Examination of low-incidence brain tumor responses in F344 rats following chemical exposures in national toxicology program carcinogenicity studies

Neoplasms in the brain are uncommon in control Fischer 344 (F344) rats; the y occur at a rate of less than 1% in 2-yr toxicity/carcinogenicity studies. Furthermore, only 10 of nearly 500 studies conducted by the National Toxic ology Program (NTP) showed any evidence of chemically related neoplastic ef fects in the brain. Generally, the brain tumor responses were considered eq uivocal, because the characteristics of potential neurocarcinogenic agents (such as statistically significant increased incidences, decreased latency and/or survival, and demonstration of dose-response relationships) were not observed. A thorough examination, including comparisons with a well-establ ished historical database, is often critical in evaluating rare brain tumor s. Chemicals that gave equivocal evidence of brain tumor responses were gen erally associated with carcinogenicity at other sites, and many chemicals w ere mutagenic when incubated with metabolic activating enzymes. Other facto rs that were supportive of the theory that marginal increases in brain tumo r incidence were related to chemical exposure were that (a) some of the tum ors were malignant, (b) no brain neoplasms were observed in concurrent cont rols from some studies, and/or (c) brain tumors were also seen following ex posure to structurally related chemicals. In 2-yr studies in F344 rats (stu dies conducted by the NTP), equivocal evidence of carcinogenicity was obser ved for the following 9 chemicals: isoprene, bromoethane, chloroethane, 3,3 '-dimethylbenzidine dihydrochloride, 3,3'-dimethoxybenzidine dihydrochlorid e, furosemide, C.I. direct blue 15, diphenhydramine hydrochloride, and l-H- benzotriazole. Glycidol was the only chemical evaluated by the NTP with whi ch there was clear evidence of brain tumor induction in F344 rats. Clarific ation of the potential neurocarcinogenic risks of chemicals that produce eq uivocal evidence of a brain tumor response in conventional 2-yr rodent stud ies may be aided by the use of transgenic mouse models that exhibit genetic alterations that reflect those present in human brain tumors as well as by the use of in utero exposures.