The literature evidencing the role of iron in promoting a range of neoplasms in humans and animals prompted us to search for a possible association between chemically induced hemosiderosis and hemangiosarcomas in the liver of mice in selected studies conducted by the National Toxicology Program (NTP). Its historical control database was examined for studies in which treatment-related liver hemangiosarcoma was noted; 130 consecutive NTP studies in B6C3F1 mice from Technical Report (TR)-340 to TR-493 were evaluated. Three compounds (2-butoxyethanol, p-nitroaniline, and para-chloroaniline) were associated with a relatively high incidence of Kupffer cell pigmentation consisting of hemosiderin in both sexes; only the male mice developed a relatively low incidence of treatment-related hemangiosarcoma. With a fourth compound (o-nitroanisole), a relatively low incidence (16/50, high-dose males) of chemical-related hemosiderosis was noted, with no associated increase of hemangiosarcoma. Two chemicals (pentachlorophenol and tetrafluoroethylene) increased the incidence of liver hemangiosarcoma in male and female mice, with no increase in Kupffer cell pigmentation. The overall association between liver hemangiosarcoma and Kupffer cell pigmentation was highly significant (p < 0.001). The cause for hemosiderosis in all cases was the erythrocytic hemolytic effect of the compounds. The reason for the sex-increased susceptibility for development of hemangiosarcoma is unknown but may be due to a hormone-related, reduced antioxidative defensive capacity through modulation of the activities of antioxidative enzymes.
ArmitageP. (1971). Statistical Methods in Medical Research. Wiley, New York.
2.
BehlC., SkutellaT., Lezoualc'hF., PostA., WidmannM., NewtonC. J., and HolsboerF. (1997). Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol51, 535–41.
3.
BlackJ. (1981). Mineral metabolism. In Biological Performance of Materials: Fundamentals of Biocompatibility. Biomedical Engineering and Instrumentation (vol. 8, PlonseyR., and KatzJ. L., eds.), pp. 158–68. Marcel Dekker, New York.
4.
BoelsterliU. A. (2003). Immune mechanisms. In Mechanistic Toxicology (BoelsterliU. A., ed.), pp. 212–36. Taylor & Francis, London and New York.
5.
BusJ. S., and PoppJ. A. (1987). Perspectives on the mechanism of action of the splenic toxicity of aniline and structurally-related compounds. Food Chem Toxicol25, 619–26.
6.
ComportiM., SignoriniC., BuonocoreG., and CiccoliL. (2002). Iron release, oxidative stress and erythrocyte ageing. Free Radi Biol Med32, 568–76.
7.
Da CostaL., WilligT. N., FixlerJ., MohandasN., and TcherniaG. (2001). Diamond-Blackfan anemia. Curr Opin Pediatr13, 10–15.
8.
ElliottB. M., and AshbyJ. (1997). Review of the genotoxicity of 2-butoxyethanol. Mutat Res387, 89–96.
9.
ErnstH., CarltonW. W., CourtneyC., RinkeM., GreavesP., IsaacsK. R., KrinkeG., KonishiG., MesfinG. M., and SanduskyG. (2001). Soft tissue and skeletal muscle. In The Mouse, International Classification of Rodent Tumors (MohrU., ed., pp. 365–6. Springer, Berlin.
10.
FracanzaniA. L., ConteD., FraquelliM., TaioliE., MattioliM., LoscoA., and FargionS. (2001). Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology33, 647–51.
11.
GhanayemB. I., and SullivanC. A. (1993). Assessment of the haemolytic activity of 2-butoxyethanol and its major metabolite, butoxyacetic acid, in various mammals including humans. Hum Exp Toxicol12, 305–11.
12.
GoodmanD. G., WardJ. M., and ReichardtW. D. (1984). Splenic fibrosis and sarcomas in F344 rats fed diets containing aniline hydrochloride, p-chloroaniline, azobenzene, o-toluidine hydrochloride, 4,4′-sulfonyldianiline, or D & C red No. 9. J Natl Cancer Inst73, 265–73.
13.
HaddowA. (1960). On the carcinogenicity of an iron-dextran complex. J Natl Cancer Inst24, 109–47.
14.
HannH. W., StahlhutM. W., and BlumbergB. S. (1988). Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice. Cancer Res48, 4168–70.
15.
HasemanJ. K., HaileyJ. R., and MorrisR. W. (1998). Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: a National Toxicology Program update. Toxicol Pathol26, 428–41.
16.
JanovA. J., LeongT., NathanD. G., and GuinanE. C. (1996). Diamond-Blackfan anemia. Natural history and sequelae of treatment. Medicine (Baltimore)75, 77–8.
17.
KakhlonO., and CabantchikZ. I. (2002). The labile iron pool: characterization, measurement, and participation in cellular processes. Free Rad Biol Med33, 1037–46.
18.
KohenR., and NyskaA. (2002). Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol31, 620–50.
19.
KwittkenJ., and TartowL. R. (1966). Haemochromatosis and Kupffer-cell sarcoma with unusual localisation of iron. J Pathol Bacteriol92, 571–3.
20.
LeN. T., and RichardsonD. R. (2002). The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim Biophys Acta1603, 31–46.
21.
LealA. M., Begona Ruiz-LarreaM., MartinezR., and LacortM. (1998). Cytoprotective actions of estrogens against tert-butyl hydroperoxide-induced toxicity in hepatocytes. Biochem Pharmacol56, 1463–9.
22.
LiptonJ. M., FedermanN., KhabbazeY., SchwartzC. L., HilliardL. M., ClarkJ. I., and VlachosA. (2001). Diamond-Blackfan Anemia Registry osteogenic sarcoma associated with Diamond-Blackfan anemia: a report from the Diamond-Blackfan Anemia Registry. J Pediatr Hematol Oncol23, 39–44.
23.
MannaS. K., and AggarwalB. B. (1999). Lipopolysaccharide inhibits TNF-induced apoptosis: role of nuclear factor-κB activation and reactive oxygen intermediates. J Immunol162, 1510–8.
24.
National Cancer Institute (1978). NCI Bioassay of nitrofen for possible carcinogenicity. (CAS No. 1836-75-5) in Osborne-Mendel Rats and B6C3F1 Mice (Feed Studies. NCI Tech Rep Ser No. 26.
25.
National Toxicology Program (1989A). NTP Toxicology and Carcinogenesis Studies of Two Pentachlorophenol Technical-Grade Mixtures (CAS No. 87-86-5) in B6C3F1 Mice (Feed Studies). Natl Toxicol Program Tech Rep Ser349, 1–265.
26.
National Toxicology Program (1989B). NTP Toxicology and Carcinogenesis Studies of Para-Chloroaniline Hydrochloride (CAS No. 20265-96-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Natl Toxicol Program Tech Rep Ser351, 1–256.
27.
National Toxicology Program (1992A). Toxicology and Carcinogenesis Studies of C.I. Pigment Red 3 (CAS No. 2425-85-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). Natl Toxicol Program Tech Rep Ser407, 1–289.
28.
National Toxicology Program (1992B). NTP Technical Report on the Toxicology and Carcinogenesis Studies of 2,4-Diaminophenol Dihydrochloride (CAS NO. 137-09-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Natl Toxicol Program Tech Rep Ser401, 1–232.
29.
National Toxicology Program (1993A). Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-9) in F344 Rats and B6C3F1 Mice(Gavage Studies). Natl Toxicol Program Tech Rep Ser402, 1–286.
30.
National Toxicology Program (1993B). NTP Toxicology and Carcinogenesis Studies of O-Nitroanisole (CAS No. 91-23-6) in F344 Rats and B6C3F1 Mice (Feed Studies). Natl Toxicol Program Tech Rep Ser416, 1–482.
31.
National Toxicology Program (1993C). NTP Toxicology and Carcinogenesis Studies of Pentachloroanisole (CAS No. 1825-21-4) in F344 Rats and B6C3F1 Mice (Feed Studies). Natl Toxicol Program Tech Rep Ser414, 1–284.
32.
National Toxicology Program (1993D). NTP Toxicology and Carcinogenesis Studies of P-Nitroaniline (CAS No. 100-01-6) in B6C3F1 Mice (Gavage Studies). Natl Toxicol Program Tech Rep Ser418, 1–203.
33.
National Toxicology Program (1997). NTP Toxicology and Carcinogenesis Studies of Tetrafluoroethylene (CAS No. 116-14-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies). Natl Toxicol Program Tech Rep Ser450, 1–321.
34.
National Toxicology Program (2000). NTP Toxicology and Carcinogenesis Studies 2- Butoxyethanol (CAS NO. 111-76-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Natl Toxicol Program Tech Rep Ser484, 1–290.
35.
ParkJ., KamendulisL. M., and KlaunigJ. E. (2002). The effect of 2-butoxyethanol on morphological transformation in Syrian hamster embryo (SHE) cells. Toxicol Sci68, 43–50.
36.
PorrecaE., UcchinoS., Di FebboC., Di BartolomeoN., AngelucciD., NapolitanoA. M., MezzettiA., and CuccurulloF. (1994). Antiproliferative effect of desferrioxamine on vascular smooth muscle cells in vitro and in vivo. Arterioscler Thromb14, 299–304.
37.
RakbaN., LoyerP., GilotD., DelcrosJ. G., GlaiseD., BaretP., PierreJ. L., BrissotP., and LescoatG. (2000). Antiproliferative and apoptotic effects of O-Trensox, a new synthetic iron chelator, on differentiated human hepatoma cell lines. Carcinogenesis21, 943–51.
38.
RichmondH. G. (1959). Induction of sarcoma in the rat by iron-dextran complex. Br Med J1, 947–9.
39.
RoseM. L., GermolecD. R., SchoonhovenR., and ThurmanR. G. (1997). Kupffer cells are causally responsible for the mitogenic effect of peroxisome proliferators. Carcinogenesis18, 1453–6.
40.
RubinE., and FarberJ. L. (1988). The liver. In Pathology, 2nd ed. (RubinE., and FarberJ. L., eds.), pp. 704–85. Lippincott Company, Philadelphia.
41.
SackM. N., RaderD. J., and CannonR. O.III (1994). Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet343, 269–70.
42.
SelbyJ. V., and FriedmanG. D. (1988). Epidemiologic evidence of an association between body iron stores and risk of cancer. Int J Cancer41, 677–82.
43.
ShuangshotiS., and ThaicharoenA. (1994). Hepatocellular adenoma in a beta-thalassemic woman having secondary iron overload. J Med Assoc Thai77, 108–12.
44.
SieskyA. M., KamendulisL. M., and KlaunigJ. E. (2002). Hepatic effects of 2-butoxyethanol in rodents. Toxicol Sci70, 252–60.
45.
StevensR. G., GraubardB. I., MicozziM. S., NeriishiK., and BlumbergB. S. (1994). Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer56, 364–9.
46.
StevensR. G., JonesD. Y., MicozziM. S., and TaylorP. R. (1988). Body iron stores and the risk of cancer. N Engl J Med319, 1047–52.
47.
TamN. N., GhatakS., and HoS. M. (2003). Sex hormone-induced alterations in the activities of antioxidant enzymes and lipid peroxidation status in the prostate of Noble rats. Prostate55, 1–8.
48.
ToyokuniS. (1996). Iron-induced carcinogenesis: the role of redox regulation. Free Rad Biol Med20, 553–66.
49.
ToyokuniS. (2002). Iron and carcinogenesis: from Fenton reaction to target genes. Redox Rept7, 189–97.
50.
ToyokuniS., TanakaT., NishiyamaY., OkamotoK., NakashimaY., HamazakiS., OkadaS., and HiaiH. (1996). Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate. Lab Invest75, 239–48.
51.
WeinbergE. D. (1983). Iron in neoplastic disease. Nutr Cancer4, 223–33.
52.
WeinbergJ. B., and HibbsJ. B.Jr. (1977). Endocytosis of red blood cells or haemoglobin byactivated macrophages inhibits their tumoricidal effect. Nature269, 245–7.
53.
WeinbergerM. A., AlbertR. H., and MontgomeryS. B. (1985). Splenotoxicity associated with splenic sarcomas in rats fed high doses of D & C Red No. 9 or aniline hydrochloride. J Natl Cancer Inst75, 681–90.
54.
WelchK. D., DavisT. Z., Van EdenM. E., and AustS. D. (2002). Deleterious iron-mediated oxidation of biomolecules. Free Rad. Biol Med32, 577–83.
55.
ZurloM. G., De StefanoP., Borgna-PignattiC., Di PalmaA., PigaA., MelevendiC., Di GregorioF., BurattiniM. G., and TerzoliS. (1989). Survival and causes of death in thalassaemia major. Lancet2, 27–30.
