Toxicological assessment of cigarette ingredients

O impacto dos aditivos do tabaco na toxicidade da fumaça do cigarro: uma avaliação crítica dos estudos patrocinados pela indústria do fumo

“…A major problem with using this in vivo gentoxicity (clastogenicity/aneugenicity) test for revealing a possible change in tobacco smoke toxicity is its poor response or even unresponsiveness to tobacco smoke 44 . Industry toxicologists justify the inclusion of such known smoke-unresponsive tests in a test battery for tobacco additives arguing that it seeks to ensure that this "lack of micronucleus activity was maintained with the addition of the ingredient" 45 (p. 122).…”

“…Tobacco industry (PMI) researchers advanced a tiered approach to assess the "safety" of cigarette ingredients/additives 45 . Industry testing scheme tiers are maximum use levels (concentration rela-Cad.…”

“…Industry testing scheme tiers are maximum use levels (concentration rela-Cad. Saúde Pública 2017; 33 Sup 3:e00132415 tive to cut filler weight, ppm) as follows: tier 0 (up to 0.025ppm): only literature review and QSAR (Quantitative Structure-Activity Relationships); tier 1 (15ppm), tier 0 plus pyrolysis and/or analysis of volatile organic compounds; tier 2 (90ppm): tier 1 plus smoke chemistry (18 smoke constituents); tier 3 (300ppm), tier 2 plus a broader smoke chemistry (Hoffman analytes); tier 4 (3,000ppm), tier 3 plus in vitro mutagenicity assays (Salmonella assay; NR uptake cytotoxicity; mouse lymphoma assay); and tier 5 (> 3,000ppm), tier 4 plus 90-day inhalation toxicity study (rats) and in vivo bone marrow micronucleus assay (mice) 45 .…”

“…The TTC concept assumes that human exposure to chemicals below the corresponding TTC are very unlikely to cause any adverse effect. According to Dempsey et al 45 , the additive level triggering in vivo inhalation studies (30,000ppm) (tier 5) was "derived from ingredient inhalation studies sponsored by PMI over more than a decade" 45 (p. 126). That is, 95% of PMI-conducted inhalation studies did not show adverse effects of tested ingredients up to concentrations as high as 30,000ppm.…”

“…That is, 95% of PMI-conducted inhalation studies did not show adverse effects of tested ingredients up to concentrations as high as 30,000ppm. The cut-off points of intermediate tiers (15,90, 300, and 3,000ppm) were derived from defined percentiles along cumulative distribution curve of the NOAELs, while the cut-off for the lowest tier 0 (0.025ppm) was based on TTC levels previously established for genotoxic substances 45 .…”