Use of Historical Control Data in Carcinogenicity Studies in Rodents

Abstract

This paper considers the use of historical control data in the evaluation of tumor incidences from carcinogenicity studies in rodents. Although the most appropriate control group for interpretative purposes is always the concurrent control, there are instances in which the use of historical control information can aid an investigator in the overall evaluation of tumor incidence data. One example is rare tumors; another is a tumor that shows a marginally significant result relative to concurrent controls. However, before historical control data can be used in a formal testing framework, a number of important issues must first be considered. The nomenclature conventions and diagnostic criteria for each study should be identical to insure unambiguous identification of all relevant tumors in the historical control database. Criteria should be established that will aid in determining whether a particular study should be included in the database. This will assure a homogeneous set of studies upon which to base statistical comparisons. Since study-to-study variability in tumor rates may exceed what would be expected by chance alone, these sources of variability should be identified and controlled. Finally, statistical procedures should be employed that adjust for extra-binomial variability. This paper also summarizes tumor incidence data from untreated Fischer 344 rats and B6C3F1 mice in the National Toxicology Program (NTP) historical control database. All studies in the database are of two years duration, and all neoplasms occurring with a frequency of 0.5% or more are reported.

Characteristics of the Spectrum of Proliferative Lesions Observed in the Kidney and Urinary Bladder of Fischer 344 Rats and B6C3F1 Mice

“…The National Toxicology Program/National Institute of Environmental Health Sciences (NTP/NIEHS) maintains a computerized data bank, the Toxicology Data Management System (TDMS), comprised of tumor incidences compiled from the NTP's 2-year carcinogenesis studies. The TDMS incorporates 5 to 7 years' worth of data from peer-reviewed studies in which Fischer 344/N (F344) rats or B6C3F 1 mice were utilized (6)(7)(8).…”

Response to the Waalkes et al., Letter to the editor concerning our “letter to the editor, Re: Lung tumors in mice induced by “whole-life” inorganic arsenic exposure at human relevant doses, Waalkes et al., Arch Toxicol, 2014”

“…Historical control data are routinely used by regulatory agencies in the assessment of chronic toxicity and carcinogenicity data. For example, according to the FDA (2001): "Historical control data can also be used as a quality control mechanism for a carcinogenicity experiment by assessing the reasonableness of the spontaneous tumor rates in the concurrent control group (Haseman 1984;Haseman et al 1984) and for evaluation of disparate findings in dual concurrent controls." The use of historical control data, particularly from the same laboratory, is a well-established method used by regulatory agencies and the National Toxicology Program (NTP) for understanding how an animal model performs and for preventing the overinterpretation of results (Keenan et al 2009).…”

Morphology of Neoplastic Lesions Induced by 1,3-Butadiene in B6C3F 1 Mice

“…Although other ovarian tumors (benign mixed adenoma, adenoma) were also noted, their incidences were low. Generally, in control B6C3F1 mice granulosa cell tumors are the third most commonly encountered ovarian tumors (20) and they are expected to be seen in less than 0.5% of control mice (9).…”

“…Since brain tumors are rare in mice (9), it was suggested that this may represent a treatment-related effect, especially since these lesions were seen in mice 66 weeks old or less. In the second 1,3-butadiene study, a few brain tumors were also found.…”

“…There were early induction and significantly increased incidences of malignant lymphomas, cardiac hemangiosarcomas, alveolar/bronchiolar neoplasms, and squamous cell neoplasms of the forestomach in males and females and adenocarcinomas of the mammary gland, granulosa cell tumors ofthe ovary, and hepatocellular tumors in female mice (7,8). Brain tumors and preputial gland carcinomas in male mice and Zymbal gland carcinomas in both sexes of mice were seen at low incidences but, because of their rare occurrence in untreated mice, they were suggested to have been possibly related to treatment (7)(8)(9).…”