Squamous cell carcinomas of the forestomach have been observed in many carcinogenicity studies in rodents, especially after oral or gavage exposure. The histopathological diagnosis of forestomach lesions and the relevance of the data for human risk estimation can be controversial. The pathological classification may be troublesome because of the low-grade malignancy and the pseudoepitheliomatous hyperplasia that may develop after ulceration and inflammation. For human risk estimation it is important to understand the mechanism of action; this is illustrated by examples using butylated hydroxyanisole, methyl bromide, and epichlorohydrin. Another feature that complicates risk estimation is the absence of a homologue for the forestomach in man. The potential risk from non-genotoxic forestomach carcinogens in man involves exposure of the mouth, pharynx, and esophagus at dose levels that exert irritating action. It is assumed that exposure to non-genotoxic chemicals at concentrations far below those having irritating potential is not hazardous to humans.
References
1.
1. Altmann H-J, Wester PW, Mattiaschk G, Grunow W, and Van Der Heijden CA (1985). Induction of early lesions in the forestomach of rats by 3-tertbutyl-4-hydroxyanisole (BHA).Fd. Chem. Tox.23: 723.
2.
2. Altmann H-J, Grunow W, Mohr U, Richter-Reichhelm HB, and Wester PW (1986). Effects of BHA and related phenols on the forestomach of rats.Fd. Chem. Tox.24: 1183–1188.
3.
3. Boorman GA, Hong HL, Jameson CW, Yoshitomi K, and Maronpot RR (1986). Regression of methyl bromide-induced forestomach lesions in the rat.Toxicol. Appl. Pharmacol.86: 131–139.
4.
4. Clayson DB, Iverson F, Nera E, Lok E, Rogers C, and Rodrigues C (1986). Histopathological and autoradiographical studies on the forestomach of F344 rats treated with butylated hydroxyanisole and related chemicals.Fd. Chem. Tox.24: 1171–1182.
5.
5. Danse LHJC, Van Velsen FL, and Van Der Heijden CA (1984). Methyl bromide: Carcinogenic effects in the rat forestomach.Toxicol. Appl. Pharmacol.72: 262–271.
6.
6. Ghanayem BI, Maronpot RR, and Matthews HB (1986). Association of chemically induced forestomach proliferation and carcinogenesis.Cancer Lett.32: 271–278.
7.
7. Grice HC (ed) (1984). Interpretation and extrapolation of chemical and biological carcinogenicity data to establish human safety standards. In: Current Issues in Toxicology.Springer Verlag, New York.
8.
8. Grice HC (1986). Food antioxidants: International perspectives.Fd. Chem. Tox.24: 997–1255.
9.
9. Hirose M, Inoue T, Asamoto M, Tagawa Y, and Ito N (1986). Comparison of the effects of 13 phenolic compounds in induction of proliferative lesions in the forestomach and increase in the labelling indices of the glandular stomach and urinary bladder epithelium of Syrian golden hamster.Carcinogenesis7: 1285–1289.
10.
10. International Agency for Research on Cancer (1982). Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Chemicals, Industrial Processes and Industries Associated with Cancer in Humans, Suppl. 4. Lyon, France, pp. 122–124.
11.
11. International Agency for Research on Cancer (1986a). Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Some Naturally Occurring and Synthetic Food Components, Furocoumarins and Ultraviolet Radiation, Vol. 40. Lyon, France, pp. 123–159.
12.
12. International Agency for Research on Cancer (1986b). Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Some Halogenated Hydrocarbons and Pesticide Exposures, Vol. 41. Lyon, France, pp. 187–212.
13.
13. Ito N, Fukushima S, Hagiwara A, Shibata M, and Ogiso T (1983). Carcinogenicity of butylated hydroxyanisole in F344 rats.J. Natl. Cancer Inst.70: 343–352.
14.
14. Ito N, Hirose M, Fukushima S, Tsuda H, Tatematsu M, and Asamoto M (1986). Modifying effects of antioxidants on chemical carcinogenesis.Toxicol. Pathol.14: 315–323.
15.
15. Konishi T, Kawabata A, Denda A, Ikeda T, Katada H, Maruyama H, and Higashiguchi H (1980). Forestomach tumors induced by orally administered epichlorohydrin in male Wistar rats.Japan. J. Cancer Res.71: 922.
16.
16. Kroes R and Wester PW (1986). Forestomach carcinogens: Possible mechanisms of action.Fd. Chem. Tox.24: 1083–1089.
17.
17. Laskin S, Sellahumar AR, Kushner M, Nelson N, La Medola S, Rush GM, Katz GV, Dulak NC, and Albert RE (1980). Inhalation carcinogenicity of epichlorohydrin in noninbred Sprague-Dawley rats.J. Natl. Cancer Inst.65: 751.
18.
18. Masui T, Hirose M, Imaida K, Fukushima S, Tamano S, and Ito N (1986). Sequential changes of the forestomach of F344 rats, Syrian golden hamsters and B6C3F1 mice treated with butylated hydroxyanisole.Japan. J. Cancer Res.77: 1083–1090.
19.
19. Nera EA, Lok E, Iverson F, Ormsby E, Karpinski KF, and Clayson DB (1984). Short-term pathological and proliferative effects of butylated hydroxyanisole and other phenolic antioxidants in the forestomach of Fischer 344 rats.Toxicology32: 197–213.
20.
20. Rodrigues R, Lok E, Nera E, Iverson F, Page D, Karpinski KF, and Clayson DB (1986). Short-term effects of various phenols and acids on the Fischer 344 male rat forestomach epithelium.Toxicology38: 103–176.
21.
21. Til HP, Woutersen RA, Feron VJ, and Clary JJ (1987). A 4-week oral toxicity study with acetaldehyde and formaldehyde in rats.Pharm. Weekbl. Sci. Ed.9: 43.
22.
22. Toledo JD (1965). Die Cytogenese des Vormagencarcinoms der Ratte durch N-methyl-N-nitrosourethan.Beiträge zur path. Anat.131: 63–120.
23.
23. Wester PW, Van Der Heijden CA, Bisschop A, and Van Esch GJ (1985). Carcinogenicity study with epichlorohydrin (CEP) by gavage in rats.Toxicology36: 325–339.
24.
24. Wilbourn J, Haroun L, Heseltine E, Kaldor J, Partenski C, and Vainio H (1986). Response of experimental animals to human carcinogens: An analysis based upon the IARC Monographs programme.Carcinogenesis7: 1853–1863.
25.
25. Williams GM (1986). Epigenetic promoting effects of butylated hydroxyanisole.Fd. Chem. Tox.24: 1163–1166.
26.
26. Zwaveling JH, De Kort WLAM, Meulenbelt J, Hezemans-Boer M, Van Vloten WA, and Sangster B (1987). Exposure of the skin to methyl-bromide: A study of six cases occupationally exposed to high concentrations during fumigation.Hum. Toxicol.6: 491–495.
