Toxicity reference values: relevance for the evaluation of toxicity and risk
Toxicity Reference Values (TRVs), for cancer and non-cancer biological effects, represent levels below which impact to human health is unlikely to occur. TRVs are derived from long-term (i.e. chronic) toxicity studies for the relevant route of exposure identifying the most sensitive endpoints. Alternatively, if weight-of-evidence (WOE) supports it, route-to-route (r-to-r) extrapolation with appropriate dosimetry adjustments may also be used. The quality and relevance of the toxicological studies used to determine benchmark values (e.g. BMDL10) to develop the TRV, should be taken into consideration. The selection of the most relevant study (i.e. critical effect) for the biological effect of interest, and the type of data-fitting model, often results in conflicting TRVs for the same analyte. Moreover, differences in terminology around TRVs often lead to multiple and differing values published nationally and internationally. The publication of third-party or research-based reviews leading to different TRVs adds debate to this topic. The evaluation of potential toxicity and risk of tobacco products is conducted by comparing exposure levels of individual analytes (e.g. smoke constituents) to their respective TRV. Lifetime exposure is estimated using relevant parameters for tobacco-product specific exposure including inhalation rate, intensity, frequency and duration. The selection of the TRV determines the level of toxicity and risk. TRVs are set for both cancer and non-cancer toxicity evaluations by National (e.g. US EPA) and International (e.g. Health Canada) agencies. In some instances, TRVs at the state level also exist, including those published by California EPA (Cal/EPA) and Texas Commission of Environmental Quality (TCEQ). This work evaluated available TRVs and their relevance for the evaluation of toxicity and risk of tobacco products. We found that TRVs should be selected on a case-by-case basis and in certain cases TRVs should be confirmed using the appropriate tool such as BMDS.