Abstract
A vision for the future should build on the past and recognize where we are today while opening the door to a new era. The biological sciences are in the throes of exponential growth in the volume of publications, in the tools for enabling deeper understandings and in the knowledge of disease and injury processes. Today, toxicologic pathology represents a primary discipline responsible for hazard identification and safety assessment of xenobiotics in research and development. The modern toxicologic pathologist has mastered the ability to define the molecular and cellular events that arise in animal tissues in response to xenobiotic injury and to leverage this knowledge in risk assessment. The evaluation of tissues from Good Laboratory Practice (GLP)-compliant toxicology studies represents a cornerstone of pathologists’ contributions. However, the field of toxicologic pathology faces several challenges to its continued growth: the potential lowering of international standards, a need for increased specialization, and a need to integrate new and more advanced technologies.
Anatomic pathology diagnoses are increasingly seen as a commodity, and commodities can be supplied by the lowest bidder. Indeed, major companies are currently outsourcing and “off-shoring” GLP-compliant toxicology studies, including the pathology component. Thus, high international standards must be established and maintained for toxicologic pathology practice. The very high standards of North America and Europe are by no means universal and have largely been driven by individuals trained and certified through the American College of Veterinary Pathologists (ACVP), and more recently, through the European College of Veterinary Pathologists and the United Kingdom’s Royal College of Pathologists. The expectation for board certification can be traced to the implementation of the GLP regulations in 1978 (Code of Federal Regulations 21, part 58), prior to which an initial draft for public comment called for slide evaluation to be conducted by diplomates of the ACVP. Although industry leaders at the time complained that there simply were not enough certified persons to meet the need, all of the major companies immediately moved to hire board-certified veterinary pathologists. However, the final regulation required only “sufficient education, training, and experience to enable the individual to perform the assigned function.” Nevertheless, because of that early draft document, and to their credit, industry managers perpetuated the practice of requiring board certification. These rigorous board certification processes need to be supported worldwide to avoid any degradation of the high standards we enjoy today.
In the last decade, Janet Woodcock, Deputy Commissioner at the United States Food and Drug Administration (FDA), called the toxicologic sciences the least changing discipline involved in research and development, despite the dramatic increases in knowledge in the biological sciences. Toxicology functions from a few major companies have arguably been the most resistant to using this new knowledge to change their testing paradigms. In the future, microscopic morphologic diagnoses in the chosen toxicology species must be considered the minimum expectation, and further specialization is imperative.
Over the longer term, a strategy for reinvention and renewal is needed in toxicologic pathology. This reinvention will depend on the expansion of the pathologist’s “tool kit,” as well as his or her adaptability and willingness to accept personal risk. Pathologists should be prepared to deal with digital imaging and the use of genomics and proteomics for diagnostic purposes and for refinement of risk assessment. The toxicologic pathologist of the future will not just be an expert in morphologic disease processes through the microscopic examination of animal tissues, but also a molecular pathway analyst, an image analyst, and an ex vivo (or in vitro) diagnostician. He or she will need to be able to confidently apply his or her knowledge and to lead colleagues’ understanding of the diverse toxicology skill sets, so that they understand and embrace his or her judgment in the extrapolation of data in risk assessment.
We are at a transformational point in toxicology testing, hazard identification, and risk assessment. Toxicologic pathologists should play a lead role in adapting testing paradigms to take advantage of technological advances. As an example, consider the traditional carcinogenicity tests that have now been conducted on thousands of molecules. The increased understanding obtained from these studies should eventually allow a gradual phase-out of now standard lifetime carcinogenicity bioassays. These consume hundreds of animals, years of time, and millions of dollars, yet still have a significant incidence of false-negative responses as well as an embarrassingly high rate of false-positives. This creates public distrust and could result in the dismissal of the results of these tests.
In this example, the biologic effects of carcinogenic pharmaceuticals fit into one or more of four fairly well-defined categories: immunosuppression, hormonal perturbation, genetic injury, and chronic tissue injury. It is clear that the lifetime rodent carcinogenicity study may not be designed to identify these biological risk factors. This is certainly true in the case of the well-known link between immunosuppression and human carcinogenesis, which does not model well, if at all, in classical rat and mouse carcinogenicity studies.
It must be incumbent on toxicologic pathologists to lead, drive, and define the pathways to improve these current toxicology testing paradigms and avoid the technological obsolescence that is implicit in inactivity. Improved predictive precision will improve confidence and increase acceptance of decisions with a heightened impact of toxicologic pathologists in safety assessment of new molecular entities.
The chemical industry, and its regulatory counterpart, have recently been called upon to test the vast array of untested products already on the market; on top of this, they face increasingly strong activism to prevent new molecular entities from commercialization. The regulatory authorities and industries linked with the many thousands of untested commercial chemicals (which are in large part essential to the standard of living we enjoy today) will require considerably more robust and higher throughput test systems than those that currently exist. Additionally, providing an in-depth assessment of currently well-characterized and -marketed, widely used, and beneficial products also presents an opportunity to apply innovative toxicology/pathology skill sets in refining the assessment of the risks in these entities.
In pharmaceutical research and development, toxicologic pathologists today are presented with an unprecedented opportunity to discover and enhance our understanding of molecular mechanisms of tissue injury. Advances in the chemical and biological sciences now enable much more specific and selective intervention in molecular response networks of interest in biology. Molecular targets in disease conditions are often selected and moved into research and development long before the precise role of the target in normal tissues has been defined. With increasing frequency, previously unknown biological and pathological responses occur because of highly selective and specific abrogation of molecular pathway targets of interest. Synthetic and medicinal chemists have an unprecedented understanding of molecular structures linked with chemical tissue reactivity, independent of the intended biologic activity; thus chemical reactivity findings, which are unrelated to the proposed pharmacologic activity of the chemical, will hopefully be relegated to the archives.
To contribute to the unraveling of xenobiotic-induced injury processes, the toxicologic pathologist must embrace and expand his or her mastery in the application of the new technologies that are almost monthly becoming available. None of the newer approaches, including toxicogenomics, toxicoproteomics, metabonomics, ex vivo and in vitro assays, and in silico structure-activity relationship (SAR) methods, will be a stand-alone solution for our safety assessment needs. Each will instead find its place as a component of a larger, multidisciplinary system, providing complementary information supporting almost continually evolving methods of whole-animal and alternative testing procedures. The whole will truly be greater than the sum of its parts!
Substantial progress is being made in defining the complex interactions of genes, proteins, and other molecules (eg, cations) that enable cells to adapt or succumb to potentially injurious influences. Definition of induced responses will allow identification of new biomarkers for cellular damage. These biomarkers, applied initially in animals and ultimately transferred into the clinic, will reduce much of the current uncertainty in predicting clinical outcomes on the basis of nonclinical testing.
The successful toxicologic pathology technologist of the future will be able to leverage and integrate diverse technologies to probe more deeply into a disease or tissue injury process and provide guidance in applying this knowledge for the betterment of mankind. The opportunities to reduce human suffering are daunting, with over one million people a year dying in the United States from cardiovascular disease and cancer. Improved therapeutic options for these patients will be pivotal in achieving this goal. Undoubtedly, novel targets whose normal biological activity remains to be defined will be central in this quest. The discovery of the function of novel targets in normal organs, tissues, and cells today represents the province of the toxicologic pathologist.
These are indeed exciting times for the discovery of new realms of biology. The tools and application of the skill sets embodied in toxicologic pathology, which will enable the rapid expansion of our understanding of biological processes, present the most attractive opportunity in the past fifty years. The future could not be brighter for our discipline if we are willing to grasp the opportunities and embrace the new technologies.