Pulmonary Immunotoxicology is a comprehensive exploration of the effects of various inhaled materials upon the immune system of the respiratory tract. It will be useful to investigators in the field of pulmonary toxicology and immunotoxicology, and to those involved in administration and regulation of matters related to inhaled materials. It can also serve as a textbook for a course in pulmonary immunotoxicology at graduate or advanced undergraduate level. Pulmonary Immunotoxicology comprises four sections. The first provides basic background concepts essential for understanding pulmonary immunotoxicology, including discussions of the normal structure and function of the respiratory system, its basic immunology, and the manner by which inhaled particles and gases are removed from the air and deposited upon respiratory tract surfaces. The second section provides an overview of the major types of pathological consequences which can arise from immunomodulation within the respiratory tract, including hypersensitivity and asthma, inflammation and fibrosis, as well as immunosuppression and autoimmunity. The third section, which comprises the largest portion of the book, deals specifically with major classes of airborne agents that are known to alter the immune function of the respiratory tract. These are arranged into major classes: organic agents, metals, gases, particles, biologics, and complex mixtures. The fourth and final section of the book explores the area of risk assessment, including discussions of the basic concepts of risk assessment as they apply specifically to immunotoxicologic effects upon the lungs, and the use of biomarkers as indices of potential pulmonary immunotoxic responses to inhaled materials.

Humans are exposed daily to low concentrations of metals that are released into the environment by both natural and industrial processes. Environmental Metal Pollutants, Reactive Oxygen Intermediaries and Genotoxicity: Molecular Approaches to Determine Mechanisms of Toxicity examines concerns about the acute and/or chronic exposure of humans to concentrations of these metals that are below the threshold levels established by various federal regulatory agencies. Some of these metals are accumulated in various tissues and over time this may result in the accumulation of a significant body burden. This could increase the risk of developing a variety of diseases later in life, at a time when thresholds for such effects may already be reduced by the processes of aging. Such possibilities could only further compromise the quality of life in the elderly population and could contribute to the rising cost of health care in this country. Studies that have been conducted to determine the possible risks associated with exposure to relatively non-toxic concentrations of environmental metals have been hampered by a lack of appropriate models and a lack of funding. It has also been difficult for researchers to demonstrate a correlation between the exposure of humans or animals to low concentrations of environmental pollutants and disease. This book examines recent technological advances in the areas of molecular biology, biochemistry, and computer-enhanced image analyses that provide researchers with the tools to begin elucidating the genotoxic effects of environmental metal pollutants and the mechanisms by which these metals cause DNA damage. Environmental Metal Pollutants, Reactive Oxygen Intermediaries and Genotoxicity: Molecular Approaches to Determine Mechanisms of Toxicity presents data that demonstrate that certain environmental metal pollutants are genotoxic. The authors describe the role of reactive oxygen intermediates in causing the DNA damage induced by environmental metal pollutants and discuss their possible role in human disease.

Voltage-gated calcium channels are critical regulators of cytoplasmic levels of calcium, the universal signaling ion. As such, calcium channels trigger a wide range of cellular functions, from muscle contraction to neurotransmitter secretion, and are important players in human disease. Prominent in the nervous, cardiovascular, and endocrine systems, members of the calcium channel family are targets for existing antihypertensive and anticonvulsant drugs. In addition, they are emerging targets for drugs to treat an extraordinarily diverse group of disorders, including pain, cerebral ischemia, cardiac arrhythmia, and migraine. This book reviews the compounds that target individual calcium channel subtypes and the cellular and behavioral functions governed by each different channel. It contains information for basic scientists using calcium channel antagonists as experimental tools, for behavioralists studying animal models of human disease, and for pharmaceutical scientists interested in creating the next generation of calcium channel-targeted drugs. Several factors make an entire book on calcium channel pharmacology timely.

This book has its origin in my experience as a teacher of pharmacokinetics in many universities in four different continents. It was not my intention to write a popular book; what distinguishes this one from many others on the same subject is its large use of algebra and calculus. For this I make no apologies; in fact a serious study of pharmacokinetics without the help of mathematics is, in my opinion, impossible. The exact definition of many pharmacokinetic quantities, even the most common, and the correct use of many equations, even the most simple, requires the constant use of mathematical language. On the other hand I have made a considerable effort to use only elementary algebra and elementary calculus, as commonly taught in most introductory university courses. For the few exceptions, when less common mathematical concepts were needed, I have supplied the necessary explanations in four appendices. The first three chapters are a general introduction to the scientific method. Chapters 4 to 12 show different specific methods to deal with pharmacokinetic pr- lems. There is considerable overlap among those chapters; this is intentional and its p- pose is to convince the reader that every problem can be solved in more than one way, including ways that were not mentioned in this book and that intelligent readers can find for their own pleasure. Chapters 13 to 17 show how different parameters of importance in pharmacokinetics can be exactly defined and measured.

This publication contains the proceedings of a seminar held in Toulouse, France, on 10th, 11th and 12th June 1980, under the auspices of the Commission of the European Communities, Directorate General for Agriculture, Division for the Coordination of Agricultural Research, as part of a programme of research on beef production. The seminar was intended to bring together available experience on the utilisation of hereditary muscular hypertrophy for meat production in the member states of the European Communities. Although the phenomenon of double muscling has been exploited in various countries, particularly France, Italy and Belgium, different breeds are used and different methods of exploitation employed. An attempt was therefore made to bring together the collective experience of participants. Contributions ranged from those on the inheritance of muscular hypertrophy to alternative production systems and from fundamental studies of muscle growth to practical ways of selling the additional musrile found in animals with muscular hypertrophy. The collection of assembled papers and discussions thus represents one of the most extensive reviews of the subject that has been attempted.

At the end of September 1984 Dr. M. Velickovi and Prof. H. Prechtl with the help of the International Cerebral Palsy Society organized an international conference on "New develop ments in the assessment of early brain damage" in Bled, Yugo slavia. I was invited as a speaker at this conference and I went there, curious, but without too much knowledge about the central theme: cerebral palsy. During the conference and a satellite meeting I became impressed by the quality of various contributions and also by the great variety of problems related to the etiology, early diagnosis, management and psychosocial aspects of cerebral palsy. Today, in many areas of biology and medicine, progress seems to require concentration on a very narrow field. As a consequence many conferences are highly specialized and most (young) scientists rightly consider this as most useful for their own work. On the other hand the care of patients and counselling of parents and other close relatives require a multidisciplinary approach. Also, advances in the study of complicated un resolved medical biological pr'oblems are often made unex pectedly by using ideas, theories, approaches or methods from other disciplines."

The 21st century will witness the unprecedented marketing of therapeutic drugs developed from cannabinoids and the endocannabinoid system. Cannabinoids is a timely volume, which represents a comprehensive review of the most important issues in cannabinoid research as well as those of most likely therapeutic relevance. For the first time, the multi-faceted aspects of cannabinoid chemistry, biology and medicine are presented in one volume.
Key topics of discussion:

-major families of phytocannabinoids;
-pharmacological activity of phytocannabinoids;
-interactions of phytocannabinoids with their proposed molecular target;
-components of the endocannabinoid system;
-molecular mechanisms of the endocannabinoid system;
-Physiological and pathological role of endocannabinoids;
-industrial applications of studies on the cannabinoids;
-therapeutic uses of agonists and antagonists of cannabinoids receptors. This book is a must for graduate and pre- and post-doctoral students in disciplines ranging from organic and natural product chemistry, pharmacology, biochemistry and medicine.

In some countries, especially on the European continent, there still exists a remarkable veal market. This type of meat production seems, irrespective of any economic forecasts, to remain unchallenged so long as consumers expect that restaurants should offer courses like "r6ti de veaux," "vitello a la casa" or "Kalbsschnitzel." Producers, at least since about the past 1-/2 decades, have been aware of the beneficial effect of anabolic agents in veal production. This is possible due to the lack of endogenous sexual hormones during the juvenile or prepuberal status of these animals. A discussion about the benefit / risk - evaluation in connection with the use of anabolic agents in general was promoted in recent years by the public. This concern occurred concomitantly with the detection of illegally treated veal calves and the occurrence of diethylstilbestrol (DES) residues in canned food containing veal. The aim of this paper is to summarize the present status of residue data in edible tissues and excreta in order to allow the evaluation of the risk (given in the paper of Hoffmann within this program) and to consider reasonable monitoring measures. We have to face the fact that without an efficient control system the illegal treatment of calves can not be excluded. Therefore, this paper will not only consider different compounds and formulations, but will also deal with practised routes of administration.

African swine fever (ASF) is caused by a virus that is classified as a member of the Iridovirinae family. The disease in the warthog, the natural host, in Africa was described in 1921 by R. E. Montgomery. The reservoir of the vi rus is inti cks. The i ntroduct i on of domestic pi gs into territory occupied by warthogs i nf ected wi th ASF in the 1960's has endangered the pig industry around the world. The domestic pig is highly sensitive to ASF and develops a devastating disease that kills the pig without giving the immune system a chance to defend the animal against the virus infection. The ability of ASF virus to infect and destroy cells of the reticuloendothelial system leaves a defenseless host that succumbs to an infection which may be described as an acquired immune deficiency di sease of domestic pi gs. Introduction of the virus into Iberia in the 1960's led to a series of ASF epidemics in Spain and Portugal . . and later in France, that caused heavy economic losses. Between 1976 and 1960, ASF virus made its appearance in Malta and Sardinia . . as well as in Brazil, The Dominican Republic . . Haiti, and later in Cuba. In 1985-6 . . ASF appeared in Belgium and The Netherlands.

For critical care of laboratory rodents, there is a scarcity of sources for comprehensive, feasible, and response-oriented information on clinical interventions specific to spontaneous and induced models of disease. With the more complex cases that need critical care management, many treatment approaches to veterinary emergencies cannot be applied directly to the laboratory rodent. The first text of its kind devoted to the challenges of critical care management for laboratory rodents, Critical Care Management for Laboratory Mice and Rats provides a specialized resource for all veterinary, husbandry, technical, and research professionals who utilize rodent models for biomedical research. The book covers the varied approaches to laboratory rodent patient care, health assessments, characteristics of specific disease models, monitoring and scoring of disease parameters, and humane interventions. Giving primary consideration to preservation of animal health and welfare, the text also considers how best to balance welfare with the achievement of proposed scientific objectives. Organized into five chapters, this full-color book covers the following topics: General Approaches for Critical Care Critical Care Management for Laboratory Mice Critical Care Management for Laboratory Rats Special Considerations for Critical Care Management in Laboratory Rodents Resources and Additional Information The author provides treatment guidelines with the expectation that they will be applied with apt professional judgment, allowing for further modification of clinical recommendations for improved patient-based care and welfare for research animals.

G. Petursson and Rikke Hoff-J0rgensen The concept of slow viral infections was first put forward in 1954 by Dr. Bjorn Sigurdsson, an Icelandic physician who had been studying some sheep diseases which were introduced into Iceland with the importation of a foreign breed of sheep in 1933. Sigurdsson's main criteria for defining slow infec tions were a very long initial period without clinical signs lasting months or even years following infection and a rather regular protracted, progres sive course, once clinical symptoms had appeared, usually ending in serious disease or death. Sigurdsson included in this list of slow infections maedi -visna, infectious adenomatosis of sheep, scrapie in sheep, Bittner's mam mary carcinoma and Gross' leukemia in mice. All of these diseases, except scrapie, are caused by retroviruses. The characteristics of slow infections as described above are of prac tical importance for epidemiology, diagnosis and control of these diseases. For many years the slow infections remained primarily a veterinary problem, mainly affecting sheep and goats in certain countries. In recent years, how ever, the human immunodeficiency virus (HIV) causing acquired immunodefici ency syndrome (AIDS), has suddenly appeared in many countries of the world and brought the slow infection concept forcefully to the attention of the medical profession. The disease problems and the economic effects of slow infections of sheep and goats are increasingly recognized in various coun tries. For the reasons stated above we feel that this book should be useful for veterinarians and physicians alike."

Radiophannaceuticals labeled with short-lived radionuclides are utilized to unravel biochemical processes, and to diagnosis and treat diseases of the living body are-developed through extensive evaluation in ~iological models. 'fhC first attempt to compile information was a volume entitled ANIMAL MODELS IN RADIOTRACER DESIGN that was edited by William C. Eckelman and myself in 1983. The volume had a focus on the animal models that investigators were using in order to design radiotracers that displayed in vivo selectivity as measured by biodistribution and pharmacokinetic studies. A concern in the early days of nuclear medicine was species differences. Often a series of labeled compounds were evaluated in a several different animal models in order to gain confidence that the selected radiotracer would behave appropriately in humans. During the past 12 years there have been remarkable advances in molecular genetics, molecular biology, synthetic radiopharmaceutical chemistry, molecular modeling and visualization, and emission tomography. Biological models can now be selected that are better defined in terms of molecular aspects of the disease process. The development of high resolution PET and SPET for clinical applications facilitates the development of new radiopharmaceuticals by the use of models to quantitatively evaluate drug effects, and progression of disease, and hence to arrive at better diagnosis and treatments for animals and humans. With these advances there is an effective use of biological models, and the refinement of alternatives for the development of new radiophannaceuticals.

Interest in the coronaviruses has never been greater. Their economic impact is considerable as they infect humans, livestock, poultry and companion animals. Murine hepatitis virus (MHV) infection of the mouse and rat central nervous systems are the subject of intense study; these investigations are providing insights into the potential role of viruses in human neurological diseases and, more generally, into mechanisms causing neurological damage. The single-stranded, positive-sense RNA genomes of two species of these enveloped viruses (IBV and MHV) have been cloned completely and one of them (lBV) sequenced in its entirety, revealing a genome size of some 27000 nucleotides. This has made possible more incisive investigations into the nature of those polypeptides, encoded by more than half of the genome, which are likely to contribute, in the main, to RNA polymerase/replicase activity. Intriguingly, ribosomal frameshifting is exhibited within the mRNA coding for these polypeptides. The cloning/sequencing phase of coronavirology for which the 1980's will be partly remembered, has provided a sound framework for furthex: studies of the virus structural proteins and also some provocative insights relevant to these studies. The large spike glycoprotein(s), responsible for membrane fusion and bearing important antigenic sites, varies amazingly in length and composition both within as well as between coronavirus species. Receptors on host cells have been identified. The integral membrane glycoprotein (M) has been shown to use internal hydrophobic sequences to direct translocation within membranes.

This is the first comprehensive work to review blood platelet biochemistry, physiology, pharmacology, and function. It provides up-to-date information on how platelets function, the biochemical mechanisms that modulate their physiology and function, as well as the pharmacology of platelet inhibitory drugs.

The third congress ofthe European Association for Veterinary Pharmacology and Toxicol ogy (EAVPT) was held in Ghent, Belgium, from 25 to 29 August 1985. Part I of the Proceedings of this congress contains the abstracts of all invited lectures, oral communi cations and poster communications, presented at the congress. The invited lectures are now published (this volume) in extenso as Part II of the Proceedings. The editors wish to thank all invited speakers for their active contribution to the success of the third congress of EAVPT. They are very grateful to Dr. P. De Backer for compiling all manuscripts, Dr. P. Lees for scientific amendments, Miss B. Vermeesch and Dr. R. Lefebvre for preparing the camera ready copy and MTP Press for literary advice and publishing. A. S. J. P. A. M. van Miert M. G. Bogaert M. Debackere xi Contributors AMEND J.F. Department of Anatomy and Physiology, Atlantic Veterinary College. University of Prince Edward Island. Charlotte town. P.E.I. CIA 4P3. Canada. ANIKA S.M. Department of Veterinary Physiology and Pharmacology. University of Nigeria, Nsukka. Nigeria. ARGENZIO R.A. Department of Anatomy, Physiological Sciences. and Radio logy, School of Veterinary Medicine. North Carolina State University. Raleigh, NC 27606. USA. ARONSON A.L. Clinical Pharmacology Unit. School of Veterinary Medicine. North Carolina State University, Raleigh. North Carolina 27606. USA. AUCOIN D.P. The Animal Medical Center. 510 E 62nd Street. New York. New York 10021. USA. xiii xiv COMPARATIVE VETERINARY PHARMACOLOGY, TOXICOLOGY AND THERAPY BAARS A.J."

Electron microscopy is frequently portrayed as a discipline that stands alone, separated from molecular biology, light microscopy, physiology, and biochemistry, among other disciplines. It is also presented as a technically demanding discipline operating largely in the sphere of "black boxes" and governed by many absolute laws of procedure. At the introductory level, this portrayal does the discipline and the student a disservice. The instrumentation we use is complex, but ultimately understandable and, more importantly, repairable. The procedures we employ for preparing tissues and cells are not totally understood, but enough information is available to allow investigators to make reasonable choices concerning the best techniques to apply to their parti cular problems. There are countless specialized techniques in the field of electron and light microscopy that require the acquisition of specialized knowledge, particularly for interpretation of results (electron tomography and energy dispersive spectroscopy immediately come to mind), but most laboratories possessing the equipment to effect these approaches have specialists to help the casual user. The advent of computer operated electron microscopes has also broadened access to these instruments, allowing users with little technical knowledge about electron microscope design to quickly become operators. This has been a welcome advance, because earlier instru ments required a level of knowledge about electron optics and vacuum systems to produce optimal photographs and to avoid "crashing" the instruments that typically made it difficult for beginners.

Why are books written? Since I have read many works by my colleagues with admiration, this question has always intrigued me. Further, writing a book takes a good deal of time and effort, and I had imagined that I would never undertake such a demanding task. A few unexpected events and circumstances have changed my mind. The first was the pleasant experience of editing Environmental Toxicology of Pesticides with Drs. Mallory Boush and Tomomasa Misato. This fine symposium volume occasioned many interesting responses, including a suggestion to prepare a more complete treatise on the grounds that such "proceedings" volumes, by their very nature, do not satisfactorily offer a complete and coherent description of the field, but cater chiefly to specialists. I myself prefer single-authored books for basic understanding of a scientific field. The second circumstance leading to the present volume was the avail ability of teaching notes from my course on the toxicology of insecticides. As the need to cultivate environmental awareness has increased, there has been a parallel increase in the enrolments of such courses both here and in other major institutions. Yet no comprehensive and up-to-date text has been available. The third factor which facilitated the effort was an especially pleasant sabbatical in Hawaii, where the availability of the excellent Hamilton Library at the University of Hawaii considerably eased my task."

This volume, the last in this series on cancer growth and Moreover, the current status of plant-derived vinca alka progression, is a companion volume to Volume IX and loids and non-alkaloid natural products is summarized. further explores established and novel approaches for the Advances in hyperthermia and additional approaches for therapy of patients with malignant neoplasms. The stra the therapy of malignancies are also presented. tegies reflected in these volumes are direct extrapolations The volume continues with chapters on bone marrow from the basic science of cancer biology, growth and pro transplantation as well as hematologic and nutritional sup gression described in earlier volumes of this series. Some port for the cancer patient. Blood pressure in the cancer approaches are directed towards the eradication or modifi patient, therapy for nausea and vomiting as well as pain are cation of the properties of heterogeneous malignant tumor discussed. The last chapter is devoted to the problems of the cells at various stages of tumor progression, while other terminally ill, including evaluations of the burden relatives approaches are directed towards modification of the host and friends of the cancer patient have to bear. antitumor defense systems, e. g., enhancement of host anti It is clear that important advances in the basic science of tumor immune reactivity."

9. REFERENCES 90 CHAPTER 9: OPPORTUNITIES FOR REPLACEMENT, REDUCTION AND REFINEMENT: HUMAN VIRAL VACCINES 93 1. INTRODUCTION 93 2. TESTS FOR EXTRANEOUS MICROORGANISMS 94 3. MUMPS VACCINE . . . 94 4. HEPATITIS B VACCINE 95 4. 1. Test for freedom from live hepatitis virus 95 4. 2. Potency test 95 5. INFLUENZA VACCINE 96 5. 1. Potency test 96 5. 2. Abnormal-toxicity test 96 6. MEASLES VACCINE. . . . . 96 6. 1. Tests for extraneous agents 97 6. 1. 1. Test for Mycobacterium tuberculosis 97 6. 1. 2. Test for extraneous viruses 97 6. 2. Abnormal-toxicity test 98 7. POLIOMYELITIS VACCINE. . . 99 7. A. Inactivated poliomyelitis vaccine 99 7. A. l. Production. . . . . . 99 7. A. 2. Test for residual live virus 99 7. A. 3. Tests for extraneous agents 100 7. A. 3. l. Test for Mycobacterium tuberculosis . . . . . 100 7. A. 3. 2. Test for extraneous viruses 100 7. A. 4. Tumourigenicity test. . . . . 100 XII 7 . A. 5. Potency test . . . . . . . 101 7. A. 6. Test for abnormal toxicity 102 7. B. Live, oral poliomyelitis vaccine 103 7. B. l. Test for extraneous agents 103 7. B. 2. Test for neurovirulence 105 7. B. 3. Test for abnormal toxicity 106 8. RABIES VACCINE 106 8. 1. Production 106 8. 2. Test for residual live virus 107 8. 3. Tests for extraneous microorganisms 107 8. 3. 1. Test for Mycobacterium tuberculosis 107 8. 3. 2. Tests for extraneous viruses 108 8. 3. 2. 1. In dogs 108 8. 3. 2. 2.

It is a great pleasure for me to introduce this great deal of information from various insti- manual for the diagnosis of parasites of domes- tutes and universities. tic animals. It is a unique publication in many The result is an impressively comprehen- respects. Books concerning parasitic anima I sive, beautifully illustrated and, above all high- diseases - comprehensive textbooks, but also ly serviceable manual. It is easy to consult. Its field manuals - abound. These generally deal systematic and colour-coded layout allows the with aetiology, c1inical signs and pathology, as user to steer swiftly and surely through a vast weil as control and treatment. However, while amount of information. Clinical pictures and methods for diagnosis are often mentioned, figures show the parasite stage of diagnostic these are rarely sufficiently practical and spe- interest, facilitating a rapid and accurate diag- cific to allow the person ne I in field laborato- nosis. The book has been designed to be used ries to reach a concise, rapid dia gnosis of the by veterinarians and technicians, by teachers parasite species involved in any particular case. and students - in fact, by anyone dealing with Parasitic Infections of Domestic Animals suc- the diagnosis of diseases in domestic animals. ceeds in redressing these shortcomings.

The funny, touching and entertaining story of how Jo Hardy, the star of BBC2's Young Vets, gets to grips with animals big and small, friendly and not-at-all-happy, on the road to becoming a fully qualified vet. 'Stand well clear. Keep your eyes on them. Oh, and make sure you have insurance.' Not the most comforting words of wisdom, but probably the most useful for a trainee vet, Jo would say. From well-equipped surgeries to windswept hills and ramshackle barns, Jo has to be able to diagnose and treat any animal, at any time of the day or night. It's not quite as easy as James Herriot made it seem. Jo's final year of training saw her race from rectal examinations of cows to spine surgery on a Great Dane, and from treating an eventing horse with a heart problem to inserting a contraceptive implant into a monkey. And then there were the owners - the tough guy who sobbed when his cat was diagnosed with cancer, the woman who was convinced her dog was embarrassed by its stomach upset, and the farmer who loved his cows as much as anyone loves their pets. Gruelling days of animal treatments and visits combined with long nights of study and revision made Jo's final year of training the most demanding and rewarding year of her life. Her book tells of the highs and lows, the pets that stole her heart, and the lifelong friends that she made - with two legs and four.

The articles published in this volume are based on the papers del ivered at a conference on the Role of Metal Ions in Biological Systems held November 20 and 21, 1972, at Argonne National Laboratory. The purpose of the conference was to present to an interdiscipl inary audience of physical scientists some recent developments illustrating the chemical and environ mental participation of the heavy metal ions in the biological system. The invited speakers at the conference are special ists in the fields they describe, and the articles presented here are at a level of interest to readers with backgrounds in physical sciences who are not necessari Iy doing research in the areas described. The articles are referenced through 1972, and in some cases early 1973, and thus should also be of value to research workers. It is hoped that the book wi II be of particular interest to chemists, biologists, workers in the fields of en vironmental science and publ ic health, as wei I as graduate and senior undergraduate students in these discipl ines. The conference was sponsored by the Central States Universities, Inc., a consortium of sixteen midwestern univer sities, the Center for Educational Affairs, Argonne National Laboratory, and the United States Atomic Energy Commission. It is my pleasure to thank the members of the conference committee for their ideas and active help in organizing the conference."