In recent years, estimating the bioavailability of trace metals/metalloids and hazardous organic compounds in terrestrial environments has received increased attention. According to Web of Knowledge database, in 2013 more than 500 papers dealing with bioavailability of different pollutants in soils were published. However, often researches use the term “bioavailability” without taking into consideration its meaning. This may be understandable and two major reasons are as follows. First, a lot of uncertainties arise from terminology used in environmental sciences, ecotoxicology, and medicine. Second, general procedures to mimic/measure bioavailable fractions of pollutants principally cannot be developed because bioavailability is dependent on properties of contaminants as well as on specific target organisms, their habitat, uptake mechanisms, etc. Adopted definitions of bioavailability should be briefly mentioned and critically analyzed prior to the discussion of methods used for the assessment of bioavailability.
The US National Research Council (NRC) defines the “bioavailability process” as “the individual physical, chemical and biological interactions that determine the exposure of organisms to chemicals associated with soils and sediments” . This definition is too generalized and may lead to a lot of different interpretations. The US Environmental Protection Agency (EPA) defines bioavailability as “the fraction of an ingested dose that crosses the gastrointestinal epithelium and becomes available for distribution to internal target tissues and organs” . This definition primarily relates to “evaluating the oral bioavailability of metals in soils for use in human health risk assessment” .
Standards ISO 11074 (2005) and ISO 17402 (2011) define bioavailability as “the degree to which chemicals present in the soil may be absorbed or metabolised by human or ecological receptors or are available for interaction with biological systems” [3, 4].
According to the revised glossary of terms used in ecotoxicology, bioavailability also can be defined as the “potential for uptake of a chemical by plants, animals or other living organisms, usually expressed as a fraction of the total amount of this substance available in the matrix of exposure” . This definition is an IUPAC Recommendation since it has been published in PAC. It should be noted that the two latter definitions have no principal contradictions.
ISO 17402 enables bioavailability to be regarded as a dynamic process that can be broken down into three distinct phases. Figure 1 illustrates the meaning and interrelation of these different aspects of bioavailability.
Step 1 – environmental availability – “the fraction of the pollutant that is potentially available to organisms as a result of physicochemical desorption processes”. The environmental availability is often defined as the concentration of a chemical in pore water. The available quantity is not constant since it depends on environmental conditions and a substance is therefore distributed in the environment as follows.
“an actual available fraction or the actual dissolved quantity (of pollutant) under ambient conditions”
“a potentially available fraction, i.e., the maximum amount (of pollutant) that can be released under the most pessimistic (predefined) conditions”
“an unavailable fraction”
Step 2 – environmental bioavailability – “the available fraction of a chemical in the environment that an organism absorbs by physiological processes”. It considers the processes in the bioinfluenced zone and means absorption of the pollutant by the organism, depending on physiological criteria of the species under consideration.
Step 3 – toxicological bioavailability – “the internal concentration that is accumulated and/or related to a toxic effect. This definition refers to internal concentrations in humans, mammals and other organisms”. This includes internal processes in the organisms such as uptake, distribution, metabolism, excretion, accumulation, and/or the (toxic) effect of the contaminant.
There is yet another aspect of bioavailability, chemical activity  that quantifies the potential for spontaneous physicochemical processes, such as diffusion, sorption, and partitioning. The authors  proposed to use chemical activity of the free molecule/ion as a complementary approach to explain the accessible quantity for potential availability (mass of contaminants, which can become available to, for example, biodegradation and biouptake). By definition, chemical activity and environmental availability are closely interrelated.
Environmental availability is also associated with bioaccessibility, as introduced by Semple et al.  to clarify which part of the soil/organism system was investigated. The authors also proposed to distinguish clearly between bioavailability and bioaccessibility. They defined bioavailable compound as that fraction of the compound present that is freely available to cross an organism’s cellular membrane from the medium the organism inhabits at a given time. Once transfer across the membrane has occurred, storage, transformation, assimilation, or degradation can take place within the organism. However, these processes are obviously distinct from the transfer between the medium (e.g., soil) into the organism. Bioaccessible compound can be defined as “that which is available to cross an organism’s cellular membrane from the environment, if the organism has access to the chemical” . To summarize, “bioaccessibility encompasses what is actually bioavailable now plus what is potentially bioavailable” , such as a chemical desorbed from a surface and held in the soil solution.
It should be mentioned that the term “bioaccessibility” is also used in standard ISO/TS 17924  where it is associated directly with humans (assessment of human exposure by ingestion of soil and soil materials). According to this standard, “bioaccessibility includes all physical, chemical and microbiological processes in the human body, from chewing in the mouth to precipitation in the intestines”. However, this definition may not be sufficiently explanatory and may not be widely acceptable.
In ecotoxicology, bioaccessibility is defined as the “potential for a substance to been exposed to a living organism” and perhaps interact with it, with the possibility of absorption into the organism” . “A substance trapped inside an insoluble particle is not bioaccessible, although substances on the surface of the same particle are bioaccessible and may also be bioavailable”. Even substances bound to the surface of particles may not be accessible to organisms because the substance has first to be liberated from the surface. Bioaccessibility, similar to bioavailability, “is a function of chemical speciation and biological properties of substances”. Bioaccessibility is a necessary precursor of bioavailability but not, on its own, equivalent to bioavailability .
It may be concluded that there are slight differences in the definitions given by Semple et al. , Nordberg et al. (glossary of terms used in ecotoxicology) , and EN ISO 17402 ; however, they reflect similar characteristic features of bioavailability as actual availability and bioaccessibility as potential availability. Despite some peculiarities, which will be discussed later, environmental availability, chemical activity, and bioaccessibility are closely interrelated and associated with similar physicochemical phenomena.
Assessment of bioavailability: main distinguishing features
In recent years a series of comprehensive reviews and reports have regarded the assessment of bioavailability and/or bioaccessibility of trace metals/metalloids [8, 10–14] and persistent organic pollutants [8, 15–17] in terrestrial environments.
It should be stressed that bioavailability depends on specific “target” organisms; its habitat, feeding, and specific uptake mechanisms; and the physicochemical properties of contaminants. In general, substances are biologically available if they can be taken up by living cells and can interact with “target” molecules, including those on the cell surface. Thus, in the strictest sense of the term, it describes availability at the ultimate receptors. Measurement of the amount reaching the receptors is usually impossible. Hence, surrogate measurements are required. For humans, these may be levels found in blood or plasma. For plants, tissue concentrations may be used. For unicells such as protozoa and bacteria, the cell content may be appropriate .
In any case, bioavailability can be measured only by biological methods (in vivo). Let us consider oral bioavailability as an example. Oral bioavailability is defined as the “fraction of the administered dose that reaches the bloodstream” . An in vivo study was carried out with adult volunteers 21–40 years old using stable lead isotopes (206Pb/207Pb) to estimate the bioavailability of lead in a residential soil near a former mine. The soil was ingested with gelatin capsules. Blood and urine samples were collected after 30 h and analyzed . However, such studies are rare due to evident ethical issues.
In vivo tests with animals are considered to be suitable for estimating bioavailability in humans since the absorption measured in animals combines all of the conditions applied during the toxicity tests. The animals used for these studies should have digestive systems similar to those of humans. In most cases these animals are swine, rats, New Zealand white rabbits, and monkeys (primates) .
For plants, in vivo tests address the concentrations of metals/metalloids [20, 21] (sometimes organic pollutants) in roots or leaves in order to measure the biological uptake (biouptake). To estimate the uptake of metals/metalloids by animals, their levels in blood, plasma, and tissues of soil invertebrates and small mammals can be determined. The biouptake of persistent organic compounds is usually estimated by measuring their concentrations in soil-dwelling organisms (mainly earthworms). These concentrations correspond to an actually available fraction of contaminants. A potentially available (biodegradable) fraction can be estimated by microbial degradation (biodegradation).
Assessment of bioaccessibility using biomimetric (in vitro) methods and correlations with in vivo tests
Bioaccessibility can be estimated in vitro using biomimetric (chemical and physicochemical) methods. The development and application of biomimetric methods are always aimed at the replacement of in vivo tests by more or less simple in vitro chemical extraction and fractionation procedures. A number of studies have shown the potential of in vitro assays to predict contaminant in vivo bioavailability in order to refine human health exposure assessment [22, 23]. Although the term “validated” has been used to describe the goodness of fit between in vivo and in vitro observations, its misuse has arisen first of all from the lack of defined criteria for establishing performance validation. While several internal validation methods may be utilized, performance validation should preferably focus on assessing the agreement of model predictions with a set of data which are independent of those used to construct the model. In order to achieve robust validated predictive models, a number of parameters (e.g., size of data set, source of independent soils, contaminant concentration range, animal model, etc.) need to be considered in addition to defined criteria for establishing performance validation which are currently lacking .
In general, a series of in vivo tests have been correlated with different biomimetric extraction methods, as illustrated in Fig. 2. The main problem is choosing appropriate methods that provide positive correlation . Let us consider most representative and promising methods used for the assessment of bioaccessibility of metals/metalloids and hazardous organic compounds in soil environments.
Metals and metalloids
Bioaccessibility for plants and soil-dwelling biota
The evaluation of soil extraction methods within a biouptake framework has only recently drawn attention . For the assessment of bioaccessibility of trace metals/metalloids, the following groups of extracting reagents are commonly used:
aqueous salt solutions: CaCl2, MgCl2, NaNO3, Ca(NO3)2, CH3 COONH4, (NH4)H2 PO4, etc.;
weak acids: diluted solutions of acetic or citric acid;
strong acids: HNO3, HCl (diluted solutions in some cases adjusted to a fixed pH, e.g., pH-stat methods);
buffered salt solutions: ammonium oxalate – oxalic acid, sodium acetate – acetic acid;
reductive extractants: sodium ascorbate, hydroxylamine hydrochloride, sodium dithionite (hydrosulphite);
complexing reagents: potassium pyrophosphate, ethylendiaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DPTA), triethylamine (TEA), etc.;
oxidizing reagents: hydrogen peroxide, sodium hypochlorite.
Peculiarities of enumerated above extracting reagents and their action on different mineral and organic phases of soils and sediments have been discussed, in detail . Correlations between results obtained by chemical (in vitro) and biological (in vivo) methods were generalized and critically evaluated. On the whole, positive correlations found for chemical extraction/fractionation and uptake of trace metals and metalloids by plants can be summarized as follows .
The data presented are empirical and may look controversial. For instance, both aqua regia digestion and “mild” CaCl2 extraction may result in satisfactory assessment of Zn phytouptake under specified conditions. However, it should always be kept in mind that phytoavailability of an element ion varies with the particular element, soil properties and with the plant species. The content of metals in plant communities may provide accurate information on actual transfer toward the ensemble of vegetation, which could be used to establish site-specific “fingerprints” of metal bioavailability .
In general, the extraction of environmental solids with diluted salt solutions, namely, 0.01 M CaCl2, 0.1 M Ca(NO3)2, 1 M NH4 OAc or 1 M (NH4)2 SO4, and DTPA is currently regarded as a suitable method for predicting the plant uptake of trace metals. CaCl2 extraction seems to be the most suitable technique for the assessment of metal availability to plants. Despite possible formation of chlorocomplexes, there are no reports about overestimation of phytoavailable metals. On the contrary, DTPA-extraction may lead to overestimation of plant uptake. In order to understand the availability of metals and metalloids to plants, one needs to mimic rhizosphere processes. Further investigation of correlations between elements chemistry, extraction and uptake mechanism is necessary for unbiased evaluation of trace metals and metalloids phytoavailability. However, soils and sediments are complex matrices and only a pragmatic approach towards assessing elements fate is feasible .
Besides, phytoavailability is only one aspect of bioavailability. Soil invertebrates and small mammals may show increased levels of metals even if metal concentrations measured in plants organs and 0.01 M CaCl2 soil extracts are low . Hence, development of a biodynamics approach to further reveal the mechanisms responsible for elements bioaccumulation in terrestrial environment and their pathways into a food chain is required.
It should be stressed that the metal (or metalloid) speciation can be a critical determinant of bioavailability . For example, iron in the oxidation state +2 (Fe2+ ions) is generally more bioavailable than iron in the oxidation state +3 (Fe3+ ions). With regard to chromium species, chromate anions (CrO42–), which correspond to the chromium oxidation state +6, are mostly bioavailable. Complexation and redox cycling are often associated with considerable differences in reactivity, kinetic lability, solubility, and, consequently, bioavailability because of resultant changes in chemical speciation. Among mercury and methylmercury species, methylmercury chloride (CH3 HgCl) is readily absorbed by living organisms due to its lipid solubility and can be bioaccumulated and then biomagnified in food chains, etc. Bioavailability of chemical species of metals and metalloids is, in general, difficult to be predicted .
Recently, a quantitative assessment tool has been proposed that characterizes typical aerobic soils in terms of their potential to sequester common divalent metal cations and mitigate their bioavailability to soil-dwelling biota . Two representative datasets were established from relevant literature; one included data from studies related to bioaccumulation, while the other contained data from studies related to toxicity. Experimental factors that affected toxicity and bioaccumulation independent of the effect of soil physicochemical properties were statistically apportioned from the variation attributed to these properties for both datasets using a linear mixed model. Residual bioaccumulation data were then used to develop a non-parametric regression tree whereby bootstrap and cross-validation techniques were used to internally validate the resulting decision rule. A similar approach was employed with the toxicity dataset as an independent external validation. This study  may be regarded as an attempt to develop a “universal” methodology to estimate metals bioavailability for soil-dwelling organisms and to formulate the decision rule for corresponding ecological risk assessment.
Oral bioaccessibility for humans and mammals
Estimating the oral bioaccessibility of metals and metalloids as well as organic contaminants by in vitro gastrointestinal extraction methods is a special case. One of the classic papers on the development of in vitro tests to evaluate in vivo oral bioaccessibility of metals was published more than 20 years by Ruby and coauthors . A screening-level in vitro test was developed to estimate the relative solubility of ingested lead from different mine wastes in the gastrointestinal tract. The in vitro method was correlated with a rabbit (New Zealand White rabbit) feeding study. It has been shown that although HCl concentration is the most important gastrointestinal component controlling Pb dissolution in the stomach, both organic (citric, acetic, lactic) acids and enzymes are necessary to retain Pb in solution during the small intestinal incubation .
In general, the developed methods for estimating the oral bioaccessibility of metals and metalloids can be divided into the following main groups .
Simple physiological tests that employ a few chemical reagents (glycine, phosphates, HCl) but physiological conditioning is required (tests run at a temperature of 37 °C). The corresponding methods are the RBALP (Relative Bioaccessibility Leaching Procedure) or SBET (Simplified Bioaccessibility Extraction Test), the test with phosphate (Exponent), the test with glycine (Exponent), the test with HCl (Health Canada). It should be noted that simple chemical tests like TCLP (Toxicity Characteristic Leaching Procedure) employing hydrochloric and acetic acids at ambient temperature also might be considered to be applicable to estimating the oral bioaccessibility . However, TCLP tests are in fact related to leaching from industrial waste. They were adopted in the United States of America to prevent metal contamination of drinking waters and intended to mimic leaching of elements species from substances that were to be disposed in landfills.
Physiological tests with gastrointestinal analogues. The approach seeks to mimic the processes of human food digestion and thus, assess the bioaccessibility of metals (and organics) from materials consumed either accidentally or intentionally. In vitro conditions are created to simulate various actions mainly in the stomach and intestines. The tests include several phases (salivary, gastric and/or intestinal) and require a greater number of reagents, in particular, complex reagents that correspond to intestinal analogues (enzymes, bile salts). Such test are PBET (Physiologically Based Extraction Test), IVG (In vitro gastro-intestinal method), the RIVM test, SHIME (Simulator of the Human Intestinal Microbial Ecosystem), the UBM (Unified BARGE Bioaccessibility Method), the DIN test (German standard), the TIM (TNO gastrointestinal model), the AOAC (Association Of Analytical Communities Pepsin Digestibility Test), the US Pharmacopeia model and the MB&SR method (Mass Balance & Soil Recapture).
With regard to metals (Pb, Cd) and metalloids (first of all, As), the application of physiological tests accepted in various countries lead to rather controversial results; the difference in values obtained for the same element being one order of magnitude . Recently the bioaccessibility of 24 inorganic contaminants in one standardized soil sample, the standard reference material NIST 2710, has been measured in 40 laboratories using a total of 17 extraction methods . The variability between methods was assessed by calculating the relative standard deviations (RSDs), where reproducibility is the sum of within-laboratory and between-laboratory variability. Whereas within-laboratory repeatability was usually better than 15 % for most elements, reproducibility RSDs were much higher, indicating more variability, although for many elements they were comparable to typical uncertainties (e.g., 30 % in commercial laboratories). For five trace elements of interest, reproducibility RSDs were: As, 2244 %; Cd, 1141 %; Cu, 1530 %; Pb, 4583 %; and Zn, 1856 % . Only one method variable, pH, was found to correlate significantly with bioaccessibility for Al, Cd, Cu, Mn, Pb, and Zn. When bioaccessibility tests were directly compared with bioavailability results for As (swine and mouse) and Pb (swine), only 4 methods among 17 ones used returned values within uncertainty ranges for both elements .
Bioaccessibility for soil-dwelling invertebrates and microorganisms
As has been mentioned above, chemical activity and bioaccessibility are closely interrelated and associated with similar physicochemical phenomena. However, there are some differences between these parameters . Bioaccessibility indicates the amount or portion of contaminant that is or can become available within a given time span, and can be measured by partial extraction methods (such as mild solvent extraction or Tenax desorption), while chemical activity refers to the energetic state of a chemical and quantifies the potential for spontaneous physicochemical processes. Chemical activity is theoretically related to freely dissolved concentration (Cfree) and can be measured by equilibrium samplers (semi-permeable membrane devices and solid-phase micro extraction equipment). Chemical activity should be a singular value in a given sample. Nevertheless, some problems may arise with passive sampling devices because of partitioning between the different phases and equilibrium shifts that are dependent on temperature, chemical matrix components, and other parameters. Bioaccessibility is always operationally defined, and dependent on the specific scenario (e.g., target organisms, sample matrix, or properties of organic contaminants) or desorption time and/conditions (e.g., solvent, temperature, shaking velocity) selected during the measurement process [6, 15].
The difference between bioaccessibility and Cfree may be further reflected in their roles in various environmental processes. For example, bioavailability in processes such as biodegradation is more closely dependent on bioaccessibility, while in other processes (e.g., baseline and acute aquatic toxicity), it is regulated by chemical activity such as Cfree. However, both parameters have been used to describe bioaccumulation of organic contaminants into invertebrates, often with similar successes. Biomimetric methods for measuring hydrophobic organic contaminants bioaccessibility and partitioning based methods for measuring their freely dissolved concentration have been critically evaluated and compared, in detail . It has been concluded  that while the performance evaluation criteria may be different for methods under consideration, publication of standard methods and adherence to clear quality assurance/quality control (QA/QC) criteria will be critical for assuring data quality and hence increasing the acceptance of biomimetic methods.
Interrelations between results obtained so far by biomimetric (in vitro) and biological (in vivo) methods have been recently generalized and evaluated . A special attention was given to the assessment of the fraction of representative organic contaminants actually available for biouptake by soil/sediment organisms and plants and to the estimation of the potentially available (biodegradable) fraction. Polynuclear aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB), phthalates, insecticides such as DDT (namely, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] or DDE (namely,1,1-dichloro-2,2-bis(p-chlorophenyl)ethane), etc. were under consideration. Positive correlations for chemical extraction/fractionation and uptake of organic substances by earthworms/clams can be summarized as follows.
Assessment of the fraction of organic compounds actually available for biouptake by soil/sediment organisms and plants theoretically may relate to measurement of freely dissolved concentration. Actually, SPME as passive sampling may lead to positive correlations. Nevertheless, SFE under mild condition as well as Tenax and HPCD extraction also look promising. At the same time experimental data of different publications are sometimes inconsistent or even contradictory in their conclusions . Hence, there is still an urgent need for further research to achieve valid correlations. These developments should include further substance classes as extraction efficiency and suitability of methods also depend on substance properties. Besides, efforts should be focused on the investigation of the release of persistent organic pollutants from soils and the pathways of contaminants into the food chain. For example, fate and plant uptake of insecticides, which can remain in farming soils for many years, needs a special concern .
With regard to the assessment of the fraction potentially available for microorganisms, it is important not only whenever considering biodegradation processes but also for estimation of the available fraction by changing environmental conditions or within a longer time window. Many researchers use sequential SFE schemes involving the use of supercritical CO2 as a solvent. In general, positive correlations for chemical extraction/fractionation and biodegradation of organic contaminants can be briefly summarized as follows .
Apart from the SFE-technique, a three-phase extraction procedure seems to be promising. The experimental conditions are comparable to real-life scenarios as soil is extracted by water and the substances in the water phase are further extracted by Tenax or HPCD. At present, the extraction with HPCD looks to be the most suitable procedure for predicting the biodegradability of different organic compounds. Nevertheless, method development should be extended to further substances classes and a pre-standardization of the methods should lead to a better comparison of elaborated results. Tenax extraction protocols are being standardized now by ISO.
Oral bioaccessibility for humans and mammals
The status of oral bioaccessibility tests with respect to the release of organic pollutants from soil and related samples of environmental importance has been reviewed in . Particular emphasis was placed on the parameters that influence gastrointestinal extraction including gastric and intestinal pH, enzymes, bile salts, food constituents and residence time. Correlations between oral bioaccessibility (in vitro tests) and oral bioavailability (in vivo tests) of organic substances in soil have been discussed for ten years [33, 34]. Recently, in vivo measurements using a mouse model have been compared to in vitro estimation and fugacity prediction of PAH bioavailability in post-remediated creosote-contaminated soils . In this case PAH bioavailability assessed by an in vitro surrogate assay (FOREhST assay) and fugacity modeling was up to 2000 times lower than measured in vivo values depending on the methodology used . DDT bioaccessibility measured using organic physiologically based extraction test (Org-PBET), unified BARGE method (UBM), and fed organic estimation human simulation test (FOREhST) in vitro assays was compared to data obtained using an in vivo mouse model (accumulation of administered DDT in adipose, kidney, or liver tissues) . The limitations of the batch in vitro methods for predicting the dynamic processes of the mammalian digestive system is demonstrated by a poor relationship between DDT bioavailability and bioaccessibility (0.28–0.47 for the applied methods according to Pearson correlations) . Hence, the problem of development of in vitro methods providing positive correlations with measured in vivo oral bioavailability remains open for organic contaminants as well as for trace metals and metalloids.
It should be stressed again that bioavailability depends on specific target organisms; its habitat, feeding, and specific uptake mechanisms; and the properties of contaminants. Therefore, general procedures to mimic/measure bioavailable fractions of pollutants are not possible. Methods that are developed for the assessment of bioaccessible fractions of pollutants should meet the following demands :
They should clearly state for which set of organisms the method is developed (bioavailability for earthworms, microorganisms, plants, etc.).
They should clearly state the considered exposure route.
They should have a mechanistic base – which processes are mimicked by the chemical extraction procedure (e.g., simulation of pore water, the bio-influenced zone or uptake in stomach or gut).
Multidisciplinary approaches are meanwhile the vital necessity for:
further critical evaluation and standardization of terms and definitions related to bioaccessibility and bioavailability of pollutants in terrestrial environments;
pre-standardization of most promising biomimetric (chemical) methods and protocols, e.g., CaCl2 extraction for the assessment of metal availability to plants; SPME, “mild” SFE as well as Tenax and HPCD extraction for the assessment of organic compounds actually available for biouptake by soil/sediment organisms, etc.; (Such a pre-standardization will enable the data obtained in different laboratories and in different counties to be compared)
further assessment and critical evaluation of correlations between results obtained by biomimetric (in vitro) and biological (in vivo) methods;
application of chemometric techniques to handling sets of data obtained both by chemical and biological methods in order to evaluate new criteria for risk assessment;
harmonization of chemical methods applicable to measuring bioaccessible fractions of trace metals/metalloids and hazardous organic compounds depending on pollutant, target organism, and its habitat. (The latter seems to be unrealizable in the nearest future since this requires infinite theoretical and experimental studies.)
The author is grateful to the Division of Chemistry and the Environment of IUPAC as well as to the Ministry of Education and Science of the Russian Federation (Program of Increasing Competitiveness of NUST “MISiS”, project No K1-2014-026) for financial support.
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