This is one of the most important aspects of speciation affecting human toxicity and risk assessment. Oxidation state can affect absorption, membrane transport, and excretion, as well as toxicity at the cellular or molecular target. Examples of elements with more
Chromium serves as a good example of the importance of oxidation state. CrIII is considered as an essential element (WHO, 1988), but CrVI is genotoxic and carcinogenic (Katz & Salem, 1994).
CrVI does not appear to bind strongly to DNA, but is reduced inside the cell to CrIII, which does. The binding of CrIII alone is insufficient to damage DNA. However, the electrons released from intermediate oxidation states during the reduction of CrVI to CrIII may do so (Wetterhahn & Hamilton, 1989; Aiyar et al., 1991; Standeven &
Wetterhahn, 1991). Bioavailability also depends on oxidation state.
CrVI is better absorbed than CrIII following both dermal and oral exposure (Rowbotham et al., 2000). CrVI is taken up by some cells than one biologically important valence are given in Table 1.
as chromate (CrO42í
) via anion transporters, whereas CrIII ions permeate the lipid membrane with difficulty (Katz & Salem, 1994).
Sulfate transporters are also involved in chromate transport through sulfate mimicry (Clarkson, 1993; Ballatori, 2002).
Table 1. Some elements with more than one biologically relevant valence (in order of atomic number)
Atomic number Namea Symbol Speciation
23 Vanadium* V IV/V
24 Chromium* Cr III/VI
25 Manganese* Mn II/III/IV
26 Iron* Fe 0/II/III
27 Cobalt* Co II/III
28 Nickel* Ni II/IV
29 Copper* Cu 0/I/II
30 Zinc* Zn 0/II
33 Arsenic* As III/V
34 Selenium* Se II/IV/VI
42 Molybdenum* Mo II/III/IV/VI
46 Palladium Pd II/IV
47 Silver* Ag 0/I/II
50 Tin* Sn II/IV
51 Antimony* Sb III/V
52 Tellurium* Te 0/II/IV/VI
78 Platinum Pt II/IV
80 Mercury* Hg 0/I/II
81 Thallium* Tl I/III
82 Lead Pb II/IV
92 Uranium* U III/VI
94 Plutonium* Pu III/IV/V/VI
a Elements marked with an asterisk are taken from Yokel et al. (2006).
At present, there is no general means of predicting how the oxidation state of a particular element will affect toxicity. Thus, inorganic MnIII species are more toxic than other oxidation states — e.g. manganese(II) chloride (MnCl2) and manganese(IV) oxide
(MnO2) are both less toxic in vitro than manganese(III) pyro- phosphate (Archibald & Tyree, 1987) — and the generally greater toxicity of MnIII compared with MnII has been confirmed by others (Chen et al., 2001; Reaney et al., 2002). One mechanism of manganese toxicity is by disruption of iron–sulfur clusters in mito- chondrial enzymes, such as Complex I and mitochondrial aconitase.
The higher oxidative behaviour of MnIII and its similarity of ionic radius to that of FeIII have been suggested as reasons for its greater ability to inhibit iron–sulfur enzymes (Chen et al., 2001). Greater complexation with and oxidation of catecholamines by MnIII have also been noted (Archibald & Tyree, 1987).
In contrast to chromium, more reduced species of inorganic arsenic are more toxic, in general following the order arsine (arsenic(III) hydride; AsH3) > arsenites (AsIII) > arsenates (AsV) (Hindmarsh & McCurdy, 1986). Also in contrast to chromium species, oxidation state does not appear to be very important in determining arsenic bioavailability, as tri- and pentavalent com- pounds have similar rates of uptake, at least in mice (Vahter &
Norin, 1980). However, phosphate transporters in renal epithelia and anion exchangers in erythrocytes can transport AsV species as a phosphate mimic (Clarkson, 1993). The same is true of VV (Clarkson, 1993), which is more toxic than VIV. One of the important determinants of the greater toxicity of arsenites is the increased propensity of AsIII to combine with thiol groups. For example, inhibition of the tricarboxylic acid cycle results in part from combination of AsIII with the dithiol group of lipoic acid, a cofactor in the decarboxylation of pyruvate and -ketoglutarate (Hindmarsh & McCurdy, 1986). Short-lived methylated species of AsIII are toxic, whereas methylated AsV species are detoxification
Oxidation state is critical for ion transport, which is exemplified by the different classes of transporters for FeII and FeIII. The divalent metal transporter DMT-1 is important in uptake of iron in the gut, and also in intracellular iron trafficking following endocytosis of transferrin-bound iron (Gunshin & Hediger, 2002). DMT-1 trans- ports the divalent FeII (but not the trivalent FeIII), as well as a number of other metals in their divalent state, including MnII, CoII, ZnII, CuII, NiII, CdII, and PbII (Gunshin et al., 1997). FeII is soluble under physiological conditions and can also diffuse across membranes. In contrast, FeIII is prone to hydrolysis in aqueous
α products (for details, see section 3.4 below).
environments, producing poorly soluble products [e.g. iron(III) hydroxide, Fe(OH)3] (Schneider & Schwyn, 1987; Schneider, 1988;
Harris, 2002). While uptake of FeIII from a number of organic chelates probably involves dissociation and reduction to FeII (Templeton, 1995), there is also evidence of non-transferrin- mediated FeIII transport in liver (Parkes & Templeton, 2002).
Whereas generation of FeII generally facilitates its cellular uptake, oxidation of mercury vapour to HgII causes it to become trapped within cells. Some bacteria possess a mercuric reductase system that reduces HgII to volatile Hg0, which then diffuses from the cell (Walsh et al., 1988; Misra, 1992). A similar activity has been reported to be inducible in human liver (Dunn et al., 1981).
3.3 Inorganic and organic compounds and complexes