Lithium industry can generate a risk of airborne transport of substances, followed by a significant risk of deposition on soils and in water. It raises concerns about chronic low-dose exposure in the general population and occupational exposure among workers. Lithium exposure induces chronic toxicities on kidney, thyroid, heart, and effects on phosphate-calcium metabolism, reproduction and development. Current toxicological knowledge is largely derived from clinical data in patients under lithium treatment, but there is a critical lack of information on health effects associated with environmental exposure levels and on occupational exposures. The establishment of human biomonitoring guidance values (HBM-GVs) allows to aggregate all exposure routes for risk characterization related to real-life exposure. In 2026, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) together with the European Partnership for the Assessment of Risks from Chemicals (PARC) derived HBM-GVs in serum/plasma of 0.035 mg Li+.L-1 for the general population and 0.10 mg Li+.L-1 for workers, based on adverse effects observed at the minimum therapeutic lithium serum/plasma level of 0.5 mmol.L-1. ANSES also established a long-term oral toxicological reference value of 0.02 mg Li+.kg bw-1.day-1. These values apply to lithium as element and all its inorganic compounds. These guidance values will allow the implementation of management measures.
Carbon tetrachloride (CTC) is classified by the United States Environmental Protection Agency (US EPA) as "likely to be carcinogenic to humans," based on evidence in mice. In 2021, under the Toxic Substances Control Act (TSCA), US EPA derived a CTC cancer existing chemical exposure limit (ECEL) of 0.03 parts per million (ppm) for occupational exposure, and in 2024, released its Final Risk Management Rule incorporating this ECEL. However, US EPA's CTC ECEL is considerably lower than global occupational exposure limits (OELs) (0.1-10 ppm), and arguably not consistent with the best available science, as mandated by TSCA. In its derivation of the liver cancer ECEL, US EPA applied the lowest observed adverse effect concentration (LOAEC)/no observed adverse effect concentration (NOAEC) approach, rather than benchmark dose (BMD) modeling, and did not use CTC-specific physiologically based pharmacokinetic (PBPK) models for animal-to-human extrapolation. Here we derive revised cancer and non-cancer CTC ECELs of 1.5 and 1.6 ppm, respectively, considering the most reliable and sensitive endpoints and scientifically supported methodologies, including BMD and PBPK modeling. The revised cancer ECEL is 50-fold higher than US EPA's ECEL, more consistent with global OELs, and well below the OSHA permissible exposure limit (PEL) of 10 ppm. Overall, this approach would be expected to be applicable to other chemicals with a similar mode of action.
New approach methods (NAMs) can accelerate chemical assessment and reduce reliance on animal testing, but their application requires quantitative extrapolation of bioactive in vitro concentrations to equivalent in vivo doses. Confidence in quantitative in vitro–in vivo extrapolation (Q-IVIVE) is impacted by uncertainty in both the in vitro concentration and the toxicokinetic parameters used for reverse dosimetry. We propose a framework to: (1) define the processes used to derive an administered equivalent dose (AED); (2) identify uncertainty sources; (3) characterize uncertainty in the data and models; and (4) propagate these uncertainties to the AED. The framework distinguishes nominal assay concentrations from blood- or plasma-equivalent concentrations that account for chemical disposition and compositional differences between in vitro and in vivo media. Parameter-specific uncertainty factors can be derived from experimental variability, model performance statistics, simulations, or expert judgement and combined using a semi-probabilistic approach. Illustrative chemical-space analyses show that nominal and blood-equivalent concentrations may be comparable for some hydrophilic, non-volatile chemicals but can differ by more than two orders of magnitude for hydrophobic or volatile chemicals. The framework provides a systematic, and tiered basis for evaluating confidence in calculated Q-IVIVE doses and supports the application of NAM data in chemical hazard and risk assessment. Ongoing chemical-specific case studies will evaluate implementation of the framework, verify the validity of the simplifying assumptions, and identify opportunities for refinement.
