 20063 Tong et al. 20061 Costa et al. 20081 Jiang et al. 20103 Costa et al. 20114 Gomaa et al. 20123 Lin et al. 20133 1 The study was identified from the background document or the substance profile for formaldehyde in the National Toxicology Program 12th Report on Carcinogens (NTP 2010, 2011). 2 The study was identified from IARC 2006 or IARC 2012. 3 The study was identified from the committee’s new literature search (see Appendix D). 4 The study was identified through additional ad hoc searches or from the reference list of other studies. Source: committee-generated. 213 

214 TABLE E-5 Mutations Positive Studies Negative Studies Cell-free systems — — Nonmammalian model organisms Reviewed in IARC (2006)2: largely positive (with and Reviewed in IARC (2006)2: largely negative for without S9) for point mutations in bacteria (Salmonella frame-shift mutations in S. typhimurium typhimurium, Escherichia coli) and nonmammalian eukaryotes (Neurospora crassa, Drosophila melanogaster, Caenorhabditis elegans) Mammalian in vitro Rodent Grafstrom et al. 19931 Merk and Speit 1998, 19991 Mackerer et al. 19961 Speit and Merk 20021 Human Goldmacher and Thilly 19831 — Grafström et al. 19851 Craft et al. 19871 Crosby et al. 19881 Liber et al. 19891 Grafström 19901 Mammalian in vivo: Rodent Recio et al. 19921 Meng et al. 20101 portal-of-entry effects Primate — — Human — — 1 Mammalian in vivo: Rodent Liu et al. 2009b — systemic effects Primate — — Human — — 1 The study was identified from the background document or the substance profile for formaldehyde in the National Toxicology Program 12th Report on Carcinogens (NTP 2010, 2011). 2 The study was identified from IARC 2006 or IARC 2012. Source: Committee generated. 

TABLE E-6 Sister-Chromatid Exchanges Positive Studies Negative Studies Cell-free systems — — Nonmammalian model organisms — — Mammalian in vitro Rodent Obe and Beek 19791 — Natarajan et al. 19831 Basler et al. 19851 Galloway et al. 19851 Merk and Speit 1998, 19991 Speit et al. 2007a1 Garcia et al. 20091 She et al. 20132 Human Obe and Beek 19791 — Kreiger and Garry 19831 Schmid et al. 19861 Schmid and Speit 20071 Neuss and Speit 2008 Zeller et al. 2011a2 Mammalian in vivo: Rodent — — portal-of-entry effects Primate — — Human — — Mammalian in vivo: Rodent — Kligerman et al. 19841 systemic effects Speit et al. 20091 Primate — — 1 Human Yager et al. 1986 Thomson et al. 19841 Shaham et al. 1997, 20021 Bauchinger and Schmid 19851 He et al. 19981 Chebotarev et al. 19861 Suruda et al. 19931 (Continued) 215 

216 TABLE E-6 Continued Positive Studies Negative Studies Ye et al. 20051 Ying et al. 19991 Costa et al. 20081 Pala et al. 20081 Costa et al. 20132 Jakab et al. 20102 Zeller et al. 2011b, 20122 1 The study was identified from the background document or the substance profile for formaldehyde in the National Toxicology Program 12th Report on Carcinogens (NTP 2010, 2011). 2 The study was identified from the committee’s new literature search (see Appendix D). Source: committee-generated. 

TABLE E-7 Micronuclei Positive Studies Negative Studies Cell-free systems — — Nonmammalian model organisms — — Mammalian in vitro Rodent Merk and Speit 19981 — Speit et al. 2007a1 Ji et al. 20133 She et al. 20133 Human Speit et al. 20001 — Schmid and Speit 20071 Speit et al. 2011a3 Ren et al. 20133 Mammalian in vivo: Rodent Migliore et al. 19891 Neuss et al. 2010c3 portal-of-entry effects Speit et al. 2011b3 Primate — — Human Ballarin et al. 19921 Titenko-Holland et al. 19961 Suruda et al. 19931 Speit et al. 2007b1 Kitaeva et al. 19961 Zeller et al. 2011b3 Titenko-Holland et al. 19961 Ying et al. 19971 Burgaz et al. 2001,20021 Ye et al. 20051 Ladeira et al. 2011, 20133 Viegas et al. 20133 Mammalian in vivo: Rodent Zhao et al. 20044 Gocke et al. 19811 systemic effects Gao et al. 20084 Natarajan et al. 19831 Gao et al. 20093 Kim et al. 19914 Katsnelson et al. 20134 Morita et al. 19971 Speit et al. 20091 (Continued) 217 

218 TABLE E-7 Continued Positive Studies Negative Studies Primate — — Human Suruda et al. 19931 Ying et al. 19971 Kitaeva et al. 19961 Pala et al. 20081 He et al. 19981 Zeller et al. 2011b3 Yu et al. 20052 Orsiere et al. 20061 Iarmarcovai et al. 20071 Costa et al. 20081 Jiang et al. 20103 Viegas et al. 20104 Brahem et al. 20113 Costa et al. 20114 Ladeira et al. 2011, 20133 Bouraoui et al. 20133 Costa et al. 20133 Lin et al. 20133 Viegas et al. 20133 Souza and Devi 20143 1 The study was identified from the background document or the substance profile for formaldehyde in the National Toxicology Program 12th Report on Carcinogens (NTP 2010, 2011). 2 The study was identified from IARC 2006 or IARC 2012. 3 The study was identified from the committee’s new literature search (see Appendix D). 4 The study was identified through additional ad hoc searches or from the reference list of other studies. Source: Committee-generated. 

TABLE E-8 Chromosomal Aberrations Positive Studies Negative Studies Cell-free systems — — Nonmammalian model organisms — — Mammalian in vitro Rodent Ishidate et al. 19811 — Natarajan et al. 19831 Galloway et al. 19851 Hikiba et al. 20051 Hagiwara et al. 20061 Human Miretskaya and Shvartsman 19821 Kuehner et al. 20122 Levy et al. 19831 Ji et al. 20132 Schmid et al. 19861 Dresp and Bauchinger 19881 Pongsavee 20112 Ren et al. 20132 Mammalian in vivo: Rodent Dallas et al. 19921 — portal-of-entry effects Primate — — Human — — Mammalian in vivo: Rodent Kitaeva et al. 19901 Fontignie-Houbrechts 19811 systemic effects Gomaa et al. 20122 Natarajan et al. 19831 Kligerman et al. 19841 Dallas et al. 19921 Speit et al. 20091 Primate — — Human Bauchinger and Schmid 19851 Fleig et al. 19821 Chebotarev et al. 19861 Thomson et al. 19841 Kitaeva et al. 19961 Vargova et al. 19921 He et al. 19981 Vasudeva and Anand 19961 Lazutka et al. 19991 Pala et al. 20081 (Continued) 219 

220 TABLE E-8 Continued Positive Studies Negative Studies Neri et al. 20061 Jakab et al. 20102 Zhang et al. 2010b1 Santovito et al. 20112 Gomaa et al. 20122 Musak et al. 20132 1 The study was identified from the background document or the substance profile for formaldehyde in the National Toxicology Program 12th Report on Carcinogens (NTP 2010, 2011). 2 The study was identified from the committee’s new literature search (see Appendix D). Source: committee-generated. 

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222 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens Casanova, M., K.T. Morgan, W.H. Steinhagen, J.I. Everitt, J.A. Popp, and H.D. Heck. 1991. Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkey: Pharmacokinetics, rat to monkey interspecies scaling, and extrapo- lation to man. Fundam. Appl. Toxicol. 17(2):409-428. Casanova, M., K.T. Morgan, E.A. Gross, O.R. Moss, and H.D. Heck. 1994. DNA-protein cross-links and cell replication at specific sites in the nose of F344 rats exposed subchronically to formaldehyde. Fundam. Appl. Toxicol. 23(4):525-536. Casanova, M., D.A. Bell, and H.D. Heck. 1997. Dichloromethane metabolism to formal- dehyde and reaction of formaldehyde with nucleic acids in hepatocytes of rodents and humans with and without glutathione S-transferase T1 and M1 genes. Fundam. Appl. Toxicol. 37(2):168-180. Casanova-Schmitz, M., T.B. Starr, and H.D. Heck. 1984a. Differentiation between meta- bolic incorporation and covalent binding in the labeling of macromolecules in the rat nasal mucosa and bone marrow by inhaled [14C]- and [3H]formaldehyde. Tox- icol. Appl. Pharmacol. 76(1):26-44. Chaw, Y.F., L.E. Crane, P. Lange, and R. Shapiro. 1980. Isolation and identification of cross-links from formaldehyde-treated nucleic acids. Biochemistry 19(24):5525- 5531. Chebotarev, A.N., N.V. Titenko, T.G. Selezneva, V.N. Fomenko, and L.M. Katosova. 1986. Comparison of chromosome aberrations, sister chromatid exchanges and un- scheduled DNA synthesis in the evaluation of the mutagenicity of environmental factors [in Russian]. Tsitol. Genet. 20(2):109-115. Cheng, G., M. Wang, P. Upadhyaya, P.W. Villalta, and S.S. Hecht. 2008. Formation of formaldehyde adducts in the reactions of DNA and deoxyribonucleosides with al- pha-acetates of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and N- nitrosodimethylamine (NDMA). Chem. Res. Toxicol. 21(3):746-751. Cosma, G.N., R. Jamasbi, and A.C. Marchok. 1988a. Growth inhibition and DNA dam- age induced by benzo[a]pyrene and formaldehyde in primary cultures of rat tra- cheal epithelial cells. Mutat. Res. 201(1):161-168. Cosma, G.N., A.S. Wilhite, and A.C. Marchok. 1988b. The detection of DNA-protein cross-links in rat tracheal implants exposed in vivo to benzo[a]pyrene and formal- dehyde. Cancer Lett. 42(1-2):13-21. Costa, M., A. Zhitkovich, M. Harris, D. Paustenbach, and M. Gargas. 1997. DNA-protein cross-links produced by various chemicals in cultured human lymphoma cells. J. Toxicol. Environ. Health 50(5):433-449. Costa, S, P. Coelho, C. Costa, S. Silva, O. Mayan, L.S. Santos, J. Gaspar, and J.P. Teixei- ra. 2008. Genotoxic damage in pathology anatomy laboratory workers exposed to formaldehyde. Toxicology 252(1-3):40-48. Costa, S., C. Pina, P. Coelho, C. Costa, S. Silva, B. Porto, B. Laffon, and J.P. Teixeira. 2011. Occupational exposure to formaldehyde: Genotoxic risk evaluation by comet assay and micronucleus test using human peripheral lymphocytes. J. Toxicol. En- viron. Health A 74(15-16):1040-1051. Costa, S., J. Garcia-Leston, M. Coelho, P. Coelho, C. Costa, S. Silva, B. Porto, B. Laffon, and J.P. Teixeira. 2013. Cytogenetic and immunological effects associated with occupational formaldehyde exposure. J. Toxicol. Environ. Health A 76(4-5):217- 229. Craft, T.R., E. Bermudez, and T.R. Skopek. 1987. Formaldehyde mutagenesis and for- mation of DNA-protein crosslinks in human lymphoblasts in vitro. Mutat. Res. 176(1):147-155. 

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224 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens Grafström, R.C., A. Fornace, and C.C. Harris. 1984. Repair of DNA damage caused by formaldehyde in human cells. Cancer Res. 44(10):4323-4327. Grafström, R.C., R.D. Curren, L.L. Yang, and C.C. Harris. 1985. Genotoxicity of formal- dehyde in cultured human bronchial fibroblasts. Science 228(4695):89-91. Grafström, R.C., J.C. Wiley, K. Sundqvist, and C.C. Harris. 1986. Pathobiological effects of tobacco smoke-related aldehydes in cultured human bronchial epithelial cells. Pp. 273-285 in Mechanisms in Tobacco Carcinogenesis, D. Hoffman, and C.C. Harris, eds. Banbury Report 23. Cold Spring Harbor, NY: CSH Press. Grafström, R.C., I.C. Hsu, and C.C. Harris. 1993. Mutagenicity of formaldehyde in Chi- nese hamster lung fibroblasts: Synergy with ionizing radiation and N-nitroso-N- methylurea. Chem. Biol. Interact. 86(1):41-49. Hagiwara, M., E. Watanabe, J.C. Barrett, and T. Tsutsui. 2006. Assessment of genotoxi- city of 14 chemical agents used in dental practice: Ability to induce chromosome aberrations in Syrian hamster embryo cells. Mutat. Res. 603(2):111-120. He, J.L., L.F. Jin, and H.Y. Jin. 1998. Detection of cytogenetic effects in peripheral lym- phocytes of students exposed to formaldehyde with cytokinesis-blocked micronu- cleus assay. Biomed. Environ. Sci. 11(1):87-92. Heck, H.A, M. Casanova, C.W. Lam, and J.A. Swenberg. 1986. The formation of DNA- protein cross-links by aldehydes present in tobacco smoke. Pp. 215-230 in Mecha- nisms in Tobacco Carcinogenesis, D. Hoffman, and C.C. Harris, eds. Banbury Re- port 23. Cold Spring Harbor, NY: CSH Press. Heck, H.A., M. Casanova, W.H. Steinhagen, J.I. Everitt, K.T. Morgan, and J.A. Popp. 1989. Formaldehyde toxicity: DNA-protein cross-linking studies in rats and non- human primates. Pp. 159-164 in Nasal Carcinogenesis in Rodents: Relevance to Human Risk, V.J. Feron, and M.C. Bosland, eds. Wageningen: Pudoc. Hikiba, H., E. Watanabe, J.C. Barrett, and T. Tsutsui. 2005. Ability of fourteen chemical agents used in dental practice to induce chromosome aberrations in Syrian hamster embryo cells. J. Pharmacol. Sci. 97(1):146-152. Huang, H., and P.B. Hopkins. 1993. DNA interstrand cross-linking by formaldehyde: Nucleotide sequence preference and covalent structure of the predominant cross- link formed in synthetic oligonucleotides. J. Am. Chem. Soc. 115(21):9402-9408. Huang, H.F., M.S. Solomon, and P.B. Hopkins. 1992. Formaldehyde preferentially inter- strand cross-links duplex DNA through deoxyadenosine residues at the sequence 5'-d(AT). J. Am. Chem. Soc. 114(23):9240-9241. IARC (International Agency for Research on Cancer). 2006. Formaldehyde. Pp. 39-325 in Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol. IARC Mono- graphs on the Evaluation of the Carcinogenic Risks to Humans Vol. 88. Lyon, France: IARC [online]. Available: http://monographs.iarc.fr/ENG/Monographs/ vol88/mono88.pdf [accessed Jan. 10, 2014]. IARC (International Agency for Research on Cancer). 2012. Formaldehyde. Pp.401-436 in Review of Human Carcinogens: Chemical Agents and Related Occupations. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans Vol. 100F. Lyon, France: IARC [online]. Available: http://monographs.iarc.fr/ ENG/Monographs/vol100F/mono100F.pdf [accessed Jan. 27, 2014]. Iarmarcovai, G., S. Bonassi, I. Sari-Minodier, M. Baciuchka-Palmaro, A. Botta, and T. Orsiere. 2007. Exposure to genotoxic agents, host factors, and lifestyle influence the number of centromeric signals in micronuclei: A pooled re-analysis. Mutat Res. 615(1-2):18-27. Im, H., E. Oh, J. Mun, J.Y. Khim, E. Lee, H.S. Kang, E. Kim, H. Kim, N.H. Won, Y.H. Kim, W.W. Jung, and D. Sul. 2006. Evaluation of toxicological monitoring mark- 

Appendix E 225 ers using proteomic analysis in rats exposed to formaldehyde. J. Proteome Res. 5(6):1354-1366. Ishidate, M., T. Sofuni, and K. Yoshikawa. 1981. Chromosomal aberration tests in vitro as a primary screening tool for environmental mutagens and/or carcinogens. Gann Monogr. Cancer Res. 27:95-108. Jakab, M.G., T. Klupp, K. Besenyei, A. Biro, J. Major, and A. Tompa. 2010. Formalde- hyde-induced chromosomal aberrations and apoptosis in peripheral blood lympho- cytes of personnel working in pathology departments. Mutat. Res. 698(1-2):11-17. Ji, Z., X. Li, M. Fromowitz, E. Mutter-Rottmayer, J. Tung, M. Smith, and L. Zhang. 2013. Formaldehyde induces micronuclei in mouse erythropoietic cells and sup- presses the expansion of human erythroid progenitor cells. Toxicol. Lett. 224(2):233-239. Jiang, S.F., L.Q. Yu, S.G. Leng, Y.S. Zhang, J. Cheng, Y.F. Dai, Y. Niu, F.S. He, and Y.X. Zheng. 2006. Association between XRCC1 gene polymorphisms and DNA damage of workers exposed to formaldehyde [in Chinese]. Wei Sheng Yan Jiu 35(6):675-677. Jiang, S.F., L. Yu, J. Cheng, S. Leng, Y. Dai, Y. Zhang, Y. Niu, H. Yan, W. Qu, C. Zhang, K. Zhang, R. Yang, L. Zhou, and Y. Zheng. 2010. Genomic damages in pe- ripheral blood lymphocytes and association with polymorphisms of three glutathi- one S-transferases in workers exposed to formaldehyde. Mutat. Res. 695(1-2):9- 15. Katsnelson, B.A., T.D. Degtyareva, L.I. Privalova, I.A. Minigaliyeva, T.V. Slyshkina, V.V. Ryzhov, and O.Y. Beresneva. 2013. Attenuation of subchronic formaldehyde inhalation toxicity with oral administration of glutamate, glycine and methionine. Toxicol. Lett. 220(2):181-186. Ke, Y.J., X.D. Qin, L. Li, J. Du, Y.C. Zhang, and S.M. Ding. 2012. Toxic effect of for- maldehyde on mouse bone marrow. China Environ. Sci. 32(6):1129-1133. Kim, C.Y., K. Kim, J.S. Shim, Y.H. Kim, and J.K. Roh. 1991. Acute toxicity and micro- nucleus formation study in mice exposed to formaldehyde by inhalation [in Kore- an]. Korean J. Toxicol 7(1):61-71. Kitaeva, L.V., E.M. Kitaev, and M.N. Pimenova. 1990. The cytopathic and cytogenetic sequelae of chronic inhalational exposure to formaldehyde on female germ cells and bone marrow cells in rats [in Russian]. Tsitologiia 32(12):1212-1216. Kitaeva, L.V., E.A. Mikheeva, L.F. Shelomova, and P. Shvartsman. 1996. Genotoxic effect of formaldehyde in somatic human cells in vivo [in Russian]. Genetika 32(9):1287-1290. Kligerman, A.D., M.C. Phelps, and G.L. Erexson. 1984. Cytogenetic analysis of lympho- cytes from rats following formaldehyde inhalation. Toxicol. Lett. 21(3):241-246. Kreiger, R.A., and V.F. Garry. 1983. Formaldehyde-induced cytotoxicity and sister- chromatid exchanges in human lymphocyte cultures. Mutat. Res. 120(1):51-55. Kuehner, S., M. Schlaier, K. Schwarz, and G. Speit. 2012. Analysis of leukemia-specific aneuploidies in cultured myeloid progenitor cells in the absence and presence of formaldehyde exposure. Toxicol. Sci. 128(1):72-78. Kumari, A., Y.X. Lim, A.H. Newell, S.B. Olson, and A.K. McCullough. 2012. Formal- dehyde-induced genome instability is suppressed by an XPF-dependent pathway. DNA Repair 11(3):236-246. Kuykendall, J.R., and M.S. Bogdanffy. 1992. Efficiency of DNA-histone crosslinking induced by saturated and unsaturated aldehydes in vitro. Mutat. Res. 283(2):131- 136. 

226 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens Ladeira, C., S. Viegas, E. Carolino, J. Prista, M.C. Gomes, and M. Brito. 2011. Genotox- icity biomarkers in occupational exposure to formaldehyde--the case of histo- pathology laboratories. Mutat. Res. 721(1):15-20. Ladeira, C., S. Viegas, E. Carolino, M.C. Gomes, and M. Brito. 2013. The influence of genetic polymorphisms in XRCC3 and ADH5 genes on the frequency of genotoxi- city biomarkers in workers exposed to formaldehyde. Environ. Mol. Mutagen. 54(3):213-221. Lam, C.W., M. Casanova, and H.D. Heck. 1985. Depletion of nasal mucosal glutathione by acrolein and enhancement of formaldehyde-induced DNA-protein cross-linking by simultaneous exposure to acrolein. Arch. Toxicol. 58(2):67-71. Lazutka, J.R., R. Lekevicius, V. Dedonyte, L. Maciuleviciute-Gervers, J. Mierauskiene, S. Rudaitiene, and G. Slapsyte. 1999. Chromosomal aberrations and sister- chromatid exchanges in Lithuanian populations: Effects of occupational and envi- ronmental exposures. Mutat. Res. 445(2):225-239. Le Curieux, F., D. Marzin, and F. Erb. 1993. Comparison of three short-term assays: Results on seven chemicals. Potential contribution to the control of water genotox- icity. Mutat. Res. 319(3):223-236. Levy, S., S. Nocentini, and C. Billardon. 1983. Induction of cytogenetic effects in human fibroblast cultures after exposure to formaldehyde or X-rays. Mutat. Res. 119(3):309-317. Liber, H.L., K. Benforado, R.M. Crosby, D. Simpson, and T.R. Skopek. 1989. Formalde- hyde-induced and spontaneous alterations in human hprt DNA sequence and mRNA expression. Mutat Res. 226(1):31-37. Lin, D., Y. Guo, J. Yi, D. Kuang, X. Li, H. Deng, K. Huang, L. Guan, Y. He, X. Zhang, D. Hu, Z. Zhang, H. Zheng, X. Zhang, C.M. McHale, L. Zhang, and T. Wu. 2013. Occupational exposure to formaldehyde and genetic damage in the peripheral blood lymphocytes of plywood workers. J. Occup. Health 55(4):284-291. Liu, Y.R., Y. Zhou, W. Qiu, J.Y. Zheng, L.L. Shen, A.P. Li, and J.W. Zhou. 2009b. Ex- posure to formaldehyde induces heritable DNA mutations in mice. J. Toxicol. En- viron. Health A 72(11-12):767-773. Liu, Y.S., C.M. Li, Z.S. Lu, S.M. Ding, X. Yang, and J.W. Mo. 2006. Studies on for- mation and repair of formaldehyde-damaged DNA by detection of DNA-protein crosslinks and DNA breaks. Front. Biosci. 11:991-997. Lu, K., G. Boysen, L. Gao, L.B. Collins, and J.A. Swenberg. 2008. Formaldehyde- induced histone modifications in vitro. Chem. Res. Toxicol. 21(8):1586-1593. Lu, K, W.J. Ye, A. Gold, L.M. Ball, J.A. Swenberg. 2009. Formation of S- 1-(N-2- deoxyguanosinyl)methyl glutathione between glutathione and DNA induced by formaldehyde. J. Am. Chem. Soc. 131(10):3414-3415. Lu, K., L.B. Collins, H. Ru, E. Bermudez, and J.A. Swenberg. 2010a. Distribution of DNA adducts caused by inhaled formaldehyde is consistent with induction of nasal carcinoma but not leukemia. Toxicol. Sci. 116(2):441-451. Lu, K., W.J. Ye, L. Zhou, L.B. Collins, X. Chen, A. Gold, L.M. Ball, and J.A. Swenberg. 2010b. Structural characterization of formaldehyde-induced cross-links between amino acids and deoxynucleosides and their oligomers. J. Am. Chem. Soc. 132(10):3388-3399. Lu, K., B. Moeller, M. Doyle-Eisele, J. McDonald, J.A. Swenberg. 2011. Molecular do- simetry of N2-hydroxymethyl-dG DNA adducts in rats exposed to formaldehyde. Chem. Res. Toxicol. 24(2):159-161. Lu, K., S. Craft, J. Nakamura, B.C. Moeller, and J.A. Swenberg. 2012. Use of LC- MS/MS and stable isotopes to differentiate hydroxymethyl and methyl DNA ad- 

Appendix E 227 ducts from formaldehyde and nitrosodimethylamine. Chem. Res. Toxicol. 25(3):664-675. Mackerer, C.R., F.A. Angelosanto, G.R. Blackburn, and C.A. Schreiner. 1996. Identifica- tion of formaldehyde as the metabolite responsible for the mutagenicity of methyl tertiary-butyl ether in the activated mouse lymphoma assay. Proc. Soc. Exp. Biol. Med. 212(4):338-341. Magana-Schwencke, N., and B. Ekert. 1978. Biochemical analysis of damage induced in yeast by formaldehyde. 2. Induction of cross-links between DNA and protein. Mu- tat. Res. 51(1):11-19. Magana-Schwencke, N., and E. Moustacchi. 1980. Biochemical analysis of damage in- duced in yeast by formaldehyde. 3. Repair of induced cross-links between DNA and proteins in the wild- type and in excision-deficient strains. Mutat. Res. 70(1):29-35. Magana-Schwencke, N., B. Ekert, and E. Moustacchi. 1978. Biochemical analysis of damage induced in yeast by formaldehyde. 1. Induction of single-strand breaks in DNA and their repair. Mutat. Res. 50(2):181-193. Meng, F., E. Bermudez, P.B. McKinzie, M.E. Andersen, H.J. Clewell, III, and B.L. Par- sons. 2010. Measurement of tumor-associated mutations in the nasal mucosa of rats exposed to varying doses of formaldehyde. Regul. Toxicol. Pharmacol. 57(2- 3):274-283. Merk, O., and G. Speit. 1998. Significance of formaldehyde-induced DNA-protein cross- links for mutagenesis. Environ. Mol. Mutagen. 32(3):260-268. Merk, O., and G. Speit. 1999. Detection of crosslinks with the comet assay in relationship to genotoxicity and cytotoxicity. Environ. Mol. Mutagen. 33(2):167-172. Migliore, L., L. Ventura, R. Barale, N. Loprieno, S. Castellino, and R. Pulci. 1989. Micro- nuclei and nuclear anomalies induced in the gastro-intestinal epithelium of rats treat- ed with formaldehyde. Mutagenesis 4(5):327-334. Miretskaya, L.M., and P. Shvartsman. 1982. Chromosome damages in human lympho- cytes as affected by formaldehyde. 1. Formaldehyde treatment of lymphocytes in culture [in Russian]. Tsitologiya 24(9):1056-1060. Moeller, B.C., K. Lu, M. Doyle-Eisele, J. McDonald, A. Gigliotti, and J.A. Swenberg. 2011. Determination of N2-hydroxymethyl-dG adducts in the nasal epithelium and bone marrow of nonhuman primates following 13CD2-formaldehyde inhalation exposure. Chem. Res. Toxicol. 24(2):162-164. Morita, T., N. Asano, T. Awogi, Y.F. Sasaki, S. Sato, H. Shimada, S. Sutou, T. Suzuki, A. Wakata, T. Sofuni, and M. Hayashi. 1997. Evaluation of the rodent micronu- cleus assay in the screening of IARC carcinogens (groups 1, 2A and 2B) the sum- mary report of the 6th collaborative study by CSGMT/JEMS MMS. Collaborative Study of the Micronucleus Group Test. Mammalian Mutagenicity Study Group. Mutat. Res. 389(1):3-122. Musak, L., Z. Smerhovsky, E. Halasova, O. Osina, L. Letkova, L. Vodickova, V. Polako- va, J. Buchancova, K. Hemminki, and P. Vodicka. 2013. Chromosomal damage among medical staff occupationally exposed to volatile anesthetics, antineoplastic drugs, and formaldehyde. Scand. J. Work Environ. Health 39(6):618-630. Natarajan, A.T., F. Darroudi, C.J. Bussman, and A.C. van Kesteren-van Leeuwen. 1983. Evaluation of the mutagenicity of formaldehyde in mammalian cytogenetic assays in vivo and vitro. Mutat. Res. 122(3-4):355-360. Neri, M., S. Bonassi, L.E. Knudsen, R.J. Sram, N. Holland, D. Ugolini, and D.F. Merlo. 2006. Children's exposure to environmental pollutants and biomarkers of genetic damage. 1. Overview and critical issues. Mutat. Res. 612(1):1-13. 

228 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens Neuss, S., and G. Speit. 2008. Further characterization of the genotoxicity of formalde- hyde in vitro by the sister chromatid exchange test and co-cultivation experiments. Mutagenesis 23(5):355-357. Neuss, S., B. Moepps, and G. Speit. 2010a. Exposure of human nasal epithelial cells to formaldehyde does not lead to DNA damage in lymphocytes after co-cultivation. Mutagenesis 25(4):359-364. Neuss, S., K. Holzmann, and G. Speit. 2010b. Gene expression changes in primary hu- man nasal epithelial cells exposed to formaldehyde in vitro. Toxicol. Lett. 198(2):289-295. Neuss, S., J. Zeller, L. Ma-Hock, and G. Speit. 2010c. Inhalation of formaldehyde does not induce genotoxic effects in broncho-alveolar lavage (BAL) cells of rats. Mutat. Res. 695(1-2):61-68. NTP (National Toxicology Program). 2010. Report on Carcinogens Background Docu- ment for Formaldehyde, January 22, 2010. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/roc/twelfth/ 2009/November/Formaldehyde_BD_Final.pdf [accessed July 17, 2013]. NTP (National Toxicology Program). 2011. Formaldehyde. Pp. 195-205 in Report on Carcinogens, 12th Ed. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/formaldehyde.pdf [accessed July 17, 2013]. Obe, G., and B. Beek. 1979. Mutagenic activity of aldehydes. Drug Alcohol Depend. 4(1- 2):91-94. O’Connor, P.M., and B.W. Fox. 1987. Comparative studies of DNA cross-linking reac- tions following methylene dimethanesulphonate and its hydrolytic product, for- maldehyde. Cancer Chemother. Pharmacol. 19(1):11-15. Olin, K.L., G.N. Cherr, E. Rifkin, and C.L. Keen. 1996. The effects of some redox-active metals and reactive aldehydes on DNA-protein cross-links in vitro. Toxicology 110(1-3):1-8. Orsiere, T., I. Sari-Minodier, G. Iarmarcovai, and A. Botta. 2006. Genotoxic risk assess- ment of pathology and anatomy laboratory workers exposed to formaldehyde by use of personal air sampling and analysis of DNA damage in peripheral lympho- cytes. Mutat. Res. 605(1-2):30-41. Pala, M., D. Ugolini, M. Ceppi, F. Rizzo, L. Maiorana, C. Bolognesi, T. Schiliro, G. Gil- li, P. Bigatti, R. Bono, and D. Vecchio. 2008. Occupational exposure to formalde- hyde and biological monitoring of Research Institute workers. Cancer Detect. Prev. 32(2):121-126. Pongsavee, M. 2011. In vitro study of lymphocyte antiproliferation and cytogenetic effect by occupational formaldehyde exposure. Toxicol. Ind. Health 27(8):719-723. Poverenny, A.M., Y.A. Siomin, A.S. Saenko, and B.I. Sinzinis. 1975. Possible mecha- nisms of lethal and mutagenic action of formaldehyde. Mutat. Res. 27(1):123-126. Recio, L., S. Sisk, L. Pluta, E. Bermudez, E.A. Gross, Z. Chen, K. Morgan, and C. Walk- er. 1992. p53 mutations in formaldehyde-induced nasal squamous cell carcinomas in rats. Cancer Res. 52(21):6113-6116. Ren, X., Z. Ji, C.M. McHale, J. Yuh, J. Bersonda, M. Tang, M.T. Smith, and L. Zhang. 2013. The impact of FANCD2 deficiency on formaldehyde-induced toxicity in human lymphoblastoid cell lines. Arch. Toxicol. 87(1):189-196. 

Appendix E 229 Ross, W.E., and N. Shipley. 1980. Relationship between DNA damage and survival in formaldehyde-treated mouse cells. Mutat. Res. 79(3):277-283. Ross, W.E., D.R. McMillan, and C.F. Ross. 1981. Comparison of DNA damage by methylmelamines and formaldehyde. J. Natl. Cancer Inst. 67(1):217-221. Saito, Y., K. Nishio, Y. Yoshida, and E. Niki. 2005. Cytotoxic effect of formaldehyde with free radicals via increment of cellular reactive oxygen species. Toxicology 210(2-3):235-245. Saladino, A.J., J.C. Willey, J.F. Lechner, R.C. Grafstrom, M. LaVeck, and C.C. Harris. 1985. Effects of formaldehyde, acetaldehyde, benzoyl peroxide, and hydrogen peroxide on cultured normal human bronchial epithelial cells. Cancer Res. 45(6):2522-2526. Santovito, A., T. Schiliro, S. Castellano, P. Cervella, M.P. Bigatti, G. Gilli, R. Bono, and M. DelPero. 2011. Combined analysis of chromosomal aberrations and glutathione S-transferase M1 and T1 polymorphisms in pathologists occupationally exposed to formaldehyde. Arch. Toxicol. 85(10):1295-1302. Schmid, E., W. Goggelmann, and M. Bauchinger. 1986. Formaldehyde-induced cytotox- ic, genotoxic and mutagenic response in human lymphocytes and Salmonella typhimurium. Mutagenesis 1(6):427-431. Schmid, O., and G. Speit. 2007. Genotoxic effects induced by formaldehyde in human blood and implications for the interpretation of biomonitoring studies. Mutagenesis 22(1):69-74. Shaham, J., Y. Bomstein, A. Meltzer, Z. Kaufman, E. Palma, and J. Ribak. 1996a. DNA - protein crosslinks, a biomarker of exposure to formaldehyde - in vitro and in vivo studies. Carcinogenesis 17(1):121-125. Shaham, J., Y. Bomstein, A. Meltzer, and J. Ribak. 1997. DNA-protein crosslinks and sister chromatid exchanges as biomarkers of exposure to formaldehyde. Int. J. Oc- cup. Environ. Health 3(2):95-104. Shaham, J., R. Gurvich, and Z. Kaufman. 2002. Sister chromatid exchange in pathology staff occupationally exposed to formaldehyde. Mutat. Res. 514(1-2):115-123. Shaham, J., Y. Bomstein, R. Gurvich, M. Rashkovsky, and Z. Kaufman. 2003. DNA- protein crosslinks and p53 protein expression in relation to occupational exposure to formaldehyde. Occup. Environ. Med. 60(6):403-409. She, Y., Y. Li, Y. Liu, G. Asai, S. Sun, J. He, Z. Pan, and Y. Cui. 2013. Formaldehyde induces toxic effects and regulates the expression of damage response genes in BM-MSCs. Acta Biochim. Biophys. Sin. 45(12):1011-1020. Snyder, R.D., and B. Van Houten. 1986. Genotoxicity of formaldehyde and an evaluation of its effects on the DNA repair process in human diploid fibroblasts. Mutat. Res. 165(1):21-30. Souza, A., and R. Devi. 2014. Cytokinesis blocked micronucleus assay of peripheral lymphocytes revealing the genotoxic effect of formaldehyde exposure. Clin. An- at.27(3):308-312. Speit, G., and O. Merk. 2002. Evaluation of mutagenic effects of formaldehyde in vitro: Detection of crosslinks and mutations in mouse lymphoma cells. Mutagenesis 17(3):183-187. Speit, G., P. Schutz, and O. Merk. 2000. Induction and repair of formaldehyde-induced DNA-protein crosslinks in repair-deficient human cell lines. Mutagenesis 15(1):85-90. Speit, G., P. Schutz, J. Hogel, and O. Schmid. 2007a. Characterization of the genotoxic potential of formaldehyde in V79 cells. Mutagenesis 22(6):387-394. 

230 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens Speit, G., O. Schmid, M. Frohler-Keller, I. Lang, and G. Triebig. 2007b. Assessment of local genotoxic effects of formaldehyde in humans measured by the micronucleus test with exfoliated buccal mucosa cells. Mutat. Res. 627(2):129-135. Speit, G., O. Schmid, S. Neuss, and P. Schutz. 2008b. Genotoxic effects of formaldehyde in the human lung cell line A549 and in primary human nasal epithelial cells. En- viron. Mol. Mutagen. 49(4):300-307. Speit, G., J. Zeller, O. Schmid, A. Elhajouji, L. Ma-Hock, and S. Neuss. 2009. Inhalation of formaldehyde does not induce systemic genotoxic effects in rats. Mutat. Res. 677(1-2):76-85. Speit, G., S. Neuss, and O. Schmid. 2010. The human lung cell line A549 does not devel- op adaptive protection against the DNA-damaging action of formaldehyde. Envi- ron. Mol. Mutagen. 51(2):130-137. Speit, G., S. Kuhner, R. Linsenmeyer, and P. Schutz. 2011a. Does formaldehyde induce aneuploidy? Mutagenesis 26(6):805-811. Speit, G., P. Schutz, I. Weber, I. Ma-Hock, W. Kaufmann, H.P. Gelbke, and S. Durrer. 2011b. Analysis of micronuclei, histopathological changes and cell proliferation in nasal epithelium cells of rats after exposure to formaldehyde by inhalation. Mutat. Res. 721(2):127-135. Suruda, A., P. Schulte, M. Boeniger, R.B. Hayes, G.K. Livingston, K. Steenland, P. Stewart, R. Herrick, D. Douthit, and M.A. Fingerhut. 1993. Cytogenetic effects of formaldehyde exposure in students of mortuary science. Cancer Epidemiol. Bi- omarkers Prev. 2(5):453-460. Swenberg, J.A., E.A. Gross, J. Martin, and J.A. Popp. 1983b. Mechanisms of formalde- hyde toxicity. Pp. 132-147 in Formaldehyde Toxicity, J.E. Gibson, ed. New York: Hemisphere Publishing. Thomson, E.J., S. Shackleton, and J.M. Harrington. 1984. Chromosome aberrations and sister-chromatid exchange frequencies in pathology staff occupationally exposed to formaldehyde. Mutat. Res. 141(2):89-93. Titenko-Holland, N., A.J. Levine, M.T. Smith, P.J. Quintana, M. Boeniger, R. Hayes, A. Suruda, and P. Schulte. 1996. Quantification of epithelial cell micronuclei by fluo- rescence in situ hybridization (FISH) in mortuary science students exposed to for- maldehyde. Mutat. Res. 371(3-4):237-248. Tong, Z.M., J. Shi, J.S. Zhao, H. Yang, R.M. Jiang, Z. Kong, and Q. Sun. 2006. Analysis on genetic toxicity of formaldehyde on occupational exposure population [in Chi- nese]. Chin. J. Public Health 22(7):783-784. Vargova, M., S. Janota, J. Karelova, M. Barancokova, and M. Sulcova. 1992. Analysis of the health risk of occupational exposure to formaldehyde using biological markers. Analusis 20(8):451-454. Vasudeva, N., and C. Anand. 1996. Cytogenetic evaluation of medical students exposed to formaldehyde vapor in the gross anatomy dissection laboratory. J. Am. Coll. Health 44(4):177-179. Viegas, S., C. Ladeira, C. Nunes, J. Malta-Vacas, M. Gomes, M. Brito, P. Mendonca, and J. Prista. 2010. Genotoxic effects in occupational exposure to formaldehyde: A study in anatomy and pathology laboratories and formaldehyde-resins production. J. Occup. Med. Toxicol. 5(1):25. Viegas, S., C. Ladeira, M. Gomes, C. Nunes, M. Brito, and J. Prista. 2013. Exposure and genotoxicity assessment methodologies: The case of formaldehyde occupational exposure. Curr. Anal. Chem. 9(3):476-484. 

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232 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens maldehyde, hematotoxicity, and leukemia-specific chromosome changes in cul- tured myeloid progenitor cells. Cancer Epidemiol. Biomarkers Prev. 19(1):80-88. Zhao, Q., L. Duan, Y. Liu, Z. Lu, O.Y. Qia, Y. Yan, and X. Yang. 2004. Effect of for- maldehyde from artificial based boards on micronucleus of mice marrow poly- chromatic erythrocyte. J. Public Health Prev. Med. 15(6):18-20. Zhitkovich, A., and M. Costa. 1992. A simple, sensitive assay to detect DNA-protein crosslinks in intact cells and in vivo. Carcinogenesis 13(8):1485-1489. Zhong, W.G., and S. Que Hee. 2004a. Quantitation of normal and formaldehyde- modified deoxynucleosides by high-performance liquid chromatography/UV de- tection. Biomed. Chromatogr. 18(7):462-469. Zhong, W.G., and S. Que Hee. 2004b. Formaldehyde-induced DNA adducts as bi- omarkers of in vitro human nasal epithelial cell exposure to formaldehyde. Mutat. Res. 563(1):13-24. Zhong, W.G., and S. Que Hee. 2005. Comparison of UV, fluorescence, and electrochem- ical detectors for the analysis of formaldehyde-induced DNA adducts. J. Anal. Toxicol. 29(3):182-187.