39EPIDEMIOLOGICAL STUDIES OFANTICHOLINESTERASE PESTICIDEPOISONING IN TURKEY

ISMET ÇOK

Faculty of Pharmacy, Department of Toxicology, Gazi University, Ankara, Turkey

39.1 Introduction 533

39.2 The Use of Pesticides in Turkey 533

39.3 Pesticide-Related Poisoning in Turkey 53539.3.1 Pesticide-Related Applications to the

National Poison Center by Year 53539.3.2 Studies Related to Pesticide Poisoning

in Turkey 537

39.3.3 Acute Pesticide Poisoning Related Deathsin Turkey 538

39.3.4 Hexachlorobenzene Poisoning in Turkey 538

39.4 Conclusions 539

References 539

39.1 INTRODUCTION

One of the major problems of our time is the rapidly grow-ing world population. Parallel to this growth there is anincreasing need for food and textiles, and to meet it whileimproving the standard of living depends entirely on adequateproduction, which in turn is tied to agricultural development.Indeed, only through such development will it be possibleto obtain abundant crops and at the same time achieve thequality and standards in production aimed at by advancedsocieties. Although agricultural development can be mostsimply defined as the elimination of insufficient production,it also includes such matters as the improvement of yieldand crop quality as a result of advances, the guaranteethat crops will be fairly distributed, and the preservation ofnatural resources. Despite continued efforts at prevention,38% of the world’s agricultural production is lost to disease,harmful insects, nematodes, and weeds. This figure repre-sents one-third of the world’s farming potential, and whenone adds the 6–12% that is lost after harvesting, this demon-strates a total crop loss of 40–48%, the monetary value ofwhich is 550 billion dollars. In addition, 455 billion dollars

is spent annually on various crop protection practices(Agrios, 2005).

As components to complement modern agriculture, pesti-cides make up an important group of weapons that havebegun to be used for beneficial purposes such as combatingpests and increasing production. Interest in pesticides hasgrown steadily, in particular because of the toxicity theyproduce over time both in human beings and in wildlife.Today, efforts are focused on developing pesticides with ahigher safety index and on reducing the number of cases ofpesticide-related poisonings and deaths.

39.2 THE USE OF PESTICIDES IN TURKEY

Turkey is unusual in boasting extremely favorable ecologicalconditions that give it the potential to be self-sufficient inagriculture. This is thanks to it having 26.6 million hectaresof arable land, with varying climatic and ecological con-ditions. So much farmland means crops that not only canfeed the nation but can also contribute to the economythrough exports (DIE, 2002). The fact that farming is

Anticholinesterase Pesticides: Metabolism, Neurotoxicity, and Epidemiology. Edited by Tetsuo Satoh and Ramesh C. GuptaCopyright # 2010 John Wiley & Sons, Inc.

533

extensive in various regions of Turkey, coupled with itsimportant role in the nation’s economy, has led to an effortto boost productivity. Spearheading these efforts is a reliance,as everywhere in the world, on the use of pesticides as themost effective weapon against pests and the causes of diseasein agriculture. In fact, although pesticides are mainly usedin agriculture, they have quietly infiltrated into daily life,as in almost every home there are insecticides used tocombat bugs and flies. Depending on the features of theplace one lives in it is possible to expand the list of pesticidevarieties found in everyday existence. However, as pointedout above, when pesticides are mentioned the scenario thatimmediately comes to mind is “agriculture,” due to the quan-tity and range of uses for these substances in that area.

As of May 2007 there were 408 licensed active substancesin Turkey for the purpose of fighting agricultural pests, and

roughly 2500–3000 commercial preparations being sold onthe market (Yucer, 2006). As summarized in Table 39.1,the 8,395,849 kg or L usage of pesticides in 1979 has risenby an annual increase of some 2% to 23,385,882 kg or L in2006. Nevertheless, the yearly consumption of active sub-stances is in the region of only 400–700 g/hectare (Delenet al., 2005). Compared with the amounts of active substanceused in Europe this figure is in general quite low, but incertain regions, such as the Aegean and Mediterranean,the amount of pesticide used is higher even than that inEuropean countries. Insecticides are the major contributorin the agricultural products sector, with 40% being used inthe production of cotton and 20% for fruit. Products con-taining phosphorous are the most important group of theinsecticides. The consumption of various types of pesticideby year is given in Table 39.1, while Table 39.2 shows thefive pesticides used most widely in 2002.

The year 2001 saw 120 million tons of crops produced inTurkey (DIE, 2002), with a monetary value representing lessthan one percent of the world market. Actually, consideringthe possible gains if losses due to disease, pests and weedswere eliminated, the potential for crop production in Turkeyis expected to be 42.2 million tons higher.

Pesticide consumption in Turkey is quite heterogeneous.For example, although its use in such regions of extensivefarming as Southeast Anatolia, Eastern Anatolia, and theBlack Sea is rather low, intensive consumption takes placein the Mediterranean and Aegean regions. According to one

TABLE 39.1 Usage of Pesticides in Turkey by Year (L or kg)

Pesticide Group 1979 1987 1994 2001 2002

Insecticides 2,287,658 3,303,446 2,064,991 2,599,521 2,250,898Acaricides 203,107 230,360 192,279 231,005 296,809Oils 1,594,526 2,147,106 1,977,281 2,483,575 2,428,238Fumigants and nematocides 315,665 322,227 530,738 876,057 1,559,489Rodenticides and molluscicides 5600 2124 2509 2342 1794Fungicides 1,537,315 2,611,960 2,201,406 2,044,440 1,964,292Herbicides 2,451,977 3,495,044 3,902,588 3,079,483 3,697,397

Total 8,395,848 12,112,267 10,871,792 11,316,423 12,198,917

Source: adapted from Delen et al. (2005).

TABLE 39.2 The Five Insecticides Most Widely Used inTurkey in 2002

InsecticideConsumption,

em, kg/LPercentage of

Insecticides in Use

Methamidophos 326,832 14.25Clorpyrifos-ethyl 287,274 12.76Parathion-methyl 246,828 10.96Diclorvos (DDVP) 182,044 8.08Azinphos-methyl 159,441 7.08

Total 1,202,419 53.13

TABLE 39.3 Pesticide Use by Regions in Turkey

Region

Year and Share of Region, %

1993 1994 1995 1996 1997 1998 1999

Aegean 19 19 15 19 17 17 19Central Anatolia 20 22 23 22 19 16 18Marmara (Northwest) 16 12 19 20 19 18 18North (Black Sea) 12 11 7 13 12 12 11South (Medit.) 21 26 26 16 22 25 24East 3 3 4 4 4 5 4Southeast 9 7 7 7 7 7 6

534 EPIDEMIOLOGICAL STUDIES OF ANTICHOLINESTERASE PESTICIDE POISONING IN TURKEY

assessment, these two regions account for nearly 50% of thenation’s consumption (Delen et al., 2005) (Table 39.3). Thisevaluation shows that in certain regions of Turkey the use ofpesticides per hectare matches that of the regions in the worldthat use pesticides most extensively. In these regions theenvironmental risk from pesticides is high.

39.3 PESTICIDE-RELATED POISONINGIN TURKEY

Pesticide poisoning caused by accidents or attempted suicideis a major source of morbidity and mortality throughout theworld. Every year between one and five million incidents ofpesticide poisoning occur in the world (suicides included).And every year 20,000 farm workers die from this type ofpoisoning (UNEP, 2004). Although only 25% of pesticidesare used in developing countries, it is in these countries that99% of deaths from pesticides occur (UNEP, 2004; WHO,1990). According to the reports of the Turkish Ministryof Health in 2002, poisoning cases accounted for 4.2% ofadmissions to emergency centers throughout the country(Minister of Health, 2002). But in Turkish epidemiologicalstudies, the percentage of poisoning cases among the totalnumber of emergency admissions was reported as 0.7–5%(Mert and Bilgin, 2006; Tufekci et al., 2004). Furthermore,no satisfactory data on demographical and etiological charac-teristics of poisonings were provided by the reports of theMinistry of Health. Among the reasons for this is the factthat records of emergency admissions are not collected andsubjected to statistical analysis. Information about poisoningsis obtained, as far as possible, either from scientific publica-tions or from a study of the number of applications made topoison centers. As shown by data mainly from the NationalPoison Center but also from other such centers, the numberone cause of poisoning admissions in Turkey is poisoningfrom drugs, followed by poisoning from pesticides andchemicals.

According to studies carried out in Turkey, the primarycause of childhood accidents is trauma, and poisoning occu-pies second place. A study of such accidents from 2000 to2006 reveals that the agent of poisoning is usually drugs

used for medical treatment, with home-use chemicals rankingsecond and pesticides third (Gecim, 2007).

The intriguing thing about pesticide poisoning in Turkeyis that rural incidents are primarily due to organophosphate(OP) insecticides. These are widely used in agricultureand gardening in Turkey. Because of their widespread useand availability, suicidal and unintentional OP poisoningsaccount for a large percentage of poisonings in Turkey,as in many developing countries (Mert and Bilgin, 2006;Sahin et al., 2003). On the other hand, bans on the use oforganochlorine pesticides (Cok et al., 1997, 2004), especiallyin the mid-1980s, have been followed by a steady reductionin the number of poisonings from this group of pesticides.And with the prohibition introduced in 2008 on the use ofendosulfan in Turkey, it is thought that cases of poisoningfrom this group of compounds will disappear. Acute orchronic exposure to endosulfan is reported rarely, althoughintentional ingestions can be life-threatening or even fatal.Indeed, although they are not frequent, incidents of poison-ing and death from endosulfan have been reported invarious regions in recent years (Bektas et al., 2007; Yavuzet al., 2007).

39.3.1 Pesticide-Related Applications to theNational Poison Center by Year

Based in Ankara, the National Poison Center is a state organ-ization that operates to reduce poisonings to a minimum,including those from pesticides, by providing informationto doctors and, over the telephone, to the public while inform-ing the public through brochures and such activities as TVprograms.

When applications (50,858) to the National Poison Centerfrom 1995 to 1999 are examined from the standpoint oftype of poisoning, it emerges that the number one cause ismedicinal drugs, followed by pesticides used agriculturallyand for home use, with chemicals used in the homecoming third (Gecim, 2007). During this period pesticidesaccounted for 8.6% of all poisoning incidents. Among pesti-cide poisonings, OP insecticides were the most frequent at29%. As shown in Table 39.4, unintentional poisoningsaccount for many pesticide cases, with suicidal poisoning

TABLE 39.4 Pesticide Poisoning to the National Poison Center in 2000–2003

Year Total Poisoning Cases

Pesticide Poisoning

Total Accidental % Suicidal %

2000 18,913 1518 844 56 604 442001 17,189 1472 783 53 512 472002 15,277 1398 644 46 576 542003 13,385 1056 492 47 421 53

Source: Delen et al. (2005).

39.3 PESTICIDE-RELATED POISONING IN TURKEY 535

(although over time there have been minor changes) alsoaccounting for an important percentage of total poisonings.The National Poison Center reported that of 4418 pesti-cide poisonings between 1995 and 1999, 57.13% wereaccidental and 42.87% suicidal. Of these pesticide-relatedpoisonings, 85.67% were through oral exposure and10.21% through respiratory exposure. It also emerges thatthese incidents occur most frequently in the spring andsummer, when pesticides are most used. This findingagrees with pesticide poisoning data in the rest of theworld. Seasonal variations in these cases are presented inFigure 39.1.

A high percentage of applications to the National PoisonCenter were made by persons based in cities. The resultsof applications to this center in 2000–2003, and the roleof pesticide in these poisonings, are summarized inTable 39.4.

Statistical studies carried out at the National Poison Centerin 2000 and 2001 showed that pesticide poisonings con-stituted 8.3% of a total of 18,913 applications in 2000,and 8.5% of a total of 17,189 cases in 2001. In both years,55% of cases were accidental and 37% suicidal. Pesticidepoisonings in these years were most frequent in the monthsof June (10%) and July (11%).

According to data for 2005 obtained from the NationalPoison Center, the total number of applications in that yearwas 15,646, of which 7.32% were for pesticide poisonings,putting the latter in the second rank behind poisoningsfrom medicinal drugs. Of the poisoning agents responsiblefor pesticide poisonings, OP insecticides were the mostcommon (28.36%), followed by rodenticides (24.87%), thepyrethrins and pyrethroids (16.14%), the carbamate (CM)group (4.36%), organochlorine insecticides (3.75%), and

fungicides and herbicides (2.3%). During this year pesticidepoisonings occurring in children and adolescents accountedfor 52% (n ¼ 1143) of all pesticide poisonings. Of all poison-ings, 21% were seen between the ages of 20–29 years, ahigh percentage in which the suicidal use of pesticides isthought to have played an important role. The distributionby ages of poisoning cases occurring in 2005 is shown inFigure 39.2. Among these cases, accidental poisoning holdsthe first rank (49.39%) in terms of cause, with suicidalpoisonings in second place (39.71%) among all pesticidepoisonings (Fig. 39.3).

According to National Poison Center data, of the totalcases of poisoning (48,929) in 2006, pesticide poison-ings accounted for 8.25%, placing them in second placebehind therapeutic drugs. Of pesticide poisonings in 2006,rodenticides (19%) occupied first place, with OPs second(18%), and pyrethroids third (12.3%). It is thought that

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Figure 39.1 Pesticide poisonings in Turkey by months between1995 and 1999, based on National Poison Center data.

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Figure 39.2 Distribution of pesticide poisoning cases seen in2005 by ages according to the National Poison Center, Ankara.

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Figure 39.3 Distribution of pesticide poisoning cases in 2005 bytype of exposure according to the National Poison Center, Ankara.

536 EPIDEMIOLOGICAL STUDIES OF ANTICHOLINESTERASE PESTICIDE POISONING IN TURKEY

rodenticides were in the first rank because most cases werecity based.

39.3.2 Studies Related to Pesticide Poisoningin Turkey

Although there is not a great deal of information in the litera-ture regarding pesticide poisoning in Turkey, the variousstudies that have been done are informative regarding theregional situation. According to results obtained from dif-ferent areas in Turkey, the characteristic features of pesticidepoisonings differ according to the social, cultural, and econ-omic characteristics of communities. The Aegean region issituated in the west of Turkey and includes areas where farm-ing is extensively practiced. There, poisoning applicationsto the Dokuz Eylul University School of Medicine poisoncenter from 1993–2001 saw medicinal drugs in first place(65%), with pesticides second at 8% (Kalkan et al., 2003a).The reason for this might be that agriculture is practicedvery extensively in the Aegean region, with pesticides thusbeing used in great amounts.

Meanwhile a study carried out in Turkey’s SoutheastAnatolia Region reported that 79.2% of 24 OP poisoningsoccurred in women, with 54.2% in the 11–20 years agegroup, five were accidental and 19 suicidal, with 17 of thelatter attempts being carried out by women (Kara et al.,2002). A study performed in the province of Samsun cityin northern Anatolia revealed that 58.3% of pesticide poison-ings were seen in women, and that the majority of caseswere in the 10–19 years age group, followed by the 0–9years age group. In total, 60% of poisonings were accidental,while of the cases for which a claim of suicide was made,70.8% were women. The fact that in these regions womenwork extensively in farming, coupled with the uninformeduse of agricultural drugs plus the carelessness of families,ultimately results in a high number of accidental poison-ings among women and children. In addition, the fact thatattempted poisoning with these drugs is seen most often inwomen supports the view that women resort to self-poisoningas a method of suicide because they have easy access totoxic substances. This situation came to the fore in a studyconducted in the province of Van in eastern Turkey. In thisstudy the sociodemographic features of OP poisonings inTurkey’s eastern Anatolian region were investigated (Sahinet al., 2003). All OP poisonings admitted to the EmergencyCenter of the Yuzuncu Yil University Medical FacultyHospital in the city of Van from April 1, 1999 to August31, 2001 were prospectively studied. Of 564 poisonings,the proportion of OP poisonings was 15.1%, and ofthese 57 (67.1%) patients were female and 28 (32.9%)male, with 56 cases (65.9%) being attempted suicides and29 cases (34.1%) due to accidental causes. The mean agewas 22+ 9.2 years in the suicidal cases, 43 (76.8%) of

them being less than 24 years of age. Among the suicideattempts, 29 patients (51.8%) were unmarried and 43 patients(76.8%) were female. The proportion of attempted suicideswas 46.4% in men and 75.4% in women. Eighty percentof the cases had a primary education level or were illiterateand 78.8% of the patients were of lower socioeconomic status.Exposure routes were gastrointestinal (88.2%), respiratory(5.9%), and dermal (4.7%). In a study also devoted to poison-ings in eastern Turkey, Orbak and colleagues (1996) foundthat in this region, among acute poisoning cases in children,exposure to pesticides and insecticides accounted for 11.6%of cases. Similar results were obtained by Mert and Bilgin(2006) in a study conducted in the province of Mersin,situated in the Mediterranean region where pesticides areused extensively.

A study carried out in Eskisehir in central Turkey revealedthat pesticide poisonings made up 11.5% of admissions tothe emergency center (0–18 years), and that among these,OP compounds were in the first rank (4.6%), with rodenti-cides in second place (3.7%). Of 323 admissions over athree-year period, one patient died due to pesticide poisoning.Hallac and colleagues (1996), in Kayseri and Hıncal et al.(1987), in Ankara (both provinces are also in the centralregion) demonstrated that insecticides were the chief causeof poisoning among non-pharmacological agents. In addi-tion, a study carried out by Dogan-Kalyoncu and collea-gues (1996) noted an increase in the number of pesticidepoisoning cases. In a study conducted in Istanbul, whichis a vast metropolis where industry rather than agricul-ture is developed, it emerged that of 284 poisoning casesadmitted to the emergency center of Istanbul UniversityCerrahpasa Medical Faculty in 2001, only 1.06% weredue to pesticides (Tufekci et al., 2004). Thus studies showthat in Turkey pesticide poisonings are more frequent inrural areas where agriculture is practiced extensively, andthat in Turkey’s most populous city, Istanbul, thereare fewer pesticide poisonings due to the fact that it is anon-agricultural region.

Amitraz is a pharmaceutical, veterinary, and agriculturalproduct used worldwide under numerous generic names asan acaricide and insecticide. Because of its widespreaduse, amitraz poisoning is frequently encountered in Turkey.Poisoning may occur by the oral or dermal route, or by inha-lation. The reported effects include central nervous system(CNS) depression, hypothermia, bradycardia, hypotension,and hyperglycemia. Complete recovery can be expected.In Turkey, amitraz formulations in veterinary formulationscontain 12.5% amitraz. According to the National PoisonCenter, in 1999 14.1% of all poison cases handled by thecenter were amitraz related (Gecim, 2007). In subsequentyears there was a very marked reduction in the numberof cases connected with amitraz. Nevertheless, over thecourse of the years there have been numerous amitraz-related

39.3 PESTICIDE-RELATED POISONING IN TURKEY 537

poisoning cases reported in various regions of Turkey, with amajority of these involving children.

39.3.3 Acute Pesticide Poisoning Related Deathsin Turkey

Deaths do occur as a result of accidental or suicidal use ofpesticides. Data were compiled from all autopsy reportsperformed between 1997 and 2001 by the Institute ofForensic Medicine (a department of the Ministry of Justice)and evaluated retrospectively. There were 3990 deaths byintoxication of one form or another. Acute agrochemical/pesticide poisoning caused 843 deaths, with almost half thevictims being under 30 years of age. Of these, 55% werefemale and 45% male. Of 205 cases in which the mannerof death was determined, 153 (75%) were suicides; themost common substance used was insecticide followed bysulfur, rodenticides, and herbicides (Nesime et al., 2004).

Meanwhile in a study dealing with 331 fatal poisoningcases in the Aegean Region of Turkey in 1996–2000, itemerged that the most common cause of fatal poisoningwas pesticides (43%; n ¼ 144). Among insecticides, OPinsecticides were responsible for 78% of total insecticidepoisonings followed by organosulfurous (12%) and organo-chlorine compounds (0.4%). All other insecticides comprised9.6% of the total. The pesticide intoxications were mostlydue to suicidal ingestion, with only two being homicidal(Duman et al., 2003). In this region it was reported that0.4% of pesticide poisonings resulted in death (Kalkanet al., 2003b).

In the provinces of Van and Gaziantep, located in theeastern and southeastern regions of Turkey where agricultureis extensively practiced, an examination of admissions tothe emergency centers of university hospitals revealed thathere too, as with other regions, OP pesticides are a leadingcause of poisoning, with 15.1% of all such cases in 1999–2001 in Van (Sahin et al., 2003) and 7.6% of cases in2000–2001 in Gaziantep (Goksu et al., 2002). In the provinceof Van, the proportion of deaths among pesticide poisonings(1999–2001) was 4.7%.

The Çukurova region in southern Turkey, with 675,000hectares of arable land, is home to the most extensive farmingin the country. The amount of pesticide used in this regionis considerable. In a study dealing with the 2229 personswho were admitted to the emergency center of the ÇukurovaMedical Faculty in Adana from 1997 to 2002 becauseof poisoning, Seydaoglu and colleagues (2005) establi-shed that pesticide poisonings were in second place afterpoisoning from medicinal drugs. During the years in questionpesticides accounted for 26.6% of all poisonings, and ofall pesticide poisonings 11.9% ended in death. The samestudy revealed that CMs and dipyridylium compounds werethe most common agents among pesticide poisonings.

39.3.4 Hexachlorobenzene Poisoning in Turkey

There is no doubt that one of the major incidents of pesticideexposure related poisoning in the entire world was experi-enced in Turkey. Caused by hexachlorobenzene (HCB),this poisoning epidemic not only caused considerableloss of life, but the impact of the epidemic continues toaffect the surviving victims. With an eye to the size of thisepidemic, its development and results are given in expandedform below.

During the period 1955–1959, approximately 4000people in southeast Anatolia were accidentally exposedto the fungicide HCB after eating contaminated seed, anddeveloped porphyria cutanea tarda-like syndromes (PCT)characterized by hepatic porphyria (called porphyria turcica)with an annual mortality rate of 10% (Peters et al., 1982,1987). The government discontinued use of the HCB-containing fungicide in 1959, but the epidemic disease didnot decline until 1961. Children between the ages of 6 and15 years made up more than 80% of the affected population,with only 10% of the patients over 16 years of age. It wasalso estimated that 1000–2000 children under the age ofone year died because of HCB exposure, either throughbreast-feeding or transplacentally (Cripps et al., 1984). Inchildren less than four years of age porphyria turcicawas rare. These children developed skin lesions ratherthan porphyria.

Since the year when the poisoning incident took place,studies have been carried out to determine the effects ofHCB exposure on the people who survived after poisoning.For example, in a follow-up study of 252 patients, 20–30years post-exposure, there were 162 males and 90 females,with an average current age of 35.7 years, an average onsetage of 7.6 years, and a duration of 2.2 years. Many patientshad dermatological, neurological, and orthopedic symptomsand signs. The observed clinical findings included scarringof the face and hands (83.7%), hyperpigmentation (65%),hypertrichosis (44.8%), pinched faces (40.1%), painlessarthritis (70.2%), small hands (66.6%), sensory shading(60.6%), myotonia (37.9%), cogwheeling (41.9%), enlargedthyroid (34.9%), and enlarged liver (4.8%) (Goksu et al.,2002). Furthermore, there were significantly elevatedlevels of HCB in the breast milk of lactating mothers whohad PCT (0.51+ 0.75 ppm in HCB-exposed mothers;0.16+ 0.23 ppm in unaffected siblings; 0.07+ 0.07 ppmin unexposed controls) 25 to 30 years after the initialexposure. Reproductive outcomes of 225 original patientsreported 15 abortions in 188 pregnancies and that 31 childrenborn to porphyric mothers died within the first few years oflife (Peters et al., 1987).

The women in Turkey who were exposed to HCB aschildren have now completed their reproductive lifetime interms of childbearing years, and have provided critical infor-mation in our understanding of measurable reproductive

538 EPIDEMIOLOGICAL STUDIES OF ANTICHOLINESTERASE PESTICIDE POISONING IN TURKEY

effects. To evaluate the human impact of HCB ingestion, along-term (45-year) follow-up study of the reproductiveeffects of those subjects from Turkey who developed por-phyria demonstrated a strong relationship of serum HCBlevels measured 40 years later and the risk of spontaneousabortion over their reproductive lifespan (Jarrell et al.,1998). This study did not reveal a connection betweenserum HCB levels and the sex ratios of the children.Studies in this area continue (Jarrell et al., 2002).

39.4 CONCLUSIONS

Pesticides remain indispensable for abundant, economicalagricultural production, and the safe consumption of thesecompounds is critically important for human and environ-mental health. As emerges from the data above (all obtainedfrom Turkey), when the proper conditions are not met duringimplementation and use of pesticides, results ensue whichthreaten both human life and the environment, with notonly acute personal consequences but mass poisoning some-times being encountered. What must not be forgotten is thatpesticides are a drug group, and as for all chemicals theyhave a dosage-related toxicity.

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