A review of the genetic and related effects of 1,3-butadiene in rodents and humans
Introduction
1,3-Butadiene (BD) is a volatile organic compound that is widely used in the production of resins and plastics such as butadiene rubber, styrene rubber, adiponitrile, polychloroprene, nitrile rubber, and styrene butadiene latex [1], [2]. Atmospheric concentrations of BD in styrene-butadiene rubber (SBR) and butadiene monomer (BDM) manufacturing plants can vary considerably depending on job category, location within the plant and time of sampling. The maximum BD exposure levels recorded from personal breathing-zone samples in five SBR manufacturing plants in the United States ranged from 0.07 ppm for process technicians working in the warehouse to 43.2 ppm for maintenance technicians. In four BDM manufacturing plants in the United States, the maximum BD exposure levels recorded ranged from 1.87 for process technicians working in control rooms to 374 ppm for laboratory technicians working in cylinder voiding areas [1]. These peak atmospheric concentrations are approximately three–four orders of magnitude higher than the concentrations reported for ambient air (i.e. urban, <1–10 ppb; suburban, 0.3–1 ppb) [3].
There has been much debate during the past 10 years over whether occupational exposure to BD under normal operating conditions is carcinogenic to humans. Himmelstein et al. [4] extensively reviewed the toxicology and epidemiology of BD. Early epidemiological studies [5], [6], [7], [8], [9], [10], [11] did not provide sufficient evidence that BD exposure in SBR or BDM manufacturing plants is associated with increased incidence of cancer. Evidence from one study [11] suggested that SBR workers in one of two plants had increased risk of leukemia from exposure to BD, but no increased risk was observed for other cancers of the lymphatic or hematopoietic system [12]. In other studies of SBR workers, evidence of an increased risk of leukemia could not clearly be linked with BD exposure alone because workers were also exposed to styrene and other chemicals that could contribute to the induction of leukemia [12].
Results from more recent follow-up studies of SBR workers have been interpreted as showing that increased leukemia mortality among long-term polymer production workers exposed to BD and styrene is associated with increasing estimated cumulative BD exposure, suggesting that BD is a leukemogen in the SBR industry. The risk of increased leukemia mortality associated with increasing estimated cumulative styrene exposure is less clear [13], [14]. These studies provide the strongest evidence that BD is carcinogenic to humans, however, the results from the SBR studies apparently were not confirmed by a retrospective study of BDM workers that showed no clear relationship between leukemia mortality and estimated BD exposure [15]. An increase in non-Hodgkin’s lymphoma (NHL) was seen in the BDM workers but it was not associated with increasing estimated BD exposure. The differences in the results of these two studies demonstrate some of the complications encountered in human risk assessment of BD and underscore the need for careful examination of the data obtained in experimental animals. One source of confusion that needs clarification is the use of the older terms leukemia and NHL as fundamentally different disease entities. More recent hematopathologic concepts suggest that certain diseases in these two categories, notably B-cell lymphocytic neoplasms, are appropriately grouped together as different aspects of the same fundamental disease entities [16]. These concepts are being incorporated into the third edition of the International Classification of Diseases of Oncology [17]. Re-classification of the lymphoid malignancies in SBR and in BDM workers in this light might be appropriate to reassess the relationship between BD exposure and the incidence of B-cell lymphocytic neoplasms.
BD is a well-established rodent carcinogen. It induced tumors at multiple target-sites in both sexes of mice, and to a lesser degree in rats [18], [19], [20], [21], [22]. Chronic (∼2 years) inhalation exposure of both female and male mice to concentrations of BD as low as 20 and 62.5 ppm, respectively, significantly increased incidence of lymphomas as well as adenomas and carcinomas of the lung and liver. Exposures to 200 ppm BD induced excess tumors in the heart, forestomach, Harderian gland, and mammary glands of both sexes [18]. Increased tumor incidence reported for rats, on the other hand, was significant only at the highest BD concentration tested (8000 ppm). Pancreatic exocrine adenomas and carcinomas and interstitial-cell tumors of the testis were induced in male rats while follicular-cell adenomas and carcinomas of the thyroid were induced in females. A statistically significant, positive trend in mammary gland tumors was also seen in the female rats [21].
The large interspecies variations in response to BD and the confounding factors that have been encountered in many of the epidemiological studies make it very difficult to evaluate the risks associated with BD exposure in humans. These complex issues require a better understanding of (1) the metabolic fate of BD in mice and rats compared to humans, and (2) the role that BD and its metabolites play in the mechanism(s) of BD-induced carcinogenicity in each species.
An IARC Working Group met during 17–24 February 1998 to reevaluate BD. This Working Group concluded that the human epidemiological data and data on genetic and related effects did not provide sufficient new evidence to reclassify BD upwards to Group 1 (carcinogenic to humans). BD therefore remains classified as ‘probably carcinogenic to humans’ — Group 2A, based on limited evidence of cancer in exposed humans and sufficient evidence of carcinogenicity to experimental animals [1]. Since then, results from a number of new studies of the metabolism and distribution and of the genetic and related effects (GRE) of BD and its metabolites in different species have been published. Moreover, a number of studies of biomarkers of exposure and effect in workers exposed to BD are soon to be published and others are in progress. In this report an interpretive review of the current, updated database on BD and its oxidative metabolites is presented with emphasis on data that have been published since IARC Monographs, Volume 71 [1].
An overview of the metabolic fate of BD and its metabolites in mice, rats and humans is given and the similarities and differences among these three species are discussed. Attention is given to the major toxification and detoxification pathways described in the published literature that lead to the formation of the reactive intermediates EB, DEB and EBdiol. The rates of metabolism and the concentrations of these epoxide metabolites reported for blood and other tissues are compared across species. The GRE of BD and its oxidative metabolites in mice, rats and humans are also reviewed. The GRE data are organized by species and endpoint and are summarized in genetic activity profiles [23] for qualitative and quantitative comparison. The importance of these data in assessing potential human health risks associated with inhalation exposure to BD and their utility in identifying potential mechanisms of BD carcinogenicity are discussed.
Section snippets
Primary metabolic pathways
BD is oxidized by cytochrome P450 enzymes to the monoepoxide, EB and its diepoxide, DEB [24], [25], [26], [27], [28], [29], [30], [31], [32]. Each of these oxidative metabolites can be further metabolized to 3,4-epoxy-1,2-butanediol (EBdiol) [33], [34], [35]. Since these epoxides can react with macromolecules such as DNA, they have been implicated in the carcinogenic response in mice and rats exposed to BD. There is evidence to suggest that interspecies differences in susceptibility to
Genetic and related effects
The results from short-term tests for the genetic and related effects (GRE) of BD and its three oxidative metabolites, EB, DEB and EBdiol in mice, rats and humans are presented in genetic activity profiles together with their corresponding data listings. The test results for DNA adducts, gene mutation, SCE, MN and CA are grouped by species for comparative purposes. The data presented here were obtained from the EPA/IARC Genetic Activity Profile database and have been supplemented with data
Discussion
BD is a genotoxic rodent carcinogen. It induces tumors at multiple sites in both sexes of mice and, to a lesser degree, in rats. It has been shown to be both mutagenic and clastogenic in numerous rodent studies, especially in mice. The three major oxidative metabolites of BD are electrophilic substances that react with the nucleophilic centers in proteins and DNA. They induce gene and/or chromosomal mutations in rodents in vivo and in vitro as well as in human cells in vitro. Positive results
Acknowledgements
The authors wish to thank Drs. Gregory Erexson, Stefano Landi, Julian Preston, and James Swenberg for their critical review and valuable comments. This document has been reviewed in accordance with US Environmental Protection Agency policy and has been approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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