Toxicologic Pathology. A Primer

1. Introduction to Toxicologic Pathology

Robert R. Maronpot and Abraham Nyska

 

2. Overview of Drug Development and Nonclinical Safety: Role of the Toxicologic Pathologist and Regulatory Aspects

Jim Fikes, John Kapeghian, and Zbigniew W. Wojcinski

 

3. Gastrointestinal System

Thomas Nolte and Judit E. Markovits

4. Liver, Gallbladder and Exocrine Pancreas

Russell C. Cattley, James A. Popp, and Steven L. Vonderfecht

5. Respiratory System

Tom McKevitt

6. Urinary System

Kendall S. Frazier and John Curtis Seely

 

7. Hematopoietic System

Hans Harleman and Stephan Schmidtbauer

 

8. Lymphoid System

Steven Laing

 

9. Bone, Cartilage, Muscle, and Tooth

Matthias Rinke and Christine Ruehl-Fehlert

 

10. Cardiovascular System

Roger H. Alison and Vasanthi Mowat

 

11. Endocrine System

Thomas J. Rosol

 

12. Male Reproductive System

Catherine Picut and Quinci Plumlee

13. Female Reproductive System

Daniel G. Rudmann

14. Integumentary System

Maurice Cary, Kelly Diegel and Lars Mecklenburg

15. Nervous System

Ian Taylor, Ingrid D. Pardo and Alok K. Sharma

 

16. Special Senses: Eye and Ear

JoAnn J. L. Schuh

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There has been an enormous growth of interest in the field of toxicologic pathology and particularly on its impact on nonclinical safety assessment in global drug development and in the environment. Toxicologic pathologists play an important role in detecting test article-related adverse effects by characterizing morphologic changes in animal tissues and/or body fluids under prescribed study conditions or less clearly defined conditions in the environment and in the interpretation of these findings relative to human risk. In fact, pathology evaluation is often the single most important decision-making factor in nonclinical safety assessments as 80% of drug candidate attrition has been attributed to pathology findings in toxicity studies. There are currently no primers or basic overviews covering the field of toxicologic pathology, whereas there are at least several basic books that cover the sister field of toxicology.

Toxicologic Pathology: A Primer is a practical, easy-to-use reference designed to contain core information provided by board-certified veterinary pathologists, all experts in the field. The Primer contains the basic, underlying principles of toxicologic pathology at the introductory level; thus it will be valuable to the veterinary pathology student who may be considering a career in the field as well as a companion to the seasoned toxicologic pathologist who wants a succinct refresher. The Primer is arranged as chapters presenting each major organ system preceded by an overview chapter covering the field of toxicologic pathology followed by a “concept” chapter describing the role of toxicologic pathology in drug development. Photomicrographs and illustrations provide visual context.

The organ system chapters provide histopathologic descriptions of lesions observed in toxicity studies of test articles in drug development and testing of chemicals that may negatively impact the environment. Each organ system chapter provides additional information related to a particular lesion to aid the reader in better understanding its toxicologic significance relative to human risk.

Each organ system chapter contains:

• A brief introduction
• A succinct description of the anatomy and physiology of the system
• Descriptions of the most important pathological lesions
• Differential diagnoses
• Biological consequences, pathogenesis, and/or mechanism of lesion formation
• Associated clinical pathology correlates

Nonclinical safety scientists such as study directors, non-pathology-oriented contributing scientists such as senior toxicology report reviewers, scientific management of Contract Research Organizations (CROs), and students should find the Primer useful in helping them understand the fundamentals of toxicologic pathology.

 

Dr. Pritam S Sahota studied for his Veterinary Medicine (BVSc) and Veterinary Pathology (MVSc and PhD) degrees at Punjab Agricultural University in India (1976). He is a Diplomate of the American Board of Toxicology. After completing his PhD, he immigrated to the USA in 1976 and worked for Dawson Research Corporation in Orlando, Florida for 10 years (1976-86) with increasing responsibilities as Toxicologic Pathologist, Senior Toxicologic Pathologist, and Scientific Director. While working briefly for Dynamac Corporation in Research Triangle Park, NC (1986-87), Dr. Sahota conducted retrospective scientific audits on 23 NTP carcinogenicity studies and participated in discussions with the representatives of NTP, FDA and EPA to summarize the results of scientific audits of approximately 200 carcinogenicity studies. In 1987, Dr. Sahota joined Ciba-Geigy Pharmaceuticals in Summit, NJ as Head/Manager of Pathologists and helped establish Pathology Peer Review, Scheduling and Quality Control systems. He continued to work primarily in this position with increasing responsibilities in Ciba-Geigy and then Novartis Pharmaceuticals (resulting from Ciba/Sandoz merger in 1997) up to 2000, when he became Head of Pathology (Director→ Executive Director: 2000-12, East Hanover, NJ). In addition to his pathology responsibilities, Dr. Sahota also served as International Project Team Representative for several marketed drugs including an antihypertensive blockbuster, Diovan, where he successfully defended company position with the FDA and various International Regulatory Authorities. During 2010-12, he successfully led following Global Preclinical Safety initiatives at Novartis: Patient Centricity, Cardiotoxicity, Ocular Toxicity, and evaluation of rodent carcinogenicity potential based on short-term toxicity and genotoxicity studies to minimize delays in regulatory submissions. Dr. Sahota also held an adjunct academic appointment of Assistant Professor in the University of Medicine and Dentistry of New Jersey, Newark, NJ for approximately 8 years. In 2013 and 2018, he co-edited as Lead Editor the First and Second Editions of the book entitled “Toxicologic Pathology, Nonclinical Safety Assessment” (CRC Press). In 2019, Dr. Sahota co-edited as Lead Editor “The Illustrated Dictionary of Toxicologic Pathology and Safety Science” (CRC Press), which was considered one of the 100 Best Pharmaceutical Books of All Time (Book Authority). Finally, Dr. Sahota as Lead-Editor, published Current Topics in Nonclinical Drug Development Volume-1 (2020) and Road to Greatness (2022).

Robert H. Spaet obtained his BS and MS degrees (Zoology) from Eastern Illinois University. He began his career as a Sr. Research Technician at the Franklin McClean Memorial Research Institute, Univ. of Chicago, before joining GD Searle Labs as a Parapathologist. He became a Research and Teaching Assistant at the Univ. of Oklahoma Health Sciences Center and completed coursework towards a PhD in Anatomic and Experimental Pathology before joining Ciba-Geigy Pharmaceuticals in June 1977 as a Scientist II in Pathology, Preclinical Safety. He also completed his oral and written exams for a PhD in Anatomic Pathology at Univ. of Medicine and Dentistry of New Jersey (UMDNJ) while working for CIBA. Robert’s core training and expertise lies in toxicologic pathology within the framework of drug safety assessment, and he is accredited by the International Academy of Toxicologic Pathology. He has also had full time experience as a Study Director and is certified as a Diplomate, American Board of Toxicology.

Post-retirement, Robert continues to remain active in toxicologic pathology and non-clinical safety having established a consultancy RSPathologics, LLC in 2013. He recently co-edited The Illustrated Dictionary of Toxicologic Pathology and Safety Science (CRC Press) which was considered the first of its kind published work in the non-clinical safety community. Post-publication, the book ranked #5 among top 100 toxicology books of all time by Bookauthority https://bookauthority.org/about. Robert is currently co-editing another work entitled Toxicologic Pathology: An Atlas. He has been a member of several high-profile groups including the Society of Toxicologic Pathology’s Science and Regulatory Policy Committee, the STP Membership, Fundraising and Tox/Path Forum Committees, and the European Society of Toxicologic Pathology Committee on the impact of AI on Toxicologic Pathology. 

 

Zbigniew W. Wojcinski is President of Toxicology & Pathology Consulting, LLC, in Hillsborough, NC and has over 35 years’ experience in pharmaceutical drug development. Dr. Wojcinski received his undergraduate degree (B.Sc.) in Zoology from the University of Toronto and his D.V.M. and D.V.Sc. (Pathology) degrees from the Ontario Veterinary College, University of Guelph. He is a certified Diplomate of the American Board of Toxicology and a Diplomate of the American College of Veterinary Pathologists.  He is also recognized as a Specialist in Veterinary Pathology by the Canadian Veterinary Medical Association and a Fellow of the International Academy of Toxicologic Pathology. Dr. Wojcinski gained experience in drug development and toxicologic pathology during his 22-year tenure with Parke-Davis\Warner-Lambert and Pfizer Global Research and Development and then 3½ years with Fulcrum Pharma Developments, Inc. In 2011, he founded Drug Development Pathology Services, LLC in Ann Arbor, MI and subsequently grew the organization into Drug Development Preclinical Services, LLC to provide toxicology, pathology, and drug metabolism and pharmacokinetic services.  Dr. Wojcinski has extensive experience as a Study Director, Study Pathologist, and Review Pathologist for numerous acute and repeated dose toxicity studies, including carcinogenicity studies. Throughout his career, he has managed successful cross-functional drug development teams in CNS, Metabolic Diseases, and Dermatology therapeutic areas. Dr. Wojcinski has been directly involved in the preparation of pre-IND documents, Nonclinical Safety Assessments for IND/IMPD/NDA/MAA, Investigator’s Brochures, and labeling (USPI, SmPC) negotiations. He has had numerous interactions with regulatory agencies in the United States, Europe, Canada, and Australia for compounds at various stages of development.  He has also provided pathology consultation and histopathology peer review on several projects in various therapeutic areas, including respiratory infections, dermatitis, oncology, and ophthalmic disease and served on Pathology Working Groups.  Dr. Wojcinski is a full member of numerous professional societies including the American College of Veterinary Pathologists, Society of Toxicologic Pathologists, Society of Toxicology, American College of Toxicology, American Veterinary Medical Association, Canadian Veterinary Medical Association, Canadian Association of Veterinary Pathologists, Regulatory Affairs Professionals Society, and Roundtable of Toxicology Consultants. He has served as President of the Dermal Toxicity Specialty Section of the Society of Toxicology, an Associate Editor for the Society of Toxicologic Pathology, Editor of The Scope for the Society of Toxicologic Pathology, and Chair of the Society of Toxicologic Pathology Recruitment Subcommittee. Dr. Wojcinski has lectured at the Ontario Veterinary College and the University of Maryland and authored/co-authored numerous scientific reports, manuscripts, and book chapters. He is Co-Editor for the following books: “The Illustrated Dictionary of Toxicologic Pathology & Safety Science” (published in 2019); “Current Topics in Nonclinical Drug Development, Volume 1” (published in 2021); “Guideposts for Veterinary Professionals” (published in 2021); “Road to Greatness” (published in 2022); “Toxicologic Pathology: An Atlas” (due to be published in 2023); “Current Topics in Nonclinical Drug Development, Volume 2” (due to be published in 2023); and “Toxicologic Pathology, Nonclinical Safety Assessment, 3^rd Edition” (due to be published in 2024). 

 

Gregory Argentieri received BS and MS Degrees in Biology from William Paterson University. He was Senior Electron Microscopy and Digital Imaging Laboratory Manager with 33 years of proven team management skills and diverse technical experience supporting pharmaceutical research and development in the medical and industrial fields at Sandoz, and Novartis Pharmaceuticals Corp. E. Hanover NJ. He is an Electron Microscopist certified by the Microscopy Society of America, with extensive experience in light and electron microscopy, image analysis, and other related techniques in medical, biological, and material sciences. Throughout his long career, he has been recognized by senior managers and peers for quality work in a high-pressure environment. Mr. Argentieri also taught Graduate and Undergraduate scanning and Transmission electron microscopy / lecture and lab as an adjunct professor at William Paterson College.  He was a contributor to New York Microscopy society newsletter. Mr. Argentieri’s ongoing  contributions  include serving as  Illustrations Editor for  the following books: The Illustrated Dictionary of Toxicologic Pathology & Safety Science” (published in 2019); “Current Topics in Nonclinical Drug Development, Volume 1” (published in 2021); “Toxicologic Pathology: An Atlas” (target publication 2023); and “Current Topics in Nonclinical Drug Development, Volume 2” (target publication 2023).