Abstract:
:Statistical issues related to the design, analysis and interpretation of carcinogenicity studies are considered. A proposed modification of the "standard" National Cancer Institute (NCI) design of carcinogenicity studies in rodents is discussed. The primary objective was to obtain a design that maintained the power of the NCI design for detecting carcinogenic effects, while increasing the precision with which the underlying dose-response model could be estimated. "Optimum" three-dose designs are presented and discussed. Data analysis issues are also considered. Comparisons of tumor incidence should include adjustments for survival differences, and, if possible, cause of death determinations should be made for each individual animal. In some instances historical control data can aid an investigator in the overall evaluation of experimental results. Several important problems are discussed that must be overcome before historical control data can be used in a meaningful way. One critical issue in the interpretation of tumor incidence data is the issue of false positives. Data from 25 recent long term feeding studies are used to derive a statistical decision rule that closely approximates the scientific judgment process used in these studies. The overall false positive rate associated with this decision rule was found to be no more than 7-8%.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Haseman JKdoi
10.1177/019262338301100113subject
Has Abstractpub_date
1983-01-01 00:00:00pages
77-82issue
1eissn
0192-6233issn
1533-1601journal_volume
11pub_type
杂志文章abstract::This report describes the findings of preclinical testing of SCH 351591, a selective phosphodiesterase 4 inhibitor, in CD-1 mice over a wide range of doses, in which the heart and reproductive organs of both sexes demonstrated toxic effects. Repeat-dose toxicity studies assessed 5, 15, 50, 100, 200, 400, and 800 mg/kg...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623310370463
更新日期:2010-06-01 00:00:00
abstract::Although arsenic exposure causes liver disease and/or hepatoma, little is known about molecular mechanisms of arsenic-induced liver toxicity or carcinogenesis. We investigated the effects of arsenic on expression of cancer-related genes in a rat liver following subchronic exposure to sodium arsenate (1, 10, 100 ppm in...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/01926230490261348
更新日期:2004-01-01 00:00:00
abstract::Progressive renal interstitial fibrosis occurs following tissue injury, resulting in chronic renal failure. In the fibrogenesis, macrophages are speculated to induce myofibroblasts producing matrix protein. The kinetics of these cells in renal fibrosis induced in rats by repeated injection of cisplatin (CDDP) (2 mg/kg...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339602400208
更新日期:1996-03-01 00:00:00
abstract::The microbiome is increasingly recognized as a critical component in human development, health, and disease. Its relevance to toxicology and pharmacology involves challenges to current concepts related to absorption, metabolism, gene:environment, and pathways of response. Framing testable hypotheses for experimental a...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623316672073
更新日期:2017-01-01 00:00:00
abstract::The relatively high incidence and variety of lesions induced in the upper respiratory tract of rodents by inhalation of xenobiotics has resulted in considerable attention given to the microscopic anatomy of this area. Specific areas of the rodent laryngeal mucosa appear to be more sensitive to inhaled materials and mo...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339202000106
更新日期:1992-01-01 00:00:00
abstract::Lung cancer is the most common cause of cancer-related deaths in humans worldwide. There is strong evidence that the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) play an important role in carcinogenesis caused ...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623317751573
更新日期:2018-02-01 00:00:00
abstract::Peroxisome proliferator-activated receptor gamma (PPARγ) agonists and PPARγ/α dual agonists are used in the treatment of type 2 diabetes mellitus and hyperlipidemias. In carcinogenicity studies, some of these agonists induced hemangiomas/hemangiosarcomas in mice, but not in rats. We hypothesized that increased endothe...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623311422080
更新日期:2011-12-01 00:00:00
abstract::One of the major roles for the toxicologic pathologists now and into the future will be to determine the biologic significance of chemically induced biochemical and molecular alterations detected in whole tissue homogenates or cell cultures. The biologically significant effects will then require further analysis to de...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/019262301301418973
更新日期:2001-01-01 00:00:00
abstract::Carbonyl sulfide (COS) is an odorless gas that produces highly reproducible lesions in the central nervous system. In the present study, the time course for the development of the neurotoxicological lesions was defined and the gene expression changes occurring in the posterior colliculus upon exposure to COS were char...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623309335631
更新日期:2009-06-01 00:00:00
abstract::Chronic ingestion of arsenic is associated with increased incidence of respiratory and cardiovascular diseases. To investigate the role of arsenic in early events in vascular pathology, C57BL/6 mice ingested drinking water with or without 50 ppb sodium arsenite (AsIII) for four, five, or eight weeks. At five and eight...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623308323919
更新日期:2008-10-01 00:00:00
abstract::The 2015 Annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri" was held in Minneapolis, Minnesota, at the American College of Veterinary Pathologists/American Society for Veterinary Clinical Pathology/Society of Toxicologic Pathology combined meeting. The goal of this symposium is to p...
journal_title:Toxicologic pathology
pub_type:
doi:10.1177/0192623316631844
更新日期:2016-06-01 00:00:00
abstract::A compendium of carcinogenesis bioassay results organized by target organ is presented for 738 chemicals that are carcinogenic in chronic-exposure, long-term bioassays in at least 1 species. This compendium is based primarily on experiments in rats or mice; results in hamsters, monkeys, and dogs are also reported. The...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1080/019262301753385979
更新日期:2001-11-01 00:00:00
abstract::When chemicals that are nongenotoxic in conventional assays produce increases in tumor incidence in rodents in chronic bioassays, the determination of the significance of these data for human safety is a challenging task. An important first step in this process is consideration of available data on the mechanism of ac...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/019262339402200206
更新日期:1994-03-01 00:00:00
abstract::Existing liver perfusion models are largely limited by high degrees of ischemic and reperfusion injury and the lack of standardization. To establish a highly standardized perfusion model and minimize reperfusion injury, a porcine liver perfusion model was developed using an artificial heart pump (Buecherl Artificial H...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/01926230590958164
更新日期:2005-01-01 00:00:00
abstract::Mer proto-oncogene tyrosine kinase (MerTK), which is expressed in the retinal pigment epithelium (RPE), regulates phagocytosis of shed photoreceptor outer segments (POS). To investigate the effects of drug-induced MerTK inhibition on the retina, UNC569, a specific MerTK inhibitor, was orally administered to male mice ...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623317749469
更新日期:2018-02-01 00:00:00
abstract::Phosphatidylinositol 3-kinases (PI3Ks) regulate intracellular signaling events for multiple cell surface receptors. Phosphatidylinositol 3-kinase δ, 1 of 4 class I PI3K isoforms, is primarily found in leukocytes and regulates immune cell functions. Here, we report changes in the immune and digestive systems that were ...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623320966238
更新日期:2020-12-01 00:00:00
abstract::A number of factors related to study design have the potential to impact clinical pathology test results during the conduct of nonclinical safety studies. A thorough understanding of these factors is paramount in drawing accurate conclusions from clinical pathology data generated during such studies, particularly when...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623316677066
更新日期:2017-02-01 00:00:00
abstract::The title of the 2016 Society of Toxicologic Pathology (STP) Symposium was the "Basis and Relevance of Variation in Toxicologic Responses." Many factors may contribute to variation in toxicologic responses and can confound results, complicate interpretation of data, interfere with reproducibility, and make extrapolati...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623316675765
更新日期:2017-01-01 00:00:00
abstract::We investigated, morphologically and immunohistochemically, 74 medullary adrenal tumors, including 64 pheochromocytomas (14 malignant and 50 benign), 9 ganglioneuromas, and 1 malignant schwannoma. The tumors were detected in 2-year-old Wistar and Sprague-Dawley rats from carcinogenicity studies. Morphologically, benig...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/01926230290105668
更新日期:2002-07-01 00:00:00
abstract::Phentolamine is a reversible competitive alpha-adrenergic antagonist with similar affinities for alphal and alpha2 receptors. It has a long history of safe clinical use, and was developed as a potential therapy for male erectile dysfunction because of its capacity to increase the arteriolar blood flow to the corpora c...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/01926230490505086
更新日期:2004-09-01 00:00:00
abstract::Neurotoxicants with similar structural features or common mechanisms of chemical action frequently produce widely divergent neuropathologic outcomes. Methylmercury (MeHg) produces marked cerebellar dysmorphogenesis during critical periods of development. The pathologic picture is characterized by complete architectura...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/019262330002800107
更新日期:2000-01-01 00:00:00
abstract::The target organ specificities of cell proliferation and histopathological lesion induction by 5 carcinogens having different target organs were evaluated using a multiorgan carcinogenesis bioassay. In Group 1, male F-344 rats aged 6 wk were sequentially treated with N-diethylnitrosamine (DEN, single 100-mg/kg ip inje...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339302100502
更新日期:1993-09-01 00:00:00
abstract::Many antisense oligonucleotides (ASOs) from several classes of molecules are currently in drug development. Despite over 20 years of pharmaceutical research, few ASOs have been marketed due to problems with clinical efficacy or preclinical toxicologic challenges. However, a number of recent developments have renewed i...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623314551840
更新日期:2015-01-01 00:00:00
abstract::The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak that started in Wuhan, China, in 2019 resulted in a pandemic not seen for a century, and there is an urgent need to develop safe and efficacious vaccines. The scientific community has made tremendous efforts to understand the disease, and unpara...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623320959090
更新日期:2020-10-01 00:00:00
abstract::Hyaline droplet formation in the proximal tubular cells of the kidney commonly occurs under different pathological conditions in experimental animals. In rats, intracytoplasmic hyaline droplet formation is predominantly associated with accumulation of the male rat-specific alpha(2u)-globulin, whereas under other (path...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/01926230390213775
更新日期:2003-07-01 00:00:00
abstract::Toxicokinetic (TK) studies are the basis for demonstrating dose-related drug exposure in animals and for ensuring that drug exposure is substantially greater in animals than that expected in humans at therapeutic doses. The usefulness of TK studies can be further enhanced by correlating TK parameters with relevant tox...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/019262339502300209
更新日期:1995-03-01 00:00:00
abstract::Age-related changes in gross and microscopic structure of the nasal cavity may alter local tissue susceptibility as well as the dose of inhaled toxicant delivered to susceptible sites. This article describes a novel method for the use of magnetic resonance imaging, 3-dimensional airway modeling, and morphometric techn...
journal_title:Toxicologic pathology
pub_type: 杂志文章,多中心研究
doi:10.1080/01926230601072343
更新日期:2007-01-01 00:00:00
abstract::Documentation of Chinese materia medica (CMM) dates back to around 1,100 BC when only dozens of drugs were first described. By the end of the 16th century, the number of drugs documented had reached close to 1,900. And by the end of the last century, published records of CMM have reached 12,800 drugs. The recorded tra...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1080/01926230600773958
更新日期:2006-01-01 00:00:00
abstract::A factor limiting widespread use of the transgenic rasH2 mouse model for carcinogenicity testing of pharmaceuticals is the paucity of published data on actual drug candidates in rasH2 mice. This report addresses this gap by highlighting rasH2 mouse study data for 10 pharmaceutical candidates. These results were compar...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623313477257
更新日期:2013-01-01 00:00:00
abstract::Parenteral administration of recombinant hematopoietic growth factors has been sporadically associated with cutaneous complications, including injection site reactions in humans and nonhuman primates. In this study, subcutaneous injection sites were evaluated from 12 cynomolgus monkeys administered a recombinant human...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339602400401
更新日期:1996-07-01 00:00:00