Selected Resources for Pathology Evaluation of Nonhuman Primates in Nonclinical Safety Assessment

Abstract

Humans and nonhuman primates (NHPs) share numerous anatomical and physiological characteristics, thereby explaining the importance of NHPs as essential animal models for translational medicine and nonclinical toxicity testing. Researchers, toxicologic pathologists, toxicologists, and regulatory reviewers must be familiar with normal and abnormal NHP biological traits when designing, performing, and interpreting data sets from NHP studies. The current compilation presents a list of essential books, journal articles, and websites that provide context to safety assessment and research scientists working with NHP models. The resources used most frequently by the authors have been briefly annotated to permit readers to rapidly ascertain their applicability to particular research endeavors. The references are aimed primarily for toxicologic pathologists working with cynomolgus and rhesus macaques and common marmosets in efficacy and safety assessment studies.

Nonhuman primates (NHPs) are essential model species for basic biological research, translational medicine, and nonclinical safety assessment.^1-6 Their importance as models is dictated by the highly conserved anatomic^7,8 (especially brain^9-12) and functional (behavioral, biochemical, physiological, and social)^2,13,14 attributes that NHPs share with humans.

With respect to pathology evaluation, expertise in primate pathology may be developed in several settings. Formal training in diagnostic and/or experimental pathology typically is obtained in various academic institutions, primate-oriented research foundations (e.g., the 7 National Primate Research Centers in the United States [https://nprc.org/]), and zoological parks. On-the-job experience in toxicologic pathology of primates may be gained in some academic institutions as well as certain contract research foundations or biopharmaceutical companies. In many cases, toxicologic pathologists must engage in considerable self-study to build the needed knowledge base to discriminate NHP species-specific anatomic features and spontaneous background findings^15-17 from potential changes related to test article exposure. The current mini-review is designed to provide a pathology-focused compilation of Internet and print resources to support a self-guided curriculum in comparative, experimental, and toxicologic pathology of common NHP models used in safety assessment. Both New World monkeys (e.g., common marmoset [Callithrix jacchus]) and Old World monkeys (e.g., cynomolgus [Macaca fascicularis] and rhesus [Macaca mulatta] macaques) are covered. The cited resources are arranged in two tables for convenience. The first provides a short list of printed materials and websites that are used most often by the authors in performing their duties as comparative and toxicologic pathologists working with NHP models; the important contents within the reference is given under the entry. The authors recommend that the annotated print items in Table 1 should be available in each pathologist’s office or departmental library due to their importance as tools in diagnosing and interpreting morphologic findings in common NHP species. The second table lists topics related to NHP pathology that may occasionally require the attention of a toxicologic pathologist but which fall outside the core expertise expected of such individuals in performing their daily tasks. These latter topics are accompanied by a list of one or more non-annotated citations that offer options for further exploration.

Table 1.

Key resources for pathology evaluation of nonhuman primates.

Title of reference	First author or editor	Type of reference	Citation
Biology of NHPs
Association of Primate Veterinarians (APV)	APV	Website	18
This online resource gives hyperlinks to many primate-related sites dealing with basic primatology, biosafety and regulatory information, and scientific procedures.
Nonhuman Primates in Biomedical Research	Abee	Book
A 2-volume compilation assembled as one of the “Blue Book” volumes produced by the American College of Laboratory Animal Medicine (ACLAM), this resource offers a comprehensive overview of NHP biology and pathology for common species used in biomedical research.
Vol 1. Biology and Management			2
Vol 2. Diseases			1
The Common Marmoset in Captivity and Biomedical Research	Marini	Book	19
This book is the best general reference concerning the biology, diseases, management, and research applications for this species.
Clinical Pathology
The Clinical Chemistry of Laboratory Animals	Kurtz	Chapter	20
This book provides a thorough review of key clinical chemistry analyses and their interpretation for multiple laboratory animal species, including NHPs.
Schalm’s Veterinary Hematology	Weiss	Chapter	21
The book delivers an extensive appraisal of blood collection and analytical methods for many species, including NHPs.
Pathology
“A primer of primate pathology: lesions and nonlesions”	Lowenstine	Article	22
This review discusses major background and treatment-related findings as well as normal variations in organs of different taxa that influence data interpretation in nonhuman primate studies.
The Nonhuman Primate in Nonclinical Drug Development and Safety Assessment	Bluemel	Book	3
This book addresses major topics that influence nonclinical toxicity testing for human risk assessment, including basic biological attributes, principles of study design, conventional experimental methods, and data acquisition and interpretation.
“Research relevant conditions and pathology in nonhuman primates”	Saravanan	Article	23
This article provides an extensive list of incidental background findings from many nonhuman primate species that may impact the interpretation of histopathology data.
Spontaneous Pathology of the Laboratory Non-human Primate	Bradley	Book	15
This resource is organized to equip pathologists involved in toxicity studies for multiple nonhuman primate species with information needed to differentiate background changes from treatment-related findings.
Strain-Specific Physiology
“Comparison of physiologic and pharmacologic parameters in Asian and mauritius cynomolgus macaques”	Kozlosky	Article	24
This paper presents biological differences between two common sources of one nonhuman primate model, thereby reinforcing that strain differences must be considered during data interpretation.

Abbreviation: NHP, nonhuman primate.

Table 2.

Supplemental references to aid in the pathology evaluation of nonhuman primates.

Subject	Citation
Anatomy	7,8,12,14,25-35
Biology	2,5,19
Clinical pathology
Baseline physiological parameters	20,21,24,36-41
Sample collection	4,42,43
Test interpretation	20,21,42,44-47
Development
Embryo, fetus, and neonate	31,48-53
Placenta	25,26
Disease	13
Animal models	54-61
Cancer	62-66
Infections	67-78
Bacteria	70,72,73,75,79-81
Parasites	44,70,72,74,79,81-85
Viruses	55,66,70,72-77,79,81,86-93
Inflammation	94-97
Multiple organ failure	98
Neurological diseases	86,94,99-102
Respiratory diseases	79,91,103-105
Genetics	61,106-110
Pathology
Diagnostic terminology	111
Incidental findings	15,16,34,36,102,112-124
Tissue responses	17,22,23,60,105,125-128
Product development and risk assessment
General	43,56,128-131
Case studies	57,127,132
Pathology	96,133
Biofluid collection	20,42
Tissue collection and trimming	134-142
Tissue interpretation	15,16,24,125,126,133,143,144
Test methods (non-pathology)
Behavior	145
Developmental and reproductive toxicity	146-149
Immunology	150-156
Inhalation	157
Species-Specific Resources
Common marmoset (Callithrix jacchus)	19,58,59,61,130
Biology	19,27,32,58,59,158-161
Pathology	16,22,23,88,120,161-164
Cynomolgus macaque (Macaca fascicularis)
Biology	24,33,34,51,62,66,70,83,107,109,131,148,149,153,165,166
Clinical pathology	24,36-39,41,44,46,167-177
Methods and nomenclature	111,131,136-138,153
Spontaneous findings	16,24,36,52,65,111-117,119,123,162,178,179
Test article-related findings	102,125,150,153,154,180,181
Rhesus macaque (Macaca mulatta)
Biology	12,29,30,35,48,49,53,62,64,86,125,145,151,167,182
Clinical pathology	38,40,45,46,167,170
Methods and nomenclature	96,111
Spontaneous findings	16,52,64,96,97,109,118,120,162,182-184
Test article-related findings	125,132
Useful Websites	14,18,108,110,185-191

A solid understanding of the core knowledge needed for proficient NHP pathology evaluation may be attained by dedicated study of the several annotated resources in Table 1. Sufficient time will have to be spent perusing these baseline resources so that the budding NHP pathologist becomes familiar with both individual facts and the location of essential topics of relevance to evaluating primate specimens. Pathologists who regularly participate in NHP pathology will also need to engage in lifelong continuing education due to the continued growth of information, skills, tools, and techniques within this field. Effort to identify other NHP pathologists to serve as mentors and eventually collaborators (e.g., the many members of the Nonhuman Primate Pathology Special Interest Group [NHP-SIG] of the Society of Toxicologic Pathologists [STP]) will facilitate the acquisition of real skill in working with NHP models.