Histologic Methods and Interspecies Variations in the Laryngeal Histology of F344/N Rats and B6C3F1 Mice
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Cited by 46 publications
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Specific regions in the rodent larynx exhibit cellular changes in response to inhaled xenobiotics. These regions include the base of the epiglottis, ventral pouch, and medial surfaces of the vocal processes of the arytenoid cartilages. There are interspecies differences among laboratory rodents in the microscopic anatomy of these sensitive areas of the laryngeal mucosa. In CRL:CD strain Sprague-Dawley rats, the mucosa covering the epiglottis differs from that of Syrian golden hamsters. The epithelium covering the base of the epiglottis is relatively thin in rats and is composed of a mixture of cell types, whereas in hamsters it is much thicker and is made up almost entirely of tall ciliated columnar cells. The cartilage supporting the ventral pouch in the larynges of hamsters is much more prominent than in rats and forms a distinct protrusion into the laryngeal lumen at the base of the epiglottis. The purpose of this paper is to describe and illustrate these and other subtle differences in rat and hamster laryngeal anatomy, which may be of toxicologic significance.
Specific regions in the rodent larynx exhibit cellular changes in response to inhaled xenobiotics. These regions include the base of the epiglottis, ventral pouch, and medial surfaces of the vocal processes of the arytenoid cartilages. There are interspecies differences among laboratory rodents in the microscopic anatomy of these sensitive areas of the laryngeal mucosa. In CRL:CD strain Sprague-Dawley rats, the mucosa covering the epiglottis differs from that of Syrian golden hamsters. The epithelium covering the base of the epiglottis is relatively thin in rats and is composed of a mixture of cell types, whereas in hamsters it is much thicker and is made up almost entirely of tall ciliated columnar cells. The cartilage supporting the ventral pouch in the larynges of hamsters is much more prominent than in rats and forms a distinct protrusion into the laryngeal lumen at the base of the epiglottis. The purpose of this paper is to describe and illustrate these and other subtle differences in rat and hamster laryngeal anatomy, which may be of toxicologic significance.
Epoxy Compounds—Olefin Oxides, Aliphatic Glycidyl Ethers and Aromatic Monoglycidyl Ethers
An epoxy compound is defined as any compound containing one or more oxirane rings. An oxirane ring (epoxide) consists of an oxygen atom linked to two adjacent (vicinal) carbon atoms. The term alpha‐epoxide is sometimes used for this structure to distinguish it from rings containing more carbon atoms. The alpha does not indicate where in a carbon chain the oxirane ring occurs. The oxirane ring is highly strained and is thus the most reactive ring of the oxacyclic carbon compounds. The strain is sufficient to force the four carbon atoms nearest the oxygen atom in 1,2‐epoxycyclohexane into a common plane, whereas in cyclohexane the carbon atoms are in a zigzag arrangement or boat structure. As a result of this strain, epoxy compounds are attacked by almost all nucleophilic substances to open the ring and form addition compounds. Among agents reacting with epoxy compounds are halogen acids, thiosulfate, carboxylic acids, hydrogen cyanide, water, amines, aldehydes, and alcohols. A major portion of this chapter presents information on the two olefin oxides, ethylene oxide and propylene oxide, which are produced in high volume and are largely used as intermediates in the production of the glycol ethers. In addition, these compounds are used in the production of several other important products (e.g., polyethylene glycols, ethanolamines, and hydroxypropylcellulose) and have minor uses as fumigants for furs and spices and as medical sterilants. The other olefin oxides discussed are used as chemical intermediates (e.g., vinylcyclohexene mono‐ and dioxide), as gasoline additives, acid scavengers, and stabilizing agents in chlorinated solvents (butylene oxide) or in limited quantities as reactive diluents for epoxy resins. The discussion of the toxicology of certain olefinic oxides may be pertinent to their respective olefin precursors. However, it must be pointed out that the olefinic precursors of these different oxides demonstrate widely varying degrees of toxicity in mammalian models, mostly attributable to pharmacokinetic/metabolism differences in metabolic conversion of olefins to their respective oxide metabolites. For example, chronic bioassay results range from repeated negatives (ethylene, propylene) to clear positives (butadiene). A major use of the glycidyl ethers discussed in this chapter are as reactive diluents in epoxy resin mixtures. However, some of these materials are also used as intermediates in chemical synthesis as well as in other industrial applications. The concept that epoxides, through their binding to nucleophilic biopolymers such as DNA, RNA, and protein, can produce toxic effects is well established. However, the magnitude and nature of physiological disruption depend on the reactivity of the particular epoxide, its molecular weight, and its solubility, all of which may control its access to critical molecular targets. In addition, the number of epoxide groups present, the dose and dose rate, the route of administration, and the affinity for the enzymes that can detoxify or activate the compound may affect the degree and nature of the physiologic response. A key enzyme for epoxide detoxification is microsomal epoxide hydrolase (EH), which is widely distributed throughout the body, but it is organ, species, and even strain variant. Acute toxic effects most commonly observed in animals have been dermatitis (either primary irritation or secondary to induction of sensitization), eye irritation, pulmonary irritation, and gastric irritation, which are found in these tissues after direct contact with the epoxy compound. Skin irritation is usually manifested by more or less sharply localized lesions that develop rapidly on contact, more frequently on the arms and hands. Signs and symptoms usually include redness, swelling, and intense itching. In severe cases, secondary infections may occur. Workers show marked differences in sensitivity. Most of the glycidyl ethers in this chapter have shown evidence of delayed contact skin sensitization, in either animals or humans. The animal and human data available on skin sensitization of epoxy compounds do not assist in determining the structural requirements necessary to produce sensitization, but do provide some practical guidance for industrial hygiene purposes. Although all of the compounds described in this chapter were mutagenic to bacteria (excluding epoxidized glycerides) as well as positive in other in vitro genotoxicity assays, not all have produced genotoxicity in in vivo studies. A number of these epoxide compounds have been found to be carcinogenic in rodents, although there has been no clear epidemiologic evidence for cancer in the workplace. In rats and/or mice, many epoxy compounds produce a carcinogenic response in the tissues of first contact. These compounds include ethylene oxide, butylene oxide, propylene oxide, styrene oxide allyl glycidyl ether, phenyl glycidyl ether, and neopentyl glycol diglycidyl ether. A few of them, such as ethylene oxide, butadiene dioxide, and vinylcyclohexene dioxide, have produced tumors at sites other than the “portal of entry.”
Epoxy Compounds—Olefin Oxides, Aliphatic Glycidyl Ethers, and Aromatic Monoglycidyl Ethers
An epoxy compound is defined as any compound containing one or more oxirane rings. An oxirane ring (epoxide) consists of an oxygen atom linked to two adjacent (vicinal) carbon atoms. The term alpha‐epoxide is sometimes used for this structure to distinguish it from rings containing more carbon atoms. The alpha does not indicate where in a carbon chain the oxirane ring occurs. The oxirane ring is highly strained and is thus the most reactive ring of the oxacyclic carbon compounds. The strain is sufficient to force the four carbon atoms nearest to the oxygen atom in 1,2‐epoxycyclohexane into a common plane, whereas in cyclohexane the carbon atoms are in a zigzag arrangement or boat structure. As a result of this strain, epoxy compounds are attacked by almost all nucleophilic substances to open the ring and form addition compounds. Agents reacting with epoxy compounds include halogen acids, thiosulfate, carboxylic acids, hydrogen cyanide, water, amines, aldehydes, and alcohols. A major portion of this chapter presents information on the two simplest olefin oxides, ethylene oxide and propylene oxide, both of which are produced in high volume and are largely used as intermediates in the production of many other products such as the glycol ethers, polyethylene glycols, ethanolamines, and hydroxypropylcellulose. These epoxides have minor uses as fumigants for furs and spices, and as medical sterilants. The other olefin oxides discussed are used as chemical intermediates (e.g., vinylcyclohexene mono‐ and dioxide), as gasoline additives, acid scavengers, and stabilizing agents in chlorinated solvents (butylene oxide) or in limited quantities as reactive diluents for epoxy resins. The discussion of the toxicology of certain olefinic oxides may be pertinent to their respective olefin precursors. However, it must be pointed out that the olefinic precursors of these different oxides demonstrate widely varying degrees of toxicity in mammalian models, mostly attributable to pharmacokinetic/metabolism differences in metabolic conversion of olefins to their respective oxide metabolites. For example, chronic bioassay results for olefins range from repeated negatives (ethylene, propylene) to clear positives (butadiene). A major use of the glycidyl ethers discussed in this chapter is as reactive diluents in epoxy resin mixtures. However, some of these materials are also used as intermediates in chemical synthesis as well as in other industrial applications. The concept that epoxides can produce toxic effects through their binding to nucleophilic macromolecules such as DNA, RNA, and protein, is well established. However, the magnitude and nature of physiological disruption depend on factors such as the reactivity of the particular epoxide, its molecular weight, and its solubility, all of which may control its access to critical molecular targets. In addition, the number of epoxide groups present, the dose and dose‐rate, the route of administration, and the affinity for enzymes that can detoxify or further activate the compound may affect the degree and nature of the physiological response. A key enzyme for epoxide detoxification is microsomal epoxide hydrolase (EH), which is widely distributed throughout the body, but can vary among different cell types and organs, and across species, and even strains. Acute toxic effects most commonly observed in animals have been dermatitis (either primary irritation or, for some, secondary to induction of sensitization), eye irritation, pulmonary irritation, and gastric irritation, which are found in these tissues after direct contact with the epoxy compound. Skin irritation is usually manifested by more or less sharply localized lesions that develop rapidly on contact, more frequently on the arms and hands. Signs and symptoms usually include redness, swelling, and intense itching. In severe cases, secondary infections may occur. Humans can show marked differences in sensitivity. Most of the glycidyl ethers in this chapter have shown evidence of delayed contact skin sensitization, in either animals or humans. The animal and human data available on skin sensitization of epoxy compounds do not assist in determining the structural requirements necessary to produce sensitization, but do provide some practical guidance for industrial hygiene purposes. Although all of the compounds described in this chapter were mutagenic to bacteria (excluding epoxidized glycerides) as well as positive in other in vitro genotoxicity assays, not all have demonstrated genotoxicity in in vivo studies by relevant exposure routes. A number of these epoxide compounds have been found to be carcinogenic in rodents, although there has been no clear epidemiologic evidence for cancer in the workplace. In rats and/or mice, many epoxy compounds produce a carcinogenic response in the tissues of first contact. These compounds include ethylene oxide, butylene oxide, propylene oxide, styrene oxide, allyl glycidyl ether, phenyl glycidyl ether, and neopentyl glycol diglycidyl ether. A few of them, such as ethylene oxide, butadiene diepoxide, and vinylcyclohexene diepoxide, have produced tumors at sites other than the “portal of entry.”
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