Abstract
Numerous environmental chemicals, both long-known toxicants such as persistent organic pollutants as well as emerging contaminants such as pharmaceuticals, are known to modulate immune parameters of wildlife species, what can have adverse consequences for the fitness of individuals including their capability to resist pathogen infections. Despite frequent field observations of impaired immunocompetence and increased disease incidence in contaminant-exposed wildlife populations, the potential relevance of immunotoxic effects for the ecological impact of chemicals is rarely considered in ecotoxicological risk assessment. A limiting factor in the assessment of immunotoxic effects might be the complexity of the immune system what makes it difficult (1) to select appropriate exposure and effect parameters out of the many immune parameters which could be measured, and (2) to evaluate the significance of the selected parameters for the overall fitness and immunocompetence of the organism. Here, we present — on the example of teleost fishes — a brief discussion of how to assess chemical impact on the immune system using parameters at different levels of complexity and integration: immune mediators, humoral immune effectors, cellular immune defenses, macroscopical and microscopical responses of lymphoid tissues and organs, and host resistance to pathogens. Importantly, adverse effects of chemicals on immunocompetence may be detectable only after immune system activation, e.g., after pathogen challenge, but not in the resting immune system of non-infected fish. Current limitations to further development and implementation of immunotoxicity assays and parameters in ecotoxicological risk assessment are not primarily due to technological constraints, but are related from insufficient knowledge of (1) possible modes of action in the immune system, (2) the importance of intra- and inter-species immune system variability for the response against chemical stressors, and (3) deficits in conceptual and mechanistic assessment of combination effects of chemicals and pathogens.
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References
Albergoni V, Viola A (1995) Effects of cadmium on catfish, Ictalurus melas, humoral immune reponse. Fish Shellfish Immunol 5:89–95
Alexander JB, Ingram CA (1992) Non-cellular non-specific defense mechanisms of fish. Ann Rev Fish Dis 2:249–277
Arkoosh MR, Casillas E, McCain B, Varanasi U (1991) Suppression of immunological memory in juvenile Chinook salmon (Oncorhynchus tshawytscha) from an urban estuary. Fish Shellfish Immunol 1:261–277
Arkoosh MR, Casillas E, Huffman P, Clemons E, Evered J, Stein JE, Varanasi U (1998) Increased susceptibility of juvenile Chinook salmon from a contaminated estuary to Vibrio anguillarum. Trans Am Fish Soc 127:360–374
Arkoosh MR, Clemons E, Hufman P, Kagley AN (2001) Increased susceptibility of juvenile Chinook salmon to vibriosis after exposure to chlorinated and aromatic compounds found in contaminated urban estuaries. J Aquat Anim Health 13:257–268
Arkoosh MR, Boylen D, Stafford CC, Johnson LL, Colliert TK (2005) Use of disease challenge assays to assesss immunotoxicity of xenobiotics to fish. In: Ostrander GK (ed) Techniques in aquatic toxicology, vol 2. Taylor & Francis, New York, pp 19–35
Bayne CJ, Gerwick L (2001) The acute phase response and innate immunity of fish. Dev Comp Immunol 25:725–743
Beinecke A, Siebert U, McLachlan M, Bruhn R, Thron K, Failing K, Müller G, Baumgärtner W (2005) Investigations of the potential influence of environmental contaminants on the thymus and spleen of harbour porpoises (Phocoena phocoena). Environ Sci Technol 39:3933–3938
Bols NC, Brubacher JL, Ganassin RC, Lee LEJ (2001) Ecotoxicology and innate immunity in fish. Dev Comp Immunol 25:853–873
Burnett KG (2005) Impact of environmental toxicants and natural variables on the immune system of fishes. In: Mommsen TP, Moon TW (eds) Biochemistry and molecular biology of fishes, vol VI, Environmental toxicology. Elsevier, Amsterdam, pp 231–253
Burns LA, Meade BJ, Munson AE (1996) Toxic responses of the immune system. In: Klaasen CD (ed) Casarett & Doull’s Toxicology. McGraw-Hill, New York, pp 355–402
Calow P, Forbes VE (2003) Does ecotoxicology inform ecological risk assessment? Environ Sci Technol 37:146A–151A
Carlson E, Zelikoff JT (2008) The immune system of fish: a target organ of toxicity. In: Di Giulio RT, Hinton DE (eds) The toxicology of fishes. CRC Press, Boca Raton, FL, pp 489–529
Carlson EA, Li Y, Zelikoff JT (2002) Exposure of Japanese medaka (Oryzias latipes) to benzo(a)pyrene suppresses immune function and host resistance against bacterial challenge. Aquat Toxicol 56:289–301
Carlson EA, Li Y, Zelikoff JT (2004) Benzo(a)pyrene-induced immunotoxicity in Japanese medaka (Oryzias latipes): relationship between lymphoid CYP1A activity and humoral immune suppression. Toxicol Appl Pharmacol 201:40–52
Casanova-Nakayama A, Wenger M, Burki R, Eppler E, Krasnov A, Segner H (2011) Endocrine disrupting compounds: can they target the immune system of fish? Mar Pollut Bull 63:412–416
Castro R, Bernard D, Lefranc MP, Six A, Benmansour A, Boudinot P (2011) T cell diversity and TcR repertoire in teleost fish. Fish Shellfish Manag 31:644–654
Chang YT, Kai YH, Chi SC, Song YL (2011) Cytotoxic CD8α+ leucocytes have heterogenous features in antigen recognition abd class I MHC restriction in grouper. Fish Shellfish Immunol 30:1283–1293
Dautremepuits C, Betoulle S, Paris-Palacios S, Vernet G (2004) Humoral immune factors modulated by copper and chitosan in healthy or parasitised carp (Cyprinus carpio L.) by Ptychobothrium sp. (Cestoda). Aquat Toxicol 68:325–338
Demas GE, Zysling DA, Beechler BR, Muehlenbein MP, French SS (2011) Beyond phytohaemaglutinin: assessing vertebrate immune function across ecologcial contexts. J Anim Ecol 80:710–730
Dietert RR (2009) Developmental immunotoxicology: focus on health risks. Chem Res Toxicol 22:17–23
Eder KJ, Clifford MA, Hedrick RP, Köhler HR, Werner I (2008) Expression of immune regulatory genes in juvenile Chinook salmon following exposure to pesticides and infectious hematopoietic necrosis virus (IHNV). Fish Shellfish Immunol 25:508–516
Evans DL, Smith EE, Brown FE (1987) Nonspecific cytotoxic cells in fish (lctalurus punctatus): VI. Flow cytometric analysis. Dev Comp Immunol 11:95–104
Faller P, Koble B, Peter A, Sumpter JP, Burkhardt-Holm P (2003) Stress status of gudgeon (Gobio gobio) from rivers in Switzerland with and without input of sewage treatment plant effluent. Environ Toxicol Chem 22:2063–2072
Fatima M, Mandiki SN, Douxfils J, Silvestre F, Coppe P, Kestemont P (2007) Combined effects of herbicides on biomarkers reflecting immune-endocrine interactions in goldfish. Immune and antioxidant effects. Aquat Toxicol 81:159–167
Fischer U, Utke K, Somamoto T, Köllner B, Ototake M, Nakanishi T (2006) Cytotoxic activities of fish leukocytes. Fish Shellfish Immunol 20:209–226
Fleeger JW, Carman KR, Nisbet RM (2003) Indirect effects of contaminants in aquatic ecosystems. Sci Total Environ 317:207–233
Galloway TS, Depledge MH (2001) Immunotoxicity in invertebrates: measurement and ecotoxicological relevance. Ecotoxicology 10:5–23
Garduno RA, Kay WW (1994) Isolation and culture of head kidney macrophages. In: Hochachka PW, Mommsen TP (eds) Biochemistry and molecular biology of fishes, vol 3, Analytical techniques. Elsevier, Amsterdam, pp 327–353
Garrigues Ph, Barth H, Walker CH, Narbonne JF (eds) (2001) Biomarkers in marine organisms. A practical approach. Elsevier, Amsterdam
Germolec DR, Kashon M, Nyska A, Kuper CF, Portier C, Kommimemi C, Johnson KA, Luster MI (2004) The accuracy of extended histopathology to detect immunotoxic chemicals. Toxicol Sci 82:504–514
Goetz FW, Planas JV, Mackenzie S (2004) Tumor necrosis factors. Dev Comp Immunol 28:487–497
Graham AL, Hayward AD, Watt KA, Pilkington JG, Pemberton JM, Nussey DH (2010) Fitness correlates of heritable variation in antibody responsiveness in a wild mammal. Science 330:662–665
Grinwis GCM, Besselink HT, van den Brandhof EJ, Bulder AS, Engelsma MY, Kuiper RV, Wester PW, Vaal MA, Vethaak AD, Vos JG (2000) Toxicity of TCDD in European flounder (Platichthys flesus) with emphasis on histopathology and cytochrome P4501A induction in several organ systems. Aquat Toxicol 50:387–401
Harford AJ, O’Halloran K, Wright PF (2006) Flow cytometric analysis and optinisation for measuring phagocytosis in three Australian freshwater fish. Fish Shellfish Immunol 20:562–573
Harms CA, Ottinger CA, Blazer VS, Densmore CL, Pieper LH, Kennedy-Stoskopf S (2000) Quantitative polymerase chain reaction for transforming growth factor-β applied to field study of fish health in Chesapeake Bay tributaries. Environ Health Perspect 108:447–452
Hinton DM (2000) US FDA “Redbook II” immunotoxicity testing guidelines and research in immunotoxicity evaluation of food chemicals and new food proteins. Toxicol Pathol 28:467–478
Hoeger B, Köllner B, Dietrich DR, Hitzfeld B (2005) Water-borne diclofenac affects kidney and gill integrity and selected immune parameters in brown trout (Salmo trutta f. fario). Aquat Toxicol 75:53–64
Hutchinson TH, Field MDR, Manning MJ (2003) Evaluation of non-specific immune functions in dab, Limanda limanda, following short-term exposure to sediments contaminated with polyaromatic hydrocarbons and/or polychlorinated biphenyls. Mar Environ Res 55:193–202
Iwanowicz LR, Blazer VS, McCormick SD, VanVeld PA, Ottinger CA (2009) Aroclor 1248 exposure leads to immunomodulation, decreased disease resistance and endocrine disruption in the brown bullhead, Ameiurus nebulosus. Aquat Toxicol 93:70–82
Jin X, Chen R, Liu W, Fu Z (2010) Effect of endocrine disrupting chemicals on the transcription of genes related to the innate immune system in the early developmental stage of zebrafish (Danio rerio). Fish Shellfish Immunol 28:854–861
Jovanovic B, Anastasova L, Rowe EW, Zhang Y, Clapp AR, Palic D (2011) Effects of nanosized titanium dioxide on innate immune system of fathead minnow (Pimephales promelas). Ecotoxicol Environ Saf 74:675–683
Kiesecker JM (2002) Synergism between trematode infection and pesticide exposure: a link to amphibian limb deformities in nature? Proc Natl Acad Sci U S A 99:9900–9904
Köllner B, Kotterba G, Fischer U (2002) Evaluation of immune functions of rainbow trout—how can environmental influences be detected? Toxicol Lett 131:83–95
Koskinen H, Pehkonen P, Vehniäinen E, Krasnov A, Rexroad C, Afanasyev S, Mölsa H, Oikari A (2004) Response of rainbow trout transcriptome to model chemical contaminants. Biochem Biophys Res Commun 320:745–753
Kreutz LC, Gil Barcellos LJ, de Faria VS, de Oliveira ST, Anziliero D, Davi dos Santos E, Pivato M, Zanatta R (2011) Altered hematological and immunological parameters in silver catfish (Rhamdia quelen) following short term exposure to sublethal concentration of glyphosate. Fish Shellfish Immunol 30:51–57
Lazarro BP, Little TJ (2009) Immunity in a variable world. Phil Trans R Soc B 364:15–26
Litman GW, Rast JP, Fugman SD (2010) The origins of vertebrate adaptive immunity. Nat Rev Immunol 10:543–552
Luebke RW, Hodson PV, Faisal M, Ross PJ, Grasman KA, Zelikoff J (1997) Aquatic pollution-induced immunotoxicity in wildlife species. Fundam Appl Toxicol 37:1–5
Luebke RW, Copeland CB, Bishop RL, Daniels MJ, Gilmour MI (2002) Mortality in dioxin-exposed mice infected with influenza-mitochondrial toxicity (Reye’s like syndrome) versus enhanced inflammation as the mode of toxic action. Toxicol Sci 69:109–116
MacKenzie S, Iliev D, Liarte C, Koskinen H, Planas JV, Goetz FW, Mölsä H, Krasnov A, Tort L (2006) Transcriptional analysis of LPS-stimulated activation of trout (Oncorhynchus mykiss) monocyte/macrophage cells in primary culture treated with cortisol. Mol Immunol 43:1340–1348
Magnadóttir I (2006) Innate immunity of fish (overview). Fish Shellfish Immunol 20:137–151
Milston RH, Fitzpatrick MS, Vella AT, Clements S, Gundersen D, Feist G, Crippen TL, Leong J, Schreck CB (2003) Short-term exposure of Chinook salmon (Oncorhynchus tshawytscha) to o, p′-DDE or DMSO during early life history stages causes long-term humoral immunosuppression. Environ Health Perspect 111:1601–1607
Moritomo T, Serata K, Teshirogi K, Aikawa H, Inoue Y, Itou T, Nakanishi T (2003) Flow cytometric analysis of the neutrophil respiratory burst of ayu, Plecoglossus altivelis: comparison with other fresh water fish. Fish Shellfish Immunol 15:29–38
Mos L, Morsey B, Jeffries SJ, Yunker MB, Raverty S, de Guise S, Ross PS (2006) Chemical and biological pollution contribute to the immunological profiles of free-ranging harbour seals. Environ Chem Toxicol 25:3110–3117
Mustafa A, Holladay SD, Goff M, Witowswky S, Kerr R, Reilly C, Spenenberg P, Gogal RM (2008) An enhanced postnatal autoimmune profile in 24 week old C56BL/6 mice developmentally exposed to TCDD. Toxicol Appl Pharmacol 232:51–59
Nakayama A, Kurokawa Y, Harino H, Kawahara E, Miyadai T, Seikai T, Kawai S (2007) Effects of tributyltin on the immune system of Japanese flounder (Paralichthys olivaceus). Aquat Toxicol 83:126–133
Nakayama A, Riesen I, Köllner B, Eppler E, Segner H (2008a) Surface marker-defined head kidney granulocytes and B-lymphocytes of rainbow trout express benzo[a]pyrene-inducible cytochrome P4501A protein. Toxicol Sci 103:86–96
Nakayama K, Kitamura SI, Murakami Y, Song JY, Oh MJ, Iwata H, Tanabe S (2008b) Toxicogenomic analysis of immune system-related genes in Japanese flounder (Paralichtys oliveaceus) exposed to heavy oil. Mar Pollut Bull 57:445–452
Nakayama A, Segner H, Kawai SI (2009) Immunotoxic effects of organotin compounds in teleost fish. In: Arai T, Harino M, Langston WJ (eds) Ecotoxicology of antifouling biocides. Springer, Tokyo, pp 207–218
Newman MC (2001) Population ecotoxicology. John Wiley & Sons, New York
Nonaka M, Smith SL (2000) Complement system of bony and cartilaginous fish. Fish Shellfish Immunol 10:215–228
Ottinger CA, Kaattari SL (2000) Long-term immune dysfunction in rainbow trout (Oncorhynchus mykiss) exposed as embryos to aflatoxin B1. Fish Shellfish Immunol 10:101–106
Owen IPF, Wilson K (1999) Immunocompetence: a neglected life history trait or conspicuous red herring? TREE 14:170–172
Pedersen AB, Babayan SA (2011) Wild immunology. Mol Ecol 20:872–880
Prabakaran M, Binuramesh C, Steinhagen D, Michael RD (2006) Immune response and disease resistance of Oreochromis mossambicus to Aeromonas hydrophila after exposure to hexavalent chromium. Dis Aquat Organ 68:189–196
Press CM, Evensen O (1999) The morphology of the immune system in teleost fishes. Fish Shellfish Immunol 9:309–318
Quabius ES, Krupp G, Secombes CJ (2005) Polychlorinated biphenyl 126 affects expression of genes involved in stress-immune interaction in primary cultures of rainbow trout anterior kidney cells. Environ Toxicol Chem 24:3053–3060
Relyea R, Hoverman J (2006) Assessing the ecology in ecotoxicology: a review and synthesis in freshwater systems. Ecol Lett 9:1157–1171
Reynaud S, Deschaux P (2006) The effects of polycyclic aromatic hydrocarbons on the immune system of fish: a review. Aquat Toxicol 77:229–238
Rice CD (2001) Fish immunotoxicology: understanding mechanisms of action. In: Schlenk D, Benson WH (eds) Target organ toxicity in marine and freshwater teleosts, vol 2. Taylor & Francis, London, pp 96–138
Rice CD, Kergosien DH, Adams MS (1996) Innate immune function as a bioindicator of pollution stress in fish. Ecotoxicol Environ Saf 33:186–192
Rohr JR, Schotthoegr AM, Raffel TR, Carrick HJ, Halstead N, Hoverman JT, Johnson VM, Lieske C, Piwoni MD, Schoff PK, Beasley VR (2008). Agrochemicals increase trematode infections in declining amphibian species. Nature 455:1235–1240
Saeij JP, Stet RJ, de Vries BJ, van Muiswinkel WB, Wiegertjes GF (2003) Molecular and functional characterization of carp TNF; a link between TNF polymorphisms and trypano-tolerance? Dev Comp Immunol 27:29–41
Schmidt V, Zander S, Körting W, Broeg K, von Westernhagn H, Dizer H, Hansen PD, Skouras A, Steinhagen D (2003) Parasites of flounder (Paralichthys flesus) from the German Bight, North Sea, and their potential use in biological effects monitoring. Helgol Mar Res 57:262–271
Schulte A, Ruehl-Fehlert C (2006) Regulatory aspects of immunotoxicology. Exp Toxicol Pathol 57:385–389
Secombes CJ, Cunningham C (2004) Cytokines: an evolutionary perspective. Dev Comp Immunol 28:373–384
Segner H (2007) Ecotoxicology—how to asses the impact of toxicants in a multifactorial environment? In: Mothersill C, Mosse I, Seymour C (eds) Multiple stressors: a challenge for the future. NATO Advanced Workshop. Environmental security. Springer, Heidelberg, pp 39–56
Segner H (2011a) Moving beyond a descriptive aquatic toxicology: the value of biological process and trait information. Aquat Toxicol, in press
Segner H (2011b) Reproductive and developmental toxicity in fishes. In: Gupta RC (ed) Reproductive and developmental toxicology. Elsevier, Amsterdam, pp 1145–1166
Segner H, Möller AM, Wenger M, Casanova-Nakayama A (2011). Fish immunotoxicology: research at the crossroads of immunology, ecology and toxicology. In: Hirawa A (ed) Interdisciplinary studies in environmental chemistry, vol 6. Terra Scientific Publishing Company, Tokyo, pp 1–15
Sheldon BC, Verhulst S (1996) Ecological immunology: costly parasite defenses and trade-offs in evolutionary ecology. TREE 11:317–321
Shen LL, Stuge TB, Zhou H, Khayat M, Barker KS (2002) Channel catfish cytotoxic cells: a mini-review. Dev Comp Immunol 26:141–149
Siwicki AK, Anderson DP (1993) An easy spectrophotometric assay for determining total protein and immunoglobulin levels in fish sera: correlation to fish health. In: Stolen JS, Fletcher TC, Anderson DP, Kaattari SL, Rowley AF (eds) Techniques in fish immunology. SOS Publications, Fair Haven, NJ, pp 23–30
Skouras A, Broeg K, Dizer H, von Westernhagen H, Hansen PD, Steinhagen D (2003) The use of innate immune responses as biomarkers in a programme of integrated biological effects monitoring on flounder (Platichthys flesus) from the southern North Sea. Helgol Mar Res 57:190–198
Smialowicz RJ, Burgin DE, Williams WC, Diliberto JJ, Setzer RW, Birnbaum LS (2004) CYP1A2 is not required for 2,3,7,8-tetrachlorodibenzo-p-dioxin-indiuced immunosuppression. Toxicology 197:15–22
Song JY, Nakayama K, Murakami Y, Jung SJ, Oh MJ, Matuoka S, Kawakami H, Kitamura SI (2008) Does heavy oil pollution induce bacterial diseases in Japanese flounder, Paralichthys oliveaceus? Mar Pollut Bull 57:889–894
Song JY, Nakayama K, Murakami Y, Kitamura SI (2011) Heavy oil exposure induces high mortalities in virus carrier Japanese flounder, Paralichthys oliveaceus. Mar Pollut Bull 63:362–365
Spitsbergen JM, Blazer VS, Bowser PR, Cheng KC, Cooper KR, Cooper TK, Fraser S, Groman DB, Harper CM, Law JM, Marty GD, Smolowitz RM, St. Leger M, Wolf DC, Wolf JC (2009) Finfish and aquatic invertebrate pathology resources for now and the future. Comp Biochem Physiol 149C:249–257
Springman KR, Kurath G, Anderson JJ, Emlen JM (2005) Contaminants as viral cofactors: assessing indirect population effects. Aquat Toxicol 71:13–23
Spromberg JA, Mador JP (2005) Relating results of chronic toxicity responses to population-level effects: modeling effects on wild Chinook salmon populations. Integr Environ Assess Manag 1:9–21
Sunyer JO, Zarkadi IK, Sahu A, Lambris JD (1996) Multiple forms of complement C3 in trout that differ in binding to complement activators. Proc Natl Acad Sci U S A 93:8456–8551
Thilagam H, Gopalokrishnan S, Bo J, Wang KJ (2009) Effect of 17β-estradiol on the immunocompetence of Japanese sea bass (Lateolabrax japonicus). Environ Toxicol Chem 28:1722–1731
Trowsdale J, Parham P (2004) Defense strategies and immunity-related genes. Eur J Immunol 34:7–17
Valdez Domingos FX, Oliveira Ribeiro CA, Pelletier E, Rouleau C (2011) Tissue distribution and depuration kinetics of waterborne 14C-labeled light PAHs in mummichog (Fundulus heteroclitus). Environ Sci Technol 45:2684–2690
Warr GW (1983) Immunogloblin of the toadfish, Spheroides glaber. Comp Biochem Physiol B 76:507–514
Weis JS, Smith G, Zou T, Santiago-Bass C, Weis P (2001) Effects of contaminants on behaviour: biochemical mechanisms and ecological consequences. Bioscience 51:209v217
Wenger M, Sattler U, Goldschmidt-Clermont E, Segner H (2011) 17beta-Estradiol affects complement components and survival of rainbow trout (Oncorhynchus mykiss) challenged by bacterial (Yersinia ruckeri) infection. Fish Shellfish Immunol 31:90–97
Winans B, Humble MC, Lawrence BP (2011) Environmental toxicants and the developing immune system: a missing link in the global battle against infectious diseases? Repro Toxicol 31:327–336
Yano T (1993) Assays of hemolytic complement activity. In: Stolen JS, Fletcher TC, Kaattari SL, Rowley AF (eds) Techniques in Fish Immunology. SOS Publications, Fair Haven, NJ, pp 131–141
Yano T (1996) The nonspecific immune system: humoral defense. In: Iwama G, Nakanishi T (eds) The fish immune system. Fish physiology, vol 15. Academic Press, San Diego, pp 106–157
Zapata AG, Chiba A, Varas A (1996) Cells and tissues of the immune system of fish. In: Iwama G, Nakanihi T (eds) The fish immune system: Organism, pathogen and the environment. Academic Press, New York, pp 1–62
Zeeman MG, Brindley WA (1981) Effects of toxic agents upon fish immune systems. A review. In: Sharma RP (ed) Immunologic considerations in toxicology. CRC Press, Boca Raton, FL, pp 3–60
Zelikoff JT, Raymond A, Carlson E, Li Y, Beaman JR, Anderson M (2000) Biomarkers of immunotoxicity in fish: from the lab to the ocean. Toxicol Lett 112(113):325–331
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This study was financially supported in part by the Swiss National Research Foundation, SNF (No. 31003A-130640) to HS.
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Segner, H., Wenger, M., Möller, A.M. et al. Immunotoxic effects of environmental toxicants in fish — how to assess them?. Environ Sci Pollut Res 19, 2465–2476 (2012). https://doi.org/10.1007/s11356-012-0978-x
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DOI: https://doi.org/10.1007/s11356-012-0978-x