Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT009
K. Krishnan, S. Isukapalli, Jonathan W. Boyd
Dose-response assessment for chemical mixtures involves the characterization of the relationship between administered dose (or more appropriately target tissue dose) and tissue response, in order to facilitate the determination of safe exposure levels for humans. When interactions among chemicals occur, the consideration of mechanisms would be necessary for the conduct of scientifically sound dose-response assessment for mixtures. The present chapter focusses on the current approaches for evaluating toxicological interactions for the dose-response assessment of chemical mixtures. The approaches described in this chapter include: (i) interaction matrix method, (ii) interaction weighting ratio method and (iii) physiologically based pharmacokinetic (PBPK) modelling. The unique use of PBPK models in predicting the change in tissue dose of mixture components as a function of dose, route, exposure scenario and mixture complexity is highlighted. Finally, the interaction-based dose-response analysis of chemical mixtures is described, along with illustrative examples. Keywords: toxic interactions; PBPK modeling; chemical mixtures; interaction matrix; interaction weighting ratio; metabolic interactions
{"title":"Evaluation of Toxicological Interactions for the Dose-Response Assessment of Chemical Mixtures","authors":"K. Krishnan, S. Isukapalli, Jonathan W. Boyd","doi":"10.1002/9780470744307.GAT009","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT009","url":null,"abstract":"Dose-response assessment for chemical mixtures involves the characterization of the relationship between administered dose (or more appropriately target tissue dose) and tissue response, in order to facilitate the determination of safe exposure levels for humans. When interactions among chemicals occur, the consideration of mechanisms would be necessary for the conduct of scientifically sound dose-response assessment for mixtures. The present chapter focusses on the current approaches for evaluating toxicological interactions for the dose-response assessment of chemical mixtures. The approaches described in this chapter include: (i) interaction matrix method, (ii) interaction weighting ratio method and (iii) physiologically based pharmacokinetic (PBPK) modelling. The unique use of PBPK models in predicting the change in tissue dose of mixture components as a function of dose, route, exposure scenario and mixture complexity is highlighted. Finally, the interaction-based dose-response analysis of chemical mixtures is described, along with illustrative examples. \u0000 \u0000 \u0000Keywords: \u0000 \u0000toxic interactions; \u0000PBPK modeling; \u0000chemical mixtures; \u0000interaction matrix; \u0000interaction weighting ratio; \u0000metabolic interactions","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":"130654537","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.GAT131
R. Maynard, R. Chilcott
Irritant or toxic chemicals have been used in warfare since ancient times and a number of international laws have attempted to prevent the use of such weapons. However, chemical warfare agents remain to be a global threat and so it is important to maintain an understanding of their mechanism of action, their clinical effects and to identify effective treatment regimes. Chemical warfare agents have traditionally been classified according to their medical effect(s) or military application. Vesicant agents (for example, sulphur mustard and lewisite) are highly potent acute contact irritants and may cause severe skin damage following dermal exposure as well as extensive damage to other epithelial surfaces (such as the lungs and eyes). Vesicants are generally considered to be non-lethal in that they cause debilitating (rather than fatal) injuries. Indeed, some chemicals are used specifically for their irritating (rather than lethal) effects. For example, the riot control agents CS and CR are potent lachrymators but generally lack any significant, systemic toxicity following respiratory or dermal exposure. In contrast, a number of chemicals have been specifically developed or used on account of their lethality and these include the nerve agents (such as sarin, tabun, soman and VX), lung damaging agents (phosgene and chlorine) and other systemic poisons such as cyanides. A large miscellany of other, more exotic chemicals exist and these include endogenous bioregulators as well as plant, animal, marine and fungal toxins. Keywords: chemical warfare; mustard gas; nerve agent; cholinesterase; decontamination; phosgene
{"title":"Toxicology of Chemical Warfare Agents","authors":"R. Maynard, R. Chilcott","doi":"10.1002/9780470744307.GAT131","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT131","url":null,"abstract":"Irritant or toxic chemicals have been used in warfare since ancient times and a number of international laws have attempted to prevent the use of such weapons. However, chemical warfare agents remain to be a global threat and so it is important to maintain an understanding of their mechanism of action, their clinical effects and to identify effective treatment regimes. Chemical warfare agents have traditionally been classified according to their medical effect(s) or military application. Vesicant agents (for example, sulphur mustard and lewisite) are highly potent acute contact irritants and may cause severe skin damage following dermal exposure as well as extensive damage to other epithelial surfaces (such as the lungs and eyes). Vesicants are generally considered to be non-lethal in that they cause debilitating (rather than fatal) injuries. Indeed, some chemicals are used specifically for their irritating (rather than lethal) effects. For example, the riot control agents CS and CR are potent lachrymators but generally lack any significant, systemic toxicity following respiratory or dermal exposure. In contrast, a number of chemicals have been specifically developed or used on account of their lethality and these include the nerve agents (such as sarin, tabun, soman and VX), lung damaging agents (phosgene and chlorine) and other systemic poisons such as cyanides. A large miscellany of other, more exotic chemicals exist and these include endogenous bioregulators as well as plant, animal, marine and fungal toxins. \u0000 \u0000 \u0000Keywords: \u0000 \u0000chemical warfare; \u0000mustard gas; \u0000nerve agent; \u0000cholinesterase; \u0000decontamination; \u0000phosgene","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":"134329689","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.GAT157
W. Bryden
Mycotoxins are secondary fungal metabolites, which when ingested cause disease syndromes called mycotoxicoses. Fungi are ubiquitous and formation of mycotoxins can occur in all agricultural and food commodities under appropriate field or storage conditions. In this increasingly complex area the salient features of fungal growth and mycotoxin production are described, with strategies to mitigate their accumulation in the food chain. As mycotoxins can be elaborated in food commodities, especially cereal grains prior to harvest, preventive measures begin with good agronomic practices, including cultivating to improve plant vigour, judicious use of insecticides to reduce insect damage, irrigation to avoid drought conditions, harvesting at maturity and, more recently, application of genomics to improve genetic resistance to fungal attack. Storage and food processing conditions can assist in reducing mycotoxin occurrence. Human populations in developing countries are more likely than people in developed economies to be exposed to mycotoxins in their food and strategies have been proposed for education and intervention to reduce the health and economic burden of these toxins. Keywords: mycotoxin; mycotoxicoses; fungi; aflatoxin; ochratoxin; trichothecenes; zearalenone; fumonisins; deoxynivalenol; ergot alkaloids; Aspergillus; Fusarium; Penicillium
{"title":"Mycotoxins and Mycotoxicoses: Significance, Occurrence and Mitigation in the Food Chain","authors":"W. Bryden","doi":"10.1002/9780470744307.GAT157","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT157","url":null,"abstract":"Mycotoxins are secondary fungal metabolites, which when ingested cause disease syndromes called mycotoxicoses. Fungi are ubiquitous and formation of mycotoxins can occur in all agricultural and food commodities under appropriate field or storage conditions. In this increasingly complex area the salient features of fungal growth and mycotoxin production are described, with strategies to mitigate their accumulation in the food chain. As mycotoxins can be elaborated in food commodities, especially cereal grains prior to harvest, preventive measures begin with good agronomic practices, including cultivating to improve plant vigour, judicious use of insecticides to reduce insect damage, irrigation to avoid drought conditions, harvesting at maturity and, more recently, application of genomics to improve genetic resistance to fungal attack. Storage and food processing conditions can assist in reducing mycotoxin occurrence. Human populations in developing countries are more likely than people in developed economies to be exposed to mycotoxins in their food and strategies have been proposed for education and intervention to reduce the health and economic burden of these toxins. \u0000 \u0000 \u0000Keywords: \u0000 \u0000mycotoxin; \u0000mycotoxicoses; \u0000fungi; \u0000aflatoxin; \u0000ochratoxin; \u0000trichothecenes; \u0000zearalenone; \u0000fumonisins; \u0000deoxynivalenol; \u0000ergot alkaloids; \u0000Aspergillus; \u0000Fusarium; \u0000Penicillium","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":"130182490","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.GAT077
D. Mcgregor
The definition of a carcinogen in an experimental context is an agent which increases the incidence of any neoplasm irrespective of whether it is lethal, potentially lethal or benign. As genetic factors are fundamental in carcinogenesis these are briefly reviewed. A description of some of the problems associated with carcinogenicity experiments and the interpretation of their results is presented. Particular emphasis is given to so-called genotoxic carcinogens. ‘So-called’ because there are unresolved difficulties in defining the weight and strength of evidence required for concluding that genotoxicity is indeed the mode of carcinogenic action (MOA), rather than simply concluding that the MOA is unknown. A genotoxic MOA that is based on reactivity with DNA may lead currently to the unverifiable and therefore counter-scientific default assumption that there is no dose without an effect on cancer incidence. Carcinogenicity test design, including the use of the maximum tolerated dose, is briefly discussed. This is followed by consideration of issues and challenges presented in the interpretation of results by the basic pathology, the grouping of tumours for statistical analysis, the use and abuse of historical control data, interpretation of high-dose effects, the use of transgenic animals and the identification of noncarcinogens. Finally, division of the roles of risk assessors and risk managers is outlined. Keywords: carcinogen; carcinogenesis; chemical; dose; false positive; genotoxic; historical control; maximum tolerated; metabolism; mouse; nongenotoxic; noncarcinogen; oncogene; pathology; rat; risk; statistic; transgenic
{"title":"Carcinogenesis and Carcinogens that are also Genotoxic","authors":"D. Mcgregor","doi":"10.1002/9780470744307.GAT077","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT077","url":null,"abstract":"The definition of a carcinogen in an experimental context is an agent which increases the incidence of any neoplasm irrespective of whether it is lethal, potentially lethal or benign. As genetic factors are fundamental in carcinogenesis these are briefly reviewed. A description of some of the problems associated with carcinogenicity experiments and the interpretation of their results is presented. Particular emphasis is given to so-called genotoxic carcinogens. ‘So-called’ because there are unresolved difficulties in defining the weight and strength of evidence required for concluding that genotoxicity is indeed the mode of carcinogenic action (MOA), rather than simply concluding that the MOA is unknown. A genotoxic MOA that is based on reactivity with DNA may lead currently to the unverifiable and therefore counter-scientific default assumption that there is no dose without an effect on cancer incidence. Carcinogenicity test design, including the use of the maximum tolerated dose, is briefly discussed. This is followed by consideration of issues and challenges presented in the interpretation of results by the basic pathology, the grouping of tumours for statistical analysis, the use and abuse of historical control data, interpretation of high-dose effects, the use of transgenic animals and the identification of noncarcinogens. Finally, division of the roles of risk assessors and risk managers is outlined. \u0000 \u0000 \u0000Keywords: \u0000 \u0000carcinogen; \u0000carcinogenesis; \u0000chemical; \u0000dose; \u0000false positive; \u0000genotoxic; \u0000historical control; \u0000maximum tolerated; \u0000metabolism; \u0000mouse; \u0000nongenotoxic; \u0000noncarcinogen; \u0000oncogene; \u0000pathology; \u0000rat; \u0000risk; \u0000statistic; \u0000transgenic","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":"114011715","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.GAT052
P. Copestake
There is a diverse array of information resources available for toxicological data. The primary scientific literature should perhaps form the basis of any robust search. This chapter describes some of the key bibliographic databases to this literature, such as the US National Library of Medicine's TOXLINE and MEDLINE files, as well as outlining some of the important factors that determine how effectively any search will find relevant data. Many useful compilations of hard toxicological data also exist, in the form of factual databanks or reviews produced by various expert groups. Many are available for free on the Internet. The Internet provides the interface with many of the key toxicological resources, as well as offering the opportunity for more general searches for data. The chapter concludes with a timely reminder about the importance of accuracy, data interpretation and verification of information when it comes to toxicology. Keywords: information retrieval; databases; databanks; scientific literature; searching; online
{"title":"Information Resources for Toxicology","authors":"P. Copestake","doi":"10.1002/9780470744307.GAT052","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT052","url":null,"abstract":"There is a diverse array of information resources available for toxicological data. The primary scientific literature should perhaps form the basis of any robust search. This chapter describes some of the key bibliographic databases to this literature, such as the US National Library of Medicine's TOXLINE and MEDLINE files, as well as outlining some of the important factors that determine how effectively any search will find relevant data. Many useful compilations of hard toxicological data also exist, in the form of factual databanks or reviews produced by various expert groups. Many are available for free on the Internet. The Internet provides the interface with many of the key toxicological resources, as well as offering the opportunity for more general searches for data. The chapter concludes with a timely reminder about the importance of accuracy, data interpretation and verification of information when it comes to toxicology. \u0000 \u0000 \u0000Keywords: \u0000 \u0000information retrieval; \u0000databases; \u0000databanks; \u0000scientific literature; \u0000searching; \u0000online","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":"114845751","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.GAT136
Alexandra C Miller
Depleted uranium (DU) is a dense heavy metal and an alpha particle emitter used in military and industrial applications. Exposure can occur via wounding, ingestion or inhalation. Several recent studies have investigated the potential health effects of this unique heavy metal. These in vitro and in vivo investigations have not only demonstrated the neoplastic transforming ability, the mutagenicity and the genotoxicity of DU, but also the neurotoxicity of DU. Studies using neoplastically transformed human cells and the athymic nude mouse assay demonstrated the carcinogenic potential of DU. DU exposure has been shown to induce genomic instability in a human cell model and alpha-particle radiation is responsible for some of the cellular damage induced by DU. Chronic long-term internal exposure to embedded DU could be a carcinogenic risk and comparisons to other types of uranium exposure, i.e., occupational inhalation of natural uranium, are problematic. Chronic internal exposure studies in vivo have demonstrated that DU is leukemogenic and neurotoxic. Epidemiological studies are inconclusive and the use of depleted uranium in armor-penetrating munitions remains a source of controversy because of the numerous unanswered questions about its long-term health effects. Keywords: Depleted uranium; internal contamination; alpha-particle radiation; heavy metal; toxicology; carcinogenesis; leukemia
{"title":"Depleted Uranium: Toxicology and Health Consequences","authors":"Alexandra C Miller","doi":"10.1002/9780470744307.GAT136","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT136","url":null,"abstract":"Depleted uranium (DU) is a dense heavy metal and an alpha particle emitter used in military and industrial applications. Exposure can occur via wounding, ingestion or inhalation. Several recent studies have investigated the potential health effects of this unique heavy metal. These in vitro and in vivo investigations have not only demonstrated the neoplastic transforming ability, the mutagenicity and the genotoxicity of DU, but also the neurotoxicity of DU. Studies using neoplastically transformed human cells and the athymic nude mouse assay demonstrated the carcinogenic potential of DU. DU exposure has been shown to induce genomic instability in a human cell model and alpha-particle radiation is responsible for some of the cellular damage induced by DU. Chronic long-term internal exposure to embedded DU could be a carcinogenic risk and comparisons to other types of uranium exposure, i.e., occupational inhalation of natural uranium, are problematic. Chronic internal exposure studies in vivo have demonstrated that DU is leukemogenic and neurotoxic. Epidemiological studies are inconclusive and the use of depleted uranium in armor-penetrating munitions remains a source of controversy because of the numerous unanswered questions about its long-term health effects. \u0000 \u0000 \u0000Keywords: \u0000 \u0000Depleted uranium; \u0000internal contamination; \u0000alpha-particle radiation; \u0000heavy metal; \u0000toxicology; \u0000carcinogenesis; \u0000leukemia","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":"128645328","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.GAT031
Mae Grace Nilos, J. Gan, D. Schlenk
Chirality is a prominent feature of the living world, and also occurs in man-made chemicals, especially pharmaceuticals and agrochemicals. The significance of chirality has long been recognized in relation to the biological activity of natural compounds and synthetic drugs. At a molecular level, chirality is ubiquitous in the building blocks of proteins, carbohydrates, nucleic acids, lipids and steroids. Thus, stereoselectivity can be expected in the interactions of chiral chemicals with biological molecules. It is not uncommon in racemic mixtures of chiral drugs or agrochemicals to have only one of its two (or more) enantiomers responsible for most or all of the desired activity. The other enantiomer(s) are all too often assumed to be inactive of little or no important activity. The last 30 years has seen a significant increase in published work highlighting the important relationship between molecular geometry and bioactivity, particularly for chiral pharmaceuticals and agrochemicals. However, a sizable number of chiral drugs and agrochemicals are still available as racemates with relatively little or no information with regard to the toxicological properties of the individual enantiomers. The persistent reluctance to acknowledge the risks associated with the chirality of a chemical is no longer justified. Chiral technology has developed to a point where we are allowed several options in enantiomer resolution and preparation techniques, which in turn offer new avenues for human and environmental toxicologists to explore the stereochemical properties of these ubiquitous agents. This chapter discusses some of the toxicological complexities that could result from chirality, in the hope of highlighting the importance of enantioselective considerations in both mammalian and ecotoxicology. Keywords: chiral; chirality; enantiomers; enantioselectivity; stereoisomers; stereoselectivity; racemate; racemic mixtures
{"title":"Effects of Chirality on Toxicity","authors":"Mae Grace Nilos, J. Gan, D. Schlenk","doi":"10.1002/9780470744307.GAT031","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT031","url":null,"abstract":"Chirality is a prominent feature of the living world, and also occurs in man-made chemicals, especially pharmaceuticals and agrochemicals. The significance of chirality has long been recognized in relation to the biological activity of natural compounds and synthetic drugs. At a molecular level, chirality is ubiquitous in the building blocks of proteins, carbohydrates, nucleic acids, lipids and steroids. Thus, stereoselectivity can be expected in the interactions of chiral chemicals with biological molecules. It is not uncommon in racemic mixtures of chiral drugs or agrochemicals to have only one of its two (or more) enantiomers responsible for most or all of the desired activity. The other enantiomer(s) are all too often assumed to be inactive of little or no important activity. The last 30 years has seen a significant increase in published work highlighting the important relationship between molecular geometry and bioactivity, particularly for chiral pharmaceuticals and agrochemicals. However, a sizable number of chiral drugs and agrochemicals are still available as racemates with relatively little or no information with regard to the toxicological properties of the individual enantiomers. The persistent reluctance to acknowledge the risks associated with the chirality of a chemical is no longer justified. Chiral technology has developed to a point where we are allowed several options in enantiomer resolution and preparation techniques, which in turn offer new avenues for human and environmental toxicologists to explore the stereochemical properties of these ubiquitous agents. This chapter discusses some of the toxicological complexities that could result from chirality, in the hope of highlighting the importance of enantioselective considerations in both mammalian and ecotoxicology. \u0000 \u0000 \u0000Keywords: \u0000 \u0000chiral; \u0000chirality; \u0000enantiomers; \u0000enantioselectivity; \u0000stereoisomers; \u0000stereoselectivity; \u0000racemate; \u0000racemic mixtures","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":"125852256","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.GAT078
C. Powell, S. C. Berry
Carcinogens are considered nongenotoxic where they cannot be shown to interact directly with DNA in a number of short-term screening assays, but which are capable of producing tumours in laboratory rodents in bioassays. Epigenetic events, either acting alone or in concert with genetically determined events, may produce tumours. A key feature is that dose-threshold effects may be identifiable. In both the rat and the mouse, the liver is the most common site of nongenotoxic carcinogenesis. A special sort of hepatic carcinogenesis is that produced in rodents by peroxisome proliferators; this is of questionable significance for humans. Other important sites of non-genotoxic carcinogenesis include endocrine glands notably the thyroid, bladder and, in the rat, the forestomach. Carcinoid tumours are tumours of the diffuse neuroendocrine cell populations, found particularly in the gastrointestinal tract. Their incidence is increased with certain drugs, notably the histamine H2 antagonists. Haemangiosarcoma, which may occur at a variety of sites, clearly arises by a number of mechanisms, some of which may be genotoxic. Mesothelioma, most often of the pleura, as a human response to asbestos, may be considered a form of non-genotoxic carcinogenesis. Keywords: carcinogens; nongenotoxic; DNA; tumours; liver; peroxisome; thyroid; bladder; forestomach; carcinoid; haemangiosarcoma; mesothelioma
{"title":"Nongenotoxic or Epigenetic Carcinogenesis","authors":"C. Powell, S. C. Berry","doi":"10.1002/9780470744307.GAT078","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT078","url":null,"abstract":"Carcinogens are considered nongenotoxic where they cannot be shown to interact directly with DNA in a number of short-term screening assays, but which are capable of producing tumours in laboratory rodents in bioassays. Epigenetic events, either acting alone or in concert with genetically determined events, may produce tumours. A key feature is that dose-threshold effects may be identifiable. In both the rat and the mouse, the liver is the most common site of nongenotoxic carcinogenesis. A special sort of hepatic carcinogenesis is that produced in rodents by peroxisome proliferators; this is of questionable significance for humans. Other important sites of non-genotoxic carcinogenesis include endocrine glands notably the thyroid, bladder and, in the rat, the forestomach. Carcinoid tumours are tumours of the diffuse neuroendocrine cell populations, found particularly in the gastrointestinal tract. Their incidence is increased with certain drugs, notably the histamine H2 antagonists. Haemangiosarcoma, which may occur at a variety of sites, clearly arises by a number of mechanisms, some of which may be genotoxic. Mesothelioma, most often of the pleura, as a human response to asbestos, may be considered a form of non-genotoxic carcinogenesis. \u0000 \u0000 \u0000Keywords: \u0000 \u0000carcinogens; \u0000nongenotoxic; \u0000DNA; \u0000tumours; \u0000liver; \u0000peroxisome; \u0000thyroid; \u0000bladder; \u0000forestomach; \u0000carcinoid; \u0000haemangiosarcoma; \u0000mesothelioma","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":"127145970","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.GAT168
D. d'Auria
Law impacts every aspect of our society. This chapter will examine key areas of interaction between toxicology and the law. These range from the regulation of chemicals through expert evidence, to the communication of toxicological science to the public. Within the context of human experience, toxicologists can contribute to many types of disputes and be drawn into a wide range of circumstances. An underlying understanding of the issues and the objectives that the law seeks to achieve can prevent the toxicologist from falling into a trap and to avoid that most damaging of experience, judicial criticism. The writer's experience has been predominantly in the United Kingdom and in common law systems generally. This chapter will begin with an overview of the legal system. It will then examine a number of areas of concern, such as expert evidence and whistle-blowing, where the law provides something of a safety net for ethical standards. Finally, it looks at a number of emerging areas of interest where toxicologists are increasingly involved.
{"title":"Medicolegal and Ethical Issues in the Practice of Toxicology: A British Perspective","authors":"D. d'Auria","doi":"10.1002/9780470744307.GAT168","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT168","url":null,"abstract":"Law impacts every aspect of our society. This chapter will examine key areas of interaction between toxicology and the law. These range from the regulation of chemicals through expert evidence, to the communication of toxicological science to the public. Within the context of human experience, toxicologists can contribute to many types of disputes and be drawn into a wide range of circumstances. An underlying understanding of the issues and the objectives that the law seeks to achieve can prevent the toxicologist from falling into a trap and to avoid that most damaging of experience, judicial criticism. The writer's experience has been predominantly in the United Kingdom and in common law systems generally. This chapter will begin with an overview of the legal system. It will then examine a number of areas of concern, such as expert evidence and whistle-blowing, where the law provides something of a safety net for ethical standards. Finally, it looks at a number of emerging areas of interest where toxicologists are increasingly involved.","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":"129283530","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.GAT098
R. Howd
{"title":"Biological Criteria for Water Quality in Relation to Human Health","authors":"R. Howd","doi":"10.1002/9780470744307.GAT098","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT098","url":null,"abstract":"","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":"127692677","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}
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