Abstract
This is the fourth edition of Toxicology of the Lung in the Target Organ Toxicology Series. The previous editions were in 1988, 1993, and 1999. This edition contains 16 chapters, each authored by highly recognized researchers. Each chapter begins with a table of contents with numbered subtopics.
Chapter 1, “Methods for Evaluating the Lung in Human Subjects,” by Stephen I. Rennard and John R. Spurzen, 21 text pages, and 107 numbered references. This chapter reviews all the common methods for respiratory tract evaluations, such as standardized flow rates and lung volume measurements, challenge tests, breath analysis, breath-condensate analysis, bron-choscopy, biopsy, and imaging methods. This is a good review and will be useful for the new investigator but most of these methods have been well known for decades.
Chapter 2, “Human Clinical Studies of Airborne Pollutants,” by Mark W. Frampton, Anthony P. Pietropaoli, Paul E. Morrow, and Mark J. Utell, 42 text pages, 195 numbered references. This chapter discusses many of the same topics covered in Chapter 1, and adds a few additional topics, such as mucociliary clearance and epithelial permeability, and then expands the discussion to include measuring cardiovascular function. Included in this chapter is a very good discussion of dose in the context of inhalation studies, which should be required reading for all researchers doing inhalation studies in either humans or animals.
Chapter 3, “Nasal Irritation—Current Understanding and Future Research Needs,” by James C. Walker, 18 text pages, 55 alphabetized references. Excellent summary of selected research methods used to study nasal irritation in humans. The chapter presents a good introduction to the differing views of those studying nasal irritation from the trigeminal nerve perspective versus the olfactory nerve perspective. This chapter highlights some of the key findings regarding the environmental stimuli that give rise to nasal irritation, and explains what is known and what is being debated concerning the neural fundamentals of nasal irritation. Much of the chapter is devoted to the work of Cometto-Muñiz and colleagues using anosmic subjects. Investigators working in the field are probably well versed on what is presented here, but this chapter will be useful for new investigators.
Chapter 4, “In Vitro Models for Lung Toxicology,” by Corrie B. Allen, 31 text pages, 261 numbered references. This chapter reviews the common in vitro models, five pages are devoted to methods such as cultured cells, continuous cell lines, airway and parenchymal explant cultures, airway smooth muscle preparations, ciliary motion preparations, and isolated perfused lung preparations. An additional five pages covers the common measurement end points used in in vitro experiments, e.g., tumor necrosis factor, ATP content, oxygen consumption, lactate production, and glutamine consumption. The variables influencing in vitro experiments, such as temperature, pH, and humidity are covered in three pages. Methods used to expose in vitro systems to gases and aerosols are covered in three pages. The newer area of gene expression and its evaluation with protein-chip technology is covered in three sentences. This chapter will be useful to the new investigator looking for an overview of the area, but will be of less value to an experienced investigator.
Chapter 5, “Dosimetry of Particles in Humans: From Children to Adults,” by Bahman Asgharian, Werner Hofmann, and Frederick J. Miller, 34 text pages, 176 numbered and alphabetized references. The authors stated purpose is to examine the current literature on the fate of particles in the lungs of children to stimulate interest in additional research and to identify research needs.
In the first six sections the authors have incorporated recent data on the development of the respiratory system and new data on infants and children along with a lot of well known data from adults. Most of the figures are very clear and informative, except for the one illustrating the geometry of the human nasal passages. A better explanation of the figure would have been helpful to the readers. Those unfamiliar with the turbinate structure and computerized three-dimensional representations may not learn much from this figure.
This chapter does a really superb job of pulling together and integrating older data on adults with the newer data on infants and children to provide a very comprehensive description of particle dosimetry. The chapter is well written and very understandable. The presentation is appropriate for both new investigators that need to learn about inhaled particle dosimetry or for the seasoned investigator who would like having a ready reference with updated information, and a superb reference list.
Chapter 6, “Influences of Dynamics, Kinetics, and Exposure on Toxicity in the Lung,” by Karl K. Rozman, William L. Roth, and John Doull, 32 text pages, 50 numbered references. These authors have presented their concepts on a unifying theory of toxicology in the literature in abbreviated form over the past 8 to 10 years. This presentation expands on that previous work where the interaction of dose, time, kinetics, and dynamics define the organism’s response to a toxic insult. The authors provide examples of toxicity driven by the dynamic of effect (reversibility, repair, or adaptation), and toxicity driven by kinetics of the agent. Five pages are devoted to developing an analogy between classical thermodynamics and their unifying theory. Most experienced inhalation toxicologists understand the vagaries of the term “dose” and the relationships between time and dose, but probably very few have considered how fundamental those variables are particularly in relation to other routes of administration.
This chapter should be required reading for all toxicologists in training and many experienced toxicologists will find useful food for thought here.
Chapter 7, “Safety Assessment of Therapeutic Agents Administered by the Respiratory Route,” by Shayne Gad, 55 text pages, and 201 alphabetized references. The subsection titled “Pulmonary Delivery of Inhaled Aerosols” contains a few noteworthy errors. For example, most current investigators would not agree with the statement that an aerosol with a geometric standard deviation of less than 2 is considered monodispersed. Current thinking puts this value more like 1.2. It is stated that particle-size distributions are usually bell shaped, which usually implies a normal distribution; however, many investigators believe aerosols follow a lognormal distribution. There is some difference of opinion regarding the shape of the distribution curve.
Most of the subchapters on excipients and delivery forms are a series of bulleted single sentences with little or no explanatory text. For example, under the heading “Liquid Nasal Formulation” the last bulleted item is “Patient compliance, cost effectiveness, and risk assessment.” Some readers may find this a less than optimal method of presentation; however, the topics are inclusive.
In the subchapter “Methods for Safety Assessment of Inhaled Therapeutics,” a single paragraph is dedicated to pulmonary sensitization, and the most current reference is 1989. One would expect a current book chapter on safety assessment of inhaled therapeutic agents to have a much more thorough and up to date treatment of this subject.
In a paragraph discussing atomizers and nebulizers, reference is made to an “elutriating atomizer.” The reference actually describes a solid particulate dust generator, which is evident from the article’s title in the reference list.
There appears to be an error that may have escaped the proofreading and correction stages during publication. Figures 7.3 and 7.4 appear to be identical except for the typeface, and the text relating to these two figures do not match either figure. This is an unfortunate oversight.
This chapter contains some useful information; however, it has all been well known for many years, and has been presented in review format in other publications. On the positive side, the data summarized in many of the tables (Marketed Nasal Products, Drugs in Development, Drugs Known to Cause Pulmonary Disease, Drugs that Adversely Affect Respiratory Function, and Drugs Known to Influence Ventilatory Control) will be very handy for the new investigator. There is a useful discussion on comparing doses between species and on normalizing dose to lung volumes and alveolar surface area.
In the final analysis, closer attention during the proof/correction stage and the inclusion of more recent references would have strengthened this chapter considerably.
Chapter 8, “Vanilloid Receptors in the Respiratory Tract,” by Christopher A. Reilly, John M. Veranth, Bellina Veronesi, and Garold S. Yost, 40 text pages and 202 alphabetized references. It is a real joy to read about a complex rapidly expanding subject where the authors make the effort to constantly remind the reader of the changes in terminology and abbreviations that plague a specialty discipline and lead to confusion. These authors present a clear and detailed account of the discovery and elucidation of the TRP/vanilloid receptor. After building this knowledge foundation, the authors go on to discuss the locations of these receptors, and how irritants such as pepper spray activate the receptors, discuss their evolvement with the cough reflex and neurogenic inflammation. The authors review the current literature relating TRP/Vanilloid receptors and responses to ambient particulate material, and offer a hypothesis for how those responses are mediated. This chapter concludes with a discussion of how these receptors may be involved with airway hypersensitivity, and how the receptor ligands may be used therapeutically.
This is a very well written and informative chapter, highly recommended.
Chapter 9, “Pulmonary Immunology,” by Mitchell D. Cohen, 50 text pages, 322 alphabetized references within topic groupings. After progressing a few pages into this chapter, the reader realizes that none of the material is referenced; well that is not quite true, none of the text material is referenced, but all the data presented in tables is referenced. The actual reference list is divided into sections, e.g., SOx and NOx, tobacco smoke, metals, etc., with the references in each section alphabetized.
The first few pages present the fundamentals of immunology in the respiratory system and the cell types involved. This is very much an overview with not many details. Next the author presents a three-page discussion of the immunologic effects of biologic agents, with four tables mentioning 35 different microorganisms with the references for each. The remainder of the chapter discusses ozone, sulfur oxides, combustion emissions (wood burning stoves, kerosene heaters, and diesel engines), tobacco smoke, and metals (arsenic, cadmium, chromium, nickel, and zinc). The text always refers to tables where specific compounds are listed with the animal species evaluated, the immune parameter analyzed, the effect found, and the references.
Considering that this is a chapter in a book and not an entire book on pulmonary immunology, the author has done a good job of summarizing a lot of very complex information. For the researcher working in this specialty, and looking for other work between about 1980 and 2000, this is a valuable reference.
Chapter 10, “Animal Models of Respiratory Allergy,” by Jürgen Pauluhn, 32 text pages, 125 alphabetized references. This chapter does a superb job of presenting the mechanisms and causes of asthma and pulmonary sensitization and describing the various animal models available for studying the phenomenon. Most of the figures are drawn from the author’s own extensive work in the field. The complete array of pulmonary function tests used to measure allergic responses in laboratory animals are presented along with examples of the resulting output data. The section “Experimental Protocols” provides a welcome discussion of the various approaches used to study respiratory sensitization, including the many variables such as dosing, dosing routes, and the timing of the doses. It was encouraging to note that the reference list was up to date with the most recent citation being from 2004.
This chapter is highly recommended for both experienced and novice investigators.
Chapter 11, “Fiber Toxicology,” by David M. Bernstein, 34 text pages, 67 alphabetized references. This chapter reviews the toxicology of man-made vitreous fibers and glass fibers in the respiratory tract emphasizing information developed since the early 1990s; earlier information on the classic fiber, asbestos, is not covered here, which is very appropriate for the purposes of this book. The main focus is on how length and biopersistence affects the toxicity of fibers. The writing style is generally very clear and informative, with a one major exception. Fibers are identified by a somewhat obscure nomenclature, such as MMVF 11 or RCF1. It would have been very helpful if the author had provided some background information about the various fiber types discussed. For example, MMVF fibers are glass fibers made by spraying or extruding molten glass and the slag types of MMVF are rich in trace metals, or that RCF1 refers to a particular fiber in the U.S. Refractory Ceramic Fiber Coalition repository and is from a bulk kaolin refractory ceramic fiber provided by the Manville Corporation. There are at least two dozen different fiber types discussed and there is very little information on what differentiates one from another, expect for length and diameter data. Researchers working in the specialty will understand the differences, but most readers will not.
The tables summarizing the results from many different studies are very valuable, and the three graphs illustrating a threshold for fiber toxicity clearly summarizes decades of work by many different researchers.
Chapter 12, “Reproductive Toxicology Testing of Inhaled Pharmaceuticals and Biotechnology Products,” by André Viau and Keith Robinson, 32 text pages, 44 alphabetized references. This chapter provides a useful overview of inhalation methods used in reproductive toxicity testing. The section on inhalation exposure systems and methods provides only general information with no substantive details. For example, when discussing nose-only exposures of rodent neonates, a highly specialized discipline, none of the very important technical details are provided about the restraining methods used. These technical details are what are needed to successfully conduct such studies. Most of the material presented about study designs for developmental toxicity and pre-and postnatal studies is available in the ICH guideline documents.
Based on validation studies conducted at CTBR, and presented in this chapter, the authors conclude that the stress of nose-only exposure methods does not have an adverse effect upon reproduction. The hematological, serum biochemical, and pulmonary function data presented on neonatal dogs will be of interest of investigators working in the field.
Chapter 13, “Effects of Engineered Nanoscale Particulates on the Lung,” by David B. Warheit, 18 text pages, and 27 alphabetized references. This chapter presents a good introduction of this relatively new area. The author makes the very important point that most of the currently available data were obtained from only two or three materials, and thus it is not advisable to draw expansive conclusions regarding potential toxicity. The author does a good job of reviewing the host of potential variables that can influence the toxicity of these materials.
The field is expanding so rapidly that it is almost impossible to have a truly up to date review in the book format, so potential readers should consider this a very good introduction to the subject but realize that other new information is also available.
Chapter 14, “Diesel Exhaust and Viral Infections,” by Ilona Jaspers, 20 text pages, 120 alphabetized references. This chapter reviews both epidemiological and laboratory work investigating the potential link between diesel exhaust particulates and respiratory tract infections. For the new investigator to this area, the author does a great service by describing in considerable detail the common respiratory viruses. Most of the chapter is devoted to detailed discussions on the cellular, subcellular and biochemical mechanisms the body uses to defend against and react to viral infections.
This chapter is very readable and highly recommended to both the new and experienced investigator.
Chapter 15, “Adaptation to Toxicant Exposure During Rodent Lung Tumorigenesis,” by Geoffrey M. Curtin, Ryan J. Potts, Paul H. Ayres, David J. Doolittle, and James E. Swauger, 26 text pages, 171 alphabetized references. This chapter summarizes current understanding of the molecular changes leading to lung tumors. The literature referenced spans many decades, from the 1950s on through the early 2000s. Except for a couple of pages on cadmium, most of the discussion focuses on tobacco smoke. The authors have taken this accumulated data and present a working hypothesis for the molecular pathology of lung tumor development.
Those investigators working in this field and not familiar with these authors’ work will want to read this chapter.
Chapter 16, “Tobacco Smoking,” by Hanspeter Witschi, 20 text pages, 83 alphabetized references. The first few pages of this chapter review the history of cigarette smoking, constituents of cigarette smoke, and the growing incidence of lung cancer in the world population. This is followed by a review of the animal models used to research tobacco smoke carcinogenesis, noting that there are no good models for this disease. The chapter wraps up with a discussion of environmental tobacco smoke and diseases related to tobacco smoke.
There is nothing new here, but the author does pull together volumes of divergent information and provides a very useful summary for those interested in or working in this specialty.
In summary, although many chapters are realistic and current assessments of the state of knowledge of lung toxicology, several other chapters are informative, but not as up to date as one would have anticipated. The book is selectively recommended as indicated above.