A significant treatment-related decrease in the incidence of mononuclear cell leukemia (MCL) was identified in Fischer-344/N rats for 20 chemicals tested in the National Toxicology Program's 2-yr carcinogenicity bioassay. Fourteen of the 20 chemicals caused decreases of MCL in both male and female rats; 6 of the 20 caused a significant decrease only in males and a marginal or no decrease in female rats. Seventeen of the chemicals associated with a decrease in MCL had a free aromatic amine or nitro functional groups that could be metabolized to free amines. With 1 exception, all 14 chemicals causing a decrease in MCL in both sexes produced spleen toxicity in the 13-wk studies. Reduced body weight and decreased survival, related either to toxicity or to an increase in other types of lethal neoplasms, did not contribute to the decreases in MCL observed in chemical exposure groups. Thirteen of the 20 chemicals were positive in Salmonella tests, and 15 were associated with increases in neoplasms at other sites in rats and/or mice, suggesting that different metabolites could be responsible for these varied biological effects.
Armitage P. (1971). Statistical Methods in Medical Research. John Wiley & Sons, New York, pp. 362-365.
2.
Ashby J. and Tennant RW (1991). Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U. S. NTP. Mutation Res. 257: 229-306.
3.
Beard RR and Noe JT (1981). Aromatic nitro and amino compounds. In: Patty's Industrial Hygiene and Toxicology, Vol. 2A, GD Clayton and FE Clayton (eds). John Wiley and Sons, New York, pp. 2413-2490.
4.
Beutler E. (1985). Chemical toxicity of the erythrocyte. In: Toxicology of the Blood and Bone Marrow, RD Irons (ed). Raven Press, New York, pp. 39-49.
5.
Boivin J. (1990). Second cancers and other late side effects of cancer treatment. Cancer65: 770-775.
6.
Bus JS and Popp JA (1987). Perspectives on the mechanism of action of the splenic toxicity of aniline and structurally-related compounds. Food Chem. Toxicol. 25: 619-626.
7.
Collins T. and Levett PN (1987). Radiometric studies on the selective inhibitors in the identification of Mycobacterium spp. J. Med. Microbiol . 30: 175-181.
8.
Dieter MP, Jameson CW, French JE, Gangjee S., Stefanski SA, Chhabra RS, and Chan PC (1989). Development and validation of a cellular, transplant model for leukemia in Fischer rats: A short-term assay for potential anti-leukemia chemicals. Leuk. Res. 13: 841-849.
9.
Dieter MP, Jameson CW, Maronpot RR, Langenbach R., and Braun AG (1990). The chemotherapeutic poteintial of glycol alkyl ethers: Structure-activity studies of nine compounds in a Fischer rat leukemia transplant model. Cancer Chemother. Pharmacol. 26: 173-180.
10.
Facchini V. and Griffiths LA (1981). The involvement of the gastrointestinal microflora in nitro-compound-induced methaemoglobinaemia in rats and its relationship to nitrogroup reduction. Biochem. Pharmacol. 30: 931-935.
11.
Finch CA (1948). Methemoglobinemia and sulfhemoglobinemia. N. Engl. J. Med. 239: 470-478.
12.
Gart JJ, Chu KC, and Tarone RE (1979). Statistical issues in interpretation of chronic bioassay tests for carcinogenicity. J. Natl. Cancer Inst. 62: 957-974.
13.
Goodman DG, Ward JM, and Reichardt WD (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 Inst.73: 265-273.
14.
Haseman JK (1984). Statistical issues in the design, analysis and interpretation of animal carcinogenicity studies. Environ. Health Perspect. 58: 385-391.
15.
Haseman JK, Arnold J., and Eustis SL (1990). Tumor incidences in Fischer rats: NTP historical data. In: Pathology of the Fischer Rat. Reference and Atlas , GA Boorman, SL Eustis, MR Elwell, CA Montgomery Jr, and WF MacKenzie (eds). Academic Press, San Diego, pp. 555-564.
16.
Haseman JK and Johnson FM (1996). Analysis of NTP rodent bioassay data for anticarcinogenic effects. Mutation Res. (in press).
17.
Haworth S., Lawlor T., Mortelmans K., Speck W., and Zeiger E. (1988). Salmonella mutagenicity tests for 250 chemicals . Env. Molec. Mutagen5(suppl.1): 3-142.
18.
Imai K., Yoshimura S., Hashimoto K., and Boorman GA (1991). Pathological endpoints in dietary restricted rodents-F344 rats and B6C3F1 mice. In: Biological Effects of Dietary Restriction , L. Fishbein (ed). Springer-Verlag, Berlin, pp. 73-86.
19.
Kiese M. (1966). The biochemical production of ferrihemoglobinforming derivatives from aromatic amines, and mechanisms of ferrihemoglobin formation . Pharmacol. Rev. 18: 1091-1161.
20.
Losco PE and Ward JM (1984). The early stage of large granular lymphocyte leukemia in the F344 rat. Vet. Pathol. 21: 286-291.
21.
Moloney WC and King VP (1971). Reduction of leukemia incidence following splenectomy in the rat. Cancer Res. 33: 573-574.
22.
Mortelmans K. , Haworth S., Lawlor T., Speck W., Tainer B., and Zeiger E. (1986). Salmonella mutagenicity tests. II. Results from the testing of 270 chemicals . Env. Molec. Mutagen8(suppl.7): 1-119.
23.
National Toxicology Program (1988). NTP Technical Report on the Toxicology and Carcinogenesis of Malonaldehyde, Sodium Salt in F344 Rats and B6C3F1 Mice. NTP Technical Report No. 331, NIH Publication No. 89-2587, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina.
24.
National Toxicology Program ( 1992). NTP Technical Report on the Toxicology and Carcinogenesis of 2,4-Diaminophenol Dihydrochloride in F344 Rats and B6C3F1 Mice. NTP Technical Report No. 401, NIH Publication No. 92-2856, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina .
25.
National Toxicology Program ( 1993). NTP Technical Report on the Toxicity Studies of Ethylene Glycol Ethers in F344/N Rats and B6C3F1 Mice. NTP Toxicity Report No. 26, NIH Publication No. 93-3349, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina.
26.
National Toxicology Program ( 1993). NTP Technical Report on the Toxicology and Carcinogenesis of p-Nitrobenzoic Acid in F344 Rats and B6C3F1 Mice. NTP Technical Report No. 442, NIH Publication No. 93-3358, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina.
27.
National Toxicology Program ( 1993). Compendium of abstracts from long-term cancer studies reported by the National Toxicology Program from 1976 to 1992. Env. Health Persp. 101(suppl.1): 1-295.
28.
National Toxicology Program ( 1994). Toxicology Data Management System Historical Control Tumor Incidence Report. Analytical Sciences, Research Triangle Park, North Carolina.
29.
National Toxicology Program ( 1994). NTP Technical Report on the Comparative Toxicology Studies of Corn Oil, Safflower Oil and Tricaprylin in Male F344 Rats. NTP Technical Report No. 426, NIH Publication No. 94-3157, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina .
30.
Rao GN and Haseman JK (1993). Influence of corn oil and diet on body weight, survival, and tumor incidences in F344/N rats. Nutr. Cancer19(1): 21-30.
31.
Rao GN, Piegorsch WW, and Haseman JK (1987). Influence of body weight on the incidence of spontaneous tumors in rats and mice in long-term studies. Am. J. Clin. Nutr. 45: 252-260.
32.
Rosenthal SM and Bauer H. (1941). Trypanocidal action of 3-nitrobenzoic acid and some derivatives. Proc. Soc. Exp. Biol. Med. 47: 335-337.
33.
Smith RP (1986). Toxic responses of the blood. In: Cassarett and Doull's Toxicology. The Basic Science of Poisons , 3rd ed., CD Klaassen , MO Amdur, and J Doull (eds). Macmillan, New York, pp. 223-244.
34.
Stromberg PC (1985). Large granular lymphocyte leukemia in F344 rats. Model for human T lymphoma, malignant histiocytosis, and T-cell chronic lymphocyteic leukemia. Am. J. Pathol. 119: 517-519.
35.
Stromberg PC , Vogtsberger LM, McMurray DN, Marsh LR, Kotur MS, and Brown CA (1985). Behavior of transplanted large granular lymphocyte leukemia in F344 rats. Lab. Invest . 53: 200-208.
36.
Thurman JD, Bucci TJ, Hart RW, and Turturro A. (1994). Survival, body weight, and spontaneous neoplasms in ad libitum-fed and food-restricted F344 rats. Toxicol. Pathol. 22(1): 1-9.
37.
Ward JM and Reynolds CW (1983). Large granular lymphocyte leukemia. A heterogeneous lymphocytic leukemia in F344/N rats. Am. J. Pathol. 111: 1-10.
38.
Weinberger MA, Albert RH, and Montgomery SB (1985). Splenotoxicity associated with splenic sarcomas in rats fed high doses of D&C Red No. 9 or aniline hydrochloride. J. Natl. Cancer Inst.75: 681-687.
39.
Zeiger E. (1990). Mutagenicity of 42 chemicals in Salmonella. Env. Molec. Mutagen16(suppl18): 32-54.
40.
Zeiger E., Anderson B., Haworth S., Lawlor T., and Mortelmans K. (1988). Salmonella mutagenicity tests. IV. Results from the testing of 300 chemicals. Env. Molec. Mutagen11(suppl12): 1-58.
41.
Zeiger E., Anderson B., Haworth S., Lawlor T., Mortelmans K., and Speck W. (1987). Salmonella mutagenicity tests. III. Results from the testing of 225 chemicals. Env. Molec. Mutagen9(suppl9): 1-109.
