Chronic dietary toxicity and carcinogenicity studies of dammar resin in F344 rats

Abstract

Dammar resin is a natural food additive and flavoring substance present in many foods and drinks. The present study evaluates the chronic toxicity and carcinogenicity of dietary dammar resin in F344 rats. Dietary concentrations in the 52 weeks chronic toxicity study were 0, 0.03, 0.125, 0.5, or 2%. The major treatment-related deleterious effects were body weight suppression, increased relative liver weight, and low hemoglobin levels in males and females. Foci of cellular alteration in the liver were observed in the male 2% group, but not in any other group. The no-observed-adverse-effect level for chronic toxicity was 0.125% for males (200.4 mg/kg b.w./day) and females (241.9 mg/kg b.w./day). Dietary concentrations in the 104-week carcinogenicity study were 0, 0.03, 0.5, or 2%. Dammar resin induced hemorrhagic diathesis in males and females, possibly via inhibition of extrinsic and intrinsic coagulation pathways. Incidences of hepatocellular adenomas and carcinomas were significantly increased in the male 2% group, but not in any other group. In the 4-week subacute toxicity study, the livers of male rats fed diets containing 2% dammar resin had increased levels of protein oxidation and increased expression of two anti-apoptotic and seven cytochrome P450 (CYP) genes. There was also an increased tendency of oxidative DNA damage. These findings demonstrate that dammar resin is hepatocarcinogenic in male F344 rats and underlines the roles of inhibition of apoptosis, induction of CYP enzymes, and oxidative stress in dammar resin-induced hepatocarcinogenesis.

Highlight report the food additive dammar resin is a rat hepatocarcinogen

“…The results of Gi and colleagues are of high relevance, since dammar resin is used as a food additive and flavoring substance in drinks, frozen desserts and in chewing gum (Gi et al 2018;Cohen et al 2017, USP 2012. It is produced as an exudate from trees of Agathis, Hopea or Shorea genera (Gi et al 2018).…”

“…The results of Gi and colleagues are of high relevance, since dammar resin is used as a food additive and flavoring substance in drinks, frozen desserts and in chewing gum (Gi et al 2018;Cohen et al 2017, USP 2012. It is produced as an exudate from trees of Agathis, Hopea or Shorea genera (Gi et al 2018). For risk evaluation, it should be considered that the concentrations of dammar resin in food are orders of magnitude lower than the doses used in the present study (Gi et al 2018).…”

“…Recently, Gi and colleagues from Osaka University in Japan published a 52-week chronic toxicity study and a 104-week carcinogenicity study of dammar resin in F344 rats (Gi et al 2018). The authors demonstrated that hepatocellular adenomas and carcinomas were induced at 2% dietary concentrations of dammar resin, corresponding to 242 mg/kg b.w./ day, while 0.5% (178 mg/kg b.w./day) was the no-observedadverse-effect level (NOAEL).…”

“…It is produced as an exudate from trees of Agathis, Hopea or Shorea genera (Gi et al 2018). For risk evaluation, it should be considered that the concentrations of dammar resin in food are orders of magnitude lower than the doses used in the present study (Gi et al 2018). Moreover, dammar resin was negative in genotoxicity and mutagenicity tests, including chromosomal aberration tests and the mouse bone marrow micronucleus assay (Hayashi et al 2000), suggesting that the compound acts as a non-genotoxic rat liver carcinogen.…”

“…Readout comprises not only the cytotoxicity but also gene expression and hepatocellular functions (Deharde et al 2016;Godoy et al 2016Godoy et al , 2018Jansen et al 2017;Reif et al 2015;Grinberg et al 2014;Stöber 2016;Hammad et al 2017Hammad et al , 2018. This is of interest, since dammar resin induces at least seven cytochrome P450 isoforms rodents in vivo and also generates reactive oxygen species in rat liver (Gi et al 2018), key events known to be associated with non-genotoxic hepatocarcinogenesis (Cohen 2010; Hall et al 2012;Leist et al 2017;Godoy et al 2013;Hewitt et al 2007;Nwosu et al 2017). Therefore, a comparison of these and similar endpoints, e.g.…”