Developing an internal threshold of toxicological concern (iTTC)

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.