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Two reports were published on cancer mortality in a population of rubber workers (Checkoway et al.,
1984; Wilcosky et al., 1984). Information on cause of death was reported earlier by McMichael et al.
(1974). They reported a significantly elevated odds ratio relating carbon tetrachloride with lymphatic
leukemia (OR = 15.3, p < 0.0001) and lymphosarcoma and reticulum cell sarcoma (OR = 4.2, p <
0.05). Attributing these outcomes to carbon tetrachloride alone is inappropriate since different solvents
were used simultaneously in a given process area. A high degree of correlation also existed between
exposure to several other solvents and the incidence of lymphatic leukemia (carbon disulfide, ethyl
acetate, acetone, and hexane) and lymphosarcoma (xylenes, carbon disulfide and hexane). Although
some of these solvents are not recognized carcinogens, these potentially confounding exposures, the
lack of association of carbon tetrachloride exposures with these cancers in other studies, and the small
number of cases (19/6678), preclude any causal inference from this study.
In summary, the epidemiological studies and human case reports are inadequate for use in a quantitative
risk assessment.
Animal Studies
Mice
Edwards (1941) and Edwards and Dalton (1942) administered carbon tetrachloride by gavage to
different strains of male and female mice (Strains A, C, CH3 and Y) two to three times a week for 8 to
23 weeks. To assess the tumor-producing ability of carbon tetrachloride , animals were necropsied 12
to 21 weeks after the last treatment. For those animals exposed to approximately 2100 mg/kg of
carbon tetrachloride the incidence of hepatoma was 88.2 percent (strain CH3). Whether the carbon
tetrachloride-induced hepatomas were malignant was not established histologically in the study. The
animals were dosed on a non-daily schedule for a maximum of 16 weeks and sacrificed starting at 4
months of age. Since tumor expression is a function of both dosage and the latency period, any risk
assessment based on these studies, with their short observational periods, will underestimate the true
carcinogenic risk. In another experiment Edwards and Dalton (1942) administered 1, 2, or 3 doses of
carbon tetrachloride (≈260 to 2100 mg/kg) followed by long-term observation in Strain A mice. The
doses were hepatotoxic, but when the animals were examined 12 months later no tumors were
observed.
Edwards et al. (1942) treated 56 male and 19 female L mice with 0.1 ml of 40% carbon tetrachloride
2 or 3 times/week over 4 months, for a total of 46 treatments. Animals were killed 3 to 3.5 months
after the last treatment. The combined hepatoma incidence of treated male and female mice was 47%
(34/73 vs. 2/152 in the untreated controls) (Table 1).
Eschenbrenner and Miller (1943; 1946) extensively examined carbon tetrachloride-induced tumor
production in Strain A mice. In the first study they administered 30 doses of carbon tetrachloride at
intervals of one to five days (0, ≈160, 315, 625, 1250 and 2500 mg/kg). All animals were examined
for tumors at 150 days following the first dose. Centrilobular liver necrosis was observed at all
exposure levels. They reported that the incidence of hepatomas was increased as the time interval
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