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Electrophilic Agents James A part 1 . PART 1 concordance between cancer in humans and in experimental CHAPTER 1 animals chapter 1. Electrophilic agents James A. Bond and Ronald L. Melnick Introduction or mice and, except for ethylene chloride), the lung (sulfur mustard), oxide, sufficient evidence of carci- the lymphohaematopoietic system In this chapter, electrophilic agents nogenicity from studies of exposed (benzene, 1,3-butadiene, and eth- include direct-acting electrophilic humans. For ethylene oxide, there ylene oxide), nasal tissue (formal- chemicals and chemicals that are was limited evidence of carcinogen- dehyde), and the kidney (TCE). For metabolized to reactive electro- icity in humans, but the classification bis(chloromethyl)ether (BCME), the philes. All of the chemicals discussed of this chemical was raised to carci- lung and the nasal cavity were iden- here are IARC Group 1 agents and nogenic to humans (Group 1) based tified as target organs in humans as such can be characterized as on strong mechanistic evidence and rats, respectively. In addition, carcinogenic to humans. Relevant of mutagenicity and clastogenici- angiosarcomas of the liver, which carcinogens discussed in this chap- ty, including the induction of sister are rare tumours, were identified in ter do not include pharmaceutical chromatid exchange (SCE), chro- humans, rats, and mice exposed to drugs classified in Group 1, which mosomal aberrations (CA), and mi- vinyl chloride. otherwise typically include alkylating cronuclei (MN) in workers exposed In several instances, tumour sites cytotoxic agents. to ethylene oxide. identified in animals were not de- Tumour sites identified in previous Among this group of chemicals, tected in epidemiological studies of IARC evaluations of the carcinogen- there is remarkable concordance in exposed workers. These apparent icity of several non-pharmaceutical tumour sites with sufficient evidence discrepancies may be due to dif- organic compounds in humans and or limited evidence of carcinogenicity ferences in susceptibility between laboratory animals are shown in in humans and sufficient evidence of humans and certain animal mod- Table 1.1. For each of these agents, carcinogenicity in rats and/or mice, els, differences in exposure con- there was sufficient evidence of car- for example for the liver (aflatoxins, ditions between studies in animals cinogenicity from studies in rats and/ trichloroethylene [TCE], and vinyl and in humans, or limitations in Part 1 • Chapter 1. Electrophilic agents 1 Table 1.1. Tumour sites in humans, rats, and mice for electrophilic agents 2 Agent Humans Rats Mice Sufficient evidence Limited evidence Sufficient evidence Sufficient evidence Aflatoxins Liver: hepatocellular Liver: hepatocellular carcinoma carcinoma Benzene Acute myeloid Acute lymphoblastic Oral cavity: carcinoma Lymphoid tissue: lymphoma leukaemia leukaemia Forestomach: squamous cell Haematopoietic tissue: granulocytic leukaemia Chronic lymphocytic carcinoma Mammary gland: adenocarcinoma leukaemia Skin: squamous cell carcinoma Lung: bronchiolo-alveolar carcinoma Multiple myeloma Zymbal gland: carcinoma Zymbal gland: carcinoma Non-Hodgkin lymphoma Preputial gland: squamous cell carcinoma Bis(chloromethyl)ether Lung Nasal cavity: olfactory Soft tissue: sarcoma (BCME) neuroblastoma 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 Brain: glioma Lung (non-Hodgkin lymphoma, Lymphoid tissue: lymphoma multiple myeloma, chronic Peritoneum: mesothelioma lymphocytic leukaemia) Breast Formaldehyde Nasopharynx Paranasal sinuses Nasal cavity: squamous cell Leukaemia carcinoma Sulfur mustard Lung Larynx Lung Trichloroethylene (TCE) Kidney Non-Hodgkin lymphoma Kidney Liver Liver Lung Vinyl chloride Liver: angiosarcoma Liver and extrahepatic: Liver and extrahepatic: angiosarcoma Liver: hepatocellular angiosarcoma Lung: bronchiolo-alveolar carcinoma carcinoma Liver: hepatocellular carcinoma Mammary gland: adenocarcinoma Mammary gland: adenocarcinoma Zymbal gland: carcinoma epidemiological studies that reduce Table 1.2. Common among these 10 interactions of organic compounds, their power to detect excess cancer agents is the electrophilic nature of or their metabolites, with DNA and risk at particular sites. For example, the parent chemical or a metabolite other critical macromolecules or re- the finding that mammary gland tu- thereof. All of these agents either ceptors are also important, because PART 1 mours were induced in female mice exist as direct-acting electrophilic these interactions can initiate the car- CHAPTER 1 exposed to benzene, 1,3-butadiene, species or can be metabolized to cinogenic process or affect its pro- or vinyl chloride, whereas breast can- reactive electrophilic species. It is gression. Determinants for metabol- cer risk was not elevated in exposed generally accepted that the abili- ism or molecular interactions are workers may be due to the fact that ty of these electrophiles, whether dependent on the exposure history women were not included in many alkylating agents, epoxides, or qui- (including the intensity, duration, occupational cohort or case–control nones, to react with nucleophiles, frequency, and route or routes of studies of these agents, sometimes such as DNA, is key to the carci- exposure, and the life stage of the because there were very few or no nogenicity of this group of agents exposed individual) and may differ women in relevant workforces, or (Table 1.1 and Table 1.2). according to the specific genotype of because they were exposed to much Because of the diversity in the the individual (i.e. genetic polymor- lower concentrations. In contrast, for biochemical and physical properties phisms in metabolic enzymes). hospital-based sterilization workers of organic electrophilic compounds, exposed to ethylene oxide, among it is useful to first examine, in a gen- Absorption whom there is a high proportion of eral way, factors that are important Organic compounds can be ab- women, increases in breast cancer for their absorption, distribution, sorbed after inhalation, dermal ex- incidence were observed. Exposure metabolism, and elimination. These posure, or ingestion. The sites and to ethylene oxide increased the inci- factors include, but are not limited extent of absorption depend on the dence of mammary gland tumours to, (i) physiological, (ii) chemical, physicochemical characteristics of in female mice but not in male mice. and (iii) metabolic determinants. the compound. Highly reactive or- Thus, limitations in human cancer Examples of physiological factors ganic chemicals typically interact databases and sex-specific tumours are alveolar ventilation rate, cardi- with tissues at the portal of entry, in animal studies need to be consid- ac output, blood flow to organs, or- and toxicity and carcinogenicity are ered in evaluations of site concor- gan volumes, and body mass and often most evident at these sites. dance for tumour induction between composition (e.g. percentage body Formaldehyde, for example, is a wa- humans and animals. fat). Examples of chemical factors ter-soluble, reactive volatile organic The carcinogenicity of organic include the stability and reactivity compound. After inhalation, form- compounds and their organ specifici- of the parent compound and its me- aldehyde interacts with the highly ty in animal models and in humans tabolites, partition coefficients that aqueous nasal mucosa, the first are influenced by numerous factors. control the distribution of organic respiratory tract tissue that is en- This chapter focuses on factors compounds between blood and air countered upon inspiration. In rats that affect tissue dosimetry, factors or blood and tissues, rates of uptake chronically exposed to formaldehyde that contribute to the multistep car- from the gastrointestinal tract, and vapours, the anterior portion of the cinogenic process for each agent, absorption through the dermis. For nasal cavity was the site of tumour and factors that might account for some organic chemicals, metabol- induction. interspecies and inter-individual ic determinants such as the cellular Sulfur mustard (also known as differences in susceptibility. capacity for metabolism and the af- finity of metabolic enzymes for the mustard gas) is another example of Chemical disposition compound are critical, both in acti- a reactive volatile organic compound vating the parent compound to the that can be absorbed after inhalation The role of metabolism in the forma- putative carcinogenic electrophilic or through dermal exposure. It is a tion of the putative carcinogenic inter- metabolite and in transforming the lipophilic substance that easily pene- mediates of the non-pharmaceutical parent compound or the electrophilic trates into the skin and mucosal sur- organic compounds that are carcino- intermediate into a metabolite that faces (Drasch et al., 1987; Somani genic to humans is summarized in can be readily eliminated. Molecular and Babu, 1989), resulting in a high Part 1 • Chapter 1. Electrophilic agents 3 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
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