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Description of key information

The results of a number of cell transformation assays indicate that acrylonitrile has the potential to reduce antioxidant status, increase xanthine oxidase activity and cause cell transformation.  The results of recent studies provide evidence for the involvement of oxidative stress in the mode of action of acrylonitrile carcinogenesis in rodent studies.

Additional information

A large number of studies have been performed in order to further elucidate the carcinogenic mode of action of acrylonitrile. Studies have focussed on the induction of oxidative stress and cell transformation. The dataset on cell transformation has also been reviewed in the EU RAR (2004), by the Sapphire Group (2004) and more recently by Albertini (2009).

Studies of oxidative stress and acrylonitrile toxicity

A number of non-standard published studies have investigated the potential for acrylonitrile to cause oxidative stress in vitro and in vivo; these studies are of relevance to the consideration of the mode of action for genotoxicity and carcinogenicity, and also when evaluating the results of studies reporting effects on other organ systems following the administration of high doses of acrylonitrile.

In a study in cultured human astrocytes, Jacob & Ahmed (2003) exposed cells to various concentrations of acrylonitrile (25 -400 uM) and assessed levels of endogenous antioxidants (GSH and catalase), levels of reactive oxygen species (ROS), secretion of TNF-α (a cellular marker for oxidative stress) and oxidative damage to nuclear DNA. The authors conclude that a redox imbalance may play a major role in acrylonitrile-induced neurotoxicity, which is indicated by compromised antioxidant defence mechanisms (depletion of GSH, increase in GSSG, inhibition of catalase, increased ROS formation and TNF- α secretion), resulting in oxidative DNA damage. Esmat et al. (2007) demonstrated that acrylonitrile induces oxidative stress in cultured rat glial cells, depleting reduced GSH and caused lipid peroxidation. The antioxidant compound N-acetylcysteine was shown to inhibit the oxidative effects of acrylonitrile. In a series of studies in cultured Syrian Hamster Embryo cells, Zhang et al. (2002) suggest that the induction of oxidative stress by acrylonitrile involves a temporal decrease in antioxidant levels and increase in xanthine oxidase activity that is mediated by the oxidative metabolism of acrylonitrile. In a study in vivo, Pu et al. (2009) investigated oxidative stress and DNA damage in rats exposed to acrylonitrile in the drinking water. No significant increase in direct DNA strand breaks was observed in the brain or WBCs from acrylonitrile-treated rats. However, oxidative DNA damage (fpg comet and 8'hydroxyl-2 -deoxyguanosine) in brain and WBC was increased in a dose-dependent manner. In addition, plasma levels of reactive oxygen species (ROS) increased in rats administered acrylonitrile. Dietary supplementation with n-acetylcysteine prevented acrylonitrile-induced oxidative DNA damage in brain and WBCs. A slight, but significant, decrease in the GSH:GSSG ratio was also seen in brain following acrylonitrile doses of >30 ppm. The authors conclude that the results of this study provide support for a mode of action for acrylonitrile-induced astrocytomas involving the induction of oxidative stress and damage. Significant associations were seen between oxidative DNA damage in WBC and brain, ROS formation in plasma and the reported tumour incidences. Since oxidative DNA damage in brain correlated with oxidative damage in WBC, the results suggest that monitoring WBC DNA damage maybe a useful tool for the assessment of acrylonitrile-induced oxidative stress in humans. Snyder et al. (2010) carried out a study to assess the formation of cyanoethylvaline (CEVal) haemoglobin adducts in blood samples from rats following the administration of acrylonitrile in drinking water. Groups of four female F344 rats were exposed for 28 days to acrylonitrile in the drinking water at levels of 0 or 100 ppm in conjunction with basal diet, or diet supplemented with Vitamin E (0.05%), green tea polyphenols (0.4%), N-acetyl cysteine (0.3%), sodium selenite (0.1 mg/kg) and taurine (10 g/kg). Globin CEVal adducts were measured in terminal blood samples by LC/MS-MS. Globin CEVal levels were markedly increased by the administration of acrylonitrile, however the administration of dietary antioxidants did not have any notable effect on CEVal levels. However a similar study reported by Klaunig & Forney (2010) demonstrated increased 8OHdG formation in rat brain and oxidative DNA damage (but not DNA strand breakage) in peripheral white blood cells. Groups of rats were administered acrylonitrile at 0 or 100 ppm in the drinking water for 28 days; groups received basal diet or diet supplemented with the anti-oxidants Vitamin E (0.05%), Green tea polyphenols (0.4%), N-acetyl cysteine (0.3%), sodium selenite (0.1mg/kg) or taurine (10g/kg). Bodyweights were measured weekly, liver weights were measured at termination. Total anti-oxidant capacity. malondialdehyde and 8 -OHdG levels were measured in samples of brain tissue. Direct and oxidative DNA damage were assessed in white blood cells by Comet assay. Acrylonitrile induced oxidative stress in the brain of female F344 rats following the administration of 100 ppm in drinking water for 28 days, as shown by increased 8OHdG formation. Acrylonitrile also induced oxidative DNA damage, but not DNA strand breakage in white blood cells. Dietary supplementation with Vitamin E, green tea polyphenols, N-acetyl cysteine in diets prevented or reduced acrylonitrile-induced 8OHdG formation. Dietary supplementation with selenium or taurine gave no significant protection against acrylonitrile-induced oxidative stress. In contrast, supplementation of all five antioxidants in diets prevented oxidative DNA damage induced by acrylonitrile in white blood cells. Acrylonitrile did not cause significant changes in total antioxidant capacity and malondialdehyde level in brain tissues.

Hamdy et al. (2012) investigated the role played by neutrophils in the gastric damage seen in rats following gavage with a high dose level of acrylonitrile. A groups of eight male Wistar rats was gavaged with acrylonitrile at a single dose of 30 mg/kg bw; a further group was administered acrylonitrile following pre-treatment with methotrexate to induce neutropoenia. Administration of acrylonitrile resulted in focal mucosal erosion in the glandular stomach; pre-treatment with methotrexate significantly decreased the severity of the gastric lesions. Cyanide levels were significantly higher in gastric homogenates from acrylonitrile-treated rats compared to those pre-treated with methotrexate. Gastric myeloperoxidase activity (a marker of neutrophil infiltration) was significantly increased in acrylonitrile-treated rats; this increase was partially prevented by pre-treatment with methotrexate. PGE2 levels were markedly reduced in the acrylonitrile-treated group; pre-treatment with methotrexate prevented the marked decrease following acrylonitrile treatment. Treatment with acrylonitrile significantly reduced the gastric glutathione concentration and increased the GSSG concentration. Glutathione peroxidase, catalase and SOD activities were significantly reduced in the group treated with acrylonitrile alone; malondialdehyde levels were significantly increased in this group. Pre-treatment with methotrexate partially or fully prevented the changes in oxidant status caused by acrylonitrile. The authors conclude that neutrophils play an important role in the induction of gastric damage by acrylonitrile. Al Abbasi (2012) also investigated the role of oxidative status in the gastric toxicity of the rat; a single oral dose of acrylonitrile (25 mg/kg bw) was found to cause a significant enhancement in xanthine oxidase activity and caused significant depletion of glutathione levels, enhanced superoxide production and increased lipid peroxidation. Acrylonitrile also accelerated the conversion of xanthine dehydrogenase to xanthine oxidase (a property associated with the oxidation of sulphydryl groups) with a significant depletion of gastric glutathione in a dose-related manner. Pre-treatment with diethyl maleate significantly exacerbated acrylonitrile-induced glutathione depletion and increased xanthine oxidase activity, and also significantly enhanced superoxide and malondialdehyde production. The authors conclude that the enhancement of xanthine oxidase activity resulting from cytotoxic hypoxia may be involved in the induction of gastric damage by acrylonitrile. The relevance of the effects of acrylonitrile on the stomach to other tissues is unclear; the stomach has much lower levels of CYP2E1 (demonstrated to be critical for acrylonitrile metabolism) compared to other tissues such as the liver.

Cell transformation

The EU RAR (2004) reviewed the extensive dataset on the potential of acrylonitrile to cause cell transformation which are informative in relation to the potential of acrylonitrile to cause carcinogenicity by non-genotoxic mechanisms.  It concludes that the various studies summarised in this review document indicate that acrylonitrile has the ability to cause cell transformation; it further states that cell transformation appears to be secondary to oxidative damage and is dependent on metabolic activation. The review by the Sapphire Group (2004) also notes that the available data indicate that acrylonitrile has the ability to cause cell transformation as a consequence of a reduction in cellular antioxidant status. It is noted that that the extensive investigations of cell transformation show that the induction of oxidative stress by acrylonitrile is dependent on its metabolism to CEO and cyanide. The draft report of the North Carolina Science Advisory Board (NCSAB, 2010) also concludes that the mechanistic work by Pu et al. suggests that ROS related to toxicity induced by high doses of acrylonitrile appear to play a critical role in its carcinogenicity in the highly sensitive rat brain. The NCSAB also state there is relevant evidence that acrylonitrile possesses genotoxic and carcinogenic activity by acting indirectly in the production of brain tumours in the rat, and that this may possibly occur via a high-dose mechanism involving oxidative stress and changes in gap junction communication.