Genotoxic Activities of Aniline and its Metabolites and Their Relationship to the Carcinogenicity of Aniline in the Spleen of Rats

Abstract

Aniline (in the form of its hydrochloride) has been shown to induce a rather rare spectrum of tumors in the spleen of Fischer 344 rats. The dose levels necessary for this carcinogenic activity were in a range where also massive effects on the blood and non-neoplastic splenotoxicity as a consequence of methemoglobinemia were to be observed. This review aimed at clarifying if aniline itself or one of its metabolites has a genotoxic potential which would explain the occurrence of the spleen tumors in rats as a result of a primary genetic activity. The database for aniline and its metabolites is extremely heterogeneous. With validated assays it ranges from a few limited Ames tests (o- and m-hydroxyacetanilide, phenylhydroxylamine, nitrosobenzene) to a broad range of studies covering all genetic endpoints partly with several studies of the same or different test systems (aniline, p-aminophenol, p-hydroxyacetanilide). This makes a direct comparison rather difficult. In addition, a varying number of results with as yet not validated systems are available for aniline and its metabolites. Most results, especially those with validated and well performed/documented studies, did not indicate a potential of aniline to induce gene mutations. In five different mouse lymphoma tests, where colony sizing was performed only in one test, aniline was positive. If this indicates a peculiar feature of a point mutagenic potential or does represent a part of the clastogenic activity for which there is evidence in vitro as well as in vivo remains to be investigated. There is little evidence for a DNA damaging potential of aniline. The clastogenic activity in vivo is confined to dose levels, which are close to lethality essentially due to hematotoxic effects. The quantitatively most important metabolites for experimental animals as well as for humans (p-aminophenol, p-hydroxyacetanilide) seem to have a potential for inducing chromosomal damage in vitro and, at relatively high dose levels, also in vivo. This could be the explanation for the clastogenic effects that have been observed after high doses/concentrations with aniline. They do not induce gene mutations and there is little evidence for a DNA damaging potential. None of these metabolites revealed a splenotoxic potential comparable to that of aniline in studies with repeated or long-term administration to rats. The genotoxicity database on those metabolites with a demonstrated and marked splenotoxic potential, i.e. phenylhydroxylamine, nitrosobenzene, is unfortunately very limited and does not allow to exclude with certainty primary genotoxic events in the development of spleen tumors. But quite a number of considerations by analogy from other investigations support the conclusion that the effects in the spleen do not develop on a primary genotoxic basis. The weight of evidences suggests that the carcinogenic effects in the spleen of rats are the endstage of a chronic high-dose damage of the blood leading to a massive overload of the spleen with iron, which causes chronic oxidative s...

Decolorization of water and oil-soluble azo dyes by Lactobacillus acidophilus and Lactobacillus fermentum

“…1a, c, 3a, b). Aniline is considered hazardous because of its toxicity and carcinogenicity [3,5]. Experimental animals that were dosed with aniline in feed developed cancer of the spleen [34].…”

Aromatic Amines Sources, Environmental Impact and Remediation

“…This became particularly apparent with the recent developments concerning aniline and structurally related amines. The discussion focused for a long time on the question: is Tests for mutagenicity gave contradictory results and because of the low genotoxic potency these data were considered not to be sufficient to explain the spleen tumours observed in rats (Wilmer et al 1984;Bomhard and Herbold 2005). The studies with the most basic aromatic amine, aniline, show how intimately genotoxic and non-genotoxic effects are connected and that genotoxicity alone will not answer the question (Zwirner-Baier et al 2003).…”

Anilina. Dokumentacja dopuszczalnych wielkości narażenia zawodowego

“…rzędu 300 ÷ 400 mg/kg) leży już jednak w zakresie dawek wywołujących methemoglobinemię i inne skutki toksyczne działania aniliny. Także obserwowane aberracje chromosomowe (tylko u szczurów) są wywoływane raczej przez duże dawki aniliny (Bomhard, Herbold 2005).…”

“…dotyczących uszkodzeń DNA przez anilinę są dość rozbieżne. Można na ich podstawie jednak przypuszczać, że zdolność aniliny do bezpośredniego uszkodzenia DNA jest bardzo niewielka, jeśli nawet nie pomijalna (Bomhard, Herbold 2005).…”

“…W warunkach in vivo obserwowano tworzenie mikrojąder w komórkach szpiku kostnego szczurów i myszy. W badaniach tych stosowano duże dawki aniliny, które generowały stosunkowo duże stężenia MetHb we krwi (Bomhard, Herbold 2005). Ogólnie genotoksyczność aniliny wydaje się być niewielka, jeżeli w ogóle ma miejsce.…”