1,3-Butadiene: Biomarkers and application to risk assessment.
1,3-Butadiene (BD) is a known rodent and human carcinogen that is metabolized mainly by P450 2E1 to three epoxides, 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB) and 1,2-epoxy-3,4-butanediol (EB-diol). The individual epoxides vary up to 200-fold in their mutagenic potency, with DEB being the most mutagenic metabolite. It is important to understand the internal formation of the individual epoxides to assign the relative risk for each metabolite and to understand the molecular mechanisms responsible for major species differences in carcinogenicity. We have conducted extensive exposure-biomarker studies on mice, rats and humans. Using low exposures that range from current occupational levels to human exposures from tobacco smoke has provided evidence that mice are very different from humans, with mice forming ∼200 times more DEB than humans at exposures of 0.1-1.5ppm BD. While no gender differences have been noted in mice and rats for globin adducts or N-7 guanine adducts, female rats and mice had 2-3-fold higher Hprt mutations and DNA-DNA cross-links, suggesting a gender difference in DNA repair. Numerous molecular epidemiology studies have evaluated globin adducts and Hprt mutations, SCEs and chromosomal abnormalities. None of the blinded studies have shown evidence of human genotoxicity at current occupational exposures and studies of globin adducts have shown similar or lower formation of adducts in females than males. If one calculates the EB dose-equivalents for the three species, mice clearly differ from rats and humans, being ∼44 and 174 times greater than rats and humans, respectively. These data provide a scientific basis for improved risk assessment of BD.
Swenberg
James A
JA
Department of Environmental Sciences and Engineering, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27559, USA. james_swenberg@unc.edu
Bordeerat
Narisa K
NK
Boysen
Gunnar
G
Carro
Sujey
S
Georgieva
Nadia I
NI
Nakamura
Jun
J
Troutman
John M
JM
Upton
Patricia B
PB
Albertini
Richard J
RJ
Vacek
Pamela M
PM
Walker
Vernon E
VE
Sram
Radim J
RJ
Goggin
Melissa
M
Tretyakova
Natalia
N
D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002070:Butadienes / Q000633:toxicity*; D018736:DNA Adducts; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008297:Male; D051379:Mice; D009154:Mutation; D051381:Rats; D018570:Risk Assessment
D015415:Biomarkers; D002070:Butadienes; D018736:DNA Adducts; D007041:Hypoxanthine Phosphoribosyltransferase; C031763:1,3-butadiene