title: Concentration-dependence of aniline-induced methemoglobinemia in dogs: a derivation of an acute reference concentration.
abstract: Four male Beagle dogs per group were head-only exposed to aniline vapor in concentrations ranging from 15.8 to 493.6 mg/m3. Each exposure session was for 4h. Additionally, one group of dogs was both head-only and whole-body exposed to approximately 241 mg/m3 to better appreciate the contribution of dermal uptake on methemoglobin (MetHb) induction. The exposure paradigm chosen was comparable to a dose-escalation type of study, however, providing adequate recovery periods between each exposure session to exclude 'carry-over' effects from one exposure session to another. This was verified by the determination of standard hematology endpoints before and after each exposure session. The time- and concentration-dependence of MetHb was analyzed as the key endpoint. The results of this study show that MetHb was maximal around the end of the 4 h exposure period. Significantly increased MetHb was observed at concentrations equal and above 30.3 mg/m3 at a duration of exposure of at least 60 min. The extent of MetHb formation observed in some hyperventilating dogs suggests that the dosing-rate is important for the outcome of test. Whole body exposed dogs displayed markedly higher MetHb values when compared to head-only exposed dogs. Taking into account the entire concentration-time-effect relationship 23.6 and 20.6 mg/m3 were estimated to be the threshold concentrations to cause 0.8% MetHb following a 4 and 8h exposure period, respectively. The C(n)xt analysis of MetHb formation is consistent with a concentration-dependent restoration kinetics of MetHb suggesting that results from high level exposures cannot readily be extrapolated to low-level exposures. In summary, this study demonstrates that for aniline, an agent known to be bioactivated by a hepatic first-pass metabolism, the rate of delivery and uptake appears to be decisive for the extent of MetHb formation. Carry-over effects related to erythrotoxicity or Heinz body formation were not observed at any exposure level.
authors.affiliation: Institute of Toxicology, BAYER HealthCare AG, Building no. 514, 42096 Wuppertal, Germany. juergen.pauluhn@bayerhealthcare.com
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
mesh_terms: D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000166:cytology; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D019570:Inhalation Exposure; D008297:Male; D008708:Methemoglobinemia / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D013990:Tidal Volume / Q000187:drug effects; D013997:Time Factors; D014835:Volatilization
chemical_list: D000814:Aniline Compounds; D006454:Hemoglobins; C023650:aniline