Recently, Santamaria and colleagues published a dermal exposure study with benzophenone-3 in pregnant mice to study the possible effects on the outcome of the progeny (Santamaria et al. 2020). Benzophenone-3 is one of the most frequently used ultraviolet light filters present in many skincare products (Krause et al. 2012; Darbre and Harvey 2015), which is detectable in the urine of exposed humans (Calafat et al. 2008; Buck Louis et al. 2014; Frederiksen et al. 2013; Zhang et al. 2013). Humans are not only exposed by the dermal application, but also via drinking water and food (Loraine and Pettigrove 2006; Kim and Choi 2014; Hayden et al. 1997; Janjua et al. 2008). The possible reproductive toxicity of benzophenone-3 has been controversially discussed (Ghazipura et al. 2017; Santamaría et al. 2019; Vela-Soria et al. 2014).
The strengths of the present study of Santamaria are the careful selection of a human-relevant dose, the dermal route of application of benzophenone-3, the selection of an interesting window of exposure and internal monitoring of the test compound in serum and amniotic fluid (Santamaria et al. 2020). A dose of 50 mg/kg body weight/day was chosen, because this corresponds to the calculated dose after controlled whole-body dermal application in humans (Janjua et al. 2008). Mice were dermally exposed during the first 7 days of pregnancy, which corresponds to the first trimester of a human pregnancy. A limitation of the study is that the effects were not studied dose-dependently. Benzophenone-3-associated key findings were:
Reduced fetal weight at gestational day 14 (gd14).
Reduced feto-placental index of first pregnancy at gd14.
Reduced offspring weight of the first progeny.
Reduced placenta weight of the second pregnancy.
Higher percentage of females in the first and second progenies of mothers exposed to benzophenone-3
These are interesting results and further studies with a similar experimental design and a predefined research hypothesis should be performed.
Currently, much effort is invested to establish in vitro tests of human developmental toxicity using human stem and precursor cells (Krug et al. 2013; Godoy et al. 2013; 2015; Sachinidis et al. 2019; Leist et al. 2017). Tests systems are available for iPSC-derived cells (Waldmann et al. 2017; Shinde et al. 2016, 2017) and transcriptomics (Balmer et al. 2014; Zimmer et al. 2014; Waldmann et al. 2014) or amino acids (Palmer et al. 2013; Kleinstreuer et al. 2011) have been shown to represent reliable readouts. These systems have been used to differentiate developmental toxicants and controls (Pallocca et al. 2016; Reif 2015) as well as different classes of developmental toxicants (Rempel et al. 2015; Sisnaiske et al. 2014). It will be interesting to learn in future if benzophenone-3 leads to positive results in these in vitro assays at concentrations relevant in human serum after application of, e.g., sun cream. In conclusion, the present study of Santamaria and colleagues gives evidence that the use of benzophenone-3 in human skincare products may cause adverse consequences and follow-up studies for clarification of the human relevance of the observation are required.
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Seidel, F. Reproductive toxicity of benzophenone-3. Arch Toxicol 94, 3593–3594 (2020). https://doi.org/10.1007/s00204-020-02865-5