The influence of diet on the acute toxicity (lethality) and distribution of glutathione as measured by tissue nonprotein sulfhydryl (NPSH) concentration following acrylonitrile (ACN) treatment was studied. The tissue distribution of radiolabeled (14C) acrylonitrile or its radioactive metabolites was also determined. The diets tested were a standard laboratory rat chow; a casein-based, complete diet; and 2 diets high in saturated fat content that were either lipotrope deficient or lipotrope supplemented. The latter 2 diets were associated with decreased weight gain in the absence of ACN and increased lethality after orally administratered ACN. The increase in lethality, while most pronounced in the group fed the lipotrope-deficient, high-fat diet, was also seen in rats fed the purified control diet. The high-fat diets were associated with increases in brain and liver NPSH concentrations (mg NPSH/100 g body weight). Following oral administration of 1–14C-ACN, blood contained the highest specific activity. In terms of fraction of administered dose, liver was found to contain the highest total fraction. In the tissues measured, a majority of radioactivity appeared bound to trichloroacetic acid (TCA) insoluble components. The sequence of tissue activity (nCi 14C per g or ml) was as follows: blood > stomach > liver, duodenum, lung, kidney > brain > adrenal. While diet affected toxicity, it did not modify this general ranking.
References
1.
1. U. S. ENVIRONMENTAL PROTECTION AGENCY (1979). Ambient Water Criteria Document: Acrylonitrile. U. S. EPA. Springfield, VA: National Technical Information Service, (NTIS PB 297–915).
2.
2. Quast, J. F., Schwetz, D. J., Balmer, M. F., Gushow, T. S., Park, C. N., and Mckenna, M. J. (1980). A two-year toxicity and oncogenicity study with acrylonitrile following inhalation exposure of rats. Prepared by the Toxicology Research Laboratory, Health and Environmental Sciences, Dow Chemical, USA, Midland MI, for the Chemical Manufacturers Association, Washington, DC. 1, 1–127.
3.
3. Dudley, H. C., and Neal, P. A. (1942). Toxicology of acrylonitrile (vinyl cyanide). I. A study of the acute toxicity. J. Ind. Hyg. Toxicol.24, 27–36.
4.
4. Szabo, S., Huttner, I., Kovacs, K., Horvath, E., Szabo, D., and Horner, H. C. (1980). Pathogenesis of experimental adrenal hemorrhagic necrosis (“apoplexy”). Ultrastructural, biochemical, neuropharmacologic and blood coagulation studies with acrylonitrile in the rat. Lab. Invest.42, 533–546.
5.
5. Szabo, S., Reynolds, E. S., and Kovacs, K. (1976). Animal model of human disease: Waterhouse- Friderichsen syndrome, animal model: acrylonitrile-induced adrenal apoplexy. Am. J. Pathol.82, 653.
6.
6. Sakurai, H., and Kusumoto, M. (1976). Epidemiological study of health impairment among acrylonitrile workers. Rodo. Kagaku.48, 273–282.
7.
7. Noel, G., Lambotte-VANDEPAER, M., Duverger-Van Bogaert, M., Roberfroid, M., and Mercier, M. (1978). Hepatotoxic effects of acrylonitrile in rats. Arch. Int. Phys. Biochim.86, 951–952.
8.
8. Gut, I., Nerudova, J., Kopecky, J., and Holecek, V. (1975) Acrylonitrile biotransformation in rats, mice, and Chinese hamsters as influenced by the route of administration and by phenobarbital, SKF 525-A, cysteine, dimercaprol, or thiosulfate. Arch. Toxicol.33, 151–161.
9.
9. Ahmed, A. E., and Patel, K. (1981). Acrylonitrile: In vivo metabolism in rats and mice. Drug Metab. Dispos.9, 219–222.
10.
10. Willhite, C. C., and Smith, R. P. (1981). The role of cyanide liberation in the acute toxicity of aliphatic nitriles. Toxicol. Appl. Pharmacol.59, 589–602.
11.
11. Szabo, S., and Selye, H. (1972). Effects of phenobarbital and steroids on the adrenal apoplexy produced by acrylonitrile in rats. Endocrinal Exp.6, 141–146.
12.
12. Szabo, S., Bailey, K. A., Boor, P. J., and Jaeger, R. J. (1977). Acrylonitrile and tissue glutathione: differential effect of acute and chronic interactions. Biochem. Biophys. Res. Comm.79, 32–37.
13.
13. Campbell, T. C., and Hayes, J. R. (1976). The role of aflatoxin metabolism in its toxic lesion. Toxicol. Appl. Pharmacol.35, 199–222.
14.
14. Wattenberg, L. W. (1975). Effects of dietary constituents on the metabolism of chemical carcinogens. Cancer Res.35, 3326–3331.
15.
15. Carroll, K. K. (1975). Experimental evidence of dietary factors and hormone-dependent cancers. Cancer Res.35, 3374–3383.
16.
16. Roebuck, B. D., Yager, J. D., Longnecker, D. S., and Wilpone, S. A. (1981). Promotion by unsaturated fat of azaserine-induced pancreatic carcinogenesis in the rat. Cancer Res.41, 1–30.
17.
17. Rogers, A. E. (1977). Reduction of N-nitrosodiethylamine carcinogenesis in rats by lipotrope or amino acid supplementation of a marginally deficient diet. Cancer Res.37, 194–199.
18.
18. Armstrong, B. K. (1977). The role of diet in human carcinogenesis with special reference to endometrial cancer. In: H. H. Hiat, J. D. Watson, and J. A. Winsten (eds.). Origins of Cancer.Cold Spring Harbor, NY, Cold Spring Harbor Laboratory, pp. 557–566.
19.
19. Silverstone, H., and Tannenbaum, A. (1951). The influence of dietary fat and riboflavin on the formation of spontaneous hepatomas in the mouse. Cancer Res.11, 200–203.
20.
20. Szepsenwol, J. (1971). Intracranial tumors in mice of two different strains maintained on fat enriched diets. Europ. J. Cancer7, 529–532.
21.
21. Rogers, A. E., and Newberne, P. M. (1971). Diet and aflatoxin B1 toxicity in rats. Toxicol. Appl. Pharmacol.20, 113–121.
22.
22. Rogers, A. E., and Newberne, P. M. (1971). Lasiocarpine: factors influencing its toxicity and effects on liver cell division. Toxicol. Appl. Pharmacol.18, 356–366.
23.
23. Rogers, A. E., and Newberne, P. M. (1980). Lipotrope deficiency in experimental carcinogenesis. Nutr. Cancer2, 104–112.
24.
24. Rogers, A. E., Lenhart, G., and Morrison, G. (1980). Influence of dietary lipotrope and lipid content on aflatoxin B1, N-2-fluorepylacetamide, and 1,2-dimethylhydrazine carcinogenesis in rats. Cancer Res.40, 2802–2807.
25.
25. Rogers, A. E., Sanchez, O., Felnsod, F. M., and Newberne, P. M. (1974). Dietary enhancement of nitrosamine carcinogenesis. Cancer Res.34, 96–99.
26.
26. Newberne, P. N., Rogers, A. E., and Wogan, G. N. (1968). Hepatorenal lesions in rats fed a low lipotrope diet and exposed to aflatoxin. J. Nutr.94, 331–343.
27.
27. Conolly, R. B., and Jaeger, R. J. (1977). Acute hepatotoxicity of ethylene and halogenated ethylenes after PCB pretreatment. Env. Health Perspect.21, 131–135.
28.
28. Jaeger, R. J., Conolly, R. B., and Murphy, S. D. (1973). Diurnal variation of hepatic glutathione concentration and its correlation with 1,1-dichloroethylene inhalation toxicity in rats. Res. Comm. Chem. Pathol. Pharmacol.6, (2), 465–471.
29.
29. Poirier, L. A., Grantham, P. H., and Rogers, A. E. (1977). The effects of marginally lipotrope-deficient diet on the hepatic levels of S-adenoxylmethionine and on the urinary metabolites of 2-acetylaminofluorene in rats. Cancer Res.37, 744–748.
30.
30. Jaeger, R. J., Cote, I. L., Silver, E. M., and Szabo, S. Acute toxicity of acrylonitrile as influenced by sex and route of administration. Manuscript in preparation.
31.
31. Cheng, L., and Jaeger, R. J. (1982). Acrylonitrile solubility in human blood: determination of the Ostwald partition coefficient. J. Appl. Toxicol.2(1), 18–20.
32.
32. Andersen, M. E., Gargas, M. L., Jones, R. A., and Jenkins, L. J., Jr. (1980). Determination of the kinetic constants for metabolism of inhaled toxicants in vivo using gas uptake measurements, Toxicol. Appl. Pharmacol.54, 100–116.
33.
33. Jaeger, R. J. (1979). Time-related variation of non-protein sulfhydryl concentrations in rat tissues and human blood. Int. Arch Environ. Health42, 141–148.
34.
34. Farooqui, M. Y. H., and Ahmed, A. E. (1982). Molecular interaction of acrylonitrile and potassium cyanide with rat blood. Chem. Biol. Interact.38, 145–159.
35.
35. Guengerich, F. P., Geiger, L. E., Hogy, L. L., and Wright, P. L. (1981). In vitro metabolism of acrylonitrile to 2-cyanoethylene oxide, reaction with glutathione, and irreversible binding to proteins and nucleic acids. Cancer Res.41, 4925–4933.
36.
36. Kopecky, J., Gut, I., Zachardova Nerudova, J., Holecek, D. V., and Filip, J. (1980). Acrylonitrile metabolism in the rat. Arch. Toxicol.4, (Suppl.) 322–324.
37.
37. Nerudova, J., Kopecky, J., Gut, I., and Holocek, V. (1980). In vitro metabolism of acrylonitrile in rats. Prac. Lek.32, 98–103.
38.
38. Conolly, R. B., and Jaeger, R. J. (1977). Acute hepatotoxicity of ethylene and halogenated ethylenes after PCB pretreatment. Env. Health Perspect.21, 131–135.
39.
39. Langvardt, P. W., Putzig, C. L., Braun, W. H., and Young, J. D. (1980). Identification of the major urinary metabolities of acrylonitrile in the rat. J. Toxicol. Env. Health6, 273–282.
40.
40. Peter, H., and Bolt, H. M. (1981). Irreversible protein binding of acrylonitrile. Xenobiotica11, 51–56.
41.
41. Kato, R. (1974). Sex-related differences in drug metabolism. Drug Metabol. Rev.3, 1–32.
42.
42. Conney, A. H. (1967). Pharmacological implications of microsomal enzyme induction, Pharmacol. Rev.,19(3), 317–365.
43.
43. Quast, J. F., Enriquez, R. M., Wade, C. E., Humiston, C. G., and Schwetz, B. A. (1977). Toxicity of drinking water containing acrylonitrile (AN) in rats: results after 12 months. Dow Chemical U. S. A.
44.
44. Maltoni, C., Ciliberti, A., and DiMAIO, V. (1977). Carcinogenicity bioassays on rats of acrylonitrile administered by inhalation and by ingestion. Med. Lavoro68, 401–411.
