Identifying And Evaluating Sources Of Variability In Rod

Environmental Health Sciences

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Abstract

The goal of this project is to identify and evaluate factors that may influence response in laboratory studies.[unreadable] [unreadable] Several short-term rodent bioassays, such as the uterotrophic bioassay, have been developed to assess estrogenic effects of chemicals. The outcomes of these assays may be affected by factors other than the chemicals under study. For example, in our studies, we have shown that the commonly used Sprague-Dawley rat is less sensitive to estrogenic chemicals than the Fischer 344 rat or the CD-1 mouse. In addition, many laboratory diets contain phytoestrogens which also have estrogenic effects. Also, some diets have more metabolic energy available than other diets. High energy consumption may interfere with the estrogenic responses. Because these bioassays are conducted at many laboratories around the world, using different diets and different rodent strains, conflicting results sometimes occur. We are conducting experiments using different laboratory diets to quantify the effects of phytoestrogens and metabolic energy availability on responses to estrogenic chemicals in several strains of rats and mice. Our goal is to be able to recommend an optimal diet and strain for these assays that minimizes extraneous sources of estrogenic responses and improves the accuracy of these assays in identifying estrogenic chemicals.[unreadable] [unreadable] Male rats excrete a low-molecular weight protein, alpha 2u-globulin or alpha 2u-g, in their urine. Some chemicals bind to this protein and cause hyaline droplets to accumulate in the kidneys, which, in turn, are thought to result in nephropathy and tumors. Because humans do not produce alpha 2u-g, carcinogenic effects of chemicals in the kidney of male rats are often dismissed. We are examining data from short-term and 2-year studies of four chemicals for which alpha 2u-g was measured, to determine whether kidney tumor incidence is related to the recent switch to the NTP-2000 diet and to determine whether cellular changes in short-term studies are related to development of tumors in the long-term studies. The NTP-2000 diet has reduced the incidence of nephropathy, but kidney tumor incidence appears to be unchanged. Furthermore, short-term cellular changes indicative of damage from alpha 2u-g are more strongly related to tumor incidence in the long-term than are cellular changes indicative of cell proliferation. We are continuing to study this issue.