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    Topic review

    Severity Indicator of Pesticide Poisoning

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    Submitted by: Wolfgang Boedeker

    Definition

    Pesticides are considered highly hazardous when presenting high acute toxicity according to internationally accepted classification systems such as the WHO Recommended Classification of Pesticides by Hazard. In addition, pesticides that cause severe or irreversible harm to health “… under conditions of use in a country” may be considered as highly hazardous.

    1. Introduction

    It took more than 30 years for an updated estimation to be published, finding that worldwide annually 385 million cases of unintentional acute pesticide poisoning are expected to occur, including around 11,000 fatalities [1]. Additionally, 110,000–168,000 fatalities were lately estimated to occur from suicidal pesticide poisoning worldwide mostly in rural agricultural areas in low- and middle-income countries [2]. During the last decades, international bodies have taken up the issue of health hazards from pesticide exposure and adopted a great number of resolutions and programs to improve their safe use [3]. Realizing, however, that despite all efforts there might be no safe use of toxic pesticides especially under conditions of poverty, the International Code of Conduct on Pesticide Management of WHO and the Food and Agriculture Organization (FAO) endorses a new policy approach by considering the prohibition of highly hazardous pesticides [4].

    Pesticides are considered highly hazardous when presenting high acute toxicity according to internationally accepted classification systems such as the WHO Recommended Classification of Pesticides by Hazard [5]. In addition, pesticides that cause severe or irreversible harm to health “… under conditions of use in a country” may be considered as highly hazardous [4].

    Case fatality and severity scores might be a more realistic indicator for human toxicity of substances than hazard classes based on animal testing. If so, the indicators should primarily point to the substance-specific toxic properties and not on the characteristics of the incident and treatment e.g., cause, dose, and time lag between exposition and treatment. A low variability of the e.g., pesticide specific case-fatality-rate (CFR) would then indicate problematic chemicals from a public health perspective as the human toxicity of an agent in general was captured rather than the clinical course of a specific poisoning. Recently, it has been suggested that a case fatality after self-poisoning greater than 5% should be used as an indicator of a highly hazardous pesticide and that a complete ban of these pesticides be targeted [6].

    In order to study whether and which indicators of the severity of poisonings can be used to prioritize pesticides of public health concern we systematically reviewed the scientific literature. We aimed at answering the following research questions: For which active ingredients in pesticides or for which group of pesticides have human case- fatality-ratios been published? What is the geographical distribution and the variability of the reported case-fatality ratios? What is the relationship between the human case-fatality and WHO hazard classes? Which factors influence the case-fatality? Which severity scores are used with respect to pesticide poisonings?

    2. Methods

    We conducted a systematic literature review without prior protocol by starting the search for publications in the database PUBMED. We used the terms “pesticides” AND (“case-fatality-ratio” OR “case-fatality-rate” OR “poisoning severity score”) and allowed for studies in English, German, Portuguese, and Spanish with a publication date between January 1990 and October 2014. The search procedure was repeated with the database SCOPUS which has a higher coverage outside medical sciences and includes the database EMBASE completely as of 1996. In a sensitivity analysis addressing our search strategy and a possibly too strict selection, we additionally searched for specific pesticides and checked these with the results in our automatic search as outlined below.

    According to the PRISMA-Statement (prisma-statement.org) all records were screened and excluded in case abstracts clearly indicated non-eligibility, e.g., when only specific symptoms of poisonings or animals were studied. Full-text-analysis was carried out on all other records. Studies were considered eligible when addressing active ingredients in pesticides or groups of active ingredients (e.g., organophosphates). Case-studies and papers which do not report or not allow to calculate a case fatality were excluded. The search was supplemented by inspecting bibliographic reference lists in all identified papers. Articles initially not identified by the automatic search were then manually back searched. Finally, 149 papers were identified of which 67 could be included after assessment. We excluded 25 papers by abstract and 57 by full-text analysis mainly because no information on active ingredients or group of pesticides was presented ( Figure 1 ).

    Figure 1. Flow chart of selection procedure and search results.

    Case fatality was extracted from all included publications. In most papers, case fatality was referred to as case-fatality-ratio (CFR) or mortality-ratio and was given as number of fatal poisonings divided by the number of all poisonings with a specific agent or group of agents respectively. When the CFR was not stated in the studies that we calculated from given numbers of incidents. Case fatality and indicators used as descriptors of the poisoning severity as well as information on the number of patients, the country, year, cause of poisoning, and timespan of the study were retrieved study-wise for each poisoning agent in a data base.

    Overall, case numbers and CFR were studied by minimum, mean, median, and maximum values. The cross-study variability of the CFR was assessed by the coefficient of variation (CV) as the ratio of the standard deviation to the mean and its normalized form which limits the CV to the interval 0–1 and adjusts for the number of observations [7]. Mathematically, a CV lower or equal 100% indicates low variability taking the exponential distribution as a reference. Calculation of CV was restricted to those pesticides which were addressed in more than three papers. All calculations were done with SAS statistical software, Version 9.4 (SAS Institute Inc., Cary, NC, USA).

    3. Results

    Sixty-seven publications [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74] reporting case fatality rates on 66 active ingredients and additionally on 13 groups of active ingredients were identified ( Table 1 ). Moreover, 58% of the active ingredients are covered by just one publication. The most mentioned active ingredient is glyphosate which is addressed in 16 papers followed by paraquat in 14 papers. With respect to groups of pesticides organophosphates are most frequently studied. Thirty-one papers report on studies from 14 different countries. In total, 20 countries are covered by the included studies with Taiwan and Sri Lanka most often addressed ( Table 2 ).

    Of the active ingredients considered, 17% show case-fatality above 20. Table 3 shows how the CFR is captured by the WHO Recommended Classification of Pesticides by Hazard.

    Thirty-two pesticide groups or active ingredients were studied by more than one paper and nine by more than three papers. Table 4 gives the coefficients of variation (CV) along with case-fatalities and WHO-classification on all pesticides addressed in more than three publications. All CFR show a coefficient of variation lower or equal 100%. Four out of the seven active ingredients are seen with a CV even well below 100% whereas only malathion and glyphosate reach 93% and 100%, respectively. Glyphosate serves as an example of how study characteristics impact on the variability of CFR. The highest value of 29% was seen in a study in Taiwan [35] recruiting in two hospitals which serve as referral hospitals and include a poisoning control center. The lowest value of 0.06% follows from two deaths in 3464 human exposure cases (98% unintentional) collected in the US National Poison Data System by telephone calls received in 57 regional poison centers [45]. If only those cases treated in health care facilities were taken as the denominator (see Mowry et al. p 1165) , the CFR would be 3.6% and further decrease the variability across countries. With respect to the normalized coefficient of variation, which adjusts for the number of publications, malathion is the active ingredient with the highest variability but also well below the possible 100%.

    Clinical indicators for the severity of poisonings were mentioned in many papers. Although the Poisoning Severity Score (PSS) was part of the search terms we found more papers reporting on the Glasgow Coma Score (GCS). Additionally, the Acute Physiology and Chronic Health Evaluation Score (APACHE), the Sequential Organ Failure Assessment (SOFA), and the Simplified Acute Physiology Score (SAPS) were used along with scores built specifically by the study authors ( Table 5 ). Studies often aim at a comparison of different indicators with respect to their performance for predicting study specific clinical outcomes. More information on the used indicators is available in some studies, e.g., mean and grading of scores. However, the number of papers in this entry is too limited to study the variability of indicators with respect to specific group of pesticides or active ingredients.

    Table 1. Study characteristics and case fatalities for reported groups of pesticides and active ingredients.
    Group of Pesticide Publications Countries Case-Fatality-Ratio (%) Cases (n) Severity Indicator 1 Country Reference
    N n Median Min Max Median Min Max
    carbamates 9 6 5.1 0.0 14.2 60 6 1433 CFR Brazil, India, Israel, Serbia, Sri Lanka, Taiwan [8][9][15][25][40][42][66][68][73]
    carbamates/OP 2 1 1 5.0     280     PSS, CFR Brazil [14]
    chloracetanilide 1 1 3.6     28     CFR, PSS Korea [55]
    coumarin 1 1 0.0     82     PSS, CFR Brazil [14]
    cyanide 1 1 24.1           CFR Taiwan [73]
    diethyl-OP 1 1 38.0     8     CFR, PSS, APACHE, SOFA, GCS Germany [30]
    dimethyl-OP 1 1 11.0     19     CFR, PSS, APACHE, SOFA, GCS Germany [30]
    fungicides 1 1 6.1     49     CFR Sri Lanka [9]
    herbicides 1 1 12.4     2783     CFR Sri Lanka [9]
    organochlorines 2 2 18.4 16.7 20.0 112 12 212 CFR India, Sri Lanka [8][9]
    organophosphate 31 14 11.1 2.9 73.0 94 16 5226 CFR, APACHE, PSS, SOFA, GCSCFR, SAPS, CFRCFR, SAPSII Australia, China, Germany, India, Iran, Israel, Japan, Jordan, Slovenia, SouthAfrica, Sri Lanka, Taiwan, Turkey, Zimbabwe [8][9][11][12][13][15][16][19][20][22][27][28][29][30][33][39][41][50][53][54][57][61][62][63][66][67][69][71][72][73][74]
    pyrethrins 1 1 0.0     5522     CFR USA [45]
    pyrethroids 3 3 0.7 0.0 1.0 203 140 23,853 PSS, CFR Brazil, Sri Lanka, USA [9][14][45]
    Active Ingredients                      
    2,4-D 1 1 5.5     20     CFR Brazil [51]
    abamectin 1 1 11.1     18     CFR Sri Lanka [9]
    acephate 1 1 29.0     14     CFR India [8]
    acetamiprid 1 1 0.0     11     CFR Sri Lanka [9]
    alachlor 2 2 8.0 4.8 11.1 36 9 63 CFR Sri Lanka, Taiwan [9][43]
    aldicarb 2 2 2.6 0.0 5.2 37 35 39 CFR, PSS France, USA [48][49]
    aldrin 1 1 13.3     49     CFR Brazil [51]
    aluminium phosphide 2 1 48.9 31.0 66.7 255 39 471 CFR, APACHE, SAPS, GCS Iran [58][59]
    bispyribac-sodium 1 1 2.9     103     CFR Sri Lanka [9]
    butachlor 1 1 0.0     70     CFR Taiwan [43]
    carbaryl 1 1 5.6     18     CFR Sri Lanka [9]
    carbofuran 3 2 2.9 1.0 4.1 209 100 479 CFR Brazil, Sri Lanka [9][10][51]
    carbosulfan 2 1 17.1 10.7 23.5 198 51 345 CFR Sri Lanka [9][10]
    chlorfluazuron 1 1 2.2     45     CFR Sri Lanka [9]
    chlorpyrifos 7 3 6.2 5.2 8.0 208 34 1376 CFR, GCS, PSS Brazil, India, Sri Lanka [8][9][10][20][23][26][51]
    cypermethrin 2 2 6.1 5.1 7.0 50 41 58 CFR Brazil, India [8][51]
    deltamethrin 1 1 0.0     11     CFR Sri Lanka [9]
    diazinon 1 1 4.8     84     CFR Sri Lanka [9]
    dichlorvos 2 1 32.3 31.3 33.3 13 9 16 CFR Japan [47][72]
    dimethoate 6 2 23.6 5.5 30.8 268 17 833 CFR, GCS, PSS Brazil, Sri Lanka [9][10][20][23][26][51]
    diquat 1 1 0.0     312     CFR USA [45]
    edifenphos 1 1 11.8     17     CFR Sri Lanka [9]
    endosulfan 6 3 22.9 20.2 29.3 86 9 400 CFR Brazil, India, Sri Lanka [8][9][10][33][46][51]
    endrin 1 1 5.0     74     CFR India [8]
    esfenvalerate 1 1 8.3     12     CFR Sri Lanka [9]
    etofenprox 1 1 0.8     121     CFR Sri Lanka [9]
    fenitrothion 2 1 15.4 9.4 21.3 40 32 47 CFR Japan [47][72]
    fenobucarb 2 1 5.6 5.3 5.8 71 38 104 CFR Sri Lanka [9][10]
    fenoxaprop-p-ethyl 1 1 0.0     74     CFR Sri Lanka [9]
    fenthion 4 1 13.9 4.3 16.2 111 23 237 CFR, GCS, PSS Sri Lanka [9][10][20][23]
    fipronil 1 1 0.0     26     CFR Sri Lanka [9]
    glufosinate 1 1 7.1     14     CFR Japan [47]
    glyphosate 16 6 6.1 0.1 29.3 102 15 3464 CFR, PSS Brazil, Japan, Korea, Sri Lanka, Taiwan, USA [9][10][15][17][18][35][36][45][47][51][52][56][60][64][65][73]
    hydrogen phosphide 1 1 2.6     152     CFR, PSS Germany [34]
    imidacloprid 2 2 0.0 0.0 0.0 39 8 70 CFR India, Sri Lanka [8][9]
    indoxacarb 1 1 14.0     7     CFR India [8]
    lindane 1 1 0.0     3     CFR Sri Lanka [9]
    malathion 7 5 6.5 0.0 25.0 23 5 209 CFR, APACHE Brazil, India, Japan, Singapore, Sri Lanka [8][9][10][37][47][51][72]
    MCPA 2 1 5.1 4.8 5.4 387 93 681 CFR Sri Lanka [9][10]
    metam sodium 1 1 0.0     102     CFR France [21]
    methamidophos 3 2 12.5 11.5 15.4 26 8 191 CFR Brazil, Sri Lanka [9][10][51]
    methomyl 2 1 7.2 0.0 14.3 31 7 54 CFR Sri Lanka [9][10]
    monocrotophos 3 3 22.2 20.4 35.0 99 54 257 CFR Brazil, India, Sri Lanka [8][10][51]
    oxydemeton-methyl 2 2 13.4 12.5 14.3 11 8 14 CFR, PSS, APACHE, SOFA, GCSCFR Germany, Sri Lanka [9][30]
    oxyfluorfen 1 1 0.0     15     CFR Sri Lanka [9]
    paraquat 14 6 54.2 1.4 83.6 115 7 1046 CFR Brazil, Japan, Korea, Sri Lanka, Taiwan, USA [9][10][15][17][25][31][32][38][44][45][47][51][70][73]
    parathion ethyl 1 1 42.9     7     CFR, PSS, APACHE, SOFA, GCS Germany [30]
    parathion methyl 1 1 60.0     5     CFR India [8]
    permethrin 1 1 0.0     13     CFR Sri Lanka [9]
    petrilachlor 1 1 0.0     11     CFR Sri Lanka [9]
    phenthoate 2 1 7.4 6.5 8.3 96 24 168 CFR Sri Lanka [9][10]
    phorate 1 1 19.0     21     CFR India [8]
    picloram 1 1 25.0     5     CFR Brazil [51]
    pirimiphos-methyl 1 1 0.0     12     CFR Sri Lanka [9]
    profenofos 2 1 5.5 0.0 11.0 84 22 146 CFR Sri Lanka [9][10]
    propamocarb 1 1 100.0     1     CFR Sri Lanka [9]
    propanil 3 1 5.0 1.6 10.9 150 64 412 CFR Sri Lanka [9][10][24]
    propoxur 1 1 0.0     16     CFR Sri Lanka [9]
    prothiofos 1 1 7.7     13     CFR Sri Lanka [9]
    quinalphos 2 2 12.1 12.0 12.1 101 78 124 CFR India, Sri Lanka [8][9]
    rotenone 1 1 0.0     54     CFR USA [45]
    spinosad 1 1 0.0     4     CFR India [8]
    triazophos 1 1 17.0     6     CFR India [8]
    trichlorfon 2 1 18.8 0.0 37.5 8 7 8 CFR Japan [47][72]
    trifuralin 1 1 0.0     17     CFR Brazil [51]
    zink phosphide 2 1 7.6 4.2 11.0 30 24 35 CFR India [46][74]
    1 CFR: case-fatality-rate, PSS: Poisoning severity score, GSC: Glasgow Coma Score, APACHE: Acute Physiology and Chronic Health Evaluation Score, SAPS: Simplified Acute Physiology Score, SOFA: Sequential Organ Failure Assessment. 2 OP: organophosphate.
     
    Table 2. Countries addressed and number of papers providing case-fatality of pesticide poisoning.
    Country No. of Paper No. of Papers Providing Case-Fatality on
    Group Level Active Ingredient Level
    Australia 1 1 -
    Brazil 3 2 1
    China 1 1 -
    France 2 - 2
    Germany 2 1 2
    India 8 7 4
    Iran 3 1 2
    Israel 4 4 -
    Japan 3 1 3
    Jordan 1 1 -
    Korea 5 1 4
    Serbia 1 1 -
    Singapore 1 - 1
    Slovenia 1 1 -
    South Africa 2 2 -
    Sri Lanka 10 5 9
    Taiwan 12 3 10
    Turkey 4 4 -
    USA 2 1 2
    Zimbabwe 1 1 -
    All 67 38 40
    e.g., India: 8 papers total with 4 exclusively on group level, 1 exclusively on active ingredient, 3 both.
    Table 3. Case fatality ratios for active pesticide ingredients by WHO classification.
    WHO Class * Median Case-Fatality-Ratio  
    <1 1 – <10 10 – <20 ≥20% All
    N % N % N % N % N %
    Ia     1 4 1 8 2 18 4 6
    Ib     3 13 5 38 2 18 10 15
    II 11 61 14 58 6 46 4 36 35 53
    III 3 17 3 13         6 9
    O     1 4 1 8     2 3
    U 4 22 1 4     2 18 7 11
    VF     1 4     1 9 2 3
    All 18 100 24 100 13 100 11 100 66 100
    * Ia = “extremely hazardous”, Ib = “highly hazardous”, II = “moderately hazardous”, III = “slightly hazardous”, U = “unlikely to present acute hazard”, O = “obsolete”, VF = “volatile fumigant not classified” see WHO [5] for details.
    Table 4. Variability of case-fatality-ratios (%) for pesticides *.
    Name WHO Class ** Publications Cases Case Fatality Ratio
    n Median Min Mean Median Max CV CV Norm
    carbamates   9 60 0 5 5 14 98 35
    organophosphate   31 94 3 15 11 73 92 17
    chlorpyrifos II 7 208 5 7 6 8 19 8
    dimethoate II 6 268 6 22 24 31 40 18
    endosulfan II 6 86 20 24 23 29 16 7
    fenthion II 4 111 4 12 14 16 44 26
    glyphosate III 16 102 0 7 6 29 100 26
    malathion III 7 23 0 10 7 25 93 38
    paraquat II 14 115 1 49 54 84 56 16
    * only pesticides addressed in more than 3 papers, ** II = “moderately hazardous”, III = “slightly hazardous”, See WHO [5] for details, min = minimum, max = maximum, CV = coefficient of variation, CV norm = normalized CV.

    The entry is from 10.3390/ijerph18168307

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