Haemotoxicity of thiamphenicol in the BALB/c mouse and Wistar Hanover rat.
Chloramphenicol (CAP) is haemotoxic in man, inducing two forms of toxicity. First, a commonly-occurring, dose-related, reversible bone marrow depression, which develops during treatment. Second, a rarer aplastic anaemia (AA), developing after treatment, is irreversible, and often fatal. Thiamphenicol (TAP) was developed as a replacement for CAP; however, there are no toxicological investigations in the mouse or rat on the dose-related haemotoxicity of TAP, in repeat dose gavage studies. Therefore, we have conducted a comprehensive investigation in these species, administering TAP for 7-17 days, to define haematological changes. Female BALB/c mice were gavaged with TAP, daily for 7-17 days at 400-1500 mg/kg; female Wistar Hanover rats were dosed with TAP daily at 50-375 mg/kg for 9 or 10 days. Haematological changes were studied at 1, 7 and 14 days post-dosing. In mice at day 1, TAP caused decreases in RBC, HCT and Hb; reticulocytes and platelets were reduced; changes were dose-related and reversible. Marrow cell counts were reduced; marrow was hypocellular, with erythroid depletion and progenitor cell vacuolation; the myeloid/erythroid (M:E) ratio was increased. In the rat, changes were not as clear-cut; there was anaemia with indications of reduced reticulocyte and platelet counts, and evidence of decreased neutrophils and lymphocytes. Marrow erythroid cells were decreased, precursor cells vacuolated, and the M:E ratio increased. We conclude that TAP induced haematological changes in the mouse and rat, parallelling the dose-dependent, reversible marrow depression reported in man; TAP is more haemotoxic in the rat than in the mouse.
Turton
J A
JA
Centre for Toxicology, Department of Pharmacology, The School of Pharmacy, University of London, 29/39 Brunswick Square, UK. john.turton@ulsop.ac.uk
Andrews
C M
CM
Havard
A C
AC
Robinson
S
S
York
M
M
Williams
T C
TC
Gibson
F M
FM
D000741:Anemia, Aplastic / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006400:Hematocrit; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006454:Hemoglobins / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010976:Platelet Count; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012156:Reticulocytes / Q000187:drug effects; D013045:Species Specificity; D013839:Thiamphenicol / Q000008:administration & dosage / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D006454:Hemoglobins; D013839:Thiamphenicol