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Peto test procedures for the statistical evaluation of carcinogenicity studies require that each tumor in an animal that died intercurrently (or was sacrificed in extremis) be classified as either fatal, probably fatal, incidental, or probably incidental. There is considerable controversy as to whether or not the cause of death can be established with accuracy in rodent studies. In the present article, the causes of death or ill-being as found in 10 consecutive carcinogenicity studies--5 studies with 2400 OFA (Sprague-Dawley-derived) and Wistar rats and 5 studies with 2400 OF1 and NMRI mice--were re-examined. A cause of death or moribund state had been established in more than 80% of the cases in rats and in more than 70% in mice. These causes were, in rats, mainly pituitary tumors, chronic progressive nephropathy (males), mammary gland tumors (females), and subcutaneous tumors (males); in mice, mainly hemolymphoreticular tumors, lung tumors, liver tumors (males), and glomerulonephropathy. The criteria used for determining the tumorous or non-tumorous lesions as the cause of death were based on in-life and pathological findings. The validity of such procedures, the possibility of improving criteria in the future, and the usefulness of establishing causes of death in safety assessment are discussed.

To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions.

Recent international summits of the International Federation of Societies of Toxicologic Pathologists have debated the desirability and potential means by which the proficiency of an individual toxicologic pathologist might be recognized and communicated throughout the world. The present article describes the advantages and disadvantages of implementing such a global recognition system by any means and provides a proposal whereby recognition might be accorded via rigorous credential review of a practitioner's education and experience.

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Although there are a few national schemes for accreditation/certification of toxicologic pathologists (e.g., in Japan and the United Kingdom), a global recognition system for bench toxicologic pathologists is missing, as are universal standards defining their core competencies. This paper summarizes basic means regarding how proficiency in toxicologic pathology is acquired, provides an overview over examinations of interest to toxicologic pathologists, and emphasizes the value of practical experience in the field. The paper then discusses basic approaches to evaluate the proficiency of toxicologic pathologists and examines potential means to recognize qualified toxicologic pathologists. With progressive globalization, it is important that the toxicologic pathology community deepens the discussion regarding a global recognition mechanism for their discipline.

Toxicology is and will be heavily influenced by advances in many scientific disciplines. For toxicologic pathology, particularly relevant are the increasing array of molecular methods providing deeper insights into toxicity pathways, in vivo imaging techniques visualizing toxicodynamics and more powerful computers anticipated to allow (partly) automated morphological diagnoses. It appears unlikely that, in a foreseeable future, animal studies can be replaced by in silico and in vitro studies or longer term in vivo studies by investigations of biomarkers including toxicogenomics of shorter term studies, though the importance of such approaches will continue to increase. In addition to changes based on scientific progress, the work of toxicopathologists is and will be affected by social and financial factors, among them stagnating budgets, globalization, and outsourcing. The number of toxicopathologists in North America, Europe, and the Far East is not expected to grow. Many toxicopathologists will likely spend less time at the microscope but will be more heavily involved in early research activities, imaging, and as generalists with a broad biological understanding in evaluation and management of toxicity. Toxicologic pathology will remain important and is indispensable for validation of new methods, quality assurance of established methods, and for areas without good alternative methods.