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Significant treatment-related increases in the combined incidence of liver tumors, hepatocellular
adenomas, and carcinomas occurred in B6C3F 1 mice exposed orally (via drinking water), 7 days/week
for two years, to lower doses (125 and 185 mg/kg/day) of methylene chloride, but were not significant
in the highest (250 mg/kg/day) exposure group (Serota et al., 1986b). Serota et al. (1986a)
considered the increase in liver tumors (combined neoplastic nodule and hepatocellular carcinoma) in
rats to be insignificant because the incidence was within the laboratory’s historical control range.
IV.
DERIVATION OF CANCER POTENCY
Basis for Cancer Potency
Methylene chloride has been observed to induce lung (alveolar and bronchiolar) and liver
(hepatocellular adenoma or carcinoma) tumors in both sexes of B6C3F 1 mice and subcutaneous
sarcomas of the ventral cervical-salivary gland region in male Sprague-Dawley rats, as described above.
CDHS (1989) decided that the tumor incidence data from studies by Dow (1980), NTP (1986) and
Mennear et al. (1988) were suitable for use in developing a quantitative risk assessment.
Methodology
DHS staff used female mouse lung tumor incidence (the most sensitive sex, species and tumor site of the
1986 NTP inhalation bioassay) to calculate the low-dose risk from exposure to MC. DHS staff fitted
several low-dose risk assessment models to the mouse lung tumor data, including the multistage
(GLOBAL82 and GLOBAL86), time-dependent multistage (Weibull 82), probit, logit, Weibull, gamma
multihit, and two-stage models. DHS staff also applied a physiologically based pharmacokinetic model
to estimate the internal dose. This model adjusts the expected exposure concentration and suggests
lower human risks than predicted by an unadjusted or applied dose approach. The application of the
pharmacokinetic approach to risk assessment is based on information developed by the U.S. EPA
(1987) and U.S. Consumer Product Safety Commission (Cohn, 1987). DHS staff recommended that
the range of risks for ambient exposures to methylene chloride be based on the upper 95% confidence
limit predicted from fitting either the multistage (GLOBAL82) model or the time-dependent multistage
(Weibull 82) model to the animal data. The unit risk for a lifetime of continuous exposure to methylene
chloride is 0.3 to 3 × 10 -6 (µg/m 3 ) -1 . The lower estimate (0.3 × 10 -6 (µg/m 3 ) -1 ) incorporates a complete
pharmacokinetic adjustment as calculated by U.S. EPA (1987). DHS staff believe that the complete
pharmacokinetic adjustment retains considerable uncertainty. In contrast, the applied dose value (3 ×
10 -6 (µg/m 3 ) -1 ) does not incorporate any pharmacokinetic information with the likely result of
overestimating the risk. The high-to-low dose adjustment used by the U.S. Consumer Product Safety
Commission (Cohn, 1987) generates a risk of 4 × 10 -6 ppb -1 which incorporates information regarding
saturation of the mixed-function oxidase pathway. After reviewing the full range of values, DHS staff
concluded that the most likely estimate of the risk of methylene chloride exposure is the adjusted value
of 4 × 10 -6 ppb -1 (1.0 × 10 -6 (µg/m 3 ) -1 ).
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