Inhalation toxicology and carcinogenicity of 1,3-butadiene in B6C3F1 mice following 65 weeks of exposure.
1,3-Butadiene, a large-production volume chemical used mainly in the manufacture of synthetic rubber, was found to induce multiple-organ carcinogenicity in male and female B6C3F1 mice at exposure concentrations (625 and 1250 ppm) equivalent to and below the OSHA standard of 1000 ppm. Since this study was terminated after 60 weeks of exposure because of reduced survival due to fatal tumors, and because dose-response relationships for 1,3-butadiene-induced neoplastic and nonneoplastic lesions were not clearly established, a second long-term inhalation study of 1,3-butadiene in B6C3F1 mice was conducted at lower exposure concentrations, ranging from 6.25 to 625 ppm. Both the histopathological findings from animals dying through week 65 and the results of evaluations of animals exposed for 40 and 65 weeks are presented in this report. Exposure to 1,3-butadiene caused a regenerative anemia at concentrations of 62.5 ppm and higher. Testicular atrophy was induced at 625 ppm, and ovarian atrophy was observed at 20 ppm and higher. During the first 50 weeks of the study, lymphocytic lymphoma was the major cause of death of mice exposed to 625 ppm 1,3-butadiene. Neoplasms of the heart, forestomach, lung, Harderian gland, mammary gland, ovary, and liver were frequently observed in 1,3-butadiene-exposed mice that died between week 40 and week 65 of the study. Studies in which exposure to 1,3-butadiene was stopped after limited periods were also included to assess the relationship between exposure levels and duration of exposures on the outcome of 1,3-butadiene-induced carcinogenicity. In these studies, lymphocytic lymphomas were induced in male mice exposed to 625 ppm 1,3-butadiene for only 13 weeks. The incidence of lymphocytic lymphoma in male mice exposed to 625 ppm 1,3-butadiene for 26 weeks was two times that in mice exposed to 625 ppm for 13 weeks. However, when the exposure concentration was reduced by half to 312 ppm and the exposure duration extended to 52 weeks, the incidence of lymphocytic lymphoma was reduced by 90%. Thus, the multiple of the exposure concentration times the exposure duration did not predict the incidence of lymphocytic lymphoma in mice. The early mortalities resulting from lymphocytic lymphomas in male mice exposed to 625 ppm 1,3-butadiene limited the expression of tumors at other sites. A clearer dose-response for 1,3-butadiene-induced neoplasia should be apparent from experiments in mice exposed to lower concentrations of this chemical for 2 years.
Melnick
R L
RL
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Huff
J E
JE
Roycroft
J H
JH
Chou
B J
BJ
Miller
R A
RA
D000395:Air Pollutants, Occupational / Q000633:toxicity*; D000818:Animals; D001773:Blood Cells / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002070:Butadienes / Q000008:administration & dosage / Q000633:toxicity*; D002273:Carcinogens; D005260:Female; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced; D009929:Organ Size / Q000187:drug effects; D013997:Time Factors
D000395:Air Pollutants, Occupational; D002070:Butadienes; D002273:Carcinogens; C031763:1,3-butadiene