Studies were conducted to characterize the toxicity of drugs and chemicals to neonates relative to adults, and to evaluate the role of lactation in the induction of neonatal toxicity. To evaluate the rat as a model for human milk excretion of chemicals and drugs, several different types of drugs were evaluated for their excretion into rat milk, and the data were compared with that previously obtained in humans. Using gas chromatography and high pressure liquid chromatography, the amounts of several drugs in rat milk and plasma were determined, as were the effects on the quantity and composition of the milk of the mothers. Water soluble, basic drugs diphenhydramine, cimetidine, and ranitidine were studied. The antihistamine diphenhydramine was present in rat milk in concentrations higher than those in plasma. There were no effects on milk composition and milk synthesis. Cimetidine has found in very high concentrations in milk relative to plasma, and studies were performed to investigate the mechanism of secretion of high amounts of cimetidine into milk. These studies examined protein binding in milk and serum, active transport into mammary gland and kidney slices in vitro, and the kinetics of elimination of cimetidine from plasma and milk. The effects of exposure to ranitidine during lactation on milk production and composition, as well as on the suckling pups, were also determined. The amount of ranitidine present in rat milk after oral dosing was greater than the concentrations in plasma and was similar to results reported in humans. Studies were initiated to determine the amount of nickel secreted into the milk after subcutaneous dosing and the subsequent effects on the suckling offspring. Future studies will examine the excretion of water soluble acidic drugs, nonionizable compounds, and other metals into rat milk.
