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1,3-Butadiene: a ubiquitous environmental mutagen and its associations with diseases

1,3-Butadiene: a ubiquitous environmental mutagen and its associations with diseases 1,3-Butadiene (BD) is a petrochemical manufactured in high volumes. It is a human carcinogen and can induce lymphohematopoietic cancers, particularly leukemia, in occupationally-exposed workers. BD is an air pollutant with the major environmental sources being automobile exhaust and tobacco smoke. It is one of the major constituents and is considered the most carcinogenic compound in cigarette smoke. The BD concentrations in urban areas usually vary between 0.01 and 3.3 μg/m but can be significantly higher in some microenvironments. For BD exposure of the general population, microenvironments, particularly indoor microenvironments, are the primary determinant and environmental tobacco smoke is the main contributor. BD has high cancer risk and has been ranked the second or the third in the environmental pollutants monitored in most urban areas, with the cancer -5 risks exceeding 10 . Mutagenicity/carcinogenicity of BD is mediated by its genotoxic metabolites but the specific metabolite(s) responsible for the effects in humans have not been determined. BD can be bioactivated to yield three mutagenic epoxide metabolites by cytochrome P450 enzymes, or potentially be biotransformed into a mutagenic chlorohydrin by myeloperoxidase, a peroxidase almost specifically present in neutrophils and monocytes. Several urinary BD biomarkers have been developed, among which N-acetyl-S-(4-hydroxy-2-buten-1-yl)- L-cysteine is the most sensitive and is suitable for biomonitoring BD exposure in the general population. Exposure to BD has been associated with leukemia, cardiovascular disease, and possibly reproductive effects, and may be associated with several cancers, autism, and asthma in children. Collectively, BD is a ubiquitous pollutant that has been associated with a range of adverse health effects and diseases with children being a subpopulation with potentially greater susceptibility. Its adverse effects on human health may have been underestimated and more studies are needed. Keywords: Butadiene, Environmental mutagen and carcinogen, Human exposure, Microenvironments, Urinary biomarkers, Cigarette smoking, Lung and larynx cancers, Adverse health effects, Children’s health Introduction one of volatile organic compounds (VOCs) monitored 1,3-Butadiene (BD), a colorless gas, is an important routinely in the ambient air. petrochemical manufactured in high volumes that is pri- BD was determined to be a human carcinogen by the marily used to produce synthetic rubber and thermo- U.S. Environmental Protection Agency (EPA) in 2002 [1] plastic resins. BD is a ubiquitously environmental and by the International Agency for Research on Cancer pollutant because it is formed as a product of incom- (IARC) in 2008 (Group 1 carcinogen) [2]. BD induces plete combustion of fossil fuels and biomass [1]. It is lymphohematopoietic cancers in occupationally-exposed workers [1, 2]. It is one of 187 hazardous air pollutants (HAPs), also known as air toxics, as defined by EPA [3]. BD was fully reviewed in the official document “Health * Correspondence: xyzhang999@shsmu.edu.cn School of Public Health, Hongqiao International Institute of Medicine, Assessment of 1,3-Butadiene” issued by EPA in 2002 [1] Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China © The Author(s). 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chen and Zhang Genes and Environment (2022) 44:3 Page 2 of 22 and in Volume 97 of the IARC Monographs on the μg/cigarette in the sidestream smoke [18]. Similarly, Evaluation of Carcinogenic Risks to Humans published smoke of other tobacco products also contains BD. Bidi, in 2008 [2]. In the two documents, almost all aspects of an indigenous form of cigarette in South Asian coun- BD were discussed in great detail. In 2012, IARC pub- tries, was reported to produce 63.8 μg BD/bidi in the lished Volume 100F and provided an update on BD mainstream smoke [19]. The BD yields in the main- based on newly available data [4]. In addition, the me- stream smoke of 60 commercial U.S. little cigars vary tabolism, DNA adducts, toxicology, genotoxicity, and the from 46 to 243 μg/cigar [20]. carcinogenic modes of action of BD were also reviewed A source that may be important for certain microenvi- in 2007 and 2010 [5–8]. However, since then many new ronments is smoke released by cooking oils at high studies, in particular, the epidemiological studies con- temperature. It has been known that heating of cooking cerning the associations with several diseases in children, oil releases BD [1]. The BD levels released depend on have been published but have not been reviewed yet. the types of cooking oil and temperature [21, 22]. For Thus, in this review, we will provide an update on major example, the vapor of unrefined Chinese rapeseed oil progress in BD-related studies over the last decade. heated to 275 °C contains ~500 μg/m of BD, which is However, we do not try to include all BD-related litera- 4- and 14-fold higher than that in the vapor generated at ture published during this period. Rather, we will focus 240 and 185 °C, respectively. This BD concentration is on progress in the following aspects: environmental also 9- and 22-fold higher than that in the vapor re- sources, airborne concentrations, human exposure, can- leased from heated soybean oil and peanut oil, respect- cer risks, metabolism, urinary biomarkers, genotoxicity ively [21]. The smoke released during cooking Sichuan, in humans, and associations with diseases. Additionally, Cantonese, and Shanghai cuisine contains BD at 12.87, because BD is one of the major constituents in tobacco 4.53, and 4.20 μg/m , respectively [23]. smoke, we discuss the possible contribution of BD to to- In recent years, many newly-identified sources have bacco smoking-associated diseases, with the focus being been reported, including emissions from oil and natural on cancers of lung and larynx. gas extraction industry [24], pyrolysis of waste plastics [25], pulp and paper industry [26], domestic waste land- The environmental sources of BD fill sites [27], household laser processing machines [28], BD has many environmental sources, including indus- and emissions from operations during electrosurgery trial emissions from production of BD, rubber, and [29–32], and from plants [33] and a soil bacterium spe- resins, automobile exhaust, tobacco smoke, and exhaust cies [34]. Among them, two types of sources are worth from biomass burning and cooking [1]. According to special attention. One of them is the surgical smoke gen- EPA, automobile exhaust and miscellaneous combustion erated during electrosurgery, which contains exceedingly sources contribute 78.8% and 19.6% of the total BD high concentrations of BD (up to 42 mg/m or 19.06 emissions in the environment, respectively. The indus- ppm [29]) and thus may pose great cancer risks for op- trial emissions account for only 1.6% of the total BD erating room personnel [29–32]. The other is the natural amounts in the environment, in spite of the fact that tre- sources; recently it was reported that BD was one of the mendous amounts of BD are produced and used in dominant non-methane hydrocarbons generated by petrochemical and synthetic rubber industries [1]. Pinus massoniana and Schima superba, two tree species Automobile exhaust is the primary source of BD in native to southern China, with the emission rates varying the environment due to the enormous amounts of fuels from 10 to 65 nmol (0.54 to 3.5 μg)/g dry leaves/h [33]. consumed by automobiles [1]. The average emission fac- BD was also reported to be generated by Bacillus artro- tor of vehicles was reported to be 2.1 ± 1.5 mg/km in phaeus LSSC22, a soil bacterium strain, and be able to 1997 [9] and 0.7 ± 0.4 mg/km in 2018 [10]. However, inhibit proliferation and chemotaxis of Ralstonia solana- the emission factors are substantially greater in con- cearum (Rsc) TBBS1, the phytopathogen causing bacter- gested traffic compared with those under highway cruise ial wilt disease in tobacco [34]. These studies are the conditions [11]. The BD emissions reduce when vehicles first reports on the natural sources of BD. use fuels containing ethanol [12] but increase for bio- Because automobile exhaust contributes a majority of diesel [13]. It has been estimated that on-road and non- the BD emissions in the environment, BD is generally road motor vehicles contribute to 51% and 20% of the accepted as a mobile source pollutant or a traffic-related BD emissions in urban counties in the United States, re- pollutant [35, 36]. Nonetheless, several population-based spectively [14]. studies have revealed that environmental tobacco smoke Cigarette smoke contains significant amounts of BD (ETS) is a primary contributor to human BD exposure and can thus be the primary source in indoor air [1]. (see below). In other words, ETS is the main source for The yields of BD in cigarette smoke are 12-92 μg/ the general population in terms of human exposure. The cigarette in the mainstream smoke [15–17] and 205-361 observation is important for epidemiological studies. Chen and Zhang Genes and Environment (2022) 44:3 Page 3 of 22 The airborne concentrations of BD The BD concentrations in microenvironments vary The BD concentrations in the ambient air vary widely widely depending on the proximity to emission sources and are dependent on locations or sites, which can be and their magnitudes. Automobile exhaust and ETS are roughly divided into two categories: industrial/industry- the major sources of BD at non-industrial sites, as a re- related sites and non-industrial sites. Obviously, the lat- sult, the microenvironments with these sources often ter is more important for the general population. show relatively high BD concentrations. Indeed, the Unsurprisingly, the BD concentrations at industrial roadside BD levels are usually higher than the back- and industry-related sites, e.g., sites close to industrial fa- ground levels [14, 35, 36]. Exhaust from biomass burn- cilities, are usually higher in comparison with those at ing is also an important source of BD in the non-industrial sites [35]. For example, a maximal BD environment, consequently, some special microenviron- concentration of 27 ppb (60 μg/m ) was observed in a ments with the source can have elevated BD levels. county downwind of a refinery facility in the Industrial Temples are one of such microenvironments due to in- Heartland of Alberta, Canada’s largest hydrocarbon pro- cense burning; an air BD concentration as high as 10.46 cessing center [37]; an overall arithmetic mean of 120 μg/m inside three temples in Thailand has been re- μg/m was reported for various industries in Italia dur- ported [49]. Important microenvironments concerning ing 1996-2015 [38]. Gallego et al. reported that the BD human exposure include: concentrations in a few Catalan urban areas in Spain 1) Vehicles. In a study to investigate the concentra- near petrochemical facilities ranged from 15 to 33 μg/m tions of VOCs in urban domestic and public microenvi- [39]. A study to measure VOCs at 16 sampling sites in ronments, Kim et al. found that the mean BD the North Industrial Complex of Tarragona, Spain, re- concentration in automobile was 7.9 μg/m , which was ported a BD range from 0.31 to 15.19 μg/m [40]. the highest in all microenvironments examined [50]. The BD concentrations at non-industrial sites vary Even the air surrounding moving vehicles contains rela- greatly. Huy et al. compiled the BD concentrations in dif- tively high concentrations of BD; a mean of 3.0 μg/m ferent countries and regions reported in the literature and a maximum of 6.9 μg/m have been reported [1]. [41]. The average concentrations range from 0.01 to 3.3 2) Rooms with smoking. Cigarette smoke contains sig- μg/m , but the developed countries or regions (e.g., Hong nificant amounts of BD, as a result, the BD concentra- Kong) have lower concentrations (0.01-0.91 μg/m )com- tions in smoke-filled rooms can be high. An experiment, 3 3 pared to the developing countries (0.35-3.3 μg/m )[41]. which was performed in a ventilated 18 m laboratory An EPA official document released in 2012 provided the chamber with 6 cigarettes being smoked, showed that range of the mean BD concentrations in U.S. cities and the BD concentrations were 122, 34, and 3.9 μg/m as suburban areas, and the average background concentra- measured at 20 min, 2 h, and 18 h after smoking had tion, which were 0.1-2 and 0.13 μg/m ,respectively [42]. ended, respectively [51]. Before a smoking ban was im- The BD concentrations in rural areas (0.002-0.125 μg/m ) plemented in Ireland, the average BD concentration in are typically one order of magnitude lower than those in pubs was reported to be 4.15 μg/m [52]. A mean BD urban areas [35, 41]. Furthermore, in urban areas, the BD concentration of 1.7 μg/m in smoking homes, which is concentrations at commercial sites, particularly at sites 3.4 times higher than that in nonsmoking homes, has close to the street level in the urban core, are usually been reported [50]. higher than those at residential sites [35]. A modeling 3) Certain restaurants and kitchens. Recently, Huang study of the BD concentrations in Minnesota, U.S., et al. reported that the dining area in a Chinese hot-pot showed that the concentrations were the highest in the restaurant had a BD concentration of 7.73 μg/m , prob- center of the metro area and decreased with distance from ably due to the use of gas stoves [23]. Kitchens, espe- there [43]. Technological advances have led to significant cially those cooking Chinese cuisine by using high- decreases in the ambient air levels of BD and other VOCs temperature oils, can be a potential microenvironment in developed countries [35, 44–47]. with relatively high BD concentrations due to the BD re- However, in terms of human exposure, the BD concen- lease from heated oils. trations in microenvironments, particularly indoor micro- 4) Operating rooms. Because the surgical smoke environments, where people spend most of time, are more generated during electrosurgery contains extremely important than those in the ambient environment. Import- high concentrations of BD [29], plus most surgeons antly, the BD concentrations in microenvironments are do not use smoke management at all [30, 32]orthe often unrelated to the ambient measurements at nearby mobile smoke evacuation systems cannot effectively monitors [48], which mostly reflect the BD concentrations remove BD in the smoke [29], the operating rooms in near-road environments [36]. A recent report also found performing electrosurgery can be an indoor micro- that there was no association between ambient VOC levels, environment with relatively high BD concentrations. including BD, and personal exposures [44]. Chen and Zhang Genes and Environment (2022) 44:3 Page 4 of 22 Human exposure to BD [61]. In a recent population study, Konkle et al. found Human exposure to BD can be divided into two categor- that, although the ambient air concentrations of 11 ies: occupational and non-occupational. Occupational VOCs in the United States, including BD, decreased exposure usually occurs at industrial sites, and the ex- from 2005 to 2013, all corresponding urinary metabo- posure levels are generally high but are dependent on lites of the VOCs increased over approximately the same the types of industry, activity sectors, and occupational timeframe except for one metabolite [44]. As pointed groups. An investigation on Italian working force indi- out by the authors, the finding indicated that these cated that the exposure levels in most activity sectors or VOCs in the ambient air were not the major source of occupational groups ranged between 10 and 200 μg/m , VOC exposure [44], thus providing indirect support for but the exposure levels in the manufacture of rubber the role of microenvironments in exposure to BD and and plastic products (320-360 μg/m ), and the manufac- other VOCs. ture of coke and refined petroleum products (340-390 For non-occupational exposure to BD, ETS can be a μg/m ) were significantly higher than those in other sec- principal contributor. Measurements of the BD concen- tors [38]. The firm size can influence the exposure levels trations in indoor air before and after the implementa- as well; micro- and small enterprises have greater prob- tion of a smoking ban in Ireland provide direct evidence ability to show higher exposure levels [38]. In a petro- of the contribution of ETS to the BD levels in indoor chemical plant in Iran, the BD exposure level reaches microenvironments. The airborne BD concentration 560.82 ± 811.36 μg/m [53]. However, technical ad- prior to the implementation of the ban, which was 4.15 3 3 vances and changes in the operating practices can μg/m , dropped down by nearly 20-fold to 0.22 μg/m greatly reduce the human exposure. For example, two after the ban was fully implemented [52]. studies published in 2016 and 2017 reported low expos- As mentioned above, BD is generally considered an ure levels in the Swedish petroleum refinery industry, automobile source pollutant or a traffic-related pollu- which varied from 0.3 to 22.4 μg/m , depending on the tant, however, the results from several population stud- occupational groups [54, 55]. Similarly, a study published ies suggest that human exposure to BD is mostly in 2017 reported that the BD exposure level in the vicin- attributed to ETS. In a study to investigate biological ity of a major petrochemical complex in Thailand was as monitoring of exposures to ETS in the general popula- low as 0.04 μg/m [56]. tion, Aquilina et al. observed that urinary concentration Recently, some newly-identified occupations outside of cotinine, a well-known ETS biomarker, showed sig- the common activity sectors are found to have low to nificant correlation with the individual exposure to air- moderate BD exposure levels, which include under- borne BD that was measured with personal exposure ground coal miners (~2.1 μg/m )[57], firefighters (23.6 samplers [62]. The finding suggests that ETS is a signifi- 3 3 μg/m ), police forensic investigators (9.68 μg/m )[58], cant source of exposure to BD for the general popula- and hairdressers [59]. It is noted that exposure of hair- tion. In a study assessing exposure to VOCs among dressers to BD was assessed through the levels of urinary pregnant women in the United States, Boyle et al. found BD biomarkers rather than through measuring the air- that smoking was positively associated with the metabol- borne BD concentrations; the median concentration of a ite levels of BD [63]. The results obtained from a recent BD biomarker among hairdressers, who were all female, study on nearly 6,000 participants indicated that tobacco was found to be more than 5 times higher compared to smoke was a major source of BD exposure in the general women in the general population [59]. U.S. population [64]. These reports are consistent with On the other hand, non-occupational exposure to BD the evaluation for residential exposures of U.S. non- is widespread and microenvironments can be the pri- smokers based on material-balance modeling; the evalu- mary determinant. Because humans usually spend most ation indicated that ETS was the dominant source of en- of time indoors rather than outdoors, human exposure vironmental inhalation intake for BD, which was to BD is mainly dependent on the concentrations in in- estimated to be 16-37 μg/day [65]. Taken together, for door microenvironments. Kim et al. determined personal the general population, it appears that the indoor micro- exposures of 12 urban dwellers to VOCs by direct mea- environments are the dominant factor in human expos- surements via personal monitoring and discovered that ure to BD, and ETS is the primary source of BD in these exposure at home contributed to 51-87% of overall indi- microenvironments. vidual exposure to BD [60]. Similarly, Huy et al. reported A special microenvironment that might lead to rela- that exposure at home dominantly contributed to the tively high exposure to BD is kitchens with the cooking total cancer risk caused by BD (56-86%) [41]. In another practice using high-temperature oils. However, the stud- study, Du et al. estimated that ~70% of the overall can- ies concerning the microenvironment have been ex- cer risks caused by 16 HAPs (including BD) in China tremely scarce. Using the levels of urinary biomarkers as was attributed to exposure to these pollutants at home the metric to assess exposure to VOCs, an investigation Chen and Zhang Genes and Environment (2022) 44:3 Page 5 of 22 on Chinese women who regularly cook at home has pollutants among 10 monitored VOCs [81]. Du et al. failed to provide support for the women to experience compiled the data of 16 HAPs mostly from 2003 to 2013 elevated BD exposure. However, the size of the study is in urban areas of China, and concluded that formalde- quite small and many confounders can have influenced hyde, 1,4-dichlorobenzene, benzene, and BD were the the outcome [66]. major risk contributors, which yielded the highest cancer -5 Interestingly, exposure to BD was found to be risks (all > 10 )[61]. Dhaini et al. investigated the can- dependent on socio-demographic characteristics. The cer risks of air pollutants in Beirut, Lebanon, and discov- populations with a high percentage of ethnic/racial mi- ered that benzene and BD were the major contributors, norities and low income tend to have higher exposure which accounted for 39-43% and 25-29% of the cumula- levels [67]. tive risks, respectively [71]. In Xi’an, China, formalde- hyde, BD, and 1,2-dichloroethane were found to be the The cancer risks of BD top three contributors to the cancer risks [70]. In two BD has high cancer risks. The inhalation unit cancer risk coastal cities in Metro Vancouver, Canada, the top pol- -5 3 determined by EPA is 3 × 10 per μg/m or 0.08 per lutants were determined to be carbon tetrachloride, ben- ppm, in other words, 0.03 μg/m of BD causes a bench- zene, and BD [72]. In Calgary, another Canadian city, -6 mark cancer risk of 1 × 10 [1, 68]. Because the ambient the same three pollutants were also listed as the top con- BD concentrations in most urban areas usually range tributors to the cancer risks [24]. from approximately 0.1 to 1 μg/m , the cancer risk for -5 the general population in cities is around 10 [41]. This The metabolism of BD has been demonstrated by many studies [24, 61, 69–73]. BD is an indirect carcinogen, i.e., it must be biotrans- The concentrations of BD in small cities and rural areas formed into metabolites to exert its mutagenicity/car- are usually lower, as a result, the cancer risks are lower cinogenicity. Actually, non-carcinogenic effects of BD -6 (approximately 10 )[74, 75]. On the other hand, the are also considered to be mediated by its metabolites [1]. cancer risks at industrial sites or in areas with industrial It has long been known that BD can be metabolized to point sources of BD are usually high [76]; the risks at form 3,4-epoxy-1-butene (EB) by cytochrome P450 en- heavily-polluted sites or those caused by occupational zymes (P450s), which can be further biotransformed into -3 exposure can even reach 10 [27, 53, 77]. Due to its 1,2,3,4-diepoxybutane (DEB) by P450s, or into 3-butene- high inhalation unit cancer risk, BD is often a major 1,2-diol (BDD) by epoxide hydrolase (Fig. 1). BDD can contributor to the total cancer risks caused by VOCs in be converted to 3,4-epoxybutane-1,2-diol (EBD) by industrial sites. For example, an investigation on P450s [1, 6], which was recently reported to undergo process-specific emission characteristics of VOCs from further bioactivation to form a bifunctional epoxy alde- petrochemical facilities in the Yangtze River Delta, hyde [82]. DEB can also be converted to EBD by epoxide China, found that the process unit producing BD had hydrolase. The three epoxides, EB, DEB, and EBD, can the largest cancer risk [78]. readily react with nucleosides and DNA to yield DNA Because human exposure to BD is dominantly attributed adducts, and are genotoxic and mutagenic [7, 83–87]. In to ETS, the cancer risks caused by residential exposure are vivo, BDD and EBD are the most abundant metabolites, usually greater than those caused by the ambient air. The and DEB is the metabolite with the lowest concentra- cancer risks caused by residential exposure for U.S. non- tions [6, 7, 88]. -5 -4 smokers have been estimated to be 4.2 × 10 -5.3 × 10 Because of the presence of two epoxy moieties in the by using material-balance modeling [65]. molecule, DEB not only has stronger reactivity in com- BD is one of the environmental pollutants with the parison with EB and EBD [89–91], but also can form highest cancer risks. In almost all studies to investigate DNA cross-links [7, 83, 92–96] and DNA-protein cross- the cancer risks of pollutants, BD has been ranked as links [97]. As a result, clastogenicity of DEB is very high; one of the top pollutants. In 2007, a U.S. study showed among ~100 IARC carcinogens (Group 1, 2A, and 2B), that among 17 pollutants, benzene, formaldehyde, and DEB shows highest level of micronucleus (MN) induc- BD were the top three pollutants with the cancer risks tion in mice [98]. DEB is the most genotoxic and muta- -5 -4 on the order of 10 -10 [79]. In another study, McCar- genic metabolite among the three epoxides with the thy et al. used the EPA national ambient air quality data relative potencies of DEB >> EB > EBD [6, 7]. However, for the period 2003 through 2005 and found that among it should be noted that the relative potencies can be dif- 65 air toxics, concentrations of benzene, carbon tetra- ferent when considering the stereochemistry of the me- chloride, arsenic, BD, and acetaldehyde exceeded the 10 tabolites. A specific EBD stereoisomer, (2R,3S)-EBD, has benchmark level at most sites in the United States [80]. been found to be at least 30-fold more mutagenic than In an investigation conducted in Tianjin, China, ben- the other three EBD stereoisomers [99]. Importantly, the zene, BD, and chloroform were listed as the top three mutagenic potency of (2R,3S)-EBD is 10-to-20-fold Chen and Zhang Genes and Environment (2022) 44:3 Page 6 of 22 Fig. 1 The metabolic pathways of BD. The P450-mediated metabolism is an established pathway and the MPO-mediated one is a proposed pathway. (P450s, cytochrome P450 enzymes; ADH, alcohol dehydrogenase; MPO, myeloperoxidase; GSH, glutathione) greater than EB stereoisomers and is only 5-to-10-fold carcinogenesis of BD in humans [101, 102], because the less than DEB stereoisomers [99]. lymphohematopoietic system, i.e., the bone marrow, is An alternative metabolic pathway has been proposed, the target organ for BD in humans on the basis of the in which BD is converted to 1-chloro-2-hydroxy-3-bu- epidemiological studies [1, 68]. tene (CHB) in the presence of hydrogen peroxide and Although it has been established that the mutagenic chloride anion (> 50 mM) by myeloperoxidase (MPO), a and carcinogenic effects of BD are caused by its geno- peroxidase almost specifically present in neutrophils and toxic metabolites, the specific metabolite(s) responsible monocytes [100–102]. CHB, a chlorohydrin, can be con- for the effects are still in debate. Among the three epox- verted to 1-chloro-2-buten-2-one (CBO) and 1-chloro- ides, DEB is often considered to be the ultimate culprit 3,4-epoxy-2-butanol (CEB) by P450s or alcohol dehydro- responsible for BD mutagenicity/carcinogenicity [95, genase (ADH) [103–105]. CBO, a strong Michael ac- 112, 113] due to its highly genotoxic and mutagenic po- ceptor, rapidly reacts with glutathione (GSH) to yield tency compared to EB and EBD [6, 7, 83, 84]. On the GSH conjugates [103], and can also readily react with other hand, EB and EBD have also been proposed to be nucleosides and DNA to form multiple DNA adducts the predominant cancer-initiating metabolites due to [106–109], among which an adenine adduct, A-2D (Fig. their much higher in vivo concentrations (especially 1), was detected in cells treated with low concentrations EBD) compared to DEB [114], and the role of EBD has of CBO [109]. Importantly, CHB is mutagenic as deter- been implicated through experiments in BDD-dosed mined by the Ames test, and CHB, CBO, and CEB are mice and rats [87]. all genotoxic as assessed by the comet assay with CBO Making the issue more complex, what metabolite(s) being much more potent than CHB, CEB, and also DEB are responsible for BD mutagenicity/carcinogenicity ap- [105, 110]. pears to be species- and BD concentration-dependent The alternative metabolic pathway may exist in the [87]. Specifically, the culprits are considered to be DEB bone marrow and blood, which contains abundant neu- in mice, and EB and/or EBD in rats; or, DEB and EBD trophils. Preliminary data showed that the MPO- are considered responsible for the toxic effects of BD at mediated metabolism of BD could occur in murine neu- low and high BD levels, respectively [87, 114]. For trophils and fresh human blood [111]. Thus, it has been humans, the issue remains to be elucidated but DEB is proposed that this pathway may play a role in thought to contribute little to BD carcinogenicity and Chen and Zhang Genes and Environment (2022) 44:3 Page 7 of 22 EBD may cause the greatest risk [115, 116]. Another DEB, and CHB are N-acetyl-S-(3,4-dihydroxybutyl)-L- study estimates that DEB and EBD contribute 7% and cysteine (DHBMA), N-acetyl-S-(2,3,4-trihydroxybutyl)- 92% to the total genotoxic dose in humans, respectively L-cysteine (THBMA), 1,4-bis(N-acetyl-L-cystein-S-yl)bu- [117]. Consistent with the observation is the finding that tane-2,3-diol (bis-BDMA), and 1,4-bis(N-acetyl-L- treosulfan, a chemotherapeutic agent that is non- cystein-S-yl)-2-butanone (NC1) (Fig. 2), respectively enzymatically converted to DEB as its bioactive form [103, 104, 113, 125, 128, 129]. [118], induces different histological subtypes of lympho- DNA adducts can be released from DNA spontan- hematopoietic neoplasms (acute myeloid leukemia) from eously or via the DNA repair process. The DNA adducts those caused by occupational exposure to BD. Therefore, released are eventually excreted in urine and thus can it has been speculated that monoepoxide metabolites also be used as urinary biomarkers. Although many BD- may play a more important role than DEB in BD car- derived DNA adducts have been identified [7], so far cinogenesis in humans [119]. only two DNA adducts, N7-[1-(hydroxymethyl)-2-pro- pen-1-yl]guanine (EB-GII) and 1,4-bis(gua-7-yl)-2,3- Urinary biomarkers of BD butanediol (bis-N7G-BD), have been used as urinary bio- Urinary BD biomarkers reported in the literature markers [130, 131]. EB, DEB, EBD, and CBO (Fig. 1) are reactive metabolites and can react with proteins (e.g., hemoglobin) and DNA. MHBMA and DHBMA The products formed, i.e., hemoglobin and DNA ad- MHBMA and DHBMA are the classic biomarkers of BD ducts, can be used as biomarkers [120, 121]. Meanwhile, and have been used for almost 30 years [124, 132, 133]. these metabolites can also undergo biotransformation They are the major metabolites of BD in urine with the via the mercapturic acid pathway to yield N-acetyl-L- sum of the amounts constituting 50-90% of the total cysteine (NAC) conjugates, which are excreted in urine amounts of all urinary metabolites in different species and can be used as biomarkers as well. BDD and CHB (mouse, rat, hamster, and monkey) [125]. In humans, need to be converted to other intermediates, presumably DHBMA is the most abundant metabolite in urine and hydroxymethyl vinyl ketone and CBO, respectively, be- is readily detected [113, 132]. MHBMA is more sensitive fore biotransformation via the mercapturic acid pathway. that DHBMA [133–136]. The two biomarkers, especially However, to detect hemoglobin and DNA adducts, DHBMA, have been used in population-based studies blood and tissue samples are usually needed, which [44, 64, 136]. greatly restricts the application of these biomarkers in Due to the difficulty in chromatographic separation of studies involving human subjects due to the difficulty in the two regioisomers, in most studies the sum of the collecting the specimens. By contrast, urine is readily amounts of MHBMA1 and MHBMA2 is used as a single available and has fewer biohazard concerns. Moreover, a biomarker (i.e., MHBMA) [124, 135–138]. In some stud- large proportion of absorbed BD (usually 30-60% as ob- ies, the two regioisomers are separated and the concen- served in mice, rats, and monkeys) is excreted in urine trations of individual regioisomers are reported. The as biotransformed products [122, 123], therefore, the data obtained show that MHBMA2 is the dominant iso- amounts of the biotransformed products in urine are ex- mer in human urine [64, 139]. pected to be larger than those in other biological matri- ces (e.g., blood and tissues). As a result, urinary BD MHBMA3 biomarkers have been widely used, particularly in studies MHBMA3 is a biomarker that is worth special attention. concerning human subjects. Thus, in this section, we The metabolite was first discovered in 1995 through the will only review progress in urinary BD biomarkers. reaction of EB with NAC under reflux; its structure was Through the mercapturic acid pathway, EB is primarily characterized but the configuration (trans-or cis-) was biotransformed into two regioisomers, N-acetyl-S-[1-(hy- not determined. However, this product failed to be de- droxymethyl)-2-propen-1-yl]-L-cysteine (MHBMA1) and tected in urine of rats and mice administered EB [126]. N-acetyl-S-(2-hydroxy-3-buten-1-yl)-L-cysteine It turned out to be an issue of sensitivity of the instru- (MHBMA2) (Fig. 2) (it should be noted that each of the mental method, because in a subsequent study, Richard- two regioisomers consists of two diastereomers), which son et al. successfully detected the metabolite in urine of are collectively called monohydroxybutenyl mercapturic rats and mice administered C-labeled EB. Nonetheless, acid (MHBMA) [2, 124, 125]. In addition, a small frac- MHBMA3 was a trace metabolite with the amounts be- tion of EB can undergo a rearrangement of double bond ing only 0.5% of the administered doses or even less to yield N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine [127]. In 1999, the metabolite was detected in urine of (configurations unspecified, presumably trans-), a trace mice exposed to C-labeled BD but accounted for only product usually called MHBMA3 [126, 127]. The corre- 0.1% of the administered doses, however, it was virtually sponding biotransformation products of BDD, EBD, not present in urine of rats under the same BD exposure Chen and Zhang Genes and Environment (2022) 44:3 Page 8 of 22 Fig. 2 The structures of the urinary BD biomarkers reported in the literature. MHBMA1, N-acetyl-S-[1-(hydroxymethyl)-2-propen-1-yl]-L-cysteine; MHBMA2, N-acetyl-S-(2-hydroxy-3-buten-1-yl)-L-cysteine; trans- and cis-MHBMA3, trans- and cis-N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine; DHBMA, N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine; THBMA, N-acetyl-S-(2,3,4-trihydroxybutyl)-L-cysteine; bis-BDMA; 1,4-bis(N-acetyl-L-cystein-S- yl)butane-2,3-diol; NC1, 1,4-bis(N-acetyl-L-cystein-S-yl)-2-butanone; NAC, N-acetyl-L-cysteine; EB-GII, N7-[1-(hydroxymethyl)-2-propen-1-yl]guanine; bis-N7G-BD, 1,4-bis(gua-7-yl)-2,3-butanediol. MHBMA1 and MHBMA2 are collectively called monohydroxybutenyl mercapturic acid (MHBMA), and trans- and cis-MHBMA3 are similarly called MHBMA3. [128]. It is noted that in the experiment, the amount of low [the mean concentration was 1.80 ± 2.10 ng/mL with MHBMA was at least 120-fold greater than that of the limit of detection (LOD) being 0.70 ng/mL] [139]. The MHBMA3 [128]. finding was confirmed by a recently published study with Probably due to its tiny amounts in urine of rats and 5,897 participants, in which the frequency of detection of mice, no studies concerning MHBMA3 have been pub- MHBMA1 and MHBMA2 in urine samples was only 0.7% lished over the following decade. The next study involving and 9.8%, respectively [64]. This is opposite to the obser- the metabolite was published in 2012, when Alwis et al. vation in animal experiments, in which MHBMA1 and detected MHBMA3 in human urine for the first time MHBMA2 were overwhelmingly dominant metabolites [139]. It is worth noting that the urine samples were col- formed, and MHBMA3 could hardly be detected [128]. lected from the general U.S. population, rather than the Following the report of Alwis et al., more than 10 subpopulation with high exposure (workers occupationally studies on the general population using MHBMA3 as exposed to BD). Furthermore, it is unexpected that the BD biomarker have been published, with most stud- MHBMA3 turned out to be the most abundant metabolite ies being conducted in the U.S. populations [44, 63, 64, in human urine among the three EB-derived metabolites 140–153]. These studies performed in the general U.S. (MHBMA1, MHBMA2, and MHBMA3, which were populations showed similar results to those reported by quantitated separately) with the concentrations being 36 ± Alwis et al. [139]. However, the results obtained in the 34 and 6.40 ± 10 ng/mL for smokers and non-smokers, re- populations in other countries and regions are different. spectively. Surprisingly, MHBMA3 had a very high fre- Chiang et al. reported that the mean MHBMA3 concen- quency of detection (99%). By sharp contrast, MHBMA1 trations in 55 Taiwanese smokers and 55 non-smokers failed to be detected in a vast majority of samples (either were 129.2 ± 99.2 and 52.3 ± 36.8 ng/mL, respectively smokers or non-smokers) and MHBMA2 was detected [140], which were considerably higher than that reported only in urine of smokers but its concentrations were very by Alwis et al., in particular, the concentrations in non- Chen and Zhang Genes and Environment (2022) 44:3 Page 9 of 22 smokers. A recently published study on the general popu- different subpopulations, including those with different lation in Wuhan, China, reported a surprisingly low fre- gender, ethnic/racial group, and age, although the results quency of detection at only 9.4% [152]. Similarly, another are not always consistent. For example, it has been discov- study performed in China even failed to detect MHBMA3 ered that the MHBMA3 levels in female smokers were sig- in 100 urine samples from children aged 6-12 years [153]. nificantly high than those in male smokers [64, 142, 149]. A possible explanation for the surprising observations re- When comparing differences among different ethnic/racial ported in the two studies is that the authors used cis- groups, the MHBMA3 levels in non-Hispanic white MHBMA3 as the reference standard and the LOD in the smokers were observed to be higher than those in non- latter study was somewhat high (3.13 ng/mL) [152, 153], Hispanic black ones [149]. Another study also found that although in the studies of Alwis et al. [139] and other au- the MHBMA3 levels in non-Hispanic white were signifi- thors [44, 63, 64, 140–148, 151], the configuration of the cantly higher than those in non-Hispanic black and His- MHBMA3 standard was not specified. panic [142]. However, the differences failed to be observed MHBMA3 is a sensitive BD biomarker. It can clearly in a recently published study [64]. distinguish non-smokers from smokers. In fact, all The differences among subpopulations with different population-based studies consistently show that there ages were consistently observed by three groups of au- are statistically significant differences in the MHBMA3 thors. Jain reported that there was a statistically signifi- concentrations between smokers and non-smokers [63, cant positive association between the MHBMA3 level 64, 139–142, 149, 151]. Quitting smoking can be and age [149], and specifically, children aged 6-11 years reflected in the change in the MHBMA3 level; in a study old had significantly higher MHBMA3 level compared on over 1,100 adult exclusive daily cigarette smokers, a to non-smoker adults aged ≥ 20 years [150]. De Jesus dramatic reduction in the MHBMA3 level was observed et al. found that after controlling for tobacco use and among those quitted tobacco use entirely [147]. The bio- other cofactors and using participants’ age of 25–34 marker can also indicate exposure to ETS; in an investi- years as the reference, young adults (18-24 years) had gation on exposure of non-smokers to VOCs from significantly lower MHBMA3 levels, but older adults (≥ secondhand smoke, St. Helen et al. observed that the 55 years) had significantly higher levels (all p ≤ 0.0001) MHBMA3 concentrations exhibited the greatest increase [142]. Similar results were also obtained in a recent (2.1-fold) from 0 to 8 h postexposure among 9 VOC bio- study reported by Nieto et al., although in this study, age markers [154]. In addition, MHBMA3 can even discrim- was categorized into somewhat different ranges from the inate between duel cigarette/e-cigarette users and preceding study. In this study, Nieto et al. reported that exclusive cigarette smokers [141]. Furthermore, the bio- the MHBMA3 concentrations in older adults (aged 40- marker can distinguish among light, average, and heavy 59 and ≥ 60 years) were significantly higher compared to smokers. In Wave 1 of the Population Assessment of those in younger adults (aged 20-39 years) [64]. Among Tobacco and Health Study, the biomarker data of more all participants (n = 5,897) and the participants who did than 2,700 U.S. adult daily cigarette smokers were ana- not use tobacco products (n = 5,171), with the exception lyzed and it was observed that the concentrations of bio- of adolescents (aged 12-19 years), all age groups, includ- markers, including MHBMA3, consistently increased ing children (aged 3-5 and 6-11 years), had higher with cigarettes smoked per day (CPD) [141]. In the MHBMA3 levels compared with young adults (aged 20– 2011-2016 U.S. National Health and Nutrition Examin- 39 years) [64], which is consistent with the observation ation Survey, by examining the urinary BD biomarkers, reported by Jain [150]. including MHBMA1, MHBMA2, MHBMA3, and A major issue concerning MHBMA3 is that its config- DHBMA, in 5,897 participants, Nieto et al. observed uration is not specified in all studies except for two re- clear dose-response relationships between the MHBMA3 cent ones [152, 153]. This compound has two or DHBMA concentrations and CPD [64]. Specifically, configurations or two stereoisomers, i.e., trans- and cis- compared to non-smokers, smoking 1-10, 11-20, and > MHBMA3 (Fig. 2), which should be well separated chro- 20 CPD was significantly associated with 475%, 849%, matographically. Unlike MHBMA, which is the mixture and 1,143% higher MHBMA3 levels, respectively (all p < of MHBMA1 and MHBMA2 and is usually used as a 0.0001). However, the corresponding increases for single biomarker in most studies, the researchers in DHBMA were only 32.8%, 44.2%, and 102%, respectively MHBMA3-related studies did not describe that this [64]. In addition, another study showed that the increase compound was a mixture of two stereoisomers. More- in number of days that the tobacco products were used over, the MHBMA3 standards available commercially during the last five days was associated with increased are either trans-or cis-isomer. Therefore, MHBMA3 de- levels of MHBMA3 (p < 0.01) but not DHBMA [149]. tected in human urine should be one of the two stereo- Besides smokers and non-smokers, significant differences isomers rather than the mixture of the two in the MHBMA3 levels have also been observed among stereoisomers. It has not been clear whether the Chen and Zhang Genes and Environment (2022) 44:3 Page 10 of 22 difference in the frequency of detection of MHBMA3 in urine of animals and humans exposed to BD has not between the studies of Qian et al. or Kuang et al. [152, been reported. 153] and those reported by other authors [44, 63, 64, 139–148, 151] is caused by the configuration of the EB-GII biomarker. EB reacts with the guanine residues in DNA at the N7- position to form two products, N7-(2-hydroxy-3-buten- 1-yl) guanine (EB-GI) and EB-GII [157]. The two ad- THBMA ducts have been detected in EB-treated cells in culture, THBMA was tentatively identified first in urine of mice and in tissues of rats and mice exposed to BD [157], and exposed to BD [155] and was confirmed later by using 14 EB-GII has been found in human blood leukocyte DNA animals exposed to C-labeled BD [128]. Interestingly, of smokers but below the LOD [158]. In 2017, the Tre- the metabolite was not detected in urine of rats and 14 tyakova laboratory developed a highly sensitive LC-MS/ mice administered C-labled EB [127]. In 2000, van Sit- MS method and was able to detect EB-GII in urine of tert et al. tried to detect THBMA in human urine but smokers and occupationally-exposed workers [130]. The the attempt was unsuccessful due to interferences from biomarker was successfully used in studies concerning the sample matrix [124]. Until 2011, the Tretyakova la- humans and animals [159–161]. boratory was able to develop an LC-MS/MS method to detect the metabolite in human urine, whose concentra- bis-N7G-BD tions in smokers and non-smokers were reported to be Bis-N7G-BD was first synthesized through the reaction 21.6 and 13.7 ng/mg creatinine with the difference being of DEB with guanosine [92]. The adduct can be detected statistically significant (p < 0.01), respectively. Further- in tissues of rats and mice exposed to BD [95]. Use of more, the THBMA concentrations in urine declined 25- bis-N7G-BD as a urinary biomarker was reported just 50% following smoking cessation [129]. The biomarker before the review is published [131]. In the study, very was also detected in urine of workers occupationally ex- low concentrations of bis-N7G-BD (~570 pg/mg creatin- posed to BD with the mean concentration being 157 ng/ ine) were detected in urine of mice exposed to 590 ppm mg creatinine [113]. A subsequent study on workers in (1,300 mg/m ) BD for two weeks [131]. Czech Republic observed statistically significant differ- ences not only between exposed workers and the con- Suitability of the urinary BD biomarkers for studies on the trol, but also between the male control and the female general population control. The MHBMA concentrations in the male con- Urinary biomarkers are particularly useful in large epi- trol were significantly higher than those in the female demiological studies because urine is much more easily control (57.1 ± 33.5 vs. 24.2 ± 16.6 ng/mL, respectively) available and has lower biohazard risks compared to even though both control groups were exposed to the 3 blood. However, it should be noted that urinary bio- same ambient BD levels (7 ± 5 μg/m )[135]. markers reflect recent exposures and are susceptible to variations [134]. Because several urinary BD biomarkers bis-BDMA have been developed, a comparison of their performance Bis-BDMA was first synthesized in 2014 by the Tretya- can help researchers make a wise selection, especially for kova group and was used as a biomarker [113]. In rat studies on the general population. urine following exposure to 200 ppm (442 mg/m )BD The urinary BD biomarkers reported can be divided for two weeks, the mean bis-BDMA concentration was into two categories: exposure biomarkers and exposure/ 4.8 ± 2.9 μg/mL, which was 16-, 44-, and 31-fold lower effect biomarkers. The former includes all NAC conju- than those of MHBMA, DHBMA, and THBMA, respect- gates and is surrogate biomarkers, because they only re- ively. However, this biomarker was not detected in urine flect the doses of internal exposure to BD or a specific of smokers and workers occupationally exposed to BD metabolite (e.g., DEB). On the other hand, the latter, [113]. In urine of mice exposed to 590 ppm (1,300 mg/ which includes EB-GII and bis-N7G-BD, is mechanistic- m ) BD for two weeks, the bis-BDMA concentration was ally relevant and cancer-related biomarkers, because the 8.09 ± 6.3 μg/mL [131]. formation of DNA adducts is considered to be the initial molecular event in carcinogenesis. NC1 First and foremost, selection of biomarkers is certainly NC1 is the urinary biomarker of CHB, the potential BD dependent on the purpose of research. However, in prac- metabolite formed via the alternative MPO pathway. It tical applications, the selection primarily depends what was first synthesized in 2017 [111, 156] and subse- subjects are used in research. Urine of laboratory ani- quently was detected in urine of CHB-administered rats mals exposed to BD usually contains high concentra- and mice [104]. Whether the biomarker can be detected tions of metabolites, thus all BD biomarkers can virtually Chen and Zhang Genes and Environment (2022) 44:3 Page 11 of 22 be used. Conversely, urine of human subjects in the gen- The Xia group in the School of Public Health of Fudan eral population is expected to contain very low concen- University used the cytokinesis-block micronucleus trations of biomarkers, as a result, selection of (CBMN) assay to examine chromosomal damage in per- biomarkers is quite restricted. Because urinary BD bio- ipheral blood lymphocytes (PBL) of 166 workers in a poly- markers are most useful in biomonitoring of human sub- butadiene latex chemical industrial plant in Ningbo, China jects and for laboratory animals, hemoglobin and DNA [163]. These workers were exposed to extremely high adducts can be freely selected as biomarkers, we will levels of BD with the range varying from 0.05 to 1,985.99 3 3 thus focus on the issue what biomarkers are suitable for mg/m (the median was 4.48 mg/m ). The mean MN fre- studies on the general population. quency of the workers was significantly higher than that Among the urinary BD biomarkers, MHBMA and bis- of the unexposed control (0.339% vs. 0.148%, p <0.01), BDMA can easily be excluded due to either very low fre- and the polymorphisms of several genes involved in bioac- quency of detection [64] or inability to be detected even tivation and detoxification of BD were observed to influ- in urine of occupationally-exposed workers [113]. ence the MN frequency [163]. In another study, the Xia Among other biomarkers, DHBMA, THBMA, and EB- group used sister-chromatid exchange (SCE) and CBMN GII have natural background that may be caused by en- assays to investigate chromosomal damage in PBL of 44 dogenous sources, thus restricting their sensitivity [113, BD-exposed workers in a rubber factory of Shandong, 124, 130, 133]. Specifically, DHBMA fails to reflect the China [164]. These workers were exposed to much lower changes in the external exposure doses in some studies levels of BD (0.06-12.41 mg/m with the median being [137, 162]; in particular, a study found that the DHBMA 1.48 mg/m ) compared with those in Ningbo, China. It levels did not change after cessation of smoking, whereas was found that the mean MN frequency in the workers the levels of MHBMA and the biomarkers of other was significantly higher than that in the control without VOCs rapidly decreased [137]. The difference in the occupational exposure to BD (0.439% vs. 0.296%, p < THBMA concentrations between smokers and non- 0.01), but the SCE frequency did not exhibit statistically smokers is small (the data of smokers is only 58% higher significant difference between the exposed workers and than that of non-smokers), although it is statistically sig- the control. In addition, it was also observed that the poly- nificant (p < 0.01) [129]. EB-GII is even worse; its con- morphisms of three glutathione S-transferase genes af- centrations in urine of smokers had no statistically fected the MN frequency [164]. significant difference from those in non-smokers [130]. The other group of Chinese researchers, the Cao and However, the levels of these biomarkers exhibited sig- Ao group in the Department of Hygiene Toxicology of nificant differences between occupationally exposed the Third Military Medical University, Chongqing, workers and the controls, suggesting that they may be China, conducted a 1:1 matched pair study in a popula- suitable for human subjects with high BD exposure. tion of workers in a large petrochemical facility in Nan- Among these biomarkers, MHBMA3 stands out from jing, China [165–167]. The workers were exposed to the rest. Many studies already demonstrate its excellent significantly higher levels of BD than did the control suitability for biomonitoring exposure of the general (5.02 vs. 1.86 mg/m , p < 0.01), and exhibited elevated populations to ambient BD [44, 63, 64, 140–153]. It is frequency of MN and nucleoplasmic bridge (NPB) (both highly responsive to the exposure dose [64] and is well p < 0.01) but lower nuclear division index (p < 0.01) in capable of reflecting exposure to ETS [154]. Compared comparison to the control [165]. The polymorphisms of with DHBMA, MHBMA3 exhibits stronger correlation some metabolism- and DNA repair-related genes, and a with the serum level of cotinine, the well-known bio- folate metabolism-related gene were observed to affect marker for smoking [139]. In addition, the MHBMA3 the NPB and nuclear bud frequency [165–167]. levels also show significant differences among a variety Additionally, it is noted that a study performed in Italy of subpopulations [64, 142, 149]. Clearly, MHBMA3 is observed a statistically significant increase in the MN the best urinary biomarker for biomonitoring BD expos- frequency of exfoliated buccal cells in petroleum refinery ure in the general population. workers and also residents living in areas close to the petroleum refinery industry [168]. However, the cohort was small (n = 50) and the BD concentrations were not Genotoxicity of BD in humans measured. Genotoxicity of BD in humans, as assessed in many mo- In summary, these studies indicate that BD at levels of lecular epidemiology studies, has been thoroughly occupational exposure is genotoxic to humans and can reviewed in 2010 by Albertini et al. [7]. After that, only cause chromosome damage as assessed by the CBMN five studies, which were performed by two groups of assay. However, a vast majority of studies published be- Chinese researchers, have been published. Therefore, we fore 2010 have failed to observe genotoxicity of BD in will only provide a brief update on the issue. humans [7]. It seems to be an issue of selection of assays Chen and Zhang Genes and Environment (2022) 44:3 Page 12 of 22 and endpoints, because the previous studies examined more than half of 63 participants were black people (n = the mutations of the hypoxanthine-guanine phosphori- 35, 55.6%) [177]. bosyltransferase (HPRT) gene, and induction of chromo- The observation that BD exposure was associated with some aberrations and SCE [7]. Thus, the CBMN assay CVD in black male was echoed by a newly published appears to be the technique of choice to detect genotoxi- study, in which the urinary levels of DHBMA were ob- city of BD in humans. Chromosome damage detected served to exhibit strong associations with the urinary with the assay may be used as an effect biomarker to as- levels of norepinephrine and normetanephrine (two sess cancer risk induced by BD [169]. CVD risk markers) in black participants of a cohort of 346 non-smokers [148]. The result suggested that expos- Associations between BD exposure and diseases ure to BD was associated with endothelial dysfunction Exposure to BD has been associated with a variety of and may contribute to elevated risk of hypertension in diseases. First and foremost, as a human carcinogen, oc- people with increased sympathetic tone, particularly in cupational exposure to BD has been causally associated black individuals [148]. with lymphohematopoietic cancers, especially leukemia Lin et al. recently reported a positive correlation be- [1, 2, 4]. With regard to specific forms of leukemia, the tween the urinary DHBMA levels and the CVD risk fac- epidemiological studies of a cohort of synthetic rubber tors, including carotid intima-media thickness, endothelial industry workers at six North American plants support microparticles, and platelet microparticles [178]. However, an association between BD exposure and lymphoid the study was conducted in young Taiwanese. leukemia, but not myeloid leukemia, non-Hodgkin’s The association between BD exposure and CVD is lymphoma, and multiple myeloma [170–173]. supported by animal experiments [179, 180]. Crotonal- BD exposure has also been associated with diseases dehyde, a minor BD metabolite, might play a role in the other than lymphohematopoietic cancers, including car- etiology [181]. diovascular disease (CVD), reproductive effects, child- hood leukemia, etc. It is worth noting that children may Reproductive effects be one of the subpopulations with greater susceptibility BD has been considered to have reproductive and devel- to the toxic effects of BD than the general population; in opmental effects [182]. However, so far the effects have fact, most epidemiological studies over the last decade been observed dominantly in rodents; these effects include have been conducted on children. Thus, the studies of reduced fetal weight, fetal death, ovarian atrophy, and tes- the adverse effects of BD on children’s health will be dis- ticular atrophy, and the most sensitive endpoints are ovar- cussed in a separate section. ian atrophy in female mice and testicular atrophy in male mice [1, 183]. DEB may be the critical metabolite to in- CVD duce the reproductive effects [1, 182]; Dong et al. reported The association between BD exposure and CVD was first that DEB caused the proliferation inhibition and marked noticed in 1990. Interestingly, the association was ob- cell cycle arrest at the G2 phase but not apoptosis in served only in a specific subpopulation, i.e., black male. mouse spermatocyte-derived GC-2 cells [86]. In a study to investigate the mortality among workers at The studies of the reproductive effects of BD on humans a BD facility, Divine reported a significantly elevated have been extremely scarce. The data from an earlier standardized mortality ratio (SMR) in non-white males study on Czech female workers exposed to BD showed no for all causes of death, including arteriosclerotic heart difference in pregnancy outcomes (e.g., miscarriage, still disease [174]. The data from another study to investigate birth, ectopic pregnancies) between exposed subjects and 12,110 male workers in eight styrene-BD polymer manu- controls. However, the numbers of the subjects and con- facturing plants indicated a significant excess SMR for trols in this study are small (n = 23 and 26, respectively) arteriosclerotic heart disease (SMR = 1.48) in black [184]. In a recently published study conducted in Portland, workers than in the general population [175]. In 1996, Oregon, U.S., Willis and Hystad used vital statistics re- Divine and Hartman reported updated data and similarly cords from 2000 to 2014 (n = 279,051 births) to assess found that, in the cohort of 2,795 male workers at a BD prenatal exposure to 19 air pollutants. They observed as- facility, the non-white workers showed a statistically sig- sociations in fully adjusted models comparing the highest nificant elevated SMR for all causes of death, including to lowest quintiles of exposure for certain pollutants, in- arteriosclerotic heart disease (SMR = 1.42) [176]. In a cluding the associations between BD and term birth cross-sectional study, Shin et al. observed that BD- weight [−16.86 g; 95% confidence interval (CI) = −29.66- related VOCs decreased diastolic blood pressure but in- −4.06; p < 0.05], and between BD and small for gestational creased heart rate and brachial artery diameter, suggest- age [odds ratio (OR) = 1.18; 95% CI = 1.07-1.30; p <0.05] ing that BD and other VOCs may have rapid impacts on [185]. Another recent study indicated that there might be the human cardiovascular system [177]. In this study, a potential association between BD exposure and male Chen and Zhang Genes and Environment (2022) 44:3 Page 13 of 22 infertility. Poli et al. reported that the urinary DHBMA risks could be attributable to mutual confounding, BD levels were negatively correlated with sperm count and was found to be a powerful independent predictor [194]. sperm abnormal forms, and oxidative stress on the male For the first time, BD was identified as a specific hazard reproductive tract may play an important role [186]. for childhood cancers, although in these studies, child- hood leukemia was not singled out [193]. Adverse effects on pulmonary functions The finding was reinforced by subsequent studies. In Occupational exposure to high concentrations of BD an ecologic study in Texas, U.S., Whitworth et al. inves- may have adverse effects on pulmonary functions, in- tigated 977 cases of childhood lymphohematopoietic cluding vital capacity, forced vital capacity, forced ex- cancer diagnosed from 1995-2004. The researchers ex- piratory volume in the first second, and peak expiratory amined whether the census tracts with the highest esti- flow. An investigation on workers in a petrochemical mated levels of benzene and BD had higher incidence plant in Iran found that compared to the control, the rates of childhood lymphohematopoietic cancer com- workers had considerably higher prevalence rates of pared with the census tracts with the lowest estimated cough, phlegm, wheezing, shortness of breath, chest levels. Indeed, among the census tracts with the highest tightness, and episodes of chest illness associated with BD levels, they observed significantly higher rates of all cold. Furthermore, their pulmonary functions were also leukemia [rate ratio (RR) = 1.40; 95% CI = 1.07-1.81], lower in comparison with the control and the differences and elevated rates of the two most common types of were statistically significant (p < 0.05) [187]. However, it childhood leukemia, acute myeloid leukemia (AML) (RR should be noted that the workers were exposed to high = 1.68; 95% CI = 0.84-3.35) and acute lymphocytic BD concentrations (the average concentration reached leukemia (ALL) (RR = 1.32; 95% CI = 0.98-1.77), but the 560.82 μg/m ), although the BD levels are still below the data for AML and ALL were not statistically significant threshold recommended by the American Conference of [195]. The same laboratory further investigated whether Governmental Industrial Hygienists [187]. in utero and early life exposure to BD and other pollut- ants was associated with childhood leukemia, and indeed Associations between BD exposure and diseases in a observed positive associations between exposure to BD specific subpopulation - children and childhood leukemia (under the age of 5) in either Most epidemiological studies over the last decade to in- single or co-pollutant models [196]. In another investiga- vestigate the associations between BD exposure and dis- tion conducted in California, U.S., Heck et al. found that eases were conducted in children. Exposure to BD has in infancy, AML was positively associated with exposure been reported to show associations with several childhood to BD (OR = 2.35; 95% CI = 1.02-5.39), o-xylene (OR = diseases, including childhood leukemia, brain tumors, aut- 1.88; 95% CI = 1.02-3.45), and toluene (OR = 2.02; 95% ism, asthma, etc. The studies are discussed below. CI = 1.03-3.94) [197]. Childhood leukemia Childhood brain tumors Childhood leukemia accounts for approximately 30% of The association between exposure to BD and childhood all childhood cancers in the United States, and a signifi- brain tumors has also been reported. Danysh et al. con- cant increase in the incidence has been observed in Eur- ducted a population-based study in Texas, U.S., and ob- ope and in other developed countries over the past 30 served that the census tracts with medium and medium- years [119]. In the meantime, the etiology of childhood high BD concentrations had higher astrocytoma inci- leukemia remains poorly understood and few established dence rates (RR = 1.46; 95% CI = 1.05-2.01 and RR = risk factors have been identified. Over the last 20 years, 1.69; 95% CI = 1.22-2.33, respectively) compared with there has been increasing focus on environmental pollut- low concentrations. Increased concentrations of BD and ants, especially, the traffic-related pollutants [188–192]. benzene were observed to be strongly associated with in- As a traffic-related air pollutant and a known human creased primitive neuroectodermal tumor (PNET) inci- carcinogen that has causally been associated with dence rates, but the associations were not statistically leukemia, BD has naturally received much attention in significant [198]. In a subsequent study, the group evalu- the investigations for the etiology of childhood leukemia. ated the influence of residential mobility on the expos- The association between childhood cancers, including ure assignment and concluded that residential mobility childhood leukemia, and exposure to a variety of air pol- of children did not significantly impact the exposure as- lutants (CO, NO , VOCs, dioxins, etc.) was first reported signment of BD [199]. In another study in California, by Knox in two successional studies, in which elevated U.S., von Ehrenstein et al. found that central nervous risks of childhood cancers were observed among chil- system PNETs were positively associated with interquar- dren whose residence was near a “hot spot” of benzene tile range (IQR) increases in prenatal exposure to acetal- or BD emissions [193, 194]. Although some increased dehyde (OR = 2.30; 95% CI = 1.44-3.67), BD (OR = 2.23; Chen and Zhang Genes and Environment (2022) 44:3 Page 14 of 22 95% CI = 1.28-3.88), benzene, and toluene; and also with Childhood asthma IQR increases in exposure during the first year of life to In a recently published article, Kuang et al. compared o-dichlorobenzene (OR = 3.27; 95% CI = 1.17-9.14), BD the differences in several biomarker levels between asth- (OR = 3.15; 95% CI = 1.57-6.32), and benzene. The au- matic and healthy children. DHBMA was used as the thors concluded that in utero and infancy exposures to biomarker of BD. The results indicated that the urinary air toxics generated by industrial and road traffic sources levels of DHBMA and biomarkers of other pollutants may increase the risk of PNETs and medulloblastoma, were significantly associated with asthma (for DHBMA, with limited support for increased risks for astrocytoma OR = 2.76; 95% CI = 1.73-4.43). Oxidative stress may in children up to age 6 [200]. play an important role, because these biomarkers exhib- ited strong correlations with 8-hydroxy-2′-deoxyguano- sine levels, which were significantly higher in asthmatic Other childhood tumors children than those in healthy children [204]. Besides childhood leukemia and brain tumors, BD ex- posure has also been found to be potentially associated The role of BD in smoking-associated diseases with other childhood cancers. Heck et al. examined am- Tobacco smoke contains over 6,000 compounds, of bient exposure to 27 air toxics in the perinatal period in which more than 70 compounds have been classified as relation to retinoblastoma development with the disease human carcinogens [205–207]. BD is one of the carcino- diagnosed during 1990-2007 in California, U.S. They ob- gens with the largest amounts in mainstream smoke; its served that retinoblastoma risk increased with pregnancy typical yield is 52 μg/cigarette, which is more than 400- exposure to benzene (OR = 1.67; 95% CI = 1.06-2.64) fold higher than 4-(methylnitrosamino)-1-(3-pyridyl)-1- and other six toxics that primarily arise from gasoline butanone (NNK), a strong tobacco-specific carcinogen and diesel combustion and are highly correlated, includ- [208]. In terms of cancer risk, BD has been ranked as ing BD (OR = 1.59; 95% CI = 1.08-2.35) [201]. Prenatal the most carcinogenic compound in cigarette smoke exposure to air toxics, including BD, was also observed among 40 carcinogens with cancer potency factors being to be positively associated with malignant germ cell tu- available [209]. mors (GCTs) in young children [202]. In a case-control Tobacco smoking has been associated with an array of study, Hall et al. identified 243 GCT cases, which were diseases, including many types of cancers (e.g., lung can- matched by birth year to cancer-free population controls cer, liver cancer, bladder cancer, and leukemia), diabetes (n = 147,100) from 1984 to 2013 in California, U.S. They mellitus, CVD, asthma, etc. [210]. In spite of the ranking observed that prenatal exposure to traffic-related air of BD as the top carcinogen in cigarette smoke, the con- toxics during the second trimester increased GCT risk, tribution of BD in tobacco smoking-associated diseases, particularly BD (OR = 1.51; 95% CI = 1.01-2.26) and m-/ in particular, cancers, has not been elucidated. p-xylene (OR = 1.56; 95% CI = 1.10-2.21). A further ana- BD is listed as a likely but minor causative agent for lysis by subtype indicated elevated ORs for yolk sac tu- cigarette smoke-related lung and larynx cancers, mostly mors but no teratomas [202]. based on its tumorigenesis in mice [205, 208, 211]. How- ever, the latest epidemiological study on more than 20,000 workers employed at eight North American syn- Childhood autism thetic rubber polymer plants from 1943 through 2009, The etiology of autism is heterogeneous and little is which is the largest cohort for occupational exposure to known about its nongenetic causes, but environmental BD, found that there was no causal association between factors have been suggested as major contributors. It has BD exposure and lung cancer [212]. This study and the been reported that in utero BD exposure is associated authors’ earlier investigations indeed observed elevated with childhood autism [203]. In a population study, von rates of lung cancer among female workers, however, Ehrenstein et al. identified 768 cases of autism from the authors thought that it may be caused by other fac- 148,722 children in Los Angeles County, California, U.S., tors rather than exposure to BD due to the lack of a during 1998-2009. They found that autism risks in- positive exposure-response trend [172, 213–215]. The creased per interquartile range increase in average con- observation also obtains support from other independent centrations during pregnancy of several correlated toxics studies, including an investigation on the relationships mostly loading on 1 factor, including BD (OR = 1.59; between several carcinogens in cigarette smoke and lung 95% CI = 1.18-2.15), m-/p-xylene (OR = 1.51; 95% CI = cancer in a Chinese cohort [216], an ecological study at 1.26-1.82), and other pollutants, adjusting for maternal the country level conducted in the United States [217], age, ethnicity/race nativity, education, insurance type, and an investigation on cancer incidence in a petro- parity, child sex, and birth year [203]. chemical industry area in Sweden [218]. Moreover, in a U.S. study to compare the BD metabolism in smokers in Chen and Zhang Genes and Environment (2022) 44:3 Page 15 of 22 three ethnic/racial groups (Native Hawaiians, whites, Discussion and perspective and Japanese Americans), Park et al. found that the The studies of BD over the last decade have brought MHBMA levels in Native Hawaiian smokers were sig- some important developments, among which the adverse nificantly lower compared to those in white smokers, effects on children’s health are probably the most pro- suggesting that Native Hawaiian smokers had lower BD found issue. However, more carefully-designed studies uptake rates or metabolized BD to EB and then are needed to provide further evidence for these MHBMA less efficiently than whites [219]. However, it findings. has been established that for the same lifetime smoking In epidemiological studies, it is a critical issue to deter- exposure, Native Hawaiian smokers have a significantly mine human exposure to BD. Currently, most epidemio- greater risk of lung cancer than do whites [220]. Thus, logical studies estimated human exposure to BD based the finding of Park et al. actually provides indirect sup- on its concentrations in the ambient air. However, the port for the epidemiological observation that BD expos- approach can cause great uncertainties for studies con- ure has no causal association with lung cancer. ducted in the general population. As pointed out by Collectively, the studies suggest that BD is not a human Fujita et al., estimates of population exposure to air pol- lung carcinogen and thus is not expected to contribute lutants extrapolated from ambient measurements at am- to smoking-associated lung cancer. bient fixed site monitors are prone to uncertainty [48]. In spite of the fact that BD is listed as a minor contrib- Multiple studies have indicated that microenvironments, uting agent for larynx cancer [205], in fact, the studies especially those at home, are the main determinant of concerning BD exposure and larynx cancer have been human exposure and the BD concentrations in microen- very scarce. A few studies to investigate the mortality in vironments are often unrelated to those in the ambient workers from the styrene-BD rubber industry and the air. Moreover, several population studies has consistently BD production industry found that certain subgroups of demonstrated that with regard to human exposure to workers had more than expected deaths from larynx BD, ETS is the primary source in the general population. cancer [175, 176, 215]. However, the results were all Therefore, for epidemiological studies on the general based on small numbers and thus were statistically im- population, a reliable estimate of human exposure to BD precise. Moreover, the excess in larynx cancer was not is desirable. Currently, the best approach can be using clearly associated with any process group, suggesting the urinary levels of BD biomarkers (preferably that the increases were not due to BD exposure [215]. It MHBMA3) as the metric for assessing human exposure, should be noted that a positive association has indeed although it should be kept in mind that the urinary bio- been observed between occupational exposures in the markers reflect only recent exposures. rubber-manufacturing industry and larynx cancer [4]. The finding that BD has natural sources from trees However, the observation is unable to relate the develop- and soil bacteria is intriguing. However, so far only two ment of larynx cancer to exposure to specific chemicals tree species and a strain of soil bacterium have been re- because the rubber-manufacturing industry uses a wide ported to release BD. Thus, it is worth further explor- variety of substances. In addition, a review of literature ation whether other species of plants and bacteria can on the contribution of various types of occupational ex- also generate BD. If the quantities generated by plants posure to rare cancers does not list BD as a possible are large enough, it may have an impact on human ex- contributor to larynx cancer [221]. posure to BD and it is also likely that BD can play a role Because cigarette smoke is a known risk factor for in atmosphere chemistry. urothelial carcinoma, a recent case-control study investi- Because BD must undergo bioactivation to exert its gated the relationships among smoking, urinary levels of toxic effects, including mutagenicity/carcinogenicity, ob- several VOC biomarkers, and urothelial carcinoma risk. viously identifying the specific BD metabolite(s) that However, no association between the levels of dominantly contribute to the toxic effects, particularly in MHBMA3 or DHBMA and the risk of urothelial carcin- humans, is at the core of the underlying molecular oma has been discovered [144]. mechanisms of BD toxicity. However, so far the issue Taken together, it appears that BD may not contribute has not been addressed, largely because the metabolism to pathogenesis of cigarette smoking-associated cancers of BD is quite complex and more than 10 potential me- of lung and larynx. Because BD has been associated with tabolites, most of which are genotoxic, can be formed [1, leukemia and some types of childhood tumors, and non- 101, 102]. Making matters worse, each of the major me- carcinogenic effects such as CVD and asthma, it is likely tabolites, e.g., EB, DEB, EBD, and CHB, contains stereo- that BD is involved in these diseases caused by smoking. isomers due to the presence of chiral carbon atoms in However, to our knowledge, so far no studies to investi- these molecules, and importantly, the stereoisomers can gate the associations have been published. have different bioactivity (e.g., cytotoxicity and mutage- nicity) [6, 7, 94, 99]. In addition, the metabolism of BD Chen and Zhang Genes and Environment (2022) 44:3 Page 16 of 22 has great species difference [1, 6, 7], leading to extra dif- bis(N-acetyl-L-cystein-S-yl)butane-2,3-diol; bis-N7G-BD: 1,4-bis(gua-7-yl)-2,3- butanediol; CBMN: cytokinesis-block micronucleus; CBO: 1-chloro-2-buten-2- ficulty for studies on humans. Nonetheless, addressing one; CEB: 1-chloro-3,4-epoxy-2-butanol; CHB: 1-chloro-2-hydroxy-3-butene; the issue should be a major research direction for future CI: confidence interval; CPD: cigarettes smoked per day; CVD: cardiovascular studies. disease; DEB: 1,2,3,4-diepoxybutane; DHBMA: N-acetyl-S-(3,4-dihydroxybutyl)- L-cysteine; EB: 3,4-epoxy-1-butene; EB-GI: N7-(2-hydroxy-3-buten-1-yl)guanine; Currently, it is generally assumed that mutagenicity/ EB-GII: N7-[1-(hydroxymethyl)-2-propen-1-yl]guanine; EBD: 3,4-epoxybutane- carcinogenicity of BD is caused by the epoxide metabo- 1,2-diol; EPA: the U.S. Environmental Protection Agency; ETS: environmental lites formed via the P450-mediated metabolism. Interest- tobacco smoke; GCTs: germ cell tumors; GSH: glutathione; HAPs: hazardous air pollutants; HMVK: hydroxymethyl vinyl ketone; HPRT: hypoxanthine- ingly, all epidemiological studies that have been guanine phosphoribosyltransferase; IARC: the International Agency for published so far have not discovered any associations be- Research on Cancer; IQR: interquartile range; LOD: limit of detection; tween BD exposure and cancers of lung, liver, and kid- MHBMA: monohydroxybutenyl mercapturic acid; MHBMA1: N-acetyl-S-[1- (hydroxymethyl)-2-propen-1-yl]-L-cysteine; MHBMA2: N-acetyl-S-(2-hydroxy-3- ney, the major organs that are responsible for uptake buten-1-yl)-L-cysteine; MHBMA3: N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L- and biotransformation of BD. Counterintuitively, the tar- cysteine; MN: micronucleus; MPO: myeloperoxidase; NAC: N-acetyl-L-cysteine; get organ for BD carcinogenicity in humans is the lym- NC1:: 1,4-bis(N-acetyl-L-cystein-S-yl)-2-butanone; NNK: 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone; NPB: nucleoplasmic bridge; OR: odds ratio; phohematopoietic system, an organ that seems not to be P450s: cytochrome P450 enzymes; PBL: peripheral blood lymphocytes; involved in the formation of P450-mediated epoxides. PNET: primitive neuroectodermal tumor; RR: rate ratio; SCE: sister-chromatid Why BD is not carcinogenic in the major human organs exchange; SMR: standardized mortality ratio; TBW: term birth weight; THBMA: N-acetyl-S-(2,3,4-trihydroxybutyl)-L-cysteine; VOCs: volatile organic for uptake and metabolism is an intriguing issue. While compounds extrahepatic toxicity is a likely explanation, the MPO- mediated metabolic pathway seems to provide an at- Acknowledgements We thank Professor Yang Luan for inviting us to submit a manuscript for the tractive alternate because the pathway is expected to special collection in the Genes and Environment journal. occur exactly in the lymphohematopoietic system. Ad- dressing the issue is an important research direction be- Authors’ contributions cause it concerns the molecular mechanisms of BD Both authors wrote the paper. Each author read and approved the final manuscript. mutagenicity/carcinogenicity and can have significant impact on the risk assessment of BD. Funding Although having been studied for 40 years, our under- Research related to this review was supported by the National Nature standing of the molecular mechanisms of BD toxicity Science Foundation of China (Nos. 21077070, 21377080, and 21976120) and the Shanghai Municipal Education Commission (No. 11ZZ90). has still been limited. Besides the associations with dis- eases that have been discovered, it is likely that BD con- Availability of data and materials tributes to other adverse effects on human health or the Not applicable. etiology of other diseases, in particular, as a factor to Declarations promote disease progression rather than as a disease- initiating factor. Considering that BD is a ubiquitous Ethics approval and consent to participate pollutant, the direction deserves more attention. Not applicable. Consent for publication Conclusions Not applicable. BD is a ubiquitous environmental mutagen/carcinogen with high cancer risk. Its major environmental sources Competing interests The authors declare that they have no competing interests. include automobile exhaust and tobacco smoke. The studies over the last decade have shown that microenvi- Received: 6 August 2021 Accepted: 27 December 2021 ronments, particularly indoor microenvironments, are the primary determinant of exposure of the general References population to BD, with tobacco smoke being the main 1. U.S. EPA. Health assessment of 1,3-butadiene. National Center for source. While it has been known for more than 20 years Environmental Assessment, Washington, DC, 2002. EPA/600/P-98/001F. that occupational exposure to BD is associated with Available at http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=54499 (accessed August 6, 2021). leukemia and CVD, recent progress shows that non- 2. IARC. 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1,3-Butadiene: a ubiquitous environmental mutagen and its associations with diseases

Genes and Environment , Volume 44 (1) – Jan 10, 2022

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Abstract

1,3-Butadiene (BD) is a petrochemical manufactured in high volumes. It is a human carcinogen and can induce lymphohematopoietic cancers, particularly leukemia, in occupationally-exposed workers. BD is an air pollutant with the major environmental sources being automobile exhaust and tobacco smoke. It is one of the major constituents and is considered the most carcinogenic compound in cigarette smoke. The BD concentrations in urban areas usually vary between 0.01 and 3.3 μg/m but can be significantly higher in some microenvironments. For BD exposure of the general population, microenvironments, particularly indoor microenvironments, are the primary determinant and environmental tobacco smoke is the main contributor. BD has high cancer risk and has been ranked the second or the third in the environmental pollutants monitored in most urban areas, with the cancer -5 risks exceeding 10 . Mutagenicity/carcinogenicity of BD is mediated by its genotoxic metabolites but the specific metabolite(s) responsible for the effects in humans have not been determined. BD can be bioactivated to yield three mutagenic epoxide metabolites by cytochrome P450 enzymes, or potentially be biotransformed into a mutagenic chlorohydrin by myeloperoxidase, a peroxidase almost specifically present in neutrophils and monocytes. Several urinary BD biomarkers have been developed, among which N-acetyl-S-(4-hydroxy-2-buten-1-yl)- L-cysteine is the most sensitive and is suitable for biomonitoring BD exposure in the general population. Exposure to BD has been associated with leukemia, cardiovascular disease, and possibly reproductive effects, and may be associated with several cancers, autism, and asthma in children. Collectively, BD is a ubiquitous pollutant that has been associated with a range of adverse health effects and diseases with children being a subpopulation with potentially greater susceptibility. Its adverse effects on human health may have been underestimated and more studies are needed. Keywords: Butadiene, Environmental mutagen and carcinogen, Human exposure, Microenvironments, Urinary biomarkers, Cigarette smoking, Lung and larynx cancers, Adverse health effects, Children’s health Introduction one of volatile organic compounds (VOCs) monitored 1,3-Butadiene (BD), a colorless gas, is an important routinely in the ambient air. petrochemical manufactured in high volumes that is pri- BD was determined to be a human carcinogen by the marily used to produce synthetic rubber and thermo- U.S. Environmental Protection Agency (EPA) in 2002 [1] plastic resins. BD is a ubiquitously environmental and by the International Agency for Research on Cancer pollutant because it is formed as a product of incom- (IARC) in 2008 (Group 1 carcinogen) [2]. BD induces plete combustion of fossil fuels and biomass [1]. It is lymphohematopoietic cancers in occupationally-exposed workers [1, 2]. It is one of 187 hazardous air pollutants (HAPs), also known as air toxics, as defined by EPA [3]. BD was fully reviewed in the official document “Health * Correspondence: xyzhang999@shsmu.edu.cn School of Public Health, Hongqiao International Institute of Medicine, Assessment of 1,3-Butadiene” issued by EPA in 2002 [1] Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China © The Author(s). 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chen and Zhang Genes and Environment (2022) 44:3 Page 2 of 22 and in Volume 97 of the IARC Monographs on the μg/cigarette in the sidestream smoke [18]. Similarly, Evaluation of Carcinogenic Risks to Humans published smoke of other tobacco products also contains BD. Bidi, in 2008 [2]. In the two documents, almost all aspects of an indigenous form of cigarette in South Asian coun- BD were discussed in great detail. In 2012, IARC pub- tries, was reported to produce 63.8 μg BD/bidi in the lished Volume 100F and provided an update on BD mainstream smoke [19]. The BD yields in the main- based on newly available data [4]. In addition, the me- stream smoke of 60 commercial U.S. little cigars vary tabolism, DNA adducts, toxicology, genotoxicity, and the from 46 to 243 μg/cigar [20]. carcinogenic modes of action of BD were also reviewed A source that may be important for certain microenvi- in 2007 and 2010 [5–8]. However, since then many new ronments is smoke released by cooking oils at high studies, in particular, the epidemiological studies con- temperature. It has been known that heating of cooking cerning the associations with several diseases in children, oil releases BD [1]. The BD levels released depend on have been published but have not been reviewed yet. the types of cooking oil and temperature [21, 22]. For Thus, in this review, we will provide an update on major example, the vapor of unrefined Chinese rapeseed oil progress in BD-related studies over the last decade. heated to 275 °C contains ~500 μg/m of BD, which is However, we do not try to include all BD-related litera- 4- and 14-fold higher than that in the vapor generated at ture published during this period. Rather, we will focus 240 and 185 °C, respectively. This BD concentration is on progress in the following aspects: environmental also 9- and 22-fold higher than that in the vapor re- sources, airborne concentrations, human exposure, can- leased from heated soybean oil and peanut oil, respect- cer risks, metabolism, urinary biomarkers, genotoxicity ively [21]. The smoke released during cooking Sichuan, in humans, and associations with diseases. Additionally, Cantonese, and Shanghai cuisine contains BD at 12.87, because BD is one of the major constituents in tobacco 4.53, and 4.20 μg/m , respectively [23]. smoke, we discuss the possible contribution of BD to to- In recent years, many newly-identified sources have bacco smoking-associated diseases, with the focus being been reported, including emissions from oil and natural on cancers of lung and larynx. gas extraction industry [24], pyrolysis of waste plastics [25], pulp and paper industry [26], domestic waste land- The environmental sources of BD fill sites [27], household laser processing machines [28], BD has many environmental sources, including indus- and emissions from operations during electrosurgery trial emissions from production of BD, rubber, and [29–32], and from plants [33] and a soil bacterium spe- resins, automobile exhaust, tobacco smoke, and exhaust cies [34]. Among them, two types of sources are worth from biomass burning and cooking [1]. According to special attention. One of them is the surgical smoke gen- EPA, automobile exhaust and miscellaneous combustion erated during electrosurgery, which contains exceedingly sources contribute 78.8% and 19.6% of the total BD high concentrations of BD (up to 42 mg/m or 19.06 emissions in the environment, respectively. The indus- ppm [29]) and thus may pose great cancer risks for op- trial emissions account for only 1.6% of the total BD erating room personnel [29–32]. The other is the natural amounts in the environment, in spite of the fact that tre- sources; recently it was reported that BD was one of the mendous amounts of BD are produced and used in dominant non-methane hydrocarbons generated by petrochemical and synthetic rubber industries [1]. Pinus massoniana and Schima superba, two tree species Automobile exhaust is the primary source of BD in native to southern China, with the emission rates varying the environment due to the enormous amounts of fuels from 10 to 65 nmol (0.54 to 3.5 μg)/g dry leaves/h [33]. consumed by automobiles [1]. The average emission fac- BD was also reported to be generated by Bacillus artro- tor of vehicles was reported to be 2.1 ± 1.5 mg/km in phaeus LSSC22, a soil bacterium strain, and be able to 1997 [9] and 0.7 ± 0.4 mg/km in 2018 [10]. However, inhibit proliferation and chemotaxis of Ralstonia solana- the emission factors are substantially greater in con- cearum (Rsc) TBBS1, the phytopathogen causing bacter- gested traffic compared with those under highway cruise ial wilt disease in tobacco [34]. These studies are the conditions [11]. The BD emissions reduce when vehicles first reports on the natural sources of BD. use fuels containing ethanol [12] but increase for bio- Because automobile exhaust contributes a majority of diesel [13]. It has been estimated that on-road and non- the BD emissions in the environment, BD is generally road motor vehicles contribute to 51% and 20% of the accepted as a mobile source pollutant or a traffic-related BD emissions in urban counties in the United States, re- pollutant [35, 36]. Nonetheless, several population-based spectively [14]. studies have revealed that environmental tobacco smoke Cigarette smoke contains significant amounts of BD (ETS) is a primary contributor to human BD exposure and can thus be the primary source in indoor air [1]. (see below). In other words, ETS is the main source for The yields of BD in cigarette smoke are 12-92 μg/ the general population in terms of human exposure. The cigarette in the mainstream smoke [15–17] and 205-361 observation is important for epidemiological studies. Chen and Zhang Genes and Environment (2022) 44:3 Page 3 of 22 The airborne concentrations of BD The BD concentrations in microenvironments vary The BD concentrations in the ambient air vary widely widely depending on the proximity to emission sources and are dependent on locations or sites, which can be and their magnitudes. Automobile exhaust and ETS are roughly divided into two categories: industrial/industry- the major sources of BD at non-industrial sites, as a re- related sites and non-industrial sites. Obviously, the lat- sult, the microenvironments with these sources often ter is more important for the general population. show relatively high BD concentrations. Indeed, the Unsurprisingly, the BD concentrations at industrial roadside BD levels are usually higher than the back- and industry-related sites, e.g., sites close to industrial fa- ground levels [14, 35, 36]. Exhaust from biomass burn- cilities, are usually higher in comparison with those at ing is also an important source of BD in the non-industrial sites [35]. For example, a maximal BD environment, consequently, some special microenviron- concentration of 27 ppb (60 μg/m ) was observed in a ments with the source can have elevated BD levels. county downwind of a refinery facility in the Industrial Temples are one of such microenvironments due to in- Heartland of Alberta, Canada’s largest hydrocarbon pro- cense burning; an air BD concentration as high as 10.46 cessing center [37]; an overall arithmetic mean of 120 μg/m inside three temples in Thailand has been re- μg/m was reported for various industries in Italia dur- ported [49]. Important microenvironments concerning ing 1996-2015 [38]. Gallego et al. reported that the BD human exposure include: concentrations in a few Catalan urban areas in Spain 1) Vehicles. In a study to investigate the concentra- near petrochemical facilities ranged from 15 to 33 μg/m tions of VOCs in urban domestic and public microenvi- [39]. A study to measure VOCs at 16 sampling sites in ronments, Kim et al. found that the mean BD the North Industrial Complex of Tarragona, Spain, re- concentration in automobile was 7.9 μg/m , which was ported a BD range from 0.31 to 15.19 μg/m [40]. the highest in all microenvironments examined [50]. The BD concentrations at non-industrial sites vary Even the air surrounding moving vehicles contains rela- greatly. Huy et al. compiled the BD concentrations in dif- tively high concentrations of BD; a mean of 3.0 μg/m ferent countries and regions reported in the literature and a maximum of 6.9 μg/m have been reported [1]. [41]. The average concentrations range from 0.01 to 3.3 2) Rooms with smoking. Cigarette smoke contains sig- μg/m , but the developed countries or regions (e.g., Hong nificant amounts of BD, as a result, the BD concentra- Kong) have lower concentrations (0.01-0.91 μg/m )com- tions in smoke-filled rooms can be high. An experiment, 3 3 pared to the developing countries (0.35-3.3 μg/m )[41]. which was performed in a ventilated 18 m laboratory An EPA official document released in 2012 provided the chamber with 6 cigarettes being smoked, showed that range of the mean BD concentrations in U.S. cities and the BD concentrations were 122, 34, and 3.9 μg/m as suburban areas, and the average background concentra- measured at 20 min, 2 h, and 18 h after smoking had tion, which were 0.1-2 and 0.13 μg/m ,respectively [42]. ended, respectively [51]. Before a smoking ban was im- The BD concentrations in rural areas (0.002-0.125 μg/m ) plemented in Ireland, the average BD concentration in are typically one order of magnitude lower than those in pubs was reported to be 4.15 μg/m [52]. A mean BD urban areas [35, 41]. Furthermore, in urban areas, the BD concentration of 1.7 μg/m in smoking homes, which is concentrations at commercial sites, particularly at sites 3.4 times higher than that in nonsmoking homes, has close to the street level in the urban core, are usually been reported [50]. higher than those at residential sites [35]. A modeling 3) Certain restaurants and kitchens. Recently, Huang study of the BD concentrations in Minnesota, U.S., et al. reported that the dining area in a Chinese hot-pot showed that the concentrations were the highest in the restaurant had a BD concentration of 7.73 μg/m , prob- center of the metro area and decreased with distance from ably due to the use of gas stoves [23]. Kitchens, espe- there [43]. Technological advances have led to significant cially those cooking Chinese cuisine by using high- decreases in the ambient air levels of BD and other VOCs temperature oils, can be a potential microenvironment in developed countries [35, 44–47]. with relatively high BD concentrations due to the BD re- However, in terms of human exposure, the BD concen- lease from heated oils. trations in microenvironments, particularly indoor micro- 4) Operating rooms. Because the surgical smoke environments, where people spend most of time, are more generated during electrosurgery contains extremely important than those in the ambient environment. Import- high concentrations of BD [29], plus most surgeons antly, the BD concentrations in microenvironments are do not use smoke management at all [30, 32]orthe often unrelated to the ambient measurements at nearby mobile smoke evacuation systems cannot effectively monitors [48], which mostly reflect the BD concentrations remove BD in the smoke [29], the operating rooms in near-road environments [36]. A recent report also found performing electrosurgery can be an indoor micro- that there was no association between ambient VOC levels, environment with relatively high BD concentrations. including BD, and personal exposures [44]. Chen and Zhang Genes and Environment (2022) 44:3 Page 4 of 22 Human exposure to BD [61]. In a recent population study, Konkle et al. found Human exposure to BD can be divided into two categor- that, although the ambient air concentrations of 11 ies: occupational and non-occupational. Occupational VOCs in the United States, including BD, decreased exposure usually occurs at industrial sites, and the ex- from 2005 to 2013, all corresponding urinary metabo- posure levels are generally high but are dependent on lites of the VOCs increased over approximately the same the types of industry, activity sectors, and occupational timeframe except for one metabolite [44]. As pointed groups. An investigation on Italian working force indi- out by the authors, the finding indicated that these cated that the exposure levels in most activity sectors or VOCs in the ambient air were not the major source of occupational groups ranged between 10 and 200 μg/m , VOC exposure [44], thus providing indirect support for but the exposure levels in the manufacture of rubber the role of microenvironments in exposure to BD and and plastic products (320-360 μg/m ), and the manufac- other VOCs. ture of coke and refined petroleum products (340-390 For non-occupational exposure to BD, ETS can be a μg/m ) were significantly higher than those in other sec- principal contributor. Measurements of the BD concen- tors [38]. The firm size can influence the exposure levels trations in indoor air before and after the implementa- as well; micro- and small enterprises have greater prob- tion of a smoking ban in Ireland provide direct evidence ability to show higher exposure levels [38]. In a petro- of the contribution of ETS to the BD levels in indoor chemical plant in Iran, the BD exposure level reaches microenvironments. The airborne BD concentration 560.82 ± 811.36 μg/m [53]. However, technical ad- prior to the implementation of the ban, which was 4.15 3 3 vances and changes in the operating practices can μg/m , dropped down by nearly 20-fold to 0.22 μg/m greatly reduce the human exposure. For example, two after the ban was fully implemented [52]. studies published in 2016 and 2017 reported low expos- As mentioned above, BD is generally considered an ure levels in the Swedish petroleum refinery industry, automobile source pollutant or a traffic-related pollu- which varied from 0.3 to 22.4 μg/m , depending on the tant, however, the results from several population stud- occupational groups [54, 55]. Similarly, a study published ies suggest that human exposure to BD is mostly in 2017 reported that the BD exposure level in the vicin- attributed to ETS. In a study to investigate biological ity of a major petrochemical complex in Thailand was as monitoring of exposures to ETS in the general popula- low as 0.04 μg/m [56]. tion, Aquilina et al. observed that urinary concentration Recently, some newly-identified occupations outside of cotinine, a well-known ETS biomarker, showed sig- the common activity sectors are found to have low to nificant correlation with the individual exposure to air- moderate BD exposure levels, which include under- borne BD that was measured with personal exposure ground coal miners (~2.1 μg/m )[57], firefighters (23.6 samplers [62]. The finding suggests that ETS is a signifi- 3 3 μg/m ), police forensic investigators (9.68 μg/m )[58], cant source of exposure to BD for the general popula- and hairdressers [59]. It is noted that exposure of hair- tion. In a study assessing exposure to VOCs among dressers to BD was assessed through the levels of urinary pregnant women in the United States, Boyle et al. found BD biomarkers rather than through measuring the air- that smoking was positively associated with the metabol- borne BD concentrations; the median concentration of a ite levels of BD [63]. The results obtained from a recent BD biomarker among hairdressers, who were all female, study on nearly 6,000 participants indicated that tobacco was found to be more than 5 times higher compared to smoke was a major source of BD exposure in the general women in the general population [59]. U.S. population [64]. These reports are consistent with On the other hand, non-occupational exposure to BD the evaluation for residential exposures of U.S. non- is widespread and microenvironments can be the pri- smokers based on material-balance modeling; the evalu- mary determinant. Because humans usually spend most ation indicated that ETS was the dominant source of en- of time indoors rather than outdoors, human exposure vironmental inhalation intake for BD, which was to BD is mainly dependent on the concentrations in in- estimated to be 16-37 μg/day [65]. Taken together, for door microenvironments. Kim et al. determined personal the general population, it appears that the indoor micro- exposures of 12 urban dwellers to VOCs by direct mea- environments are the dominant factor in human expos- surements via personal monitoring and discovered that ure to BD, and ETS is the primary source of BD in these exposure at home contributed to 51-87% of overall indi- microenvironments. vidual exposure to BD [60]. Similarly, Huy et al. reported A special microenvironment that might lead to rela- that exposure at home dominantly contributed to the tively high exposure to BD is kitchens with the cooking total cancer risk caused by BD (56-86%) [41]. In another practice using high-temperature oils. However, the stud- study, Du et al. estimated that ~70% of the overall can- ies concerning the microenvironment have been ex- cer risks caused by 16 HAPs (including BD) in China tremely scarce. Using the levels of urinary biomarkers as was attributed to exposure to these pollutants at home the metric to assess exposure to VOCs, an investigation Chen and Zhang Genes and Environment (2022) 44:3 Page 5 of 22 on Chinese women who regularly cook at home has pollutants among 10 monitored VOCs [81]. Du et al. failed to provide support for the women to experience compiled the data of 16 HAPs mostly from 2003 to 2013 elevated BD exposure. However, the size of the study is in urban areas of China, and concluded that formalde- quite small and many confounders can have influenced hyde, 1,4-dichlorobenzene, benzene, and BD were the the outcome [66]. major risk contributors, which yielded the highest cancer -5 Interestingly, exposure to BD was found to be risks (all > 10 )[61]. Dhaini et al. investigated the can- dependent on socio-demographic characteristics. The cer risks of air pollutants in Beirut, Lebanon, and discov- populations with a high percentage of ethnic/racial mi- ered that benzene and BD were the major contributors, norities and low income tend to have higher exposure which accounted for 39-43% and 25-29% of the cumula- levels [67]. tive risks, respectively [71]. In Xi’an, China, formalde- hyde, BD, and 1,2-dichloroethane were found to be the The cancer risks of BD top three contributors to the cancer risks [70]. In two BD has high cancer risks. The inhalation unit cancer risk coastal cities in Metro Vancouver, Canada, the top pol- -5 3 determined by EPA is 3 × 10 per μg/m or 0.08 per lutants were determined to be carbon tetrachloride, ben- ppm, in other words, 0.03 μg/m of BD causes a bench- zene, and BD [72]. In Calgary, another Canadian city, -6 mark cancer risk of 1 × 10 [1, 68]. Because the ambient the same three pollutants were also listed as the top con- BD concentrations in most urban areas usually range tributors to the cancer risks [24]. from approximately 0.1 to 1 μg/m , the cancer risk for -5 the general population in cities is around 10 [41]. This The metabolism of BD has been demonstrated by many studies [24, 61, 69–73]. BD is an indirect carcinogen, i.e., it must be biotrans- The concentrations of BD in small cities and rural areas formed into metabolites to exert its mutagenicity/car- are usually lower, as a result, the cancer risks are lower cinogenicity. Actually, non-carcinogenic effects of BD -6 (approximately 10 )[74, 75]. On the other hand, the are also considered to be mediated by its metabolites [1]. cancer risks at industrial sites or in areas with industrial It has long been known that BD can be metabolized to point sources of BD are usually high [76]; the risks at form 3,4-epoxy-1-butene (EB) by cytochrome P450 en- heavily-polluted sites or those caused by occupational zymes (P450s), which can be further biotransformed into -3 exposure can even reach 10 [27, 53, 77]. Due to its 1,2,3,4-diepoxybutane (DEB) by P450s, or into 3-butene- high inhalation unit cancer risk, BD is often a major 1,2-diol (BDD) by epoxide hydrolase (Fig. 1). BDD can contributor to the total cancer risks caused by VOCs in be converted to 3,4-epoxybutane-1,2-diol (EBD) by industrial sites. For example, an investigation on P450s [1, 6], which was recently reported to undergo process-specific emission characteristics of VOCs from further bioactivation to form a bifunctional epoxy alde- petrochemical facilities in the Yangtze River Delta, hyde [82]. DEB can also be converted to EBD by epoxide China, found that the process unit producing BD had hydrolase. The three epoxides, EB, DEB, and EBD, can the largest cancer risk [78]. readily react with nucleosides and DNA to yield DNA Because human exposure to BD is dominantly attributed adducts, and are genotoxic and mutagenic [7, 83–87]. In to ETS, the cancer risks caused by residential exposure are vivo, BDD and EBD are the most abundant metabolites, usually greater than those caused by the ambient air. The and DEB is the metabolite with the lowest concentra- cancer risks caused by residential exposure for U.S. non- tions [6, 7, 88]. -5 -4 smokers have been estimated to be 4.2 × 10 -5.3 × 10 Because of the presence of two epoxy moieties in the by using material-balance modeling [65]. molecule, DEB not only has stronger reactivity in com- BD is one of the environmental pollutants with the parison with EB and EBD [89–91], but also can form highest cancer risks. In almost all studies to investigate DNA cross-links [7, 83, 92–96] and DNA-protein cross- the cancer risks of pollutants, BD has been ranked as links [97]. As a result, clastogenicity of DEB is very high; one of the top pollutants. In 2007, a U.S. study showed among ~100 IARC carcinogens (Group 1, 2A, and 2B), that among 17 pollutants, benzene, formaldehyde, and DEB shows highest level of micronucleus (MN) induc- BD were the top three pollutants with the cancer risks tion in mice [98]. DEB is the most genotoxic and muta- -5 -4 on the order of 10 -10 [79]. In another study, McCar- genic metabolite among the three epoxides with the thy et al. used the EPA national ambient air quality data relative potencies of DEB >> EB > EBD [6, 7]. However, for the period 2003 through 2005 and found that among it should be noted that the relative potencies can be dif- 65 air toxics, concentrations of benzene, carbon tetra- ferent when considering the stereochemistry of the me- chloride, arsenic, BD, and acetaldehyde exceeded the 10 tabolites. A specific EBD stereoisomer, (2R,3S)-EBD, has benchmark level at most sites in the United States [80]. been found to be at least 30-fold more mutagenic than In an investigation conducted in Tianjin, China, ben- the other three EBD stereoisomers [99]. Importantly, the zene, BD, and chloroform were listed as the top three mutagenic potency of (2R,3S)-EBD is 10-to-20-fold Chen and Zhang Genes and Environment (2022) 44:3 Page 6 of 22 Fig. 1 The metabolic pathways of BD. The P450-mediated metabolism is an established pathway and the MPO-mediated one is a proposed pathway. (P450s, cytochrome P450 enzymes; ADH, alcohol dehydrogenase; MPO, myeloperoxidase; GSH, glutathione) greater than EB stereoisomers and is only 5-to-10-fold carcinogenesis of BD in humans [101, 102], because the less than DEB stereoisomers [99]. lymphohematopoietic system, i.e., the bone marrow, is An alternative metabolic pathway has been proposed, the target organ for BD in humans on the basis of the in which BD is converted to 1-chloro-2-hydroxy-3-bu- epidemiological studies [1, 68]. tene (CHB) in the presence of hydrogen peroxide and Although it has been established that the mutagenic chloride anion (> 50 mM) by myeloperoxidase (MPO), a and carcinogenic effects of BD are caused by its geno- peroxidase almost specifically present in neutrophils and toxic metabolites, the specific metabolite(s) responsible monocytes [100–102]. CHB, a chlorohydrin, can be con- for the effects are still in debate. Among the three epox- verted to 1-chloro-2-buten-2-one (CBO) and 1-chloro- ides, DEB is often considered to be the ultimate culprit 3,4-epoxy-2-butanol (CEB) by P450s or alcohol dehydro- responsible for BD mutagenicity/carcinogenicity [95, genase (ADH) [103–105]. CBO, a strong Michael ac- 112, 113] due to its highly genotoxic and mutagenic po- ceptor, rapidly reacts with glutathione (GSH) to yield tency compared to EB and EBD [6, 7, 83, 84]. On the GSH conjugates [103], and can also readily react with other hand, EB and EBD have also been proposed to be nucleosides and DNA to form multiple DNA adducts the predominant cancer-initiating metabolites due to [106–109], among which an adenine adduct, A-2D (Fig. their much higher in vivo concentrations (especially 1), was detected in cells treated with low concentrations EBD) compared to DEB [114], and the role of EBD has of CBO [109]. Importantly, CHB is mutagenic as deter- been implicated through experiments in BDD-dosed mined by the Ames test, and CHB, CBO, and CEB are mice and rats [87]. all genotoxic as assessed by the comet assay with CBO Making the issue more complex, what metabolite(s) being much more potent than CHB, CEB, and also DEB are responsible for BD mutagenicity/carcinogenicity ap- [105, 110]. pears to be species- and BD concentration-dependent The alternative metabolic pathway may exist in the [87]. Specifically, the culprits are considered to be DEB bone marrow and blood, which contains abundant neu- in mice, and EB and/or EBD in rats; or, DEB and EBD trophils. Preliminary data showed that the MPO- are considered responsible for the toxic effects of BD at mediated metabolism of BD could occur in murine neu- low and high BD levels, respectively [87, 114]. For trophils and fresh human blood [111]. Thus, it has been humans, the issue remains to be elucidated but DEB is proposed that this pathway may play a role in thought to contribute little to BD carcinogenicity and Chen and Zhang Genes and Environment (2022) 44:3 Page 7 of 22 EBD may cause the greatest risk [115, 116]. Another DEB, and CHB are N-acetyl-S-(3,4-dihydroxybutyl)-L- study estimates that DEB and EBD contribute 7% and cysteine (DHBMA), N-acetyl-S-(2,3,4-trihydroxybutyl)- 92% to the total genotoxic dose in humans, respectively L-cysteine (THBMA), 1,4-bis(N-acetyl-L-cystein-S-yl)bu- [117]. Consistent with the observation is the finding that tane-2,3-diol (bis-BDMA), and 1,4-bis(N-acetyl-L- treosulfan, a chemotherapeutic agent that is non- cystein-S-yl)-2-butanone (NC1) (Fig. 2), respectively enzymatically converted to DEB as its bioactive form [103, 104, 113, 125, 128, 129]. [118], induces different histological subtypes of lympho- DNA adducts can be released from DNA spontan- hematopoietic neoplasms (acute myeloid leukemia) from eously or via the DNA repair process. The DNA adducts those caused by occupational exposure to BD. Therefore, released are eventually excreted in urine and thus can it has been speculated that monoepoxide metabolites also be used as urinary biomarkers. Although many BD- may play a more important role than DEB in BD car- derived DNA adducts have been identified [7], so far cinogenesis in humans [119]. only two DNA adducts, N7-[1-(hydroxymethyl)-2-pro- pen-1-yl]guanine (EB-GII) and 1,4-bis(gua-7-yl)-2,3- Urinary biomarkers of BD butanediol (bis-N7G-BD), have been used as urinary bio- Urinary BD biomarkers reported in the literature markers [130, 131]. EB, DEB, EBD, and CBO (Fig. 1) are reactive metabolites and can react with proteins (e.g., hemoglobin) and DNA. MHBMA and DHBMA The products formed, i.e., hemoglobin and DNA ad- MHBMA and DHBMA are the classic biomarkers of BD ducts, can be used as biomarkers [120, 121]. Meanwhile, and have been used for almost 30 years [124, 132, 133]. these metabolites can also undergo biotransformation They are the major metabolites of BD in urine with the via the mercapturic acid pathway to yield N-acetyl-L- sum of the amounts constituting 50-90% of the total cysteine (NAC) conjugates, which are excreted in urine amounts of all urinary metabolites in different species and can be used as biomarkers as well. BDD and CHB (mouse, rat, hamster, and monkey) [125]. In humans, need to be converted to other intermediates, presumably DHBMA is the most abundant metabolite in urine and hydroxymethyl vinyl ketone and CBO, respectively, be- is readily detected [113, 132]. MHBMA is more sensitive fore biotransformation via the mercapturic acid pathway. that DHBMA [133–136]. The two biomarkers, especially However, to detect hemoglobin and DNA adducts, DHBMA, have been used in population-based studies blood and tissue samples are usually needed, which [44, 64, 136]. greatly restricts the application of these biomarkers in Due to the difficulty in chromatographic separation of studies involving human subjects due to the difficulty in the two regioisomers, in most studies the sum of the collecting the specimens. By contrast, urine is readily amounts of MHBMA1 and MHBMA2 is used as a single available and has fewer biohazard concerns. Moreover, a biomarker (i.e., MHBMA) [124, 135–138]. In some stud- large proportion of absorbed BD (usually 30-60% as ob- ies, the two regioisomers are separated and the concen- served in mice, rats, and monkeys) is excreted in urine trations of individual regioisomers are reported. The as biotransformed products [122, 123], therefore, the data obtained show that MHBMA2 is the dominant iso- amounts of the biotransformed products in urine are ex- mer in human urine [64, 139]. pected to be larger than those in other biological matri- ces (e.g., blood and tissues). As a result, urinary BD MHBMA3 biomarkers have been widely used, particularly in studies MHBMA3 is a biomarker that is worth special attention. concerning human subjects. Thus, in this section, we The metabolite was first discovered in 1995 through the will only review progress in urinary BD biomarkers. reaction of EB with NAC under reflux; its structure was Through the mercapturic acid pathway, EB is primarily characterized but the configuration (trans-or cis-) was biotransformed into two regioisomers, N-acetyl-S-[1-(hy- not determined. However, this product failed to be de- droxymethyl)-2-propen-1-yl]-L-cysteine (MHBMA1) and tected in urine of rats and mice administered EB [126]. N-acetyl-S-(2-hydroxy-3-buten-1-yl)-L-cysteine It turned out to be an issue of sensitivity of the instru- (MHBMA2) (Fig. 2) (it should be noted that each of the mental method, because in a subsequent study, Richard- two regioisomers consists of two diastereomers), which son et al. successfully detected the metabolite in urine of are collectively called monohydroxybutenyl mercapturic rats and mice administered C-labeled EB. Nonetheless, acid (MHBMA) [2, 124, 125]. In addition, a small frac- MHBMA3 was a trace metabolite with the amounts be- tion of EB can undergo a rearrangement of double bond ing only 0.5% of the administered doses or even less to yield N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine [127]. In 1999, the metabolite was detected in urine of (configurations unspecified, presumably trans-), a trace mice exposed to C-labeled BD but accounted for only product usually called MHBMA3 [126, 127]. The corre- 0.1% of the administered doses, however, it was virtually sponding biotransformation products of BDD, EBD, not present in urine of rats under the same BD exposure Chen and Zhang Genes and Environment (2022) 44:3 Page 8 of 22 Fig. 2 The structures of the urinary BD biomarkers reported in the literature. MHBMA1, N-acetyl-S-[1-(hydroxymethyl)-2-propen-1-yl]-L-cysteine; MHBMA2, N-acetyl-S-(2-hydroxy-3-buten-1-yl)-L-cysteine; trans- and cis-MHBMA3, trans- and cis-N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine; DHBMA, N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine; THBMA, N-acetyl-S-(2,3,4-trihydroxybutyl)-L-cysteine; bis-BDMA; 1,4-bis(N-acetyl-L-cystein-S- yl)butane-2,3-diol; NC1, 1,4-bis(N-acetyl-L-cystein-S-yl)-2-butanone; NAC, N-acetyl-L-cysteine; EB-GII, N7-[1-(hydroxymethyl)-2-propen-1-yl]guanine; bis-N7G-BD, 1,4-bis(gua-7-yl)-2,3-butanediol. MHBMA1 and MHBMA2 are collectively called monohydroxybutenyl mercapturic acid (MHBMA), and trans- and cis-MHBMA3 are similarly called MHBMA3. [128]. It is noted that in the experiment, the amount of low [the mean concentration was 1.80 ± 2.10 ng/mL with MHBMA was at least 120-fold greater than that of the limit of detection (LOD) being 0.70 ng/mL] [139]. The MHBMA3 [128]. finding was confirmed by a recently published study with Probably due to its tiny amounts in urine of rats and 5,897 participants, in which the frequency of detection of mice, no studies concerning MHBMA3 have been pub- MHBMA1 and MHBMA2 in urine samples was only 0.7% lished over the following decade. The next study involving and 9.8%, respectively [64]. This is opposite to the obser- the metabolite was published in 2012, when Alwis et al. vation in animal experiments, in which MHBMA1 and detected MHBMA3 in human urine for the first time MHBMA2 were overwhelmingly dominant metabolites [139]. It is worth noting that the urine samples were col- formed, and MHBMA3 could hardly be detected [128]. lected from the general U.S. population, rather than the Following the report of Alwis et al., more than 10 subpopulation with high exposure (workers occupationally studies on the general population using MHBMA3 as exposed to BD). Furthermore, it is unexpected that the BD biomarker have been published, with most stud- MHBMA3 turned out to be the most abundant metabolite ies being conducted in the U.S. populations [44, 63, 64, in human urine among the three EB-derived metabolites 140–153]. These studies performed in the general U.S. (MHBMA1, MHBMA2, and MHBMA3, which were populations showed similar results to those reported by quantitated separately) with the concentrations being 36 ± Alwis et al. [139]. However, the results obtained in the 34 and 6.40 ± 10 ng/mL for smokers and non-smokers, re- populations in other countries and regions are different. spectively. Surprisingly, MHBMA3 had a very high fre- Chiang et al. reported that the mean MHBMA3 concen- quency of detection (99%). By sharp contrast, MHBMA1 trations in 55 Taiwanese smokers and 55 non-smokers failed to be detected in a vast majority of samples (either were 129.2 ± 99.2 and 52.3 ± 36.8 ng/mL, respectively smokers or non-smokers) and MHBMA2 was detected [140], which were considerably higher than that reported only in urine of smokers but its concentrations were very by Alwis et al., in particular, the concentrations in non- Chen and Zhang Genes and Environment (2022) 44:3 Page 9 of 22 smokers. A recently published study on the general popu- different subpopulations, including those with different lation in Wuhan, China, reported a surprisingly low fre- gender, ethnic/racial group, and age, although the results quency of detection at only 9.4% [152]. Similarly, another are not always consistent. For example, it has been discov- study performed in China even failed to detect MHBMA3 ered that the MHBMA3 levels in female smokers were sig- in 100 urine samples from children aged 6-12 years [153]. nificantly high than those in male smokers [64, 142, 149]. A possible explanation for the surprising observations re- When comparing differences among different ethnic/racial ported in the two studies is that the authors used cis- groups, the MHBMA3 levels in non-Hispanic white MHBMA3 as the reference standard and the LOD in the smokers were observed to be higher than those in non- latter study was somewhat high (3.13 ng/mL) [152, 153], Hispanic black ones [149]. Another study also found that although in the studies of Alwis et al. [139] and other au- the MHBMA3 levels in non-Hispanic white were signifi- thors [44, 63, 64, 140–148, 151], the configuration of the cantly higher than those in non-Hispanic black and His- MHBMA3 standard was not specified. panic [142]. However, the differences failed to be observed MHBMA3 is a sensitive BD biomarker. It can clearly in a recently published study [64]. distinguish non-smokers from smokers. In fact, all The differences among subpopulations with different population-based studies consistently show that there ages were consistently observed by three groups of au- are statistically significant differences in the MHBMA3 thors. Jain reported that there was a statistically signifi- concentrations between smokers and non-smokers [63, cant positive association between the MHBMA3 level 64, 139–142, 149, 151]. Quitting smoking can be and age [149], and specifically, children aged 6-11 years reflected in the change in the MHBMA3 level; in a study old had significantly higher MHBMA3 level compared on over 1,100 adult exclusive daily cigarette smokers, a to non-smoker adults aged ≥ 20 years [150]. De Jesus dramatic reduction in the MHBMA3 level was observed et al. found that after controlling for tobacco use and among those quitted tobacco use entirely [147]. The bio- other cofactors and using participants’ age of 25–34 marker can also indicate exposure to ETS; in an investi- years as the reference, young adults (18-24 years) had gation on exposure of non-smokers to VOCs from significantly lower MHBMA3 levels, but older adults (≥ secondhand smoke, St. Helen et al. observed that the 55 years) had significantly higher levels (all p ≤ 0.0001) MHBMA3 concentrations exhibited the greatest increase [142]. Similar results were also obtained in a recent (2.1-fold) from 0 to 8 h postexposure among 9 VOC bio- study reported by Nieto et al., although in this study, age markers [154]. In addition, MHBMA3 can even discrim- was categorized into somewhat different ranges from the inate between duel cigarette/e-cigarette users and preceding study. In this study, Nieto et al. reported that exclusive cigarette smokers [141]. Furthermore, the bio- the MHBMA3 concentrations in older adults (aged 40- marker can distinguish among light, average, and heavy 59 and ≥ 60 years) were significantly higher compared to smokers. In Wave 1 of the Population Assessment of those in younger adults (aged 20-39 years) [64]. Among Tobacco and Health Study, the biomarker data of more all participants (n = 5,897) and the participants who did than 2,700 U.S. adult daily cigarette smokers were ana- not use tobacco products (n = 5,171), with the exception lyzed and it was observed that the concentrations of bio- of adolescents (aged 12-19 years), all age groups, includ- markers, including MHBMA3, consistently increased ing children (aged 3-5 and 6-11 years), had higher with cigarettes smoked per day (CPD) [141]. In the MHBMA3 levels compared with young adults (aged 20– 2011-2016 U.S. National Health and Nutrition Examin- 39 years) [64], which is consistent with the observation ation Survey, by examining the urinary BD biomarkers, reported by Jain [150]. including MHBMA1, MHBMA2, MHBMA3, and A major issue concerning MHBMA3 is that its config- DHBMA, in 5,897 participants, Nieto et al. observed uration is not specified in all studies except for two re- clear dose-response relationships between the MHBMA3 cent ones [152, 153]. This compound has two or DHBMA concentrations and CPD [64]. Specifically, configurations or two stereoisomers, i.e., trans- and cis- compared to non-smokers, smoking 1-10, 11-20, and > MHBMA3 (Fig. 2), which should be well separated chro- 20 CPD was significantly associated with 475%, 849%, matographically. Unlike MHBMA, which is the mixture and 1,143% higher MHBMA3 levels, respectively (all p < of MHBMA1 and MHBMA2 and is usually used as a 0.0001). However, the corresponding increases for single biomarker in most studies, the researchers in DHBMA were only 32.8%, 44.2%, and 102%, respectively MHBMA3-related studies did not describe that this [64]. In addition, another study showed that the increase compound was a mixture of two stereoisomers. More- in number of days that the tobacco products were used over, the MHBMA3 standards available commercially during the last five days was associated with increased are either trans-or cis-isomer. Therefore, MHBMA3 de- levels of MHBMA3 (p < 0.01) but not DHBMA [149]. tected in human urine should be one of the two stereo- Besides smokers and non-smokers, significant differences isomers rather than the mixture of the two in the MHBMA3 levels have also been observed among stereoisomers. It has not been clear whether the Chen and Zhang Genes and Environment (2022) 44:3 Page 10 of 22 difference in the frequency of detection of MHBMA3 in urine of animals and humans exposed to BD has not between the studies of Qian et al. or Kuang et al. [152, been reported. 153] and those reported by other authors [44, 63, 64, 139–148, 151] is caused by the configuration of the EB-GII biomarker. EB reacts with the guanine residues in DNA at the N7- position to form two products, N7-(2-hydroxy-3-buten- 1-yl) guanine (EB-GI) and EB-GII [157]. The two ad- THBMA ducts have been detected in EB-treated cells in culture, THBMA was tentatively identified first in urine of mice and in tissues of rats and mice exposed to BD [157], and exposed to BD [155] and was confirmed later by using 14 EB-GII has been found in human blood leukocyte DNA animals exposed to C-labeled BD [128]. Interestingly, of smokers but below the LOD [158]. In 2017, the Tre- the metabolite was not detected in urine of rats and 14 tyakova laboratory developed a highly sensitive LC-MS/ mice administered C-labled EB [127]. In 2000, van Sit- MS method and was able to detect EB-GII in urine of tert et al. tried to detect THBMA in human urine but smokers and occupationally-exposed workers [130]. The the attempt was unsuccessful due to interferences from biomarker was successfully used in studies concerning the sample matrix [124]. Until 2011, the Tretyakova la- humans and animals [159–161]. boratory was able to develop an LC-MS/MS method to detect the metabolite in human urine, whose concentra- bis-N7G-BD tions in smokers and non-smokers were reported to be Bis-N7G-BD was first synthesized through the reaction 21.6 and 13.7 ng/mg creatinine with the difference being of DEB with guanosine [92]. The adduct can be detected statistically significant (p < 0.01), respectively. Further- in tissues of rats and mice exposed to BD [95]. Use of more, the THBMA concentrations in urine declined 25- bis-N7G-BD as a urinary biomarker was reported just 50% following smoking cessation [129]. The biomarker before the review is published [131]. In the study, very was also detected in urine of workers occupationally ex- low concentrations of bis-N7G-BD (~570 pg/mg creatin- posed to BD with the mean concentration being 157 ng/ ine) were detected in urine of mice exposed to 590 ppm mg creatinine [113]. A subsequent study on workers in (1,300 mg/m ) BD for two weeks [131]. Czech Republic observed statistically significant differ- ences not only between exposed workers and the con- Suitability of the urinary BD biomarkers for studies on the trol, but also between the male control and the female general population control. The MHBMA concentrations in the male con- Urinary biomarkers are particularly useful in large epi- trol were significantly higher than those in the female demiological studies because urine is much more easily control (57.1 ± 33.5 vs. 24.2 ± 16.6 ng/mL, respectively) available and has lower biohazard risks compared to even though both control groups were exposed to the 3 blood. However, it should be noted that urinary bio- same ambient BD levels (7 ± 5 μg/m )[135]. markers reflect recent exposures and are susceptible to variations [134]. Because several urinary BD biomarkers bis-BDMA have been developed, a comparison of their performance Bis-BDMA was first synthesized in 2014 by the Tretya- can help researchers make a wise selection, especially for kova group and was used as a biomarker [113]. In rat studies on the general population. urine following exposure to 200 ppm (442 mg/m )BD The urinary BD biomarkers reported can be divided for two weeks, the mean bis-BDMA concentration was into two categories: exposure biomarkers and exposure/ 4.8 ± 2.9 μg/mL, which was 16-, 44-, and 31-fold lower effect biomarkers. The former includes all NAC conju- than those of MHBMA, DHBMA, and THBMA, respect- gates and is surrogate biomarkers, because they only re- ively. However, this biomarker was not detected in urine flect the doses of internal exposure to BD or a specific of smokers and workers occupationally exposed to BD metabolite (e.g., DEB). On the other hand, the latter, [113]. In urine of mice exposed to 590 ppm (1,300 mg/ which includes EB-GII and bis-N7G-BD, is mechanistic- m ) BD for two weeks, the bis-BDMA concentration was ally relevant and cancer-related biomarkers, because the 8.09 ± 6.3 μg/mL [131]. formation of DNA adducts is considered to be the initial molecular event in carcinogenesis. NC1 First and foremost, selection of biomarkers is certainly NC1 is the urinary biomarker of CHB, the potential BD dependent on the purpose of research. However, in prac- metabolite formed via the alternative MPO pathway. It tical applications, the selection primarily depends what was first synthesized in 2017 [111, 156] and subse- subjects are used in research. Urine of laboratory ani- quently was detected in urine of CHB-administered rats mals exposed to BD usually contains high concentra- and mice [104]. Whether the biomarker can be detected tions of metabolites, thus all BD biomarkers can virtually Chen and Zhang Genes and Environment (2022) 44:3 Page 11 of 22 be used. Conversely, urine of human subjects in the gen- The Xia group in the School of Public Health of Fudan eral population is expected to contain very low concen- University used the cytokinesis-block micronucleus trations of biomarkers, as a result, selection of (CBMN) assay to examine chromosomal damage in per- biomarkers is quite restricted. Because urinary BD bio- ipheral blood lymphocytes (PBL) of 166 workers in a poly- markers are most useful in biomonitoring of human sub- butadiene latex chemical industrial plant in Ningbo, China jects and for laboratory animals, hemoglobin and DNA [163]. These workers were exposed to extremely high adducts can be freely selected as biomarkers, we will levels of BD with the range varying from 0.05 to 1,985.99 3 3 thus focus on the issue what biomarkers are suitable for mg/m (the median was 4.48 mg/m ). The mean MN fre- studies on the general population. quency of the workers was significantly higher than that Among the urinary BD biomarkers, MHBMA and bis- of the unexposed control (0.339% vs. 0.148%, p <0.01), BDMA can easily be excluded due to either very low fre- and the polymorphisms of several genes involved in bioac- quency of detection [64] or inability to be detected even tivation and detoxification of BD were observed to influ- in urine of occupationally-exposed workers [113]. ence the MN frequency [163]. In another study, the Xia Among other biomarkers, DHBMA, THBMA, and EB- group used sister-chromatid exchange (SCE) and CBMN GII have natural background that may be caused by en- assays to investigate chromosomal damage in PBL of 44 dogenous sources, thus restricting their sensitivity [113, BD-exposed workers in a rubber factory of Shandong, 124, 130, 133]. Specifically, DHBMA fails to reflect the China [164]. These workers were exposed to much lower changes in the external exposure doses in some studies levels of BD (0.06-12.41 mg/m with the median being [137, 162]; in particular, a study found that the DHBMA 1.48 mg/m ) compared with those in Ningbo, China. It levels did not change after cessation of smoking, whereas was found that the mean MN frequency in the workers the levels of MHBMA and the biomarkers of other was significantly higher than that in the control without VOCs rapidly decreased [137]. The difference in the occupational exposure to BD (0.439% vs. 0.296%, p < THBMA concentrations between smokers and non- 0.01), but the SCE frequency did not exhibit statistically smokers is small (the data of smokers is only 58% higher significant difference between the exposed workers and than that of non-smokers), although it is statistically sig- the control. In addition, it was also observed that the poly- nificant (p < 0.01) [129]. EB-GII is even worse; its con- morphisms of three glutathione S-transferase genes af- centrations in urine of smokers had no statistically fected the MN frequency [164]. significant difference from those in non-smokers [130]. The other group of Chinese researchers, the Cao and However, the levels of these biomarkers exhibited sig- Ao group in the Department of Hygiene Toxicology of nificant differences between occupationally exposed the Third Military Medical University, Chongqing, workers and the controls, suggesting that they may be China, conducted a 1:1 matched pair study in a popula- suitable for human subjects with high BD exposure. tion of workers in a large petrochemical facility in Nan- Among these biomarkers, MHBMA3 stands out from jing, China [165–167]. The workers were exposed to the rest. Many studies already demonstrate its excellent significantly higher levels of BD than did the control suitability for biomonitoring exposure of the general (5.02 vs. 1.86 mg/m , p < 0.01), and exhibited elevated populations to ambient BD [44, 63, 64, 140–153]. It is frequency of MN and nucleoplasmic bridge (NPB) (both highly responsive to the exposure dose [64] and is well p < 0.01) but lower nuclear division index (p < 0.01) in capable of reflecting exposure to ETS [154]. Compared comparison to the control [165]. The polymorphisms of with DHBMA, MHBMA3 exhibits stronger correlation some metabolism- and DNA repair-related genes, and a with the serum level of cotinine, the well-known bio- folate metabolism-related gene were observed to affect marker for smoking [139]. In addition, the MHBMA3 the NPB and nuclear bud frequency [165–167]. levels also show significant differences among a variety Additionally, it is noted that a study performed in Italy of subpopulations [64, 142, 149]. Clearly, MHBMA3 is observed a statistically significant increase in the MN the best urinary biomarker for biomonitoring BD expos- frequency of exfoliated buccal cells in petroleum refinery ure in the general population. workers and also residents living in areas close to the petroleum refinery industry [168]. However, the cohort was small (n = 50) and the BD concentrations were not Genotoxicity of BD in humans measured. Genotoxicity of BD in humans, as assessed in many mo- In summary, these studies indicate that BD at levels of lecular epidemiology studies, has been thoroughly occupational exposure is genotoxic to humans and can reviewed in 2010 by Albertini et al. [7]. After that, only cause chromosome damage as assessed by the CBMN five studies, which were performed by two groups of assay. However, a vast majority of studies published be- Chinese researchers, have been published. Therefore, we fore 2010 have failed to observe genotoxicity of BD in will only provide a brief update on the issue. humans [7]. It seems to be an issue of selection of assays Chen and Zhang Genes and Environment (2022) 44:3 Page 12 of 22 and endpoints, because the previous studies examined more than half of 63 participants were black people (n = the mutations of the hypoxanthine-guanine phosphori- 35, 55.6%) [177]. bosyltransferase (HPRT) gene, and induction of chromo- The observation that BD exposure was associated with some aberrations and SCE [7]. Thus, the CBMN assay CVD in black male was echoed by a newly published appears to be the technique of choice to detect genotoxi- study, in which the urinary levels of DHBMA were ob- city of BD in humans. Chromosome damage detected served to exhibit strong associations with the urinary with the assay may be used as an effect biomarker to as- levels of norepinephrine and normetanephrine (two sess cancer risk induced by BD [169]. CVD risk markers) in black participants of a cohort of 346 non-smokers [148]. The result suggested that expos- Associations between BD exposure and diseases ure to BD was associated with endothelial dysfunction Exposure to BD has been associated with a variety of and may contribute to elevated risk of hypertension in diseases. First and foremost, as a human carcinogen, oc- people with increased sympathetic tone, particularly in cupational exposure to BD has been causally associated black individuals [148]. with lymphohematopoietic cancers, especially leukemia Lin et al. recently reported a positive correlation be- [1, 2, 4]. With regard to specific forms of leukemia, the tween the urinary DHBMA levels and the CVD risk fac- epidemiological studies of a cohort of synthetic rubber tors, including carotid intima-media thickness, endothelial industry workers at six North American plants support microparticles, and platelet microparticles [178]. However, an association between BD exposure and lymphoid the study was conducted in young Taiwanese. leukemia, but not myeloid leukemia, non-Hodgkin’s The association between BD exposure and CVD is lymphoma, and multiple myeloma [170–173]. supported by animal experiments [179, 180]. Crotonal- BD exposure has also been associated with diseases dehyde, a minor BD metabolite, might play a role in the other than lymphohematopoietic cancers, including car- etiology [181]. diovascular disease (CVD), reproductive effects, child- hood leukemia, etc. It is worth noting that children may Reproductive effects be one of the subpopulations with greater susceptibility BD has been considered to have reproductive and devel- to the toxic effects of BD than the general population; in opmental effects [182]. However, so far the effects have fact, most epidemiological studies over the last decade been observed dominantly in rodents; these effects include have been conducted on children. Thus, the studies of reduced fetal weight, fetal death, ovarian atrophy, and tes- the adverse effects of BD on children’s health will be dis- ticular atrophy, and the most sensitive endpoints are ovar- cussed in a separate section. ian atrophy in female mice and testicular atrophy in male mice [1, 183]. DEB may be the critical metabolite to in- CVD duce the reproductive effects [1, 182]; Dong et al. reported The association between BD exposure and CVD was first that DEB caused the proliferation inhibition and marked noticed in 1990. Interestingly, the association was ob- cell cycle arrest at the G2 phase but not apoptosis in served only in a specific subpopulation, i.e., black male. mouse spermatocyte-derived GC-2 cells [86]. In a study to investigate the mortality among workers at The studies of the reproductive effects of BD on humans a BD facility, Divine reported a significantly elevated have been extremely scarce. The data from an earlier standardized mortality ratio (SMR) in non-white males study on Czech female workers exposed to BD showed no for all causes of death, including arteriosclerotic heart difference in pregnancy outcomes (e.g., miscarriage, still disease [174]. The data from another study to investigate birth, ectopic pregnancies) between exposed subjects and 12,110 male workers in eight styrene-BD polymer manu- controls. However, the numbers of the subjects and con- facturing plants indicated a significant excess SMR for trols in this study are small (n = 23 and 26, respectively) arteriosclerotic heart disease (SMR = 1.48) in black [184]. In a recently published study conducted in Portland, workers than in the general population [175]. In 1996, Oregon, U.S., Willis and Hystad used vital statistics re- Divine and Hartman reported updated data and similarly cords from 2000 to 2014 (n = 279,051 births) to assess found that, in the cohort of 2,795 male workers at a BD prenatal exposure to 19 air pollutants. They observed as- facility, the non-white workers showed a statistically sig- sociations in fully adjusted models comparing the highest nificant elevated SMR for all causes of death, including to lowest quintiles of exposure for certain pollutants, in- arteriosclerotic heart disease (SMR = 1.42) [176]. In a cluding the associations between BD and term birth cross-sectional study, Shin et al. observed that BD- weight [−16.86 g; 95% confidence interval (CI) = −29.66- related VOCs decreased diastolic blood pressure but in- −4.06; p < 0.05], and between BD and small for gestational creased heart rate and brachial artery diameter, suggest- age [odds ratio (OR) = 1.18; 95% CI = 1.07-1.30; p <0.05] ing that BD and other VOCs may have rapid impacts on [185]. Another recent study indicated that there might be the human cardiovascular system [177]. In this study, a potential association between BD exposure and male Chen and Zhang Genes and Environment (2022) 44:3 Page 13 of 22 infertility. Poli et al. reported that the urinary DHBMA risks could be attributable to mutual confounding, BD levels were negatively correlated with sperm count and was found to be a powerful independent predictor [194]. sperm abnormal forms, and oxidative stress on the male For the first time, BD was identified as a specific hazard reproductive tract may play an important role [186]. for childhood cancers, although in these studies, child- hood leukemia was not singled out [193]. Adverse effects on pulmonary functions The finding was reinforced by subsequent studies. In Occupational exposure to high concentrations of BD an ecologic study in Texas, U.S., Whitworth et al. inves- may have adverse effects on pulmonary functions, in- tigated 977 cases of childhood lymphohematopoietic cluding vital capacity, forced vital capacity, forced ex- cancer diagnosed from 1995-2004. The researchers ex- piratory volume in the first second, and peak expiratory amined whether the census tracts with the highest esti- flow. An investigation on workers in a petrochemical mated levels of benzene and BD had higher incidence plant in Iran found that compared to the control, the rates of childhood lymphohematopoietic cancer com- workers had considerably higher prevalence rates of pared with the census tracts with the lowest estimated cough, phlegm, wheezing, shortness of breath, chest levels. Indeed, among the census tracts with the highest tightness, and episodes of chest illness associated with BD levels, they observed significantly higher rates of all cold. Furthermore, their pulmonary functions were also leukemia [rate ratio (RR) = 1.40; 95% CI = 1.07-1.81], lower in comparison with the control and the differences and elevated rates of the two most common types of were statistically significant (p < 0.05) [187]. However, it childhood leukemia, acute myeloid leukemia (AML) (RR should be noted that the workers were exposed to high = 1.68; 95% CI = 0.84-3.35) and acute lymphocytic BD concentrations (the average concentration reached leukemia (ALL) (RR = 1.32; 95% CI = 0.98-1.77), but the 560.82 μg/m ), although the BD levels are still below the data for AML and ALL were not statistically significant threshold recommended by the American Conference of [195]. The same laboratory further investigated whether Governmental Industrial Hygienists [187]. in utero and early life exposure to BD and other pollut- ants was associated with childhood leukemia, and indeed Associations between BD exposure and diseases in a observed positive associations between exposure to BD specific subpopulation - children and childhood leukemia (under the age of 5) in either Most epidemiological studies over the last decade to in- single or co-pollutant models [196]. In another investiga- vestigate the associations between BD exposure and dis- tion conducted in California, U.S., Heck et al. found that eases were conducted in children. Exposure to BD has in infancy, AML was positively associated with exposure been reported to show associations with several childhood to BD (OR = 2.35; 95% CI = 1.02-5.39), o-xylene (OR = diseases, including childhood leukemia, brain tumors, aut- 1.88; 95% CI = 1.02-3.45), and toluene (OR = 2.02; 95% ism, asthma, etc. The studies are discussed below. CI = 1.03-3.94) [197]. Childhood leukemia Childhood brain tumors Childhood leukemia accounts for approximately 30% of The association between exposure to BD and childhood all childhood cancers in the United States, and a signifi- brain tumors has also been reported. Danysh et al. con- cant increase in the incidence has been observed in Eur- ducted a population-based study in Texas, U.S., and ob- ope and in other developed countries over the past 30 served that the census tracts with medium and medium- years [119]. In the meantime, the etiology of childhood high BD concentrations had higher astrocytoma inci- leukemia remains poorly understood and few established dence rates (RR = 1.46; 95% CI = 1.05-2.01 and RR = risk factors have been identified. Over the last 20 years, 1.69; 95% CI = 1.22-2.33, respectively) compared with there has been increasing focus on environmental pollut- low concentrations. Increased concentrations of BD and ants, especially, the traffic-related pollutants [188–192]. benzene were observed to be strongly associated with in- As a traffic-related air pollutant and a known human creased primitive neuroectodermal tumor (PNET) inci- carcinogen that has causally been associated with dence rates, but the associations were not statistically leukemia, BD has naturally received much attention in significant [198]. In a subsequent study, the group evalu- the investigations for the etiology of childhood leukemia. ated the influence of residential mobility on the expos- The association between childhood cancers, including ure assignment and concluded that residential mobility childhood leukemia, and exposure to a variety of air pol- of children did not significantly impact the exposure as- lutants (CO, NO , VOCs, dioxins, etc.) was first reported signment of BD [199]. In another study in California, by Knox in two successional studies, in which elevated U.S., von Ehrenstein et al. found that central nervous risks of childhood cancers were observed among chil- system PNETs were positively associated with interquar- dren whose residence was near a “hot spot” of benzene tile range (IQR) increases in prenatal exposure to acetal- or BD emissions [193, 194]. Although some increased dehyde (OR = 2.30; 95% CI = 1.44-3.67), BD (OR = 2.23; Chen and Zhang Genes and Environment (2022) 44:3 Page 14 of 22 95% CI = 1.28-3.88), benzene, and toluene; and also with Childhood asthma IQR increases in exposure during the first year of life to In a recently published article, Kuang et al. compared o-dichlorobenzene (OR = 3.27; 95% CI = 1.17-9.14), BD the differences in several biomarker levels between asth- (OR = 3.15; 95% CI = 1.57-6.32), and benzene. The au- matic and healthy children. DHBMA was used as the thors concluded that in utero and infancy exposures to biomarker of BD. The results indicated that the urinary air toxics generated by industrial and road traffic sources levels of DHBMA and biomarkers of other pollutants may increase the risk of PNETs and medulloblastoma, were significantly associated with asthma (for DHBMA, with limited support for increased risks for astrocytoma OR = 2.76; 95% CI = 1.73-4.43). Oxidative stress may in children up to age 6 [200]. play an important role, because these biomarkers exhib- ited strong correlations with 8-hydroxy-2′-deoxyguano- sine levels, which were significantly higher in asthmatic Other childhood tumors children than those in healthy children [204]. Besides childhood leukemia and brain tumors, BD ex- posure has also been found to be potentially associated The role of BD in smoking-associated diseases with other childhood cancers. Heck et al. examined am- Tobacco smoke contains over 6,000 compounds, of bient exposure to 27 air toxics in the perinatal period in which more than 70 compounds have been classified as relation to retinoblastoma development with the disease human carcinogens [205–207]. BD is one of the carcino- diagnosed during 1990-2007 in California, U.S. They ob- gens with the largest amounts in mainstream smoke; its served that retinoblastoma risk increased with pregnancy typical yield is 52 μg/cigarette, which is more than 400- exposure to benzene (OR = 1.67; 95% CI = 1.06-2.64) fold higher than 4-(methylnitrosamino)-1-(3-pyridyl)-1- and other six toxics that primarily arise from gasoline butanone (NNK), a strong tobacco-specific carcinogen and diesel combustion and are highly correlated, includ- [208]. In terms of cancer risk, BD has been ranked as ing BD (OR = 1.59; 95% CI = 1.08-2.35) [201]. Prenatal the most carcinogenic compound in cigarette smoke exposure to air toxics, including BD, was also observed among 40 carcinogens with cancer potency factors being to be positively associated with malignant germ cell tu- available [209]. mors (GCTs) in young children [202]. In a case-control Tobacco smoking has been associated with an array of study, Hall et al. identified 243 GCT cases, which were diseases, including many types of cancers (e.g., lung can- matched by birth year to cancer-free population controls cer, liver cancer, bladder cancer, and leukemia), diabetes (n = 147,100) from 1984 to 2013 in California, U.S. They mellitus, CVD, asthma, etc. [210]. In spite of the ranking observed that prenatal exposure to traffic-related air of BD as the top carcinogen in cigarette smoke, the con- toxics during the second trimester increased GCT risk, tribution of BD in tobacco smoking-associated diseases, particularly BD (OR = 1.51; 95% CI = 1.01-2.26) and m-/ in particular, cancers, has not been elucidated. p-xylene (OR = 1.56; 95% CI = 1.10-2.21). A further ana- BD is listed as a likely but minor causative agent for lysis by subtype indicated elevated ORs for yolk sac tu- cigarette smoke-related lung and larynx cancers, mostly mors but no teratomas [202]. based on its tumorigenesis in mice [205, 208, 211]. How- ever, the latest epidemiological study on more than 20,000 workers employed at eight North American syn- Childhood autism thetic rubber polymer plants from 1943 through 2009, The etiology of autism is heterogeneous and little is which is the largest cohort for occupational exposure to known about its nongenetic causes, but environmental BD, found that there was no causal association between factors have been suggested as major contributors. It has BD exposure and lung cancer [212]. This study and the been reported that in utero BD exposure is associated authors’ earlier investigations indeed observed elevated with childhood autism [203]. In a population study, von rates of lung cancer among female workers, however, Ehrenstein et al. identified 768 cases of autism from the authors thought that it may be caused by other fac- 148,722 children in Los Angeles County, California, U.S., tors rather than exposure to BD due to the lack of a during 1998-2009. They found that autism risks in- positive exposure-response trend [172, 213–215]. The creased per interquartile range increase in average con- observation also obtains support from other independent centrations during pregnancy of several correlated toxics studies, including an investigation on the relationships mostly loading on 1 factor, including BD (OR = 1.59; between several carcinogens in cigarette smoke and lung 95% CI = 1.18-2.15), m-/p-xylene (OR = 1.51; 95% CI = cancer in a Chinese cohort [216], an ecological study at 1.26-1.82), and other pollutants, adjusting for maternal the country level conducted in the United States [217], age, ethnicity/race nativity, education, insurance type, and an investigation on cancer incidence in a petro- parity, child sex, and birth year [203]. chemical industry area in Sweden [218]. Moreover, in a U.S. study to compare the BD metabolism in smokers in Chen and Zhang Genes and Environment (2022) 44:3 Page 15 of 22 three ethnic/racial groups (Native Hawaiians, whites, Discussion and perspective and Japanese Americans), Park et al. found that the The studies of BD over the last decade have brought MHBMA levels in Native Hawaiian smokers were sig- some important developments, among which the adverse nificantly lower compared to those in white smokers, effects on children’s health are probably the most pro- suggesting that Native Hawaiian smokers had lower BD found issue. However, more carefully-designed studies uptake rates or metabolized BD to EB and then are needed to provide further evidence for these MHBMA less efficiently than whites [219]. However, it findings. has been established that for the same lifetime smoking In epidemiological studies, it is a critical issue to deter- exposure, Native Hawaiian smokers have a significantly mine human exposure to BD. Currently, most epidemio- greater risk of lung cancer than do whites [220]. Thus, logical studies estimated human exposure to BD based the finding of Park et al. actually provides indirect sup- on its concentrations in the ambient air. However, the port for the epidemiological observation that BD expos- approach can cause great uncertainties for studies con- ure has no causal association with lung cancer. ducted in the general population. As pointed out by Collectively, the studies suggest that BD is not a human Fujita et al., estimates of population exposure to air pol- lung carcinogen and thus is not expected to contribute lutants extrapolated from ambient measurements at am- to smoking-associated lung cancer. bient fixed site monitors are prone to uncertainty [48]. In spite of the fact that BD is listed as a minor contrib- Multiple studies have indicated that microenvironments, uting agent for larynx cancer [205], in fact, the studies especially those at home, are the main determinant of concerning BD exposure and larynx cancer have been human exposure and the BD concentrations in microen- very scarce. A few studies to investigate the mortality in vironments are often unrelated to those in the ambient workers from the styrene-BD rubber industry and the air. Moreover, several population studies has consistently BD production industry found that certain subgroups of demonstrated that with regard to human exposure to workers had more than expected deaths from larynx BD, ETS is the primary source in the general population. cancer [175, 176, 215]. However, the results were all Therefore, for epidemiological studies on the general based on small numbers and thus were statistically im- population, a reliable estimate of human exposure to BD precise. Moreover, the excess in larynx cancer was not is desirable. Currently, the best approach can be using clearly associated with any process group, suggesting the urinary levels of BD biomarkers (preferably that the increases were not due to BD exposure [215]. It MHBMA3) as the metric for assessing human exposure, should be noted that a positive association has indeed although it should be kept in mind that the urinary bio- been observed between occupational exposures in the markers reflect only recent exposures. rubber-manufacturing industry and larynx cancer [4]. The finding that BD has natural sources from trees However, the observation is unable to relate the develop- and soil bacteria is intriguing. However, so far only two ment of larynx cancer to exposure to specific chemicals tree species and a strain of soil bacterium have been re- because the rubber-manufacturing industry uses a wide ported to release BD. Thus, it is worth further explor- variety of substances. In addition, a review of literature ation whether other species of plants and bacteria can on the contribution of various types of occupational ex- also generate BD. If the quantities generated by plants posure to rare cancers does not list BD as a possible are large enough, it may have an impact on human ex- contributor to larynx cancer [221]. posure to BD and it is also likely that BD can play a role Because cigarette smoke is a known risk factor for in atmosphere chemistry. urothelial carcinoma, a recent case-control study investi- Because BD must undergo bioactivation to exert its gated the relationships among smoking, urinary levels of toxic effects, including mutagenicity/carcinogenicity, ob- several VOC biomarkers, and urothelial carcinoma risk. viously identifying the specific BD metabolite(s) that However, no association between the levels of dominantly contribute to the toxic effects, particularly in MHBMA3 or DHBMA and the risk of urothelial carcin- humans, is at the core of the underlying molecular oma has been discovered [144]. mechanisms of BD toxicity. However, so far the issue Taken together, it appears that BD may not contribute has not been addressed, largely because the metabolism to pathogenesis of cigarette smoking-associated cancers of BD is quite complex and more than 10 potential me- of lung and larynx. Because BD has been associated with tabolites, most of which are genotoxic, can be formed [1, leukemia and some types of childhood tumors, and non- 101, 102]. Making matters worse, each of the major me- carcinogenic effects such as CVD and asthma, it is likely tabolites, e.g., EB, DEB, EBD, and CHB, contains stereo- that BD is involved in these diseases caused by smoking. isomers due to the presence of chiral carbon atoms in However, to our knowledge, so far no studies to investi- these molecules, and importantly, the stereoisomers can gate the associations have been published. have different bioactivity (e.g., cytotoxicity and mutage- nicity) [6, 7, 94, 99]. In addition, the metabolism of BD Chen and Zhang Genes and Environment (2022) 44:3 Page 16 of 22 has great species difference [1, 6, 7], leading to extra dif- bis(N-acetyl-L-cystein-S-yl)butane-2,3-diol; bis-N7G-BD: 1,4-bis(gua-7-yl)-2,3- butanediol; CBMN: cytokinesis-block micronucleus; CBO: 1-chloro-2-buten-2- ficulty for studies on humans. Nonetheless, addressing one; CEB: 1-chloro-3,4-epoxy-2-butanol; CHB: 1-chloro-2-hydroxy-3-butene; the issue should be a major research direction for future CI: confidence interval; CPD: cigarettes smoked per day; CVD: cardiovascular studies. disease; DEB: 1,2,3,4-diepoxybutane; DHBMA: N-acetyl-S-(3,4-dihydroxybutyl)- L-cysteine; EB: 3,4-epoxy-1-butene; EB-GI: N7-(2-hydroxy-3-buten-1-yl)guanine; Currently, it is generally assumed that mutagenicity/ EB-GII: N7-[1-(hydroxymethyl)-2-propen-1-yl]guanine; EBD: 3,4-epoxybutane- carcinogenicity of BD is caused by the epoxide metabo- 1,2-diol; EPA: the U.S. Environmental Protection Agency; ETS: environmental lites formed via the P450-mediated metabolism. Interest- tobacco smoke; GCTs: germ cell tumors; GSH: glutathione; HAPs: hazardous air pollutants; HMVK: hydroxymethyl vinyl ketone; HPRT: hypoxanthine- ingly, all epidemiological studies that have been guanine phosphoribosyltransferase; IARC: the International Agency for published so far have not discovered any associations be- Research on Cancer; IQR: interquartile range; LOD: limit of detection; tween BD exposure and cancers of lung, liver, and kid- MHBMA: monohydroxybutenyl mercapturic acid; MHBMA1: N-acetyl-S-[1- (hydroxymethyl)-2-propen-1-yl]-L-cysteine; MHBMA2: N-acetyl-S-(2-hydroxy-3- ney, the major organs that are responsible for uptake buten-1-yl)-L-cysteine; MHBMA3: N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L- and biotransformation of BD. Counterintuitively, the tar- cysteine; MN: micronucleus; MPO: myeloperoxidase; NAC: N-acetyl-L-cysteine; get organ for BD carcinogenicity in humans is the lym- NC1:: 1,4-bis(N-acetyl-L-cystein-S-yl)-2-butanone; NNK: 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone; NPB: nucleoplasmic bridge; OR: odds ratio; phohematopoietic system, an organ that seems not to be P450s: cytochrome P450 enzymes; PBL: peripheral blood lymphocytes; involved in the formation of P450-mediated epoxides. PNET: primitive neuroectodermal tumor; RR: rate ratio; SCE: sister-chromatid Why BD is not carcinogenic in the major human organs exchange; SMR: standardized mortality ratio; TBW: term birth weight; THBMA: N-acetyl-S-(2,3,4-trihydroxybutyl)-L-cysteine; VOCs: volatile organic for uptake and metabolism is an intriguing issue. While compounds extrahepatic toxicity is a likely explanation, the MPO- mediated metabolic pathway seems to provide an at- Acknowledgements We thank Professor Yang Luan for inviting us to submit a manuscript for the tractive alternate because the pathway is expected to special collection in the Genes and Environment journal. occur exactly in the lymphohematopoietic system. Ad- dressing the issue is an important research direction be- Authors’ contributions cause it concerns the molecular mechanisms of BD Both authors wrote the paper. Each author read and approved the final manuscript. mutagenicity/carcinogenicity and can have significant impact on the risk assessment of BD. Funding Although having been studied for 40 years, our under- Research related to this review was supported by the National Nature standing of the molecular mechanisms of BD toxicity Science Foundation of China (Nos. 21077070, 21377080, and 21976120) and the Shanghai Municipal Education Commission (No. 11ZZ90). has still been limited. Besides the associations with dis- eases that have been discovered, it is likely that BD con- Availability of data and materials tributes to other adverse effects on human health or the Not applicable. etiology of other diseases, in particular, as a factor to Declarations promote disease progression rather than as a disease- initiating factor. Considering that BD is a ubiquitous Ethics approval and consent to participate pollutant, the direction deserves more attention. Not applicable. Consent for publication Conclusions Not applicable. BD is a ubiquitous environmental mutagen/carcinogen with high cancer risk. Its major environmental sources Competing interests The authors declare that they have no competing interests. include automobile exhaust and tobacco smoke. The studies over the last decade have shown that microenvi- Received: 6 August 2021 Accepted: 27 December 2021 ronments, particularly indoor microenvironments, are the primary determinant of exposure of the general References population to BD, with tobacco smoke being the main 1. U.S. EPA. Health assessment of 1,3-butadiene. National Center for source. While it has been known for more than 20 years Environmental Assessment, Washington, DC, 2002. EPA/600/P-98/001F. that occupational exposure to BD is associated with Available at http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=54499 (accessed August 6, 2021). leukemia and CVD, recent progress shows that non- 2. IARC. 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Journal

Genes and EnvironmentSpringer Journals

Published: Jan 10, 2022

Keywords: Butadiene; Environmental mutagen and carcinogen; Human exposure; Microenvironments; Urinary biomarkers; Cigarette smoking; Lung and larynx cancers; Adverse health effects; Children’s health

References