General, Applied and Systems Toxicology最新文献

{"title":"Susceptibility of Neonatal Rats to Xenobiotics","authors":"M. Hirata‐Koizumi, R. Hasegawa, A. Hirose, M. Ema","doi":"10.1002/9780470744307.GAT172","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT172","url":null,"abstract":"Current risk assessments of xenobiotics, especially industrial chemicals, are usually based on animal studies. Although many types of toxicity studies are conducted to cover different developmental stages, evaluation for the early postnatal period is not adequate. In this chapter, special attention is directed to the susceptibility of neonatal animals to chemical toxicity. We introduce comparative analysis of the toxic susceptibility of neonatal and young rats to 20 chemicals as examples, and discuss a range of uncertainty factors important in the risk assessment of susceptible groups such as neonates and infants. The results reveal higher susceptibility of neonates to 11 chemicals and lower susceptibility to six chemicals compared with young rats, and one exceptional case of highly specific toxicity in neonates. These phenomena show the importance of studying sensitivity to toxic insults in the early stages of life. It suggests that an uncertainty factor of 10-fold for human variability can be considered appropriate for risk assessment, unless particular toxicity in neonates or infants has been demonstrated, or there is other relevant and credible information regarding the chemical. \u0000 \u0000 \u0000Keywords: \u0000 \u0000toxic susceptibility; \u0000neonates; \u0000infants; \u0000children; \u0000neonatal rats; \u0000risk assessment; \u0000uncertainty factors; \u0000xenobiotics, industrial chemicals","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":"127793087","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}

{"title":"Toxicology of the Exocrine Pancreas","authors":"J. Foster","doi":"10.1002/9780470744307.GAT069","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT069","url":null,"abstract":"The exocrine pancreas is not a common target organ for toxic drugs and chemicals. It is however the fifth most common human cancer in the western world, and acute and chronic pancreatitis, through various identifiable and unidentified causes, is a common disease in both the developed and developing countries of the world. Both inflammatory disease and cancer of the pancreas is correlated to lifestyle with poor diet and habits, such as moderate to high alcohol intake and smoking, having positive correlations to developing the disease. The chapter describes the functional anatomy of the organ together with its biochemistry that determines toxicity, in particular the role of oxidant damage in the development of cell and tissue damage is thought to be important. The consequences of toxic damage to the acinar cells are severe and primarily result from the auto-activation and hence autodigestion of the tissue by the digestive enzymes normally contained within the exocrine cells, a cascade of apoptosis/necrosis and fibrosis with the ultimate collapse of the organ, subsequent shock, multi-organ collapse and death. The organ has complex molecular mechanisms to prevent premature activation of the digestive enzymes and also has defence mechanisms present to neutralise any premature enzyme activation but these can be rendered ineffectual by factors such as alcohol abuse and a poor diet. \u0000 \u0000 \u0000 \u0000Chemical exposure, through both occupational and consumer product usage, has been associated with the development of both pancreatic neoplastic and non-neoplastic disease but the relationship between exposure and disease has never developed further than a simple association and it is likely that the development of pancreatic disease is a multi-faceted combination of inter-related events, none of which in isolation can induce disease. The pancreas has its own array of phase 1 and 2 metabolic enzyme systems and the role of pancreatic drug and chemical activation and detoxification in inducing toxicity is discussed together with the possible secondary effects of hepatic drug/chemical activation and detoxification. \u0000 \u0000 \u0000 \u0000Finally the role of animal models of pancreatic disease is discussed in terms of their contribution to understanding the aetiology of the human conditions and the possible use of therapeutic intervention in treating the disease. \u0000 \u0000 \u0000Keywords: \u0000 \u0000acute pancreatitis; \u0000chronic pancreatitis; \u0000pancreatic cancer; \u0000drug metabolism; \u0000phase 1 and 2 enzymes; \u0000ethanol; \u0000chlorinated hydrocarbons; \u0000anti-oxidants; \u0000reactive oxidant species; \u0000acinar; \u0000ductal; \u0000exocrine; \u0000microanatomy; \u0000functional morphology; \u0000diet; \u0000occupation; \u0000glutathione; \u0000solvents; \u0000animal models","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":"132570719","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}

{"title":"Imaging Techniques in Neurotoxicology Research and Development","authors":"P. Hantson, T. Duprez","doi":"10.1002/9780470744307.GAT042","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT042","url":null,"abstract":"The impact of neuroimaging techniques in the work up of intoxicated patients is nowadays increasing regarding both macroscopic anatomical damage (CT and MR) and ultrastructural damage (DWI), but also regarding metabolic (MR spectroscopy) and functional impairment (fMRI). Perfusional status of diseased areas may also be investigated by magnetic resonance imaging (MRI) using exogenous or even endogenous tracers, and the density of membrane receptors can be investigated using isotopic techniques (positron emission tomography (PET), single photon emission computed tomography (SPECT)). There is growing evidence for elective sensitivity of defined brain areas like basal ganglia towards toxic exposure and for relative specificity of topographical brain damage for some substances, but with significant overlapping between toxins. Uncertain relationships between severity of brain abnormalities on CT or MR images at an acute phase and functional clinical outcome renders mandatory the investigation of better early prognostic parameters which could mainly involve DWI and 1H-MRS data in clinical routine, and fMRI data, perfusion parameters, and receptors density in the investigational field. \u0000 \u0000 \u0000Keywords: \u0000 \u0000neurotoxicity; \u0000morphological imaging; \u0000functional imaging; \u0000carbon monoxide; \u0000cyanide; \u0000alcohols; \u0000illicit drugs; \u0000nicotine; \u0000metals; \u0000solvents","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":"127239900","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}

{"title":"Toxicokinetics of Xenobiotic and Metabolite Distribution and Excretion","authors":"M. Inchiosa, M. Inchiosa","doi":"10.1002/9780470744307.GAT006","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT006","url":null,"abstract":"The first portion of this chapter focusses on physicochemical characteristics of therapeutic and nontherapeutic xenobiotics that have a major influence in determining the rate of onset of pharmacodynamic or toxicodynamic effects in living organisms. This discussion is then extended to the role of these and other factors that affect the extent of distribution and accumulation of xenobiotic and xenobiotic metabolites in the animal or human body. The final portions of the chapter consider the kinetics of excretion of xenobiotics from the body. Simple one-compartment kinetics are reviewed first, followed by multicompartmental systems. In all cases, procedures are proposed that may allow quantification of the systemic ‘dose’ of a xenobiotic exposure to individuals in an environmental or occupational setting, where there is usually little information on the actual exposure. Finally, kinetic models are proposed that may permit determination of the amount of time that it will take for the plasma to be cleared of the xenobiotic, or metabolite, and how this might differ in time for the total body burden to be reduced of the same substances. \u0000 \u0000 \u0000Keywords: \u0000 \u0000kinetics of toxicodynamic onset; \u0000kinetics of distribution and accumulation; \u0000kinetics of elimination: one compartment; \u0000multicompartmental; \u0000dose and exposure determination from kinetic principles; \u0000kinetics of plasma clearing in multicompartmental systems; \u0000kinetics of clearing of body burden in multicompartmental systems; \u0000context-sensitive elimination kinetics","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":"123549949","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}

{"title":"Toxicology and Disasters","authors":"H. Illing","doi":"10.1002/9780470744307.GAT137","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT137","url":null,"abstract":"Although disasters may take many forms, they include the toxic consequences of large-scale exposure to chemicals due to nature, major accident or deliberate terrorism. This chapter first examines some of the definitions associated with major accident hazards. It then classifies and examines major incidents involving toxic chemicals, including those resulting from nature, those resulting from human activity and those resulting from the interaction between nature and human activity. Included under human activity are disasters arising from escapes from industrial plant, from fire, from food and drink and from environmental pollution. Finally disaster prevention and mitigation is examined, with particular reference to the toxicological inputs into land use and emergency planning. \u0000 \u0000 \u0000Keywords: \u0000 \u0000risk analysis; \u0000major industrial and natural hazards involving toxicants; \u0000examples; \u0000fire; \u0000food-supply contamination; \u0000industrial plant failure; \u0000meteorological events; \u0000terrorist attacks","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":"128105121","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}

{"title":"Xenobiotic‐Induced Inflammation: Pathogenesis and Mediators","authors":"P. Clements","doi":"10.1002/9780470744307.GAT167","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT167","url":null,"abstract":"Inflammation is an extremely complex and fascinating adaptive process by which fluid, electrolytes, plasma proteins and leukocytes accumulate in the extravascular spaces, in response to a variety of noxious stimuli. These inducers of inflammation include trauma, infectious agents, neoplastic cells and xenobiotics. Such stimuli are sensed by various cellular mechanisms via complex pathways of intracellular signalling resulting in the release of inflammatory mediators. These mediators comprise a large number of molecules ranging from nitric oxide to small amines, peptides, proteins, lysosomal enzymes and lipid derivatives, which act on target effector cells such as leukocytes, endothelial cells and fibroblasts to change their phenotype and orchestrate the inflammatory process. The function of inflammation is to dilute, contain and remove the inducing stimuli in preparation for healing and regeneration. However, inflammation can persist, resulting in tissue damage and possibly functional compromise. Xenobiotics can induce inflammation by a variety of different mechanisms, many of which result in cell injury, degeneration and/or necrosis, either directly or indirectly, by parent or metabolite. This cytotoxicity may be related to pharmacology or to the generation of toxic intermediates in the affected cells. Xenobiotics may also activate inflammatory/immune cells to release inflammatory mediators in nonspecific ways, or by stimulating a specific immune response. The pattern of morphologic and functional changes induced by these mechanisms differs according to the target cell population affected and persistence of inducing stimuli. The pathogenesis of inflammation at the tissue, cellular and molecular levels is reviewed: these mechanisms also apply to inflammation induced by xenobiotics. It is important to note that superantigen-mediated cytokine release, or immune-mediated mechanisms of inflammation may be poorly predicted by preclinical toxicity studies. A detailed knowledge of the pathogenesis and molecular mechanisms involved in inflammation can facilitate the design of in vitro or in vivo studies to predict or investigate these responses when associated with xenobiotic administration. \u0000 \u0000 \u0000Keywords: \u0000 \u0000inflammation; \u0000pathogenesis; \u0000xenobiotic; \u0000eicosanoids; \u0000cytokines; \u0000chemokines; \u0000toxicology; \u0000hypersensitivity","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":"114737822","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}

{"title":"Skeletal Muscle Toxicology","authors":"M. A. Kenaston, Ellen M. Abramson, Matthew E. Pfeiffer, E. Mills","doi":"10.1002/9780470744307.GAT070","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT070","url":null,"abstract":"The skeletal musculature is necessary for normal motor functions such as walking or breathing. It accounts for between 35 and 45% of total body weight in humans and is the most energetically demanding tissue in the body. Skeletal muscle is a unique tissue with intricate organizational arrangement, requiring precise regulation of intracellular ions and cooperation by a multitude of cellular proteins. As a result, it also has susceptibilities to a diverse array of toxic insults. Derangements of skeletal muscle function can cause loss of movement, multiorgan involvement and even organismal demise. In addition to direct effects on skeletal muscle, this tissue can also be responsible for damage to distant tissues and organs by release of large intracellular proteins into the vasculature. As a specific topic, skeletal muscle toxicology has been largely absent from the majority of textbooks. However, it represents an important and specific target of a variety of natural and synthetic toxicants. Here we present an overview of skeletal muscle physiology, including tissue architecture, energetic substrate preferences, and function. Laboratory methods and diagnostic observations to be used for investigating skeletal muscle injury in a research and clinical setting are also discussed. Finally, we provide an in-depth outline of skeletal muscle toxicants arranged according to their proposed mechanism of action. \u0000 \u0000 \u0000Keywords: \u0000 \u0000skeletal muscle; \u0000toxicology; \u0000rhabdomyolysis; \u0000myopathy; \u0000sarcoplasmic; \u0000myotube; \u0000hyperthermia; \u0000thermogenesis; \u0000myotoxic","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":"124255542","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}

{"title":"Space Toxicology: Toxicological Risk Management of Human Health during Space Exploration","authors":"N. Khan-Mayberry, J. James","doi":"10.1002/9780470744307.GAT169","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT169","url":null,"abstract":"Since the beginning of manned spaceflight, NASA has considered the overall health of astronaut crew members as vital for individual performance and wellbeing, as well as overall mission success. This was the impetus for the birth of space toxicology. Humans interacting with chemical constituents in enclosed or closed-loop environments are intrinsic to spaceflight; therefore these chemical exposures must be controlled and maintained at a level that is not detrimental to crew health. Despite engineering efforts, hundreds of chemicals will potentially be encountered in the closed-loop environment during spaceflight. Some chemicals that must be considered are those produced biologically by the crew members, as well as those originating from vehicular components, payload experiments and use of utility compounds. This chapter will ‘voyage’ to various facets of the discipline of space toxicology and its history, the unique astronaut population and spaceflight-induced physiological changes, air revitalization and water recovery, risk assessment and management, sources of chemical toxins and NASA's vision for future exploration. \u0000 \u0000 \u0000Keywords: \u0000 \u0000space; \u0000space toxicology; \u0000space environment; \u0000closed-loop environment; \u0000astronauts; \u0000crew health; \u0000risk assessment; \u0000space toxicant; \u0000manned spaceflight; \u0000spacecraft; \u0000space habitat","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":"115060558","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}

{"title":"Safety Assessment of Foods Obtained from Crops Developed Using Biotechnology","authors":"B. Delaney","doi":"10.1002/9780470744307.GAT139","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT139","url":null,"abstract":"The current chapter discusses historical perspectives on the development and commercialization of genetically engineered (GE) crops developed using biotechnology, and the safety assessment of foods obtained from these crops. Most currently commercialized GE crops express transgenic proteins that confer agronomic traits, including insect resistance and herbicide tolerance that are intended to increase crop yield. Methods to assess the safety of transgenic proteins used in GE crops for potential allergenicity and toxicity are discussed. Additionally, the principles of substantial equivalence as applied to the safety assessment of foods obtained from GE crops are discussed. Numerous examples are presented to emphasize the comprehensive nature of the safety-assessment process conducted for these products prior to commercialization to demonstrate that the transgenic proteins are safe and that the foods obtained from the currently marketed GE crops are as safe as those obtained from non-GE crops. \u0000 \u0000 \u0000Keywords: \u0000 \u0000biotechnology; \u0000food; \u0000Bacillus thuringiensis; \u0000risk assessment; \u0000qualitative risk assessment; \u0000substantial equivalence; \u0000pleiotropism; \u0000allergenicity","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":"115633211","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}

{"title":"Pathological Techniques in Toxicology","authors":"P. Greaves","doi":"10.1002/9780470744307.GAT039","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT039","url":null,"abstract":"Histopathological evaluation remains an important part of the assessment of the adverse effects of xenobiotics on the whole organism. In addition to conventional special staining techniques and electron microscopy, new techniques involving immunocytochemistry, molecular biology and novel visualization procedures have provided additional objective techniques that have enabled better functional and morphological characterization of induced alterations in organs of the body. This chapter covers both conventional and new methods involved in the microscopical assessment of tissue changes induced by xenobiotics. \u0000 \u0000 \u0000Keywords: \u0000 \u0000necropsy; \u0000organs; \u0000tissues; \u0000fixation; \u0000histotechnology; \u0000histological stains; \u0000histochemistry; \u0000immunohistochemistry; \u0000light microscopic techniques; \u0000electron microscopy; \u0000morphometry; \u0000molecular techniques","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":"115354170","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}