Structure-bioaccumulation relationships

Bioaccumulation, phenols, flow-through-fish-test, lipophilicity, dissociation, 2,4-dinitro-substitution, structure-bioaccumulation relationships. 

The octanol-water partition coefficient, Kow, is the most widely used descriptor of hydrophobicity in quantitative structure activity relationships (QSAR), which are used to describe sorption to organic matter, soil, and sediments [15], bioaccumulation [104], and toxicity [105 107J. Octanol is an amphiphilic bulk solvent with a molar volume of 0.12 dm3 mol when saturated with water. In the octanol-water system, octanol contains 2.3 mol dm 3 of water (one molecule of water per four molecules of octanol) and water is saturated with 4.5 x 10-3 mol dm 3 octanol. Octanol is more suitable than any other solvent system (for) mimicking biological membranes and organic matter properties, because it contains an aliphatic alkyl chain for pure van der Waals interactions plus the alcohol group, which can act as a hydrogen donor and acceptor. 

Thus, structure-activity relationships developed to estimate levels in biological media based on the partitioning properties of a chemical may not provide accurate information for isophorone. Furthermore, only one bioaccumulation study was available. In this study, which indicated a low potential for bioaccumulation, fish were exposed to isophorone in water rather than in food. From these data, it appears that food chain bioaccumulation may be occurring, and a clearer understanding of the potential for this would aid in determining how levels in the environment affect the food chain and potentially impact on human exposure levels. 

There are several properties of a chemical that are related to exposure potential or overall reactivity for which structure-based predictive models are available. The relevant properties discussed here are bioaccumulation, oral, dermal, and inhalation bioavailability and reactivity. These prediction methods are based on a combination of in vitro assays and quantitative structure-activity relationships (QSARs) [3]. QSARs are simple, usually linear, mathematical models that use chemical structure descriptors to predict first-order physicochemical properties, such as water solubility. Other, similar models can then be constructed that use the first-order physicochemical properties to predict more complex properties, including those of interest here. Chemical descriptors are properties that can be calculated directly from a chemical structure graph and can include abstract quantities, such as connectivity indices, or more intuitive properties, such as dipole moment or total surface area. QSAR models are parameterized using training data from sets of chemicals for which both structure and chemical properties are known, and are validated against other (independent) sets of chemicals. 

Nendza (1998) has defined bioaccumulation as uptake by an organism of a chemical from the environment via any possible pathway, and this can be subdivided into biomagnification (uptake via the food chain) and bioconcentration (uptake from the surrounding milieu). As we shall see, it is the latter that has been the subject of by far the greater number of quantitative structure-activity relationship (QSAR) studies of bioaccumulation. The bioconcentration factor (BCF) is defined as ... 

Macdonald, D., Breton, R., Sutcliffe, R., and Walker, J., Uses and limitations of quantitative structure-activity relationships (QS ARs) to categorize substances on the Canadian Domestic Substance List as persistent and/or bioaccumulative, and inherently toxic to non-human organisms, SAR QSAR Environ. Res., 13, 43-55, 2002. 

Carbonyl sulfide is not expected to bioaccumulate in fish or other aquatic organisms. The United States Environmental Protection Agency reported that quantitative structure activity relationship estimates of acute toxicity for fish, daphnid, and algae are greater than 1000 mg... 

Ivanciuc T, Ivanciuc O, Klein DJ. Modeling the bioconcentration factors and bioaccumulation factors of polychlorinated biphenyls with posetic quantitative super-structure/activity relationships (QSSAR). Mol Divers 2006 10 133-45. 

Many structure-activity relationships can be used to deal with mixture toxicity. Bio accumulation models in combination with internal effect concentration may provide a good means to better predict when organisms are at risk. It must be noted, however, that in many cases there is significant variation in these internal effect concentrations, although even larger variation is found for external effect concentrations. The variation in the external effect concentrations is partly related to the variation in bioaccumulation and partly to interspecies and intraspecies variation. 

Numerous relationships exist among the structural characteristics, physicochemical properties, and/or biological qualities of classes of related compounds. Simple examples include bivariate correlations between physicochemical properties such as aqueous solubility and octanol-water partition coefficients (Jtow) and correlations between equilibrium constants of related sets of compounds. Perhaps the best-known attribute relationships to chemists are the correlations between reaction rate constants and equilibrium constants for related reactions commonly known as linear free-energy relationships or LFERs. The LFER concept also leads to the broader concepts of property-activity and structure-activity relationships (PARs and SARs), which seek to predict the environmental fate of related compounds or their bioactivity (bioaccumulation, biodegradation, toxicity) based on correlations with physicochemical properties or structural features of the compounds. Table 1 summarizes the types of attribute relationships that have been used in chemical fate studies and defines some important terms used in these relationships. 

Variables commonly used in PARs and SARs are summarized in Table 4. The main processes of interest relative to the bioactivity of aquatic contaminants are bioaccumulation, biodegradation, and acute toxicity (LC50), but inhibition of key biological processes such as respiration rate and photosynthesis also are used in some PARs and SARs as measures of a compound s toxicity. The physicochemical properties listed in Table 4 reflect molecular structure, but they are not structural characteristics themselves. Relationships based on these properties thus should be called property-activity relationships (PARs), and the term (quantitative) structure-activity relationship, (Q)SAR should be restricted to relationships based on structural or topological parameters. However, the literature is not consistent in this terminology, and the line between structural characteristics and properties resulting from structure is not always clear. 

In many cases, at least for screening purposes and for preliminary comparisons of several compounds, approximate information on the intrinsic stability of a molecule, taken as an index of persistence potential that is independent of environmental variables, can be useful. In these cases the use of predictive approaches based on the molecular properties and structure (QSAR quantitative structure-activity relationships) could be very helpful in the absence of experimental information. Although the application of QSARs for the prediction of persistence has not yet been developed for screening as it has for other ecotoxicological aspects (e.g. prediction of toxic effects or bioaccumulation), in the last few years there has been some promising progress (Tremolada et al, 1991 Vasseur etal., 1993 Macalady and Schwarzenbach, 1993). 

QSARs for Pand B. Since experimental data for persistence and bioaccumulation (as well as ecotoxicity) are often unavailable, quantitative structure activity relationship (QSAR) models are commonly used by Environment Canada, the US EPA, and other government agencies to predict values for these hazards. For the purposes of assigning levels of concern in the Green Screen for persistence and bioaccumulation, when measurable data are absent, QSARs are considered acceptable (for further discussion of the use and limits of QSARs to fill data gaps see section 4.4). 

The bioaccumulation of a substance into an organism is not an adverse effect hazard in itself. Bioconcentration and bioaccumulation may lead to an increase in body burden which may cause toxic effects due to direct and/or indirect exposure. Bioaccumulative substances characterized by high persistence and toxicity, negligible metabolism and a log ATow between 5 and 8 may represent a concern when widely dispersed in the environment. The potential of a substance to bioaccumulate is primarily related to its lipophilicity. A surrogate measure of this quality is the n-octanol - water partition coefficient (/fow), which is correlated with bioconcentration potential. Therefore, /fow values are normally used as predictors in quantitative structure - activity relationships (QSARs) for bioconcentration factors (BCFs) of organic non-polar substances. 

Chemical reactivity and biological activity can be related to molecular structure and physicochemical properties. QSAR models can be established among hydrophobic-lipophilic, electronic, and steric properties, between quantum-mechanics-related parameters and toxicity and between environmental fate parameters such as sorption and tendency for bioaccumulation. The main objective of a QSAR study is to develop quantitative relationships between given properties of a set of chemicals and their molecular descriptors. To develop a valid QSAR model, the following steps are essential ... 

The linear solvation energy relationship (LSER) can be a useful predictive tool for environmental property estimations (Hickey 1999). In LSER, the solution behavior of a substance (e.g., solubility, bioaccumulation, and toxicity) is directly related to several aspects of its chemical structure. Eor example, a LSER equation is depicted in Equation (3.73) ... 

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