A review of sources, pathways, and toxic effects of human exposure to benzophenone ultraviolet light filters

Abstract

Benzophenone ultraviolet light filters (BPs) are high-production-volume chemicals extensively used in personal care products, leading to widespread human exposure. Given their estrogenic properties, the potential health risks associated with exposure to BPs have become a public health concern. This review aims to summarize sources and pathways of exposure to BPs and associated health risks. Dermal exposure, primarily through the use of sunscreens, constitutes a major pathway for BP exposure. At a recommended application rate, dermal exposure of BP-3 via the application of sunscreens may reach or exceed the suggested reference dose. Other exposure pathways to BPs, such as drinking water, seafood, and packaged foods, contribute minimal to the overall dose. Inhalation is a minor pathway of exposure; however, its contribution cannot be ignored. Human exposure to BPs is an order of magnitude higher in North America than in Asia and Europe. Studies conducted on laboratory animals and cells have consistently demonstrated the toxic effects of BP exposure. BPs are estrogenic and elicit reproductive and developmental toxicities. Furthermore, neurotoxicity, hepatotoxicity, nephrotoxicity, and carcinogenicity have been reported from chronic BP exposure. In addition to animal and cell studies, epidemiological investigations have identified associations between BPs and couples' fecundity and other reproductive disorders, as well as adverse birth outcomes. Further studies are urgently needed to understand the risks posed by BPs on human health.

Keywords: BP-3; Benzophenone ultraviolet light filters; Health effects; Human exposure; Risk assessment.

Graphical abstract

Fig. 1

Chemical structures of BPs reviewed in this study. BP-11 is a mixture of BP-2 and BP-6, so it is omitted. Full names of all BPs are given below: BP, benzophenone; BP-1, 2,4-dihydroxybenzophenone; BP-2, 2,2′,4,4′-tetrahydroxybenzophenone; BP-3, 2-hydroxy-4-methoxybenzophenone; BP-4, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid; BP-5, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid sodium salt; BP-6, 2,2′-dihydroxy-4,4′-dimethoxybenzophenone; BP-7, 5-chloro-2-hydroxybenzopenone; BP-8, 2,2′-hydroxy-4-methoxybenzophenone; BP-9, 2,2′-dihydroxy-4,4′-dimethoxybenzophenone-5,5′-disulfonic acid; BP-10, 2-hydroxy-4-methoxy-4′-methylbenzophenone; BP-11, 2,2′4,4′-tetrahydroxybenzophenone and 2,2′-dihydroxy-4,4′-dimethoxybenzophenone; BP-12, 2-hydroxy-4-n-octyloxybenzophenone; 2,3,4-THB, 2,3,4-trihydroxy-benzophenone; 2,4,5-THB, 2,4,5-trihydroxy-benzophenone; 2,4,4′-THB, 2,4,4′-trihydroxy-benzophenone; 4-DHB, 4,4-dihydroxy-benzophenone; 4-OH-BP, 4-hydroxy-benzophenone; 4-MBP, 4-methyl-benzophenone. More detailed information on these BPs is provided in Table S1 and Table S2 of Supporting Information.

Fig. 2

Global comparison of BP concentrations in human fluids, including urine, blood, breast milk, amniotic fluid, and semen. The blood concentration values include whole blood, serum, and plasma.

Fig. 3

Summary of sources and pathways of human exposure to BPs [23,64,[66], [67], [68]].

Fig. 4

Illustration of measured and estimated exposures to BPs for the general populations from various sources. Solid horizontal bars show centiles, and whiskers show minimum and maximum, where available. The European Food Safety Authority (EFSA) recommends a tolerable daily intake (TDI) of 0.03 mg/(kg-bw·day) for BP [69]. For BP-3, the reference dose of 2.0 mg/(kg-bw·day) was obtained by further dividing the no observed adverse effect level (NOAEL) value [200 mg/(kg-bw·day)] obtained from the oral teratogenicity study in rodents (Wistar rats) by a safety factor of 100 [70]. However, for other BPs, no human toxicity data are currently available.

Fig. 5

Proposed mechanisms of toxicity of BPs. Apoptosis-inducing, endocrine-disrupting, and oxidative stress-mediated modes of action are proposed for BPs. The mode of action of apoptosis induction was selected from the frontal cortex of the brain [123,124]. Apoptosis was induced by increased activity of caspase-3 and caspase-9, including the pro-apoptotic proteins Bax and Bak, and increased number of cells with apoptotic DNA fragments. With regard to endocrine disruption, the first one is through action on thyroid hormone levels, as evidenced by the upregulation of dio1 and ugt1ab, and the decrease of TRH and TSH receptors and their respective encoded genes Trhr and Tshβ downregulation [125]. The second is through hormonal activity, which reduces its binding by competing with the hormone receptors [[126], [127], [128]]. Oxidative stress-mediated mode of action is illustrated for the liver [129,130]. Increased generation of ROS, as well as an alteration in the antioxidant status, may induce lipid, protein, and DNA oxidation. CAT, catalase; CYP450, cytochrome P450; dio1, deiodinase 1; GSH, glutathione; GST, glutathione S-transferase; ROS, reactive oxygen species; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine; Trhr, thyrotropin-releasing hormone receptor; Tshβ, thyroid stimulating hormone beta; Trβ, thyroid hormone receptor beta; ugt1ab, uridine diphosphate glucuronosyltransferase 1 family a, b.