Enhanced Toxicity of Bisphenols Together with UV Filters in Water: Identification of Synergy and Antagonism in Three-Component Mixtures

Abstract

Contaminants of emerging concern (CEC) localize in the biome in variable combinations of complex mixtures that are often environmentally persistent, bioaccumulate and biomagnify, prompting a need for extensive monitoring. Many cosmetics include UV filters that are listed as CECs, such as benzophenone derivatives (oxybenzone, OXYB), cinnamates (2-ethylhexyl 4-methoxycinnamate, EMC) and camphor derivatives (4-methylbenzylidene-camphor, 4MBC). Furthermore, in numerous water sources, these UV filters have been detected together with Bisphenols (BPs), which are commonly used in plastics and can be physiologically detrimental. We utilized bioluminescent bacteria (Microtox assay) to monitor these CEC mixtures at environmentally relevant doses, and performed the first systematic study involving three sunscreen components (OXYB, 4MBC and EMC) and three BPs (BPA, BPS or BPF). Moreover, a breast cell line and cell viability assay were employed to determine the possible effect of these mixtures on human cells. Toxicity modeling, with concentration addition (CA) and independent action (IA) approaches, was performed, followed by data interpretation using Model Deviation Ratio (MDR) evaluation. The results show that UV filter sunscreen constituents and BPs interact at environmentally relevant concentrations. Of notable interest, mixtures containing any pair of three BPs (e.g., BPA + BPS, BPA + BPF and BPS + BPF), together with one sunscreen component (OXYB, 4MBC or EMC), showed strong synergy or overadditive effects. On the other hand, mixtures containing two UV filters (any pair of OXYB, 4MBC and EMC) and one BP (BPA, BPS or BPF) had a strong propensity towards concentration dependent underestimation. The three-component mixtures of UV filters (4MBC, EMC and OXYB) acted in an antagonistic manner toward each other, which was confirmed using a human cell line model. This study is one of the most comprehensive involving sunscreen constituents and BPs in complex mixtures, and provides new insights into potentially important interactions between these compounds.

Acute toxicity assessment of nine organic UV filters using a set of biotests

“…In general, so far little is known about the interactions of chemicals in mixtures. On the one hand, it is commonly found that mixed toxic chemicals result in synergistic or additive effects, however, on the other hand, there are also some pieces of evidence about antagonistic interactions between UV filters [ 102 – 104 ]. Based on the results presented in Table 3 it can be summarized that the calculated total TU value of 16 out of 20 binary and ternary mixtures was greater than 1, indicating that the toxicity of mixtures on Allivibrio fisheri was antagonistic.…”

The effect of sunscreen 4‐methylbenzylidene camphor in different and reproductive models, its bioaccumulation and molecular effects on ligand‐receptor interaction, and protein expression

“…This can occur even if there are no obvious adverse effect levels (NOAELs) individually 43,44 . In a recent study where mixtures of BPs and UV‐filters were tested as a mixture, it was found that mixing any three BPs with 4‐MBC can lead to strong synergy effects 45 . The particular mixtures contained any pair of three BPs (e.g., BPA + BPS, BPA + BPF and BPS + BPF), together with one sunscreen component, that is, oxybenzone, OXYB, 4‐MBC or cinnamates (2‐ethylhexyl 4‐methoxycinnamate, EMC).…”

Generation of Endogenous Promoter-Driven Luciferase Reporter System Using CRISPR/Cas9 for Investigating Transcriptional Regulation of the Core Clock Gene BMAL1

“…Mixtures of these contaminants may synergistically exert biological effects and no longer conform to the stoichiometric response curve [ 10 , 11 , 13 ]. The biological effects of chemicals or mixtures are difficult to assess using traditional toxicological methods [ 14 , 15 , 16 ]. We lack validated models and methods to study the damage from exposure to high numbers of chemicals and their mixtures in humans.…”