Biomonitoring of aromatic amines VI: determination of hemoglobin adducts after feeding aniline hydrochloride in the diet of rats for 4 weeks

Abstract

The assessment of the carcinogenic properties of aniline is still controversial. Aniline has, if at all, genotoxic properties but is also acutely toxic and it has been proposed that the hematotoxic effects are responsible for the formation of hemangiosarcomas and fibrosarcomas in the spleen of male rats. As part of a bigger project in which the pathology of male Fischer F344 rats was studied after feeding 10, 30, or 100 mg/kg body weight aniline hydrochloride for 1 and 4 weeks in the diet, the aniline–hemoglobin (Hb) adducts were determined as a biochemical effect marker during those periods. An improved method for the work-up procedure and the adduct analysis was developed for this purpose. The Hb adduct levels increased proportionately with dose after 1 week, which indicates that metabolic activation was not saturated. After 4 weeks of feeding, the adduct levels increased less than proportionately, which suggests that a saturation process is involved. Since it is unlikely that metabolic activation was saturated, the results could be explained by a more rapid clearance of stressed erythrocytes at the carcinogenic dose level. The latter interpretation is supported by other observations which indicate that erythrocytes are damaged dose dependently. A no-observed-effect level (NOEL) has not been reached but could be close to the low dose of 10 mg/kg body weight per day. The Hb adduct formation at the low dose, however, indicates that this should not be considered a no-effect level (NEL). The results support the conclusion that hemolytic anemia is an essential prerequisite for aniline toxicity and tumor development, but they do not fully explain the tissue specificity.