Quantifying Synergy: A Systematic Review of Mixture Toxicity Studies within Environmental Toxicology
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{"title"=>"Quantifying synergy: A systematic review of mixture toxicity studies within environmental toxicology", "type"=>"generic", "authors"=>[{"first_name"=>"Nina", "last_name"=>"Cedergreen", "scopus_author_id"=>"6602404992"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"373071858", "sgr"=>"84900413101", "pmid"=>"24794244", "scopus"=>"2-s2.0-84900413101", "isbn"=>"1932-6203", "doi"=>"10.1371/journal.pone.0096580", "issn"=>"19326203"}, "id"=>"d0147b71-7973-3cf5-918a-d1dd2ea2888f", "abstract"=>"Cocktail effects and synergistic interactions of chemicals in mixtures are an area of great concern to both the public and regulatory authorities. The main concern is whether some chemicals can enhance the effect of other chemicals, so that they jointly exert a larger effect than predicted. This phenomenon is called synergy. Here we present a review of the scientific literature on three main groups of environmentally relevant chemical toxicants: pesticides, metal ions and antifouling compounds. The aim of the review is to determine 1) the frequency of synergy, 2) the extent of synergy, 3) whether any particular groups or classes of chemicals tend to induce synergy, and 4) which physiological mechanisms might be responsible for this synergy. Synergy is here defined as mixtures with minimum two-fold difference between observed and predicted effect concentrations using Concentration Addition (CA) as a reference model and including both lethal and sub-lethal endpoints. The results showed that synergy occurred in 7%, 3% and 26% of the 194, 21 and 136 binary pesticide, metal and antifoulants mixtures included in the data compilation on frequency. The difference between observed and predicted effect concentrations was rarely more than 10-fold. For pesticides, synergistic mixtures included cholinesterase inhibitors or azole fungicides in 95% of 69 described cases. Both groups of pesticides are known to interfere with metabolic degradation of other xenobiotics. For the four synergistic metal and 47 synergistic antifoulant mixtures the pattern in terms of chemical groups inducing synergy was less clear. Hypotheses in terms of mechanisms governing these interactions are discussed. It was concluded that true synergistic interactions between chemicals are rare and often occur at high concentrations. Addressing the cumulative rather than synergistic effect of co-occurring chemicals, using standard models as CA, is therefore regarded as the most important step in the risk assessment of chemical cocktails.", "link"=>"http://www.mendeley.com/research/quantifying-synergy-systematic-review-mixture-toxicity-studies-within-environmental-toxicology", "reader_count"=>229, "reader_count_by_academic_status"=>{"Unspecified"=>8, "Professor > Associate Professor"=>10, "Researcher"=>46, "Student > Doctoral Student"=>18, "Student > Ph. D. Student"=>52, "Student > Postgraduate"=>3, "Student > Master"=>46, "Other"=>12, "Student > Bachelor"=>23, "Lecturer"=>2, "Professor"=>9}, "reader_count_by_user_role"=>{"Unspecified"=>8, "Professor > Associate Professor"=>10, "Researcher"=>46, "Student > Doctoral Student"=>18, "Student > Ph. D. Student"=>52, "Student > Postgraduate"=>3, "Student > Master"=>46, "Other"=>12, "Student > Bachelor"=>23, "Lecturer"=>2, "Professor"=>9}, "reader_count_by_subject_area"=>{"Unspecified"=>19, "Engineering"=>5, "Environmental Science"=>76, "Nursing and Health Professions"=>1, "Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>98, "Medicine and Dentistry"=>6, "Pharmacology, Toxicology and Pharmaceutical Science"=>3, "Veterinary Science and Veterinary Medicine"=>2, "Chemistry"=>9, "Earth and Planetary Sciences"=>3, "Energy"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>5}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>9}, "Energy"=>{"Energy"=>1}, "Earth and Planetary Sciences"=>{"Earth and Planetary Sciences"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>98}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>19}, "Environmental Science"=>{"Environmental Science"=>76}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>3}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>2}}, "reader_count_by_country"=>{"Argentina"=>1, "Italy"=>2, "United Kingdom"=>2, "Australia"=>1, "Chile"=>1, "France"=>1, "Portugal"=>3, "Germany"=>2}, "group_count"=>12}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1483557"], "description"=>"<p><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096580#pone-0096580-g003\" target=\"_blank\">Figure 3A</a> shows the number of times each of the antifoulants occur in a binary mixture resulting in antagony (blue bars), concentration additivity (CA) (red bars) or synergy (green bars). Antifoulants occurring in less than 1% of the mixtures were excluded. In figure B and C, the number of binary combinations of photosystem II herbicides (PSII) metal ions or metal containing compounds (Metal) and other organic compounds (Other) resulting in either antagony, concentration additivity or synergy are shown for mixtures tested on B) auto-tropic organisms (plants and algae, <i>n</i> = 23) or C) heterotrophic organisms (microorganisms and animals, <i>n</i> = 80).</p>", "links"=>[], "tags"=>["agriculture", "agrochemicals", "Biochemistry", "chemical biology", "toxicology", "marine and aquatic sciences", "chemistry", "Applied chemistry", "Environmental chemistry", "Model organisms", "antifoulant", "additivity"], "article_id"=>1015120, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Nina Cedergreen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096580.g004", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Frequency_of_antifoulant_antagony_additivity_and_synergy_/1015120", "title"=>"Frequency of antifoulant antagony, additivity and synergy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-02 03:38:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1483558"], "description"=>"<p>The number of times each of the antifoulants occur in a ternary (<i>n</i> = 23) or quaternary (<i>n</i> = 10) mixture resulting in antagony (blue bars), concentration additivity (CA) (red bars) or synergy (green bars).</p>", "links"=>[], "tags"=>["agriculture", "agrochemicals", "Biochemistry", "chemical biology", "toxicology", "marine and aquatic sciences", "chemistry", "Applied chemistry", "Environmental chemistry", "Model organisms", "antifoulant", "interactions", "ternary", "quaternary"], "article_id"=>1015121, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Nina Cedergreen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096580.g005", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Frequency_of_antifoulant_interactions_in_ternary_and_quaternary_mixtures_/1015121", "title"=>"Frequency of antifoulant interactions in ternary and quaternary mixtures.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-02 03:38:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1483559"], "description"=>"a<p>Altenburger, 2011 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096580#pone.0096580-Altenburger3\" target=\"_blank\">[88]</a>.</p>b<p>Walker, 2009 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096580#pone.0096580-Walker1\" target=\"_blank\">[49]</a>.</p>c<p>Fernandez-Alba et al, 2002 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096580#pone.0096580-FernandezAlba1\" target=\"_blank\">[89]</a>.</p>d<p>Zhou et al, 2006 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096580#pone.0096580-Zhou1\" target=\"_blank\">[40]</a>.</p><p>Particularly for the fungicides, which have multiple and often undefined modes of action, different target sites are given in different references. For herbicides and fungicides used as pesticides we use the definition of Tomlin 2002 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096580#pone.0096580-Tomlin1\" target=\"_blank\">[29]</a>. For the remaining compounds, the source of the MoA are given as footnotes.</p>", "links"=>[], "tags"=>["agriculture", "agrochemicals", "Biochemistry", "chemical biology", "toxicology", "marine and aquatic sciences", "chemistry", "Applied chemistry", "Environmental chemistry", "Model organisms", "modes", "antifouling"], "article_id"=>1015122, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Nina Cedergreen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096580.t001", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_overall_group_name_and_proposed_Modes_of_Action_MoA_of_the_antifouling_compounds_/1015122", "title"=>"The overall group, name and proposed Modes of Action (MoA) of the antifouling compounds.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-05-02 03:38:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1483560", "https://ndownloader.figshare.com/files/1483561"], "description"=>"<div><p>Cocktail effects and synergistic interactions of chemicals in mixtures are an area of great concern to both the public and regulatory authorities. The main concern is whether some chemicals can enhance the effect of other chemicals, so that they jointly exert a larger effect than predicted. This phenomenon is called synergy. Here we present a review of the scientific literature on three main groups of environmentally relevant chemical toxicants: pesticides, metal ions and antifouling compounds. The aim of the review is to determine 1) the frequency of synergy, 2) the extent of synergy, 3) whether any particular groups or classes of chemicals tend to induce synergy, and 4) which physiological mechanisms might be responsible for this synergy. Synergy is here defined as mixtures with minimum two-fold difference between observed and predicted effect concentrations using Concentration Addition (CA) as a reference model and including both lethal and sub-lethal endpoints. The results showed that synergy occurred in 7%, 3% and 26% of the 194, 21 and 136 binary pesticide, metal and antifoulants mixtures included in the data compilation on frequency. The difference between observed and predicted effect concentrations was rarely more than 10-fold. For pesticides, synergistic mixtures included cholinesterase inhibitors or azole fungicides in 95% of 69 described cases. Both groups of pesticides are known to interfere with metabolic degradation of other xenobiotics. For the four synergistic metal and 47 synergistic antifoulant mixtures the pattern in terms of chemical groups inducing synergy was less clear. Hypotheses in terms of mechanisms governing these interactions are discussed. It was concluded that true synergistic interactions between chemicals are rare and often occur at high concentrations. Addressing the cumulative rather than synergistic effect of co-occurring chemicals, using standard models as CA, is therefore regarded as the most important step in the risk assessment of chemical cocktails.</p></div>", "links"=>[], "tags"=>["agriculture", "agrochemicals", "Biochemistry", "chemical biology", "toxicology", "marine and aquatic sciences", "chemistry", "Applied chemistry", "Environmental chemistry", "Model organisms", "systematic", "toxicity", "studies"], "article_id"=>1015123, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Nina Cedergreen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0096580.s001", "https://dx.doi.org/10.1371/journal.pone.0096580.s002"], "stats"=>{"downloads"=>8, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantifying_Synergy_A_Systematic_Review_of_Mixture_Toxicity_Studies_within_Environmental_Toxicology_/1015123", "title"=>"Quantifying Synergy: A Systematic Review of Mixture Toxicity Studies within Environmental Toxicology", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-05-02 03:38:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1483554"], "description"=>"<p>A flow diagram depicting the process of selection of records used in the review for the three main groups of toxicants: Pesticides, metals and antifoulants. Data selection has, for pesticides and metals, been built on previous reviews and data compilations, given in the top right text-box, supplemented with database searched using ISI Web of Science. Search criteria and criteria for selecting eligible records are given in the Material and Methods section. For each toxicant the search resulted in two types of databases: One to determine the frequency of synergy in a randomly selected number of mixtures studies, and another focussing only on defined synergistic mixtures. It should be noted that many records contain data on several independent mixtures studies; hence the number of records given in the figure does not match the number of selected studies reported in the results section. References to tables in supporting material giving the raw data on specific chemical mixtures, test species, endpoint and timecourse of the experiment, and the record providing the information are given in the figure.</p>", "links"=>[], "tags"=>["agriculture", "agrochemicals", "Biochemistry", "chemical biology", "toxicology", "marine and aquatic sciences", "chemistry", "Applied chemistry", "Environmental chemistry", "Model organisms", "2009", "diagram"], "article_id"=>1015117, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Nina Cedergreen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096580.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PRISMA_2009_Flow_Diagram_90_/1015117", "title"=>"PRISMA 2009 Flow Diagram [90].", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-02 03:38:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1483555"], "description"=>"<p>Cummulated frequency of Model Deviation Ratios. (MDR) of binary mixtures of pesticides (<i>n</i> = 195), metals (<i>n</i> = 20), and antifoulants (<i>n</i> = 103). The hatched interval where 0.5≤MDR≤2 defines the mixtures that deviates less than two-fold from a Concentration Addition predictions. Mixtures having MDR values<0.5 are termed antagonistic, while mixtures with MDR values>2 are synergistic.</p>", "links"=>[], "tags"=>["agriculture", "agrochemicals", "Biochemistry", "chemical biology", "toxicology", "marine and aquatic sciences", "chemistry", "Applied chemistry", "Environmental chemistry", "Model organisms", "deviation"], "article_id"=>1015118, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Nina Cedergreen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096580.g002", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cummulated_frequency_of_Model_Deviation_Ratios_/1015118", "title"=>"Cummulated frequency of Model Deviation Ratios.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-02 03:38:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1483556"], "description"=>"<p><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096580#pone-0096580-g002\" target=\"_blank\">Figure 2A</a> shows the number of times a pesticide belonging to the group of organophosphates, carbamates, azoles, triazines, pyrethroids or some other Mode of Action (other MoA) occur in a binary mixture resulting in antagony (blue bars), concentration additivity (CA) (red bars) or synergy (green bars). In figure B and C, the number of binary combinations of cholinesterase inhibitors (ChE) (The organophosphates and carbamates), azoles (AZ), triazines (TZ) and other Modes of Action (Other) resulting in either antagony, concentration additivity or synergy are shown for mixtures tested on B) auto-tropic organisms (plants and algae, <i>n</i> = 120) or C) heterotrophic organisms (microorganisms and animals, <i>n</i> = 128).</p>", "links"=>[], "tags"=>["agriculture", "agrochemicals", "Biochemistry", "chemical biology", "toxicology", "marine and aquatic sciences", "chemistry", "Applied chemistry", "Environmental chemistry", "Model organisms", "pesticide", "additivity"], "article_id"=>1015119, "categories"=>["Biological Sciences", "Ecology"], "users"=>["Nina Cedergreen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096580.g003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Frequency_of_pesticide_antagony_additivity_and_synergy_/1015119", "title"=>"Frequency of pesticide antagony, additivity and synergy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-02 03:38:00"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"146", "full-text"=>"168", "pdf"=>"45", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"14", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
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  • {"unique-ip"=>"136", "full-text"=>"171", "pdf"=>"19", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"10", "supp-data"=>"1", "cited-by"=>"1", "year"=>"2017", "month"=>"3"}
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  • {"unique-ip"=>"113", "full-text"=>"134", "pdf"=>"39", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"5"}
  • {"unique-ip"=>"131", "full-text"=>"175", "pdf"=>"27", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"15", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2017", "month"=>"6"}
  • {"unique-ip"=>"89", "full-text"=>"128", "pdf"=>"21", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2017", "month"=>"7"}
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  • {"unique-ip"=>"141", "full-text"=>"165", "pdf"=>"40", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"10", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
  • {"unique-ip"=>"153", "full-text"=>"185", "pdf"=>"43", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"38", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
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Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Agriculture", "average_usage"=>[282]}, {"subject_area"=>"/Medicine and health sciences", "average_usage"=>[285]}, {"subject_area"=>"/Medicine and health sciences/Pathology and laboratory medicine", "average_usage"=>[287]}]}
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