NTP Toxicology and Carcinogenesis Studies of Chrysotile Asbestos (CAS No. 12001-29-5) in F344/N Rats (Feed Studies).
Lifetime toxicology and carcinogenesis studies of short-range (SR) and intermediate-range (IR) fiber length chrysotile asbestos were conducted in groups of 88-250 male and female F344/N rats. Both forms of asbestos were administered at a concentration of 1% in pelleted diet for the lifetime of the rats, starting with the dams of the test animals. Subgroups of 100 male and female IR chrysotile-exposed rats also received 0.47 mg/g IR chrysotile asbestos in water by gavage during lactation (preweaning [PW]). At 9 weeks of age, additional subgroups (125-175) of control and IR chrysotile-exposed rats received 7.5 mg/kg (male) or 15 mg/kg (female) 1,2-dimethylhydrazine dihydrochloride (DMH) by gavage every other week for a total of five doses. When the survival of either the control or test group reached 10%, both groups were killed. Neither type of fiber affected fertility or litter size. The offspring from mothers exposed to SR chrysotile were similar in body weight to the controls at birth but were slightly smaller (13%) at weaning and remained so throughout their lifetimes. Feed consumption and survival were comparable among the SR and IR chrysotile asbestos groups and controls. The DMH-exposed groups showed decreased survival due primarily to the development of lethal neoplasms. The administration of SR chrysotile for the lifetime of exposed male and female rats did not cause any overt toxicity. In addition, no neoplastic or nonneoplastic disease was associated with SR chrysotile exposure. Male and female rats exposed to IR chrysotile asbestos did not show any adverse clinical signs. Benign epithelial neoplasms (adenomatous polyps) were observed in the large intestine of IR chrysotile asbestos male rats (9/250, 3.6%). Although not statistically significant (P=0.08) compared with concurrent controls (0/85), the incidence of these neoplasms was highly significant (P=0.003) when compared with the incidence of epithelial neoplasms (benign and malignant combined) of the large intestine in the pooled male control groups of all the NTP oral asbestos lifetime studies (3/524, 0.6%). The biologic importance of this finding was supported by the observation of lesions of similar morphology in the small intestine or glandular stomach of four additional IR chrysotile male rats and by a low incidence (2/100, 2.0%) of adenomatous polyps in the large intestine of male rats in the IR/PW group. A significant (P<0.05) increase in keratoacanthomas of the skin was observed in male IR (19/250, 7.6%) and IR/PW (8/100, 8.0%) chrysotile-exposed rats compared with the concurrent controls (1/88, 1.1%). The biologic importance of this observation was discounted because the incidence in these groups did not greatly exceed the rate observed in the combined male control groups from all the other NTP oral asbestos studies (19/441, 4.3%). An apparent increase in the incidence of clitoral gland neoplasms in female IR (18/250, 7.2%) and IR/PW (4/100, 4.0%) chrysotile-exposed rats compared with that in the concurrent controls (1/88, 1.1%) was also discounted because of a lack of statistical significance when compared with the pooled female control groups from the other NTP oral asbestos studies (21/441, 4.8%). Rats exposed to DMH and DMH plus IR chrysotile asbestos exhibited neoplasia in those organs known to be targets for DMH (gastrointestinal tract, Zymbal gland, liver, and kidney). There was a significant difference (P<0.05) in the incidence of DMH-induced mixed-cell tumors of the kidney between the DMH alone (13/125, 10%) and DMH plus IR chrysotile asbestos (34/175, 19%) female groups. An increased incidence of thyroid follicular cell tumors was observed in DMH plus IR chrysotile male rats (28/175, 16.0%) compared with the DMH alone group (9/124, 7.3%). The biologic importance of both observations is questionable, since neither organ represents a primary target organ for asbestos and no difference between DMH and DMH plus IR chrysotile was observed for the primary target organs (intestine and mesothelium). An audit of the experimental data was conducteIR chrysotile was observed for the primary target organs (intestine and mesothelium). An audit of the experimental data was conducted for these lifetime carcinogenesis studies of chrysotile asbestos. No data discrepancies were found that influenced the final interpretations. Under the conditions of these lifetime studies, short-range and intermediate-range chrysotile asbestos did not induce overt toxicity and did not affect survival when ingested at a level of 1&percnt; in the diet by male and female F344/N rats. There was no evidence of carcinogenicity in male or female rats exposed to SR chrysotile asbestos or in female rats exposed to IR chrysotile asbestos. There was some evidence of carcinogenicity in male rats exposed to IR chrysotile asbestos as indicated by an increased incidence of adenomatous polyps in the large intestine. The cocarcinogenesis studies of 1,2-dimethylhydrazine dihydrochloride and IR chrysotile asbestos were considered inconclusive for determining whether IR chrysotile asbestos had either a tumor-enhancing or protective effect, although an increased incidence of neoplasms was observed in the kidneys of female rats exposed to DMH plus IR chrysotile as compared with those exposed to DMH alone.