The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that is based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health. The concept that there are levels of exposure that do not cause adverse effects is inherent in setting acceptable daily intakes (ADIs) for chemicals with known toxicological profiles. The TTC principle extends this concept by proposing that a de minimis value can be identified for many chemicals, in the absence of a full toxicity database, based on their chemical structures and the known toxicity of chemicals which share similar structural characteristics. The establishment and application of widely accepted TTC values would benefit consumers, industry and regulators. By avoiding unnecessary toxicity testing and safety evaluations when human intakes are below such a threshold, application of the TTC approach would focus limited resources of time, cost, animal use and expertise on the testing and evaluation of substances with the greatest potential to pose risks to human health and thereby contribute to a reduction in the use of animals. An Expert Group of the European branch of the International Life Sciences Institute-ILSI Europe-has examined the TTC principle for its wider applicability in food safety evaluation. The Expert Group examined metabolism and accumulation, structural alerts, endocrine disrupting chemicals and specific endpoints, such as neurotoxicity, teratogenicity, developmental toxicity, allergenicity and immunotoxicity, and determined whether such properties or endpoints had to be taken into consideration specifically in a step-wise approach. The Expert Group concluded that the TTC principle can be applied for low concentrations in food of chemicals that lack toxicity data, provided that there is a sound intake estimate. The use of a decision tree to apply the TTC principle is proposed, and this paper describes the step-wise process in detail. Proteins, heavy metals and polyhalogenated-dibenzodioxins and related compounds were excluded from this approach. When assessing a chemical, a review of prior knowledge and context of use should always precede the use of the TTC decision tree. The initial step is the identification and evaluation of possible genotoxic and/or high potency carcinogens. Following this step, non-genotoxic substances are evaluated in a sequence of steps related to the concerns that would be associated with increasing intakes. For organophosphates a TTC of 18microg per person per day (0.3 microg/kg bw/day) is proposed, and when the compound is not an OP, the TTC values for the Cramer structural classes III, II and I, with their respective TTC levels (e.g. 1800, 540 and 90 microg per person per day; or 30, 9 and 1.5 microg/kg bw /day), would be applied sequentially. All other endpoints or properties were shown to have a distribution of no observed effect levels (NOELs) similar to the distribution of NOELs for general toxicity endpoints in Cramer classes I, II and III. The document was discussed with a wider audience during a workshop held in March 2003 (see list of workshop participants).

Structure-Based Thresholds of Toxicological Concern (TTC): Guidance for Application to Substances Present at Low Levels in the Diet

Predictive Models for Acute Oral Systemic Toxicity: A Workshop to Bridge the Gap from Research to Regulation.

Current computational technologies hold promise for prioritizing the testing of the thousands of chemicals in commerce. Here, a case study is presented demonstrating comparative risk-prioritization approaches based on the ratio of surrogate hazard and exposure data, called margins of exposure (MoEs). Exposures were estimated using a U.S. EPA’s ExpoCast predictive model (SEEM3) results and estimates of bioactivity were predicted using: 1) Oral equivalent doses (OEDs) derived from U.S. EPA’s ToxCast high-throughput screening program, together with in vitro to in vivo extrapolation and 2) thresholds of toxicological concern (TTCs) determined using a structure-based decision-tree using the Toxtree open source software. To ground-truth these computational approaches, we compared the MoEs based on predicted noncancer TTC and OED values to those derived using the traditional method of deriving points of departure from no-observed adverse effect levels (NOAELs) from in vivo oral exposures in rodents. TTC-based MoEs were lower than NOAEL-based MoEs for 520 out of 522 (99.6%) compounds in this smaller overlapping dataset, but were relatively well correlated with the same (r 2 = 0.59). TTC-based MoEs were also lower than OED-based MoEs for 590 (83.2%) of the 709 evaluated chemicals, indicating that TTCs may serve as a conservative surrogate in the absence of chemical-specific experimental data. The TTC-based MoE prioritization process was then applied to over 45,000 curated environmental chemical structures as a proof-of-concept for high-throughput prioritization using TTC-based MoEs. This study demonstrates the utility of exploiting existing computational methods at the pre-assessment phase of a tiered risk-based approach to quickly, and conservatively, prioritize thousands of untested chemicals for further study.

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Estimating provisional margins of exposure for data-poor chemicals using high-throughput computational methods

Evaluating the utility of the Threshold of Toxicological Concern (TTC) and its exclusions in the biocompatibility assessment of extractable chemical substances from medical devices.

Threshold of toxicological concern (TTC) is a concept that has been around for decades in human health sciences. Ecotoxicology recently adopted a variant of this concept as eco-TTC. Adoption of the concept of TTC considerably reduces the amount of animal testing required for regulatory purposes. We provide an application of a universal TTC for the entirety of acute fish toxicity data (i.e., establishment of an exposure level below which there would be minimal probability of acute fish toxicity for any chemical, without consideration of mechanism of action). We calculated TTC values for a number of subgroups using various approaches. These approaches were evaluated using data from a cohort of 69 999 acute fish toxicological assays. This database was normalized/curated for units, exposure duration, quality assurance/control, and duplicates, which reduced it to 47 694 assays. Data were not normally but log-normally distributed, making geometric means the most appropriate statistical parameter. Thus, we developed descriptive statistics using geometric means with 95, 99, and 99.9% confidence intervals. Various assessment factors (akin to predicted-no-effect concentration derivation) were applied to the geometric means to derive TTCs. Other approaches employed were the calculation of y = 0 intercepts as well as development of 95 and 99.75% cutoffs of cumulative data as well as modular uncertainty scoring tool (MUST) analysis. All of the methodologies derived highly congruent TTCs ranging from to 2 to 8 μg/L except for the 99.75th percentile cutoff of 0.3 μg/L. The data would be most useful in making a binary testing/no testing required decision. For acute fish toxicity, a TTC value of 2 μg/L was most appropriate, based on the 95th percentile of data distribution without any assessment factor. Environ Toxicol Chem 2021;40:1740-1749. © 2021 SETAC.

Jeremy Fitzpatrick

Papers

The TTC Data Mart: An interactive browser for threshold of toxicological concern calculations

Using Chemical and Biological Descriptors to Develop Predictive Models for Rat Acute Oral Toxicity