Repeated Exposure Toxicity

Abstract

Acute toxicity studies are essential preliminaries to repeated‐dosing studies, but the former give limited information about organ‐specific toxicity. Many toxic effects are not detected in acute studies because of the need for cumulative toxicity to develop or because of a long latency to development of toxicity. Evaluation of repeated‐exposure toxicity requires that studies be conducted by an appropriate route for a sufficient number of exposures. The initial concentrations or doses chosen will be determined by findings from acute studies, when these permit the detection of toxicity. Short‐term repeated‐dose studies vary in length from a few (5‐9) days to 28 days, while subchronic studies are usually 90 days, and chronic studies 18 months or more, in rodents. The material to be tested should be of known purity. Most repeated‐exposure studies are conducted using rats or mice, with some regulatory agencies also requiring the use of a larger species (e.g. dog), for subchronic studies. The choice of species is heavily constrained by regulatory authorities and the requirement for normative data. Dosing may be by various routes, that chosen depending largely on the likely route of human exposure. Oral dosing can be gavage, or incorporation of test material into the diet or drinking water. In‐life observations include clinical observation, food and water consumption and body weight determinations. Standard haematology, clinical chemistry and urinalysis measurements are necessary in all studies. At termination, necropsy is carried out, selected organs are weighed and selected organs processed for histopathology.