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Derivation of New Threshold of Toxicological Concern Values for Exposure via Inhalation for Environmentally-Relevant Chemicals
Citation:
Nelms, M. AND G. Patlewicz. Derivation of New Threshold of Toxicological Concern Values for Exposure via Inhalation for Environmentally-Relevant Chemicals. Frontiers in Toxicology. Frontiers, Lausanne, Switzerland, 2:580347, (2020). https://doi.org/10.3389/ftox.2020.580347
Impact/Purpose:
The oral non-cancer TTC values were developed on a dataset that aimed to cover a broad spectrum of chemicals. The dataset is over 20 years old and it is pertinent to question how relevant the established TTC values are for chemicals of interest to the agency. This work intends to derive new TTC values based on an expanded dataset, compare the new TTC values with the existing TTC values and rationalize the reasons for any differences. The interest in applying TTC approaches as a method to identify chemicals that may need further review in the risk context stresses the importance of bring these methods in line with our chemical domain and for relevant routes of administration. Further work will investigate the feasibility of deriving TTCs for other routes of entry (inhalation route) and other exposures durations e.g. short-term vs long-term. Efforts will also be made to provide greater specificity around the exclusion rules for TTC (notably chemicals that are dioxin like, steroids, high potency carcinogens or organometallics) and how these have been encoded into software tools such as Toxtree.
Description:
The requirements of amended Toxic Substances Control Act (TSCA) stipulates that the US Environmental Protection Agency (US EPA) evaluate existing chemicals and make risk based assessments. There are ~33,000 substances that are active in commerce on the TSCA public non-confidential inventory, many of which lack available toxicity and exposure information to inform risk-based decision making. One approach to facilitate the assessment of these substances being considered is the Threshold of Toxicological Concern (TTC). TTC values are intended to identify safe levels of exposure for data poor substances. TTC values derived based on non-cancer data notably by Munro et al. (1996) are well-established and are in routine use for food additive applications however far less attention has been focused on developing TTC values where inhalation is the route of exposure. Here, an effort was made to derive new inhalation TTC values using the EPA's Toxicity Values database, ToxValDB. A total of 4,703 substances captured in ToxValDB were assigned into their respective TTC categories using the Kroes module within the Toxtree software tool and custom profilers developed in Nelms et al. (2019) and Patlewicz et al. (2018). For the substances assigned into the 3 Cramer classes, the 5th percentiles were calculated from the empirical cumulative distributions of No observed (adverse) effect level (concentration) values. The 5th percentiles were converted to their respective TTC values and compared with published values reported by Escher et al. (2010) and Carthew et al. (2009). The TTC values derived from ToxValDB were orders of magnitude more conservative, further, Cramer classification was not found to be effective at discriminating potencies. Instead, use of aquatic toxicity modes of action such as Verhaar et al. (1992) were found to be effective at separating substances in terms of their potencies and new TTC thresholds were derived.
URLs/Downloads:
DOI: Derivation of New Threshold of Toxicological Concern Values for Exposure via Inhalation for Environmentally-Relevant Chemicals