A study of the mechanism of butachlor-associated gastric neoplasms in Sprague-Dawley rats.

Summary Long term administration of butachlor to Sprague-Dawley rats in a previous bioassay, resulted in the induction of gastric neoplasms which occurred only in the highest dose group (3000 ppm in the diet), primarily in females and specifically in the fundic region. The tumors were a composite of highly undifferentiated enterochromaffin-like (ECL) cells and mucus producing cells with morphologic characteristics unlike those previously described in the rat stomach. Mucosal atrophy of marked intensity was a consistent feature of the gastric mucosa in animals from the highest dose group. An additional long term study was conducted in female Sprague-Dawley rats at dietary levels of 0, 100, 1000 and 3000 ppm to explore the mechanism(s) involved in the formation of these neoplasms. Cell proliferation was evaluated in both fundic and pyloric regions of the stomachs of rats at multiple time periods from 14 days to 26 months. Mucosal thickness was determined in the fundic region at the same time intervals as were used for cell proliferation studies. Gastric pH and gastric acid production were measured after approximately 21 months of exposure. Serum gastrin levels were analyzed at 14, 60, and 120 days and at 6, 18 and 20 months. Cholecystokinin (CCK)/gastrin receptor binding studies were conducted on samples of four tumors and pooled fundic mucosa from five animals in the control group. Cell proliferation was increased in both the neck and base regions of the fundic mucosa at nearly all time points measured from 14 days to 26 months. The magnitude of the changes in the base region were substantially greater than those in the neck region. Fundic mucosal thickness was decreased beginning at the 30-day time point and continued at all intervals, being less than one half that of controls at 20 and 26 months. Gastric pH in rats from the highest dose was elevated to nearly twice control levels at 21 months. Gastric acid secretion was dramatically decreased in animals from the 3000 ppm group and was moderately decreased in the 1000 ppm group at 21 months. Hypergastrinemia was observed at the 3000 ppm level only, beginning at 120 days with progression to extremely high levels by 18 months. CCK/gastrin receptor binding was demonstrated in all tumors studied, at levels comparable to or higher than that of the pooled control sample. All changes involved only the fundic region, the site of tumor formation. Tumors occurred only in animals from the 3000 ppm level, the only level at which hypergastrinemia occurred. The mechanism responsible for these tumors is unique for chemical-induced gastric neoplasia in that, fundic mucosal atrophy with loss of parietal cells was an early change which resulted in neoplasia through a series of events involving hyperplasia of the gastric epithelium, sustained hypochlorhydria and hypergastrinemia. Feedback proliferation and hypergastrinemia resulted in prolonged and sustained stimulation of stem cells and ECL cells which resulted in the unusual neoplasms associated with butachlor administration.