AbstractNanotechnology has become one of the leading technologies in the past two decades due to its unique applications in many areas. However, the health effects of nanomaterials have caused people great concerns, mainly due to the small particle sizes and unique properties of the nanomaterials. The large specific surface areas of the nanomaterials make them very reactive in the cellular environment, and may impose very different biological effects than those of the bulk materials. Consequently, the levels of toxicity of nanomaterials are potentially higher than those of bulk materials. A large amount of research, bothin vitroandin vivo, has been conducted and the data have shown that several types of nanomaterials are highly toxic. This chapter mainly summarizes the work being done in the area of nanotoxicology and the proper ways to carry out nanotoxicology studies to assure that valid data can be obtained, including characterization of nanomaterials, proposed mechanisms of nanomaterials, types of biomarkers and analytical techniques that were used to assess the levels of nanotoxicity, and experimental design forin vitroandin vivonanotoxicology studies. In conclusion, this chapter serves as a short version of a handbook to assist nanotoxicology researchers in experimental designs, assessment, and data evaluations.
AbstractToxicokinetics is essentially the study of the kinetics, or movement, of a toxic chemical into and around the body as well as its fate within the body. Thus, there are four basic processes involved in toxicokinetics: absorption, distribution, metabolism, and excretion, all of which are characterized descriptively and mathematically in terms of rate and extent. Toxicokinetics represents an important part of the safety evaluation of chemicals, but because the subject is perceived as being mathematically based it tends to be regarded as difficult and rather unapproachable by biologists. This chapter relates the underlying physiological and biochemical processes to the basic pharmacokinetic parameters and constants. This is followed by a consideration of the types of experimental data that are needed in order to determine the various parameters. The chapter concludes with a consideration of specific aspects related to the interpretation of high‐dose, chronic animal studies.
AbstractIndoor 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.
AbstractThis 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.
AbstractTesting for acute toxicity is the most fundamental of toxicological investigations and is routinely performed as a regulatory requirement for a number of different substance and product types in order to ensure human safety. The results of these studies are used to characterize the hazard, to assign the substance to a classification category, to provide information on the likely medical treatment of an overexposure and to inform the design of subsequent longer‐term toxicity studies where these are required. The relative simplicity of the study design and the endpoints investigated makes acute toxicity studies obvious candidates for replacement by alternative (in silicoandin vitro) methods, and while there has been some progress in the development of these alternatives, regulatory acceptance is currently limited. Incorporation of the use of read‐across and the availablein vitroandin silicomethods, within vivostudies performed only when required, is recommended in order to give an intelligent and integrated strategy to the assessment of acute toxicity.
AbstractAntidotes for poisons may act in a variety of ways and, in some cases, two (or more) antidotes using different antidotal approaches, are used together. Antidote development depends on an extensive knowledge of the action of the poison, which the antidote is expected to counteract. Poisons and their antidotes may be studiedin vitro,in experimental animals or in humans. The design of experimental studies in animals and experimental and observational ones in humans presents major challenges. In the case of animal studies, the aim is to simulate realistic treatment scenarios.
Terrorism has a very long history. Terrorism has been defined terrorism as deliberately and violently targeting civilians for political purposes. One of the objectives of terrorism may be to generate a disproportionate response and thereby alienate the population against the state. The range of weaponry potentially available to terrorists is wide and variable: weapons used may include guns or explosive devices, radioactive/nuclear sources, biological organisms and toxins (bioterrorism) or xenobiotic chemicals (chemical terrorism). Chemicals that might be used include irritant and/or disorienting materials, nauseating materials, psychogenic materials and severely toxic and lethal agents. The only major chemical terrorist action to date was the two instances of use in Japan of sarin, an organophosphorus ester G‐agents, where there was large‐scale mass casualties. While many other compounds could be used in chemical terrorism (eg cyanide, arsine), the only other mass casualty situation to date involving terrorism was the death of many innocent citizens in an anti‐hostage situation in Moscow; this appears to have caused by the authorities' response, rather than the action of the terrorists.
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.
AbstractBiomarkers hold tremendous promise for diagnostic devices and are useful for monitoring the effectiveness of clinical interventions. Biomarkers are also used to stratify oncology patients to the most appropriate treatment. Effective biomarkers for the early detection of cancer can provide a patient with a better outcome which will translate into more efficient delivery of healthcare. Early detection technologies applied to population‐based screening for cancer have resulted in reductions in disease‐associated mortalities from cancers that are otherwise deadly if allowed to progress to an advanced stage. These screening technologies have proven that early detection will decrease the morbidity and mortality from cancer. Biomarkers can provide prognostic information on disease, enabling interventions with the appropriate therapeutic agents as well as early decisions and corrections of cancer treatment. There is a plethora of novel genomic, proteomic and metabolomic technologies that can be used to discover and validate tumour biomarkers individually and, where necessary, in combinations. Although biomarkers have the potential to provide personalized diagnostic, prognostic and therapeutic information, the devices to implement them clinically must supply healthcare providers with simple algorithms for step‐by‐step approaches to their patients.
AbstractThis chapter reviews the subject of occupation, toxic exposures and human health. A brief historic update of occupational illness is mentioned. Further, the chapter reviews processes involving chemicals and their uses, with summaries of some forms of occupational diseases found. Current knowledge of toxicological exposure is dealt with briefly and discusses attempts to develop means of improving the safety of the work environment in which they occur. It is pointed out that the occupational physicians must be aware of toxic effects of materials in the workplace. The prevention of hazards and management of occupational illnesses will rely on collaboration between managers, industrial hygienists and medical officers, all intimately involved. Routes of exposure, target organs affected and control of those hazards are discussed in this chapter. Medical evaluation of health in industry is revised and an outline presented for the establishment of a medical surveillance programme.
AbstractIn human exposure assessment a biomarker is a parent substance, metabolite or addition product (adduct) that can be measured in blood, urine, exhaled air or in other biological tissues. The biomarker provides information on the internal exposure to a chemical substance. Biomarkers can be used to evaluate exposure to carcinogenic substances in the workplace or in the general environment. If the parent compound is used as a biomarker, information on uptake from different sources and via different routes can be obtained. Use of a metabolite or adduct to DNA or proteins also provides information on bioavailability and metabolic activation. The half‐life of biomarkers determines the moment of sample collection relative to time of exposure. Some biomarkers are mechanism‐based and provide useful information on the formation of genotoxic intermediates. Most biomarkers reflect systemic bioavailability rather than a target dose, which sometimes limits the interpretation in terms of assessment of cancer risk. The method of sample collection, pretreatment, transportation, storage and a reproducible and sensitive method of analysis should be selected with care. Background values and biological limit values provide a framework for interpretation. The study protocol should comply with international standards in ethics of biomedical studies involving human subjects.
AbstractThe endocrine system plays a critical role in regulating virtually every aspect of the body's functions and systems, including behaviour, nutritional processes, reproduction, growth and development, gastrointestinal tract, cardiovascular system and homeostasis. It includes various endocrine glands, for example, hypothalamus, pituitary, adrenals, gonads, thyroid and pancreas, that secrete specific hormones (or messengers) as well as specific receptors in target organs throughout the body, which are activated or deactivated by a series of biochemical reactions upon contact with the proper hormone, which ultimately modifies the target organ's activity. This is a complex and interactive system and malfunctions may have serious consequences. Disorders can arise internally from overactive or underactive hormone production, or they can arise from external exposures. Both can have life‐threatening effects on survival. It has been shown that many drugs and chemicals and some environmental chemicals can perturb the chemical balance of the endocrine system. Some chemicals may directly affect the normal function of the endocrine system by inhibiting specific enzymes, while others produce indirect effects that result in a pharmacological interaction between the hormone and the chemical which modulates the effect of the hormone. There are many variations on these mechanisms and effects and these are detailed in this chapter.
AbstractThe use of drugs to enhance performance has become a matter of increasing concern in recent years. However, with the advent of a greater range of pharmacologically active substances, and the possibility of psychological or financial reward, the temptation to use drugs in the pursuit of enhanced sporting performance or body image has increased.Regulation of drugs in sport seeks to prevent the use of banned substances and techniques whilst allowing the legitimate use of therapeutic interventions for genuine medical conditions. The use of performance enhancing drugs may be accompanied by serious, even life threatening side effects.Performance enhancing drugs may be used at the time of competition, or as a ‘training aid’ outside the competitive season, for example to increase muscle bulk. Their effect may be to increase strength or to allow a greater power output, for example by increasing oxygen delivery to tissues. Abused drugs include androgenic anabolic steroids, creatine, beta‐2 agonists, beta blockers, peptide hormones and diuretics. Techniques to improve oxygen delivery include the use of high altitude training, autologous blood transfusions and the use of erythropoietin.Successful detection of abused drugs is fundamental for regulatory programs to be successful. Such programs should include random out of season testing, rigorous sample handling protocols and reliable analytical techniques. The advent of synthetic hormones with structures similar or identical to endogenous hormones presents significant regulatory challenges. Determination of the use of proscribed substances may involve setting threshold concentrations or defining acceptable ratios of different hormones. As more sophisticated techniques of abuse develop it may become necessary for regulatory programs to use increasingly invasive sampling techniques, to determine hormone profiles for individual athletes and even to undertake challenge tests which seek to differentiate endogenous from exogenous hormone production.
AbstractRegulatory 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.
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.
AbstractMitochondria generate >90% of the energy in aerobically poised cells, but are also a major source of cytotoxic free radicals. These organelles contain their own genome, and they replicate independent of cell division. It is widely appreciated that chronic exposures to some antibacterial and antiviral drugs can interfere with mitochondrial gene expression and/or replication, leading to various toxicities, including hearing loss, lipodystrophy and lipoatrophies. It is now increasingly appreciated that xenobiotics also can directly undermine mitochondrial function on more acute time scales, either by inhibiting respiration, or by uncoupling electron transport from phosphorylation, and in some cases, by both mechanisms. Such drug‐induced mitochondrial dysfunction varies across important classes of therapeutics, and potency is in accord with clinical disposition; compounds that most profoundly impair mitochondrial function have been withdrawn from the market, or dropped before the clinic because of various organ toxicities. Examples of drugs with known mitochondrial liabilities are discussed, especially in the context of modern drug development. Such drug toxicity was not widely detected because of inadequacies in typical cell‐based and in vitro assays, but new, high throughput assays have been designed to reveal mitochondrial impairment earlier in drug development. Drug‐induced organ toxicity is a function organ history and physiological scope, i.e., the bioenergetic and antioxidative reserve capacity that has to be eroded before crossing a threshold of toxicity. This threshold model supports a new model of idiosyncratic drug toxicity that also incorporates all the known risk factors for such a response.
AbstractMedical devices and their component materials are potential sources of toxins that may produce undesirable local and/or systemic toxic responses when used clinically. The evaluation of toxic responses of medical devices using various toxicological test methods is also called biocompatibility evaluation of medical devices. The evaluation of toxicity (biocompatibility) of medical devices has been a complex task, because the devices are made of a diverse range of materials and have various intended uses, with body contact ranging from transient skin contact to permanent implantation. The safety and effectiveness of medical devices marketed in the United States (USA) is regulated by the Center for Devices and Radiological Health (CDRH) of the US Food and Drug Administration (FDA). The medical devices marketed in the European Union (EU) are required to comply with EU Medical Devices Directive 93/42/EEC, which specifies requirements for safety assessment. There are several national and international standards that address the toxicological evaluation of medical devices. In recent years the FDA—in particular the CDRH—uses and accepts toxicological data generated using the national and international biocompatibility standards to evaluate the safety of medical devices. The EU and Japan (MHLW) also use and accept toxicological data generated using international standards. This chapter is an introduction to a relatively new and rather complicated field in toxicology—the toxicological testing of medical devices. It discusses the toxicological considerations for establishing the safety of medical devices to meet the requirements of regulatory agencies. The guidelines for testing of medical devices are discussed and a general description of the various test procedures given. Developments in the field of biocompatibility regarding international harmonization are also addressed.
Abstract Systems biology has been defined as the iterative and integrative study of biological systems as they respond to perturbations. This chapter highlights the application of the systems biology approach to enhance the understanding of complex biological processes such as neurodegeneration in the developing brain. Although not yet fully delineated, the working model for anesthetic (e.g., ketamine)‐induced neurodegeneration during development involves the modulation of normally occurring brain‐sculpting mechanisms that control CNS development. Exposure of the developing mammal to anesthetics such as ketamine perturbs the endogenous N ‐methyl‐ d ‐aspartate (NMDA) receptor system and results in enhanced neuronal cell death. The working model is that prolonged ketamine exposure produces up‐regulation of NMDA receptors and subsequent over‐stimulation of the glutamatergic system by endogenous glutamate, triggering enhanced apoptosis of developing neurons. When the nervous system was perturbed with ketamine‐induced anesthesia and gene expression changes were monitored, NMDA receptor genes were significantly up‐regulated and this finding was confirmed by in situ hybridization studies. Systems biology, as applied to toxicology, provides a framework in which information can be arranged in the form of a biological model and various global datasets can be collected and integrated to determine whether they support the model. Discrepancies can be identified and hypotheses‐driven studies conducted in order to address them. Thus, data generated via iteration of this process can be used to reformulate the model in light of the new data.
AbstractThe full range of development that is subject to injury—be it a consequence of maternal disease, nutritional excess or deficiency, xenobiotic or radiation exposure or as a result of infectious agents ‐ begins with the primordial germ cells of the individual's parents, proceeds through gametogenesis and concludes at the end of a person's natural life. The present chapter is focused upon understanding adverse reproductive outcome as a result of embryonic exposure to selected environmental chemicals and therapeutic drugs. The chapter begins with examples from ancient history and contemporary motion pictures, from the scientific literature and from the popular press. The text explains some of the fundamental steps taken and the genes involved in establishment of the vertebrate body plan. Examples are provided to illustrate how failure of proper gene expression and coordination at precise embryonic stages is responsible for the pathogenesis of specific congenital malformations. Consolidated presentations of experimental teratology and developmental toxicity studies are provided, along with the steps required to interpret the results of those studies in the context of human health risk assessment. The chapter contrasts the risks associated with misdirected speculation, irrational public fear and chemical rumors compared to the real public health consequences associated with maternal disease (e.g., alcoholism, diabetes, obesity) and nutritional deficiency (e.g., vitamin A, folates). The chapter concludes with the fundamental role of inappropriate embryonic gene expression in carcinogenesis. Increased understanding of genomic regulatory circuits in embryos has contributed to increased understanding of normal cell regeneration and turnover and how disturbances in those circuits lead to neoplasia and other degenerative diseases in children and adults.
AbstractThe Toxicologist as Expert Witness is a primer for toxicologists new to expert testimony and consulting. An expert toxicologist may serve in a variety of civil, criminal and regulatory capacities. The author discusses the academic credentials and personality traits that make an effective witness. The toxicologist must be familiar with legal and scientific concepts such as burden of proof, causality and risk. An expert may be retained to serve a variety of disparate functions, everything from consultation to research and investigation. Experts must be capable of explaining complex scientific issues in everyday language. Advice for effective communication during deposition and testimony is included. The witness must be prepared to have their professional judgement, academic history, publications and previous testimony scrutinized by opposing counsel and the experts that they have retained. The spectrum of legal proceedings, from deposition to trial, is described in detail so that even a novice will be completely prepared for the often adversarial legal process. Finally, the chapter addresses practical concerns such as fee structures, professional reputation, ethical obligations and marketing.
