TY - JOUR
KW - Animal Testing Alternatives
KW - Animals
KW - Benzophenones
KW - Humans
KW - Risk Assessment
KW - Sunscreening Agents
KW - Alternative approaches
KW - animal-free risk-assessment
KW - cosmetics safety
KW - exposure scenario
KW - New Approach Methodologies (NAMs)
KW - Next-Generation Risk Assessment (NGRA)
AU - Maria T. Baltazar
AU - Sophie Cable
AU - Richard Cubberley
AU - Nicola J. Hewitt
AU - Jade Houghton
AU - Predrag Kukic
AU - Hequn Li
AU - Sophie Malcomber
AU - Beate Nicol
AU - Ruth Pendlington
AU - Ans Punt
AU - Joe Reynolds
AU - Sharon Scott
AU - Sandrine Spriggs
AU - Matthew P. Dent
AB - 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 0.44 μM, 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, 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 PoDNAM values 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.
BT - ALTEX
DA - 2025
DO - 10.14573/altex.2501201
IS - 3
LA - eng
N2 - 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 0.44 μM, 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, 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 PoDNAM values 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.
PY - 2025
SP - 511
EP - 530
ST - Making safety decisions for a sunscreen active ingredient using next-generation risk assessment
T2 - ALTEX
TI - Making safety decisions for a sunscreen active ingredient using next-generation risk assessment: Benzophenone-4 case study
VL - 42
SN - 1868-8551
ER -