Appropriateness of Methods for Slide Evaluation in the Practice of Toxicologic Pathology

In the history of safety assessment, the issue of blind review of histologic slides has surfaced on several occasions. Four years ago in this Journal, Morris A. Weinberger (ToxicoJ. PathoJ. 7: 14-17, 1979) very aptly reviewed the subject. His conclusions, which reflected the views of the overwhelming majority of practicing toxicologic pathologists, were that the advantages of the blind review were ". insufficiently well-known or defined to offset the formidable array of disadvantages and therefore the method should not be routinely employed in histopathology examinations that are part of toxicity studies. " What constitutes a blind review? It seems that pathologists should answer this question without hesitation. In practical terms, it is the review of histoIogic slides from toxicity studies by the pathologist without prior knowledge of the study dose groups. Any other information such as species, strain, sex, and age should be known to the reviewing pathologist. It appears that pathologists should refresh their memory in finding advantages for supporting a blind review. The only advantage seems to be that by not knowing the dose groups, the study is reduced into one large group, thus removing observer bias. Such a premise would be important if safety assessment was a rather simple process; unfortunately, it is not. In addition, the strengths of a blind review are obvious when the changes to be evaluated or corroborated are subtle. But, what are the major disadvantages? First, the blind review misses all subtle changes, which are only detectable by comparing the study controls (and also the historic controls) to the highest dose group first and then to the other dose groups as is the case in the standard, open review. Second, no quantitation of histopathologic changes can be performed with a blind review. Such quantitation requires an awareness of the full range or severity of changes throughout all dose groups, especially the control range. Third, proper diagnosis requires knowledge of treatment-related clinical, laboratory, and pathologic data from animals in the study; these data cannot be made available to a reviewer on a blind basis. Consequently, no clinicopathologic correlation takes place, a process which is extremely important and fundamental to accurate diagnostic pathology. In the world of science, i t is customary for a given discipline to determine which approaches and methods are appropriate in answering questions from various areas of research. Pathology in the framework of toxicology and safety assessment is a distinct and fundamental discipline. In many ways, when compared to other biologic disciplines, it tends to be more subjective than others. Perhaps this relative subjectivity has led some nonpathologists involved in the safety assessment process to think that, just as with clinical investigators, a bias based on this subjectivity exists. In the opinion of pathologists. it is exactly this subjectivity that conceivably minimizes bias in the process of interpreting tissue changes. In pathologic evaluations the more that is known about a collection of cases, a group of diagnoses, associated events, or concurrent laboratory findings, the better can be explained what happened. This is true for pathologists who are integrators in toxicology. These specialists put the various pieces of the puzzle together. Accepting the diametrically opposite route of blind review is like refusing vital information, with grave consequences, such as inaccurate diagnosis, and thus failing to gather key elements to establish human risk. This does not mean, of course, that there is no bias in the review of histology slides in safety assessment studies. The most important bias is based on the use of different diagnostic terms. This bias is limited in scope and can be remedied by means of the explanation of terms used. It has always worked in the past (despite the myth that where there are two pathologists you may have three diagnoses). Another bias is the difference in educational background and experience of practicing toxicologic pathologists. Unfortunately, this bias will always exist in a population of professionals trained in different universities and originating in many countries. Some bias is generated by differences in the amount of information at the pathologist's disposal about a given change,