A 90-DAY CHLOROFORM INHALATION STUDY IN FEMALE AND MALE B6C3F(1) MICE- IMPLICATIONS FOR CANCER RISK ASSESSMENT

High doses of chloroform induced liver cancer in male and female B6C3F (1) mice when administered by gavage, kidney cancer in male Osborne-Me ndel rats when given by gavage or in the drinking water, and kidney ca ncer in male BDF1 mice when administered by inhalation. The weight of evidence indicates that chloroform is acting through a nongenotoxic-cy totoxic mode of action. The present study was designed to investigate the dose-response relationships for chloroform-induced lesions and reg enerative cell proliferation in B6C3F(1) mice as the basis for formula tion of a biologically based risk assessment for inhaled chloroform. D ifferent groups of female and male B6C3F(1) mice were exposed to atmos pheric concentrations of 0, 0.3, 2, 10, 30, and 90 ppm chloroform 6 hr /day, 7 days/week for exposure periods of 4 days or 3, 6, or 13 consec utive weeks. Some additional exposure groups were exposed for 5 days/w eek for 13 weeks or were exposed for 6 weeks and then examined at 13 w eeks. Bromodeoxyuridine was administered via osmotic pumps implanted 3 .5 days prior to necropsy, and the labeling index (LI, percentage of n uclei in S-phase) was evaluated immunohistochemically from histologica l sections. Complete necropsy and microscopic evaluation revealed trea tment-induced dose- and time-dependent lesions only in the livers and nasal passages of the female and male mice and in the kidneys of the m ale mice. Large, sustained increases in the liver LI were seen in the 90-ppm groups at all time points. The female mice were most sensitive, with a no-observed-adverse-effect level (NOAEL) for induced hepatic c ell proliferation of 10 ppm. The hepatic LI in the 5 days/week groups were about half of those seen in the 7 days/week groups and had return ed to the normal baseline in the 6-week recovery groups. Induced renal histologic changes and regenerative cell proliferation were seen in t he male mice at 30 and 90 ppm with 7 days/week exposures and also at 1 0 ppm with the 5 days/week regimen. Nasal lesions were transient and c onfined to mice exposed to 10, 30, or 90 ppm for 4 days. In a previous cancer bioassay, a gavage dose of 477 mg/kg/day produced a 95% liver tumor incidence in female B6C3F(1) mice. This gavage dose is equivalen t to a daily 6 hr/day inhalation exposure of approximately 80 ppm, bas ed on the observed induced increases in the LI as an internal dosimete r. The United States Environmental Protection Agency currently uses th e linearized multistage model applied to the mouse liver tumor data fr om the chloroform gavage study to estimate a virtually safe dose (VSD) as a one in a million increased lifetime risk of cancer. The resultin g value is an airborne exposure concentration of 0.000008 ppm. Assumin g that chloroform-induced female mouse liver cancer is secondary to ev ents associated with necrosis and regenerative cell proliferation, the n no increases in liver cancer in female mice would be predicted at th e NOAEL of 10 ppm or below based on the results reported here. Applyin g an uncertainty factor of 1000 yields an estimate of a VSD at 0.01 pp m. This estimate relies on inhalation data and is more consistent with the mode of action of chloroform. (C) 1996 Society of Toxicology