Past and Present Proposed Alternative Strategies to Reduce Reliance on the Two-Year Rodent Bioassay
The role of the toxicologic pathology throughout this pre-genomic era was to apply his or her expertise in the morphological characterization of the treatment-related tissue changes, including cancer. This has traditionally involved diagnosis of hematoxylin and eosin-stained tissue sections and integration with in-life and clinical data for overall interpretation at the conclusion of a toxicity or carcinogenicity animal study. Traditional medical and veterinary pathology training programs did not, and most still do not, provide specific training in the type of toxicologic pathology needed to evaluate the various animal toxicity and cancer testing studies. Thus, most of the toxicologic pathology training has occurred “on-the-job.”
Thus, the pre-genomic era can be summarized as a time period when epidemiological links between chemical exposures and human disease and life styles and human disease were identified and scientists began using animal studies to understand disease and predict potential risk for human disease. It was an era when the rodent cancer bioassay was used to identify safety of products already present or soon to be entering commerce. It was also the time when we began to search for alternatives to the resource-intensive 2-year rodent cancer bioassay and then realized that the various initially promising alternatives did not adequately fulfill enough of our hopes for a cost-effective, rapid, and relevant screening procedure to replace two-year rodent cancer studies. We also realized that the various animal studies were sometimes of questionable relevance to human health risk.
The Genomic Era
We are in the genomic era. The dividing line between the pre-genomic and the current genomic eras is not sharp, with carryover from the pre-genomic era. The genomic era started in the early 1990s and its science is progressing at warp speed. It is a time when the genetic underpinnings of normal biological and pathologic processes are being discovered and documented. We have moved beyond oncogenes and tumor suppressor genes to sequencing entire genomes and deliberately silencing relevant segments of that genome to see what each segment controls and if that silencing leads to increased susceptibility to disease. What remains to be charted in this genomic era is the complex interaction of genes, gene segments, post-translational modifications of encoded proteins, and effects of exposure on the epigenome.
Several significant biomedical and toxicological events occurred in the genomic era. In the biomedical arena we have seen the cloning of the sheep, Dolly; establishment of the human genome project and sequencing of the human genome; sequence of the mouse genome; and active research using stem cells. In the toxicological arena use of transgenic mouse bioassays; establishment of the International Conference on Harmonization (ICH); the “omics” revolution accompanied by anticipated excitement that toxicogenomics will lessen our dependence on conventional animal toxicity and carcinogenicity bioassays; high throughput screening of chemicals; and the building of informative databases to ultimately permit knowledge-based predictive toxicology14.
All this effort has created a new breed of researcher, the molecular biologist. The molecular biologist is a new player on the scene bringing the promise that teasing out the molecular underpinnings of toxicity and cancer induction by using molecular screening will quickly identify toxicities and obviate the necessity for as many animal studies. Many of the new scientists come from academic programs focused on molecular biology, without comprehensive veterinary or medical training, and with a type of “tunnel vision” centered on a particular molecular pathway. However, we are also generating DVM, PhD’s and MD, PhD’s with graduate credentials in molecular biology.
The newly emerging DVM and MD scientists enter the work arena with a PhD in pathology often based on a very focused aspect of molecular biology or molecular pathology research. For these individuals wishing to remain in the molecular research arena (in contrast to traditional diagnostic toxicologic pathologists), the almost daily advances in technology require complete dedication to remain at the cutting edge of molecular science. On the other hand, we have the diagnostic toxicologic pathologist.
Traditional diagnostic toxicologic pathology is a morphological discipline. Like other morphological disciplines, it is based largely on experience and requires fully engaged daily examination of pathology material to maintain a well-trained eye capable of distilling specific information from stained tissue slides, a dedicated effort that cannot be easily done as an intermezzo sandwiched between other tasks. It will be a rare individual that has in-depth expertise in molecular biology as well as finely honed skills in diagnostic pathology. In this genomic era, the newly emerging DVM-PhD or MD-PhD pathologist enters a marketplace without many job opportunities in contrast to the pre-genomic era. Many face a type of identity crisis needing to decide to become a competent diagnostic toxicologic pathologist or, alternatively, a competent molecular pathologist. It is hard for most to be excellent and at the cutting edge of both disciplines. At the same time, more PhD molecular biologists without training in pathology are members of the research teams working in drug development and toxicology. These individuals do not have the appropriate training and credentials to evaluate and render histopathological diagnoses. This necessitates that a sufficient population of certified toxicologic pathologists will be needed for diagnostic histopathology in support of toxicity and carcinogenicity studies and the anticipated development of specialized animal models.
How best can the toxicologic pathologist interact in the contemporary team approach in toxicology research and testing? Based on their biomedical training, toxic