bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral Chemosensory Irritation: Fundamentals, Investigation and Applied Considerations
Authors: Ballantyne Bryan
Published: December 2009

Peripheral 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

Chemically 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

Immunotoxicity 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

Ototoxicity 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

The 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

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.
Immunotoxicology
Authors: Luebke Robert W. , Beamer Celine A. , Bowman Christal , DeWitt Jamie , Gowdy Kymberly , Johnson Victor J. , Shepherd David M. , Germolec Dori M.
Published: December 2009

The immune system is a complex set of cellular and soluble mediators that protects the body against infectious agents and neoplasias. Innate immune responses do not require antigen recognition or clonal expansion and thus provide a rapid defence response against pathogenic organisms. The adaptive immune response is more complex, requiring recognition of foreign antigens via cell‐surface receptors, production of growth factors, proliferation of antigen‐specific lymphocytes and activation of effector mechanisms that are ultimately directed against infectious agents or cancerous cells. While immune responses are usually beneficial, hypersensitivity reactions and autoimmune diseases are examples of inappropriate responses that may occur in genetically susceptible individuals following exposure to an environmental trigger. Immunotoxicology is the subdiscipline of toxicology that focusses on the unintended effects of chemical exposure on the immune system. There is extensive evidence to suggest that following exposure to particular chemicals unintended immunosuppression, unintended immunostimulation, hypersensitivity or autoimmunity may occur. Chemical‐induced modulation of the immune system may result in adverse outcomes such as increased incidences of infectious or neoplastic diseases, allergy/asthma or autoimmune diseases. This chapter presents an overview of immune responses and how these responses may be affected by xenobiotics.
Genetic Toxicology Testing and its Relevance to Human Risk and Safety Evaluation
Authors: Lorge Elisabeth
Published: December 2009

Genotoxicity is a major concern in toxicity evaluation as it may cause carcinogenicity and/or genetic diseases. Therefore genotoxicity has become a part of the toxicity regulatory assessment. Over 30 years of practice in genotoxicity, various tests and tools have been developed, validated and refined. The protocols of the most currently used tests were improved and the experimental conditions were monitored more satisfactorily. In this chapter, the main genotoxicity tests required by the current International Conference on Harmonisation (ICH) battery are reviewed, as well as the most commonly used experimental systems added to the battery for follow‐up testing, with their advantages and limits. The evaluation of genotoxicity results is also extensively considered. In this exercise, it is shown how the knowledge accumulated in the last years can be used to improve results evaluation with special references to the assessment and level of cytotoxicity, metabolic activation, aneuploidy, non‐DNA reacting mutagens, thresholds and risk assessment.
Carcinogenesis and Carcinogens that are also Genotoxic
Authors: McGregor Douglas
Published: December 2009

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.
Structure–Activity Relationships for Carcinogenic Potential
Authors: Venkatapathy Raghuraman , Wang Nina Ching Y. , Martin Todd M. , Harten Paul F. , Young Douglas
Published: December 2009

Two important disadvantages of long‐term animal bioassays are that testing involves substantial amounts of time and money, and that high doses are usually used in the testing process. These disadvantages can be circumvented using (quantitative) structure‐activity relationships ((Q)SARs). In the field of computational toxicology, (Q)SARs are predictive models that provide a quantitative measure of the relationship between the chemical structure and a measure of a given health‐related end point. Such relationships can be expressed in terms of continuous dose‐response data (e.g. carcinogenic potency) based on some type of regression analysis for quantitative end points, or a dichotomous classification (e.g. yes/no‐type answers for carcinogenicity, etc.) based on discriminant analysis or other pattern recognition techniques for qualitative end points. There are a limited number of (Q)SAR models to predict the carcinogenicity of various chemicals, a majority of which relate the carcinogenic potency to measures of carcinogenicity such as mutagenicity, lethal dose (LD50) or the maximum tolerated dose (MTD). Other (Q)SAR models relate the carcinogenicity of a chemical to its structure, either in terms of its chemical fragments (groups of one or more atoms that make up the chemical structure) or in terms of its physical and chemical properties. In addition, a variety of commercial and noncommercial software that contain modules to predict the carcinogenicity of chemicals are also available.
Short‐term Tests for the Determination of Genotoxic and Carcinogenic Potential of Xenobiotics
Authors: Dhawan Alok
Published: December 2009

The advent of industrial revolution has seen a significant increase in the number of chemicals being released into the environment and it becomes imperative to check their toxic potential. Exposure to such compounds produces chemical changes in DNA, which are generally repaired by the DNA‐repair enzymes. Hence, adequate tests have to be conducted for risk assessment and hazard prediction of these chemicals. Earlier, only long‐term animal bioassays, involving lifetime studies on animals, were used to classify substances as mutagens/carcinogens. These tests were cumbersome, time‐consuming, resource‐intensive and expensive. Therefore, rapid, sensitive and less resource intensive short‐term tests were developed for testing of new chemical entities. A ‘battery’ of three to four of these short‐term tests has now been proposed by a number of regulatory agencies for classification of the compounds as mutagenic or carcinogenic. Although several short‐term tests are available, molecular biology andin silicomethods are now being developed to predict the genotoxicity and carcinogenicity of chemicals at an early stage for interventional strategies to be implemented in time.
Reproductive Toxicology
Authors: Makori Norbert , Oneda Satoru , McElhatton Patricia R. , Ratcliffe Jennifer M. , Sullivan Frank
Published: December 2009

This article introduces some of the newer approaches for biopharmaceuticals reproductive toxicity testing, and includes the classical small molecules testing paradigms. The scientific basis for concern about exposure to agents that cause reproductive toxicity is discussed in various contexts, including aspects of adult male or female sexual function and fertility, embryology and teratology, and the F1 offspring and lactation in the context of interfere with the production or development of normal offspring which could be reared to sexual maturity, capable in turn of reproducing the species. Reproductive toxicology is divided into two major classes: (i) adverse effects on reproductive ability or capacity in adult males and females, i.e. effects on sexual behavior and fertility and (ii) adverse effects on maintenance of pregnancy (embryo‐fetal loss) and developmental outcome of the offspring, i.e. developmental toxicity. The former is assessed in both males and females as exposure of a toxicant applies to both, while the latter is assessed in only female and their concepti/offsprings as exposure only occurs during pregnancy where the male is used only for mating purposes and is not exposed to the reproductive toxicant.
Drug Toxicity in Neonates, Infants and Young Children
Authors: Choonara Imti
Published: December 2009

Neonates, infants and young children may experience the same drug toxicity as adults. They may also experience specific drug toxicity that adults do not experience. This may be associated with toxicity related to growth and development, for example the adverse effect of corticosteroids on growth or development of the brain following exposure in the early period of neonatal life. Alternatively they may develop a specific toxicity in relation to a condition that does not occur in adults, for example Reye's syndrome following exposure to salicylates during the presence of a viral infection. The altered drug metabolism within paediatric patients is an additional risk factor for drug toxicity. This is most marked in the neonatal period and is illustrated by the impaired metabolism of chloramphenicol which results in cardiovascular collapse. Similarly, the altered metabolism of antiepileptic drugs such as sodium valproate in children less than two years of age predisposes this particular age group to hepatotoxicity. Other specific examples of drug toxicity in paediatric patients are given in this chapter and these include examples of percutaneous and excipient toxicity.
Air Pollution
Authors: Maynard Robert L.
Published: December 2009

Air pollution science has undergone a renaissance in the last two decades. Common air pollutants are now known to have effects on health at low concentrations such as occur in many developed countries. Epidemiological studies have led to this new appreciation, toxicological studies have tended to lag behind. Particles have attracted much attention and current attention is focused on particles of very small diameter. Both short term variation in concentrations of, and long term exposure to particles have been shown to have effects on range of health end‐points including premature death, hospital admissions and symptoms. That such low concentrations, indeed there is no discernable threshold, should have effects has been difficult to explain toxicologically. Recent work, however, has shown that effects on the cardiovascular system, perhaps due to metallic species included in or on particles may explain the effects. Work on gases has lagged a little behind that on particles but work on the oxidative properties of ozone and nitrogen dioxide and the finding that concentrations of ozone are increasing, in part due to climate change, is now leading to increased interest in these pollutants. Air pollution science is developing rapidly and is receiving further stimulus from new work in the nano‐toxicology area. That further advances will be made in the coming decade is certain.
Indoor Air Quality
Authors: Jørgensen Rikke B. , Hanssen Sten O. , Bakke Jan V. , Jensen Ellen K.
Published: December 2009

Indoor air quality depends on a number of factors, including the outdoor air quality, ventilation, the amount of fresh air provided indoors, and the amount of air pollution derived from numerous indoor sources. Indoor environments are usually characterized by exposure to a complex mixture of different agents at very low exposures, mostly far below any known threshold level of biological effect. However, since people spend more than 90% of their time indoors, these low concentrations may have an impact on health and wellbeing. Those with asthma, allergies and other hypersensitivities are particularly vulnerable to inferior indoor environments. Dampness in buildings and combustion processes are probably the major pollution sources. The most important effects on public health are probably allergic respiratory sensitization, aggravation of allergic diseases, increased susceptability to respiratory infection and worsening of chronic obstructive lung diseases. The pollutants in the indoor air are gases and particles. The most typical inorganic gases are CO, NO2, CO2and O3. Important organic gases are volatile organic compounds (VOCs) including formaldehyde, phthalates and flame retardants. Combustion processes (tobacco smoke, heating, cooking, frying, grilling) are the main indoor sources of smaller nonbiological particles. Biological particles originate typically from pet allergens, house dust mites, pollen and micro‐organisms.
Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms
Authors: Pall Martin L.
Published: December 2009

Cases of multiple chemical sensitivity (MCS) are initiated by exposure to organic solvents and three classes of pesticides. Each of these can act indirectly to increase NMDA activity and the toxic effects of members of each of these classes can be lowered by using NMDA antagonists. Other chemicals, mercury, H2S and CO exposure may also initiate cases of MCS and have toxic responses mediated through increased NMDA activity. Thus each of these types of chemicals appears to act as a toxicant through increased NMDA activity. Six additional types of evidence suggest roles for elevated NMDA activity in MCS, suggesting that this response is involved, not only in MCS case initiation, but also in response to low‐level chemicals in those who are already sensitive. The inference that chemicals act as toxicants in MCS is confirmed by three genetic studies showing that five genes that encode enzymes that metabolize these chemicals act to determine MCS susceptibility.

The chronic nature of MCS is thought to be produced by a local biochemical vicious cycle mechanism, the NO/ONOO−cycle, which is initiated by nitric oxide acting through its oxidant product peroxynitrite, which are both produced in MCS in response to excessive NMDA activity. Cycle elements, including NMDA activity, intracellular calcium, nitric oxide and peroxynitrite are thought to interact with other mechanisms, including neural sensitization in the brain and neurogenic inflammation in peripheral tissues to produce the high‐level chemical sensitivity that is the hallmark of MCS. This complex model of MCS is supported by the following types of observations: MCS correlates in the chronic phase of illness, extensive animal model studies implicating almost all NO/ONOO−cycle elements, clinical trial data in the related illnesses chronic fatigue syndrome and fibromyalgia, and a variety of objectively measurable responses to low‐level chemical exposure in MCS patients, responses that should be further studied as possible specific biomarker tests for MCS. While plausible mechanisms are proposed for the generation of both shared and specific symptoms and signs in MCS, there are little data on whether these mechanisms are actually involved in generating these symptoms and signs in MCS. Previous claims that MCS is produced by some sort of psychogenic mechanism have multiple flaws and are inconsistent with the various types of evidence discussed above. Several areas of research are discussed in which the author argues that research will be richly rewarded.
Assessing Impacts of Environmental Contaminants on Wildlife
Authors: Sullivan Joseph P. , Hill Elwood F.
Published: December 2009

The impact of a toxic xenobiotic, natural or anthropogenic, on wildlife is difficult to evaluate because factors that influence exposure and risk vary widely among natural systems. Then, when considering the confounding influences of chemical interactions and the presence of natural toxics and toxins, widely diverse studies are needed to assess impacts of contamination on wildlife. In brief, wildlife toxicology has been described as the integration of three principal strategies: (i) laboratory screening to predict which chemicals may be acutely toxic or cause more subtle effects, such as reproductive impairment, behavioural aberrations or developmental changes; (ii) controlled studies where subjects are confined to a simulated natural environment and (iii) studies of natural populations. This chapter presents an overview of wildlife toxicology and contaminant risk assessment as traditionally evaluated, but also includes discussion of recent concepts of immunotoxicology, endocrine disruption and the presence of pharmaceuticals in nature. The focus is on anthropogenic chemicals and avian wildlife with comparisons to other taxa as appropriate. Birds have served as primary models because they have diverse behaviours and habitat associations and can be effectively studied in captivity and nature.
Soil and Fresh Water
Authors: Flaten Trond Peder , Steinnes Eiliv
Published: December 2009

In nature, soil and water systems are intimately inter‐related through a complex web of interactions. In this chapter, the nature and properties of soils are reviewed with emphasis on chemical composition and the binding, cycling and transformation of chemical substances in soil. The main focus is on metals, but organic compounds are also discussed. Water is discussed mainly as an exposure route from soil to humans. Various aspects of pollution of soil and water systems are discussed, including industry and mining, long‐range atmospheric transport, pesticides and fertilizers and waste disposal sites. The possible health effects of soil and water acidification are treated, with emphasis on cadmium, lead, mercury and aluminium. Finally, some health aspects of drinking water are discussed, with emphasis on instances where toxic substances at least partly have their origin in soils, and where drinking water constitutes an important exposure pathway from soils to humans. This includes arsenic, with a focus on West Bengal, fluoride, water hardness, nitrate and chlorination by‐products.
Biological Criteria for Water Quality in Relation to Human Health
Authors: Howd Robert A.
Published: December 2009

Development of regulatory criteria for contaminants in drinking water has been formalized with widely accepted risk assessment conventions and guidelines in North America and Europe. Acceptable levels for chemicals which are considered noncarcinogenic are estimated using an uncertainty‐factor approach, while for carcinogens a quantitative extrapolation is performed, based on cancer incidence in humans or animals. These methods incorporate a precautionary approach in order to minimize the risk of any adverse effects from exposure to drinking water, considering variability in both exposure and sensitivity to potential toxic effects. The wide variety of toxic agents and end points provide more than ample opportunities for controversies and disagreements, as well as further research. However, the current regulatory system is responsible for delivering consistently high‐quality water, which has resulted in a tremendous improvement in public health.
Interactions between Occupational and Environmental Factors in Toxicology, Hazard Evaluation and Risk Assessment
Authors: Gomes James , Meek B.
Published: December 2009

Occupational and environmental exposures to toxicants rarely occur in isolation or singly and the potential for multiple exposures occurring with different degrees of overlap and multiple numbers of toxicants is high. Interactions occur when multiple chemicals are present in biological systems at the same time. The nature and the intensity of the interactions vary greatly from individual to individual and are dependent upon a number of factors. Primarily, the interaction response is dependent both upon the chemicals in question and the individual that is exposed. Chemical‐associated factors include mechanisms or modes of action of the chemicals, timing of exposure and dose of exposure. Individual‐associated factors include personal characteristics, lifestyle factors, physiological factors and genetic factors. An integrated systems‐biology approach is necessary to evaluate the exposure, the interaction and the biological response. Newer technologies (omics) could play a significant role in assessing the risk of interaction from exposure to multiple toxins.
Susceptibility of Children to Environmental Xenobiotics
Authors: Woolf Alan D. , Sandel Megan
Published: December 2009

The growth of interest in paediatric environmental health reflects a widespread recognition that the impact of the environment on children's health is of major importance for this and succeeding generations. Children have a greater vulnerability to the adverse health effects of many environmental toxicants and xenobiotics than do adults, by virtue of their smaller size, increased weight‐adjusted intake of toxicants, developmental differences in body systems and functions, overall physiological and toxicodynamic differences, and differences in the environments they inhabit, the air they breathe, the foods they eat and the behaviours they display every day. The overall impact of such adverse effects of the environment, manifested by subsequent poorer health and the need for costly healthcare services, is amplified by the longer lifespans of children and is associated with intergenerational transmission of harmful effects, to the detriment of mankind. Conversely there is also great potential for averting such harmful effects by improving the quality of the environment and sparing children the consequences of such exposures.
Occupational Toxicology
Authors: Jin Chuanfang , Werntz Charles M. , Ducatman Alan M.
Published: December 2009

Occupational diseases are both over‐ and underdiagnosed. Both problems are important, but underdiagnosis in populations dwarfs the intermittent problem of occasional overdiagnosis in individuals. A Venn‐diagram approach to occupational disease includes: (i) a correct clinical diagnosis (specific ICD code or else a clear description of the clinical presentation), (ii) an understanding of the patient's exposure history (toxic exposures, including some sense of ‘dose’) and (iii) an understanding of the actual human toxicology/epidemiology of the exposure(s) in question (evidence‐based exposure‐outcome assessment). Incomplete understanding of the clinical presentation or failure to understand the exposure explains the large background of missed diagnoses. Fanciful attributions of exposure‐outcome relationships explain intermittent overdiagnoses. Following an overview of the occupational history, and laboratory testing, this chapter surveys the literature covering a broad range of toxic exposure‐outcome information.
Veterinary Toxicology
Authors: Oehme Frederick W. , Rumbeiha Wilson K.
Published: December 2009

The toxicology of domestic and wild animals is complicated by its excitement and diversity. The numerous species represented in their unique environments present anatomical, physiological, dietary and husbandry differences that allow the same toxins to exert unique and unusual effects on the varying animal species exposed to similar compounds, while at the same time effects may vary from none to acute lethality depending upon exposure scenarios. All the common synthetic and naturally occurring toxins are potentially lethal to all animal species. It is the circumstances of exposure that differentiates the dog or the cow becoming ill from the waters that contain the xenobiotic. Differences in response also emphasis the common variations in toxic effect observed in humans and the array of domestic animals and wildlife. Although humans and animal life have the potential to be exposed to insecticides, hazardous plants, drug overdoses, household and commercial chemicals, feed contaminants, pest‐control agents, spoiled feeds/diets/garbage, metallic substances, fungi, naturally produced toxins, gases and mixtures of chemical agents offered to animals in their confined man‐made environments, the range of such exposures are challenges to the diagnostic and management skills of veterinarians. The excitement of clinical and public‐health veterinary toxicology is embodied in the topics of this tome.
Aviation Toxicology
Authors: Kupiec Thomas C. , Raj Vishnu
Published: December 2009

There has been an increasing interest and awareness of the effects of prescription and illicit drugs on pilot performance with the concomitant rise in the use of prescription medications and the frequency of air travel. Aviation toxicology addresses the effects of prescription and illicit drugs on pilot performance as well as the contribution of these agents to the cause or manner of death in aviation fatalities. Specimen collection, specimen suitability and analytical techniques for the investigation of the role of carbon monoxide, hydrogen cyanide, ethanol, drugs of abuse and so on in aviation accidents are discussed. The prevalence of use and impairing effects of commonly encountered drugs such as ethanol, antihistamines, antidepressants, cannabinoids and opiates are outlined. Issues in toxicological interpretation, including the delineation of post‐mortem from ante‐mortem ethanol, the analysis of glucose and post‐mortem drug redistribution, are presented. Some unique challenges in aviation toxicology, such as the identification of admixed specimens and the genetic variability in the degree of drug‐induced impairment, as well as future opportunities for research, are discussed in the concluding portion of the chapter.
Regulatory Toxicology
Authors: Illing H. Paul A. , Marrs Timothy C.
Published: December 2009

Regulatory toxicology is the process whereby information relevant to the evaluation of the toxicity of agents is obtained by organizations and evaluated by or on behalf of governmental or international organizations. The aim is to protect workers, consumers, the public generally and the environment. The requirements of many regulatory systems are closely defined in terms of both the studies required and the interpretations to be placed upon the results obtained. There are various models for the regulation of chemicals, which may be based upon equity, utility or technical feasibility criteria, or a combination of these. Some chemicals are subject to premarketing authorization systems, so that the organization which wishes to market the substance needs permission before doing so. In most countries, the marketing of human and veterinary pharmaceuticals follows this pattern. Other systems have lists of allowed or proscribed substances or are simply notification schemes. With the latter, the individual substance does not need to be authorized but its use/sale/manufacture has to notified, together with the basic properties of the compound. There has been a recent trend to harmonize regulatory systems within trading blocks such as the European Union (EU) and North American Free Trade Area (NAFTA) and also between these blocks.
Toxicological Considerations for Pharmaceutical Products
Authors: Reid Lynnda
Published: December 2009

This chapter is designed to highlight some of the general toxicologic concepts, for example species selection, duration and dosing, which should be taken into consideration when designing a nonclinical investigatory programme intended to support development of pharmaceutical agents. The extent and types of studies needed as well as their timing relevant to the stage of clinical development are discussed. For questions regarding nonclinical development programmes for specific products, regional regulatory agencies should be consulted.
Combustion Toxicology and Implications for Adverse Human Health Effects
Authors: Ballantyne Bryan
Published: December 2009

Combustion toxicology is basically concerned with a study of the nature of and potential for adverse health effects with products resulting from the heating and burning of materials. Combustion products are multiple, of a wide range of chemical structures, and are variable in absolute and relative amounts from fire to fire and at different phases in the same fire situation. Depending on the nature of the materials involved in a conflagration, the composition of the smoke produced may result in various acute, short‐term repeated and long‐term adverse consequences. Effects produced include local irritation and tissue injury, incapacitation and systemic toxicity, including lethality. This chapter reviews the incidence and causation of fires, the nature and toxicity of fire atmospheres, factors influencing the generation and effects of combustion products, incapacitating effects, investigation of the toxicological aspects of fires and hazard evaluations. A separate section is devoted to the potential for adverse health effects to fire‐fighters from acute and repeated exposures to fire atmospheres; notably respiratory, cardiovascular, reproductive and carcinogenic hazards.
Radiation Toxicology
Authors: Harley Naomi H.
Published: December 2009

The risk from ionizing radiation is that it damages DNA in specific genes. The radiation can be from internally deposited alpha or beta ray radionuclides or external X‐ray or gamma ray radiation. To date the health effects or risk from exposure is the risk of cancer in a particular organ or tissue. There are four epidemiologic studies to evaluate actual human health effects from ionizing radiation exposure. These are the studies of the radium dial painters, the underground uranium miners exposed to radon and its decay products, the A bomb survivors and the X‐ray exposures that were given at one time as a cure for ringworm of the scalp (tinea capitis).

These studies provide quantitative risk estimates for internal and external exposure. A few radionuclides are also described although no health effects have been documented because they are abundant in crustal earth.
Risk Assessment of Chemicals
Authors: Stuchal Leah D. , Roberts Stephen M.
Published: December 2009

Risk assessment of chemicals is a process that results in a quantitative and/or qualitative estimate of risk posed by chemical exposure. It includes identification of the hazard, a dose‐response assessment, exposure assessment and risk characterization. The process of risk assessment continually evolves as science refines estimates of exposure and toxicity. There are two main types of risk assessment, human health and ecological, which have evolved separately to a large extent. Human health risk assessment is concerned with the protection of individuals. It considers hazard and risk to sensitive subpopulations, such as children and the elderly. Ecological risk assessment is concerned with protecting the environment and considers multiple species. Because the entity of concern is the ecosystem, the focus is on protection of populations rather than individuals. Both types of risk assessments typically utilize models to estimate the dose of chemical received and the likelihood that toxicity will occur in a particular exposure scenario. These models incorporate assumptions about exposure and toxicity, and must address both variability and uncertainty associated with risk estimates. Risk assessment is an important tool in managing potential public health and environmental impacts resulting from the use of chemicals.
Dose–Response Analysis in Experimental Toxicology and Risk Assessment
Authors: Sussman Robert G. , Sargent Edward V. , Davidson Todd L.
Published: December 2009

Dose–Response, one of the primary underlying principles of toxicology, also provides us with the basis for risk assessment. It is the process of determining the point at which the response changes from an acceptable endpoint to an unacceptable one. This chapter describes the terminology used to describe some of the parameters used in risk assessment, including the concept of a threshold. Additionally, we discuss the validity of specific studies, the relevance of their endpoints to humans and the applicability of different routes of exposure to risk assessment. The process of assembling available data for review and evaluation is also discussed, as are sources of uncertainty and the different methods used in deriving risk values. Finally, the acceptability of risk is discussed as one of the critical variables in the risk‐assessment process.
Hormesis and Risk Assessment
Authors: Calabrese Edward J. , Ricci Paolo F.
Published: December 2009

The hormetic dose‐response model has experienced a strong resurgence of interest in toxicology, risk assessment and pharmacology. This is based on its capacity for validation, reproducibility, generalizability, and its demonstrated ability to predict low‐dose responses far more accurately than threshold and linear‐at‐low‐dose models. This paper assesses capacity of hormesis models to impact the current risk assessment process, as well as the implications for risk assessment if regulatory agencies were to accept the hormetic dose‐response as the default model.
Chemical Incidents—Emergency Planning, Preparedness, Response and Recovery. Community Considerations
Authors: Russell David , Simpson John
Published: December 2009

Chemicals are an integral part of modern society with large volumes transported and stored to support requirements for a myriad of processes. Chemical incidents are surprisingly common and occasionally large enough to result in large numbers of casualties, such as Bhopal (1984). Other disasters reflect widespread global transportation of chemicals. In addition, in the present climate, deliberate release of chemicals is a concern, with the release of chemicals now used industrially (chlorine and phosgene) resulting in widespread casualties during the First World War. More recently, the nerve agent sarin was released on the Tokyo underground (1995). Therefore emergency planning for chemical incidents must take account of a large number of potential scenarios, deliberate and accidental alike. Planning should be undertaken following a risk assessment process and should focus on residual risk. Planning should be multidisciplinary and produce dovetailed national, regional and local plans, and be sufficiently flexible to cover major and minor incident alike, whilst recognizing the role of the community. Preparedness is closely related and reflects readiness. It has several components including training, detecting and alerting, surveillance, communication, provision of advice and medical/nonmedical equipment as well as pharmaceutical interventions. The response to an incident needs to be rapid, coordinated and efficient, with a rapid risk assessment and the establishment of command and control structures; risk communication is an essential component. Decontamination, first aid and medical treatment of casualties may be necessary, together with evacuation and/or sheltering. Exposure and risk assessment may be further facilitated by environmental and biological sampling; in the longer term, clinical and epidemiological follow up may be needed. Recovery encompasses the economy, the environment and health and may require remediation and rehabilitation.
Biomonitoring of the Workplace and Environment
Authors: Boogaard Peter J.
Published: December 2009

Biomonitoring is a powerful tool to assess exposure to a wide variety of substances. It is superior to many other exposure assessment methodologies since it allows assessment of the actual exposure on the individual level. For decades, biomonitoring has been applied in occupational settings to assess exposure, with the main goal of checking for compliance with occupational exposure limits and the effectiveness of hygienic measures. Increasing analytical capabilities have led to continuously decreasing limits of detection, and have hence opened up biomonitoring for environmental exposure assessment. When biomonitoring is not simply used as exposure monitoring in occupational settings, but rather to assess human health risks either in the workplace or for the general public, specific criteria must be met. These criteria cover (pre‐) analytical methodology, specificity of the biomarker, dose–response relationships, toxicokinetics (e.g. biological half‐life) and reference values or control groups. If any of these criteria cannot be met, more research is needed before a valid health risk assessment can be made. Risk assessment is a function of hazard and exposure over time. A major problem in health risk assessment is the general lack of knowledge about low‐dose‐effect relationships, which prevents a reliable health risk assessment at the low exposure levels commonly found. Toxicogenomics may provide useful data to fill these voids. In addition to scientific criteria, a number of nonscientific and ethical criteria for biomonitoring studies should be addressed, such as the feasibility, the cost/benefit balance, support by the people involved, and the possibility of intervention (e.g. individual treatment, environmental measures, behavioural changes).
The Role ofPoisonCentres in Basic and Clinical Toxicology
Authors: Hall Alan H. , Bismuth Chantal
Published: December 2009

Poison Centres have a variety of roles in both basic and clinical toxicology, regardless of the general model followed—telephone consultation either with healthcare professionals only, or with both healthcare professionals and the general public. First and foremost, Poison Centres provide telephone consultations on acute poisoning exposures to include product and/or ingredient identification and information, expected clinical signs and symptoms, probability of developing toxicity and potential severity, recommendations for decontamination when appropriate, and treatment recommendations. Telephone follow‐up of cases is an important activity. In addition, many Poison Centres are involved in a variety of other activities, such as education of healthcare professionals and the public, poison prevention and Poison Centre awareness activities, basic and clinical toxicology research, systematic poison exposure/poisoning data collection, and dealing with chronic toxicity, exotoxicity and animal poison exposures/poisonings.
Ethical, Legal, Social and Professional Issues in Toxicology
Authors: Gilbert Steven G. , Eaton David L.
Published: December 2009

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.