NITROGEN MUSTARD 269 41Sunderman, F.W., Jr, Maenza, R.M., Hopfer, S.M., Mitchell, J.M., Allpass, P.R. & Darnjanov, 1. (1979) Induction of renal cancers in rats by intrarenal injection of nickel subsulfide. J. environ. Pathol. Toxicol.,21, 1511-1527 42Damjanov, 1., Sunderman, F.W., Jr, Mitchell, J.M. & Allpass, P.R. (1978) Induction oftesticular sarcomas in Fischer rats by intratesticular injection of nickel subsulfide. Cancer Res., 38, 268-276 43Albert, D.M., Gonder, J.R., Papale, J., Craft, J.L., Dohlman, H.G., Reid, M.C. & Sunderman, F.W., Jr (1980) Induction of ocular neoplasms in Fischer rats by intraocular injection o/nickel subsulfde. ln: Brown, S.S. & Sunderman, F.W., Jr, eds, Nickel Toxicology, New York, Academic Press, pp. 55-58 44Yarita, T. & Nettesheim, P. (1978) Carcinogenicity of nickel subsulfide for respiratory tract rnucosa. Cancer Res., 38,3140-3145 45Hildebrand, H.F. & Biserte, G. (1979) Cylindricallaminated bodies in nickel-subsulphide-induced rhabdornyosarcoma in rabbits. Eur. J. Cel! BioL., 19, 276-280 46Hildebrand, H.F. & Biserte, G. (1979) Nickel sub-sulphide-induced leiomyosarcoma in rabbit white skeletal muscle. A light microscopical and ultrastructural study. Cancer, 43, 1358-1374 47Hildebrand, H.F. & Tetaert, D. (1981) Ni3S2-induced leiomyosarcomas in rabbit skeletal muscle: analysis of the tumoral myosin and its significance in the retrodifferentiation concept. Oncodev. Biol. Med., 2, 101-108 48Kasprzak, K.S., Gabryel, P. & Jarczewska, K. (1983) Carcinogenicity of nickel(II)hydroxides and nickel(II)sulfate in Wistar rats and its relation to the in vitro dissolution rates. Carcinogenesis,4, 275-279 49Stoner, G.D., Shimkin, M.B., Troxell, M.C., Thompson, T.L. & Terry, L.S. (1976) Test for carcinogenicity of metallic compounds by the pulmonary tumor response in strain A mice. Cancer Res., 36, 1744-1747 50Sunderman, F.W., Jr, McCully, K.S. & Hopfer, S.M. (1984) Association between erythrocytosis and renal cancers in rats following intrarenal injection of nickel compounds. Carcinogenesis,5, 1511-1517 51Torjussen, W. (1979) Nickel as carcinogenic factor in nasal carcinoma. Acta otolaryngol., Suppl. 360, 125 52Barton, R.T. & HØgetveit, A.C. (1980) Nickel-related cancers of the respiratory tract. Cancer, 45, 3061 -3064 53Torjussen, W. (1985) Occupational nasal cancer caused by nickel and nickel cornpounds. Rhinology,23, 101-105 54IARC Monographs, Suppl. 6,417-420, 1987 NITROGEN MUS TARD (Group 2A) A. Evidence for carcinogenicity to humans (limited) No epidemiological study of nitrogen mustard as a single agent was available to the Working. Group. However, it is the principal alkylating agent in leukaemogenic combination chemotherapy given for Hodgkin's disease, and other alkylating agents are clearly ~.,"-~..__._.- IARC MONOGRAPHS SUPPLEMENT 7 270 leukaemogenic (see p. 254). The many case reports of cancer following topical application of nitrogen mustard cannot be interpreted with certainty because concurrent treatment with radiation and other potent drugs has been the rule rather than the exception, and occasionally such associations would be expected by chance. Squamous-cell carcinomas of the skin following long-term topical application of nitrogen mustard alone or in combination with systemic therapy for mycosis fungoidesl-4 and psoriasiss-7 have been observed to appear on skin surfaces not exposed to the sun. B. Evidence for carcinogenicity to animaIs (sufficíent) Nitrogen mustard, administered mainly as the hydrochloride, has been tested for carcinogenicity in mice and rats by subcutaneous, intravenous and intraperitoneal administration ce after and by skin painting. It produced mainly lung tumours and lymphomas in mi subcutaneous, intravenous and intraperitoneal administration. Intravenous injection of nitrogen mustard to rats induced tumours in different organs8. Application by skin painting produced local tumours in mice in a dose-dependent manner9,lO. C. Other relevant data Nitrogen mustard is a bifunctional alkylating agent. ln one study, it induced chromosomal aberrations in lymphocytes of treated patients!!. Nitrogen mustard induced dominant lethal mutations and induced micronuclei in bone-marrow cells of mice exposed in vivo and alkylated DNA of ascites cells in experomal aberrations, sister chromatid exchanges and unscheduled DNA synthesis in human cells in vitro. ln rodent cells in vitro, it imental animaIs treated in vivo. It induced chromos induced sister chromatid exchanges, chromos omal aberrations and DN A damage; studies on the induction of mutation were inconclusive. It transformed mouse C3H lOTlj2 cells. Nitrogen mustard induced aneuploidy and somatic mutation and recombination in Drosophila, chromosomal aberrations in plants, mitotic recombination and mutation in fungi, and mutation and DNA damage in bacterialI. References IDu Vivier, A., Vonderheid, E.C., Van Scott, E.J. & Urbach, F. (1978) Mycosis fungoides, nitrogen mustard and skin cancer. Br. J. Dermatol., 99, 61-63 2Kravitz, P.H. & McDonald, C.J. (1978) Topical nitrogen mustard induced carcinogenesis. Acta dermatol. venereol., 58, 421-425 3Lee, L.A., Fritz, K.A., Golitz, L., Fritz, T.J. & Weston, W.L. (1982) Second cutaneous malignancies in patients with mycosis fungoides treated with topical nitrogen mustard. J. Am. Acad. Dermatol., 7,590-598 4Abel, E.A., Sendagorta, E. & Hoppe, R.T. (1986) Cutaneous malignancies and metastaticsquamous cell carcinoma following topical therapies for mycosis fungoides. J. Am. Acad. Dermatol., 14, 1029-1038 5Halprin, K.M., Comerford, M. & Taylor, J.R. (1982) Cancer in patients with psoriasis. J. Am. Acad. Dermatol, 7, 633-638 OCHRA TOXIN A 271 6Ganor, S. (1983) Skin cancer in psoriatics treated with nitrogen mustard. J. Am. Acad. Dermatol., 9, 164 7Halprin, K.M., Comerford, M. & Taylor, J.R. (1982) Skin cancer in psoriatics treated with nitrogen mustard. J. Am. Acad. Dermatol., 8, 164-165 8/ARC Monographs, 9, 193-207, 1975 9Zackheim, H.S. & Smuckler, E.A. (1980) Tumorigenic effect oftopical mechlorethamine, BCNU and CCNU in mice. Experientia,36, 1211-1212 10 Epstein, J.H. (1984) Nitrogen mustard (mechlorethamine) and UVB photocarcinogenesis: a dose response effect. J. invest. Dermatol., 83, 320-322 II/ARC Monographs, Suppl. 6,421-424, 1987 oeHRATOXIN A (Group 3) A. Evidence for carcinogenicity to humans (inadequate) Incidence of and mortality from urothelial urinary-tract tumours have been correlated with the geographical distribution of Balkan endemic nephropathy in Bulgaria and Yugoslavia. A relatively high frequency of contamination of cereals and bread with ochratoxin A has been reported in an area of Yugoslavia where Balkan endemic nephropathy is present. No report of a direct association between ochratoxin A and human cancer is availablel. B. Evidence for carcinogenicity to animais (limited) When ochratoxin A was administered in the diet of mice for 24 months, renal adenornas and carcinomas were observed in males and sorne hepatocellular carcinomas were observed in females in one study2 andhepatomas and renal-cell tumours in male miee in another study3. Other studies by oral administration and studies by subcutaneous injection to mice and rats were inadequate in terms ofthe numbers of animaIs used and survival rates!. C. Other relevant data No data were available on the genetic and related effects of ochratoxin A in humans. Ochratoxin A did not induce sister chromatid exchanges in bone-marrow cells of Chinese hamsters treated in vivo or mutation in rodent cells treated in vitro; conflcting results were obtained for induction of unscheduled DNA synthesis in rodent hepatocytes. Ochratoxin A did not induce mutation in yeast or bacteria4. References I/ARC Monographs, 31, 191-206, 1983 2Bendele, A.M., Carlton, W.W., Krogh, P.A. & Lilehoj, E.B. (1985) Ochratoxin A carcinogenesis in the (C57BL/6J x C3H)F1 mouse. J. natl Cancer /nst., 75, 733-742 Äi"""'.."_,._____