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Recombinant human erythropoietin (rhEPO) was administered intravenously to Beagle dogs in daily doses of 100, 500 and 3000 units/kg/day for 3 months. The high dose was more than 200-fold the therapeutic human maintenance dose. Such excessive rhEPO doses elicited extreme erythropoiesis. There was a dose-dependent stimulation of bone marrow fibroblasts, leading to bone marrow fibrosis in some of the high dose animals. The extent of myelofibrosis was intra- and interindividually different in various bones. Sternebrae proved to be practical for morphometric studies. The point-counting method was used for measurement. The portion of fatty tissue, sinusoids and fibrous tissue in the medullary space as well as the number of blood vessels and megakaryocytes were calculated. Such experimental conditions are not of relevance in human patients whose rhEPO therapy is interrupted as soon as their PCV reaches 35 vol%. Experimentally induced myelofibrosis should therefore not be considered as a risk in patients receiving therapeutic doses of rhEPO.

Evaluation of histopathological slides is a subjective science; objectivity is needed, especially with minimal alterations. Quantitation using measurement procedures is of special value in toxicological studies. The present study tests a method in which the hepatocytic nuclei were measured per area of liver tissue, excluding the sinusoidal space. Different grades of hepatocellular enlargement were induced by different dose levels of a test compound (combination of two diuretics). The method demonstrates the well-established dose dependence of liver cell enlargement and permits differentiation between slight drug-induced enlargement and the normal variation in cell size. Special reference is made to avoid measurement artefacts.