Biomarkers of exposure to 1,3-butadiene as a basis for cancer risk assessment.
1,3-Butadiene (BD) is carcinogenic in mice and rats, with mice being considerably more sensitive than rats. Urine metabolites are 1, 2-dihydroxybutyl mercapturic acid (DHBMA) and a mixture of monohydroxy-3-butenyl mercapturic acids (MHBMA). The reactive metabolite 1,2-epoxy-3-butene forms 1- and 2-hydroxy-3-butenyl valine adducts in hemoglobin (MHBVal). The objectives of the study were (1) to compare the suitability of MHBMA, DHBMA, and MHBVal as biomarkers for low levels of exposure to BD, and (2) to explore relative pathways of metabolism of BD in humans for comparison with mice and rats, which is important in relation to cancer risk assessment in man. Analytical methods of measuring MHBMA, DHBMA, and MHBVal were modified and applied in 2 studies to workers engaged in the manufacture and use of BD. Airborne BD concentrations were assessed by personal air monitoring. MHBMA in urine was more sensitive for monitoring recent exposures to BD when compared to DHBMA and could measure 8-h time weighted average exposures as low as 0.13 ppm. Relatively high natural background levels in urine restricted the sensitivity of DHBMA. The origin of this background is currently unknown. The measurement of MHBVal adducts in hemoglobin was a sensitive method for monitoring cumulative exposures to BD at or above 0.35 ppm. Statistically significant relationships were found between urinary MHBMA and DHBMA concentrations, between either of these variables and 8-h airborne BD levels and between MHBVal adducts and average airborne BD levels over 60 days. The data on biomarkers demonstrated a much higher rate of hydrolytic metabolism of 1,2-epoxy-3-butene in humans compared to mice and rats, which was reflected in a much higher DHBMA/(DHBMA + MHBMA) ratio and in much lower levels of MHBVal in humans. Assuming a genotoxic mechanism, the data of this study, coupled with other published data on DNA and hemoglobin binding in mice and rats, suggest that the cancer risk for man from exposure to BD is expected to be less than for the rat and much less than for the mouse.
van Sittert
N J
NJ
Department of Molecular Toxicology, Shell International Chemicals BV, SRTCA, PO Box 38000, 1030 BN Amsterdam, The Netherlands.
Megens
H J
HJ
Watson
W P
WP
Boogaard
P J
PJ
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000652:urine; D000395:Air Pollutants, Occupational / Q000032:analysis; D000818:Animals; D015415:Biomarkers / Q000652:urine; D002070:Butadienes / Q000378:metabolism* / Q000652:urine; D002273:Carcinogens / Q000378:metabolism*; D004784:Environmental Monitoring; D008401:Gas Chromatography-Mass Spectrometry; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016273:Occupational Exposure; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity; D014633:Valine / Q000378:metabolism
C076892:1,2-dihydroxy-4-(N-acetylcysteinyl)butane; D000395:Air Pollutants, Occupational; D015415:Biomarkers; D002070:Butadienes; D002273:Carcinogens; D006454:Hemoglobins; C088614:1-hydroxy-2-(N-acetylcysteinyl)-3-butene; D014633:Valine; C031763:1,3-butadiene; D000111:Acetylcysteine