**d.** Neglect of available dose-effect studies

Akesson et al. [37] have analyzed the effects of low environmental cadmium exposure in an epidemiological study of Swedish women in the Lund area, being 53-64 years of age, excluding women from areas with soils heavily polluted by cadmium. Akesson et al. [37] found associations between the internal dose of cadmium and tubular and glomerular kidney effects, which may represent early signs of adverse effects. Women with diabetes seemed to be at increased risk of experiencing such early signs. In view of these data it seems plausible that at a background exposure that is common in Sweden, old women in the general population may be at risk for adverse cadmium effects [34] and that even a modest increase in cadmium exposure due to polluted soil may lead to added risk. However, when establishing soil clean-up standards in Sweden this background exposure has been neglected [34]. Nawrot et al. [35] have studied the relation between mortality and cadmium body burden in Belgium. They obtained evidence that total mortality and noncardiovascular mortality may be elevated at cadmium body burdens which can be found among the population not living on soils that are currently considered to be a health risk. Similarly there are now strong indications that the negative effects of lead on the neurophy‐ siologic and sexual development may well be found at the level of background exposure common in Western European and US cities [37], though soil pollution policy, at least in European counties, assumes that such background exposure is safe [14].

#### *2.10.2. Ecotoxicological risks*

Maximum acceptable or maximum tolerable ecotoxicological risks are usually derived from a limited number of studies concerning single species under laboratory conditions. Laboratory conditions may be very different from actual conditions in the field, and thus findings in the field are often at variance with laboratory studies [35]. In field studies it has been found that several factors which tend to be neglected in laboratory studies may strongly impact toxic effects of soil pollutants. These include among others: density and adaptability of populations of affected organisms, the presence of other environmental stress factors and the presence or absence of specific landscape elements such as buffer strips [35].

#### *2.10.3. Biological availability*

Biologically available pollutants determine risk [3]. Biological availability may vary strongly for different types of organisms [36]. Biological availability of a compound in a specific soil is also dependent on physical, chemical and biological and spatial factors [35]. Examples of such factors are pH, the amount and nature of organic and mineral compounds also present and the presence of organisms that can mobilize soil pollutants [37-39]. In practice, biological availability may be much at variance with total concentrations [40].

#### *2.10.4. Combination effects*

#### **a.** Limited accounting of combination effects

As to the overall risk of soil pollutants, cumulative effects of the combination of substances present in soils should be considered. However actual standard setting practice has largely focused on criteria relating to one element or compound. In some cases there are criteria for groups of compounds [34]. Such criteria limit the amount (in g/kg soil) of groups of compounds but often do not address the possibility that the risk per unit of weight may be different for different compounds. An exception to this is criteria for the presence of halogenated dioxins and benzofurans and planar biphenyls. The establishment of risk in case of exposure to these compounds uses addition on the basis of equivalent toxicity [40]. This is a major improvement, though it has been pointed out that this approach may still underestimate the risk of neuro‐ development effects [41].

### **b.** Importance of combination effects

modest increase in cadmium exposure due to polluted soil may lead to added risk. However, when establishing soil clean-up standards in Sweden this background exposure has been neglected [34]. Nawrot et al. [35] have studied the relation between mortality and cadmium body burden in Belgium. They obtained evidence that total mortality and noncardiovascular mortality may be elevated at cadmium body burdens which can be found among the population not living on soils that are currently considered to be a health risk. Similarly there are now strong indications that the negative effects of lead on the neurophy‐ siologic and sexual development may well be found at the level of background exposure common in Western European and US cities [37], though soil pollution policy, at least in

Maximum acceptable or maximum tolerable ecotoxicological risks are usually derived from a limited number of studies concerning single species under laboratory conditions. Laboratory conditions may be very different from actual conditions in the field, and thus findings in the field are often at variance with laboratory studies [35]. In field studies it has been found that several factors which tend to be neglected in laboratory studies may strongly impact toxic effects of soil pollutants. These include among others: density and adaptability of populations of affected organisms, the presence of other environmental stress factors and the presence or

Biologically available pollutants determine risk [3]. Biological availability may vary strongly for different types of organisms [36]. Biological availability of a compound in a specific soil is also dependent on physical, chemical and biological and spatial factors [35]. Examples of such factors are pH, the amount and nature of organic and mineral compounds also present and the presence of organisms that can mobilize soil pollutants [37-39]. In practice, biological

As to the overall risk of soil pollutants, cumulative effects of the combination of substances present in soils should be considered. However actual standard setting practice has largely focused on criteria relating to one element or compound. In some cases there are criteria for groups of compounds [34]. Such criteria limit the amount (in g/kg soil) of groups of compounds but often do not address the possibility that the risk per unit of weight may be different for different compounds. An exception to this is criteria for the presence of halogenated dioxins and benzofurans and planar biphenyls. The establishment of risk in case of exposure to these compounds uses addition on the basis of equivalent toxicity [40]. This is a major improvement, though it has been pointed out that this approach may still underestimate the risk of neuro‐

European counties, assumes that such background exposure is safe [14].

absence of specific landscape elements such as buffer strips [35].

availability may be much at variance with total concentrations [40].

*2.10.2. Ecotoxicological risks*

18 Environmental Risk Assessment of Soil Contamination

*2.10.3. Biological availability*

*2.10.4. Combination effects*

development effects [41].

**a.** Limited accounting of combination effects

Combination effects may be important in two respects. Firstly, coexisting soil contaminants may impact each others' biological availability [43]. Secondly, exposure to a combination of pollutants may be associated with antagonistic, synergistic and additive interactions of these pollutants, impacting their effect on organisms [44-47]. Some risks of pollutant mixtures can be predicted on the basis of existing knowledge. For instance there is a fair chance that there will be dose additivity when effects are receptor mediated [48]. Also in case of narcotic effects, joint-mixture ecotoxicological effects may be predicted [48]. If responses are dissimilar, response addition may be used [49]. A methodology to deal with the ecotoxicity of mixtures giving rise to both dose-additive and response-additive effects has been proposed [48]. This two step model evaluates mixture toxicity for the same mode of action with concentration additivity and the toxicity for different modes of action with response additivity. For deter‐ mining the severity of ecotoxicological effects in case of heavily polluted soils (in which legal maximum tolerable levels for one or more substances are exceeded), a systematic approach to combination effects based on a mixture of concentration addition and response addition has been proposed [41].

#### *2.10.5. Remedies for shortcomings*

Remedies would seem possible which would allow for a significant improvement in risk estimates. Unregulated substances can get standards. Standards may be regularly updated on the basis of new dose-effect studies. Risk estimates can include both background exposure and all exposure routes for local soil pollution. Estimates of biological availability can be integrated in risk assessments and improved by better testing of bioavailability or by in-vivo monitoring [51]. The deficiencies in taking account of combination effects in ecotoxicity, discussed in section may be addressed by directly testing of ecotoxicity, when the focus is on ecosystem functioning [52,53]. However it should be noted that small effects on the functioning of ecosystems may have large effects over time [35]. This necessitates large numbers of replicate tests that may well be beyond routine practice [35].

In determining combination effects on human health, direct testing on humans is an 'unethical option'. However biomarker-based monitoring of some aspects of soil pollution relevant to humans may be an option. For instance Roos et al. [54] have applied a biomarker based test to original and remediated soils that were contaminated by a variety of polycyclic aromatic hydrocarbons (PAH). They tested the expression profile of cytochromes P 450 [54]. Xiao et al. [55] have measured genotoxic risk of soil contamination using an in-vitro assay with Salmo‐ nella. Though the relation between such biomarker-based data gathered and the in-vivo risks awaits further elucidation, the application of tests based on biomarkers for soil pollution is an interesting option in dealing with combination effects on humans.

Also, estimates of risk may be derived from biomarkers which may be monitored in people exposed to soil pollution. Such biomarkers have emerged from epidemiological studies considering the combined effect of substances. An illustration thereof is the study by Lee et al. [56] which found a graded association of the concentration of blood lead and urinary cadmium concentrations with oxidative stress related markers in the US population. This suggests that oxidative stress may be useful as a biomarker for combination effects. It has furthermore been proposed to evaluate effects of exposure to nitroarenes by measuring haemoglobin adducts [57], and of mixtures of volatile organochlorines by measuring glutathione conjugative metabolites [58]. Bioassays based on aryl hydrocarbon (Ah) receptor mediated mechanisms have been proposed which will allow a better alternative to the measurement of polyhalogen‐ ated aromatic hydrocarbons [41]. Another option is to estimate risks to human health by taking into account cumulative combination effects in line with established cause-effect relations and research into the effects of actual combinations. It has been shown that risks of compounds with the same targets and the same modes of action may be estimated on the basis of concen‐ tration addition, while including toxicity equivalence factors for the compounds involved [59].

This has been shown to apply to receptor-mediated-and reactive mechanisms of toxicity, provided that no chemical reactions occur between the components of the mixture considered [60]. Currently this approach is applied to halogenated dioxins, benzofurans and planar polybiphenyls, though non-linear interactions are not completely absent in this category of compounds [61], and neurodevelopment effects may be underestimated, as pointed out before [41]. Extension of this approach is possible to e.g. polycyclic aromatics, including heterocyclic polycyclic aromatics [18,62] organophosphates that inhibit the enzyme cholinesterase [44,63], compounds that bind to estrogen receptors [64-66], carcinogens [67], a variety of petroleum products [68] and compounds that inhibit the MXR efflux pump [69].
