Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT155
M. Ward, C. Pucheu-Haston
The immune system functions to establish and maintain homeostasis to protect the body from infectious agents and certain tumours. However, the interaction between the immune system and some xenobiotics can perturb this homeostasis, resulting in adverse health events, including the development of hypersensitivity reactions in genetically predisposed individuals. The dramatic increase in protein-induced respiratory hypersensitivity in the USA and other industrialized nations over the last few decades is presumably the result of changes in environment, lifestyle and/or medical practices. This chapter provides an overview of selected laboratory methods used in the identification and health-risk assessment of potential respiratory sensitizers. We describe animal models of hypersensitivity that have been used to elucidate disease pathogenesis and hazard identification. Methods for animal exposure, sample collection and end-point assessment are also discussed. In addition to in vivo models, the development of in vitro screening techniques and the utility of technologies such as protein and gene expression microarrays, PCR and multiplexing systems in hazard screening are also described. The models and methods discussed in this chapter have been used in our laboratory and others, not only to determine the risks associated with bioaerosol exposure, but also to elucidate disease mechanism and potential intervention targets. Keywords: hypersensitivity; allergy; hypersensitivity pneumonitis; animal models; cell culture
{"title":"Laboratory Recognition of Potential Xenobiotic Respiratory Sensitizers","authors":"M. Ward, C. Pucheu-Haston","doi":"10.1002/9780470744307.GAT155","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT155","url":null,"abstract":"The immune system functions to establish and maintain homeostasis to protect the body from infectious agents and certain tumours. However, the interaction between the immune system and some xenobiotics can perturb this homeostasis, resulting in adverse health events, including the development of hypersensitivity reactions in genetically predisposed individuals. The dramatic increase in protein-induced respiratory hypersensitivity in the USA and other industrialized nations over the last few decades is presumably the result of changes in environment, lifestyle and/or medical practices. This chapter provides an overview of selected laboratory methods used in the identification and health-risk assessment of potential respiratory sensitizers. We describe animal models of hypersensitivity that have been used to elucidate disease pathogenesis and hazard identification. Methods for animal exposure, sample collection and end-point assessment are also discussed. In addition to in vivo models, the development of in vitro screening techniques and the utility of technologies such as protein and gene expression microarrays, PCR and multiplexing systems in hazard screening are also described. The models and methods discussed in this chapter have been used in our laboratory and others, not only to determine the risks associated with bioaerosol exposure, but also to elucidate disease mechanism and potential intervention targets. \u0000 \u0000 \u0000Keywords: \u0000 \u0000hypersensitivity; \u0000allergy; \u0000hypersensitivity pneumonitis; \u0000animal models; \u0000cell culture","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126656367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT173
G. Woodall, J. Gift, G. Foureman
This contribution is concerned with exploring the relationship of the duration or time and concentration components of exposure. Under many exposure scenarios, especially those characterized as acute (i.e. brief duration to high concentrations), both components are critical in eliciting the toxic response. Historical guidance on the inter-relationship of these components has been based in large part on mathematical models and theory (e.g. the ‘Haber’ C × t = k relationship and toxic load or TL phenomenon) and limited to lethality as the toxic response. This report features a suite of methods and approaches accommodating empirical data that characterize both lethal and nonlethal responses. Case studies are used to demonstrate the flexibility of these methods with regard to the type and amount of available data, as well as providing examples and insight into other aspects, including how variability arises, its consequences and how it may be addressed. Keywords: concentration × time; duration; duration extrapolation; categorical regression; acute inhalation
这一贡献是关于探索暴露的持续时间或时间和浓度成分的关系。在许多暴露情况下，特别是那些以急性暴露为特征的暴露(即短暂持续到高浓度)，这两种成分在引起毒性反应方面都是至关重要的。关于这些成分之间相互关系的历史指导在很大程度上是基于数学模型和理论(例如“Haber”C × t = k关系和毒性负荷或TL现象)，并且仅限于作为毒性反应的致命性。本报告提供了一套方法和方法，以适应致命和非致命反应特征的经验数据。案例研究用于展示这些方法在可用数据的类型和数量方面的灵活性，并提供示例和对其他方面的见解，包括可变性如何产生，其后果以及如何解决。关键词:浓度×时间;持续时间;持续时间推断;分类回归;急性吸入
{"title":"Empirical Methods and Default Approaches in Consideration of Exposure Duration in Dose–Response Relationships","authors":"G. Woodall, J. Gift, G. Foureman","doi":"10.1002/9780470744307.GAT173","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT173","url":null,"abstract":"This contribution is concerned with exploring the relationship of the duration or time and concentration components of exposure. Under many exposure scenarios, especially those characterized as acute (i.e. brief duration to high concentrations), both components are critical in eliciting the toxic response. Historical guidance on the inter-relationship of these components has been based in large part on mathematical models and theory (e.g. the ‘Haber’ C × t = k relationship and toxic load or TL phenomenon) and limited to lethality as the toxic response. This report features a suite of methods and approaches accommodating empirical data that characterize both lethal and nonlethal responses. Case studies are used to demonstrate the flexibility of these methods with regard to the type and amount of available data, as well as providing examples and insight into other aspects, including how variability arises, its consequences and how it may be addressed. \u0000 \u0000 \u0000Keywords: \u0000 \u0000concentration × time; \u0000duration; \u0000duration extrapolation; \u0000categorical regression; \u0000acute inhalation","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129307955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT158
D. Hobson
Product safety has become a keystone in the market success and longevity of many different types of products, such as pharmaceuticals, medical devices and a wide diversity of consumer products, including toys, health products, cosmetics, toys, food products and so on. Toxicologic testing for some types of products is required for registration by various international agencies, for example, pharmaceuticals, pesticides, medical devices and bulk chemicals. Other products, while not having strict registration testing requirements, should be evaluated for safety due to the potential for liability and loss of market share, as well as branding, should the product prove to have toxicologic issues while in routine consumer use. Toxicologists with appropriate training and experience, and the product-safety programmes they develop can, therefore, can have a significant impact on the success and longevity of a wide variety of products, if they are involved throughout the product life cycle, from the design of the product, through development and manufacturing, then on into the marketplace in postmarket surveillance. Basic toxicological issues to be addressed in a complete product-safety programme include the gathering of information to aid in product design, the development of specific toxicological tests and the design of toxicological-testing programmes, as well as postmarket vigilance activities. Keywords: product; safety; toxicology; testing; evaluation; nanotechnology; nanomaterials; US FDA; OECD; US EPA; consumer products; REACH; industrial chemicals; QSAR; alternative methods
{"title":"Basic Toxicological Issues in Product‐Safety Evaluations","authors":"D. Hobson","doi":"10.1002/9780470744307.GAT158","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT158","url":null,"abstract":"Product safety has become a keystone in the market success and longevity of many different types of products, such as pharmaceuticals, medical devices and a wide diversity of consumer products, including toys, health products, cosmetics, toys, food products and so on. Toxicologic testing for some types of products is required for registration by various international agencies, for example, pharmaceuticals, pesticides, medical devices and bulk chemicals. Other products, while not having strict registration testing requirements, should be evaluated for safety due to the potential for liability and loss of market share, as well as branding, should the product prove to have toxicologic issues while in routine consumer use. Toxicologists with appropriate training and experience, and the product-safety programmes they develop can, therefore, can have a significant impact on the success and longevity of a wide variety of products, if they are involved throughout the product life cycle, from the design of the product, through development and manufacturing, then on into the marketplace in postmarket surveillance. Basic toxicological issues to be addressed in a complete product-safety programme include the gathering of information to aid in product design, the development of specific toxicological tests and the design of toxicological-testing programmes, as well as postmarket vigilance activities. \u0000 \u0000 \u0000Keywords: \u0000 \u0000product; \u0000safety; \u0000toxicology; \u0000testing; \u0000evaluation; \u0000nanotechnology; \u0000nanomaterials; \u0000US FDA; \u0000OECD; \u0000US EPA; \u0000consumer products; \u0000REACH; \u0000industrial chemicals; \u0000QSAR; \u0000alternative methods","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129917678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT145
M. Nordberg, G. Nordberg
There are 67 elements classified as metals and the present chapter presents a review of the toxicology and evidence for useful biological monitoring of 29 of these elements and their various chemi ...
{"title":"Toxicology and Biological Monitoring of Metals","authors":"M. Nordberg, G. Nordberg","doi":"10.1002/9780470744307.GAT145","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT145","url":null,"abstract":"There are 67 elements classified as metals and the present chapter presents a review of the toxicology and evidence for useful biological monitoring of 29 of these elements and their various chemi ...","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"113973979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT057
J. J. Clary
While many human exposures to chemicals are by multiple exposure routes, one route usually predominates and there may be a tendency to think of the predominant route as the only route of concern. In environmental exposures a toxic material may be in the air, on food and/or in drinking water. Dermal exposure is possible if contaminated water is used for bathing. Inhalation exposure is also possible if the toxic material is volatile in hot water. The route of exposure(s) is a factor both in the design of toxicity studies and in the evaluation of a chemical's effect in humans. When testing a chemical for toxicity in animals, the route of primary concern should be the route of exposure(s) during human use. A whole-body exposure or a nose-only exposure might be used to judge the effect of pulmonary exposure. Whole-body inhalation will result in test material being deposited on the fur of experimental animals. Dermal and oral exposure, as a result of grooming, may result in a significant exposure under these conditions. The length of exposure period, short time, such as intravenous (instantaneous) or oral (bolus), compared with longer exposures such as in drinking water, inhalation exposure over a six hour period per day or continuous dermal exposure, may also be important for the response if multiple routes of exposure are of concern. A workplace exposure could result in both inhalation and dermal exposure. Absorption and metabolism most likely will proceed at different rates, and this possibly could affect the course and nature of the toxic response. Many regulatory agencies and industries rely on risk assessment in making risk management decisions. Risk assessments usually examine several routes of exposure, independently, and then the different routes of exposures are added together to define the total exposure and risk. Many times very conservative default assumptions are used. Keywords: nose-only; whole body; group versus individual housing; grooming; occupational exposure; environmental exposure; biological markers; risk assessment
{"title":"Mixed Routes of Exposure","authors":"J. J. Clary","doi":"10.1002/9780470744307.GAT057","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT057","url":null,"abstract":"While many human exposures to chemicals are by multiple exposure routes, one route usually predominates and there may be a tendency to think of the predominant route as the only route of concern. In environmental exposures a toxic material may be in the air, on food and/or in drinking water. Dermal exposure is possible if contaminated water is used for bathing. Inhalation exposure is also possible if the toxic material is volatile in hot water. The route of exposure(s) is a factor both in the design of toxicity studies and in the evaluation of a chemical's effect in humans. When testing a chemical for toxicity in animals, the route of primary concern should be the route of exposure(s) during human use. A whole-body exposure or a nose-only exposure might be used to judge the effect of pulmonary exposure. Whole-body inhalation will result in test material being deposited on the fur of experimental animals. Dermal and oral exposure, as a result of grooming, may result in a significant exposure under these conditions. The length of exposure period, short time, such as intravenous (instantaneous) or oral (bolus), compared with longer exposures such as in drinking water, inhalation exposure over a six hour period per day or continuous dermal exposure, may also be important for the response if multiple routes of exposure are of concern. A workplace exposure could result in both inhalation and dermal exposure. Absorption and metabolism most likely will proceed at different rates, and this possibly could affect the course and nature of the toxic response. Many regulatory agencies and industries rely on risk assessment in making risk management decisions. Risk assessments usually examine several routes of exposure, independently, and then the different routes of exposures are added together to define the total exposure and risk. Many times very conservative default assumptions are used. \u0000 \u0000 \u0000Keywords: \u0000 \u0000nose-only; \u0000whole body; \u0000group versus individual housing; \u0000grooming; \u0000occupational exposure; \u0000environmental exposure; \u0000biological markers; \u0000risk assessment","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124148585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT171
J. Behari
Biological effects of electromagnetic-field exposure have been a subject of continuing concern for a number of reasons. The effects have been broadly divided into two parts: thermal and nonthermal, though the demarcation between the two is not well defined. Recently, a large amount of experimental data has accumulated, indicating a variety of biological effects much below the accepted criteria for safe exposure. The biological effects, which may or may not involve health implications, are many. This includes the blood-brain barrier, ornithidine decarboxylase, the role of Ca2+, melatonin, DNA strand breakage and free-radical formation. Some of these parameters are often implicated in tumour promotion. Propagation of the signal through plasma membrane has raised questions regarding the modality of its amplification. While a number of mechanisms have been proposed (e.g. stochastic resonance, cooperativism, etc.), they may be active separately or in unison to bring about the desired amplification and control the cellular function. The formulation for setting the criteria for safety standards then needs further scrutiny, particularly for health risks from microwave exposure from wireless communication. The role of other exposure parameters, such as frequency, modulation, polarization and intermittence of exposure, may also be considered. This then suggests the necessity to have a re-look at the concept of specific absorption rate (SAR) defining dosimetry and criteria for safety standards. The possibility of application of cross fields to restrict the formation of free radicals, and possibly cancer promotion, is also presented. Keywords: electromagnetic field; mobile phone; dosimetry; biomarkers; infertility; stochastic resonance; tumour promotion; DNA strand break; free-radical formation; calcium efflux
{"title":"Biological Correlates of Low-Level Electromagnetic-Field Exposure","authors":"J. Behari","doi":"10.1002/9780470744307.GAT171","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT171","url":null,"abstract":"Biological effects of electromagnetic-field exposure have been a subject of continuing concern for a number of reasons. The effects have been broadly divided into two parts: thermal and nonthermal, though the demarcation between the two is not well defined. Recently, a large amount of experimental data has accumulated, indicating a variety of biological effects much below the accepted criteria for safe exposure. The biological effects, which may or may not involve health implications, are many. This includes the blood-brain barrier, ornithidine decarboxylase, the role of Ca2+, melatonin, DNA strand breakage and free-radical formation. Some of these parameters are often implicated in tumour promotion. Propagation of the signal through plasma membrane has raised questions regarding the modality of its amplification. While a number of mechanisms have been proposed (e.g. stochastic resonance, cooperativism, etc.), they may be active separately or in unison to bring about the desired amplification and control the cellular function. The formulation for setting the criteria for safety standards then needs further scrutiny, particularly for health risks from microwave exposure from wireless communication. The role of other exposure parameters, such as frequency, modulation, polarization and intermittence of exposure, may also be considered. This then suggests the necessity to have a re-look at the concept of specific absorption rate (SAR) defining dosimetry and criteria for safety standards. The possibility of application of cross fields to restrict the formation of free radicals, and possibly cancer promotion, is also presented. \u0000 \u0000 \u0000Keywords: \u0000 \u0000electromagnetic field; \u0000mobile phone; \u0000dosimetry; \u0000biomarkers; \u0000infertility; \u0000stochastic resonance; \u0000tumour promotion; \u0000DNA strand break; \u0000free-radical formation; \u0000calcium efflux","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121695173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT138
S. Barlow
Chemicals have been used to preserve food and to add colour and taste to food for centuries. Following the considerable increase in the use of food additives in processed foods from the mid-twentieth century, safety assessment of food additives has been conducted on a formal basis at national and international levels. Currently, over 400 individual additives are listed by the international Codex Alimentarius for use in food traded around the world. Current approaches to the safety assessment of food additives generally require an extensive database of kinetic, metabolic and toxicity studies to be generated. Toxicity studies are usually conducted in laboratory animals and the types of study generally cover all the various life-stages. Human studies are rarely available, but human data on absorption, metabolism and tolerance may be available. Studies are designed to show, not only any adverse effects, but also to identify doses below which no adverse effects occur (the no observed adverse-effect level or NOAEL). Acceptable daily intakes (ADIs) for food additives are derived by examination of the outcomes of the toxicity studies, and usually are based on the overall NOAEL for the most sensitive effect in the most sensitive species. In order to ensure absence of toxic effects in the exposed human population, conservative ADIs are derived by application of safety or uncertainty factors to the overall NOAEL. Keywords: food additives; safety; Codex Alimentarius; JECFA; SCF; EFSA; FDA; E numbers
{"title":"Toxicology of Food Additives","authors":"S. Barlow","doi":"10.1002/9780470744307.GAT138","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT138","url":null,"abstract":"Chemicals have been used to preserve food and to add colour and taste to food for centuries. Following the considerable increase in the use of food additives in processed foods from the mid-twentieth century, safety assessment of food additives has been conducted on a formal basis at national and international levels. Currently, over 400 individual additives are listed by the international Codex Alimentarius for use in food traded around the world. Current approaches to the safety assessment of food additives generally require an extensive database of kinetic, metabolic and toxicity studies to be generated. Toxicity studies are usually conducted in laboratory animals and the types of study generally cover all the various life-stages. Human studies are rarely available, but human data on absorption, metabolism and tolerance may be available. Studies are designed to show, not only any adverse effects, but also to identify doses below which no adverse effects occur (the no observed adverse-effect level or NOAEL). Acceptable daily intakes (ADIs) for food additives are derived by examination of the outcomes of the toxicity studies, and usually are based on the overall NOAEL for the most sensitive effect in the most sensitive species. In order to ensure absence of toxic effects in the exposed human population, conservative ADIs are derived by application of safety or uncertainty factors to the overall NOAEL. \u0000 \u0000 \u0000Keywords: \u0000 \u0000food additives; \u0000safety; \u0000Codex Alimentarius; \u0000JECFA; \u0000SCF; \u0000EFSA; \u0000FDA; \u0000E numbers","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131249309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT166
Xianchun Li
Glutathione (GSH) and glutathione-S-transferases (GSTs) are two primary lines of defence against both acute and chronic toxicities of electrophiles and reactive oxygen/nitrogen species. GSH confers cellular protection by directly or enzymatically reducing free radicals and reactive species (RS), and conjugating endogenous and exogenous electrophiles. GSTs are a superfamily of Phase 2 detoxification enzymes that detoxify both RS and toxic xenobiotics, primarily by catalysing GSH-dependent conjugation and redox reactions. Both GSH content and GST enzyme activities are under tight homeostatic control. Under normal conditions, neither GST enzyme activities nor GSH levels operate at their maximum capacity. Upon exposure to mild oxidative and electrophilic stress, they are concomitantly induced to achieve efficient protection. This chapter provides an updated understanding about GSH synthesis, the utilization of GSH for detoxification against RS, drugs and toxic xenobiotics, and its recycling from glutathione disulfide (GSSG) and GSH conjugates. This chapter also reviews the united classification/nomenclature system, structure, catalytic mechanism and functions of GST enzymes. Another focus of this chapter is the well-characterized antioxidant response element (ARE)/nuclear factor-erythroid-2-related factor 2 (Nrf2)-Kelch-like ECH associating protein 1 (Keap1) signalling pathway that regulates the basal and induced expression of GST and GSH homeostasis genes in mammals. Keywords: antioxidant response element (ARE); cytoprotection; electrophiles; glutathione (GSH); GSH homeostasis; glutathione-S-transferase (GST); induction; oxidative stress; nuclear factor-erythroid-2-related factor 2 (Nrf2); reaction
{"title":"Glutathione and Glutathione‐S‐Transferase in Detoxification Mechanisms","authors":"Xianchun Li","doi":"10.1002/9780470744307.GAT166","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT166","url":null,"abstract":"Glutathione (GSH) and glutathione-S-transferases (GSTs) are two primary lines of defence against both acute and chronic toxicities of electrophiles and reactive oxygen/nitrogen species. GSH confers cellular protection by directly or enzymatically reducing free radicals and reactive species (RS), and conjugating endogenous and exogenous electrophiles. GSTs are a superfamily of Phase 2 detoxification enzymes that detoxify both RS and toxic xenobiotics, primarily by catalysing GSH-dependent conjugation and redox reactions. Both GSH content and GST enzyme activities are under tight homeostatic control. Under normal conditions, neither GST enzyme activities nor GSH levels operate at their maximum capacity. Upon exposure to mild oxidative and electrophilic stress, they are concomitantly induced to achieve efficient protection. This chapter provides an updated understanding about GSH synthesis, the utilization of GSH for detoxification against RS, drugs and toxic xenobiotics, and its recycling from glutathione disulfide (GSSG) and GSH conjugates. This chapter also reviews the united classification/nomenclature system, structure, catalytic mechanism and functions of GST enzymes. Another focus of this chapter is the well-characterized antioxidant response element (ARE)/nuclear factor-erythroid-2-related factor 2 (Nrf2)-Kelch-like ECH associating protein 1 (Keap1) signalling pathway that regulates the basal and induced expression of GST and GSH homeostasis genes in mammals. \u0000 \u0000 \u0000Keywords: \u0000 \u0000antioxidant response element (ARE); \u0000cytoprotection; \u0000electrophiles; \u0000glutathione (GSH); \u0000GSH homeostasis; \u0000glutathione-S-transferase (GST); \u0000induction; \u0000oxidative stress; \u0000nuclear factor-erythroid-2-related factor 2 (Nrf2); \u0000reaction","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128849977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT020
J. Laskin, D. Heck, D. Laskin
The host response to chemically induced tissue injury is complex, involving a variety of cell types and soluble mediators. One of the most intensely investigated mediators implicated in the pathogenic process is nitric oxide, a highly reactive small-molecular-weight gas. Almost all cells in the body have the capacity to generate nitric oxide from l-arginine via one of three isoforms of the enzyme, nitric oxide synthase. These include the high-output isoform, inducible nitric oxide synthase, and the low-output isoforms, endothelial and neuronal nitric oxide synthases. Toxicants stimulate production of nitric oxide in target tissues by up-regulating expression and/or activity of nitric oxide synthases. This can occur directly by reaction of the chemicals or their metabolites with target cells, or indirectly, via cytokines, growth factors and lipid mediators generated following tissue injury. Whereas low levels of nitric oxide function to activate biochemical and molecular signalling cascades in target cells, high levels induce nitrosative stress. Both of these actions can contribute to toxicity. Selective pharmacological inhibitors and knockout mice have been used to delineate the role of the different isoforms of nitric oxide synthase in chemical toxicity. Further studies on the pathways by which excessive production of reactive nitrogen species leads to pathology will be key for a more complete understanding of the mechanisms of xenobiotic-induced cytotoxicity and tissue injury. Keywords: nitric oxide; peroxynitrite; nitric oxide synthase; inflammation; toxicity; apoptosis
{"title":"Nitric Oxide Pathways in Toxic Responses","authors":"J. Laskin, D. Heck, D. Laskin","doi":"10.1002/9780470744307.GAT020","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT020","url":null,"abstract":"The host response to chemically induced tissue injury is complex, involving a variety of cell types and soluble mediators. One of the most intensely investigated mediators implicated in the pathogenic process is nitric oxide, a highly reactive small-molecular-weight gas. Almost all cells in the body have the capacity to generate nitric oxide from l-arginine via one of three isoforms of the enzyme, nitric oxide synthase. These include the high-output isoform, inducible nitric oxide synthase, and the low-output isoforms, endothelial and neuronal nitric oxide synthases. Toxicants stimulate production of nitric oxide in target tissues by up-regulating expression and/or activity of nitric oxide synthases. This can occur directly by reaction of the chemicals or their metabolites with target cells, or indirectly, via cytokines, growth factors and lipid mediators generated following tissue injury. Whereas low levels of nitric oxide function to activate biochemical and molecular signalling cascades in target cells, high levels induce nitrosative stress. Both of these actions can contribute to toxicity. Selective pharmacological inhibitors and knockout mice have been used to delineate the role of the different isoforms of nitric oxide synthase in chemical toxicity. Further studies on the pathways by which excessive production of reactive nitrogen species leads to pathology will be key for a more complete understanding of the mechanisms of xenobiotic-induced cytotoxicity and tissue injury. \u0000 \u0000 \u0000Keywords: \u0000 \u0000nitric oxide; \u0000peroxynitrite; \u0000nitric oxide synthase; \u0000inflammation; \u0000toxicity; \u0000apoptosis","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131679691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT128
S. Gilbert, D. Eaton
Toxicologists gather and assess data on the effects of chemicals on human health and the environment. Toxicological data can have significant finical implications as well individual and societal implications. It is thus important for a toxicologist to give careful consideration to values and ethics that underlie scientific research and decision making. The fundamental principles that an ethical toxicologist should consider can be summarized as: (i) dignity, which includes respect for the autonym of human and animal subjects; (ii) veracity, an adherence to transparency and presentation of all the facts so all parties can discover the truth; (iii) justice, which includes an equitable distributions of the costs, hazards, and gains; (iv) integrity, an honest and forthright approach; (v) responsibility, an acknowledgement of responsibility and accountability to all parties involved; and (vi) sustainability, consideration that actions are sustainable over a long period of time. The ethical toxicologist must move beyond adherence to the legal regulatory requirements or best practices and develop a deeper ethical foundation grounded in a consistent philosophy of basic values and principles. This chapter explores various historical and current ethical aspects of issues that professional toxicologists must address. Keywords: ethics; precautionary principle; justice; dignity; integrity; responsibility; veracity; sustainability; code of ethics
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