Download Electrophilic agents and more Schemes and Mind Maps Acting in PDF only on Docsity!
Introduction
In this chapter, electrophilic agents include direct-acting electrophilic chemicals and chemicals that are metabolized to reactive electro- philes. All of the chemicals discussed here are IARC Group 1 agents and as such can be characterized as carcinogenic to humans. Relevant carcinogens discussed in this chap- ter do not include pharmaceutical drugs classified in Group 1, which otherwise typically include alkylating cytotoxic agents. Tumour sites identified in previous IARC evaluations of the carcinogen- icity of several non-pharmaceutical organic compounds in humans and laboratory animals are shown in Table 1.1. For each of these agents, there was sufficient evidence of car- cinogenicity from studies in rats and/ or mice and, except for ethylene oxide, sufficient evidence of carci- nogenicity from studies of exposed humans. For ethylene oxide, there was limited evidence of carcinogen- icity in humans, but the classification of this chemical was raised to carci- nogenic to humans (Group 1) based on strong mechanistic evidence of mutagenicity and clastogenici- ty, including the induction of sister chromatid exchange (SCE), chro- mosomal aberrations (CA), and mi- cronuclei (MN) in workers exposed to ethylene oxide. Among this group of chemicals, there is remarkable concordance in tumour sites with sufficient evidence or limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in rats and/or mice, for example for the liver (aflatoxins, trichloroethylene [TCE], and vinyl chloride), the lung (sulfur mustard), the lymphohaematopoietic system (benzene, 1,3-butadiene, and eth- ylene oxide), nasal tissue (formal- dehyde), and the kidney (TCE). For bis(chloromethyl)ether (BCME), the lung and the nasal cavity were iden- tified as target organs in humans and rats, respectively. In addition, angiosarcomas of the liver, which are rare tumours, were identified in humans, rats, and mice exposed to vinyl chloride. In several instances, tumour sites identified in animals were not de- tected in epidemiological studies of exposed workers. These apparent discrepancies may be due to dif- ferences in susceptibility between humans and certain animal mod- els, differences in exposure con- ditions between studies in animals and in humans, or limitations in Part 1 • Chapter 1. Electrophilic agents
part 1.
concordance between cancer in humans and in experimental animals chapter 1.
Electrophilic agents
James A. Bond and Ronald L. Melnick PART 1 CHAPTER 1
Table 1.1. Tumour sites in humans, rats, and mice for electrophilic agents Agent Humans Rats Mice Sufficient evidence Limited evidence Sufficient evidence Sufficient evidence Aflatoxins Liver: hepatocellular carcinoma Liver: hepatocellular carcinoma Benzene Acute myeloid leukaemia Acute lymphoblastic leukaemia Chronic lymphocytic leukaemia Multiple myeloma Non-Hodgkin lymphoma Oral cavity: carcinoma Forestomach: squamous cell carcinoma Skin: squamous cell carcinoma Zymbal gland: carcinoma Lymphoid tissue: lymphoma Haematopoietic tissue: granulocytic leukaemia Mammary gland: adenocarcinoma Lung: bronchiolo-alveolar carcinoma Zymbal gland: carcinoma Preputial gland: squamous cell carcinoma Bis(chloromethyl)ether (BCME) Lung Nasal cavity: olfactory neuroblastoma Soft tissue: sarcoma Skin: fibrosarcoma 1,3-Butadiene Lymphohaematopoietic Lymphoid tissue: lymphoma Soft tissue: haemangiosarcoma Liver: hepatocellular carcinoma Mammary gland: adenocarcinoma Lung: bronchiolo-alveolar carcinoma Forestomach: squamous cell carcinoma Harderian gland: carcinoma Preputial gland: squamous cell carcinoma Ethylene oxide Lymphohaematopoietic (non-Hodgkin lymphoma, multiple myeloma, chronic lymphocytic leukaemia) Breast Brain: glioma Lymphoid tissue: lymphoma Peritoneum: mesothelioma Lung Formaldehyde Nasopharynx Leukaemia Paranasal sinuses Nasal cavity: squamous cell carcinoma Sulfur mustard Lung Larynx Lung Trichloroethylene (TCE) Kidney Non-Hodgkin lymphoma Liver Kidney Liver Lung Vinyl chloride Liver: angiosarcoma Liver: hepatocellular carcinoma Liver and extrahepatic: angiosarcoma Liver: hepatocellular carcinoma Mammary gland: adenocarcinoma Zymbal gland: carcinoma Liver and extrahepatic: angiosarcoma Lung: bronchiolo-alveolar carcinoma Mammary gland: adenocarcinoma
degree of bioavailability. Sulfur mus- tard is a bifunctional alkylating agent (IARC, 1987). Like for formaldehyde, there is evidence that DNA alkylation by sulfur mustard leads to forma- tion of cross-links, inhibition of DNA synthesis and repair, and induction of point mutations and chromo- some-type and chromatid-type ab- errations (ATSDR, 2003). Some of these changes are observed in nasal tissue, consistent with the nose be- ing a target organ for sulfur mustard. BCME and chloromethyl methyl ether (CMME) are highly reactive or- ganic compounds that belong to the group of chloroalkyl ethers, which are flammable, volatile, colourless liquids with highly irritating odours. In water and aqueous biological fluids, these substances are rapid- ly hydrolysed to form hydrochloric acid, methanol, and formaldehyde (Nichols and Merritt, 1973; National Toxicology Program, 2004). The car- cinogenic effects of BCME are re- stricted to the epithelial tissue where exposure occurs, namely the lung for humans and respiratory tract tis- sues for laboratory animals exposed to BCME by inhalation. This por- tal-of-entry effect is consistent with the short half-life of BCME in aque- ous media (ATSDR, 1989). BCME is among the most potent animal and human carcinogens known. The fact that BCME and CMME are powerful alkylating agents provides moderate to strong evidence that they oper- ate by a genotoxic mechanism. This mechanism is likely to be similar to that of other strong alkylating agents, involving modification of DNA and resultant mutations. BCME can also be absorbed through the skin, and studies in which mice were ex- posed to BCME by dermal applica- tion demonstrated that this agent is a potent complete skin carcinogen, producing both papillomas and squa- mous cell carcinomas (Van Duuren et al., 1969). Ethylene oxide is a water-soluble volatile organic compound that is rel- atively stable in aqueous solutions at neutral pH (half-life, approximately 72 hours). Because it is completely miscible with water, inhaled ethylene oxide will dissolve in the aqueous lin- ing of the respiratory tract and diffuse into the blood. Thus, uptake of this organic compound will be substantial throughout the respiratory tract. Volatile organic compounds that are not reactive or water-soluble are generally absorbed into the blood, primarily in the pulmonary region of the respiratory tract because of the large blood–tissue interface of the alveoli in that region. The blood–air partition coefficient is a key factor in determining the maximum levels of the organic compound that can be attained in the blood at any given concentration of the compound in air. For example, the blood–air partition coefficients for the carcinogens vinyl chloride, 1,3-butadiene, benzene, and TCE are 1.2, 1.5, 7.8, and 10 respectively. At equivalent air con- centrations, higher levels of benzene and TCE will be present in the blood at steady state, compared with vinyl chloride and 1,3-butadiene. The organic compounds dis- cussed here can also be absorbed after oral exposure. Ingestion and subsequent oral absorption repre- sent the greatest potential route of exposure to non-volatile organic compounds. Organic chemicals may enter the body via food or in liquids. Aflatoxin is a compound for which ingestion is considered the most important route of exposure. For ex- ample, human uptake of aflatoxins in quantities of nanograms to micro- grams per day occurs mainly through consumption of contaminated maize and peanuts, which are dietary sta- ples in some tropical countries. Uptake of aflatoxin M 1 in quantities Table 1.2. Mechanisms for formation of electrophilic species Agent Mechanism Electrophilic species Bis(chloromethyl)ether (BCME) Direct-acting Chloroalkyl ether Chloromethyl methyl ether (CMME) Direct-acting Chloroalkyl ether Ethylene oxide Direct-acting Epoxide Formaldehyde Direct-acting Aldehyde Sulfur mustard Direct-acting Sulfonium ion Aflatoxins Metabolic activation Epoxide Benzene Metabolic activation Quinone, epoxide, aldehyde 1,3-Butadiene Metabolic activation Epoxides Trichloroethylene (TCE) Metabolic activation Epoxide, thioketene Vinyl chloride Metabolic activation Epoxide
of nanograms per day occurs main- ly via consumption of aflatoxin-con- taminated milk, including breast milk (IARC, 2002). Once absorbed from the gastrointestinal tract, aflatoxins are transported via the hepatic por- tal blood to the liver, where they are metabolized. As discussed below, metabolism is key to understanding the carcinogenicity of aflatoxins.
Metabolic activation or
detoxification and elimination
Metabolism plays a key role in both the activation and the detoxification of many organic compounds. The first step, generally called phase I metabolism, is oxidation to a meta- bolic intermediate. This intermediate becomes the substrate for the sec- ond step, phase II, in which it is en- zymatically hydrolysed or conjugated with one of a variety of biological sub- strates, such as sulfate, glucuronic acid, or glutathione (GSH). Phase II reactions increase the water solubil- ity of the chemical, which facilitates its excretion in urine, or increase the molecular weight, so that the agent is more readily eliminated in bile. Phase I metabolism of organic com- pounds can also result in formation of reactive intermediates that can spontaneously interact with critical macromolecules. For many organic chemicals, this is the first key step in the carcinogenic process. Cytochrome P450 (CYP450) is the collective name of the family of enzymes responsible for the initial phase I metabolism of many organ- ic compounds. Metabolic activation by various CYP450 isozymes is a key first step in the carcinogen- ic process for aflatoxin, benzene, 1,3-butadiene, TCE, and vinyl chlo- ride. For example, in the mechanism of carcinogenicity of aflatoxins, the key steps involve: metabolism to a reactive exo -epoxide; binding of the exo -epoxide to DNA, resulting in the formation of DNA adducts; and miscoding during DNA replication, which leads to development of mu- tations, with eventual progression to tumours. Aflatoxin B 1 , the most com- mon and potent of the aflatoxins, is metabolized predominantly in the liver. In humans, CYP1A2, CYP2B6, CYP3A4, CYP3A5, and CYP3A7, as well as the phase II enzyme glu- tathione- S -transferase M1 (GSTM1; see below) are hepatic enzymes that mediate aflatoxin metabolism. In humans, the relative contribution of these enzymes in vivo depends not only on their affinity but also on their expression level in the liv- er, where CYP3A4 is predominant, mediating the formation of the afla- toxin B 1 exo -epoxide and aflatoxin Q 1. In humans, as in other species, the DNA binding and carcinogenicity of aflatoxin B 1 result from its con- version to the exo -8,9-epoxide by CYP3A4 (Essigmann et al., 1982). This epoxide is highly reactive and is the main mediator of cellular injury (McLean and Dutton, 1995). In con- trast, CYP1A2 can generate some exo -epoxide but also a high propor- tion of endo -epoxide and aflatoxin M 1. Aflatoxins M 1 and Q 1 , produced from aflatoxin B 1 by CYP1A2 and CYP3A4, respectively, are present in the urine of individuals exposed to aflatoxins (Ross et al., 1992; Qian et al., 1994). Benzene is also a substrate for CYP450 enzymes. In common with other compounds discussed in this section, benzene must be metabo- lized to become carcinogenic (Ross, 2000 ; Snyder, 2004 ). The initial metabolic step involves CYP450- dependent oxidation to benzene ox- ide, which exists in equilibrium with its tautomer oxepin. It has been re- ported that benzene is most likely to be metabolized via two CYP enzymes, rather than just one, and that the putative, high-affinity enzyme is active primarily at ben- zene concentrations below 1 ppm (Rappaport et al., 2009). Whereas CYP2E1 is the primary enzyme re- sponsible for mammalian metabol- ism of benzene at higher levels of exposure (Valentine et al., 1996 ; Nedelcheva et al., 1999), CYP2F and CYP2A13 have been proposed as enzymes that metabolize ben- zene at environmental levels of expo- sure, i.e. below 1 ppm (Powley and Carlson, 2000; Sheets et al., 2004; Rappaport et al., 2009). A large proportion of benzene oxide spontaneously rearranges to phenol, which is either eliminated via phase II conjugation or further metab- olized to hydroquinone and 1,4-ben- zoquinone. The remaining benzene oxide is either hydrolysed to produce benzene-1,2-dihydrodiol (catechol), which is further oxidized to 1,2-ben- zoquinone, or conjugated with GSH to produce S -phenylmercapturic acid. Metabolism of the oxepin tau- tomer of benzene oxide is thought to open the aromatic ring; this yields the reactive muconaldehydes and mu- conic acid. Benzene oxide, the ben- zoquinones, the muconaldehydes, and the benzene dihydrodiol epox- ides (formed from CYP450-mediated oxidation of benzene dihydrodiol) are electrophiles that react readily with peptides, proteins, and DNA (Bechtold et al., 1992 ; McDonald et al., 1993 ; Bodell et al., 1996 ; Gaskell et al., 2005; Henderson et al., 2005 ; Waidyanatha and Rappaport, 2005 ), thereby interfering with cellu- lar function (Smith, 1996). The role of these different metabolites in the car- cinogenicity of benzene remains un- clear, but formation of benzoquinone from hydroquinone via myeloperoxi- dase in the bone marrow has been Part 1 • Chapter 1. Electrophilic agents PART 1 CHAPTER 1
species at higher exposures, but at lower exposures oxidation is limited by the hepatic blood flow. Conjugation with GSH is another important metabolic pathway for TCE, resulting in the formation of short- lived and reactive metabolites. The initial conjugation reaction occurs primarily in the liver to form (1,2-di- chlorovinyl)glutathione (DCVG). Subsequent processing of DCVG occurs primarily in the kidney, which is a tumour target site in rats and hu- mans. In the kidney, DCVG can be hydrolysed by γ-glutamyltransferase and cysteinylglycine dipeptidase to 1,2-dichlorovinyl-cysteine (DCVC), which may be N -acetylated to form a mercapturate or converted by β-lyase to generate a reactive thi- olate that rearranges to form either chlorothioketene or chlorothioacetyl chloride (Dekant et al., 1988; Völkel and Dekant, 1998). Chlorothioketene and chlorothioacetyl chloride are highly reactive and chemically un- stable, and are thought to be the molecular forms responsible for ad- duct formation with nucleic acids in the kidney (Müller et al., 1998a, b). For both humans and rodents, the information on urinary excretion of stable end-products is much more extensive for the oxidative pathway than for the GSH conjugation path- way. However, this is not an accurate indication of the overall flux through each pathway, because it does not account for the formation of reactive and chemically unstable metabolites via the GSH conjugation pathway. As noted above, CYP450 en- zymes are not the only enzymes involved in the metabolism of organ- ic compounds. Formaldehyde, an important intermediate in one-car- bon metabolism, is a substrate for several enzymes, including cyto- solic ADH, mitochondrial ALDH, cytosolic GSH-dependent formal- dehyde dehydrogenase, and cat- alase, as well as CYP2E1. One- carbon metabolism not mediated by CYP450 is central to many biologi- cal processes. In aqueous solution, formaldehyde is rapidly converted to its dihydroxy form, methanediol (CH 2 (OH) 2 , also known as formalde- hyde hydrate or methylene glycol), which is in dynamic equilibrium with formaldehyde.
Direct-acting compounds
Some organic compounds discussed here are sufficiently reactive that they do not require metabolic activation as the first step in the carcinogenic process. Formaldehyde reacts read- ily and reversibly with amino groups to form Schiff bases, and with sulf- hydryl groups resulting in the forma- tion of S -hydroxymethylglutathione, which is oxidized by ADH3 to S -formylglutathione. S -formylglu- tathione is further metabolized by S -formylglutathione hydrolase to generate formate and GSH. Formate can also be formed non-enzymati- cally (Hedberg et al., 2002). Because formaldehyde reacts non-enzymat- ically with critical macromolecules (DNA and others), many of these en- zymatic processes can be viewed as detoxification steps, especially those that lead to incorporation of the com- pound into the one-carbon pool. Ethylene oxide is another di- rect-acting alkylating agent that re- acts with nucleophiles without the need for metabolic transformation. The direct reaction of ethylene ox- ide with DNA is thought to initiate the cascade of genetic and related events that lead to cancer (Swenberg et al., 1990). The pathways of ethyl- ene oxide metabolism can thus be considered detoxification pathways that increase the elimination of the parent chemical. Ethylene oxide is converted (i) by enzymatic and non-enzymatic hydrolysis to ethyl- ene glycol, which is partly excreted as such and partly metabolized fur- ther via glycolaldehyde, glycolic acid, and glyoxylic acid to oxalic acid, for- mic acid, and carbon dioxide; and (ii) by conjugation with GSH. Sulfur mustard, BCME, and CMME can also react spontaneous- ly with biological molecules without the need for metabolic activation. For example, the reactivity of sulfur mustard with a wide variety of cel- lular macromolecules is well docu- mented (IARC, 1975, 1987 ; ATSDR, 2003 ). The presence of two chlorine atoms makes it a strong bifunctional alkylating agent with a high chemi- cal reactivity (Dacre and Goldman, 1996 ). The chlorine atom is typically released under formation of a car- bonium ion, which then undergoes intramolecular cyclization to create a highly reactive compound. Formation of the carbonium ion is facilitated in aqueous solutions (Somani and Babu, 1989); this explains the sensi- tivity of mucosal tissues, such as the eye, to its effect (Solberg et al., 1997). Elevated concentrations of thiodigly- col, the major hydrolysis product of mustard gas, were detected in hu- man urine after exposure to mustard gas vapour and aerosol (Jakubowski et al., 2000). BCME and CMME are rapidly hydrolysed in water and in aqueous biological fluids to form hy- drochloric acid, methanol, and form- aldehyde (Nichols and Merritt, 1973; National Toxicology Program, 2004).
Molecular interactions (DNA
adducts, genetic alterations,
etc.)
A common feature of the above-men- tioned agents is that they either are direct-acting electrophiles or are Part 1 • Chapter 1. Electrophilic agents PART 1 CHAPTER 1
metabolized to electrophiles. The carcinogenicity of these chemicals is considered to be initiated by reaction of the electrophile with nucleophilic sites in DNA, leading to the induction of mutations, DNA strand breaks, and/or CA. However, additional pro- cesses may also be involved, for ex- ample free-radical-mediated oxida- tive stress, inhibition of DNA repair, inhibition of topoisomerase II, and immunosuppression. In addition to time-dependent variation in tissue concentrations of DNA-reactive me- tabolites of the chemicals described above, the likelihood that these compounds or their metabolites will bind to DNA and induce site-spe- cific genetic alterations that lead to tumour development is a function of the physicochemical properties of the reactive agent (e.g. binding affinity for DNA or protein), sever- al cellular features (including tissue concentrations of alternative binding biomolecules such as GSH, rates of cell division and cell death, and the activities and effectiveness of repair enzymes for DNA adducts), other physiological characteristics (e.g. age, sex, health status, and immu- nocompetence), and lifestyle factors (e.g. other exposures). Thus, multiple factors and mechanistic processes affect the tissue and species speci- ficity for tumour development asso- ciated with exposures to each of the carcinogenic chemicals discussed in this chapter. Table 1.3 presents 10 key char- acteristics of carcinogens (see Chapter 10, by Smith) that have been identified in in vivo and/or in vitro studies on the electrophilic agents reviewed in this chapter. What is most evident from Table 1.3 is that all these compounds produce DNA adducts in humans and animals, and cause mutations and cytogenetic alterations. Entries with weak ev- idence may reflect the availability of few or no published studies for certain characteristics of particular agents in animal or human tissues, rather than negative responses (Table 1.3).
BCME and CMME
The chloroalkyl ethers BCME and CMME are often referred to as pow- erful alkylating agents. However, because these compounds are short-lived in aqueous solution and undergo rapid hydrolysis, genotoxic- ity studies of BCME and CMME are sparse and have produced mixed re- sults (IARC, 1987). Both compounds were mutagenic in bacteria (Mukai and Hawryluk, 1973 ; Anderson and Styles, 1978) and caused an increase in the frequency of CA in peripheral lymphocytes of exposed workers (Srám et al., 1983). BCME binds to guanine and adenine res- idues of calf thymus DNA in vitro (Goldschmidt et al., 1975). Both com- pounds induced unscheduled DNA synthesis in cultured human cells (Agrelo and Severn, 1981; Perocco et al., 1983 ) and cell transforma- tion in Syrian hamster embryo cells (Casto, 1983) and cultured human fibroblasts (Kurian et al., 1990). The carcinogenicity of BCME is widely thought to involve mutagenesis re- sulting from alkylation of DNA bases (Bernucci et al., 1997). BCME and CMME may act synergistically with formaldehyde, one of their hydrolysis products. The likelihood of BCME– DNA adducts leading to mutations depends on the cellular content and activity of DNA repair enzymes such as methylguanine methyltransferase, and enzymes involved in mismatch repair and excision repair (Bernucci et al., 1997).
Sulfur mustard
The elimination of a chloride ion from sulfur mustard creates a highly re- active cyclic sulfonium ion that can alkylate cellular macromolecules including DNA, RNA, and proteins. Because of the presence of two chlo- rine atoms, sulfur mustard can act as a bifunctional alkylating agent, pro- ducing DNA interstrand or intrastrand cross-links, for example by binding to guanines on opposite strands or to neighbouring guanines on the same strand (Roberts et al., 1971; Walker, 1971 ; Shahin et al., 2001 ; Saladi et al., 2006). Such cross-links can in- hibit DNA synthesis and cell division. Sulfur mustard-specific 2-hydroxy- ethylthioethyl–DNA adducts have been detected in in vitro systems and in multiple tissues of exposed animals (Somani and Babu, 1989; Fidder et al., 1994; van der Schans et al., 1994; Niu et al., 1996). Similar to the binding pattern for other alkyl- ating agents, sulfur mustard-derived DNA adducts have been identified at N7 of guanine, N3 of adenine, and O6 of guanine (Fidder et al., 1994 ). O^6 -alkylguanine DNA alkyl- transferase is ineffective in repairing O^6 -ethylthioethylguanine adducts (Ludlum et al., 1986). Thus, sulfur mustard can inhibit cell division by cross-linking of DNA strands and can produce mutations by inducing errors in DNA replication or repair. Sulfur mustard induced mutations and CA in exposed animals and in a variety of in vitro systems (IARC, 1987 ). Further, TP53 mutations (pre- dominantly G → A transitions) were detected in DNA extracted from lung tumours of individuals exposed to sulfur mustard (Hosseini-khalili
et al., 2009). The base excision re- pair and nucleotide excision repair pathways were activated in human lymphoblastoid cell lines exposed to the sulfur mustard analogue 2-chlo- roethyl-ethylsulphide (Jowsey et al., 2009 ).
Ethylene oxide
Ethylene oxide is a direct-acting al- kylating agent that reacts with nu- cleophiles, resulting in the formation of a variety of adducts in DNA, RNA, and protein. Numerous studies have demonstrated that ethylene oxide induces gene mutations and chro- mosomal changes in in vitro systems and in prokaryotic and eukaryotic organisms. 2-Hydroxyethyl–DNA adducts formed upon exposure to ethylene oxide have been observed in vivo at N7 of guanine, N3 of ad- enine, and O6 of guanine (Walker et al., 1992) and in vitro at N1 and N6 of adenine and at the N3 posi- tion of cytosine, uracil, and thymine (Tates et al., 1999). Genotoxicity re- sulting from ethylene oxide-induced DNA adducts may involve mispairing of altered bases, formation of aba- sic sites upon depurination of the adducts at N7 of guanine followed by insertion of a different base dur- ing DNA synthesis, or DNA strand breaks and subsequent chromo- some breakage (Tates et al., 1999; Houle et al., 2006). In mice, ethylene oxide induced large deletion muta- tions, base-pair substitutions, and frameshift mutations (Walker and Skopek, 1993; Walker et al., 1997a, b). In tumours obtained from mice exposed to ethylene oxide, increas- es in K- Ras mutations with frequent G → T transversions at codon 12 and G → C transversions at codon 13 were reported (Houle et al., 2006; Hong et al., 2007). Evidence was also provided for the involvement of mutations in p. The carcinogenicity of ethylene oxide is thought to be due to the induction of gene mutations and/ or chromosomal changes resulting from the formation of ethylene ox- ide-derived DNA adducts. Although evidence for the carcinogenicity of ethylene oxide was sufficient in ex- perimental animals and limited in humans, the observed increases in the frequencies of CA, SCE, and MN in lymphocytes of exposed workers served as the basis for raising the classification of this alkylating agent to carcinogenic to humans (Group 1) (IARC, 1994, 2008 ).
Formaldehyde
Formaldehyde can react directly with cellular macromolecules including proteins and nucleic acids. The for- maldehyde-specific DNA adduct N^6 - hydroxymethyl-deoxyadenosine has been identified in lymphocytes of smokers (Wang et al., 2009). The ge- notoxicity of formaldehyde is well es- tablished: it induces mutations (point mutations, deletions, and insertions), CA, SCE, MN, DNA strand breaks, and DNA–protein cross-links in sev- eral in vitro and in vivo systems, in- cluding CA, SCE, and MN in nasal mucosal cells and/or lymphocytes of exposed humans (IARC, 2006). In animals exposed to formaldehyde, genotoxic effects were more con- sistently found in nasal tissues than in blood lymphocytes. In addition, formaldehyde produces irritation of the nose and pharynx in humans and laboratory animals. Genotoxicity and increased cell proliferation appear to be the major determinants of the na- sal carcinogenicity of formaldehyde in humans and laboratory animals. A mechanism for formalde- hyde-induced myeloid leukae- mogenesis might involve pancytope- nia caused by genotoxicity leading to damage of primitive progenitor cells in the bone marrow; mutation of myeloid progenitor cells by form- aldehyde and subsequent growth of a mutant phenotype may then lead to myeloid leukaemia. Evidence of a mild pancytopenic effect of formal- dehyde or changes in ratios of lym- phocyte subsets has been reported in exposed workers (Kuo et al., 1997; Ye et al., 2005; Tang et al., 2009; Zhang et al., 2010). In addition, col- ony formation by cultured progenitor cells that give rise to myeloid cells is inhibited by low concentrations of formaldehyde (Zhang et al., 2010). The observation of increased mon- osomy (loss) of chromosome 7 and trisomy (gain) of chromosome 8 in cultured myeloid progenitor cells obtained from the blood of workers exposed to formaldehyde may be rel- evant to the potential involvement of formaldehyde in leukaemogenesis, because these types of cytogenetic changes are frequently seen in my- eloid leukaemia and myelodysplastic syndromes (Zhang et al., 2010).
1,3-Butadiene
1,3-Butadiene can be metabolized to three different DNA-reactive epoxide intermediates, which are direct-act- ing mutagens (IARC, 2008). The ma- jor DNA adducts formed from these epoxide intermediates in rats and mice exposed to 1,3-butadiene are at the N7 position of guanine. These N7-guanine adducts can undergo spontaneous or glycosylase-medi- ated depurination, which leaves an apurinic site in the DNA. Epoxide
metabolites of 1,3-butadiene can also react at sites involved in base pairing and form adducts at the N position of cytosine, at N1 and N6 of adenine, and at N1 and N2 of guanine (Selzer and Elfarra, 1996a, b, 1997 ; Zhao et al., 1998; Zhang and Elfarra, 2004 ). An increase in the number of N1-trihydroxybutyladenine adducts was detected in lymphocytes of work- ers exposed to 1,3-butadiene (Zhao et al., 2000). Alkylation of N1-adenine by epoxybutene followed by hydro- lytic deamination forms the highly mutagenic deoxyinosine (Rodriguez et al., 2001), which codes for incor- poration of cytosine during DNA rep- lication, leading to the generation of A → G mutations. Diepoxybutane is a bifunctional alkylating agent that can form monoadducts in DNA simi- lar to those formed by epoxybutane- diol, or DNA–DNA cross-links by binding at the N7 position of guanine of one DNA strand and at another site elsewhere in the DNA, such as the N7 of another guanine or the N of an adenine (Goggin et al., 2009). Depurination of these interstrand or intrastrand lesions can induce point mutations and large deletions. However, if diepoxybutane alkylates an adenine at N6 in DNA, an exocy- clic adenine adduct is formed pref- erentially to DNA–DNA cross-linked products (Antsypovich et al., 2007). 1,3-Butadiene is genotoxic at multiple tissue sites in mice and rats, and its epoxide metabolites are mu- tagenic in a variety of in vitro sys- tems. Deletion mutations and base substitution mutations induced by these alkylating agents are consis- tent with their DNA adduct profiles and include G → A transition muta- tions, G → C transversions, A → T transversions, and A → G transitions (Lee et al., 2002). Other genotoxic effects of 1,3-butadiene and its me- tabolites are induction of CA, SCE, and MN. Genetic alterations in 1,3-butadi- ene-induced tumours in mice are of the same type as those frequently involved in the development of a va- riety of human cancers. The K- Ras , H- Ras , p53 , p16 / p15 , and β-cate- nin mutations detected in tumours from exposed mice are probably the result of the DNA reactivity and the genotoxic effects of 1,3-butadi- ene-derived epoxides. Other DNA- alkylating metabolites of 1,3-butadi- ene (hydroxymethylvinylketone and crotonaldehyde) may also contribute to the mutagenicity and carcino- genicity of this compound. A con- sistent pattern of K- Ras mutations (G → C transversions at codon 13) was observed at multiple organ sites of 1,3-butadiene-induced cancers (Hong et al., 2000; Sills et al., 2001; Ton et al., 2007). Alterations in the p53 gene in brain tumours in mice were mostly G → A transition muta- tions (Kim et al., 2005) that probably arose from miscoding at apurinic sites resulting from depurination of N7-guanine adducts. Inactivation of the tumour suppressor genes p and p15 may also be important in the development of 1,3-butadiene-in- duced lymphomas (Zhuang et al., 2000 ). Mammary gland adenocarci- nomas induced by 1,3-butadiene in mice frequently had mutations in the p53 , H- Ras , and β-catenin genes (Zhuang et al., 2002). Overall, these observations point to a genotoxic mechanism underlying the devel- opment of 1,3-butadiene-induced cancers.
Vinyl chloride
The carcinogenicity of vinyl chloride is probably caused by its highly re- active metabolite chloroethylene oxide and/or by the rearrangement product chloroacetaldehyde (Bonse et al., 1975). Both intermediates can bind to proteins, RNA, and DNA (Guengerich and Watanabe, 1979). Vinyl chloride is mutagenic in bac- teria and mammalian cells. It is also clastogenic in vivo and in vitro, caus- ing increases in the frequencies of CA, SCE, and MN (IARC, 2008 ). The major DNA adduct formed from chloroethylene oxide is at the N7 po- sition of guanine. In addition, etheno DNA adducts (1, N^6 -ethenoadenine, 3, N^4 -ethenocytosine, N^2 ,3-etheno- guanine, and 1, N^2 -ethenoguanine) have been identified after in vitro in- cubations with chloroethylene oxide, and levels of these adducts are in- creased in multiple organs of rats ex- posed to vinyl chloride by inhalation (Ciroussel et al., 1990; Guengerich, 1992 ; Swenberg et al., 2000). The etheno adducts, which may be in- volved in base-pair substitutions, are much more persistent than the N7- guanine adduct (Fedtke et al., 1990) and have demonstrated miscoding potential in vitro and in vivo, causing A → G transitions, A → T transver- sions, C → A transversions, C → T transitions, and G → A transitions (Singer et al., 1987; Cheng et al., 1991 ; Mroczkowska and Kuśmierek, 1991 ; Singer et al., 1991; Basu et al., 1993 ). The same types of mutation have been observed in the TP and RAS genes in vinyl chloride-in- duced tumours. TP53 mutations associated with exposure to vinyl chloride (frequently A → T transver- sions) were found in angiosarcomas in both humans and rats, and muta- tions in K- RAS were also associated with vinyl chloride-induced angio- sarcomas in humans (IARC, 2008). Polymorphisms in XRCC1 , a gene that encodes an enzyme that repairs etheno DNA adducts, may account Part 1 • Chapter 1. Electrophilic agents PART 1 CHAPTER 1
a genotoxic mechanism of kidney carcinogenesis is strong. The evi- dence for the liver as a target tissue for TCE, from cancer assays and tox- icity findings in laboratory animals, is strong. The evidence for non-geno- toxic and/or genotoxic mechanisms of liver carcinogenesis is moderate. The available data suggest multiple non-genotoxic mechanisms and the potential for genotoxic mechanisms from the TCE metabolites dichloro- acetate and chloral hydrate.
Benzene
Benzene induced CA, SCE, and MN in bone marrow cells of exposed mice, CA in bone marrow cells of exposed rats, and CA and mutations in human cells in vitro_._ CA in human peripheral lymphocytes have long been associated with occupational exposure to benzene (Forni, 1979; IARC, 1982; Eastmond, 1993; Zhang et al., 2002; Holecková et al., 2004). As noted above, metabolism of ben- zene produces several electrophilic agents (benzene oxide, in equilibrium with its tautomer oxepin, muconalde- hyde, benzoquinone, and benzene dihydrodiol epoxide) that can react with DNA or proteins. DNA binding and adduct formation may not be the major steps in the development of benzene-induced leukaemias (Whysner et al., 2004). Although the mechanisms of benzene-induced carcinogenesis and the potential relative roles of each of these me- tabolites are not fully known, there is strong support for the involvement of clastogenic and aneugenic effects, such as formation of CA, MN, and DNA strand breaks. Exposure to benzene has been associated with chromosomal changes that are commonly ob- served in acute myeloid leukaemia, including those comprising loss of various parts of the long arm of chromosome 5 or 7, or complete loss of these chromosomes, gain of the entire chromosome 8, and an increased frequency of transloca- tions between chromosomes 8 and 21 in peripheral lymphocytes of ex- posed workers (Smith et al., 1998; Zhang et al., 1999, 2002 ). Benzene and its quinone metabolites are in- hibitors of topoisomerase II, leading to increased frequencies of DNA cleavage complexes and DNA dou- ble-strand breaks; this effect can re- sult in the formation of chromosome translocations and inversions (Hutt and Kalf, 1996; Lindsey et al., 2004, 2005 ; Deweese and Osheroff, 2009). Other potential pathways involved in benzene-induced acute myeloid leu- kaemia include mutagenesis (pos- sibly through generation of reactive oxygen species), epigenetic changes due to altered methylation status, de- creased immunosurveillance (Cho, 2008 ; Li et al., 2009), haematotoxicity and alterations in stem cell pool size (Rothman et al., 1997), and inhibition of gap-junction intercellular commu- nication (Rivedal and Witz, 2005). Thus, multiple mechanisms are likely to be involved in benzene-induced leukaemogenesis. Benzene produc- es multiple cytogenetic abnormalities in human lymphocytes (Tough and Brown, 1965; Picciano, 1979; Smith and Zhang, 1998; Zhang et al., 2002) and induces specific chromosomal changes associated with non-Hodg- kin lymphoma in human lympho- cytes (Zhang et al., 2007). Induction of DNA double-strand breaks and chromosomal rearrangements in lymphoid cells in combination with immunosuppression by benzene might be the cause of lymphoma. The carcinogenicity of the group of electrophilic chemicals dis- cussed above is likely to be due to interaction between the parent elec- trophile or one or more electrophilic metabolites and nucleophilic DNA, leading to point mutations and induc- tion of CA. These effects have been observed in humans, in animals, and in in vitro systems. In addition, pro- duction of reactive oxygen species, inhibition of DNA synthesis or repair, and cytotoxicity/cell proliferation could complement DNA modification to enhance DNA damage. Tumour outcome can result from certain DNA adducts leading to mutations and dysregulation initially described with reference to proto-oncogenes and tumour suppressor genes. For benzene, chromosomal transloca- tions, in combination with haemato- toxicity or immunosuppression, are associated with increased risk of haematopoietic cancer in humans. The extent to which other process- es (inflammation, oxidative stress, immunosuppression, epigenetic al- terations, and immortalization) might contribute to the carcinogenicity of this class of chemicals in general is limited by the availability of few or no published studies that address these effects.
Polymorphisms and
susceptibility
Susceptibility to the carcinogenic effects of organic compounds may derive from acquired characteristics, such as altered expression of certain enzymes, or from genetic factors, such as enzyme polymorphisms. Polymorphisms of enzymes involved in the metabolism of organic com- pounds are likely to be responsible for individual differences in activa- tion and detoxification reactions that control tissue levels of electrophilic intermediates. The enzymes that catalyse epoxide formation and elim- ination are polymorphic in human Part 1 • Chapter 1. Electrophilic agents PART 1 CHAPTER 1
populations, and some isozymes may be induced by a variety of en- vironmental and pharmaceutical agents. For example, factors that explain differences in the response to aflatoxin between human individ- uals and between animal species and strains include the proportion of aflatoxin metabolized to the exo - 8,9-epoxide (mainly by CYP enzymes) relative to other, much less toxic metabolites, and the prev- alence of pathways that lead to the formation of non-toxic conjugates with reduced mutagenicity and cyto- toxicity (Guengerich et al., 1998). Similarly, the expression of en- zymes involved in aflatoxin metabol- ism can be modulated with che- mopreventive agents, resulting in inhibition of DNA adduct formation and hepatocarcinogenesis, as has been demonstrated in rats. Oltipraz is a chemopreventive agent that in- creases GSH conjugation and inhib- its the activity of some CYP450 en- zymes (e.g. CYP1A2). Results from clinical trials with oltipraz in China are consistent with experimental data in showing that after dietary exposure to aflatoxins, modulation of the metabolism of aflatoxins with oltipraz can lead to reduced levels of DNA adducts (IARC, 2002; Kensler et al., 2005). Increased susceptibility to the toxic effects of benzene has been linked to genetic polymorphisms that increase the rate of metabolism of benzene to active intermediates or decrease the rate of detoxification of these active intermediates (Rothman et al., 1997; Xu et al., 1998; Kim et al., 2004 ). Enzyme polymorphisms also af- fect the metabolism of 1,3-butadi- ene. Genetic polymorphisms in GST and microsomal EH affect the in vitro mutagenicity of 1,3-butadiene- derived epoxides or the in vivo muta- genicity of 1,3-butadiene in occupa- tionally exposed workers (Wiencke et al., 1995; Abdel-Rahman et al., 2003 ). The extent to which these enzyme polymorphisms influence the carcinogenicity of 1,3-butadiene is not known. The genotoxic effects of 1,3-butadiene can be modulated by alterations in key determinants of its metabolism; this suggests that markers of individual susceptibility can be identified. For example, mice that lack a functional microsomal EH ( mEH ) gene were more sus- ceptible than wild-type mice to the mutagenic effects of 1,3-butadiene or diepoxybutane (Wickliffe et al., 2003 ). EH activity varies consider- ably among humans. 1,3-Butadiene- exposed workers with the genotype for low-activity EH were reported to be more susceptible to 1,3-butadi- ene-induced genotoxicity (assessed by HPRT mutant frequency in lym- phocytes) than individuals with the more common EH genotype (Abdel- Rahman et al., 2001, 2003 ). No sig- nificant effects were observed for induction of HPRT mutations or SCE in individuals with GSTM1 or GSTT polymorphisms (Abdel-Rahman et al., 2001). MN frequencies were higher among 1,3-butadiene-ex- posed workers in China with poly- morphisms in GSTM1 and/or GSTT compared with workers with the wild-type genes (Cheng et al., 2013). These differences in response are consistent with the known important roles of EH and GST in the detoxi- fication of 1,3-butadiene epoxides in tissues in which these intermediates are produced. Ethylene oxide is a substrate of the GST isozyme T1 (Hayes et al., 2005 ). This detoxifying enzyme is polymorphic, and a relatively large proportion of the population (about 20% of Caucasians and almost 50% of Asians) has a homozygous de- letion ( GSTT1 -null genotype) (Bolt and Thier, 2006). As expected, these individuals show a significantly ele- vated level of hydroxyethyl valine in their haemoglobin, due to the pres- ence of endogenous ethylene oxide (Thier et al., 2001). Nevertheless, the influence of this genetic trait on the formation of this type of adduct as a result of exposure to exogenous eth- ylene oxide in the workplace is less clear. In the cytoplasm of erythrocytes obtained from 36 individuals, ethyl- ene oxide was eliminated 3–6 times as fast in samples from so-called conjugators (defined by a standard- ized conjugation reaction of methyl bromide and GSH; 75% of the popu- lation) as in samples from individuals who lack this GST-specific activity (the remaining 25%). In whole-blood samples incubated with ethylene ox- ide, an increase in the frequency of SCE was observed in lymphocytes from the non-conjugators but not in lymphocytes from the conjugators (Hallier et al., 1993). The carcinogenicity and toxic- ity of TCE, particularly in the liver and kidney, are associated with its metabolism. There are inter-individ- ual differences, both in humans and in rodents, in the formation of TCE metabolites that are thought to be responsible for the toxic and carcino- genic effects of TCE in the kidney and liver. The susceptibility to adverse health effects of TCE may be influ- enced by genetics, sex, life stage, and other conditions that influence the extent and nature of the metabol- ism of this chemical. Polymorphisms in metabolism genes in both ox- idative (e.g. CYP2E1 , ADH , and ALDH ) and GSH conjugation (e.g. GSTs) pathways have been studied
References
Abdel-Rahman SZ, Ammenheuser MM, Ward JB Jr (2001). Human sensitivity to 1,3-butadiene: role of microsomal epoxide hydrolase polymorphisms. Carcinogenesis. 22(3):415–23. http://dx.doi.org/10.1093/ carcin/22.3.415 PMID: 11238181 Abdel-Rahman SZ, El-Zein RA, Ammenheuser MM, Yang Z, Stock TH, Morandi M, et al_._ (2003). Variability in human sensitivity to 1,3-butadiene: influence of the allelic variants of the microsomal epoxide hydrolase gene. Environ Mol Mutagen. 41(2):140–6. http:// dx.doi.org/10.1002/em.10142 PMID: 12605384 Agrelo CE, Severn BJ (1981). A simplified method for measuring scheduled and unscheduled DNA synthesis in human fibroblasts. Toxicology. 21(2):151–8. http:// dx.doi.org/10.1016/0300- 483X(81)90125- PMID: 7281203 Anderson D, Styles JA (1978). The bacterial mutation test. Six tests for carcinogenicity. Br J Cancer. 37(6):924–30. http://dx.doi. org/0.1038/bjc.1978.134 PMID: 354673 Antsypovich S, Quirk-Dorr D, Pitts C, Tretyakova N (2007). Site specific N^6 - (2 - hy d r ox y - 3 , 4 - e p ox y b u t -1- y l) a d e n i n e oligodeoxynucleotide adducts of 1,2,3,4- diepooxybutane: synthesis and stability at physiological pH. Chem Res Toxicol. 20(4):641–9. http://dx.doi.org/10.1021/ tx060178k PMID: 17355152 ATSDR (1989). Toxicological profile for bis(chloromethyl) ether. Atlanta (GA), USA: Agency for Toxic Substances and Disease Registry. Available from: https://www.atsdr. cdc.gov/toxprofiles/tp128.pdf. ATSDR (2003). Toxicological profile for mustard gas. Draft for public comment. Update. Atlanta (GA), USA: Agency for Toxic Substances and Disease Registry. ATSDR (2006). Toxicological profile for vinyl chloride. Atlanta (GA), USA: Agency for Toxic Substances and Disease Registry. Available from: http://www.atsdr.cdc.gov/toxprofiles/ tp20.pdf. Bailey EA, Iyer RS, Stone MP, Harris TM, Essigmann JM (1996). Mutational properties of the primary aflatoxin B 1 -DNA adduct. Proc Natl Acad Sci U S A. 93(4):1535–9. http://dx.doi.org/10.1073/pnas.93.4. PMID: 8643667 Barbin A, Bartsch H (1989). Nucleophilic selectivity as a determinant of carcinogenic potency (TD 50 ) in rodents: a comparison of mono- and bi-functional alkylating agents and vinyl chloride metabolites. Mutat Res. 215(1):95–106. http://dx.doi. o r g / 1 0 .1 0 1 6 / 0 0 2 7 - 5 1 0 7 ( 8 9 ) 9 0 2 2 2 - 4 PMID: 2811916 Barbin A, Brésil H, Croisy A, Jacquignon P, Malaveille C, Montesano R, et al_._ (1975). Liver- microsome-mediated formation of alkylating agents from vinyl bromide and vinyl chloride. Biochem Biophys Res Commun. 67(2):596–
- http://dx.doi.org/10.1016/0006- 291X(75)90854-2 PMID: 1201042 Basu AK, Wood ML, Niedernhofer LJ, Ramos LA, Essigmann JM (1993). Mutagenic and genotoxic effects of three vinyl chloride- induced DNA lesions: 1, N^6 -ethenoadenine, 3, N^4 -ethenocytosine, and 4-amino-5- (imidazol-2-yl)imidazole. Biochemistry. 32(47):12793–801. http://dx.doi.org/10.1021/ bi00210a031 PMID: 8251500 Bechtold WE, Willis JK, Sun JD, Griffith WC, Reddy TV (1992). Biological markers of exposure to benzene: S -phenylcysteine in albumin. Carcinogenesis. 13(7):1217–20. http://dx.doi.org/10.1093/carcin/13.7. PMID: 1638689 Bernucci I, Turrini D, Landi MT (1997). Bis- chloromethyl ether and carcinogenesis of alkylating agents [in Italian]. Med Lav. 88(5):347–55. PMID: 9489299 Bodell WJ, Pathak DN, Lévay G, Ye Q, Pongracz K (1996). Investigation of the DNA adducts formed in B6C3F1 mice treated with benzene: implications for molecular dosimetry. Environ Health Perspect. 104(Suppl 6):1189–
- http://dx.doi.org/10.1289/ehp. PMID: 9118892 Bolt HM (2005). Vinyl chloride – a classical industrial toxicant of new interest. Crit Rev Toxicol. 35(4):307–23. http://dx.doi. o r g / 1 0. 1 0 8 0 / 1 0 4 0 8 4 4 0 4 9 0 9 1 5 9 7 5 PMID: 15989139 Bolt HM, Thier R (2006). Relevance of the deletion polymorphisms of the glutathione S -transferases GSTT1 and GSTM1 in pharmacology and toxicology. Curr Drug Metab. 7(6):613–28. http:// dx.doi.org/10.2174/ PMID: 16918316 Bonse G, Urban T, Reichert D, Henschler D (1975). Chemical reactivity, metabolic oxirane formation and biological reactivity of chlorinated ethylenes in the isolated perfused rat liver preparation. Biochem Pharmacol. 24(19):1829–34. http://dx.doi. o r g / 1 0 .1 0 1 6 / 0 0 0 6 - 2 9 5 2 ( 7 5 ) 9 0 4 6 8 - 2 PMID: 1233985 Boogaard PJ, Sumner SCJ, Bond JA (1996). Glutathione conjugation of 1,2:3,4-diepoxybutane in human liver and rat and mouse liver and lung in vitro. Toxicol Appl Pharmacol. 136(2):307–16. http://dx.doi. org/10.1006/taap.1996.0037 PMID: 8619238 Brauch H, Weirich G, Hornauer MA, Störkel S, Wöhl T, Brüning T (1999). Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma. J Natl Cancer Inst. 91(10):854–61. http://dx.doi. org/10.1006/taap.1996.0037 PMID: 8619238 Brüning T, Weirich G, Hornauer MA, Höfler H, Brauch H (1997). Renal cell carcinomas in trichloroethene (TRI) exposed persons are associated with somatic mutations in the von Hippel-Lindau ( VHL ) tumour suppressor gene. Arch Toxicol. 71(5):332–5. http://dx.doi. org/10.1007/s002040050394 PMID: 9137812 Cai H, Guengerich FP (2001). Reaction of trichloroethylene oxide with proteins and DNA: instability of adducts and modulation of functions. Chem Res Toxicol. 14(1):54–
- http://dx.doi.org/10.1021/tx000185n PMID: 11170508 Casto BC (1983). Comparison of the sensitivity of rodent and human cells to chemical carcinogens using viral transformation, DNA damage, and cytotoxicity assays. Basic Life Sci. 24:429–49. PMID: 6305332 Cheng KC, Preston BD, Cahill DS, Dosanjh MK, Singer B, Loeb LA (1991). The vinyl chloride DNA derivative N^2 ,3-ethenoguanine produces G → A transitions in Escherichia coli. Proc Natl Acad Sci U S A. 88(22):9974–
- http://dx.doi.org/10.1073/pnas.88.22. PMID: 1946466 Cheng X, Zhang T, Zhao J, Zhou J, Shao H, Zhou Z, et al_._ (2013). The association between genetic damage in peripheral blood lymphocytes and polymorphisms of three glutathione S -transferases in Chinese workers exposed to 1,3-butadiene. Mutat Res. 750(1–2):139–46. http://dx.doi.org/10.1016/j. mrgentox.2012.10.008 PMID: 23159492 Cho JY (2008). Suppressive effect of hydroquinone, a benzene metabolite, on in vitro inflammatory responses mediated by macrophages, monocytes, and lymphocytes. Mediators Inflamm. 2008:298010. h t t p: //d x .d o i .o r g /10 .115 5 / 2 0 0 8 / 2 9 8 010 PMID: 19148301 Ciroussel F, Barbin A, Eberle G, Bartsch H (1990). Investigations on the relationship between DNA ethenobase adduct levels in several organs of vinyl chloride-exposed rats and cancer susceptibility. Biochem Pharmacol. 39(6):1109–13. http://dx.doi. o r g / 1 0 .1 0 1 6 / 0 0 0 6 - 2 9 5 2 ( 9 0 ) 9 0 2 9 1 - R PMID: 2322297 Csanády GA, Guengerich FP, Bond JA (1992). Comparison of the biotransformation of 1,3-butadiene and its metabolite, butadiene monoepoxide, by hepatic and pulmonary tissues from humans, rats and mice. Carcinogenesis. 13(7):1143–53. http://dx.doi. org/10.1093/carcin/13.7.1143 PMID: 1638680
Dacre JC, Goldman M (1996). Toxicology and pharmacology of the chemical warfare agent sulfur mustard. Pharmacol Rev. 48(2):289–
- PMID: 8804107 Dekant W, Berthold K, Vamvakas S, Henschler D, Anders MW (1988). Thioacylating intermediates as metabolites of S -(1,2-dichlorovinyl)-l-cysteine and S -(1,2,2-trichlorovinyl)-l-cysteine formed by cysteine conjugate β-lyase. Chem Res Toxicol. 1(3):175–8. http://dx.doi.org/10.1021/ tx00003a008 PMID: 2979728 Deweese JE, Osheroff N (2009). The DNA cleavage reaction of topoisomerase II: wolf in sheep’s clothing. Nucleic Acids Res. 37(3):738–48. http://dx.doi.org/10.1093/nar/ gkn937 PMID: 19042970 Dogliotti E (2006). Molecular mechanisms of carcinogenesis by vinyl chloride. Ann Ist Super Sanita. 42(2):163–9. PMID: 17033136 Drasch G, Kretschmer E, Kauert G, von Meyer L (1987). Concentrations of mustard gas [bis(2-chloroethyl)sulfide] in the tissues of a victim of a vesicant exposure. J Forensic Sci. 32(6):1788–93. http://dx.doi.org/10.1520/ JFS11235J PMID: 3430139 Eastmond DA (1993). Induction of micronuclei and aneuploidy by the quinone-forming agents benzene and o -phenylphenol. Toxicol Lett. 67(1–3):105–18. http://dx.doi. o r g / 1 0 .1 0 1 6 / 0 3 7 8 - 4 2 74 ( 9 3 ) 9 0 0 4 9 - 4 PMID: 8451753 Essigmann JM, Croy RG, Bennett RA, Wogan GN (1982). Metabolic activation of aflatoxin B 1 : patterns of DNA adduct formation, removal, and excretion in relation to carcinogenesis. Drug Metab Rev. 13(4):581–602. http:// dx.doi.org/10.3109/03602538209 011088 PMID: 6813091 Fedtke N, Boucheron JA, Walker VE, Swenberg JA (1990). Vinyl chloride- induced DNA adducts. II: Formation and persistence of 7-(2′-oxoethyl)guanine and N^2 ,3-ethenoguanine in rat tissue DNA. Carcinogenesis. 11(8):1287–92. http://dx.doi. org/10.1093/carcin/11.8.1287 PMID: 2387014 Fidder A, Moes GWH, Scheffer AG, van der Schans GP, Baan RA, de Jong LPA, et al_._ (1994). Synthesis, characterization, and quantitation of the major adducts formed between sulfur mustard and DNA of calf thymus and human blood. Chem Res Toxicol. 7(2):199–204. http://dx.doi.org/10.1021/ tx00038a013 PMID: 8199309 Forni A (1979). Chromosome changes and benzene exposure. A review. Rev Environ Health. 3(1):5–17. PMID: 395589 Gaskell M, McLuckie KI, Farmer PB (2005). Genotoxicity of the benzene metabolites para- benzoquinone and hydroquinone. Chem Biol Interact. 153-154:267–70. http://dx.doi.org/10.1016/j.cbi.2005.03. PMID: 15935826 Goggin M, Swenberg JA, Walker VE, Tretyakova N (2009). Molecular dosimetry of 1,2,3,4-diepoxybutane-induced DNA- DNA cross-links in B6C3F1 mice and F rats exposed to 1,3-butadiene by inhalation. Cancer Res. 69(6):2479–86. http://dx.doi. o r g /10 .115 8 / 0 0 0 8 - 5 47 2. C A N - 0 8 - 415 2 PMID: 19276346 Goldschmidt BM, van Duuren BL, Frenkel K (1975). The reaction of 14 C-labelled bis(chloromethyl) ether with DNA. Proc Am Assoc Cancer Res. 16:66. Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD (2008). Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol. 14(27):4300–8. http://dx.doi.org/10.3748/ wjg.14.4300 PMID: 18666317 Gopalakrishnan S, Harris TM, Stone MP (1990). Intercalation of aflatoxin B 1 in two oligodeoxynucleotide adducts: comparative (^1) H NMR analysis of d(ATCAFBGAT).d(ATCGAT) and d(ATAFBGCAT) 2. Biochemistry. 29(46):10438–48. http://dx.doi.org/10.1021/ bi00498a002 PMID: 2125491 Groopman JD, Croy RG, Wogan GN (1981). In vitro reactions of aflatoxin B 1 -adducted DNA. Proc Natl Acad Sci U S A. 78(9):5445–9. http://dx.doi.org/10.1073/pnas.78.9.5 445 PMID: 6795633 Guengerich FP (1992). Roles of the vinyl chloride oxidation products 1-chlorooxirane and 2-chloroacetaldehyde in the in vitro formation of etheno adducts of nucleic acid bases [corrected]. Chem Res Toxicol. 5(1):2–
- http://dx.doi.org/10.1021/tx00025a PMID: 1581532 Guengerich FP, Johnson WW, Shimada T, Ueng Y-F, Yamazaki H, Langouët S (1998). Activation and detoxication of aflatoxin B 1. Mutat Res. 402(1–2):121–8. http://dx.doi. o r g / 1 0 .1 0 1 6 / S 0 0 2 7- 51 0 7( 9 7 ) 0 0 2 8 9 - 3 PMID: 9675258 Guengerich FP, Watanabe PG (1979). Metabolism of [^14 C]- and [^36 C]-labeled vinyl chloride in vivo and in vitro. Biochem Pharmacol. 28(5):589–96. http://dx.doi. o r g / 1 0 .1 0 1 6 / 0 0 0 6 - 2 9 5 2 ( 7 9 ) 9 0 1 4 0 - 0 PMID: 444246 Hallier E, Langhof T, Dannappel D, Leutbecher M, Schröder K, Goergens HW, et al_._ (1993). Polymorphism of glutathione conjugation of methyl bromide, ethylene oxide and dichloromethane in human blood: influence on the induction of sister chromatid exchanges (SCE) in lymphocytes. Arch Toxicol. 67(3):173–8. http://dx.doi. org/10.1007/BF01973304 PMID: 8494496 Hayes JD, Flanagan JU, Jowsey IR (2005). Glutathione transferases. Annu Rev Pharmacol Toxicol. 45(1):51–88. h t t p : / / d x. d o i. o r g / 1 0 .1 1 4 6 / a n n u r e v. pharmtox.45.120403.095857 PMID: 15822171 Hedberg JJ, Hoog JO, Grafstrom RC (2002). Assessment of formaldehyde metabolizing enzymes in human oral mucosa and cultured oral keratinocytes indicate high capacity for detoxification of formaldehyde. In: Heinrich U, Mohr U, editors. Crucial issues in inhalation research — mechanistic, clinical and epidemiologic (INIS Monographs). Stuttgart, Germany: Fraunhofer IRB Verlag; pp. 103–15. Henderson AP, Bleasdale C, Delaney K, Lindstrom AB, Rappaport SM, Waidyanatha S, et al_._ (2005). Evidence for the formation of Michael adducts from reactions of ( E , E )- muconaldehyde with glutathione and other thiols. Bioorg Chem. 33(5):363–73. http:// dx.doi.org/10.1016/j.bioorg. 20 05.05.0 0 4 PMID: 16005934 Himmelstein MW, Acquavella JF, Recio L, Medinsky MA, Bond JA (1997). Toxicology and epidemiology of 1,3-butadiene. Crit Rev Toxicol. 27(1):1–108. http://dx.doi. o r g / 1 0. 3 1 0 9 / 1 0 4 0 8 4 4 9 7 0 9 0 3 7 4 8 2 PMID: 9115622 Holecková B, Piesová E, Sivikova K, Dianovskỳ J (2004). Chromosomal aberrations in humans induced by benzene. Ann Agric Environ Med. 11:175–9. PMID: 15627321 Hong HH, Devereux TR, Melnick RL, Moomaw CR, Boorman GA, Sills RC (2000). Mutations of ras protooncogenes and p53 tumor suppressor gene in cardiac hemangiosarcomas from B6C3F1 mice exposed to 1,3-butadiene for 2 years. Toxicol Pathol. 28(4):529–34. http:// dx.doi.org/10.1177/ PMID: 10930038 Hong H-HL, Houle CD, Ton T-VT, Sills RC (2007). K- ras mutations in lung tumors and tumors from other organs are consistent with a common mechanism of ethylene oxide tumorigenesis in the B6C3F mouse. Toxicol Pathol. 35(1):81–5. http:// dx.doi.org/10.1080/01926230 6010 63839 PMID: 17325976 Hosseini-khalili A, Haines DD, Modirian E, Soroush M, Khateri S, Joshi R, et al_._ (2009). Mustard gas exposure and carcinogenesis of lung. Mutat Res. 678(1):1–6. http:// dx.doi.org/10.1016/j.mrgentox.2009.05. PMID: 19559099 Houle CD, Ton T-VT, Clayton N, Huff J, Hong H-H, Sills RC (2006). Frequent p53 and H- ras mutations in benzene- and ethylene oxide-induced mammary gland carcinomas from B6C3F1 mice. Toxicol Pathol. 34(6):752–62. http:// dx.doi.org/10.1080/01926230 60 0935912 PMID: 17162533 Hrelia P, Maffei F, Vigagni F, Fimognari C, Flori P, Stanzani R, et al_._ (1994). Interactive effects between trichloroethylene and pesticides at metabolic and genetic level in mice. Environ Health Perspect. 102(Suppl 9):31–4. http://dx.doi.org/10.1289/ehp.9 4102s PMID: 7698080 Part 1 • Chapter 1. Electrophilic agents PART 1 CHAPTER 1
Mazzullo M, Bartoli S, Bonora B, Colacci A, Lattanzi G, Niero A, et al_._ (1992). In vivo and in vitro interaction of trichloroethylene with macromolecules from various organs of rat and mouse. Res Commun Chem Pathol Pharmacol. 76(2):192–208. PMID: 1376481 McDonald TA, Waidyanatha S, Rappaport SM (1993). Production of benzoquinone adducts with hemoglobin and bone-marrow proteins following administration of [^13 C6] benzene to rats. Carcinogenesis. 14(9):1921–
- http://dx.doi.org/10.1093/carcin/14.9. PMID: 8403219 McLean M, Dutton MF (1995). Cellular interactions and metabolism of aflatoxin: an update. Pharmacol Ther. 65(2):163–92. http:// dx.doi.org/10.1016/0163-7258(94)00054- PMID: 7540767 Mroczkowska MM, Kuśmierek JT (1991). Miscoding potential of N^2 ,3-ethenoguanine studied in an Escherichia coli DNA-dependent RNA polymerase in vitro system and possible role of this adduct in vinyl chloride-induced mutagenesis. Mutagenesis. 6(5):385–90. http://dx.doi.org/10.1093/mutage/6.5. PMID: 1795643 Mukai FH, Hawryluk I (1973). Mutagenicity of some halo-ethers and halo-ketones. Mutat Res. 21(4):228. http://dx.doi. org/10.1016/0165-1161(73)90241- Müller M, Birner G, Dekant W (1998a). Reactivity of haloketenes and halothioketenes with nucleobases: chemical characterization of reaction products. Chem Res Toxicol. 11(5):454–63. http://dx.doi.org/10.1021/ tx9701438 PMID: 9585476 Müller M, Birner G, Sander M, Dekant W (1998b). Reactivity of haloketenes and halothioketenes with nucleobases: reactions in vitro with DNA. Chem Res Toxicol. 11(5):464–70. http://dx.doi.org/10.1021/ tx9701440 PMID: 9585477 National Toxicology Program (2004). NTP 11th report on carcinogens. Rep Carcinog. 11:1–A32. PMID: 19826456 Nedelcheva V, Gut I, Soucek P, Tichavská B, Týnkova L, Mráz J, et al_._ (1999). Metabolism of benzene in human liver microsomes: individual variations in relation to CYP2E expression. Arch Toxicol. 73(1):33–40. http://dx.doi.org/10.1007/s PMID: 10207612 Nichols RW, Merritt RF (1973). Relative solvolytic reactivities of chloromethyl ether and bis(chloromethyl)ether. J Natl Cancer Inst. 50(5):1373–4. PMID: 4712596 Niu T, Matijasevic Z, Austin-Ritchie P, Stering A, Ludlum DB (1996). A 32 P-postlabeling method for the detection of adducts in the DNA of human fibroblasts exposed to sulfur mustard. Chem Biol Interact. 100(1):77–
- http://dx.doi.org/10.1016/S0009- 2797(96)03690-3 PMID: 8599857 Perocco P, Bolognesi S, Alberghini W (1983). Toxic activity of seventeen industrial solvents and halogenated compounds on human lymphocytes cultured in vitro. Toxicol Lett. 16:69–76. http://dx.doi.org/10.1016/0378- 4274(83)90012-7 PMID: 6836616 Picciano D (1979). Cytogenetic study of workers exposed to benzene. Environ Res. 19(1):33–8. http://dx.doi.org/10.1016/0013- 9351(79)90031-8 PMID: 510268 Plugge H, Safe S (1977). Vinyl chloride metabolism – a review. Chemosphere. 6(6):309–25. http://dx.doi.org/10.1016/0045- 6535(77)90095- Poulsen HE, Loft S, Wassermann K (1993). Cancer risk related to genetic polymorphisms in carcinogen metabolism and DNA repair. Pharmacol Toxicol. 72(Suppl 1):93–103. http://dx.doi.org/10.1111/j.1600-0773.1993. tb01676.x PMID: 8474997 Powley MW, Carlson GP (2000). Cytochromes P450 involved with benzene metabolism in hepatic and pulmonary microsomes. J Biochem Mol Toxicol. 14(6):303–9. http://dx.doi.org/10.1002/1099- 0461(2000)14:6<303::AID-JBT2>3.0.CO;2- PMID: 11083083 Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, et al_._ (1994). A follow- up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People’s Republic of China. Cancer Epidemiol Biomarkers Prev. 3(1):3–10. PMID: 8118382 Rappaport SM, Kim S, Lan Q, Vermeulen R, Waidyanatha S, Zhang L, et al_._ (2009). Evidence that humans metabolize benzene via two pathways. Environ Health Perspect. 117(6):946–52. http://dx.doi.org/10.1289/ ehp.0800510 PMID: 19590688 Ren X, Lim S, Smith MT, Zhang L (2009). Werner syndrome protein, WRN, protects cells from DNA damage induced by the benzene metabolite hydroquinone. Toxicol Sci. 107(2):367–75. http://dx.doi.org/10.1093/ toxsci/kfn254 PMID: 19064679 Reynolds ES, Moslen MT, Szabo S, Jaeger RJ (1975). Vinyl chloride-induced deactivation of cytochrome P-450 and other components of the liver mixed function oxidase system: an in vivo study. Res Commun Chem Pathol Pharmacol. 12(4):685–94. PMID: 175418 Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, et al_._ (2007). Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde. Cancer Res. 67(23):11117–22. http://dx.doi.org/10.1158/0008-5472.CAN-07- 3028 PMID: 18056434 Rivedal E, Witz G (2005). Metabolites of benzene are potent inhibitors of gap-junction intercellular communication. Arch Toxicol. 79(6):303–11. http://dx.doi.org/10.1007/ s00204-004-0638-0 PMID: 15690152 Robbiano L, Baroni D, Carrozzino R, Mereto E, Brambilla G (2004). DNA damage and micronuclei induced in rat and human kidney cells by six chemicals carcinogenic to the rat kidney. Toxicology. 204(2–3):187–95. http://dx.doi.org/10.1016/j.tox.2004.06. PMID: 15388244 Roberts JJ, Brent TP, Crathorn AR (1971). Evidence for the inactivation and repair of the mammalian DNA template after alkylation by mustard gas and half mustard gas. Eur J Cancer. 7(6):515–24. http:// dx.doi.org/10.1016/0014-2964(71)90056- PMID: 5143809 Rodriguez DA, Kowalczyk A, Ward JB Jr, Harris CM, Harris TM, Lloyd RS (2001). Point mutations induced by 1,2-epoxy-3-butene N^1 deoxyinosine adducts. Environ Mol Mutagen. 38(4):292–6. http://dx.doi.org/10.1002/ em.10026 PMID: 11774359 Ross D (2000). The role of metabolism and specific metabolites in benzene-induced toxicity: evidence and issues. J Toxicol Environ Health A. 61(5–6):357–72. http:// dx.doi.org/10.1080/0 098 410 0 050166361 PMID: 11086940 Ross RK, Yuan J-M, Yu MC, Wogan GN, Qian GS, Tu JT, et al_._ (1992). Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet. 339(8799):943–6. http:// dx.doi.org/10.1016/0140-6736(92)91528-G PMID: 1348796 Rothman N, Smith MT, Hayes RB, Traver RD, Hoener B, Campleman S, et al_._ (1997). Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1^609 C→T mutation and rapid fractional excretion of chlorzoxazone. Cancer Res. 57(14):2839–42. PMID: 9230185 Saladi RN, Smith E, Persaud AN (2006). Mustard: a potential agent of chemical warfare and terrorism. Clin Exp Dermatol. 31(1):1–5. http://dx.doi.org/10.1111/j.1365- 2230.2005.01945.x PMID: 16309468 Seaton MJ, Follansbee MH, Bond JA (1995). Oxidation of 1,2-epoxy-3-butene to 1,2:3,4-diepoxybutane by cDNA-expressed human cytochromes P450 2E1 and 3A4 and human, mouse and rat liver microsomes. Carcinogenesis 16(10):2287–93. http://dx.doi. org/10.1093/carcin/16.10.2287 PMID: 7586124 Selzer RR, Elfarra AA (1996a). Characterization of N^1 - and N^6 -adenosine adducts and N^1 -inosine adducts formed by the reaction of butadiene monoxide with adenosine: evidence for the N^1 -adenosine adducts as major initial products. Chem Res Toxicol. 9(5):875–81. http://dx.doi. org/10.1021/tx960039a PMID: 8828924 Selzer RR, Elfarra AA (1996b). Synthesis and biochemical characterization of N^1 -, N^2 -, and N^7 -guanosine adducts of butadiene monoxide. Chem Res Toxicol. 9(1):126–32. http://dx.doi. org/10.1021/tx950101o PMID: 8924581 Part 1 • Chapter 1. Electrophilic agents PART 1 CHAPTER 1
Selzer RR, Elfarra AA (1997). Chemical modification of deoxycytidine at different sites yields adducts of different stabilities: characterization of N^3 - and O^2 -deoxycytidine and N^3 -deoxyuridine adducts of butadiene monoxide. Arch Biochem Biophys. 343(1):63–
- http://dx.doi.org/10.1016/S0009- 2797(01)00275-7 PMID: 11714481 Shahin S, Cullinane C, Gray PJ (2001). Mitochondrial and nuclear DNA damage induced by sulphur mustard in keratinocytes. Chem Biol Interact. 138(3):231–45. http:// dx.doi.org/10.1016/S0009-2797(01)00275- PMID: 11714481 Sheets PL, Yost GS, Carlson GP (2004). Benzene metabolism in human lung cell lines BEAS-2B and A549 and cells overexpressing CYP2F1. J Biochem Mol Toxicol. 18(2):92–
- http://dx.doi.org/10.1002/jbt. PMID: 15122651 Shen M, Lan Q, Zhang L, Chanock S, Li G, Vermeulen R, et al_._ (2006). Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene- induced hematotoxicity. Carcinogenesis. 27(10):2083–9. http://dx.doi.org/10.1093/ carcin/bgl061 PMID: 16728435 Sills RC, Hong HL, Boorman GA, Devereux TR, Melnick RL (2001). Point mutations of K- ras and H- ras genes in forestomach neoplasms from control B6C3F1 mice and following exposure to 1,3-butadiene, isoprene or chloroprene for up to 2-years. Chem Biol Interact. 135-136:373–86. http:// dx.doi.org/10.1016/S0009-2797(01)00179-X PMID: 11397402 Singer B, Kuśmierek JT, Folkman W, Chavez F, Dosanjh MK (1991). Evidence for the mutagenic potential of the vinyl chloride induced adduct, N^2 ,3-etheno- deoxyguanosine, using a site-directed kinetic assay. Carcinogenesis. 12(4):745–7. http://dx.doi.org/10.1093/carcin/12.4. PMID: 2013138 Singer B, Spengler SJ, Chavez F, Kuśmierek JT (1987). The vinyl chloride-derived nucleoside, N^2 ,3-ethenoguanosine, is a highly efficient mutagen in transcription. Carcinogenesis. 8(5):745–7. http://dx.doi. org/10.1093/carcin/8.5.745 PMID: 3581434 Smith MT (1996). The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect. 104(Suppl 6):1219–
- http://dx.doi.org/10.1289/ehp. PMID: 9118896 Smith MT, Zhang L (1998). Biomarkers of leukemia risk: benzene as a model. Environ Health Perspect. 106(Suppl 4):937–46. http://dx.doi.org/10.1289/ehp.98106s PMID: 9703476 Smith MT, Zhang L, Wang Y, Hayes RB, Li G, Wiemels J, et al. (1998). Increased translocations and aneusomy in chromosomes 8 and 21 among workers exposed to benzene. Cancer Res. 58(10):2176–81. PMID: 9605763 Snyder R (2004). Xenobiotic metabolism and the mechanism(s) of benzene toxicity. Drug Metab Rev. 36(3–4):531–47. http:// d x. d o i. o r g / 1 0 .1 0 8 1 / D M R - 2 0 0 0 3 3 4 4 5 PMID: 15554234 Solberg Y, Alcalay M, Belkin M (1997). Ocular injury by mustard gas. Surv Ophthalmol. 41(6):461–6. http://dx.doi.org/10.1016/S0039- 6257(97)00021-0 PMID: 9220568 Somani SM, Babu SR (1989). Toxicodynamics of sulfur mustard. Int J Clin Pharmacol Ther Toxicol. 27(9):419–35. PMID: 2681003 Srám RJ, Samková I, Holá N (1983). High- dose ascorbic acid prophylaxis in workers occupationally exposed to halogenated ethers. J Hyg Epidemiol Microbiol Immunol. 27(3):305–18. PMID: 6227657 Swenberg JA, Fedtke N, Fennell TR, Walker VE (1990). Relationships between carcinogen exposure, DNA adducts and carcinogenesis. In: Clayson DB, Munro IC, Shubik P, Swenberg JA, editors. Progress in predictive toxicology. Amsterdam, Netherlands: Elsevier Scientific Publications; pp. 161–84. Swenberg JA, Ham A, Koc H, Morinello E, Ranasinghe A, Tretyakova N, et al. (2000). DNA adducts: effects of low exposure to ethylene oxide, vinyl chloride and butadiene. Mutat Res. 464(1):77–86. http://dx.doi. o r g / 1 0 .1 0 1 6 / S 13 8 3 - 5 71 8 ( 9 9 ) 0 0 1 6 8 - 0 PMID: 10633179 Tabrez S, Ahmad M (2009). Toxicity, biomarkers, genotoxicity, and carcinogenicity of trichloroethylene and its metabolites: a review. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 27(3):178–96. http:// dx.doi.org/10.1080/1059 05009 030913 40 PMID: 19657920 Tang X, Bai Y, Duong A, Smith MT, Li L, Zhang L (2009). Formaldehyde in China: production, consumption, exposure levels, and health effects. Environ Int. 35(8):1210–24. http:// dx.doi.org/10.1016/j.envint. 20 0 9.0 6.0 02 PMID: 19589601 Tates AD, van Dam FJ, Natarajan AT, van Teylingen CMM, de Zwart FA, Zwinderman AH, et al_._ (1999). Measurement of HPRT mutations in splenic lymphocytes and haemoglobin adducts in erythrocytes of Lewis rats exposed to ethylene oxide. Mutat Res. 431(2):397–415. http://dx.doi.org/10.1016/ S0027-5107(99)00182-7 PMID: 10636004 Thier R, Balkenhol H, Lewalter J, Selinski S, Dommermuth A, Bolt HM (2001). Influence of polymorphisms of the human glutathione transferases and cytochrome P450 2E enzyme on the metabolism and toxicity of ethylene oxide and acrylonitrile. Mutat Res. 482(1–2):41–6. http://dx.doi.org/10.1016/ S0027-5107(01)00208-1 PMID: 11535247 Ton TV, Hong HH, Devereux TR, Melnick RL, Sills RC, Kim Y (2007). Evaluation of genetic alterations in cancer-related genes in lung and brain tumors from B6C3F1 mice exposed to 1,3-butadiene or chloroprene. Chem Biol Interact. 166(1–3):112–20. http://dx.doi.org/10.1016/j.cbi.2006.04. PMID: 16860786 Tough IM, Brown WM (1965). Chromosome aberrations and exposure to ambient benzene. Lancet. 1(7387):684. http://dx.doi. o r g / 1 0 .1 0 1 6 / S 0 14 0 - 6 7 3 6 ( 6 5 ) 9 18 3 5 - 0 PMID: 14258551 Valentine JL, Lee SS, Seaton MJ, Asgharian B, Farris G, Corton JC, et al_._ (1996). Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression. Toxicol Appl Pharmacol. 141(1):205–13. http:// dx.doi.org/10.1016/S0041-008X(96)80026- PMID: 8917693 van der Schans GP, Scheffer AG, Mars- Groenendijk RH, Fidder A, Benschop HP, Baan RA (1994). Immunochemical detection of adducts of sulfur mustard to DNA of calf thymus and human white blood cells. Chem Res Toxicol. 7(3):408–13. http://dx.doi. org/10.1021/tx00039a019 PMID: 8075373 Van Duuren BL, Sivak A, Goldschmidt BM, Katz C, Melchionne S (1969). Carcinogenicity of halo-ethers. J Natl Cancer Inst. 43(2):481–
- PMID: 5805453 Völkel W, Dekant W (1998). Chlorothioketene, the ultimate reactive intermediate formed by cysteine conjugate β-lyase-mediated cleavage of the trichloroethene metabolite S -(1,2-Dichlorovinyl)-l-cysteine, forms cytosine adducts in organic solvents, but not in aqueous solution. Chem Res Toxicol. 11(9):1082–8. http://dx.doi.org/10.1021/ tx980084d PMID: 9760283 Waidyanatha S, Rappaport SM (2005). Investigation of cysteinyl protein adducts of benzene diolepoxide. Chem Biol Interact. 153-154:261–6. http://dx.doi.org/10.1016/j. cbi.2005.03.033 PMID: 15935825 Walker IG (1971). Intrastrand bifunctional alkylation of DNA in mammalian cells treated with mustard gas. Can J Biochem. 49(3):332–6. http://dx.doi.org/10.1139/o71- 049 PMID: 5549736 Walker VE, Fennell TR, Upton PB, Skopek TR, Prevost V, Shuker DE, et al_._ (1992). Molecular dosimetry of ethylene oxide: formation and persistence of 7-(2-hydroxyethyl)guanine in DNA following repeated exposures of rats and mice. Cancer Res. 52(16):4328–34. PMID: 1643630 Walker VE, Meng Q, Clement NL (1997a). Spectra of mutations in hprt exon 3 of T-cells from F344 rats and lacI transgenic and nontransgenic B6C3F1 mice exposed by inhalation to ethylene oxide. Environmental and Molecular Mutagenesis. 29:2854. Walker VE, Sisk SC, Upton PB, Wong BA, Recio L (1997b). In vivo mutagenicity of ethylene oxide at the hprt locus in T-lymphocytes of B6C3F1 lacI transgenic mice following inhalation exposure. Mutat Res. 392(3):211–22. http://dx.doi.org/10.1016/ S1383-5718(97)00062-4 PMID: 9294020 Walker VE, Skopek TR (1993). A mouse model for the study of in vivo mutational spectra: sequence specificity of ethylene oxide at the hprt locus. Mutat Res. 288(1):151–62. http:// dx.doi.org/10.1016/0027-5107(93)90216- PMID: 7686258
