bluuebunny/crossref_metadata_2025 huggingface dataset:
Cartilage and Bone as Target Tissues for Toxic Materials
Authors: Lansdown Alan B.G.
Published: December 2009

Bone and cartilage are important in providing functional rigidity to the body, but have central function in modulating mineral metabolism in the body. Both tissues are subject to toxic and genetically determined influences on mucopolysaccharide (ground substance) synthesis, hormonal changes and defects in mineral homeostasis. In prenatal development, skeletal development is sensitive to abnormalities in the intrauterine environment and in the availability ofS‐amino acids, trace metals and vitamin balances. Animal models have provided beneficial information on mechanisms of teratogenesis involving cartilage and bone, notably on the action of salicylates and hypervitaminosis, both of which involve impairment in mucopolysaccharide synthesis, ossification and osteoclast activity. Toxic changes in adult skeletal tissues are largely associated with functional impairment of bone as a source of minerals—calcium, phosphate, zinc, and so on, and the property of calcium hydroxyapatite to bind xenobiotic cations including lead and cadmium with no trace metal nutrient value. Toxic changes range from osteoporosis, and impairment in bone strength and functional capacity. Radioactive bone‐seeking metals including90Sr are a potential cause of bone tumours. Much remains to be understood concerning the interaction between the calcium‐binding capacity of hydroxyapatite and the putative nutritional importance of silicon and strontium. Further studies are needed to investigate the cytotoxic action of lead and cadmium in bone and cartilage and to understand the implication of chronic exposure to low levels of these and toxic metals on bone structure and function.
Toxicology of the Endocrine System
Authors: Kapp Robert W. , Thomas John A.
Published: December 2009

The 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.
Cytogenetics
Authors: Anderson Diana , Baumgartner Adolf , Cemeli Eduardo
Published: December 2009

Various types of cytogenetic change can be detected in chromosomes, including structural chromosome aberrations, aneuploidy or sister chromatid exchanges. Chromosome aberration assays are used to detect chromosome damage (clastogenesis) in somatic and germinal cells by direct observation during metaphase analysis, or by indirect observation of micronuclei. Aberrations are mostly lethal to the cell during the cell cycle following their induction; they also indicate a potential to induce more subtle and transmissible chromosomal damage which survives cell division, producing heritable cytogenetic changes. Cytogenetic damage is usually accompanied by gene mutation. Structural and numerical abnormalities in somatic cells are involved in the aetiology of neoplasia, while in germ cells they can lead to perinatal mortality, dominant lethality or congenital malformations in the offspring. Over 80% of all structural aberrations in humans occurde novoand are of paternal origin. This chapter addresses the different cytogenetic changes and assays which measure gross chromosomal damage in human somatic and germ cellsin vitroandin vivo, as well as regulatory requirements for measuring them. Also to be considered are the growing importance of modern molecular cytogenetics, the Human Genome project and the awakening awareness of epigenetics as a biological concern.
Nongenotoxic or Epigenetic Carcinogenesis
Authors: Powell Christopher J. , Berry Sir Colin
Published: December 2009

Carcinogens are considered nongenotoxic where they cannot be shown to interact directly with DNA in a number of short‐term screening assays, but which are capable of producing tumours in laboratory rodents in bioassays. Epigenetic events, either acting alone or in concert with genetically determined events, may produce tumours. A key feature is that dose‐threshold effects may be identifiable. In both the rat and the mouse, the liver is the most common site of nongenotoxic carcinogenesis. A special sort of hepatic carcinogenesis is that produced in rodents by peroxisome proliferators; this is of questionable significance for humans. Other important sites of non‐genotoxic carcinogenesis include endocrine glands notably the thyroid, bladder and, in the rat, the forestomach. Carcinoid tumours are tumours of the diffuse neuroendocrine cell populations, found particularly in the gastrointestinal tract. Their incidence is increased with certain drugs, notably the histamine H2 antagonists. Haemangiosarcoma, which may occur at a variety of sites, clearly arises by a number of mechanisms, some of which may be genotoxic. Mesothelioma, most often of the pleura, as a human response to asbestos, may be considered a form of non‐genotoxic carcinogenesis.
Epigenetic Mechanisms and their Toxicological Significance
Authors: Watson Rebecca E.
Published: December 2009

Epigenetic mechanisms are processes that exert control over gene expression without altering the DNA sequence. These mechanisms essentially work as genetic switches, turning gene expression levels on and off in response to various stimuli. Currently, DNA methylation and histone modifications (particularly histone acetylation and methylation) are the best characterized and most commonly recognized epigenetic mechanisms, although in recent years attention has turned to additional epigenetic processes such as microRNAs. Together, these mechanisms form the epigenome, a dynamic, reversible construct necessary for differentiation, tissue‐specific functions, development and neurological function in eutherian mammals. However, aberrant epigenetic function may lead to untoward effects and can be a contributing factor to a variety of diseases including cancer and developmental/neurological disorders. This chapter summarizes major epigenetic mechanisms and their relevance to toxicologists, including their role in normal biological functions vs. disease‐associated processes, as well as how nutrition and xenobiotic stimuli influence the epigenome. An enhanced understanding of factors that affect the epigenome can assist in both predicting undesirable toxic outcomes and in designing therapeutic strategies.
Developmental Toxicology
Authors: DeSesso John M. , Willhite Calvin C.
Published: December 2009

The 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.
Developmental Neurotoxicity
Authors: Makris Susan L. , Raffaele Kathleen C.
Published: December 2009

This chapter describes the essential elements of the developmental neurotoxicity (DNT) study, which is intended to screen for adverse effects of pre‐ and postnatal exposure on the development and function of the nervous system. The background and history of the guideline are discussed, illustrating the extensive research, collaborative international scientific efforts and interlaboratory studies that have contributed to its development, and thus demonstrating its validity, sensitivity, reliability and cross‐species comparability. The end points assessed in the guideline DNT study are addressed in detail; these include functional observations, developmental landmarks, auditory startle, motor activity, learning and memory (cognitive) testing and postmortem evaluations (brain weight, qualitative neuropathology and quantitative morphometry). End‐point‐specific issues, consideration of critical windows of development, special vulnerabilities of the developing nervous system and interpretation of the data are discussed. A review of the use of DNT study data in human‐health risk assessment demonstrates the value of the study.
Toxicology of the Placenta
Authors: Gupta Ramesh C.
Published: December 2009

Placental toxicology deals with the adverse effects of toxic substances on the placenta, the mother and the foetus. It is a fascinating subject which receives attention from biologists, toxicologists, teratologists, pharmacologists, physicians and regulatory agencies. Structural or functional damage to the placenta can lead to abortion, birth defects, stillbirth, premature birth and many other complications. Since the placenta is an entry organ to the foetus, and the ‘placental barrier’ is merely a false notion, the placenta remains vulnerable to the adverse effects of many toxicants. The placenta is a complex organ to study since it continually changes throughout gestation. This organ is further complicated by multiple pregnancies in many species, including humans. The placenta plays several roles in the development of the foetus by serving as the lung, gut, kidney and endocrine/exocrine gland. Additionally, it supplies vital nutrients and gases to the foetus. This chapter describes the placental toxicity of drugs of abuse, alcohol, tobacco products, metals, pesticides, environmental toxicants and mycotoxins.
Aquatic Toxicology: Concepts, Practice, New Directions
Authors: Wells Peter G.
Published: December 2009

This chapter presents a broad overview of the principles, practice and some of the new developments in aquatic toxicology. The field has matured rapidly over the past 30‐40 years. Many acute and chronic toxicity testing methods have been developed and standardized for application in environmental protection. Basic research has been conducted with many species across the aquatic phyla, with a wide range of contaminants. Critical linkages have been made to other aquatic disciplines ensuring that a comprehensive understanding of exposure, uptake, metabolism and discharge of chemicals, in many aquatic species under many conditions, is fully realized. New issues, such as the effects of pharmaceuticals, are being investigated with urgency. Aquatic toxicology is now supported in many countries by a wide range of research programmes, graduate programmes, training courses and publications, assuring its place in basic and applied toxicology.
Environmental Endocrine Toxicology
Authors: Bjerregaard Poul
Published: December 2009

Disorders in sexual development have increased in frequency in certain geographical regions during the latter half of the 20th century. In humans, this is expressed as elevated prevalence of testicular cancer, cryptorchidism and hypospadias and decreased sperm counts, collectively termed the ‘Testicular Dysgenesis Syndrome’ (TDS). A fairly large number of chemicals in widespread use (i.e. alkylphenols, phthalates, bisphenol, PCBs, pesticides) have been shown to interfere with the synthesis and/or the function of sex hormones, and exposure to some of these chemicals (individually or in mixtures) compromises normal sexual development in animals in tests in the laboratory. The occurrence of TDS in humans seems to be associated with general life style factors, but although associations between TDS and exposure to certain chemicals (e.g. PCBs, phthalates, pesticides) have been demonstrated, firm causal relationships have not yet been established. In nature, effects caused by exposure to discharged hormones or chemicals with endocrine disrupting properties have been firmly documented among snails, fish, amphibians, reptiles, birds and mammals: The anti‐fouling biocide tributyltin masculinizes female snails, synthetic p‐pill estrogens and natural estrogens feminize male fish downstream discharges from sewage treatment plants, effluents from pulp and paper mills masculinize female fish and various chlorinated hydrocarbons have feminized higher vertebrates such as alligators and birds.
Occupational Toxicology and Occupational Hygiene within the
E
uropean
U
nion (
EU
) Chemicals Regulation
Authors: Fairhurst Steven , Ball Elanor
Published: December 2009

The purpose of this chapter is to discuss the interplay between the disciplines of toxicology and occupational (or industrial) hygiene in understanding and controlling the hazards and risks to health posed by chemicals, in an occupational setting. Ten years ago, the chapter ‘Industrial Toxicology and Hygiene’, produced for the second edition of
General and Applied Toxicology
, offered a perspective on the main approaches, roles and responsibilities that, in a regulatory context, had held for a considerable period of time within chemical legislation. This updated chapter is written from within the European Union (EU) at a time when it is embarking on a new era of chemicals legislation that promises to change things profoundly. On 1 June 2007 the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation came into force in the EU. This legislation changes the nature and balance of roles between industry and regulatory authorities—and modifies the conventional approaches to, and interplay between, toxicology and occupational hygiene—in regulating industrial and commercial chemicals within the EU. In its information requirements for registration purposes, REACH creates a tension between desires to improve the extent and quality of data available on chemicals, but also to minimize experimental animal testing. In relation to toxicology, this poses challenges to all concerned. REACH removes the distinction and associated data‐expectation requirements between ‘new’ and ‘existing’ substances within the EU. REACH also expands and reinforces the ‘customer care’ principle that suppliers of chemicals take responsibility for understanding the uses to which their chemicals are to be put and specifying the risk management measures that should be followed in such uses. This will be a big challenge to the occupational hygiene profession. And all of this also comes at a time when the EU is in the process of adopting the globally harmonized system (GHS) of classification and labelling (C&L) of chemicals, which will modify the EU C&L system that has operated for the previous several decades. So it is a time of change—and no one is quite sure how things will work out in the next 10 years. This chapter attempts to portray how these recent developments build on, or change, what has gone before, and discusses some of the key issues that are ahead for the toxicology and occupational‐hygiene fields, operating in this new regulatory context.
Forensic Toxicology
Authors: Vuori Erkki , Ojanperä Ilkka
Published: December 2009

Forensic toxicology is today much more than a part of investigating causes of death or identifying those driving under the influence of intoxicants. Society needs forensic toxicology services in a wider context in the name of safety and legal protection. The need is manifested in workplace testing, child welfare, drug‐facilitated crime investigations and doping control. The discipline also has responsibility for investigating acts of terrorism and environmental pollution. Forensic toxicological analysis typically consists of an initial analysis and, in positive cases, a confirmatory analysis with mass spectrometry. The samples analyzed depend on the question to be answered. If being under the influence is to be ascertained, a blood sample is obligatory. A positive urine laboratory result reveals use or exposure to a foreign substance. Alternative samples include hair, which opens a large window for detecting drug use, and oral fluid, which is easy to collect noninvasively and without embarrassment. The results of forensic toxicological investigations, compiled in databases for later research, can also be used to reveal changing trends in illicit drug abuse and to improve drug safety in general. Because of the legal contexts in forensic toxicological investigations, legislation concerning sampling and civil rights must be strictly followed, and the same also applies to the chain of custody regarding the handling of samples.
Essentials of Epidemiology for Toxicologists
Authors: Coggon David
Published: December 2009

Epidemiology is concerned with the distribution and determinants of health in populations. The applications of epidemiology that are of most relevance to toxicology lie in the identification and characterization of toxic hazards, the assessment of risks from toxic exposures, and the evaluation of measures designed to control such risks. Most epidemiological studies focus on the occurrence of disease, but other health outcomes such as symptoms and disability may also be investigated.

Incidence (the rate at which new cases of disease occur in a population) is the measure of disease frequency of most relevance to study of causation. Other measures such as mortality (the incidence of death from a disease) and prevalence (the proportion of a population who are cases at a point in time or during a specified period) may be used as a proxy for incidence, but results must then be interpreted with added care. Where disease rates vary importantly by sex and age, comparison between populations may be enhanced by use of sex‐ and age‐specific rates, or by standardizing rates for sex and age.

Various statistics are used to summarize associations between ‘risk factors’ and health outcomes, each with its particular applications. Attributable risk is relevant when making decisions in risk management for individuals. Relative risk (RR) (or the closely related odds ratio) is most useful when considering whether associations are likely to be causal. Population attributable risk and attributable proportion are useful in risk management for populations. The attributable fraction in exposed (AFexp) is used when determining causal attribution for purposes of compensation.

Major considerations in the design and interpretation of epidemiological studies are bias (a systematic tendency to underestimate or overestimate a parameter of interest), chance and confounding (which occurs when the risk factor of interest is associated with a ‘confounding’ factor that independently determines the risk of developing the health outcome under study). Assessment of the potential impact of chance is helped by statistical inference using either hypothesis‐testing (p‐values) or confidence intervals.

Categories of epidemiological investigation include descriptive studies, ecological studies, cohort studies, case–control studies, cross‐sectional surveys and randomized and nonrandomized experiments. Each of these study methods has its particular applications, strengths and limitations.

In addition to bias, chance and confounding, other considerations when interpreting and comparing epidemiological findings are the ways in which exposures and health outcomes have been classified, and the potential for biological modification of causal associations by ‘effect modifiers’. In addition, epidemiological results should always be viewed in the context of relevant biology, including what is known from toxicological studies in the laboratory.
Toxicogenomics in Risk Assessment
Authors: Makris Susan L. , Euling Susan Y.
Published: December 2009

Toxicogenomicsis defined as the application of genomic technologies to study the adverse effects of environmental and pharmaceutical chemicals on human health and the environment. It integrates toxicant‐specific alterations in gene, protein, and metabolite expression patterns with phenotypic responses of cells, tissues and organisms. These data, depending on the type of data and study design, have the potential for use in various stages of risk assessment; that is, hazard characterization, dose‐response assessment and exposure identification. As genomic technologies produce global molecular response data, they provide a new and unique source of information that can inform mode of action, intraspecies variability and susceptibility, interspecies variability and/or cross‐species extrapolation, and/or cumulative risk. Considerations and future challenges regarding the use of toxicogenomic data in risk assessment such as variability in response, experimental design, analysis of data, and training, are described, and regulatory agency guidance and efforts in this field are summarized.
Education of the Toxicologist
Authors: Snyder Robert , Richardson Jason R.
Published: December 2009

The aim of this chapter is to describe the training of toxicologists. It stresses the need for students to understand the development of toxicology as a distinct discipline despite its close ties to other disciplines such as pharmacology, pathology, and so on. It emphasizes the need for students to be broadly and firmly grounded in each of the basic medical sciences. The study of past discoveries and the early initiation of their own research efforts should lead students into the appreciation of hypothesis building and the application of scientific methods to challenge their hypotheses. It is essential that students learn to use the extensive toxicological literature, much of which is now available online. Students should be trained to write scientific papers and should be prepared to describe the results of their work in well‐organized discussions. Ultimately, the success of the student will be a measure of the scholarly interaction with the student's mentor. Toxicology training should permit the student to enter into a career in basic or applied research. Many students opt for postdoctoral fellowships to help them decide upon how best to build a career. It is recognized that some differences can be identified when comparing training programs, for example, in the USA, Great Britain and Germany. However, experience has shown that each has prepared students to meet the challenges faced by modern toxicologists.
Radiation Terrorism
Authors: McFee Robin Beverly
Published: December 2009

Among the categories of Weapons of Mass Destruction (WMD)—chemical, biological, radiological, nuclear and explosive, the two that revive images of horror on a par with ‘doomsday’ scenarios are the radiological and nuclear agents. While all five pose a serious risk to health, and have been used by nations, terrorists and insurgents throughout human history, most healthcare professionals are familiar with treating trauma and have a background—at least rudimentary—in treating pathogens and certain chemical toxicants, although the WMD versions of pathogens and chemicals are clearly more dangerous. But few healthcare professionals have had the experience of working with, let alone recognizing or treating, a radiation‐induced illness or injury. In the December World at Risk Report published by the Commission on Weapons of Mass Destruction Proliferation and Terrorism impanelled by the US Government, their conclusion in terms of the availability of radiological and nuclear materials, entities willing to use them and the increased opportunity to develop weapons—rudimentary or otherwise was as follows: ‘The sobering reality is the risks are growing faster than our multilayered defences. Our margin of safety is shrinking, not growing’. Mass exposures to a radiological or nuclear event will pose a unique and unprecedented challenge—at least in the last 50 years—a challenge that health‐care professionals remain undertrained for, and most facilities continue to be untested and underprepared. Yet emergency medical services, hospitals and medical professionals are looked upon as the critical response arm of preparedness. While a nuclear or radiological event may be considered a low likelihood—it is clearly a high consequence exigency. As such, our facilities and healthcare professionals need to update or develop plans, increase training and implement more skills‐based efforts. The analogy is simple—our communities are depending upon us to save them… yet we do so with little more than perhaps annual drills or table‐top exercises. Would we allow a colleague to intubate one of our loved ones based upon practising that skill only once a year? Why then, facing the complexities of diagnosing and managing a radiation event in our region, would we be satisfied with single annual exercises? In the aftermath of the Litvinenko murder with polonium‐210, the increasing likelihood of Iran and other nations acquiring some form of radiological weaponry, re‐emergence of nuclear energy as an alternative to fossil fuels and the resulting proliferation of radioactive waste—now is the time to address radiation preparedness. Towards that end, this chapter will discuss the global threats, key medical considerations, essential equipment and other important issues necessary to enhance preparedness.
Depleted Uranium: Toxicology and Health Consequences
Authors: Miller Alexandra C.
Published: December 2009

Depleted uranium (DU) is a dense heavy metal and an alpha particle emitter used in military and industrial applications. Exposure can occur via wounding, ingestion or inhalation. Several recent studies have investigated the potential health effects of this unique heavy metal. Thesein vitroandin vivoinvestigations have not only demonstrated the neoplastic transforming ability, the mutagenicity and the genotoxicity of DU, but also the neurotoxicity of DU. Studies using neoplastically transformed human cells and the athymic nude mouse assay demonstrated the carcinogenic potential of DU. DU exposure has been shown to induce genomic instability in a human cell model and alpha‐particle radiation is responsible for some of the cellular damage induced by DU. Chronic long‐term internal exposure to embedded DU could be a carcinogenic risk and comparisons to other types of uranium exposure, i.e., occupational inhalation of natural uranium, are problematic. Chronic internal exposure studiesin vivohave demonstrated that DU is leukemogenic and neurotoxic. Epidemiological studies are inconclusive and the use of depleted uranium in armor‐penetrating munitions remains a source of controversy because of the numerous unanswered questions about its long‐term health effects.
Toxicology of Food Additives
Authors: Barlow Susan M.
Published: December 2009

Chemicals have been used to preserve food and to add colour and taste to food for centuries. Following the considerable increase in the use of food additives in processed foods from the mid‐twentieth century, safety assessment of food additives has been conducted on a formal basis at national and international levels. Currently, over 400 individual additives are listed by the international Codex Alimentarius for use in food traded around the world. Current approaches to the safety assessment of food additives generally require an extensive database of kinetic, metabolic and toxicity studies to be generated. Toxicity studies are usually conducted in laboratory animals and the types of study generally cover all the various life‐stages. Human studies are rarely available, but human data on absorption, metabolism and tolerance may be available. Studies are designed to show, not only any adverse effects, but also to identify doses below which no adverse effects occur (the no observed adverse‐effect level or NOAEL). Acceptable daily intakes (ADIs) for food additives are derived by examination of the outcomes of the toxicity studies, and usually are based on the overall NOAEL for the most sensitive effect in the most sensitive species. In order to ensure absence of toxic effects in the exposed human population, conservative ADIs are derived by application of safety or uncertainty factors to the overall NOAEL.
Safety Assessment of Foods Obtained from Crops Developed Using Biotechnology
Authors: Delaney Bryan
Published: December 2009

The current chapter discusses historical perspectives on the development and commercialization of genetically engineered (GE) crops developed using biotechnology, and the safety assessment of foods obtained from these crops. Most currently commercialized GE crops express transgenic proteins that confer agronomic traits, including insect resistance and herbicide tolerance that are intended to increase crop yield. Methods to assess the safety of transgenic proteins used in GE crops for potential allergenicity and toxicity are discussed. Additionally, the principles of substantial equivalence as applied to the safety assessment of foods obtained from GE crops are discussed. Numerous examples are presented to emphasize the comprehensive nature of the safety‐assessment process conducted for these products prior to commercialization to demonstrate that the transgenic proteins are safe and that the foods obtained from the currently marketed GE crops are as safe as those obtained from non‐GE crops.
Toxicology of Biocides
Authors: Ballantyne Bryan
Published: December 2009

Biocides are generally defined as chemicals or biological agents that are capable of destroying, preventing or rendering harmless, pathogenic organisms. In terms of regulatory activity, the scope of biocides has expanded to the extent that they are regarded as nonagricultural biocides. Their use requires that they be registered and approved through national and international regulatory schemes. Biocides are extensively used in industry, domestically, agriculturally and with medical and veterinary applications. Thus, they find widespread use, particularly in pulp and paper manufacturing, in personal care products, preservatives and as sanitizers, disinfectants and sterilants. Because they are reactive with pathogenic organisms, biocides are potentially toxic and, through misuse, can result in adverse health effects. This review discusses the use patterns, chemistry, toxicology, human health effects and environmental aspects, of several representative biocides of a wide range of chemical structures and applications.
Toxicology and Biological Monitoring of Metals
Authors: Nordberg Monica , Nordberg Gunnar F.
Published: December 2009

There are 67 elements classified as metals and the present chapter presents a review of the toxicology and evidence for useful biological monitoring of 29 of these elements and their various chemical compounds. Introductory sections of the chapter deals with general aspects of metal toxicology. Emphasis is given to the fundamental importance of speciation of metals. The chemical species is defined as the specific form of an element defined as to isotopic composition, electronic or oxidation state and /or complex or molecular structure. Consideration of specific chemical species is of fundamental importance in toxicology and biological monitoring. Advances in chemical analytical methods has made it possible in recent years to use biological monitoring i.e., repeated measurements of metallic compounds in tissues or biological fluids in order to evaluate occupational or environmental exposures and health risks. For all the elements dealt with in this chapter the importance of chemical species is considered when reviewing the uptake, metabolism and excretion; toxic effects and dose‐response relationships; carcinogenicity; genotoxicity as well as biological monitoring. The following metals and their compounds are covered in the present chapter: Aluminium, Antimony, Arsenic, Barium, Beryllium, Bismuth, Cadmium, Chromium, Cobalt, Copper, Gallium and Semiconductor compounds, Germanium, Indium, Iron, Lead, Manganese, Mercury, Molybdenum, Nickel, Palladium, Platinum, Selenium, Silver, Tellurium, Thallium, Tin, Titanium, Tungsten and Zinc.
Poisons of Animal Origin
Authors: Wedin Gregory P. , Keyler Daniel E. , Bilden Elisabeth F.
Published: December 2009

A great number of species in the animal kingdom possess means by which they subdue prey or defend against predators. Human encounters with these species may result in bites or stings that produce local injury or systemic toxicity ranging from local pain and varying degrees of tissue injury to systemic illness, organ failure and even death. Most of these animals deliver a dose of venom when they bite or sting, but some produce or accumulate toxin in their flesh that may produce illness if ingested. Venoms are generally complex mixtures of proteins and enzymes, but few are very well understood. Antivenoms have been produced to treat exposures to some species, but treatment generally consists of supportive measures and treatment of symptoms. This chapter presents an overview of some of more common animal species found throughout the world, the toxic syndromes they produce and current therapeutic strategies.
Ricin: Chemistry, Sources, Exposures, Toxicology and Medical Aspects
Authors: Lord J. Michael , Griffiths Gareth D.
Published: December 2009

The chapter covers the origins of ricin toxin, which is present in the seeds of the many cultivars of the castor oil plant. The structure and biogenesis of the dimeric (A and B chain toxin) ricin (RCA60) is described, compared with the related, but less toxic,Ricinusagglutinin (RCA120) and the toxic activity of ricin, theN‐glycosidase activity of the A chain, is explained. The intoxication process is further described and developed throughin vitroandin vivostudies, which then focus on several possible routes of exposure. These include inhalation, that route which has been the primary focus of military‐oriented research through oral and parenteral routes of intoxication; histopathology and symptomatology are described, using evidence from human cases of ricin poisoning, wherever possible. Information is then presented on the development of medical countermeasures against ricin poisoning, including pretreatment approaches (vaccines) and postexposure approaches, which include antitoxins. More novel and currently research‐based studies are considered, including inhibitors ofN‐glycosidase, substrate competitors or approaches to interfere with the binding of the ricin B chain to galactose moieties.
Biotechnology: Safety Assessment of Biotherapeutics and Agribiotechnology‐Derived Foods
Authors: Thomas John A.
Published: December 2009

The advent of recombinant DNA (rDNA) technologies has accelerated progress in developing large proteinaceous molecules with therapeutic properties. Such development has resulted in alternative sources for hormones (e.g. insulin, growth hormone), for immunomodulators, selected neurological disease therapies and for human monoclonal antibodies (Mab).
Not only have advances occurred in human therapies, but considerable progress has been made in designing genetically modified (GM) food crops(e.g. soy beans, corn, etc.) that require the use of less chemical herbicides, can be grown with high yields, and are often more nutritious.

These advances in rDNA have provided both medicine and agriculture with new avenues for therapeutic agents and food crops. Many of the safety evaluation protocols involving rDNA products necessitate a battery of pre‐clinical tests that include protein allergenicity and immunotoxicity, genotoxicity, and other specific assays.
Basic Toxicological Issues in Product‐Safety Evaluations
Authors: Hobson David W.
Published: December 2009

Product safety has become a keystone in the market success and longevity of many different types of products, such as pharmaceuticals, medical devices and a wide diversity of consumer products, including toys, health products, cosmetics, toys, food products and so on. Toxicologic testing for some types of products is required for registration by various international agencies, for example, pharmaceuticals, pesticides, medical devices and bulk chemicals. Other products, while not having strict registration testing requirements, should be evaluated for safety due to the potential for liability and loss of market share, as well as branding, should the product prove to have toxicologic issues while in routine consumer use. Toxicologists with appropriate training and experience, and the product‐safety programmes they develop can, therefore, can have a significant impact on the success and longevity of a wide variety of products, if they are involved throughout the product life cycle, from the design of the product, through development and manufacturing, then on into the marketplace in postmarket surveillance. Basic toxicological issues to be addressed in a complete product‐safety programme include the gathering of information to aid in product design, the development of specific toxicological tests and the design of toxicological‐testing programmes, as well as postmarket vigilance activities.
Oncology Biomarkers
Authors: Tainsky Michael A.
Published: December 2009

Biomarkers 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.
Developmental Immunotoxicology
Authors: Dietert Rodney R.
Published: December 2009

Developmental immunotoxicology (DIT) is the study of the impact of chemicals, drugs, physical factors and other agents on the immune system of the nonadult (prenatal, neonatal and juvenile). To achieve complete maturation and full competence, the immune system undergoes a series of novel maturational events during critical windows of development. These events lack exact equivalents in the adult. Not surprisingly, disruption of these early‐life events can have profound and persistent adverse consequences impacting the health and wellbeing of the affected child or adult. Because the developing immune system has been shown to be more sensitive to environmentally induced disruption than is the fully matured immune system of an adult, determination or of immuntoxic risk for the non adult is a growing concern. A dysfunctional immune system appears to be linked to many of the most prevalent chronic diseases of children and adults. For this reason, improved DIT safety testing and resulting immunotoxicity‐associated risk reduction, could have a significant health benefit. This chapter describes: (i) the windows of vulnerability for the developing immune system, (ii) toxicants reported to disrupt immune development, (iii) the importance of gender in risk of developmental immunotoxicity, (iv) the nature of the adverse health outcomes resulting from developmental immunotoxicity and (v) approaches to developmental immunotoxicity safety testing.
Biological Correlates of Low‐Level Electromagnetic‐Field Exposure
Authors: Behari Jitendra
Published: December 2009

Biological effects of electromagnetic‐field exposure have been a subject of continuing concern for a number of reasons. The effects have been broadly divided into two parts: thermal and nonthermal, though the demarcation between the two is not well defined. Recently, a large amount of experimental data has accumulated, indicating a variety of biological effects much below the accepted criteria for safe exposure. The biological effects, which may or may not involve health implications, are many. This includes the blood‐brain barrier, ornithidine decarboxylase, the role of Ca2+, melatonin, DNA strand breakage and free‐radical formation. Some of these parameters are often implicated in tumour promotion. Propagation of the signal through plasma membrane has raised questions regarding the modality of its amplification. While a number of mechanisms have been proposed (e.g. stochastic resonance, cooperativism, etc.), they may be active separately or in unison to bring about the desired amplification and control the cellular function. The formulation for setting the criteria for safety standards then needs further scrutiny, particularly for health risks from microwave exposure from wireless communication. The role of other exposure parameters, such as frequency, modulation, polarization and intermittence of exposure, may also be considered. This then suggests the necessity to have a re‐look at the concept of specific absorption rate (SAR) defining dosimetry and criteria for safety standards. The possibility of application of cross fields to restrict the formation of free radicals, and possibly cancer promotion, is also presented.
Susceptibility of Neonatal Rats to Xenobiotics
Authors: Hirata‐Koizumi Mutsuko , Hasegawa Ryuichi , Hirose Akihiko , Ema Makoto
Published: December 2009

Current risk assessments of xenobiotics, especially industrial chemicals, are usually based on animal studies. Although many types of toxicity studies are conducted to cover different developmental stages, evaluation for the early postnatal period is not adequate. In this chapter, special attention is directed to the susceptibility of neonatal animals to chemical toxicity. We introduce comparative analysis of the toxic susceptibility of neonatal and young rats to 20 chemicals as examples, and discuss a range of uncertainty factors important in the risk assessment of susceptible groups such as neonates and infants. The results reveal higher susceptibility of neonates to 11 chemicals and lower susceptibility to six chemicals compared with young rats, and one exceptional case of highly specific toxicity in neonates. These phenomena show the importance of studying sensitivity to toxic insults in the early stages of life. It suggests that an uncertainty factor of 10‐fold for human variability can be considered appropriate for risk assessment, unless particular toxicity in neonates or infants has been demonstrated, or there is other relevant and credible information regarding the chemical.
Phototoxicology
Authors: Nash J. Frank
Published: December 2009

Phototoxicology is the study of adverse events resulting from the interaction between light and a test material. Measurement of the target chromophore absorption profile is the first step in a phototoxicological assessment. Determination of acute photoirritation potential is achieved using thein vitro3T3 neutral red uptake phototoxicity assay. The photoirritation or photoallergenicity potential of a test material may be evaluated usingin vivoanimal testing. Human evaluations of photoirritation or photoallergy potential are available to confirm the absence of such effects. Long‐term photo co‐carcinogenicity testing has been evaluated using the SKH1 albino hairless mouse model. This is often preceded or replaced by photogenotoxicity testing; for example,in vitrophoto‐Ames, photoclastogenicity studies. For either photo co‐carcinogenicity or photogenotoxicity testing, the outcome interpretation is often uncertain due to the absence of known human positive controls and the predictive validity of such studies. In the USA and Europe, there are regulatory guidelines for photosafety testing of pharmaceutical/cosmetic test materials. The multivariate nature of phototoxicology requires careful attention to the experimental conditions and photobiological considerations, for example light source and dosimetry. Any potential photohazard identified usingin vitroorin vivomethods must be judged in the context of product use and light exposure.
Biomarkers of Exposure to Carcinogens
Authors: Scheepers Paul T.J.
Published: December 2009

In 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.