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likelihood of exposure to butadiene, although they may have been exposed to other substances that are,
or may be, linked to some of these cancers. While it is difficult to establish a causal relation with
butadiene exposure, the fact that cancers of the lymphohematopoietic system were reported in mice
suggests that the association deserves close attention in future studies.
Animal Studies
Inhalation of butadiene has been shown to induce tumors in mice and rats at multiple sites. These sites
include the heart, lung, mammary gland, ovaries, forestomach, liver, pancreas, Zymbal gland, thyroid,
testes, and hematopoietic system. Butadiene is only one of two chemicals known to induce cancer of
the heart in laboratory animals.
Mice
The most detailed evaluations of the carcinogenicity of butadiene are the mouse inhalation studies
sponsored by the National Toxicology Program (NTP), mouse I (NTP, 1984), and mouse II (Melnick
et al., 1990). The nominal doses of study I were 0, 652 or 1,250 ppm administered 6 hours/day, 5
days/week for either 60 weeks (males) or 61 weeks (females). Fifty animals per sex/dose were used.
Although the study was designed for 103 weeks, early deaths resulted largely from malignant neoplasms
involving multiple organs (heart, hematopoietic lymphomas, lung, mammary gland, ovaries, forestomach,
and liver). The incidences of total significant tumor bearing animals (i.e., the number of animals bearing
one or more significant tumors) at control, middle, and high doses were 2/50, 43/49, and 40/45 in the
males and 4/48, 31/48, and 45/49 in the females. Tumor incidence data are provided in Table 1.
In study II, lower exposure concentrations of butadiene (i.e., 0, 6.25, 20, 62.5, 200, and 625 ppm)
were used than had been employed in the first study. Interim sacrifices at 40 and 65 weeks of exposure
were also added to the original study design in order to follow progression of lesions. As in the
previous study, hemangiosarcomas of the heart, hematopoietic lymphomas, squamous cell neoplasms of
the forestomach, alveolar-bronchiolar neoplasms, and/or adenocarcinomas of the mammary gland were
frequently observed in mice which died between weeks 40 and 65 of the study. Tumor incidence data
used in the quantitative risk assessment are given in Table 2.
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