bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternatives toIn vivoStudies in Toxicology
Authors: Gad Shayne C. 
Published: December 2009

AbstractToxicology or its appplied product evaluation function (also called safety assessment) has now been in the forefront of the public's interest and expectations since at least the Second World War. As our understanding increased, a range of test designs and experimental methods using intact higher animals rapidly developed and came to be accepted in regulation and law.However, as we have come to understand more of both how biological systems work and of the molecular and cellular mechanisms that underlie specific toxicities, we have also come to understand that intact higher animals may not be the only model system that allows us to identify and evaluate adverse effects resulting from exposure to a drug or chemical. Since the early 1980s, this has lead to extensive efforts to develop and validate non‐animal methods. And to use these to the extent possible to take the place of intact animals in the identification and evaluation of hazards for regulatory purposes. This chapter seeks to capture the current breadth and status of that journey.
Toxicity Data Obtained From Human Studies
Authors: Wilks Martin F. , Kupferschmidt Hugo 
Published: December 2009

AbstractThe purpose of this chapter is to look at the ethical, scientific and practical issues concerning human data which may be helpful in chemical risk assessment. Such data can come from a variety of sources; case reports, case series and toxicosurveillance data often contain a high level of detail and may allow an estimate of the likelihood of adverse effects occurring. However, they are dependent on relatively few data collection systems, for example those of poison control centres. Exposure studies, in particular those involving biomonitoring, provide insight into individual exposure to chemicals in the workplace or environment. However, it is generally difficult to link the often very low levels of chemicals or their metabolites to health outcomes. Conversely, health surveillance may pick up an increased burden of disease but the degree of underlying chemical exposure is often unknown. Human volunteer studies with nonpharmaceutical chemicals have the advantage of well‐characterized exposure combined with information on the pharmacokinetic behaviour and/or effects of the compound. Nevertheless, outside the area of consumer products their usefulness is limited by ethical concerns and scientific challenges such as study design and small study populations. It is hoped that the present controversy surrounding some aspects of volunteer studies can be resolved through rational, scientific debate involving all stakeholders.
Quality Assurance in Toxicology Studies
Authors: Pateman J. Rodney 
Published: December 2009

AbstractQuality systems have been introduced into several areas of toxicology, usually following the discovery of unreliable or fraudulent data. The requirements of regulatory Good Laboratory Practice are described, with some background to those requirements. Other areas of toxicology involved in legal systems are also addressed. The consequences of incorrect data emanating from apparently respected sources are illustrated, and the benefit of implementing quality processes even in the absence of statutory requirement is expounded.
Animal Welfare in the Toxicology Laboratory
Authors: Myers Roy C. , Varsho Bennett J. 
Published: December 2009

AbstractBecause of ethical, scientific, social and legal considerations, toxicological research with animals must be conducted humanely and with careful attention to proper animal care. Animal welfare legislation specifies facility construction, primary enclosure space, feed, water, temperature, lighting, humidity, sanitation and staff requirements for maintaining animal health. For technical personnel, experience and training should be confirmed by the American Association for Laboratory Animal Science (or equivalent) certification. The animal research facility itself should be certified in the appropriate care and use of animals by an agency such as the Association for Assessment and Accreditation of Laboratory Animal Care International. Humane research in animals should be guided by the ‘three Rs’: reduction of numbers of test animals, refinement towards less pain or distress and replacement with alternatives to whole‐animal models. Increasingly, alternative models are being validated and incorporated into protocols and regulatory guidelines. Everyone involved in animal research must be cognizant of, and committed to, standards for humane animal research. To this end, the Institutional Animal Care and Use Committee oversees test justification, adequacy of facility and staff, prevention of pain or suffering and concerns about animal treatment. Conflicts must be resolved through a balance between study goals and animal welfare.
Chemical and Biological Occupational Hazards in the Toxicology Laboratory
Authors: Ballantyne Bryan 
Published: December 2009

AbstractIn addition to the chemical, physical, flammability, thermal, electrical and radiation hazards common to laboratories in general, toxicology laboratories have specific occupational hazards that require their recognition, appreciation and development of management practices for protective and precautionary measures. These include exposure to test chemicals of poorly understood toxicology and to control chemicals of high biological potency. Additionally there may be exposure to allergenic materials such as latex or animal allergens, and to transmissible animal diseases. This chapter reviews the routes and natures of hazardous exposures in the toxicology laboratory, specific allergenic and infective problem areas, and necessary protective and precautionary measures.
Information Resources for Toxicology
Authors: Copestake Philip Thomas 
Published: December 2009

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.
Toxicities Associated with Parenteral Nutrition
Authors: Aschner Judy L. , Furlong Heather M. 
Published: December 2009

AbstractParenteral nutrition is a life‐sustaining therapy for patients with structural or functional intestinal diseases who are unable to tolerate sufficient enteral intake or absorb sufficient calories to support energy requirements. Despite its unquestionable value under these circumstances, prolonged dependence on parenteral nutrition is fraught with potentially life‐threatening complications related to the presence of unintended chemical and microbial contaminants of parenteral nutrition solutions, and insufficient knowledge of the optimal dosing of various parenteral nutrition additives thought to be essential to human nutrition. Infants and children with congenital or acquired gastrointestinal tract diseases who are dependent on parenteral nutrition to supply essential nutrients and calories for growth and development are particularly vulnerable. This chapter will review the potential toxicities associated with both unintended contaminants in parenteral nutrition, including microbes, phthalates, bisphenol‐A, particulates, lipid peroxidation products and aluminium, as well as intentional supplementation with potentially toxic substances, including trace metals, amino‐acid mixtures and lipid emulsions, when provided in excessive amounts or suboptimal ratios, or when normal metabolism or excretion are altered by an underlying medical condition. Practical applications and areas in need of further laboratory and human research are highlighted.
Peroral Toxicity
Authors: Brock William J. 
Published: December 2009

AbstractNumerous factors will affect the passage of drugs and chemicals through the gastrointestinal tract and into systemic circulation. These factors involve anatomical and physiological features, species differences and biochemical features, including intestinal metabolism and effects on transporters. With regard to assessing potential risk of humans to chemicals, these features will need to be considered as there will be differences between experimental animals and humans. The cellular environment of the gastrointestinal tract and the molecular mechanisms of absorption will have a major influence on the bioavailability of drugs and chemicals. The pH of the local cell environment will affect the ionization status of the compound, whereas a drug may inhibit cellular transport of other substances, for example, nutrients, potentially having an affect on the nutritional status of the animal. Moreover, there has been demonstrated evidence that some xenobiotics will affect the metabolic status of the gastrointestinal tract. Cytochrome P450 3A is the more common form of cytochrome isoforms found in the intestine, but there are numerous examples that can inhibit, or induce, metabolism much in the same way that hepatic metabolism is affected by chemicals. In addition, the bacterial content of the gastrointestinal tract can affect the absorption of substances primarily by bacterial metabolism. The fasting status of the animal also will affect absorption, and is probably one the more important considerations in the design of a toxicology study. It has been clearly shown that absorption occurs more readily in the fasted animal, and that toxicity may be enhanced since there is a greater surface area of the gastrointestinal tract available for absorption. Finally, chemical interactions will potentially modify absorption through binding of the compound or changing the local cellular environment. From a practical perspective, oral administration of compounds is the most common method for compound administration in toxicology studies. In oral toxicity studies, one will need to consider the drug formulation and the potential effects of the vehicle on the stability as well as the potential toxicity of the vehicle. For the most part, a majority of the vehicles being used currently in laboratories have a long history of use such that toxicity of the vehicle does not become too much of a concern, but the principle of toxicology, the dose makes the poison, should always be a consideration.
Cutaneous Toxicology
Authors: Riviere Jim E. , Monteiro‐Riviere Nancy A. 
Published: December 2009

AbstractSkin is one of the largest organs in the body and is both a route for systemic absorption as well as a direct target after topical exposure in dermatologic formulations, cosmetics or occupational incidents. Compounds cross the stratum corneum epidermal barrier by passive diffusion through the intercellular lipids. Toxicity to this organ is manifested by alteration to one of its biological functions including loss of barrier, damage to the underlying dermis, hair loss, damage to adnexial structures, carcinogenic transformation to cellular constituents or activation of its resident immune system. Factors that result in absorption through or toxicity to skin will be reviewed.
Inhalation Toxicity
Authors: Pigott Geoff H. 
Published: December 2009

Abstract

Inhalation is an important route for entry of toxicants into the body. The structure of the lung is described with emphasis on those features that influence particle penetration. Properties that provide primary defence against pollutants, especially particulates are discussed. Gases aerosols and particulates which penetrate the lung defences may induce a variety of responses, both systemic and localized in the lung. The nature and aetiology of these reactions, especially those induced by particulates, (including fibrous particles) is described. The principles for modelling these responses, both in animals and
in vitro
, and for estimating dosimetry are discussed, together with their limitations.
Neurotoxicology
Authors: Fonnum Frode 
Published: December 2009

AbstractThe chapter describes the effect of several different toxic compounds on different targets in the nervous system. Special emphasis is put on the mechanism of excitotoxicity and the effect of oxidative stress on the brain. Several examples are given of compounds which seem to act on specific regions of the brain. The effects of environmental toxic compounds, such as polychlorinated biphenyls, flame retardants and methylmercury on brain function are discussed. Examples are given of compounds causing degeneration of axons and myelinopathy.
The Role of Behavioural Toxicity in Risk Assessment
Authors: Weiss Bernard 
Published: December 2009

AbstractBehaviour is now established as a fundamental dimension of toxicity and risk assessment. It emerged as a criterion of adverse effects because many questions about health risks centred on measures such as IQ and other neuropsychological indices. Methylmercury and lead risks are quantified in such terms and clinical entities such as autism and attention deficit hyperactivity disorder are basically behavioural disorders. Behavioural methods, as a consequence, are essential research tools for determining the risks of exposure to environmental chemicals, for studying the mechanisms by which drugs act on nervous system diseases and for determining the potential of new pharmaceuticals to alter behaviour, either therapeutically or adversely. To fulfil these roles effectively, behavioural research must examine a variety of end points. These range from naturalistic behaviours, such as those involved in reproduction, to activity patterns, to motor and sensory function and to complex cognitive processes. At the same time, behavioural methods must encompass techniques applicable to both laboratory animals and humans.
Peripheral Chemosensory Irritation: Fundamentals, Investigation and Applied Considerations
Authors: Ballantyne Bryan 
Published: December 2009

AbstractPeripheral chemosensory irritation (PCSI) is a pharmacological effect in which xenobiotics interact with sensory nerve receptors in skin and mucosae to produce local sensation (discomfort, itching, burning sensation or pain), together the development of local reflexes and systemic (autonomic) reflexes. The effects subside after removal of the irritant stimulus and do not result in long‐term adverse sequelae. The principal sites where PCSI effects develop are the eye, respiratory tract and skin. The effects produced are protective in nature. For example, with the eye there is pain, increased lacrimation and blepharospasm; these effects give a biological warning of the presence of a PCSI material in the immediate environment, and are protective in nature. The peripheral sensory effects may underlie some of the characteristics associated with the various types of idiopathic environmental intolerance, including multiple chemical sensitivity. Since the local sensory and reflex effects resulting from exposure to a potent sensory irritation (PSI) substance may be detrimental to safe and efficient working conditions, in many cases they may be used as a basis for assigning airborne occupational exposure limits. This review chapter discusses the nature of the PCSI response, receptor interactions and mechanisms, factors influencing response to PCSI effects, quantitation of the response, methods for measuring the PCSI response and the practical implications and applications of chemosensory irritation.
Responses of the Kidney to Toxic Compounds
Authors: Lock Edward A. 
Published: December 2009

AbstractChemically induced injury to the kidney can occur as a result of the direct effect of a chemical or a metabolite on renal cells or indirectly by altering renal haemodynamics, or by a combination of both. The site along the nephron which is damaged is frequently the site of cellular accumulation of the chemical or a metabolite. Nephrotoxic chemicals may enter the renal tubular cells by endocytosis either as the chemical per se or a chemical‐protein complex. Alternatively some chemicals are actively transported into renal cells on endogenous transport systems. Once concentrated inside cells, the chemical may be released from its intracellular binding site and cause cytotoxicity. Alternatively, renal specific metabolism by enzymes such as cytochrome P450 or cysteine conjugate β‐lyase may lead to the generation of reactive electrophiles that can cause cytotoxicity. The precise subcellular biochemical mechanism leading to cytotoxicity for most chemicals has not been established, but mitochondria are frequently, but not exclusively, a critical target for toxicity.
Allergic Asthma and Rhinitis: Toxicological Considerations
Authors: Regal Jean F. 
Published: December 2009

AbstractImmunotoxicity can manifest as an exaggerated immune response to a normally innocuous substance and lead to hypersensitivity or allergic reactions in the lung. Allergens are encountered environmentally or in the workplace and can be low‐ and high‐molecular‐weight substances. Allergic asthma and allergic rhinitis are examples of allergic reactions in the lung with immediate, late and chronic phases contributing to respiratory tract pathology. Mechanistically, allergic asthma and rhinitis reflect a combination of antibody and cell‐mediated immune reactions involving IgE antibody to allergen in the early stages and Th2 cell involvement as the disease progresses to late‐phase reactions and chronic allergic inflammation. Multiple cell types and mediators are involved in the inflammatory response in the lung. Mechanistic differences leading to the asthma/rhinitis phenotype have been noted with different allergens, primarily low‐molecular‐weight substances. Xenobiotics that are not allergens themselves may enhance the immune response to allergens or exacerbate pre‐existing asthma and airway hyper‐responsiveness. The complexity of the allergic response in terms of humoral and cell‐mediated immunity, as well as potential differences in mechanisms depending on the allergen, present a very challenging scenario for the toxicologist to predict the exposures that will result in allergic rhinitis or asthma.
Ototoxicity
Authors: Forge Andrew , Taylor Ruth , Harpur Ernest S. 
Published: December 2009

AbstractOtotoxicity is the process by which chemicals cause damage to the end organs of hearing (the cochlea) or balance (the vestibular system). Hearing loss is the common effect of ototoxins, although many also affect the vestibular system. Some cause temporary hearing loss (e.g. the ‘loop’ diuretics or salicylates). However, the most significant group of ototoxic agents cause death of the sensory hair cells (HCs) and permanent hearing loss, for example aminoglycoside antibiotics,cis‐platinum and organic solvents. In mammalian species the HC losses caused by these agents are permanent because, unlike the sensory epithelia in the inner ear in birds and other nonmammalian vertebrates, there is no capacity for HC regeneration. The effects generally develop only after repeated administration, but in some cases a single administration is sufficient (e.g. trimethyltin). Drug interactions can result in much greater damage than would be expected from the single agents. Excess noise can also cause HC death and can act synergistically with ototoxic chemicals. The most characteristic pattern of damage is predominantly death of outer HCs initially at the base of the cochlea (affecting high frequency hearing). Among humans, some individuals may be genetically predisposed to ototoxic damage.
Cardiac Toxicology
Authors: Bharadwaj Lalita A. 
Published: December 2009

AbstractThe cardiovascular system is the most important organ system required for human life. Toxicity to the component parts of the cardiovascular system can lead to death or devastating irreparable damage to the normal functioning of the organ systems of the human body. Many industrial and pharmaceutical chemicals can exert toxic action on various components of the cardiovascular system. Chemicals that target the heart are classed as cardiotoxins and can exert their effects directly or indirectly. The dosage and exposure period influence the effects these chemicals may exert on the heart. Cardiotoxins can alter the heart functionally or structurally. Functional alterations, such as the induction of arrhythmias, affect the normal physiological performance of the heart. Cardiotoxins may also selectively induce structural damage by altering the heart's cellular components. Structural cardiotoxins may directly affect cardiomyocyte membrane integrity, ion transport and energy supply systems. Cardiotoxic agents, chemically classed as plant‐ and animal‐derived toxins, heavy metals, aliphatic alcohols and hydrocarbons, aldehydes, gases (CO), carcinogens, and pharmaceutical agents utilized in the treatment of cancer, high blood pressure (antihypertensive drugs), arrythmias and depression (tricyclic antidepressants), and anesthetics (such as bupivacaine and halogenated hydrocarbon anesthetics) and their mechanisms of toxicity are reviewed. Environmental pollutants, including particulate matter, polyaromatic hydrocarbons and metals, which are suspected cardiotoxic agents, are briefly highlighted.
Skeletal Muscle Toxicology
Authors: Kenaston M. Alexander , Abramson Ellen M. , Pfeiffer Matthew E. , Mills Edward M. 
Published: December 2009

AbstractThe 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.