Abstract
National Toxicology Program (NTP) pathologists are engaged in important initiatives that have significant global impact. These initiatives build on its leadership in pathology peer review and publications in the areas of toxicologic pathology, clinical pathology, and laboratory animal medicine. Over the past decade, NTP/National Institute of Environmental Health Sciences research initiatives have focused on cancer and noncancer hazard identification, with the goal of understanding cellular and molecular mechanisms of disease. New initiatives of significant global impact include the web-based nonneoplastic lesion atlas and an NTP partnership with international scientists to investigate molecular mechanisms at the whole genome level, which will be used to inform potential mechanisms of environmental exposures in human cancers. Also, we are dedicated to contributing to pathology and toxicology organizations through service on executive committees and editorial boards, participating in international projects and symposiums, and providing training for future leaders in toxicologic pathology. Herein, we provide highlights of our global contributions.
Keywords
National Toxicology Program (NTP) Pathology
NTP pathologists evaluate, interpret, and report the pathology findings from NTP studies in the NTP technical report (TR) series for long-term toxicology and carcinogenicity studies, NTP TR series for short-term studies, and NTP genetically modified models (GMMs) report series (https://ntp.niehs.nih.gov). These publicly peer-reviewed documents and the final book-length monographs contain the full study details and the formal NTP interpretation of the toxicologic and carcinogenic potential of the substances tested, which are used by national and international regulatory agencies and scientists from various disciplines. Since 1978, there have been nearly 600 chronic TRs, approximately 100 NTP toxicity reports (90-day and other special studies) and 15 GMM reports. New NTP report series in immunopathology/immunotoxicology and developmental and reproductive toxicity studies are in progress.
Laboratory Animal Medicine (LAM)
The LAM discipline in the NTP is a part of the toxicologic pathology team. Consistent with the refinement component of the replacement, reduction, and refinement (3Rs), which is being implemented globally, recent studies assessed the effect of the use of enrichment devices (nesting paper and polycarbonate shelters) in NTP studies. The enriched animals used the devices often and displayed species typical behaviors such as nest building and burrowing. The studies demonstrated that enrichment devices did not impact end points typically evaluated by the NTP. Based on these findings, the NTP refined and implemented the use of nesting material and polycarbonate shelters in acute, subchronic, and chronic toxicity/carcinogenicity studies; developmental/reproductive studies; immunotoxicology studies; absorption, distribution, metabolism, and excretion studies; and toxicokinetic studies of animals exposed via dosed feed, dosed water, and gavage routes.
Nonneoplastic Lesion Atlas (NNLA)
NTP pathologists created the online NNLA to allow for the use of consistent terminology across all studies. It is a unique resource for toxicologic pathologists, researchers, and students. The NNLA includes thousands of high-quality images of nonneoplastic lesions seen in NTP studies and provides descriptions, diagnostic guidelines, references, and other useful information for each lesion. It is a searchable, online database that is being used by scientists worldwide. The database was built by the NTP to make it easy to navigate and to make the details in the downloadable photographs easy to visualize. The NNLA web address is https://ntp.niehs.nih.gov/nnl/.
International Harmonization of Nomenclature and Diagnostic Criteria (INHAND)
Pathologists at the NTP also take active roles in the INHAND global collaborative initiative to establish a comprehensive set of standardized nomenclature and diagnostic criteria that is being used by toxicologic pathologists worldwide. Our pathologists serve as members or chairs of each of the Organ System Working Groups. In addition, an NTP pathologist has served as 1 of the 3 North American representatives on the 12-member INHAND Global Editorial Steering Committee comprised of internationally recognized pathologists from each of the major international toxicologic pathology societies.
The National Institute of Environmental Health Sciences (NIEHS)/NTP Archives
The NTP maintains a state-of-the-art archive facility of an unmatched collection of research specimens and supporting data from NTP studies. Archival materials, including histology slides, can be accessed by national and international pathologists and scientists. World-class collections of educational and training materials on rodent pathology are available upon request. Digital images of common, unusual, and rare rodent microscopic lesions and collateral data sets are maintained in a web-based database accessible both at the archives and via the Internet. Pathology images from the NTP archives were used for the INHAND initiative.
NTP Partnerships to Examine Genomic Alterations in Rodent Tumors
The NTP archives has been an important resource for molecular pathology research, and the NTP/NIEHS has used this material to identify mutations in rodent tumors resulting from various chemical exposures. The early mutation data were based on examination of hot-spot mutations in cancer genes relevant to humans using the low throughput gold standard Sanger sequencing technology. The advent of next generation sequencing technologies enables sequencing the entire genome or the whole exome (coding genome) of the tumors. In order to greatly expand the scope of this undertaking, the NTP is collaborating with various national and international partners such as the University of San Francisco, the Wellcome Trust Sanger Institute (WTSI), and the International Agency for Research on Cancer (IARC). WTSI was recently awarded US$24.4 million by Cancer Research United Kingdom to “identify preventable causes of cancer.” The genetic alterations identified in rodent tumors from NTP studies will be correlated with the somatic mutations and mutation signatures from human cancer databases such as the Catalog of Somatic Mutations in Human Cancers and The Cancer Genome Atlas. Examining NTP rodent tumors with well-defined exposures is expected to facilitate discovery of novel cancer genes and chemical-specific mutation signatures as well as underlying mechanisms that could translate to human cancers resulting from various environmental exposures.
Translational Research/Human Relevance/Investigative Pathology
NTP pathologists have conducted and collaborated on many studies of either direct human relevance or a translational nature. Pathologists have systematically evaluated numerous uterine fibroid specimens collected from more than 100 women in the NIEHS fibroid study and tabulated the histologic features of these tumors into a searchable computer database. These studies have allowed the correlation of the gross and microscopic features of the tumors with clinical characteristics of the patients such as body mass index, age, and ethnicity. The literature review published by NTP pathologists on the etiology and pathogenesis of uterine fibroids has been one of the most cited papers in this field. In addition, NTP pathologists have partnered with NIEHS scientists to develop a chemically induced rat model of bronchiolitis obliterans that has been used for the study of the pathogenesis and progression of this human disease. NTP pathologists also play critical roles in pioneering investigative research on the role of estrogen receptors in health and disease. Efforts include determining the roles of SOX8, estrogen receptor, and calcium channel protein in male fertility; the importance of transcription factors Glis2 and Glis3 in maintenance of normal renal function; environmental chemical effects on women’s and children’s health; mechanisms of pulmonary pathology; and genetic and epigenetic molecular events during chemical-induced carcinogenesis in rodents. These are just a few examples of much larger scientific contributions with a global impact.
IARC
Our pathologists have been invited to contribute to the IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans from substances of public health concern in Lyon, France. NTP pathologists have served as members or chairs of the IARC Monograph Animal Carcinogenesis Working Subgroup. The monographs are a series of publications that identify environmental factors that can increase the risk of human cancer. Health agencies from around the world use information from the monographs to support their actions to prevent exposure to potential carcinogens.
NTP Satellite Symposium and International Outreach
The NTP Satellite Symposium, attended by pathologists from around the world, is a 1-day meeting that is held in conjunction with the annual Society of Toxicologic Pathology meeting and is organized and chaired by an NTP pathologist. This symposium began in 2000 and now has a yearly theme of “Pathology Potpourri,” allowing for the presentation of a variety of topics, lesions, and organ systems. The main objective of this symposium is to provide continuing education on interpreting histopathology slides or other challenging toxicologic pathology–related issues. Both anatomic and clinical pathology issues are discussed, and the presentation has expanded to include topics such as medical devices, embryos, and quantitative pathology. The session is interactive in that each speaker presents images for audience voting via wireless keypads. Once the votes are tallied, the results are displayed for all to view. The speaker generally provides a preferred diagnosis and additional background information, after which lively and constructive discussion ensues. The proceedings of the meeting are published in the annual symposium issue of
Toxicologic Pathology Journal
An NTP pathologist has had the privilege of serving as the editor in chief for the
White Papers, Position Papers, Review Papers, Books
NTP pathologists have published high-impact manuscripts that have influenced toxicologic pathology worldwide. These manuscripts include papers reviewing the histology of organ systems, enhanced immunopathology, vaginal cytology, timely topics in pathology, and pathology methods. Additionally, the NTP has published several atlases of normal embryonic and early postnatal organ system development. Recently, NTP/NIEHS pathologists have edited a revised edition of the text
Postdoctoral and Undergraduate Training Programs in Toxicologic Pathology/LAM
The NTP offers a unique training program in toxicologic pathology that has been training toxicologic pathologists for over 25 years. The program is designed for the intensive training of veterinary postdoctoral fellows (anatomic and clinical pathology). Postdoctoral fellows learn rodent and toxicologic pathology, participate in NTP and other NIEHS research projects, and have the opportunity to pursue a PhD from North Carolina State University College of Veterinary Medicine, University of North Carolina at Chapel Hill, or other schools by arrangement. In 2003, the programs were formally established and there have been 17 pathology postdoctoral trainees, with all becoming certified by the American College of Veterinary Pathologists (ACVP). Trainees have accepted permanent positions at NIEHS, contract research organizations, academia, Food and Drug Administration (FDA), pharmaceutical companies, or biotech companies.
The NTP also offers training for, and collaboration with, visiting scientists from around the world and provides research experiences for veterinary student externs. Over 70 veterinary students and 12 visiting scientists have participated in the program.
The postdoctoral fellowship program in LAM, established in 2006, is designed to give veterinarians training in LAM, as it relates to toxicologic studies conducted by the NTP and research conducted by the Division of Intramural Research. The training and mentored research experience allows the fellow to meet the eligibility requirements for the American College of Laboratory Animal Medicine (ACLAM) certifying examination. The program has been highly successful with all trainees passing the ACLAM exam during their last year of the program. The NTP has also hosted a number of undergraduate and veterinary students and veterinarians interested in pursuing the specialty field of LAM.
The NTP Molecular Pathology group also offers research training for postdoctoral fellows, postbaccalaureate fellows, and summer research internships for high school, undergraduate, and graduate students. The NTP has also hosted sabbatical research programs for several international scientists from various countries such as China, India, Italy, and Japan.
STP and ACVP Contributions
NTP pathologists make impacts at national and global levels through extensive participation in the ACVP and the STP. Notably, the NTP is home to pathologists who have been elected to serve on the executive committees as councilors and past presidents of both organizations. Also, NTP pathologists contribute by serving on or chairing committees including the ACVP/STP Coalition for Veterinary Pathology Fellow Board of Governors as well as the STP Annual Symposium Committee, Awards Committee, Career Development and Outreach Committee, Education Committee, and the Joint Education Based Committee. They have also served as session chairs or cochairs at ACVP and STP annual meetings. NTP pathologists participate in STP special interest groups such as Digital Pathology and Image Analysis, Environmental Toxicologic Pathology, Immune System, Juvenile Pathology, Neuropathology, and Reproductive Pathology.
Additional NTP/NIEHS Global Contributions
NTP pathologists are also involved in the organization and presentation of biennial Research Triangle Park Rodent Pathology Courses featuring topics of current importance in the toxicologic pathology community. These meetings showcase local pathology talent but also include international experts. The course attracts local, national, and international scientists and pathologists (approximately 150 attendees per course). In addition, NTP pathologists have been invited to serve on FDA advisory panels and on a National Oceanic and Atmospheric Administration panel regarding the environmental effects of the Gulf Oil spill on dolphins. NTP pathologists have also been internationally recognized for their efforts as fellows of the International Academy of Toxicologic Pathology.
Footnotes
Authors’ Note
References for each section can be found in Supplementary Table 1.
Acknowledgments
This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences.
Author Contribution
All authors (SE, RS, AB, MC, SC, MCC, DD, MD, GF, RH, RK, KJ, AK, DM, AP, GT, CW) contributed to conception or design; data acquisition, analysis, or interpretation; drafting the manuscript; and critically revising the manuscript. All authors gave final approval and agreed to be accountable for all aspects of work in ensuring that questions relating to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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