Making safety decisions for a sunscreen active ingredient using next-generation risk assessment: Benzophenone-4 case study
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Abstract
A next generation risk assessment was carried out to evaluate the safety of benzophenone-4 (BP-4), a UV filter present at 5% in a body lotion, to compare a non-animal approach with a traditional safety assessment based on historical animal data. Exposure characterization indicated that BP-4 is poorly absorbed through the skin, poorly metabolized by the liver, a substrate of influx and efflux transporters, and excreted by the kidney. The resulting physiologically-based kinetic model predicted an upper bound (95th percentile) plasma Cmax of 1.27 µM, and liver and kidney concentrations of 0.32 µM and 0.44µM, respectively. To characterize bioactivity, in silico and in vitro new approach methodologies were used. Points of departure (PoDs) were derived from four bioactivity platforms, including in vitro pharmacological profiling, CALUX assays, high-throughput transcriptomics, and a cell stress panel. By dividing the in vitro PoDs (PoDNAM) from these assays by the 95th percentile plasma Cmax value, so-called bioactivity:exposure ratios (BERs) were calculated. The lowest PoD was from a single gene expression change, and the highest PoD from phenotypic biomarkers using a primary renal cell model. Most BERs were above 11, except for those from gene-level PoDNAM in HepG2 and MCF-7 cells, which were 3.3 and 4.3. These lowest PoDNAMs are linked to gene transcription changes and are likely indicative of adaptive biological activity rather than adverse health effects. This work demonstrates the usefulness of next generation risk assessment in addressing pressing relevant regulatory questions without using animals.
Plain language summary
This study on benzophenone-4 (BP-4) highlights the potential of modern, non-animal testing methods to provide comprehensive safety evaluations. By demonstrating that BP-4 is poorly absorbed through the skin and efficiently excreted by the kidneys, the research underscores the compound's low systemic exposure. The use of advanced in silico and in vitro techniques allowed for detailed bioactivity assessments, revealing that most biological responses occurred at levels higher than the predicted consumer exposure and were likely adaptive. This approach not only aligns with the 3Rs principle by reducing reliance on animal testing but also offers a more ethical and potentially faster pathway for regulatory safety assessments. The findings suggest that next-generation risk assessments can effectively address safety concerns while paving the way for broader acceptance and implementation of these innovative methods in the regulatory landscape.
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