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IV.
DERIVATION OF CANCER POTENCY
Basis for Cancer Potency
OSHA (1990) has classified butadiene as a “potential occupational carcinogen”. U.S. EPA (1985) and
IARC (1987) have concluded that the evidence for carcinogenicity of butadiene in animals is sufficient.
These organizations have classified the chemical as Group B2 and 2B respectively in their schemes of
ranking potential human carcinogens.
With respect to quantitative risk assessment, the epidemiological data base is still considered inadequate
for predicting risks of community exposure to butadiene. Thus, the quantitative risk assessment
presented in this document relies on data from animal bioassays rather than epidemiologic studies.
Cancer potencies were calculated using tumor incidence data from NTP (1984), Melnick et al. (1990),
and Hazelton Europe (1981).
Methodology
Cancer potency estimates were made for mice and rats using total significant tumor incidences and
individual site incidences, three measures of dose, and the linearized multistage procedure of low dose
extrapolation. The most sensitive tumor site was the lung alveolar and bronchiolar neoplasms in female
mice (mouse II bioassay data of Melnick et al., 1990). The continuous internal dose was considered to
be the best measure of dose available. When interspecies equivalent units of mg/m 2 surface area were
used, the resulting upper range of human cancer potency based on all rodent assays was 4.4 × 10 -6 to
3.6 × 10 -4 (µg/m 3 ) -1 . The range of upper bound risk is based on the two orders of magnitude difference
between potency figures for the mouse and the rat. This difference has been the subject of much
additional metabolic and kinetic investigation. In addition to a higher metabolic rate for butadiene in the
mouse, limited detoxification and accumulation of the primary reactive genotoxic metabolite (BMO) may
be a significant factor in the increased susceptibility of mice to butadiene-induced carcinogenesis. The
most detailed evaluation of the carcinogenicity of butadiene has been conducted in the mouse.
The staff of the Office of Environmental Health Hazard Assessment concluded that, for use in risk
assessment, the quality of the mouse II bioassay data is superior to that of the rat data. The primary
reasons for this conclusion are: 1) the use of lower, more relevant dose levels in the mouse II study; 2)
the use of five dose levels in the mouse II study, compared to two in the rat study; 3) the presence of
two mouse studies; 4) the fact that the rat study has not been replicated; 5) the consistency in sites of
carcinogenicity between the two mouse studies; 6) the greater detail in the available mouse data which
allows in-depth analysis; and 7) suggestions from limited epidemiological observations that butadiene
exposure may be associated in humans with lymphatic and hematopoietic cancers, effects that were
seen in mice. The analysis above using lung alveolar and bronchiolar neoplasm incidences in female mice
(mouse II bioassay data of Melnick et al., 1990) resulted in a cancer potency of 6.0 (mg/kg-day) -1 , and
a cancer unit risk of 1.7 × 10 -4 (µg/m 3 ) -1 .
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