The increased formation of reactive oxygen species (ROS) is a central process responsible for the negative consequences of UV radiation. The link between UV radiation and skin cancer development is supported by a remarkable number of epidemiological studies (IARC, 1992). According to the World Health Organization (WHO), the global incidences of non-melanoma skin cancers (with 2 to 3 million cases per year) and of melanoma skin cancers (with 132,000 cases per year) have increased up to 5-fold over the past three decades (Leiter et al., 2014; WHO, 2018).To protect the skin from the detrimental consequences of UV exposure, UV filters are frequently applied that should ideally scatter, reflect, or absorb solar UV radiation and subsequently convert the irradiation energy into harmless energy, like heat, in order to attenuate the damaging effects without the production of radicals (Karsili et al., 2014). Such compounds can be of inorganic nature, for example titanium dioxide (physical UV filters), or are organ-
In 2012, 20 key questions related to hazard and exposure assessment and environmental and health risks of pharmaceuticals and personal care products in the natural environment were identified. A decade later, this article examines the current level of knowledge around one of the lowest‐ranking questions at that time, number 19: “Can nonanimal testing methods be developed that will provide equivalent or better hazard data compared with current in vivo methods?” The inclusion of alternative methods that replace, reduce, or refine animal testing within the regulatory context of risk and hazard assessment of chemicals generally faces many hurdles, although this varies both by organism (human‐centric vs. other), sector, and geographical region or country. Focusing on the past 10 years, only works that might reasonably be considered to contribute to advancements in the field of aquatic environmental risk assessment are highlighted. Particular attention is paid to methods of contemporary interest and importance, representing progress in (1) the development of methods which provide equivalent or better data compared with current in vivo methods such as bioaccumulation, (2) weight of evidence, or (3) ‐omic‐based applications. Evolution and convergence of these risk assessment areas offer the basis for fundamental frameshifts in how data are collated and used for the protection of taxa across the breadth of the aquatic environment. Looking to the future, we are at a tipping point, with a need for a global and inclusive approach to establish consensus. Bringing together these methods (both new and old) for regulatory assessment and decision‐making will require a concerted effort and orchestration. Environ Toxicol Chem 2023;00:1–15. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
In a recently published article, Daley et al. (2022) emphasized the need for a new approach to assess cardiotoxicity of environmental compounds, an issue that has been neglected to date. They described how efforts for the evaluation of cardiotoxicity have so far focused on pharmaceuticals and the necessity of new approach methodologies (NAMs) that do not directly rely on animals beyond the pharmaco-regulatory sector.Here, we aim to add to that paper by providing information on the specific limitations of the current regulations for a) chemicals, biocides, and pesticides substances, b) human variability including the elderly population, and c) chemical mixtures. We also briefly indicate how each of these specific limitations could be overcome using NAMs. Limitations of regulatory test guidelines for cardiotoxicity assessment of chemicals, biocides, and pesticidesAs described in Daley et al. (2022), "cardiovascular diseases (CVD) [are] the leading cause of mortality worldwide … [and] an estimated 7-23% of CVD can be attributed to environmental factors such as air pollution, occupational hazards, and agricultural run-off … [but]… there is a shortage of knowledge regarding the cardiac-specific risks presented by environmental toxicants". Methods to specifically evaluate effects on the cardiovascular system are currently described in the ICH guidelines for pharmaceuticals. However, the available methods are too limited for a sufficient evaluation of pharmaceuticals and environmental contaminants (Daley et al., 2022). The in vivo guideline studies are in conflict with the 3R goals, are economically and time resource intensive, and are generally subject to uncertainties in extrapolation between different animal species and humans. The existing in vitro guideline studies (hERG channel tests) do not adequately cover all relevant mechanisms. Novel human-relevant NAMs are based, among others, on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), in 2D or 3D cultures, and focus not only on electrophysiological but also structural and/or contractility endpoints, as discussed by Daley et al. (2022). They may provide a more accurate, species-specific assessment for the clinical risk of proarrhythmia and structural and contractile toxicity. Adding to the observations of Daley et al. (2022), we note that cardiotoxicity has been vastly neglected in the evaluation of chemicals, pesticides, and biocides. Currently, their production and use is regulated by the REACH regulation (EC) No 1907/2006 (EU, 2006), the plant protection products regulation (EC) No 1107/2009 (EU, 2009), and the biocidal products regulation (EU) No 528/2012 (EU , 2012), respectively. The regulation of pesticides and biocides requires toxicological data from a number of OECD Test Guidelines (TGs), including information on potential toxicity to specific target organs. Similar requirements are applied under REACH for chemicals that are produced in large quantities. More specifically, toxicological data must be collected from repeated toxicity...
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