Tripropylene Glycol Diacrylate but Not Ethyl Acrylate Induces Skin Tumors in a Twenty-Week Short-Term Tumorigenesis Study in Tg.AC (v-Ha-ras) Mice

Abstract

The toxicity of the esters of acrylic acid are poorly understood even though significant human exposure occurs. To conduct rapid comparative short-term bioassays, we used the Tg.AC (v-Ha-ras) transgenic mouse model to determine the toxicity and potential carcinogenicity of tripropylene glycol diacrylate (TPGDA) alone and in a reference formulated ultraviolet radiation curable lacquer (Lacquer A), which is used in the ultraviolet radiation curable surface coatings. For comparison, ethyl acrylate (EA) was used as a reference acrylate. Insertion of the zeta-globin promoted v-Ha-ras transgene into the FVB mouse genome (Tg.AC) introduced a defined genetic lesion, which is critical but insufficient by itself to induce benign or malignant tumors in the skin unless activated. Activation and expression of the transgenic ras oncoprotein in this mouse line induces a dose-related increase in papillomas (skin reporter phenotype) within weeks. Based on dose-related increases in skin hyperplasia following dermal exposure to EA, TPGDA, or Lacquer A (applied equimolar for TPGDA concentration), the dosing regimen was selected. Starting at 12 wk of age, the agents were administered topically (200 microliters of acetone vehicle) 3 times/wk for 20 wk to the shaved dorsal skin of female Tg.AC mice (n = 10/group). TPGDA and reference Lacquer A (equimolar for TPGDA) at 5 or 10 mumoles/mouse but not EA (60, 300, or 600 mumoles/mouse) or TPGDA or Lacquer A at 1 mumole/mouse induced a dose-related increase in papillomas between 6 and 12 wk of treatment that reached a maximum number of papillomas per mouse between 19 and 20 wk of treatment. These results indicate that TPGDA is significantly more potent than EA for inducing the skin reporter phenotype and may be predicted to be carcinogenic in long-term cancer bioassays at the site of contact.