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. 2022 Nov;32(6):877-884.
doi: 10.1038/s41370-022-00494-x. Epub 2022 Nov 8.

Developing an internal threshold of toxicological concern (iTTC)

Jon A Arnot  1   2   3 , Liisa Toose  4 , James M Armitage  4 , Alessandro Sangion  4   5 , Alexandra Looky  4 , Trevor N Brown  4 , Li Li  6 , Richard A Becker  7
Affiliations

Developing an internal threshold of toxicological concern (iTTC)

Jon A Arnot et al. J Expo Sci Environ Epidemiol. 2022 Nov.

Erratum in

Abstract

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.

Keywords: Exposure modeling, Dermal exposure, Dietary exposure, Inhalation exposure, New approach methodologies (NAMs), PBPK modeling.

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Conflict of interest statement

JAA, LT, JMA, AS, AL, TNB and LL acknowledge funding from the American Chemistry Council Long-Range Research Initiative (ACC-LRI). ARC Arnot Research and Consulting receives research funding from Health Canada, Environment and Climate Change Canada, and various chemical companies and industry groups. RB is a Senior Toxicologist and Director of the ACC-LRI at American Chemistry Council.

Figures

Fig. 1
Fig. 1. Conceptual overview of the approaches used in this study to derive iTTCs.
External dose NOELs were converted using a general toxicokinetic model to generate the cumulative distribution of internal NOELs, and then lower 5th percentile internal NOEL value was divided by a 100-fold adjustment factor to calculate the iTTC.
Fig. 2
Fig. 2. Tiered approach and workflow for parameterizing toxicokinetics models with whole-body total (terminal) elimination rate constant (kT) and whole-body biotransformation rate constant (kB) data to calculate internal doses from the reported NOELs in the Munro TTC database [11, 39] as derived from external oral doses.
Blood concentrations (CB or Cblood) are then calculated from whole body concentrations (CWB) as shown in Eq. (3). Absorption efficiency (AE) is used in the parameterization of the default and alternative #1 models while oral bioavailability (F) is used in the alternative model #2 calculations.
Fig. 3
Fig. 3. External and internal doses corresponding to NOELs in the Munro TTC database [11, 39].
The dashed diagonal line represents the 1:1 line.
Fig. 4
Fig. 4. Cumulative distribution of modeled blood concentrations corresponding to NOELs reported in the Munro TTC database [11, 39] using the default and alternative assumptions (Alt #1, Alt #2, see “Methods” section).
The figure on the right provides a better view of the lower 20% of the data in the cumulative distribution.
Fig. 5
Fig. 5. Cumulative distribution of modeled whole-body concentrations corresponding to NOELs reported in the Munro TTC database [11, 39] using the default and alternative assumptions (Alt #1, Alt #2, see “Methods” section).
The figure on the right provides a better view of the lower 20% of the data in the cumulative distribution.
See this image and copyright information in PMC

Comment in

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