Chronic dietary toxicity and carcinogenicity studies of dammar resin in F344 rats
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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-week 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 the 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 rat-fed diet-containing 2% dammar resin had increased levels of protein oxidation and increased the 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.
KeywordsDammar resin Food additive Liver tumor Hepatocarcinogen Male F344 rats Hemorrhagic diathesis
This work was supported by Health and Labour Sciences Research Grants from the Ministry of Health, Labor and Welfare of Japan, and a grant from The Japan Food Chemical Research Foundation. We are grateful to Dr. Robert R. Maronpot (Maronpot Consulting LLC, Raleigh, NC, USA) for reviewing this manuscript. The authors gratefully acknowledge the technical assistance of Masahiko Kushida (Sumika Partners, Osaka, Japan), Kaori Nakakubo, Rie Onodera, Keiko Sakata, Yuko Hisabayashi, and Yukiko Iura (Department of Molecular Pathology, Osaka City University Graduate School of Medicine School, Osaka, Japan), and Shiota Masayuki and Yukimi Kira (Research Support Platform, Osaka City University Graduate School of Medicine, Osaka, Japan).
Compliance with ethical standards
The manuscript does not contain clinical studies or patient data.
Conflict of interest
The authors declare that they have no conflict of interest.
- Bloom JC, Brandt JT (2007) Toxic responses of the blood. In: Klaassen C (ed) Casarett & Doull’s toxicology: the basic science of poisons. Seventh Edition edn. McGraw-Hill Education, New YorkGoogle Scholar
- Cohen SM, Fukushima S, G FP et al (2017) 2017 GRAS flavoring substances 28. https://www.femaflavor.org/publications/gras-publications/gras-28
- FSCJ (2010) Guideline for assessment of the effect of food on human health regarding food additives, Food Safety Commission of Japan (FSCJ) http://www.fsc.go.jp/english/standardsforriskassessment/guideline_assessment_foodadditives_e2.pdf
- Gibson GG, Plant NJ, Swales KE, Ayrton A, El-Sankary W (2002) Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man. Xenobiotica 32(3):165–206. https://doi.org/10.1080/00498250110102674 CrossRefPubMedGoogle Scholar
- Hayashi M, Matsui M, Ishii K, Kawasaki M (2000) Environmental mutagen research 22:27–44. http://ci.nii.ac.jp/naid/110001710452/en (in Japanese)
- INHAND. International harmonization of nomenclature and diagnostic criteria for lesions in rats and mice. Society of Toxicologic Pathology. https://www.goreni.org/gr3_nom_inhand_publ.php
- JECFA (1986) Evaluation of certain food-additives and contaminants (twenty-ninth report of the Joint FAO/WHO Expert Committee on Food Additives). WHO Technical Report Series Evaluation of Certain Food Additives and Contaminants. vol 733, p 16Google Scholar
- Mammen E (2002) Thrombohemorrhagic defects in liver and renal diseases. In: Bick RL (ed) Disorders of thrombosis and hemostasis: clinical and laboratory practice. 3rd Edition edition edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
- NTP (2011) NTP historical controls report: all routes and vehicles: F344/N rats. http://ntp.niehs.nih.gov/ntp/historical_controls/ntp2000_2010/2010-03-22-hist-ratsallroutes.pdf. Washington, DC
- USP (2012) Food chemicals codex, 8th edn. The United States Pharmacopeial Convention, Washington, DCGoogle Scholar
- Xie XL, Wei M, Kakehashi A et al (2012) Dammar resin, a non-mutagen, induces [corrected] oxidative stress and metabolic enzymes in the liver of gpt delta transgenic mouse which is different from a mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline. Mutat Res 748(1–2):29–35. https://doi.org/10.1016/j.mrgentox.2012.06.005 CrossRefPubMedGoogle Scholar