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ToxSci Advance Access published online on June 8, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh187
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received March 8, 2004
Accepted June 1, 2004

Respiratory Toxicology

Subacute Inhalation Toxicity of Aniline in Rats: Analysis of Time- and Concentration-Dependence of Hematotoxic and Splenic Effects

Jürgen Pauluhn 1*

1 Institute of Toxicology, BAYER HealthCare AG, 42096 Wuppertal, Germany

* To whom correspondence should be addressed. E-mail: juergen.pauluhn{at}bayerhealthcare.com.


  Abstract

In this study, thirty male Wistar rats/group were exposed nose-only to mean analytical concentrations of 9.2, 32.4, 96.5, and 274.9 mg aniline/m3 using an exposure regimen of 6 hr/day, 5 days/wk for 2 wks (days 0-11), followed by a 2-wk post-exposure period (up to day 28). Serial sacrifices for specialized examinations were performed on days 0, 4, 11, 14, and 28. Clinical signs of toxicity, body weights, hematology and clinical chemistry tests, including total iron in liver and spleen, splenic lipid peroxidation, organ weights, gross and histological changes in target organs were recorded. No mortality was observed during the study. Rats exposed to 96.5 mg/m3 and above displayed cyanosis, with no apparent progression during the exposure period. The predominant manifestation of toxicity was methemoglobin formation and associated erythrocytotoxicity. The changes observed included anemia, red blood cell morphological alterations (e.g., Heinz bodies), decreased hemoglobin and hematocrit, reticulocytosis, and effects on the spleen (splenomegaly, hemosiderin accumulation, and increased hematopoietic cell proliferation) which gained significance at 96.5 and 274.9 mg/m3. In regard to increased splenic extramedullary hematopoiesis borderline effects occurred at 32.4 mg/m3. The total content of iron in spleen homogenates increased in a concentration- and time-dependent manner with increasing duration of exposure. The maximum accumulation of iron in the liver and spleen exceeded the respective control levels by {approx}60% and {approx}500%, respectively. Splenic lipid peroxidation and total iron were highly correlated (r2 = 0.93) towards the end of the exposure period. A hepatic hemosiderosis was observed at 274.9 mg/m3. Thus, in regard to erythrocytotoxicity and associated increased splenic sequestration of erythrocytes, iron accumulation and lipid peroxidation 32.4 mg/m3 constitutes the no-observed-adverse-effect concentration (NOAEC). However, spleens of the 32.4 mg/m3 exposure group exhibited a minimal increase in extramedullary hematopoiesis. Exposure to 9.2 mg/m3 was devoid of any significant effect.

Key Words: Methemoglobin, bone marrow, spleen, liver, hematotoxicity, aniline, lipid peroxidation, iron, oxidative stress, inhalation .


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