bluuebunny/crossref_metadata_2025_split huggingface dataset:
Formation, Chemistry and Structure of Organomagnesium Species in Solvent‐Free Environments
Authors: A. J. O'Hair Richard 
Published: December 2009

Abstract

Introduction

Formation of Organomagnesium Species in Solvent‐Free Environments

Bimolecular Reactions of Organomagnesium Ions in the Gas Phase

Unimolecular Reactions of Organomagnesium Ions in the Gas Phase

Structures of Organomagnesiums and Magnesium Halides in the Gas Phase

Concluding Remarks

Acknowledgments
The Chemistry of Magnesium Carbenoids
Authors: Satoh Tsuyoshi 
Published: December 2009

Abstract

Introduction

Generation of Magnesium Carbenoids

Reactions and Synthetic Uses of Magnesium Carbenoids

Magnesium Cyclopropylidenes

Magnesium Alkylidene Carbenoids

Magnesium β‐Oxido Carbenoids

Other Magnesium Carbenoids

Conclusions and Perspective
Catalytic Enantioselective Conjugate Addition and Allylic Alkylation Reactions Using Grignard Reagents
Authors: López Fernando , Minnaard Adriaan J. , Feringa Ben L. 
Published: December 2009

Abstract

Introduction

Enantioselective Conjugate Addition to Cyclic Enones

Enantioselective Conjugate Addition to Acyclic Enones

Enantioselective Conjugate Addition to α,β‐Unsaturated Esters and Thioesters

Application of the Conjugate Addition of Grignard Reagents to α,β‐Unsaturated Thioesters in the Synthesis of Natural Products

Mechanistic Studies

Enantioselective Allylic Alkylation with Grignard Reagents

Conclusions
Biotransformation of Xenobiotics
Authors: Timbrell John A. , Marrs Timothy C. 
Published: December 2009

AbstractXenobiotics, which are absorbed into biological systems by passive diffusion across membranes are usually lipid soluble and not ideally suited for excretion. Indeed very lipophilic substances may remain in the mammalian body for many years. After a xenobiotic has been absorbed, it may undergo biotransformation to products which are rapidly excreted and therefore elimination of the compound from the animal is facilitated. However, biotransformation may also change the biological activity of the substance. Hence, the metabolic fate of the compound can have an important bearing on its toxic potential, the disposition of the compound in the body and the excretion of the compound. The metabolic reactions involved are usually divided into phase 1 and phase 2 reactions, the latter being conjugation reactions. The products of metabolism are usually more water soluble than the original compound. Although usually detoxifying, these reactions, especially phase 1 ones, sometimes increase toxicity.
Toxicokinetics of Xenobiotic and Metabolite Distribution and Excretion
Authors: Inchiosa Mario A. , Inchiosa Mario E. 
Published: December 2009

AbstractThe first portion of this chapter focusses on physicochemical characteristics of therapeutic and nontherapeutic xenobiotics that have a major influence in determining the rate of onset of pharmacodynamic or toxicodynamic effects in living organisms. This discussion is then extended to the role of these and other factors that affect the extent of distribution and accumulation of xenobiotic and xenobiotic metabolites in the animal or human body. The final portions of the chapter consider the kinetics of excretion of xenobiotics from the body. Simple one‐compartment kinetics are reviewed first, followed by multicompartmental systems. In all cases, procedures are proposed that may allow quantification of the systemic ‘dose’ of a xenobiotic exposure to individuals in an environmental or occupational setting, where there is usually little information on the actual exposure. Finally, kinetic models are proposed that may permit determination of the amount of time that it will take for the plasma to be cleared of the xenobiotic, or metabolite, and how this might differ in time for the total body burden to be reduced of the same substances.
Toxicokinetics
Authors: Roberts Ashley , Renwick Andrew G. 
Published: December 2009

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.
Evaluation of Toxicological Interactions for the Dose‐Response Assessment of Chemical Mixtures
Authors: Krishnan Kannan , Isukapalli Sastry , Boyd Jonathan 
Published: December 2009

AbstractDose‐response assessment for chemical mixtures involves the characterization of the relationship between administered dose (or more appropriately target tissue dose) and tissue response, in order to facilitate the determination of safe exposure levels for humans. When interactions among chemicals occur, the consideration of mechanisms would be necessary for the conduct of scientifically sound dose‐response assessment for mixtures. The present chapter focusses on the current approaches for evaluating toxicological interactions for the dose‐response assessment of chemical mixtures. The approaches described in this chapter include: (i) interaction matrix method, (ii) interaction weighting ratio method and (iii) physiologically based pharmacokinetic (PBPK) modelling. The unique use of PBPK models in predicting the change in tissue dose of mixture components as a function of dose, route, exposure scenario and mixture complexity is highlighted. Finally, the interaction‐based dose‐response analysis of chemical mixtures is described, along with illustrative examples.
Toxicology of Chemical Mixtures
Authors: Krishnan Kannan , Boyd Jonathan 
Published: December 2009

AbstractThe toxicity of chemical mixtures is determined by the effects of components as well as interactions, if any, among components occurring at the exposure, toxicokinetic or toxicodynamic phases. This chapter describes the concepts and methods essential for evaluating the toxicity of chemical mixtures. Approaches applicable toin vitroandin vivoconditions are discussed with particular emphasis on the assessment approaches that use whole mixtures, similar mixtures or mixture components. The approaches based on mixture components require a thorough understanding of the theory and models of additivity (dose, response). Accordingly, the notions of additivity for similarly acting and dissimilarly acting chemicals are considered and their use in the prediction of the toxicity of chemical mixtures discussed. An illustrative example of anin vitroevaluation of a ternary mixture of rotenone, deguelin and pyridaben is also presented.
Molecular and Cellular Concepts in Toxicology
Authors: Lynes Michael A. 
Published: December 2009

AbstractToxins and toxicants that modify cellular or molecular processes can have repercussions throughout the organism. These interactions can be common to all cell types, or may reflect unique targets or unique bioactivations that are to be found in limited subpopulations of cells. The consequences of these modifications will produce a host of different changes. These changes can be characterized by measurements of transcription factor activity, gene expression at the RNA or protein level, by cellular molecular responses that attempt to re‐establish homoeostasis, and by the consequences to cellular organelle structure and function. This chapter provides an overview of the inter‐relationships between toxicant effect and cellular response, and also describes current technologies that can be used to assess the myriad of changes that may characterize toxin and toxicant exposure at the molecular and cellular levels.
Cell Death and Apoptosis
Authors: Ray Sidhartha D. , Corcoran George B. 
Published: December 2009

AbstractToxicants cause cell death via apoptosis, necrosis and apocrosis. The last decade of the twentieth century and the first decade of the new millennium witnessed over one million reports exploring the occurrence of apoptosis, its mechanisms, and therapeutic implications. Cooperative efforts of every compartment of the cell, as well as various micro and macromolecules, orchestrate this form of cell death. Apoptosis has captured the attention of scientists because retrospective analyses of the mechanisms of human disease show that apoptotic factors either contribute to disease development or, in large measure, account for it. Although apoptosis has been viewed as diametrically opposed to necrotic cell death, they share a number of key features in common. Apoptosis can be viewed as versatile and even malleable, whereas other forms of cell death are not; apoptosis signaling pathways are sharply defined but others are not. This chapter discusses the overall mechanistic frameworks that come under the influence of drugs, chemicals, and stressors, the initiation and progression of apoptosis during organ toxicity, and an up‐to‐date account of the morphological, biochemical, genetic and molecular events that characterize apoptosis. Emphasis has been placed upon insights from bothin vivoandin vitromodels. This chapter is intended to serve a resource that presents the current fundamentals of apoptosis and its scientific bases in this significant and rapidly evolving field.
Endocrine Disruption in Toxic Responses
Authors: Kitamura Shigeyuki , Sugihara Kazumi , Nakamura Kazuo , Kotake Yaichiro , Kashiwagi Akihiko , Fujimoto Nariaki 
Published: December 2009

AbstractMany endocrine‐disrupting agents, including industrial materials, pesticides, pharmaceuticals and phytochemicals, have been identified with their use byin vitroassay systems andin vivostudies in laboratory animals. These chemicals are widely distributed in the environment, and are able to mimic or antagonize the biological functions of natural hormones. Indeed, abnormalities thought to be due to such agents have been found in animals throughout the world. There is also thought to be a risk to humans, for example, DES syndrome. Xenoestrogens can accumulate in our environment, and may play a role in the increasing incidences of breast cancer, testicular cancer and other problems of the reproductive system in humans. Risks due to endocrine disruptors in the environment are discussed in this chapter.
Nitric Oxide Pathways in Toxic Responses
Authors: Laskin Jeffrey D. , Heck Diane E. , Laskin Debra L. 
Published: December 2009

AbstractThe host response to chemically induced tissue injury is complex, involving a variety of cell types and soluble mediators. One of the most intensely investigated mediators implicated in the pathogenic process is nitric oxide, a highly reactive small‐molecular‐weight gas. Almost all cells in the body have the capacity to generate nitric oxide fromL‐arginine via one of three isoforms of the enzyme, nitric oxide synthase. These include the high‐output isoform, inducible nitric oxide synthase, and the low‐output isoforms, endothelial and neuronal nitric oxide synthases. Toxicants stimulate production of nitric oxide in target tissues by up‐regulating expression and/or activity of nitric oxide synthases. This can occur directly by reaction of the chemicals or their metabolites with target cells, or indirectly, via cytokines, growth factors and lipid mediators generated following tissue injury. Whereas low levels of nitric oxide function to activate biochemical and molecular signalling cascades in target cells, high levels induce nitrosative stress. Both of these actions can contribute to toxicity. Selective pharmacological inhibitors and knockout mice have been used to delineate the role of the different isoforms of nitric oxide synthase in chemical toxicity. Further studies on the pathways by which excessive production of reactive nitrogen species leads to pathology will be key for a more complete understanding of the mechanisms of xenobiotic‐induced cytotoxicity and tissue injury.
Introduction to Mitochondrial Toxicity
Authors: Will Yvonne , Dykens James A. 
Published: December 2009

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.
Toxicity of Peroxisome Proliferators
Authors: Vanden Heuvel John P. 
Published: December 2009

AbstractPeroxisome proliferators (PPs) are an important group of chemicals that include certain hypolipidemic drugs, plasticizers and pollutants. Chemicals that are classified as PPs are known rodent liver tumor promoters, although there is debate whether humans are at increased cancer risk upon exposure. The effects observed upon long‐term treatment of rodents to PPs include hepatic peroxisome proliferation, hepatomegaly, regulation of gene expression, alteration in cell cycle control and ultimately, carcinogenesis. The majority of the physiological, toxicological and carcinogenic effects induced by PPs are mediated by a nuclear hormone receptor, Peroxisome Proliferator‐Activated Receptor‐α (PPARα). Although humans respond to PPs via PPARα activation resulting in altered lipid metabolism, there is little evidence for peroxisome proliferation or liver cancer. In the present chapter, the current understanding of how PPARs are involved in tumorigenesis, and what this may mean to human risk assessment, will be discussed.
Reactive Oxygen Species in the Induction of Toxicity
Authors: Lenaz Giorgio , Strocchi Paola 
Published: December 2009

AbstractOxidative stress is among the major causes of toxicity due to interaction of reactive oxygen species (ROS) with cellular macromolecules and structures and interference with signal transduction pathways. ROS originate from exogenous and endogenous sources; among the former are UV and ionizing radiation and xenobiotics, the latter are represented by a number of metabolic reactions. The mitochondrial respiratory chain, specially from Complexes I and III, is considered the main origin of ROS particularly under conditions of high membrane potential, but several other sources may be important for ROS generation, such as mitochondrial p66Shc, monoamine oxidase, α‐ketoglutarate dehydrogenase and extramitochondrial xanthine oxidase, cytochrome P450, nitric oxide synthase, peroxisomal enzymes, plasma membrane NADPH oxidases, and lipoxygenase, with the participation of redox‐active metal ions. ROS are able to oxidatively modify lipids, proteins, carbohydrates and nucleic acids and to activate/inactivate signalling pathways by oxidative modification of redox‐active factors. Cells are endowed with several defence mechanisms, including repair or removal of damaged molecules, and antioxidant systems, either enzymatic or nonenzymatic. Oxidative stress is at the basis of ageing and many pathological disorders, such as ischaemic diseases, neurodegenerative diseases, diabetes and cancer, although the underlying mechanisms are not always completely understood.
Toxicogenomics and the Evolution of Systems Toxicology
Authors: Waters Michael D. , Alex Merrick B. 
Published: December 2009

AbstractToxicogenomics combines toxicology with genetics and genomics to provide a comprehensive view of the function of the genetic and biochemical machinery (genes, proteins and metabolites) of the living cell. A critical part of the study of toxicology, and by extension, toxicogenomics, is the empirical and contextual characterization of adverse effects at the various levels of organization of the organism—ranging from animal health and function to organs, tissues, cells and intracellular and intercellular molecular systems. Thus, toxicology and toxicogenomics are rapidly evolving into systems toxicology. The modern achievements of sequencing whole genomes have been quickly followed by gene expression profiling technologies that allow comprehensive queries of the transcriptome, to the refinement of traditional proteomics, and to the creation of other ‐omic technologies. Toxicogenomics evolved from the desire to characterize how genomes respond to environmental stressors or toxicants by combining genome‐wide mRNA expression profiling (transcriptomics) with global protein expression patterns (proteomics) that are interpreted by the use of bioinformatics to understand the role of gene–environment interactions in disease and dysfunction. The inherently reductive nature of toxicogenomic analysis down to the level of DNA, mRNA and protein sequences is being counterbalanced by a concerted attempt to reassemble these molecular pieces of information into pathways and networks that form the new field of systems toxicology. The result of these concurrent reductive and assembly activities in gene expression information is a much greater depth of field now possible for examining toxicant responses. The ability to discern mechanisms of toxicity as related to health issues is an important challenge facing scientists, public health decision‐makers and regulatory authorities, whose aim is to protect humans and the environment from exposures to hazardous drugs, chemicals and environmental stressors. The problems of performing safety and risk assessments for drugs and chemicals and of identifying environmental factors involved in the aetiology of human disease have long been formidable issues. Genomic technologies offer the potential to change the way in which toxicity and human health risk are assessed. This review explores the new field of toxicogenomics, delineates some of its research approaches and success stories and describes the challenges it faces as it enters the new world of systems toxicology.
Chronotoxicology*Dedicated to the memory of Dr Charles A. Walker who pioneered chronotoxicology
Authors: Soliman Karam F. , Mazzio Elizabeth A. 
Published: December 2009

AbstractThe study of kinetics, dynamics, toxicological responses and side effects of drugs, poisons or toxic substances relative to temporal rhythms occurring in living organisms is referred to as ‘chronotoxicology’. Temporal rhythms are guided by solar time cycles (circadian = 24 hours) based upon photoperiodic stimuli derived from sunlight and further influenced by local external time cues. The ‘main biological clock’ by which rhythms are established is the suprachiasmatic nucleus (SCN) housed proximal to the optic chiasm, which receives transmitted blue light (460–480 nm) through non‐visual photosensitive retinal ganglion cells containing melanopsin in the retinohypothalamic tract. The SCN's basic ‘free‐running’ circadian rhythm then orchestrates dynamic rhythms in millions of peripheral oscillators located within the body's cells, tissues and organs that are not responsive to light, but respond through neural and humoral SCN outputs. Together these orchestrate the precisely timed events to sustain biological life by regulating physiological function of the cardiovascular, nervous, digestive, immune, reproductive, endocrine and nervous systems. Cyclical fluctuations in absorption, distribution, metabolism and excretion regulate toxic substance detoxification, drug toxicity and effectiveness. Many of these processes are further regulated at the genetic level by clock genes which establish basic transcriptional‐translation feedback oscillation loops under the control ofPer1–3,Cry1,2, Rev‐erbα, Rev‐erbβ, Rorα, Rorβ, cAMP response element‐binding protein (CREB) and the circadian locomotor output cycles kaput/brain and muscle ARNT‐like protein 1 (CLOCK/BMAL1) heterodimers.
Statistics for Toxicology
Authors: Lee Peter N. , Lovell David 
Published: December 2009

AbstractThis chapter discusses statistical issues in the design, analysis and interpretation of toxicological data. Aimed at the statistically unqualified reader, its concern is principles rather than techniques. Although discussion is often in relation to the long‐term rodent carcinogenicity study, the principles and methods described apply widely in toxicology. After describing the statistician's role, some general issues including bias, hypothesis testing,p‐values and multiple comparisons are referred to. The chapter then discusses the relevance of Good Laboratory Practice (GLP) and quality assurance (QA), before considering various aspects of experimental design and conduct, including numbers of animals, choice of controls, dose levels, duration, stratification and randomization. Various considerations general to statistical analysis are discussed next, including combining, pooling and stratification, trend analysis, multiple control groups, age adjustment, missing data, historical controls and the need to take context of observation into account in pathology data. The chapter advocates the use of simple statistical methods and recommends the appropriate techniques to use in many standard situations. Details of the actual methods are not presented, the reader being pointed to appropriate publications and software.
Haematology and Toxicology
Authors: Marrs Timothy C. , Warren Simon 
Published: December 2009

AbstractHaematological investigations are of importance in toxicology because toxicological effects on the blood and associated organs may occur. Further, toxicological parameters are routinely measured during regulatory toxicological studies. There are important practical considerations in obtaining blood and/or bone marrow for toxicological studies. Toxicants can cause abnormalities in toxicological tests by a variety of means. Many of the techniques used in human and veterinary medicine have not been widely applied to laboratory animal toxicology studies.