Guide for Combining Primary Tumors for Statistical Analysis in Rodent Carcinogenicity Studies.

The Tumor Combination Guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology, the Food and Drug Administration (FDA), and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, to assist pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer review pathologists in interpreting the tumor data. This guide provides a higher-level hierarchy of tumor types or categories correlating the tumor names from the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) publications with those available in the NEOPLASM controlled terminology (CT) code list in SEND. The version of CT used in a study should be referenced in the nonclinical study data reviewer's guide (SDRG) (section 3.1) of electronic submissions to the FDA. The tumor combination guide instructions and examples are in a tabular format to make informed decisions for combining tumor data for statistical analysis. The strategy for combining tumor types for statistical analysis is based on scientific criteria gleaned from the current scientific literature; as SEND and INHAND terminology and information evolve, this guide will be updated.

Diet and Physical Activity Prevention Research Supported by the U.S. NIH From 2012-2017.

INTRODUCTION: Poor diet and inadequate physical activity are common contributors to preventable death in the U.S. This paper provides a summary of the NIH-sponsored research on disease prevention that underlies public health and clinical recommendations to improve diet and physical activity. METHODS: A representative sample (n=11,082) of research grants and cooperative agreements (research projects) representing the NIH prevention research portfolio between 2012 and 2017 were hand coded by trained analysts in 2017-2018. This manuscript describes the rationale(s), exposure(s), outcome(s), population(s), and study design(s) in prevention research focused on diet and physical activity and compares this research to identified research gaps in the field. RESULTS: A relatively stable 7.8% (95% CI=7.0%, 8.8%) and 5.0% (95% CI=4.4%, 5.7%) of the NIH prevention research projects were focused on diet and physical activity, respectively, during 2012-2017. These projects often explored diet and physical activity together in the context of obesity, included observational studies, and focused on a general adult population. Few of these projects focused on development of improved assessment methods. Approximately 50% of these studies were related to research gaps identified by the 2015 Dietary or 2018 Physical Activity Guidelines Advisory Committee Scientific Reports. CONCLUSIONS: Opportunities exist for more engagement by NIH and scientific investigators in diet- and physical activity-focused prevention research, particularly around assessment and known research gaps.

Dietary supplement research portfolio at the NIH, 2009-2011.

The U.S. dietary supplement market increased by 7.5% in 2012 compared with 2011, reaching $32.5 billion in sales. Therefore, federally supported research on dietary supplements is important to determine their health effects, safety, and efficacy. A portfolio analysis was performed across the NIH and the Office of Dietary Supplements (ODS) for fiscal years (FYs) 2009-2011 by using the databases Human Nutrition Research Information Management (HNRIM) and Computer Access to Research on Dietary Supplements (CARDS). The results indicated that total NIH dietary supplement-related funding for FYs 2009-2011 was $855 million ($295 million in 2009, $311 million in 2010, and $249 million in 2011). The institutes and centers with the highest investment in dietary supplement research were as follows: the National Heart, Lung, and Blood Institute ($135 million); the National Cancer Institute ($188 million); the National Center for Complementary and Alternative Medicine ($99 million); the National Institute of Diabetes and Digestive and Kidney Diseases ($68 million); the National Institute of Environmental Health Sciences ($58 million); and the ODS ($32 million). The dietary supplement ingredients receiving the most funding were botanicals (22%), vitamins (20%), lipids (14%), and minerals and trace elements (10%). The top 3 outcome research areas were cancer (61% of total dietary supplement investment), cardiovascular disease (47%), and women's reproductive health (38%). In FYs 2009, 2010, and 2011, the ODS provided 3.5%, 3.6%, and 4.1%, respectively, of the NIH investment in dietary supplement research. ODS funding focused on cellular, enzymatic, or molecular mechanisms (64% of total ODS funding). This portfolio analysis demonstrates that the NIH has committed substantial funding to dietary supplement research in an effort to expand the scientific knowledge base on the efficacy and safety of dietary supplements.

Renal histopathology in toxicity and carcinogenicity studies with tert-butyl alcohol administered in drinking water to F344 rats: a pathology working group review and re-evaluation.

An independent Pathology Working Group (PWG) re-evaluated the kidney changes in National Toxicology Program (NTP) toxicology/carcinogenicity studies of tert-butyl alcohol (TBA) in F344/N rats to determine possible mode(s) of action underlying renal tubule tumors in male rats at 2-years. In the 13-week study, the PWG confirmed that the normal pattern of round hyaline droplets in proximal convoluted tubules was replaced by angular droplet accumulation, and identified precursors of granular casts in the outer medulla, changes typical of alpha(2u)-globulin (α(2u)-g) nephropathy. In the 2-year study, the PWG confirmed the NTP observation of increased renal tubule tumors in treated male groups. Linear papillary mineralization, another hallmark of the α(2u)-g pathway was present only in treated male rats. Chronic progressive nephropathy (CPN) was exacerbated in high-dose males and females, with a relationship between advanced grades of CPN and renal tumor occurrence. Hyperplasia of the papilla lining was a component of CPN in both sexes, but there was no pelvic urothelial hyperplasia. High-dose females showed no TBA-related nephrotoxicity. The PWG concluded that both α(2u)-g nephropathy and exacerbated CPN modes of action were operative in TBA renal tumorigenicity in male rats, neither of which has relevance for human cancer risk.

NIH and USDA funding of dietary supplement research, 1999-2007.

Over one-half of U.S. adults use dietary supplements, so federally supported research into the safety and effectiveness of these compounds is important for the health of many Americans. Data collected in the Computer Access to Research on Dietary Supplements database, which compiles federally sponsored dietary supplement-related research, are useful to scientists in determining the type of dietary supplement research that federal agencies are currently funding and where research gaps exist. This article describes the dietary supplement-related research funded by the NIH and the USDA. Between fiscal years 1999 and 2007, the number of research projects and funding for dietary supplement research more than doubled. During that period, NIH funded 6748 dietary supplement-related projects at a cost of $1.9 billion and the USDA funded 2258 projects at a cost of $347 million. The top funded dietary supplement ingredient categories were vitamins and minerals, botanicals, phytochemicals, and fatty acids. Cancer was by far the most frequent health outcome in dietary supplement research funding, nearly double the next closest health outcome category. Other health outcomes with the greatest funding were cellular and molecular mechanisms, cardiovascular health, women's reproductive health, and immune function. The greatest number of dietary supplement research projects are funded by the NIH National Cancer Institute, the NIH National Center for Complementary and Alternative Medicine, the NIH Office of Dietary Supplements, and the USDA Agricultural Research Service.

Histopathologic changes in the kidneys of male F344 rats from a 2-year inhalation carcinogenicity study of tetrahydrofuran: a pathology working group review and re-evaluation.

Risk evaluation and hazard classification for tetrahydrofuran (THF) is based partly on the incidences of renal tumors in male F344/N rats reported in a 2-year carcinogenicity study by the National Toxicology Program (NTP). A Pathology Working Group (PWG) was commissioned to conduct an independent review of the kidney slides from this bioassay (along with two subchronic studies) to assess renal changes in light of recent scientific work on pathogenesis of pre-neoplastic and neoplastic lesions in rat kidney. PWG pathologists confirmed the NTP assessment that adenomas were non-statistically increased in animals exposed to the highest level of THF. However, when pre-neoplastic and neoplastic lesions were combined, there was no difference between control and THF-exposed groups. Also, the majority of these proliferative lesions were in rats with severe chronic progressive nephropathy (CPN). Accordingly, the PWG concluded that renal lesions in the control and THF-exposed groups resulted primarily from regenerative processes associated with advanced CPN. Based on an alpha(2u)-globulin/hyaline droplet response observed in a 4-week study with THF, the PWG could not exclude the possibility of both advanced CPN and low-grade alpha2u-g nephropathy contributing to the renal proliferative lesions developing chronically in high-dose males. Neither condition has a pathologic counterpart in humans.

Computer access to research on dietary supplements: a database of federally funded dietary supplement research.

Dietary supplement use is prevalent in the United States, but support for supplement research has been relatively modest and only recently emphasized at the NIH. The Dietary Supplement Health and Education Act of 1994 led to the creation of the Office of Dietary Supplements (ODS) at the NIH to promote research on dietary supplements. In order to track federally funded dietary supplement research, the ODS developed a database known as Computer Access to Research on Dietary Supplements (CARDS). This article provides an overview of the development and potential uses of the CARDS database. In addition, we report that NIH-funded dietary supplement research steadily increased from fiscal year (FY) 1999 through 2002. The majority of NIH institutes or centers (ICs) funded research relevant to dietary supplements during this time, led by the National Cancer Institute and one of the newest NIH ICs, the National Center for Complementary and Alternative Medicine. CARDS data indicate that NIH-funded dietary supplement research from FY 1999 through 2002 involved primarily vitamins, minerals, botanicals and phytochemicals. Cancer and cardiovascular disease, two of the leading causes of morbidity and mortality in the United States, collectively accounted for almost 45% of the research related to dietary supplements. A variety of types of research studies were funded, with the majority consisting of human intervention studies. This information is useful to evaluate trends in federally funded dietary supplement research, identify research gaps, and help research scientists identify potential sources of NIH funding.

Recommended tissue list for histopathologic examination in repeat-dose toxicity and carcinogenicity studies: a proposal of the Society of Toxicologic Pathology (STP).

The Executive Committee of the Society of Toxicologic Pathology (STP) appointed an ad hoc task force to devise and recommend a standard list of tissues to be evaluated histopathologically in repeat-dose toxicity and carcinogenicity studies that are used to support the registration of new pharmaceutical products. The recommended tissue list is intended to be a minimum core list that can be used for all types of repeat-dose toxicity and carcinogenicity studies, regardless of route of administration, species or strain of mammalian laboratory animal, duration, or class of drug to be tested. The resulting recommendations of the task force, presented here, were subsequently reviewed by the STP membership and endorsed by the STP Executive Committee.