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. Below is a sampling of the laboratory studies in which we are involved. For the past several years, some F344/N rats in the 2-year NTP carcinogenicity studies have suffered seizures. Seizures have occurred only in animals that are individually housed for inhalation or dermal studies and are more common in females. While the seizures have been short in duration and relatively mild, NTP is concerned about whether they may compromise the findings of the studies. For the six completed studies in which seizures occurred, we searched for associations between seizure incidence and a variety of factors including brain lesions, pituitary gland lesions, liver lesions, kidney lesions, adrenal gland lesions, dose, cage location, body weight, and survival. We found no significant associations between any organ lesion and seizures in any of the studies. In three studies, seizures increased slightly with dose in females and in another study, animals in cages near the center of the rack appeared to be more prone to seizures. Body weight and survival were unrelated to seizures. We also closely examined serial sections of brains of selected affected and unaffected animals. Nothing was found in the serial sections that could explain the occurrence of seizures. NTP held a workshop on rodent strains and stocks in June 2005, in part, to discuss seizures and other problems with the F344/N rat. NTP is now considering the suggestions for improving or switching strains. 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. B6C3F1 mice used in NTP studies frequently develop spontaneous liver tumors and sometimes these tumors metastasize to other organs. We examined data from 86 2-year studies to determine if metastasis rates of liver tumors and the locations of these metastases were associated with sex, diet, route of exposure, treated/control status, date of study, and laboratory. Primary liver tumors and liver tumor metastases occurred more frequently in male mice than in female mice. Primary liver tumors were less common with the NTP-2000 diet than with the NIH-07 diet for both males and females. In females, liver tumors metastasized less frequently with the NTP-2000 diet than with the NIH-07 diet; in males, liver tumors metastasized at similar rates for the two diets. Location of liver tumor metastases differed with route of exposure for control males and females, but not for treated males or females. Metastasis rates of liver tumors varied over the years, but the pattern was not consistent. Rates and locations of liver tumors metastases were similar among laboratories.