CARCINOGENICITY ASSESSMENT FOR CHLOROFORM
Cancer Assessment of Chloroform
The cancer inhalation unit risk for chloroform is 2.3 × 10-5 per (μg/m3) (EPA 2001, 2012), and is based on a tumorigenic response (hepatocellular carcinomas) in B6C3F1 mice administered chloroform by gavage (NCI 1976). On the basis of this unit risk, the upper-bound unit risks of 10-4 to 10-7 are 4 × 10-3 to 4 × 10-6 mg/m3, assuming an inhalation rate of 20 m3/day for a 70 kg individual. At the 10-4 risk level, the virtually safe dose (d) is 4 μg/m3.
A 70-year exposure may be converted to a 24-h exposure by the following calculation:
To account for uncertainty in the variability in the stage at which chloroform or its metabolites may act on the cancer process, a multistage factor of 6 is applied (Crump and Howe 1984):
Therefore, based on the potential carcinogenicity of chloroform, an acceptable 24-h exposure would be 17.07 mg/m3 (3.58 ppm). If the exposure is limited to a fraction (f) of a 24-h period, the fractional exposure becomes 1/f × 24 h (NRC 1984), resulting in the following values:
The AEGL-2 values based on acute toxicity were somewhat greater than the values derived based on potential carcinogenicity. However, the data are compelling that the carcinogenic response to chloroform has a threshold, such that repeated exposures are needed that result in tissue necrosis and regeneration.
A virtually safe dose of 0.01 ppm (48.7 μg/m3) was derived by Butterworth et al. (1995) and Wolf and Butterworth (1997) based on a no-observedadverse-effect level of 10 ppm in mice and the assumption that the tumorigenic response was secondary to necrosis and regenerative cell proliferation (a threshold response). Cancer risk based on this approach is 12-fold less than those derived from the 10-4 unit risk number.