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Recent changes in the risk assessment landscape underscore the need to be able to compare the results of toxicity and dose-response testing between a growing list of animal models and, quite possibly, an array of in vitro screening assays. How do we compare test results for a given compound between vastly different species? For example, what dose level in the ambient water of a small fish model would be equivalent to 10 ppm of a given compound in the rat's drinking water? Where do we begin? To initially address these questions, and in order to compare dose-response tests in a standard rodent model with a fish model, we used the concept of molecular dose. Assays that quantify types of DNA damage that are directly relevant to carcinogenesis integrate the factors such as chemical exposure, uptake, distribution, metabolism, etc. that tend to vary so widely between different phyletic levels. We performed parallel exposures in F344 rats and Japanese medaka (Oryzias latipes) to the alkylating hepatocarcinogen, dimethylnitrosamine (DMN). In both models, we measured the DNA adducts 8-hydroxyguanine, N(7)-methylguanine and O(6)-methylguanine in the liver; mutation frequency using lambda cII transgenic medaka and lambda cII transgenic (Big Blue(R)) rats; and early morphological changes in the livers of both models using histopathology and immunohistochemistry. Pulse dose levels in fish were 0, 10, 25, 50, or 100 ppm DMN in the ambient water for 14 days. Since rats are reported to be especially sensitive to DMN, they received 0, 0.1, 1, 5, 10, or 25 ppm DMN in the drinking water for the same time period. While liver DNA adduct concentrations were similar in magnitude, mutant frequencies in the DMN-exposed medaka were up to 20 times higher than in the Big Blue rats. Future work with other compounds will generate a more complete picture of comparative dose response between different phyletic levels and will help guide risk assessors using "alternative" models.

The study of disease is, at its core, the study of abnormal structure and function spanning levels of organization from molecules to cells to tissues to organisms (and including populations and ecosystems in the disciplines of epidemiology and epizootiology). Fish and invertebrates from marine and freshwater environments have long provided valuable models for the study of basic biological processes. Some of the earliest studies of non-self recognition and phagocytosis were conducted using sea urchins (leading to the 1908 Nobel prize for Mechnikov) while the principles of signal propagation in axons were elucidated from studies of the giant axon of squid (leading a Nobel prize in 1963 for Hodgkin & Huxley). Aquatic invertebrates and fishes have proved to be valuable model organisms based on specific physical features, such as giant axons, as well as by providing an evolutionary perspective on structure and function in higher vertebrate systems. Less recognized, however, are the contributions that these organisms have made to the study of disease. Historically, such studies have tended to fall into two very broad categories, natural versus laboratory experiments. Natural experiments are those in which spontaneously occurring disease states are discovered in wild or laboratory animal populations as a result of injurious environmental factors, infectious agents and/or mutations. Outbreaks, or epizootics, of these diseases often serve as a first warning of serious environmental problems, such as when flatfish with liver tumors were found in high numbers in Eagle Harbor in the Puget Sound area of Washington State, USA (Myers et al, 2003). This observation led to the detection of high levels of polycyclic aromatic hydrocarbons in sediments at this site, resulting in the designation of the harbor as a “superfund site” and the eventual remediation of the toxic sediments. In laboratory experiments disease states are induced under controlled circumstances, often in an attempt to determine the causes and mechanisms of spontaneously occurring diseases or to evaluate the potential injurious effects of toxins or drugs. Disease research on aquatic animals involves a wide variety of disciplines such as physiology, pathology, toxicology, immunology, microbiology, embryology, molecular biology and genetics working and a wide phylogenetic range of organisms. To bring together investigators working in such varied fields of disease research, a series of meetings focusing on use of aquatic organisms as models of human disease was begun in 2000. This special issue of Comparative Biochemistry and Physiology contains 16 manuscripts from a conference entitled “Aquatic Animal Models of Human Disease” held from September 29 to October 2, 2005, at the University of Georgia, Athens, Georgia. This volume joins similar special issues developed from the two previous meetings in this series held in 2000 and 2003 (Walter 2001; Schmale, 2004). The studies presented in this volume demonstrate that fish models can be used to investigate a wide range of disease related questions and can provide unique models for human disease processes.