Genotoxicity of acrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and ethyl methacrylate in l5178y mouse lymphoma cells

Abstract

A series of monomeric acrylate/methacrylate esters (methyl acrylate, ethyl acrylate, methyl methacrylate, and ethyl methacrylate) as well as acrylic acid were examined for genotoxic activity in L5178Y mouse lymphoma cells without exogenous activation. All five compounds induced concentration-dependent increases in mutant frequency. Small-colony, trifluorothymidine-resistant mutants were primarily induced, which suggests that these compounds may act via a clastogenic mechanism. This prediction was confirmed by the finding that all five compounds produced gross chromosome aberrations in mouse lymphoma cells. The two acrylates were much more potent in their response than acrylic acid. Methyl acrylate (22 micrograms/ml, survival = 18%) induced 385 mutants/10(6) survivors (total mutant frequency less the spontaneous mutant frequency) and 45 chromosome aberrations/100 cells analyzed (total aberrations less the spontaneous background). Ethyl acrylate (37.5 micrograms/ml, survival = 15%) induced 683 mutants/10(6) survivors and 48 aberrations/50 cells analyzed. Acrylic acid (500 micrograms/ml, survival = 22%) induced 245 mutants/10(6) survivors and 37 aberrations/100 cells analyzed. The two methacrylates required higher concentrations to induce a positive response. Methyl methacrylate (2,799 micrograms/ml, survival = 11%) induced 230 mutants/10(6) survivors and 29 aberrations/200 cells analyzed. Ethyl methacrylate was extremely difficult to test because of a plateau in the dose response, over which the toxicity fluctuated from 2% to 37% survival. Positive responses (twice the spontaneous background) were only obtained at toxicity levels with less than approximately 20% survival. A concentration of 1,626 micrograms/ml (survival = 16%) induced 83 mutants/10(6) survivors and 11 aberrations/200 cells analyzed. The evidence suggests that the genotoxicity of these compounds is most likely due to a clastogenic mechanism.

Demonstration of a Temporal Relationship Between Ethyl Acrylate-Induced Forestomach Cell Proliferation and Carcinogenicity

“…(6,33) in organs such as the forestomach (13,17), liver (20), upper respiratory tract (25), kidney (31), and urinary bladder (5,7 (3,30). In studies with the L5178Y mouse lymphoma cell system (26). EA induced a positive response.…”

Joint FAO/WHO Expert Committee on Food Additives (JECFA)

“…Other experiments also showed induction of chromosomal aberrations in CHO cells (Anderson et al, 1990) and mouse lymphoma L5178Y cells (Moore et al, 1988;Doerr et al, 1989) and of sister chromatid exchanges in CHO cells (Anderson et al, 1990) following treatment with methyl 2-methyl-2-propenoate. Sister chromatid exchange experiments conducted with human lymphocytes were negative (Cannas et al, 1987).…”

“…In several mouse lymphoma mutation assays in L5178Y cells, methyl 2-methyl-2-propenoate showed positive results in the presence of metabolic activation (Rohm & Haas Co., 1985;Amtower et al, 1986;National Toxicology Program, 1986;Myhr et al, 1990;Dearfield et al, 1991). In the absence of metabolic activation, one assay revealed negative results (Rohm & Haas Co., 1985), one revealed ambiguous results (National Toxicology Program, 1986) and four revealed positive (or weakly positive) results (Moore et al, 1988;Doerr et al, 1989;Myhr et al, 1990;Dearfield et al, 1991). The positive results were mainly observed at cytotoxic concentrations.…”

Scientific Opinion on Flavouring Group Evaluation 72, Revision 1 (FGE.72Rev1): Consideration of aliphatic, branched‐chain saturated and unsaturated alcohols, aldehydes, acids, and related esters evaluated by the JECFA (61st meeting) structurally related to branched‐ and straight‐chain unsaturated carboxylic acids, esters of these and straight‐chain aliphatic saturated alcohols evaluated by EFSA in FGE.05Rev2

“…L5178Y TK+/-cells 1000 -3000 µg/ml (10 -30 mM) Positive 3 (Moore et al, 1988) Mutagenic responses and increases of small colonies were small, not clearly dose-related and observed only at concentrations above 10 mM. Dose-dependent effects on survival, with 60 % survival at 1000 µg/ml; approximately 15 % survival at 3000 µg/ml.…”