How could mechanistic approaches improve risk assessment and advance the 3Rs?

Abstract

Historically, satellite groups are often used for rodent toxicokinetic profiling because of the haematological consequences of blood sampling. If microsampling is shown to be toxicologically benign, its adoption in rat studies would enable comparison of exposure and toxicity in individual animals (as happens in non-rodent studies) as well as obviating need for satellite groups.Groups of 10 male (200–300 g) and female (150–250 g) rats aged 10 weeks were vehicle dosed and either left unsampled, conventional blood volume sampled (6 × 200 μL) or microsampled (6 × 32 μL) on Days 1 and 14. At termination on Day 15, clinical pathology plus liver and spleen weights and histopathology were obtained.All clinical pathology parameters were within background range. However, compared to unsampled controls, conventional volume sampled rats showed a statistically significant (p < 0.001) decrease in haemaglobin, haematocrit and red blood cell count, an increase in reticulocytes (at least p < 0.01), increased AST and GLDH and, in males only, an increase in monocytes and neutrophils. In contrast, microsampled animals showed no changes except for a slight, toxicologically insignificant decrease in haemoglobin concentration (15.0 g/dL compared to the unsampled group mean of 14.4 g/dL) in females (p < 0.05) and a small increase in monocytes (p < 0.05) in males.Microsampling of adult rats is possible without adverse toxicological consequences.