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Robert R. Maronpot
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An era can be defined as a period in time identified by distinctive character, events, or practices. We are now in the genomic era. The pre-genomic era: There was a pre-genomic era. It started many years ago with novel and seminal animal experiments, primarily directed at studying cancer. It is marked by the development of the two-year rodent cancer bioassay and the ultimate realization that alternative approaches and short-term animal models were needed to replace this resource-intensive and time-consuming method for predicting human health risk. Many alternatives approaches and short-term animal models were proposed and tried but, to date, none have completely replaced our dependence upon the two-year rodent bioassay. However, the alternative approaches and models themselves have made tangible contributions to basic research, clinical medicine and to our understanding of cancer and they remain useful tools to address hypothesis-driven research questions. The pre-genomic era was a time when toxicologic pathologists played a major role in drug development, evaluating the cancer bioassay and the associated dose-setting toxicity studies, and exploring the utility of proposed alternative animal models. It was a time when there was shortage of qualified toxicologic pathologists.The genomic era: We are in the genomic era. It is a time when the genetic underpinnings of normal biological and pathologic processes are being discovered and documented. It is a time for sequencing entire genomes and deliberately silencing relevant segments of the mouse 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 environmental factors that affect genomic expression. In this current genomic era, the toxicologic pathologist has had to make room for a growing population of molecular biologists. In this present era newly emerging DVM and MD scientists enter the work arena with a PhD in pathology often based on some aspect of molecular biology or molecular pathology research. In molecular biology, the almost daily technological advances require one’s complete dedication to remain at the cutting edge of the science. Similarly, the practice of toxicologic pathology, like other morphological disciplines, is based largely on experience and requires dedicated 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 well done as an intermezzo between other tasks. It is a rare individual that has true expertise in both molecular biology and 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 an identity crisis needing to decide to become a competent pathologist or, alternatively, to become a competent molecular biologist. At the same time, more PhD molecular biologists without training in pathology are members of the research teams working in drug development and toxicology. How best can the toxicologic pathologist interact in the contemporary team approach in drug development, toxicology research and safety testing? Based on their biomedical training, toxicologic pathologists are in an ideal position to link data from the emerging technologies with their knowledge of pathobiology and toxicology. To enable this linkage and obtain the synergy it provides, the bench-level, slide-reading expert pathologist will need to have some basic understanding and appreciation of molecular biology methods and tools. On the other hand, it is not likely that the typical molecular biologist could competently evaluate and diagnose stained tissue slides from a toxicology study or a cancer bioassay.The post-genomic era: The post-genomic era will likely arrive approximately around 2050 at which time entire genomes from multiple species will exist in massive databases, data from thousands of robotic high throughput chemical screenings will exist in other databases, genetic toxicity and chemical structure-activity-relationships will reside in yet other databases. All databases will be linked and relevant information will be extracted and analyzed by appropriate algorithms following input of the latest molecular, submolecular, genetic, experimental, pathology and clinical data. Knowledge gained will permit the genetic components of many diseases to be amenable to therapeutic prevention and/or intervention. Much like computerized algorithms are currently used to forecast weather or to predict political elections, computerized sophisticated algorithms based largely on scientific data mining will categorize new drugs and chemicals relative to their health benefits versus their health risks for defined human populations and subpopulations. However, this form of a virtual toxicity study or cancer bioassay will only identify probabilities of adverse consequences from interaction of particular environmental and/or chemical/drug exposure(s) with specific genomic variables. Proof in many situations will require confirmation in intact in vivo mammalian animal models. The toxicologic pathologist in the post-genomic era will be the best suited scientist to confirm the data mining and its probability predictions for safety or adverse consequences with the actual tissue morphological features in test species that define specific test agent pathobiology and human health risk.

Keywords: genomic era, history of toxicologic pathology, molecular biology

 

An era can generally be defined as a period in time identified by distinctive character, events, or practices. We are now in the genomic era. The genomic era was preceded by a pre-genomic era and will ultimately be followed by a post-genomic era (Fig. 1).

Toxicologic Pathologist in the Post-Genomic Era

Fig. 1. Timeline representing the spans of the pre-genomic and genomic eras with a projection for the post-genomic era.

The Pre-Genomic Era

For practical purposes I have arbitrarily categorized the pre-genomic era as beginning around the year 1900 and ending in 1990. Prior to 1900, several key historical events identified environmental & occupational factors associated with cancer development in humans. In 1713 Bernadino Ramazzini, the father of occupational medicine, identified a high prevalence of breast cancer in nuns relate to nulliparity1. Perceival Pott documented occupational association of scrotal cancer in chimney sweeps in England in 17752. Further evidence linking a causative role of environmental exposure and cancer was reported by William Jackson Elmslie in 1866 when he linked induction of abdominal epitheliomas in Kashmir natives who sustained recurrent burns by warming themselves using braziers containing live coals held against their abdomen under their clothing3. Identification of the association of bladder cancer in aniline dye workers by Rehn in 1895 made us aware of the concept of chemical carcinogenesis associated with an industrial process4. Additional documentation of environmental or workplace exposures linked to cancer development followed over the next several years. Copies of the original papers for these and other seminal papers on experimental oncology are readily available2.

The pre-genomic era (~1900 to 1990) is characterized by several significant events and seminal animal experiments that constitute the historical underpinnings of toxicologic pathology. From the very beginning, many of these events focused on studies of cancer. The development of inbred mice and studies on transmission of spontaneously occurring cancer began in the U.S. at Harvard University and the Bussey Institute in the first two decades of the 1900’s and led to the establishment of the Jackson Laboratory in 1929 through the efforts of Clarence Cook Little5,6,7. The seminal publication by Yamagiwa and Ichikawa in 1915 in which they demonstrated that tar and soot (hydrocarbons & aromatic hydrocarbons) produced cancer on the skin of rabbits and mice, providing the first experimental evidence to confirm the observation by Perceival Pott in 17751,8. In 1925 Murphy and Sturm demonstrated skin-painting mice with polycyclic aromatic hydrocarbons led to systemic exposure with subsequent induction of lung tumors9. In 1935 Sasaki and Yoshida’s studies show that dietary administration of o-amidoazotoluene produced liver cancer in rats10. They further demonstrated the effects of dose on latency and carried out what is perhaps the earliest use of stop-exposure studies. Isaac Berenblum’s work in the early 1941’s defined the concept of co-carcinogenesis and early versions of the operational components of cancer, viz., initiation, promotion, and progression11. A variety of other biomedical and toxicolo