An interim internal Threshold of Toxicologic Concern (iTTC) for chemicals in consumer products, with support from an automated assessment of ToxCast™ dose response data

Blackburn, Karen; Carr, Gregory J.; Rose, Jane; Selman, Bastian

doi:10.1016/j.yrtph.2020.104656

Cited by 15 publications

(15 citation statements)

References 122 publications

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“…For example, while existing oral-dose based TTCs have been compared with high-throughput external exposure estimates for risk-based priority setting [20], the new iTTC can be used with internal aggregate exposure estimates using tools like the PROduction-To-EXposure High Throughput (PROTEX-HT) model [33]. Blackburn et al, [25] have previously proposed an in vitro derived iTTC of 1 µmol/L for cosmetics; however, this proposed value was associated with several caveats and exclusions making it difficult to directly compare with the new in vivo blood iTTC derived herein, i.e., 0.10 nmol/L-blood. We are not aware of any other reported iTTCs for blood and whole-body level.…”

Section: Discussionmentioning

confidence: 99%

“…Following the general approach for ingestion based TTCs, inhalation TTCs, e.g., [21], and dermal TTCs, e.g., [22], have also been developed. Partosch et al [23] proposed a route-to-route extrapolation method by revising the TTC to account for oral bioavailability; however, this proposed method does not adequately address the situation because it ignores other toxicokinetic (TK) processes [24,25]. The concept of an internal TTC (iTTC) has been proposed, e.g., [26][27][28] to address current limitations of the TTC so the approach can be applied more broadly including comparisons with aggregate exposure estimates.…”

Section: Introductionmentioning

confidence: 99%

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Developing an internal threshold of toxicological concern (iTTC)

Arnot

Toose

Armitage

et al. 2022

J Expo Sci Environ Epidemiol

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Background Threshold of Toxicological Concern (TTC) approaches are used for chemical safety assessment and risk-based priority setting for data poor chemicals. TTCs are derived from in vivo No Observed Effect Level (NOEL) datasets involving an external administered dose from a single exposure route, e.g., oral intake rate. Thus, a route-specific TTC can only be compared to a route-specific exposure estimate and such TTCs cannot be used for other exposure scenarios such as aggregate exposures. Objective Develop and apply a method for deriving internal TTCs (iTTCs) that can be used in chemical assessments for multiple route-specific exposures (e.g., oral, inhalation or dermal) or aggregate exposures. Methods Chemical-specific toxicokinetics (TK) data and models are applied to calculate internal concentrations (whole-body and blood) from the reported administered oral dose NOELs used to derive the Munro TTCs. The new iTTCs are calculated from the 5th percentile of cumulative distributions of internal NOELs and the commonly applied uncertainty factor of 100 to extrapolate animal testing data for applications in human health assessment. Results The new iTTCs for whole-body and blood are 0.5 nmol/kg and 0.1 nmol/L, respectively. Because the iTTCs are expressed on a molar basis they are readily converted to chemical mass iTTCs using the molar mass of the chemical of interest. For example, the median molar mass in the dataset is 220 g/mol corresponding to an iTTC of 22 ng/L-blood (22 pg/mL-blood). The iTTCs are considered broadly applicable for many organic chemicals except those that are genotoxic or acetylcholinesterase inhibitors. The new iTTCs can be compared with measured or estimated whole-body or blood exposure concentrations for chemical safety screening and priority-setting. Significance Existing Threshold of Toxicological Concern (TTC) approaches are limited in their applications for route-specific exposure scenarios only and are not suitable for chemical risk and safety assessments under conditions of aggregate exposure. New internal Threshold of Toxicological Concern (iTTC) values are developed to address data gaps in chemical safety estimation for multi-route and aggregate exposures.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Developing an internal threshold of toxicological concern (iTTC)

Arnot

Toose

Armitage

et al. 2022

J Expo Sci Environ Epidemiol

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“…Which compounds are important to include in biomonitoring studies? Databanks of potentially relevant compounds according to the lists published recently (Egeghy et al 2016;Ring et al 2019;Wang et al 2020) should be used, a thorough prioritization of compounds should be undertaken, and the following values should be considered and introduced in the selection process: production volumes, toxicity, and predicted exposure levels (Blackburn et al 2020;Dong et al 2019;Sobus et al 2019). From the selected list of compounds, the metabolism should be elucidated using experimental data, or predicted data from software such as QSAR Toolbox, Metaprint 2D, FAME, and Toxtree (Cronin et al 2019;Kirchmair et al 2015;Norinder et al 2018;Shapiro et al 2018;Suarez-Torres et al 2020;Tan and Kirchmair 2014;Tian et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Quo vadis blood protein adductomics?

Sabbioni

Day²

2021

Arch Toxicol

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Chemicals are measured regularly in air, food, the environment, and the workplace. Biomonitoring of chemicals in biological fluids is a tool to determine the individual exposure. Blood protein adducts of xenobiotics are a marker of both exposure and the biologically effective dose. Urinary metabolites and blood metabolites are short term exposure markers. Stable hemoglobin adducts are exposure markers of up to 120 days. Blood protein adducts are formed with many xenobiotics at different sites of the blood proteins. Newer methods apply the techniques developed in the field of proteomics. Larger adducted peptides with 20 amino acids are used for quantitation. Unfortunately, at present the methods do not reach the limits of detection obtained with the methods looking at single amino acid adducts or at chemically cleaved adducts. Therefore, to progress in the field new approaches are needed.

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“…Current well-established human health TTC values are focused on exposures that are assessed as external oral ingestion, whereas internal exposures based on blood concentrations can be more relevant for other exposure routes, such as inhalation (Tluczkiewicz et al, 2016 ) or for substances with low oral absorption. Additionally, recent efforts in human health TTCs have focused on deriving an internal threshold of toxicological concern (iTTC) that may ultimately enable route-to-route extrapolation and TTC development for multi-route exposures (Ellison et al, 2019 ; Blackburn et al, 2020 ). Because aquatic organism exposures mainly occur through water, there is less need to address multi-exposure routes.…”

Section: Future Developments and Research Needsmentioning

confidence: 99%

Ecological Thresholds of Toxicological Concern: A Review

et al. 2021

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The ecological threshold of toxicological concern (ecoTTC) is analogous to traditional human health-based TTCs but with derivation and application to ecological species. An ecoTTC is computed from the probability distribution of predicted no effect concentrations (PNECs) derived from either chronic or extrapolated acute toxicity data for toxicologically or chemically similar groups of chemicals. There has been increasing interest in using ecoTTCs in screening level environmental risk assessments and a computational platform has been developed for derivation with aquatic species toxicity data (https://envirotoxdatabase.org/). Current research and development areas include assessing mode of action-based chemical groupings, conservatism in estimated PNECs and ecoTTCs compared to existing regulatory values, and the influence of taxa (e.g., algae, invertebrates, and fish) composition in the distribution of PNEC values. The ecoTTC continues to develop as a valuable alternative strategy within the toolbox of traditional and new approach methods for ecological chemical assessment. This brief review article describes the ecoTTC concept and potential applications in ecological risk assessment, provides an overview of the ecoTTC workflow and how the values can be derived, and highlights recent developments and ongoing research. Future applications of ecoTTC concept in different disciplines are discussed along with opportunities for its use.

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An interim internal Threshold of Toxicologic Concern (iTTC) for chemicals in consumer products, with support from an automated assessment of ToxCast™ dose response data

Cited by 15 publications

References 122 publications

Developing an internal threshold of toxicological concern (iTTC)

Developing an internal threshold of toxicological concern (iTTC)

Quo vadis blood protein adductomics?

Ecological Thresholds of Toxicological Concern: A Review

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