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Investigation of Critical Body Residues and Modes of Toxic Action Based on Injection and Aquatic Exposure in Fish

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Investigation of Critical Body Residues and Modes of Toxic Action Based on Injection and Aquatic Exposure in Fish View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by LJMU Research Online Investigation of Critical Body Residues and Modes of Toxic Action Based on Injection and Aquatic Exposure in Fish Yang Wen & Limin Su & Weichao Qin & Yuanhui Zhao & Judith C. Madden & Fabian P. Steinmetz & Mark T. D. Cronin Abstract The internal concentration represented by the reactive compounds, but greater than the average CBR critical body residue (CBR) is an ideal indicator to for baseline compounds. This difference is due to the reflect the intrinsic toxicity of a chemical. Whilst some lipid fraction being the major storage site for most of the studies have been performed on CBR, the effect of baseline compounds. Investigation on the calculated exposure route on internal toxicity has not been investi- and observed CBRs shows that calculated CBRs are gated for fish. In this paper, acute toxicity data to fish close to observed CBRs for most of compounds. comprising LC50 and LD50 values were used to investi- However, systemic deviations of calculated CBRs gate CBR. The results showed that exposure route can have been observed for some compounds. The reasons significantly affect the internal concentration. LD50 and for these systemic deviations may be attributed to BCF, CBR calculated from LC50 and BCF both vary indepen- equilibrium time and experimental error of LC50. These dently of hydrophobicity as expressed by log Kow; factors are important and should be considered in the conversely, LC50 is related to log Kow. A poor relation- calculation of CBRs. ship was observed between LC and LD , but the 50 50 relationship can be improved significantly by introduc- Keywords Critical body residue . Exposure route . tion of log K because log CBR is positively related to ow Bioconcentration factor . Hydrophobicity . Fish log LD50. The parallel relationship of log CBR-log Kow and log LD50-log Kow indicates that LD50 does not reflect the actual internal concentration. The average LD50 is close to the average CBR for less inert and 1 Introduction Global industrialisation has resulted in a large number of Electronic supplementary material The online version of this organic pollutants entering the aquatic environment. article (doi:10.1007/s11270-015-2427-1) contains supplementary material, which is available to authorized users. These organic pollutants can be accumulated in aquatic : : : organisms following several exposure routes, such as Y. Wen L. Su W. Qin Y. Zhao (*) oral, inhalation, injection (through in vivo testing) or State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, dermal exposure, as well as from the food chain. The Northeast Normal University, Changchun, Jilin 130117, exposure routes play an important role in assessing the People’s Republic of China internal concentration. If the concentration of organic e-mail: [email protected] pollutants in an organism exceeds the critical body J. C. Madden : F. P. Steinmetz : M. T. D. Cronin (*) residue, the result to the organism may be lethality. School of Pharmacy and Biomolecular Sciences, Liverpool The critical body residue (CBR) is defined as the John Moores University, Liverpool L3 3AF England, UK concentration expressed in moles per kg body weight e-mail: [email protected] (mol/kg), which exerts a specific toxic effect such as death or reduction in growth (McCarty 1987). has been reached within some bio-phase site of action in Barron et al. (2002) questioned the utility of CBR the organism. However, target site concentrations of approach for assessing toxicant effects in aquatic organic compounds are difficult to obtain directly. As biota. The conclusion of this review was that large a surrogate, the total concentration in an organism that variability existed among species and toxicants when elicits a critical effect, termed the CBR, has been used. tissue concentrations were used as the dose metric Early studies used measurements of bioconcentration and that variability was not reduced over that observed factor (BCF) and the external concentration causing for external exposure concentrations. Thus, the study of 50 % lethality (LC50) to estimate the residue concentra- CBRs based on different exposure routes is useful tion for 50 % mortality. Estimating the body residue for the evaluation of toxic mechanisms of organic associated with a toxic biological response from chemicals to aquatic organisms. QSARs for toxicity and bioconcentration appears to be The modes of toxic action play an important role in reasonably successful for neutral narcotic organic the assessment of the ecotoxicity of organic compounds. chemicals (McCarty 1987; McCarty et al. 1992; The Verhaar classification scheme is well recognised as Meador 2006). McCarty et al. (1992) first reported that a means to classify compounds acting by baseline (or the body residue values for organic compounds vary non-polar) and less inert (or polar) narcosis, as well as across different modes of toxic action. For narcotic reactive and specific mechanisms (Verhaar et al. 1992). compounds (both baseline and less inert chemicals), This scheme has been updated by Enoch et al. (2008). the CBR for a toxic effect such as lethality or growth The Verhaar scheme represents a well-established deci- inhibition is constant, independent of either compound sion tree constructed using a series of structural alerts or exposure time (McCarty et al. 1993; Van Wezel and designed to enable simple organic compounds to be Opperhuizen 1995; Meador et al. 2008). The baseline assigned to one of four categories. Chemicals acting compounds cause mortality within a very narrow range by baseline are those that are not reactive when consid- of whole body tissue concentrations (2–8 mmol/g wet ering overall acute effects and that do not interact with weight or about 50 mmol/g lipid) in small aquatic or- specific receptors in an organism. These chemicals act ganisms; the range for less inert compounds is also non-specifically on the cell membranes, and therefore, narrow, but lower (0.6–2 mmol/g) (Meador et al. their toxicity can well be predicted from their octanol/ 2011). However, the CBR for reactive compounds is water partition coefficient (Kow) for a number of species different. These compounds are either receptor mediated (Cronin and Dearden 1995; Dearden et al. 2000; Su or involve a direct chemical reaction with a biological et al. 2012). Less inert chemicals are slightly more toxic substrate (macromolecule). than baseline toxicity and are commonly identified as With the advent of CBR as the dose metric, it be- possessing hydrogen bond donor acidity on an aromatic comes possible to focus on the internal dose required to ring. Reactive chemicals can react covalently and unse- produce toxicity in aquatic organisms. However, the lectively with nucleophilic sites commonly found in internal toxicity is directly related to the exposure route. biomolecules or are metabolised into more toxic species. The exposure route influences toxicokinetic properties In principle, the toxicity of reactive compounds is diffi- (i.e. absorption, distribution, metabolism, elimination) cult to model, especially when different reaction mech- and thus toxicity (Klaassen and Rozman 1991). anisms are considered. Specifically acting chemicals Although acute toxicity to rat and rainbow trout was exhibit toxicity due to (specific) interactions with certain compared from different exposure routes, the relation- receptor molecules (specific or receptor toxicity). A ships between toxic effect and exposure routes have not series of structural rules which aimed to classify com- been investigated systematically and reported in the pounds according to modes of toxic action have been literature. The comparison of acute toxicity within and reported historically in the literature (Hermens 1990; between rat and rainbow trout over various exposure von der Ohe et al. 2005; Enoch et al. 2008, 2011) and routes shows that they are likely to be based on similar were the basis of those defined by Verhaar et al. (1992). toxicokinetics and interspecies correlations were good, Target site concentration is an ideal indicator to re- when matched on exposure routes between trout and flect the intrinsic toxicity of a chemical. Chemicals rats (Delistraty et al. 1998). Wolf et al. (2004) observed acting by a lethal narcosis mechanism achieve their that after establishing a lethal narcosis mechanism effect once a critical concentration, or critical volume, through the inhalation exposure route, a compound’s oral toxicity can be reliably estimated. The toxicity homologues based on their functional groups. The details related with the exposure routes has been observed by of classification, together with CAS numbers and descrip- many people (Klaassen and Rozman 1991; Delistraty tors calculated for each compound, are reported in 1999, 2000). Table S1 of Supplementary material. Although studies on CBR for narcotic compounds The toxicity data expressed by the dose required to were reported in the literature (McCarty et al. 1992, kill 50 % of fish (LD50) were taken from the most 1993; Barron et al. 1997), the data are limited, and there extensive, publicly available data compilation, the is a lack of information regarding how the exposure Environmental Residue Effects Database (ERED, route affects the concentration of the biologically active http://el.erdc.usace.army.mil/ered/). The LD50 toxicity material at the site of action. By comparing
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