Commentary: Roles for Pathologists in a High-throughput Image Analysis Team.

Historically, pathologists perform manual evaluation of H&E- or immunohistochemically-stained slides, which can be subjective, inconsistent, and, at best, semiquantitative. As the complexity of staining and demand for increased precision of manual evaluation increase, the pathologist's assessment will include automated analyses (i.e., "digital pathology") to increase the accuracy, efficiency, and speed of diagnosis and hypothesis testing and as an important biomedical research and diagnostic tool. This commentary introduces the many roles for pathologists in designing and conducting high-throughput digital image analysis. Pathology review is central to the entire course of a digital pathology study, including experimental design, sample quality verification, specimen annotation, analytical algorithm development, and report preparation. The pathologist performs these roles by reviewing work undertaken by technicians and scientists with training and expertise in image analysis instruments and software. These roles require regular, face-to-face interactions between team members and the lead pathologist. Traditional pathology training is suitable preparation for entry-level participation on image analysis teams. The future of pathology is very exciting, with the expanding utilization of digital image analysis set to expand pathology roles in research and drug development with increasing and new career opportunities for pathologists.

Regulatory forum opinion piece: obligatory microscopic examination of intermediate dose groups in non-rodent toxicity studies--is it necessary?

In non-rodent toxicity studies supporting pharmaceutical or chemical product registration, the value of histopathology evaluation of all tissues from all animals from all dose groups is an ongoing discussion topic among pathologists. This manuscript documents an examination of this topic through a retrospective review of internal nonclinical study data from non-rodent toxicity studies performed at three pharmaceutical companies (Abbott Laboratories, Eli Lilly, and Pfizer, Inc.) and an informal survey of the current practices within the toxicological pathology community. The retrospective review of 325 non-rodent studies in which all organs in all dose groups were examined revealed no evidence that risk assessment would have changed if only the control and high-dose animals and target organs only in intermediate dose groups had been examined. One study had target tissues in a lower-dose group that were not identified in the high-dose group; however, there was no impact on the overall study interpretation. The recently revised European Medicines Agency guideline regarding repeated-dose toxicity studies encourages the examination of all tissues at all dose levels in non-rodent studies. In conclusion, the evaluation of all tissues from all animals may not be justified as a routine practice; however, regulatory guidance with input from toxicologic pathologists will influence these policy decisions.

An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: support for a proposal to modify current regulatory guidelines.

Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.

Revised guides for organ sampling and trimming in rats and mice--part 1.

This is the first part of a series of three articles on trimming instructions of rat and mouse protocol organs and tissues in regulatory type toxicity studies. It is based on the experience made in the European RITA and American NACAD working groups and is an extended revision of trimming guides published in 1995 (Bahnemann et al.). The optimum localization for tissue preparation, the sample size, the direction of sectioning and the number of sections to be prepared is described organ by organ. These descriptions are illustrated for each organ by a schematic drawing and a macro-photograph showing the plane of section as well as a low power view of the H&E stained slide demonstrating the optimum "end-product". This revision will improve the quality and efficiency of routine procedures and facilitate daily work in the histotechnical lab. It will promote intra- and inter-study reproducibility and comparability and thus lead to a further coherence within each study and improvement of the validity of historical control data.

The north american control animal database: a resource based on standardized nomenclature and diagnostic criteria.

Historical control data have been shown to be valuable in the interpretation and evaluation of results from rodent carcinogenicity studies. Standardization of terminology and histopathology procedures is a prerequisite for meaningful comparison of control data across studies and analysis of potential carcinogenic effects. Standardization is particularly critical for the construction of a database that includes incidence data from different studies evaluated by pathologists in different laboratories. Standardized nomenclature and diagnostic criteria have been established for neoplasms and proliferative lesions. Efforts of the National Toxicology Program, the Society of Toxicologic Pathology (STP), and the Registry of Industrial Toxicology Animal-data (RITA) have led to a harmonized pathology nomenclature for the rat and the mouse. This nomenclature with detailed descriptions of lesions is available in publications by the STP and International Agency for Research on Cancer (IARC). A listing of these terms is available on the World Wide Web. Utilizing the model established by RITA and working with the International Life Sciences Institute (ILSI), companies with laboratories in North America formed a working group in 1994 to establish and maintain a database of neoplastic and proliferative lesions from control animals in carcinogenicity studies. The rationale for development of the North American Control Animal Database (NACAD), the factors that influence tumor incidence, operation of the database, and the benefits to be realized by using a standardized approach are discussed.