bluuebunny/crossref_metadata_2025 huggingface dataset:
Functionalized Organozinc Compounds
Authors: Knochel Paul , Leuser Helena , Gong Liu‐Zhu , Perrone Sylvie , Kneisel Florian F.
Published: December 2009

Introduction

Methods of Preparation of Polyfunctional Organozinc Reagents

Reactions of Organozinc Reagents

Conclusion
Photochemical Transformations Involving Zinc Porphyrins and Phthalocyanines
Authors: Senge Mathias O. , Sergeeva Natalia N.
Published: December 2009

Introduction

Basic Photochemistry of Porphyrins

Donor–Acceptor Compounds for
PET

Applied Photochemistry

Acknowledgment
Palladium‐ or Nickel‐Catalyzed Cross‐Coupling Reactions with Organozincs and Related Organometals
Authors: Negishi Ei‐Ichi , Hu Qian , Huang Zhihong , Wang Guangwei , Yin Ning
Published: December 2009

Introduction

Overview of thePd‐ orNi‐Catalyzed Cross‐Coupling of Organozincs

Recent Advances in thePd‐ orNi‐Catalyzed Cross‐Coupling with Organometals ContainingZn,Mg,AlandZr

Acknowledgment
Enantioselective Addition of Organozinc Compounds
Authors: Soai Kenso , Kawasaki Tsuneomi , Sato Itaru
Published: December 2009

Introduction

The Mechanism of Catalysis for Diorganozinc Addition to Carbonyl Compounds

Enantioselective Addition of Organozincs to Carbonyl Compounds

Enantioselective Addition of Diorganozincs to Imine Derivatives

Asymmetric Amplification

Asymmetric Autocatalysis in the Asymmetric Addition of Dialkylzincs to Aldehydes

Conclusion

Acknowledgment
Rearrangements of Organozinc Compounds
Authors: Aggarwal Varinder K. , Sommer Knut
Published: December 2009

1,2‐Metallate Rearrangements

Other Types of Rearrangements

Conclusions
1,1‐Bismetallated Species
Authors: Matsubara Seijiro
Published: December 2009

Introduction

Preparation ofsp3‐Geminated Organodizinc Reagents

Reaction ofsp3‐Geminated Organodizinc Reagents

Preparation and Reaction ofsp2‐Geminated Organodizinc Reagents

Conclusion
Fluorinated Organozinc Reagents
Authors: Davis Charles R. , Burton Donald J.
Published: December 2009

Introduction

Fluoroalkenylzinc Reagents

Perfluoroaryl Zinc Reagents

Fluorinated Allyl and Propargylzinc Reagents

Perfluoroalkynylzinc Reagents

Perfluoroalkylzinc Reagents

Dialkoxyphosphinyldifluoromethylzinc Reagents

Carboalkoxydifluoromethylenezinc Reagents
Electrochemical Generation and Reaction of Zinc Reagents
Authors: Périchon Jacques , Gosmini Corinne , Buriez Olivier
Published: December 2009

Introduction

Electrochemical Generation of a Reactive Zinc for the Formation of Stable or Transient Organozinc Reagents and their Reactivity

Electrochemical Preparation of Organozinc Reagents Using Nickel or Cobalt Catalysis

Conclusion
Carbozincation of Alkenes and Alkynes
Authors: Lorthiois Edwige , Meyer Christophe
Published: December 2009

Introduction

Reactivity of Alkyl and Aryl Organozinc Reagents

Reactivity of Allylic Organozinc Reagents

Reactivity of Allenylzinc Reagents

Reactivity of Zinc Enolates and Aza‐Enolates

Conclusion
Anilines: Historical Background
Authors: Travis Anthony S.
Published: December 2009

Introduction

Identifying Aniline

The Aniline Dyes

Technology Transfer

Azo Dyes and their Intermediates

Patent Law inGermany

Aniline Red and the Structures of Aniline Dyes

Contributions to Academic Chemistry

Anilines for Explosives

Industrial Research

Indigo

Aminoanthraquinone Vat Dyes

TheUnitedStates Synthetic Dye Industry

Other Innovations

Medical Research and Sulfa Drugs

Antimalarials

Rubber Products and Polymers

Melamine

Anilines and Instrumentation

Strategic Anilines

Polyurethanes

Fiber‐Reactive Dyes and After

Organic Reaction Mechanisms

Celebration and History

Conclusion
General and Theoretical Aspects of Anilines
Authors: Nguyen Minh Tho
Published: December 2009

Introduction

Molecular Structure and Bonding

Energetics of Some Fundamental Processes

Some Special Features

Acknowledgments
Structural Chemistry of Anilines
Authors: Wójcik Graz̈yna Maria
Published: December 2009

Introduction

Methodology

Statistical Analysis of Structural Data Retrieved from theCSD

Molecular Packing and Hydrogen Bonds in the Crystals of Aniline Derivatives

Conclusions
Thermochemistry of Anilines
Authors: Slayden Suzanne W. , Liebman Joel F.
Published: December 2009

Introduction: Scope and Definitions

Alkylated Anilines and Related Species

Arylated Anilines and Related Species

Polyamino Benzenes

Anilines with Oxygen‐Bonded Functional Groups

Anilines with Sulfur‐Containing Functional Groups

Anilines with Halogen Substituents

Amidoanilines

Anilines with π‐Electron‐Withdrawing Substituents

Biochemically Relevant Anilines
Mass Spectrometry and Gas‐Phase Chemistry of Anilines
Authors: Eberlin Marcos N. , Augusti Daniella Vasconcellos , Augusti Rodinei
Published: December 2009

Introduction

Ionization Energies (IE) and Proton Affinities (PA) of Anilines: The Influence of the Substituents

70eV EIMass Spectrometry of Anilines: The Influence of the Nature of Substituents on Unimolecular Dissociation

OrthoEffects in Substituted Anilines

Miscellaneous Dissociations of Ionized Anilines

Chemical Ionization and Electrospray Ionization Mass Spectrometry of Anilines

Gas‐Phase Reactivity of Anilines

Acknowledgments
NMRSpectra of Anilines
Authors: Kolehmainen Erkki , Gawinecki Ryszard , Ośmiałowski Borys
Published: December 2009

Introduction

Ring andN‐Substituted Anilines

MultinuclearNMRStudies ofp‐F‐Aniline Derivatives

DynamicNMRof Aniline Derivatives

Anilines with Other (Fused) Aromatic Rings

NMRRelaxation Studies of Aniline Derivatives

Solid StateNMRStudies

Theoretical Calculations of AnilineNMRParameters
Substituted Anilines as Solvatochromic Probes
Authors: Marcus Yizhak
Published: December 2009

Introduction

Ring‐Substituted Anilines with an NH2Group

Ring‐Substituted Anilines with an NHAlkGroup

Ring‐SubstitutedN,N‐Dialkylanilines

More Complex Anilines

Solvatochromic Scales Based on Anilines

Acknowledgment
Synthesis of Anilines
Authors: Hartwig John F. , Shekhar Shashank , Shen Qilong , Barrios‐Landeros Fabiola
Published: December 2009

Introduction

Uncatalyzed Reactions

Palladium‐Catalyzed Methods

Mechanism of Palladium‐Catalyzed Amination of Aryl Halides

Copper‐Mediated Methods

Mechanism of Copper‐Mediated/Catalyzed Reactions
Anilines as Nucleophiles
Authors: Lee Ikchoon , Sung Dae Dong
Published: December 2009

Introduction

Nucleophilic Reactions at Aliphatic Carbons

Nucleophilic Reactions at Unsaturated Carbons

Nucleophilic Reactions at Heteroatoms

Anilines asC‐Nucleophiles

Kinetic Isotope Effects Involving Deuteriated Anilines

Acknowledgments
Rearrangements of Anilines and Their Derivatives
Authors: Lukyanov Sergei M. , Koblik Alla V.
Published: December 2009

Introduction

Rearrangements of Anilines

Rearrangements ofN‐Substituted Anilines

Rearrangements of Other Compounds to Form Anilines
Analytical Aspects of Aromatic Amines
Authors: Zabicky Jacob
Published: December 2009

Introduction

Sample Preparation

End Analysis

Structural Characterization
Manufacture and Uses of the Anilines: A Vast Array of Processes and Products
Authors: Travis Anthony S.
Published: December 2009

Introduction

Manufacture of Aniline

Diisocyanates and Polyurethanes

Intermediates for Dyestuffs

Azo Dyes

Anthraquinone Vat Dye Intermediates

Anthraquinone Vat Dyes

Sulfur Dyes

Indigo

Application of Dyes. Anchoring Dye on Fiber

Pigments

Agricultural Chemicals

Pharmaceutical Products

Rubber Products

Explosives

Heterocyclic Anilines

Photographic Chemicals

Liquid Crystals and Liquid‐Crystal Polymers

Other Polymers

Curing Agents for Epoxy Resins

The Aniline Point

Future Directions for Commercial Anilines

Conclusion
The Spectroscopy, Photophysics and Photochemistry of Anilines
Authors: Yang Jye‐Shane
Published: December 2009

Introduction

Spectroscopy and Photophysics

Photochemistry
Electrochemistry of Anilines
Authors: Jaworski Jan S. , Kalinowski Marek K.
Published: December 2009

Introduction

Anodic Oxidation of Aniline

Electrochemistry of Nitrogen‐Substituted Aniline Derivatives

Ring‐Substituted Anilines

Epilogue
Structural Organomagnesium Chemistry
Authors: Jastrzebski Johann T. B. H. , Boersma Jaap , Koten Gerard Van
Published: December 2009

Introduction

Organomagnesiates

Diorganomagnesium Compounds

HeterolepticRMgYCompounds

Mixed Organomagnesium Transition‐Metal Compounds

Conclusions
The Thermochemistry of Organomagnesium Compounds
Authors: Liebman Joel F. , Holm Torkil , Slayden Suzanne W.
Published: December 2009

Introduction: Scope and Definitions

Compounds Composed Solely of Magnesium and Carbon

TheSchlenk Equilibrium

Organomagnesium Halides

Diorganomagnesium Compounds

Organomagnesia and Rings

Magnesium Sandwich Species

Magnesium Complexes with Carbon Monoxide
NMR
of Organomagnesium Compounds
Authors: Heard Peter J.
Published: December 2009

Introduction

Concentration of Reagent Solutions

Alkyl and Aryl Compounds

Allylic and Vinylic Compounds

Alkoxide and Peroxide Compounds

Co‐Ordination Complexes

25
Mg
NMR
Studies
Formation, Chemistry and Structure of Organomagnesium Species in Solvent‐Free Environments
Authors: A. J. O'Hair Richard
Published: December 2009

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
Photochemical Transformations Involving Magnesium Porphyrins and Phthalocyanines
Authors: Sergeeva Natalia N. , Senge Mathias O.
Published: December 2009

Introduction

Basic Photochemistry of Porphyrins

Photosynthesis

Electron Transfer Systems

Photochemical Reactions

Applied Photochemistry

Acknowledgment
Biochemistry of Magnesium
Authors: Weston James
Published: December 2009

Magnesium in Biological Systems

Magnesium as an Essential Cofactor

Basic Coordination Sphere

Fundamental Binding Modes

Magnesium Transport Systems

Universal Energy Currency of Life

Interactions withDNAandRNA

Protein‐Based Enzymes
Theoretical Studies of the Addition ofRMgXto Carbonyl Compounds
Authors: Yamabe Shinichi , Yamazaki Shoko
Published: December 2009

Introduction

Experimental Background

Calculations of Grignard Reagents

Calculations of Model Grignard Reactions

A Comprehensive Computational Study of Grignard Reactions
Organomagnesium‐Group 15‐ and Organomagnesium‐Group 16‐Bonded Complexes
Authors: Hull Katherine L. , Henderson Kenneth W.
Published: December 2009

Introduction

Organomagnesium‐Group 15‐Bonded Complexes

Organomagnesium‐Group 16‐Bonded Complexes
Preparation and Reactivity of Magnesium Enolates
Authors: Grison Claude
Published: December 2009

Introduction

Preparation of Magnesium Enolates

Reactivity of Enolates
Functionalized Organomagnesium Compounds: Synthesis and Reactivity
Authors: Knochel Paul , Gavryushin Andrey , Brade Katja
Published: December 2009

Introduction

Preparation of Functionalized Grignard Reagents

Reactivity of Grignard Reagents
The Chemistry of Organomagnesium Ate Complexes
Authors: Yorimitsu Hideki , Oshima Koichiro
Published: December 2009

Introduction

Preparation of Triorganomagnesates

Reactions of Triorganomagnesates

Additional Important Chemistry of Organomagnesates
The Chemistry of Magnesium Carbenoids
Authors: Satoh Tsuyoshi
Published: December 2009

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

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

Xenobiotics, 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

The 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

Toxicokinetics 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

Dose‐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

The 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

Toxins 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

Toxicants 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

Many 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

The 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

Mitochondria 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

Peroxisome 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

Oxidative 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

Toxicogenomics 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

The 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

This 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

Haematological 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.
Alternatives toIn vivoStudies in Toxicology
Authors: Gad Shayne C.
Published: December 2009

Toxicology or its appplied product evaluation function (also called safety assessment) has now been in the forefront of the public's interest and expectations since at least the Second World War. As our understanding increased, a range of test designs and experimental methods using intact higher animals rapidly developed and came to be accepted in regulation and law.

However, as we have come to understand more of both how biological systems work and of the molecular and cellular mechanisms that underlie specific toxicities, we have also come to understand that intact higher animals may not be the only model system that allows us to identify and evaluate adverse effects resulting from exposure to a drug or chemical. Since the early 1980s, this has lead to extensive efforts to develop and validate non‐animal methods. And to use these to the extent possible to take the place of intact animals in the identification and evaluation of hazards for regulatory purposes. This chapter seeks to capture the current breadth and status of that journey.
Toxicity Data Obtained From Human Studies
Authors: Wilks Martin F. , Kupferschmidt Hugo
Published: December 2009

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

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

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

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

There is a diverse array of information resources available for toxicological data. The primary scientific literature should perhaps form the basis of any robust search. This chapter describes some of the key bibliographic databases to this literature, such as the US National Library of Medicine's TOXLINE and MEDLINE files, as well as outlining some of the important factors that determine how effectively any search will find relevant data. Many useful compilations of hard toxicological data also exist, in the form of factual databanks or reviews produced by various expert groups. Many are available for free on the Internet. The Internet provides the interface with many of the key toxicological resources, as well as offering the opportunity for more general searches for data. The chapter concludes with a timely reminder about the importance of accuracy, data interpretation and verification of information when it comes to toxicology.
Toxicities Associated with Parenteral Nutrition
Authors: Aschner Judy L. , Furlong Heather M.
Published: December 2009

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

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

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

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

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

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