Health effects and toxicity mechanisms of rare earth elements—Knowledge gaps and research prospects
Introduction
The widespread and growing relevance of REE in a number of industrial, agricultural and medical technologies has become evident in the last decades (USEPA, 2012). Established and growing evidence points to REE-related marine, freshwater and soil pollution, along with REE bioaccumulation (Tu et al., 1994, Moermond et al., 2001, Hu et al., 2002, Bustamante and Miramand, 2005, Kulaksız and Bau, 2011, Tranchida et al., 2011, Censi et al., 2013, Fu et al., 2014, Liang et al., 2014). Despite the sharp rise in REE extraction and manufacturing, hence growing environmental and human exposures, the toxicological investigations on REE-associated health effects have been relatively scarce up to recent years. By comparing the toxicologic literature on other inorganic xenobiotics, the PubMed database provides approx. 1200 citations for REE, vs., e.g., some 10,000 citations for cadmium. This state-of-art leaves a number of unsolved questions as to any adverse effects of REE pollution, toxicity mechanisms to biota, as well as occupational or iatrogenic or environmental human exposures.
Previous reviews on REE-associated biological effects have been scanty, since the early paper by Haley (1965) rarely encompassing more than one REE (Hirano and Suzuki, 1996, Cassee et al., 2011, Rim et al., 2013). The present review is aimed at providing a comprehensive survey of the literature focused on REE-associated health effects from studies conducted in vitro, in animals, and in plants, along with few case reports or geographic studies from human exposures, in the attempt to highlight the major knowledge gaps, and pointing to the roles of three relevant phenomena involved in REE-related effects, i.e. oxidative stress, hormesis, and medium acidification.
An outstanding limitation of REE-associated health effects shows that the toxicological database is mostly confined to Ce and La, with lesser information available for Gd and Nd, and scanty data available for the other REE, especially for heavy REE. These are, nonetheless, relevant to manufacturing several technological products as, e.g., alloys and magnets, hence with realistic impact related to occupational and environmental exposures.
An apparent controversy between favorable and adverse REE-associated health effects is discussed and attributed to the well-known hormesis phenomenon that has been reported for broad-ranging xenobiotics and physical agents (reviewed by Calabrese, 2013; Mattson, 2008), consisting of a concentration- or dose-related shift from stimulatory to inhibitory effects. Clear-cut REE-induced hormetic effects have been reported for extensive numbers of agents (Calabrese, 2010) and one may envision that hormesis is displayed by several REE, thus recognizing that both stimulatory and inhibitory findings can be recognized in a unified scenario (Jenkins et al., 2011, Wang et al., 2012).
The role for redox imbalance leading to oxidative stress (OS) has been established for several REE in a number of independent studies conducted both in plant and animal models, suggesting that OS may underlie REE-induced toxicity for most, if not all, REE (Tseng et al., 2012, Wang et al., 2012, Zhao et al., 2013). It should be noted that other studies have reported on antioxidant effects of some REE, e.g. Ce oxide (CeO2), suggesting ad hoc clinical applications (Wong and McGinnis, 2014).
Human exposures to REE range from iatrogenic to occupational routes, and likely or suspect environmental exposure routes. A recognized iatrogenic exposure consists of Gd use as a contrast agent in magnetic resonance imaging, up to reports on renal toxicity (nephrogenic systemic fibrosis) in the last decade (Thomsen, 2006, Chien et al., 2011, Bernstein et al., 2012). Occupational exposures to REE dusts have been associated with observations of pneumoconiosis since early case reports (Sabbioni et al., 1982, McDonald et al., 1995), yet no case-control or cohort study has been retrieved in this review. Environmental exposures in populations residing close to REE mining areas showed REE bioaccumulation related to distance from mining sites (Peng et al., 2003, Tong et al., 2004).
Another outcome of REE toxicity relates to the induction of cytogenetic effects that have been detected both in plant and in animal cells, such as inhibition of mitotic activity, mitotic aberrations and induction of micronuclei (Huang et al., 2007, Oral et al., 2010).
A few studies reported on pH-induced modulation of REE toxicity, in some cases referring to “acid rain” (Liang and Wang, 2013), and other reports showed the toxicity modulation of acidic ligands (Ould-Moussa et al., 2014). This limited body of literature may be anticipated to predict a broader and environmentally relevant event, both due to the established notion of pH-modulated toxicity of several metals (Luís et al., 2014, Pardo et al., 2014) and, even more so, due to the concomitant pollution by REE and inorganic acids in the areas surrounding-or downstream-REE mining and manufacturing facilities (Tong et al., 2004, Olías et al., 2005, Grawunder et al., 2014).
Altogether, the present review may offer some insights into the current database on REE-associated health effects and its major gaps, by addressing proper study design aimed at elucidating presently open questions.
Section snippets
Methods
A MedLine retrieval up to January 2015 was carried out for reports on individual REE or for REE mixtures. The papers reporting on toxicity of each REE were evaluated according to: (a) health effects; (b) OS endpoints; (c) hormetic effects, (d) cytogenetic effects, and (e) pH-related effects. The reports failing to provide clear-cut data for concentrations were not included for evaluation, nor were included self-repeating reports of previous or contemporary studies. The reports on radioactive
State-of-art in REE-associated health effects
Most of REE technological applications have been developed in the last two decades, thus the early database on REE biological effects has been scarce up to 1990s (Haley, 1965, Hirano and Suzuki, 1996). As shown in Fig. 1a, the reports on REE-induced effects only started to grow in the last decade and at a faster pace since 2010; this trend appears more remarkable in Fig. 1b, showing the number of reports per year that was more than doubled in the last approx. five years (95 papers/yr) vs. the
Redox mechanisms in REE-associated health effects
The role for redox mechanisms in the toxicity of several transition elements (primarily, yet not confined to iron and copper) has been long recognized since early reports dating back to 1980s (reviewed by Stohs and Bagchi, 1995; Toyokuni, 1996). The occurrence of redox mechanisms in the biological effects of REE has been reported by few papers on Tb and Yb toxicity (Shimada et al., 1996, Hongyan et al., 2002), and found to result in either antioxidant or prooxidant activity (Kawagoe et al., 2005
Gadolinium iatrogenic exposure
Gadolinium is routinely utilized as a magnetic resonance imaging contrast agent (CA). Favorable safety profiles of Gd-based CA had been reported in previous studies (reviewed by Kirchin and Runge, 2003). However, a severe reaction known as nephrogenic systemic fibrosis was reported in patients (Thomsen, 2006, Chien et al., 2011, Bernstein et al., 2012, Chang et al., 2013). Darrah et al. (2009) found excess Gd concentrations in the femoral head bones of patients exposed to chelated Gd used as a
Hormesis in REE-associated health effects
The literature on REE-associated health effects displays apparently controversial findings of stimulatory and beneficial effects as well as of inhibitory and adverse effects. The current state-of-art has led to opposite views and strategies, ranging from the agricultural use of REE mixtures as fertilizers-mainly in China – (reviewed by Pang et al., 2002; USEPA, 2012) up to concern for REE-associated threats to environmental health (see below).
The observation of such opposite effects is not new
REE-induced cytogenetic effects
One of the adverse effects of REE consists of changes in mitotic activity or cytogenetic anomalies. As shown in Table 3, few independent reports have focused on these outcomes following REE exposures. Cerium was tested as Ce(III) or Ce(IV) salts in two independent studies utilizing maize and sea urchin embryos and gametes, respectively (Huang et al., 2007, Oral et al., 2010); cytogenetic anomalies included increased micronuclei formation in maize root tips (Huang et al., 2007) and excess
pH-dependent modulation of REE toxicity
A pH-dependent toxicity modulation of several metals has long been established as related to environmental acidification including, yet not confined to, acid rain (reviewed by Goyer et al., 1985; Soskolne et al., 1989; Singh and Agrawal, 2008). Likewise, REE toxicity has been found to be modulated by medium acidification, and a few studies reported on pH-induced modulation of REE toxicity, as reported in Table 4.
Combined exposures to La(III) (from 6 μM to 0.85 mM) and pH decrease (4.5–3) were
Overview and conclusions
Broadly neglected as xenobiotics up to recent years, REE have undergone an unprecedented boost of technological utilization in the last two decades that implies the current-and growing-spread of REE in environmental and occupational exposures. REE-associated action mechanisms have been associated with redox reactivity, involving ROS formation, lipid peroxidation and modulation of antioxidant activities. In turn, REE exposures involve a number of endpoints such as cell growth and
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