Vinyl acetate monomer (VAM) produced rat nasal tumors at concentrations in the hundreds of parts per million. However, VAM is weakly genotoxic in vitro and shows no genotoxicity in vivo. A European Union Risk Assessment concluded that VAM's hydrolysis to acetaldehyde (AA), via carboxylesterase, is a critical key event in VAM's carcinogenic potential. In the following study, we observed increases in micronuclei (MN) and thymidine kinase (Tk) mutants that were dependent on the ability of TK6 cell culture conditions to rapidly hydrolyze VAM to AA. Heat-inactivated horse serum demonstrated a high capacity to hydrolyze VAM to AA; this activity was highly correlated with a concomitant increase in MN. In contrast, heat-inactivated fetal bovine serum (FBS) did not hydrolyze VAM and no increase in MN was observed. AA's ability to induce MN was not impacted by either serum since it directly forms Schiff bases with DNA and proteins. Increased mutant frequency at the Tk locus was similarly mitigated when AA formation was not sufficiently rapid, such as incubating VAM in the presence of FBS for 4 hr. Interestingly, neither VAM nor AA induced mutations at the HPRT locus. Finally, cytotoxicity paralleled genotoxicity demonstrating that a small degree of cytotoxicity occurred prior to increases in MN. These results established 0.25 mM as a consistent concentration where genotoxicity first occurred for both VAM and AA provided VAM is hydrolyzed to AA. This information further informs significant key events related to the mode of action of VAM-induced nasal mucosal tumors in rats.
A variety of test methods were used to study the gradation, bioaccumulation, and toxicity of nicotine. Studies included determination of the octanol-water partition coefficient, conversion to CO2 in soil and activated sludge, and evaluation of the effects on microbiological and algal inhibition as well as plant germination and root elongation. The partitioning of nicotine between octanol and water indicated that nicotine will not bioaccumulate regardless of the pH of the medium. The aqueous and soil-based biodegradation studies indicated that nicotine is readily biodegradable in both types of media. The microbiological inhibition and aquatic and terrestrial toxicity tests indicated that nicotine has low toxicity. The U.S. Environmental Protection Agency Persistence, Bioaccumulation, and Toxicity Profiler model, based on the structure of nicotine and the predictive rates of hydroxyl radical and ozone reactions, estimated an atmospheric half-life of less than 5.0 h. Using this value in the Canadian Environmental Modeling Center level III model, the half-life of nicotine was estimated as 3.0 d in water and 0.5 d in soil. This model also estimated nicotine discharge into the environment; nicotine would be expected to be found predominantly in water (93%), followed by soil (4%), air (3%), and sediment (0.4%). Using the estimated nicotine concentrations in water, soil, and sediment and the proper median effective concentrations derived from the algal growth, biomass inhibition, and buttercrunch lettuce (Lactuca sativa) seed germination and root elongation studies, hazard quotients of between 10(-7) and 10(-8) were calculated, providing further support for the conclusion that the potential for nicotine toxicity to aquatic and terrestrial species in the environment is extremely low.
A tiered testing strategy has been developed to evaluate the potential for new ingredients, tobacco processes, and technological developments to increase or reduce the biological activity that results from burning tobacco. In the manufacture of cigarettes, honey is used as a casing ingredient to impart both aroma and taste. The primary objective of this document is to summarize and interpret chemical and toxicological studies that have been conducted to evaluate the potential impact of honey on the biological activity of either mainstream cigarette smoke or cigarette smoke condensate. As part of ongoing stewardship efforts, cigarettes produced with honey (5% wet weight) as an alternative to invert sugar in tobacco casing material were subjected to extensive evaluation. Principal components of this evaluation were a determination of selected mainstream smoke constituent yields, Ames assay, sister chromatid exchange assay in Chinese hamster ovary cells, a 30-wk dermal tumor promotion evaluation of cigarette smoke condensate in SENCAR mice, and a 13-wk inhalation study of cigarette smoke in Sprague-Dawley rats. Comparative analytical evaluations demonstrated that the substitution of honey for invert sugar as a casing material in cigarettes had no significant impact on mainstream smoke chemistry. In addition, in vitro and in vivo studies demonstrated that cigarettes containing tobacco cased with honey had comparable biological activity to cigarettes containing invert sugar. Collectively, these data demonstrate that the use of honey as an alternative casing material in the manufacture of cigarettes does not alter the potential toxicity of cigarette smoke condensate (CSC) or cigarette smoke; therefore the use of honey as an ingredient added to cigarette tobacco is acceptable from a toxicological perspective.
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