Is carbaryl a carcinogen

Effects of plant protection products on human health. Options for reducing exposure

Table of Contents

Table of Contents

List of abbreviations

1 Introduction

2 basics

3 Human Health Effects
3.1 Autism Spectrum Disorders
3.2 Diabetes mellitus
3.3 Cancer
3.3.1 Lung Cancer
3.3.2 Breast Cancer
3.3.3 Prostate Cancer
3.3.4 Childhood leukemia
3.4 Alzheimer's disease
3.5 Parkinson's disease

4 ways to reduce exposure
4.1 Integrated plant protection
4.2 Organic farming
4.3 Biological plant protection
4.3.1 Entomophagous insects (beneficial insects)
4.3.2 Entomopathogenic nematodes
4.3.3 Bacillus thuringiensis
4.3.4 Plant extracts (botanicals)
4.3.5 Sterile insect technology
4.3.6 Use of pheromones
4.4 Personal protective equipment
4.5 Removal of pesticides through manufacturing processes
4.6 Further recommended measures to reduce exposure

5 conclusion

thanksgiving

bibliography

Summary

In order to meet the food demand and the quality requirements of the growing world population, the use of chemical-synthetic pesticides (pesticides) has increased significantly since the 1950s. Since these chemical substances are also widely used outside of agriculture, they are now ubiquitous to be found all over the world. Even pesticides that have already been banned can still be detected in the human body. Because of their persistent properties and their ability to bioaccumulate, some pesticides have already found their way into the food chain and accumulated there. Due to the worldwide use of pesticides, humans are exposed to the resulting risks from various sources of exposure. The aim of this master’s thesis is to use a literature research to show what health effects synthetic chemical pesticides can have on human health and what possibilities there are to reduce exposure to pesticides.

In the first part of this master's thesis, various sources of exposure and particularly exposed groups of people are described. It also looks at acute health effects from exposure to pesticides and the potential links between pesticide exposure and the development of autism, diabetes, Alzheimer's disease, Parkinson's disease and the most common types of cancer in adults, such as lung, breast and prostate cancer and leukemia Children. Other chronic diseases and disorders, such as asthma, reproductive disorders, birth defects, kidney diseases and epigenetic changes, which are also associated with pesticides, cannot be dealt with in this paper, as this would exceed the given framework.

The second part of the master's thesis deals with various measures to reduce the use of pesticides and the associated reduction in exposure. Among other things, integrated pest management is discussed here, the basic principles of which are primarily based on non-chemical pest control measures, as long as the economic damage threshold is not exceeded in the event of a pest infestation and therefore no major economic damage is to be expected. In addition, it describes how organic farming, in the event of a complete conversion, can help to save the use of chemical-synthetic pesticides and theoretically contribute to the food security of the growing world population. Furthermore, various biological plant protection measures, including the use of beneficial insects, Bacillus thuringiensis, entomopathogenic nematodes, plant extracts, pheromones and the sterile insect technique. These have an important role in integrated pest management and organic farming. In addition, further measures are discussed that farmers can take to protect themselves and other people from pesticides during application, but also to protect their families from exposure to pesticides after work. Measures are also listed through which regulatory authorities can contribute to reducing pesticides. In addition, preventive measures are mentioned through which the general population can also achieve a reduction in exposure.

Pesticides have attracted the focus of research in recent decades not only because of their achievements in increasing yield, food security and vector control in public health, but also because of their harmful effects on human health. Various studies have shown that exposure to pesticides leads to acute poisoning and is associated with the chronic diseases described here, which affect millions of people around the world. However, it is difficult to establish a causal relationship between pesticides and the development of chronic diseases, as it often takes several years for the first symptoms to appear and the respective diseases can be triggered by several factors. For this reason, more research is needed in order to decipher possible mechanisms of toxicity of individual substances, but also substance mixtures.

Even if it is currently not one hundred percent possible to hold pesticides solely responsible for certain diseases, with regard to environmental protection and the possible health effects on humans in the sense of precaution, the use of pesticides should be limited to a necessary level and whenever possible to less dangerous alternatives are used.

Abstract

In order to meet food demand and the quality requirements of the growing world population, the use of synthetic pesticides has increased significantly since the 1950s. Since these chemicals are also used extensively outside of agriculture, they are now found ubiquitous around the world. Even already banned pesticides can be partially detected today in the human body. Some pesticides have already entered the food chain because of their persistent properties and their ability to bioaccumulate. Because of this they accumulated there. As pesticides are used around the world and humans are exposed to them through various sources of exposure, the aim of this Master's Thesis is to use epidemiological studies in a literature review to identify what health effects synthetic pesticides can have on human health and what options are available to reduce exposure to pesticides.

The first part of this Master's thesis describes different sources of exposure and particularly exposed groups of people. It also highlights the acute health effects of exposure to pesticides and potential links between pesticide exposure and the development of autism, diabetes, Alzheimer's disease, Parkinson's disease and the most common cancers in adults, such as lung, breast and prostate cancer and leukemia children received . Other chronic diseases and disorders, such as asthma, reproductive disorders, birth defects, kidney disease and epigenetic changes, which are also associated with pesticides, cannot be addressed in this paper, as this would go beyond the prescribed range.

The second part of the Master's thesis deals with various measures to reduce the use of pesticides and the associated reduction in exposure. Among other things, this article deals with Integrated Pest Management, the basic principles of which are based primarily on non-chemical plant protection measures, as long as the economic damage threshold is not exceeded in the case of a pest infestation and thus no major economic damage is to be expected. It also describes how organic farming can help to reduce the use of synthetic pesticides and how it can theoretically contribute to food security for the world's growing population. Furthermore, various measures of biological plant protection, such as the use of beneficial organisms, Bacillus thuringiensis, entomopathogenic nematodes, plant extracts, pheromones and the sterile insects technique are explained. In addition, further measures are discussed that farmers can perform to protect themselves and others from pesticides during application, as well as to protect their families from exposure to pesticides after work has been done. Likewise measures are listed that can be used by regulatory authorities to reduce pesticides and prevention measures are mentioned that can also reduce the exposure of the general population.

Pesticides have come under scrutiny in recent decades, not only because of their achievements in increasing yields, food security and vector control in public health, but also because of their harmful effects on human health. Several studies have shown that exposures to pesticides lead to acute intoxication and are associated with the chronic diseases described here that affect millions of people around the world. However, it is difficult to establish a causal relationship between pesticides and the development of chronic diseases, as it often takes several years before the first symptoms appear and the respective diseases can be triggered by several factors. For this reason, there is still a need for further research in order to decipher possible toxicity mechanisms of individual substances as well as substance mixtures.

Although it is currently not 100% possible to blame pesticides alone for certain diseases, the use of pesticides should be limited to a necessary level in view of the possible links between pesticide exposures and short-term and long-term human health effects and whenever possible resort to less dangerous alternatives.

List of abbreviations

Figure not included in this excerpt

1 Introduction

The human population has doubled since 1950. This has put enormous pressure on the availability of food on limited acreage at affordable prices. In order to do justice to the provision of food, chemical-synthetic plant protection products (pesticides) have been used extensively in agriculture since the 1950s (Bind and Kumar, 2019). These serve to meet the quality requirements for agricultural products and to increase yields.According to estimates, the global yield losses due to pests, weeds and diseases in the most important agricultural crops, such as sugar beet, potato, barley, maize or wheat, are between 50% and 80% without the use of pesticides in our temperate latitudes. However, even when using pesticides for these crops, the loss of yield is usually more than 30% (Sanvido et al., 2012).

Currently around 2 million tons of pesticides are used annually around the world. Of these, 47.5% are herbicides, 29.5% insecticides, 17.5% fungicides and 5.5% belong to other pesticides. Countries such as China, the USA, Argentina, Thailand, Brazil, Italy, France, Canada, Japan and India have the highest levels of pesticide use. It is assumed that by 2020 the worldwide use will increase to up to 3.5 tons (Sharma et al., 2019). Agriculture has the highest consumption of pesticides for chemical control of various pests, accounting for around 85% of global production. Pesticides are still used, among other things, in public health to combat vector-borne diseases such as malaria and dengue fever and to eliminate unwanted plants (grasses and weeds) in decorative landscaping, parks and gardens (Kim et al., 2017). Ideally, the pesticides used should only be toxic to the target organisms, biodegradable and to some extent environmentally friendly. However, this is seldom the case because most pesticides are non-specific and can kill harmless organisms that are beneficial to the ecosystem (Gill and Garg, 2014).

The repeated use of persistent and non-biodegradable pesticides has contaminated various components of water, air and soil ecosystems. In addition, these chemical substances have penetrated the food chain and accumulated there in the higher trophic levels of humans and other large mammals (Gill and Garg, 2014). This means that pesticides have become a ubiquitous part of our environment. Due to their widespread use, they can be detected in people's homes and bodies (Alavanja et al., 2004). Pesticides can enter the human body through direct contact, through residues on food (especially fruit and vegetables), contaminated water and / or polluted air (Gill and Garg, 2014). Farmers in particular have a high exposure risk due to the frequent non-compliance with the instructions for use, a lack of knowledge of the toxicology of pesticides, faulty and poorly maintained spraying equipment and the lack of personal protective equipment (El-Wakeil, 2013).

Various health risks associated with pesticides in humans can occur in the form of short-term effects (e.g. headaches and nausea) to chronic effects such as Alzheimer's, autism, diabetes, various types of cancer and Parkinson's (Singh et al., 2018; Moustafalou and Abdollahi, 2017). In order to reduce the use of pesticides and the associated exposure of people, various measures can be taken, such as the use of integrated pest management, the switch to organic farming, the inclusion of organic pest management and other measures explained in this master's thesis (Börner et al., 2009; Tamm et al., 2018).

The aim of this master’s thesis is to show possible causal relationships between pesticide exposure and harmful effects on human health by means of epidemiological studies in the form of a literature search. Furthermore, various possibilities are presented that can reduce the use of pesticides and thus contribute to a reduction in exposure. For this reason, this master's thesis is divided into two larger sections, the precise structure of which can be found in the table of contents.

2 basics

Plant protection products, for which the synonym pesticide is also used, are substances or mixtures that are used to prevent, destroy, ward off or minimize pests (insects, animals, weeds and microorganisms) (Alavanja et al., 2004; Allsop et al., 2015). Pesticides are also used as growth regulators for plants and to preserve plant products (Schäffer et al., 2018). But they are also used in the fight against vector-borne diseases in humans, such as malaria, dengue fever and schistosomiasis. However, pesticides have numerous uses outside of agriculture and public health. They are still used, for example, for the improvement and maintenance of public green spaces and sports facilities, as animal shampoos, in building materials and the floors of boats to combat or prevent unwanted pests (Nicolopoulou-Stamati et al., 2016).

In Germany, around 280 active ingredients are currently approved for chemical crop protection. However, the number of formulations, agents and products is even greater. In addition to the active ingredients, these also contain other additives such as carriers or preservatives. These can be useful for various technical functions, for example by improving the properties and making the active substances more effective (Schäffer et al., 2018).

The classification of pesticides is often based on the target pest that is to be controlled (Allsop et al., 2015). Table 1 shows the different active groups and the associated target pests according to Kim et al. (2017). In the case of insecticides, there is also often a subdivision according to their active substance class, such as organophosphates, organochlorine pesticides, carbamates, synthetic pyrethroids and neonicotinoids (Allsop et al., 2015). Individuals are often exposed to many different pesticides or mixtures of pesticides at the same time or continuously. This makes it difficult to identify the effects of certain plant protection products (Kamel and Hoppin, 2004).

Tab. 1: Classification of pesticides based on the target pest (source: Kim et al., 2017)

Figure not included in this excerpt

Pesticides can enter the human body dermally, orally, by inhalation, through the eyes and through the placenta (Gilden et al., 2010; Kim et al., 2017). Exposure to pesticides can occur through direct use at work, in agriculture and in the household (Kim et al., 2017). But the general population can also be exposed to pesticides through drift, water and food contamination, and accumulation in the food chain (Blair et al., 2015). For example, organochlorine pesticides can accumulate in the food chain and in the human body. They are mainly found in high-fat foods of animal origin, such as meat, fish and dairy products (Muresan et al., 2015). In most cases, however, the maximum residue levels set by the legislator are exceeded in fruit and vegetables (Bakirci et al., 2014). According to the "Environmental Working Group", a study of 47 types of fruit and vegetable showed that 12 types had high levels of pesticide residues. These included peaches, apples, peppers, celery, nectarines, strawberries, cherries, kale, lettuce, grapes, carrots and pears (Asghar et al., 2016). Even if the maximum residue levels, which are set by the legislature and considered safe, are largely not exceeded in residue analyzes, they cannot provide an accurate estimate of the health risks from simultaneous exposure to two or more chemical substances. This takes place under real environmental conditions and can possibly lead to synergistic effects (Nicolopoulou-Stamati et al., 2016). Furthermore, exposure to pesticides can take place via the air, soot and the soil (Gilden et al., 2010). Another significant source of exposure, especially indoors, is the use of pesticides for vector control and annoying vermin for a considerable part of the world population (Blair et al., 2015). Children are particularly exposed to pesticides in their garden and on playgrounds and sports fields (Gilden et al., 2010). In the picture below from Allsop et al. (2015) the most important sources of exposure are summarized in pictures.

Figure not included in this excerpt

Fig. 1: Different exposure pathways through which pesticides can be absorbed

(Source: Allsop et al., 2015)

These different exposure pathways have resulted in such ubiquitous exposure that persistent pesticides or their metabolites can be detected in low concentrations in the biological tissues of many people around the world. This also applies to those groups of people who may be particularly susceptible to the harmful effects of pesticide exposure (Blair et al., 2015). These include farmers and their families, infants, toddlers and children in the womb (Allsop et al., 2015). Blair et al. (2015) also list older people and immunosuppressed people.

Compared to the general population, farmers and their families may be more exposed to synthetic chemical pesticides. Farmers who apply, mix and transport pesticides experience the highest exposure (Allsop et al., 2015; Singh et al., 2018). Greenhouse employees can also be exposed to high levels of pesticide exposure. Farmer families who live near agricultural areas may also be more exposed to pesticides than the population average. The reasons for this are that pesticides that have been applied to the fields can drift into the houses of these families and agricultural workers can contaminate the homes with pesticide-contaminated clothing and shoes.This can be a potential risk, especially for infants and children, as they are more susceptible to the harmful effects of pesticides than adults. Even during pregnancy or breastfeeding, children can come into contact with these substances through exposure of the mother to pesticides, because some pesticides can be transmitted to the unborn child via the placenta and to the breastfed infant via the breast milk. The child's organs are not fully developed in early development, which is why they can be particularly susceptible to the negative effects of toxic chemicals. Children's brains, which are still developing, can also be sensitive to exposure to neurotoxic substances. In addition, children are likely to ingest higher doses of pesticides because of their weight and small size. In addition, they have an incomplete enzymatic detoxification function, since they have a smaller number of detoxifying enzymes and these also show less activity than in adult humans. Because toddlers spend a lot of time at home or outside on the floor and like to put their hands or objects in their mouths, there is an increased likelihood that they will ingest pesticides through ingestion (Allsop et al., 2015).

3 Human Health Effects

Approximately 3 million acute pesticide poisoning cases are reported each year. Of these 3 million cases, 2 million represent suicidal pesticide poisoning (Gill and Garg, 2014). In developing countries in particular, pesticides are often used for attempted suicide (Raufhake et al., 2002). The rest of the poisoning cases are due to occupational exposure or accidental ingestion (Gill and Garg, 2014; Raufhake et al., 2002). The actual number of intoxications is likely to be even higher because many cases are untreated or misdiagnosed. In addition, there are often no medical records (Sánchez-Santed et al., 2016). Acute effects of intoxication occur immediately or within 24 hours after exposure to a pesticide (Singh et al., 2018). Acute poisoning with pesticides can cause various symptoms, such as rashes, visual disturbances, headaches, body aches, poor concentration, dizziness, nausea, tiredness, vomiting, abdominal pain, cramps and panic attacks (Gill and Garg, 2014; Singh et al., 2018). In severe cases, poisoning can even lead to coma and death (Gill and Garg, 2014). Since many of the symptoms are similar or identical to those caused by other illnesses, misdiagnosis is common and the result is occasional death (Singh et al., 2018). The severity of the poisoning is usually related to the toxicity and amount of the active ingredients used, their mode of action, the type of application, the duration and frequency of exposure and the person exposed (Gill and Garg, 2014). Compared to time-delayed effects, those that are acute are easier to diagnose. With rapid and appropriate medical care, acute poisoning can often be cured (Singh et al., 2018).

Continued exposure to sub-lethal concentrations of pesticides over long periods of time (years to decades) can lead to chronic diseases in humans. Symptoms are not immediately recognizable. They usually manifest themselves at a later stage of exposure. Farmers in particular are at increased risk here, but so is the general population. They face the risk of developing chronic diseases, particularly due to contaminated food and water or from pesticide drift (Gill and Garg, 2014). In the following chapters, the relationship between exposure to pesticides and the development of the chronic diseases autism, diabetes, the four most common cancers in adults and children (lung, breast and prostate cancer as well as childhood leukemia), Alzheimer's disease and Parkinson's disease are explained in more detail. According to Mostafalou and Abdollahi (2017) there are other associations with other diseases in humans, such as amyotrophic lateral sclerosis, asthma, bronchitis, reproductive disorders, birth defects, attention deficit hyperactivity disorder and obesity. It is also assumed that pesticides can lead to epigenetic changes (Mostafalou and Abdollahi, 2017). In this master's thesis, only some of the chronic diseases associated with pesticides are dealt with, as this would otherwise exceed the scope of this thesis.

3.1 Autism Spectrum Disorders

The autism spectrum disorders, also known as autism, belong to the "profound developmental disorders" that exist for a lifetime and are very complex (Kalkbrenner et al., 2014; cutter et al., 2017; Ye et al., 2017). Autism spectrum disorders are referred to as heterogeneous neurodegenerative disorders that are characterized by deficits in social interactions, verbal and non-verbal communication, repetitive and stereotypical behavior patterns, and limited interests (Freitag and Jarczok, 2016; Sealey et al., 2016; Ye et al., 2017). In about 50% of those affected, there is also an intellectual disability and in about 32% there is a decline in the skills learned (Schneider et al., 2017; Friday and Jarczok, 2016). According to ICD-10, autism spectrum disorders include early childhood autism, atypical autism and Asperger's syndrome (Freitag and Jarczok, 2016). Similarities and differences between the individual forms of autism can be seen in Figure 2 below (Remschmidt and Kamp-Becker, 2007).

Figure not included in this excerpt

Fig. 2: Similarities and differences between the various autism spectrum disorders (source: Remschmidt and Kamp-Becker, 2007)

Another characteristic of autism spectrum disorders is that those affected avoid eye contact and seek little or no physical contact. The reaction to this can sometimes be extremely sensitive and defensive. Such hypersensitivity is also known in sensory organs, such as the sense of smell. About 68% of those affected also show aggressive and self-harming behavior. Presumably this is especially the case with patients with a low intelligence quotient (Schneider et al., 2017).

In the case of autism spectrum disorders, the severity of symptoms in children and adolescents can vary greatly (Freitag and Jarczok, 2016). More than 70% of those affected have comorbidities in the form of other developmental disorders or mental illnesses. Neurological or internal diseases can also occur together with autism. The most important neurological comorbidity is epilepsy, from which up to 30% of all those affected suffer. In up to 5% of cases, genetic syndromes such as Down syndrome, Rett syndrome or phenylketonuria can occur comorbidly with autism spectrum disorders. Common additional developmental disorders include abnormalities in language or motor skills. With regard to mental illnesses, attention deficit disorder (ADD) (up to 44%), depression (up to 70%), anxiety (up to 56%) or tic disorders (up to 38%) can appear together with autism spectrum disorders. On the other hand, there are seldom psychotic disorders, eating disorders or addictions (Schneider et al., 2017). Autistic symptoms also occur in various somatic and genetic diseases, such as Rett syndrome, tuberous sclerosis, fragile X syndrome, infantile cerebral sclerosis, congenital rubella infections and cerebral lipoidosis (Weber-Papen et al., 2016).

Clinically, the diagnosis is made based on the symptoms present (Sappok et al., 2010). The diagnosis includes a detailed anamnesis, neuropsychological test procedures, behavioral observations and the clarification of the organs. The diagnosis is usually made during childhood. In Asperger's syndrome in particular, autism spectrum disorders are in some cases only diagnosed in adulthood (Schneider et al., 2017). The core symptoms are usually still evident in adults, but there is a slight improvement in social skills as people get older (Sappok et al., 2010; Weber-Papen et al., 2016). Whether those affected can live independently and without help depends in particular on the intelligence quotient, the degree of social impairment, language skills and the presence of other diseases such as epilepsy (Sappok et al., 2010; cutter et al., 2017). Many of those affected can graduate from school with a normal intelligence quotient. However, problems often arise in the workplace, which is why many autistic people remain unemployed (Schneider et al., 2017). The prognosis for Asperger's syndrome is more favorable than for early childhood autism. There is no cure for autism spectrum disorders (Sappok et al., 2010). The aim of treatment is to reduce symptoms or the behavioral disorders that occur (Weber-Papen et al., 2016). Psychotherapy and sociotherapy have proven to be particularly important here. Therapy with psychotropic drugs can also help alleviate symptoms of the disorder (Schneider et al., 2017). With sufficient cognitive function, appropriate therapy can improve contact and interaction behavior over time and alleviate certain impairments (Weber-Papen et al., 2016). Autism spectrum disorders not only have an impact on those affected and their families, but also directly and indirectly on the health, care and education sectors as well as the labor market and housing construction, in that they lead to a high economic burden. It is estimated that medical, non-medical, and productivity costs due to autism spectrum disorders will cost approximately $ 500 billion annually in the United States alone by 2025 (Masi et al., 2017).

Autism spectrum disorders are diagnosed in approximately 1% of the world population (Weber-Papen et al., 2016). The frequency has shown an increasing trend in recent years. While 1 in 150 children was affected by autism in 2002, the number rose to 1 in 59 children in 2014 (Cheng et al., 2019; Pelch et al., 2019). The prevalence of autism appears to be gender specific, with boys four times more likely to be affected than girls. The reasons for this are not yet known (Chaste and Leboyer, 2012; Ye et al., 2017). Cultural, socio-economic or geographical factors should not be important for the prevalence of autism spectrum disorders (Schneider et al., 2017). The increased rates of autism diagnoses can have many causes. This includes improved diagnostics, increased 8 perception and increased knowledge of these disorders (Cheslack-Postava et al., 2013; cutter et al., 2017). Another reason can also be the increase in environmental pollution (Cheslack-Postava et al., 2013).

It appears that there is a strong genetic component in the development process of autism spectrum disorders, in which a number of genes and epigenetic processes are believed to play a role in the pathogenesis. Chromosomal abnormalities have also repeatedly been detected in studies. Twin and family studies show a high heritability of around 40 to 80% (Schneider et al., 2017). Among all child psychiatric diseases, autism spectrum disorders are among the disorders that have the strongest genetic influence (Holtmann et al., 2006). But changes in brain morphology can also be related to the etiology of autism. In neurobiological studies, multiple differences in brain morphology could be demonstrated in patients with autism spectrum disorders. The brain volume showed an enlargement at the beginning of development. However, this decreased considerably in the course of growth compared to healthy children (Schneider et al., 2017). Changes should be visible especially in the frontal and temporal brain areas, in the limbic system and in the cerebellum (Weber-Papen et al., 2016). The distribution of gray matter (amygdala, hippocampus and precuneus) and white matter (uncinatus fasciculus and arcuatus fasciculus) is striking. Furthermore, it appears that the range of neurotransmitters has changed. Changes due to hyperserotoninemia and reduced GABA receptors (Schneider et al., 2017). It is also assumed that autoimmune processes and disorders of mitochondrial function can be involved in the pathogenesis (Weber-Papen et al., 2016).

Even if research has dealt intensively with autism spectrum disorders over the past decade, the underlying etiology remains largely unknown (Sealey et al., 2016; Ye et al., 2017). Autism varies significantly in appearance among sufferers. It is therefore not surprising that the etiology of autism spectrum disorders appears to be similarly heterogeneous and complex (Sealey et al., 2016). Although autism spectrum disorders are predominantly genetic, there are some known risk factors that can promote development. Above all, these include an increased age of the parents when the child is born, birth complications, viral infections during pregnancy (rubella infections) and exposure to certain drugs during pregnancy, such as valproic acid and thalidomide (Freitag and Jarczok, 2016; Schneider et al., 2017). Environmental agents that can influence the autism pathogenesis are pesticides, phthalates, polychlorinated biphenyls, solvents, air pollution, fragrances and heavy metals (aluminum, lead and mercury) (Sealey et al., 2016; Ye et al., 2017). However, the exact relationships are not yet known and there is no consistent causality (Schneider et al., 2017). Increasing evidence suggests that environmental factors and environmental-gene interactions may contribute to the etiology of autism spectrum disorders (Pelch et al., 2019). Environmental agents can influence epigenetic processes through modifications of gene expression and rather less through changes in the DNA sequence. In some individuals, such changes in gene expression can make them more sensitive to the effects of certain toxins (Cheng et al., 2019).

An increasing number of studies have shown that the developing brain of fetuses is particularly sensitive to environmental toxins (Ye et al., 2017). Prenatal exposures to various types of pesticides have been linked to impaired nervous system development. It is also believed that organophosphates and organochlorine pesticides can increase the risk of autism spectrum disorders. In experimental in vivo and in viiro -Studies on autism revealed changes in neuroprotein concentrations, altered gene expression and behavioral neurological abnormalities after exposure to certain pesticides. For example, it could be shown in mice that when the organophosphate chlorpyrifos was administered prenatally at subtoxic concentrations, the male offspring exhibited delayed motor skills and increased behavioral characteristics associated with autism. Overall, however, knowledge about pesticide exposure in reality and the risk of autism spectrum disorders is so far sparse (Von Ehrenstein et al.,2019).

Roberts et al. (2007) reported an increased risk in the first trimester of Autism Spectrum Disorder in children whose mothers lived within 500 m of locations where organochlorine pesticides were applied to California fields during pregnancy. Dicofol and Endosulfan were the two pesticides that were mainly applied in this category. The risk of autism spectrum disorders increased with increasing application rates of organochlorine pesticides and decreased with increasing distance from the application site. Dicofol in particular is chemically similar to the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT). The difference, however, is that Dicofol has a hydroxy part on one of its two aliphatic carbon atoms. Dicofol is not metabolized to dichlorodiphenyldichloroethene (DDE). However, it is removed from the body faster than DDT because it bioaccumulates less. For this reason, it is believed that DDT may have a similar, but possibly stronger, association with autism (Roberts et al., 2007).

Shelton et al. (2014) investigated whether the proximity of residence to agricultural pesticides during pregnancy is linked to autism spectrum disorders or developmental delays. Therefore, for their study, they compared 970 California mothers who lived within a 1.25 to 1.75 km radius of fields treated with pesticides. Data on treatment with pesticides were taken from the California Pesticide Use Reports. These included data on the place of application, the amount used, the type of plant protection product and the period of application. The California Pesticide Use Reports showed that pesticides from the group of organophosphates, pyrethroids and carbamates were used most frequently. Using questionnaires, Shelton et al. (2014) also determine the places where the mothers stayed during their pregnancy. This information was then used to create GIS maps. These showed the locations of application of certain pesticides as well as the frequency and spatial distribution of autism and developmental delays.

After evaluating the maps, the researchers came to the conclusion that around a third of the study participants lived within a radius of 1.5 km from the application of agricultural pesticides during pregnancy. They also found that mothers who lived within 1.25 to 1.75 km of sprayed fields during their pregnancy and were exposed to organophosphates at any point in pregnancy were 60% more likely to have a child Get with Autism Spectrum Disorders. For exposures to organophosphates as a whole, a high odds ratio was found for autism spectrum disorders in the third third of pregnancy1 of 2.0 and a 95% confidence interval of 1.1 to 3.6. In contrast, an odds ratio of 3.3 and a 95% confidence interval between 1.5 and 7.4 could be determined for exposure to chlorpyrifos in the second trimester. Children born to mothers who lived near pyrethroid insecticide exposure were at higher risk of both autism spectrum disorders and developmental delays only when exposed during conception or the third trimester of pregnancy. Odds ratios between 1.7 and 2.3 could be determined for this. The risk of developmental delays was increased in children whose mothers lived near a carbamate application. However, no specific period of time for sensitivity could be identified. Thus, the results of this study show that children of mothers who live near an agricultural area or are otherwise exposed to organophosphates, pyrethroids and carbamates during pregnancy may have an increased risk of disorders in the development of the nervous system.The researchers believe that the fetus's brain is particularly sensitive to pesticides during its development. For this reason, they warn women not to stay in places that are close to pesticide application during pregnancy and advise them to avoid direct contact with pesticides (Shelton et al., 2014).

Brown et al. (2018) investigated in a case-control study whether increased concentrations of persistent organic pollutants in the mother's blood are associated with autism in the offspring.They examined blood samples taken from 1987 to 2005 for the Finnish Prenatal Studies pregnant women for their DDT content. The researchers compared the blood of pregnant women whose children later had autism with an adapted control group of pregnant women whose children did not have autism. It was found that the mothers of the children suffering from autism had significantly higher concentrations of DDT and the metabolite p, p'-dichlorodiphenyldichloroethene (p, p'-DDE) in their blood during pregnancy compared with the control group. The risk of autism among the offspring was significantly increased with maternal p, p'-DDE concentrations above the 75th percentile. After excluding the influencing factors age of the mother, number of children and psychiatric disorders of the mother, an odds ratio (OR) of 1.32 (95% CI: 1.021.71) was determined. For autism with an intellectual disability, the risk was more than twofold when maternal p, p'-DDE concentrations exceeded the 75th percentile. An OR of 2.21 (95% CI: 1.32-3.69) was determined for this (Brown et al., 2018).

From Ehrenstein et al. (2019) investigated in a population-based case-control study the connection between the occurrence of autism spectrum disorders and the use of pesticides within a radius of 2,000 m from the mother's place of residence during pregnancy and the child's first year of life. For this purpose, data from the “California Pesticide Use Reports” were integrated into GIS maps and compared with 2,961 cases of autism spectrum disorders, including 445 cases with comorbid intellectual disabilities, in order to estimate the exposure of unborn babies and infants to pesticides. In addition, the researchers compared the exposure of the sick children with the exposure of a control group in a ratio of 10: 1, who had the same year of birth and gender. From Ehrenstein et al. (2019) selected 11 pesticides for their study that were frequently in use and caused by in vivo and in viiro -Studies evidence of toxicity on the development of the nervous system existed. An increased risk of developing autism spectrum disorders could be determined for 6 out of 11 of the examined pesticides. Glyphosate had the highest odds ratio after prenatal exposure (OR: 1.16; 95% CI: 1.06-1.27), followed by chlorpyrifos (OR: 1.13; 95% CI: 1.05- 1.23), diazinon (OR: 1.11; 95% CI: 1.01-1.21), malathion (OR: 1.11; 95% CI: 1.01-1.22), avermectin (OR : 1.12; CI: 1.04-1.22) and permethrin (OR: 1.10; 95% CI 1.01-1.20) (Von Ehrenstein et al., 2019).

For an autism spectrum disorder with intellectual disability, the estimated odds ratios were approximately 30% higher for prenatal exposure to glyphosate (OR: 1.33; 95% CI: 1,051.69), chlorpyrifos (OR: 1 , 27; 95% CI: 1.04-1.56), diazinon (OR: 1.41; 95% CI: 1.15-1.73), permethrin (OR: 1.46; 95% CI: 1 , 20-1.78), methyl bromide (OR: 1.33; 95% CI: 1.07-1.64) and myclobutanil (OR: 1.32; 95% CI: 1.09-1.60). For some substances, exposure in the first year of life increased the likelihood of autism spectrum disorders with comorbid intellectual disabilities by up to 50% (Von Ehrenstein et al., 2019).

The results suggest that the risk of autism spectrum disorders increases in offspring who are prenatally exposed to surrounding pesticides within 2,000 m of maternal residence during pregnancy compared to offspring of women who are in the same agricultural region without live such an exposure. Exposure in early childhood can also contribute to a risk of more impaired phenotypes with comorbid intellectual disabilities (Von Ehrenstein et al., 2019). Like Shelton et al., (2014), the authors of this study also recommend avoiding exposure to pesticides during pregnancy and in infants in order to protect early brain development (Von Ehrenstein et al., 2019).

3.2 Diabetes mellitus

Diabetes mellitus is the generic term for heterogeneous metabolic disorders that are characterized by chronic hyperglycaemia. The reasons for this are either reduced insulin production, impaired insulin action or both together (Evangelou et al., 2016; MüllerWieland et al., 2016). Insulin is important for the uptake of glucose by cells so that it can be used as an energy source (Rafaat et al., 2012).

Diabetes is a major public health problem (Juntarawijit and Juntarawijit, 2018). In 2017, 8.8% of the world's population, i.e. 425 million people, between the ages of 20 and 79 were affected by diabetes. This number is expected to rise to 629 million people (9.9%) by 2045. It is believed that approximately 4 million adults worldwide died from diabetes in 2017. This means that every eight seconds someone died of diabetes. The economic burden of diabetes is also increasing. Worldwide, annual health care for diabetes already cost 232 billion US dollars in 2007. These costs rose significantly to $ 727 billion in 2017. The complications of diabetes include foot ulcers, visual impairment, kidney failure, and cognitive dysfunction. Long-term exposure to persistent hyperglycemia triggers significant changes in the peripheral and central nervous system. Diabetes is linked to cognitive dysfunction and memory disorders. Because of this, people with diabetes are at high risk of developing depression, dementia, and Alzheimer's disease. All of these changes appear as secondary to chronic hyperglycaemia, which has remained undetected for a long period of time, and impair the quality of life of diabetic patients (Park et al., 2019).

Diabetes is divided into several types: Type 1 diabetes is characterized by ß-cell destruction, which triggers a complete insulin deficiency. This type of diabetes is usually mediated immunologically (Müller-Wieland et al., 2016). However, autoantibodies cannot be detected in all type 1 diabetics. In addition, not all people with proven autoantibodies develop diabetes. 85% of newly diagnosed type 1 diabetics do not have a first-degree family member with type 1 diabetes. For this reason, external factors, such as chemicals that have endocrine disrupting or immunomodulating effects, may be a cause of the development of type 1 diabetes (Friedrichsen, 2014).

Type 2 diabetes accounts for around 90% of all diabetes cases (Evangelou et al., 2016). Until a few decades ago, type 2 diabetes was mostly common in adults. This type of diabetes arises from insufficient insulin release and / or insulin resistance (Friedrichsen, 2014). Insulin resistance occurs when the insulin produced by the pancreas cannot get into the cells. This subsequently leads to an increase in blood sugar levels. For now, this will be compensated by an increase in insulin production. Over time, however, the pancreas no longer manages to produce enough insulin. This leads to hyperglycemia and type 2 diabetes (Rafaat et al., 2012). This type of diabetes is often associated with a metabolic syndrome (Müller-Wieland et al., 2016). Type 2 diabetes used to be known as "age diabetes". However, this has also occurred increasingly in children for a number of years. A genetic predisposition, diet, obesity and lack of exercise are considered to be the main causes (Friedrichsen, 2014). Other causal factors are sleeping habits, cigarette and alcohol consumption (Juntarawijit and Juntarawijit, 2018). However, approximately 20% of type 2 diabetics are of normal weight or are of lean stature. In these sufferers, obesity cannot be the cause of diabetes. In this case, so-called endocrine disruptors could play a role in the development of diabetes, because the drastic increase in the incidence of diabetes cannot be explained by genetic predisposition alone (Friedrichsen, 2014).

The third form of diabetes is so-called gestational diabetes. This manifests itself as a glucose tolerance disorder that occurs for the first time during pregnancy or is first diagnosed at this time. In addition to these three main types, there are other specific types of diabetes. These include diseases of the exocrine part of the pancreas, endocrinopathies, drug-chemically induced diabetes, genetic defects in ß-cell function and insulin effect, as well as rare forms of autoimmune-mediated diabetes. The diagnosis of diabetes mellitus is made when the HbA1c is> 6.5% (> 48 mmol / mol), the occasional plasma glucose value is> 200 mg / dL (> 11.1 mmol / L), a fasting plasma glucose value of > 126mg / dL (> 7.0 mmol / L) is reached or the oral glucose tolerance test (oGTT) shows a 2 hour value in the venous plasma of> 200 mg / dL (> 11.1 mmol / L) (Müller-Wieland et al., 2016).

Diabetes mellitus is a multifactorial disease with a strong genetic component and many environmental and lifestyle influences. However, increasing evidence suggests that environmental pollutants, including pesticides, may play a significant role in the pathogenesis of diabetes (Evangelou et al., 2016). Among these factors are persistent organic pollutants such as dioxins, polychlorinated biphenyls and organochlorine pesticides. These are lipophilic and are stored in adipose tissue. Furthermore, these generally have a very long half-life of months to several years (Park et al., 2019; Starling et al., 2014). Agents with a shorter half-life, such as organophosphate insecticides and chlorophenoxy herbicides, are also suspected of causing diabetes (Starling et al., 2014).

The biological mechanisms underlying the link between pesticide exposure and the pathogenesis of type 2 diabetes remain largely unknown. Background exposure to organochlorine pesticides is believed to be strongly linked to the development of type 2 diabetes.Organochlorine pesticides can be ingested either through direct exposure or through food. These chemicals are lipophilic, hydrophobic, and very resistant to metabolic breakdown. Therefore, they are accumulated in adipose tissue for many years. Their serum concentration serves as a good reflection for lifetime exposure (Evangelou et al., 2016). In addition, most individuals are exposed to different pesticides at the same time. This multiple exposure can increase the risk of developing diabetes because the effects of these pesticides can be additive or synergistic. But sometimes they can also be contradicting each other (Sylvie Azandjeme et al., 2013).

Since the production and use of most organochlorine pesticides were banned in western countries forty years ago, the average absolute values ​​in most populations are falling compared to those in previous years. Nevertheless, organochlorine pesticides are continuously released from fat deposits in the blood and can thus reach important organs, where they can lead to the disruption of some biological functions. This class of pesticides has variable molecular and cellular targets. For this reason, they cannot be assumed to have a single mechanism of action. The primary mechanisms underlying the pathogenesis of type 2 diabetes are inflammation in adipose tissue, ectopic lipid deposits (lipotoxicity) in the liver, muscles and pancreas, and mitochondrial dysfunction. All of them have been linked to organochlorine pesticides (Evangelou et al., 2016). In addition, at low doses, organochlorine pesticides can act as endocrine disruptors over time. Persistent organochlorine pesticides accumulate in adipose tissue and are successively released into the bloodstream, where they can mimic or block cellular receptors and hormones. They reduce insulin sensitivity by mimicking estrogen receptors that are present in insulin-sensitive tissue and the ß-cells of the pancreas (Sylvie Azandjeme et al., 2013). Oxidative damage represents an additional mechanism. This leads to impairment of mitochondrial function and development of insulin resistance and thus to type 2 diabetes. Experimental studies showed that rats fed salmon oil containing levels of persistent organic pollutants including organochlorine pesticides found in the environment, insulin resistance, visceral obesity, dyslipidemia, non-alcoholic fatty liver, and developed chronic mild inflammation. Furthermore, at in vitro - Studies have shown reduced insulin effects after treatment with organochlorine pesticides. This effect was seen at low doses but not at high doses. This leads to the assumption of a non-monotonic dose-response curve instead of a clear dose-response relationship (Evangelou et al., 2016).

However, the precise mechanisms by which pesticides can trigger diabetes remain largely unclear. In the case of organophosphates, however, various mechanisms are assumed to be likely (Everett and Matheson, 2010). Organophosphate insecticides are one of the most widely used classes of pesticides in agricultural and landscaping pest control. Due to their low toxicity towards mammals compared to the organochlorine pesticides and their low persistence, the use of organophosphates has increased significantly. Organophosphates are liquid at room temperature. In this state, they can emit a vapor that is able to penetrate the skin, the airway epithelium and the cornea (Rezg et al., 2010). Organophosphates can be absorbed through the intact skin and also from the gastrointestinal tract after ingestion of contaminated food (Swaminathan, 2013). The ingested organophosphates then go through many biotransformation reactions that lead to very toxic metabolites. Although these are formed in small quantities, they can still be important from a toxicological point of view (Rezg et al.,2010).

Organophosphates can influence glucose metabolism through inhibition of cholinesterase activity, through oxidative, nitrosative and physiological stress, through adrenal stimulation and through inhibition of paraoxonase (Everett and Matheson, 2010). In the pathogenesis of type 2 diabetes, the pancreas is unable to produce sufficient insulin. This leads to hyperglycemia and consequently type 2 diabetes. Pancreatic ß-cells have acetylcholine receptors, which are involved in insulin production depending on the blood sugar level. In animal models, the organophosphates acted as an inhibitor of acetylcholinesterase, which consequently led to an accumulation of acetylcholine and a decrease in insulin production (Park et al., 2019).

Various studies have shown that organophosphate insecticides disrupt glucose homeostasis in animal models. In humans, they can lead to hyperglycaemia after poisoning (Rafaat et al., 2012). It is known that the enzymes that are linked to the antioxidant defense are changed under the influence of organophosphates. It is believed that the pancreas is more sensitive to oxidative stress than other tissues and organs. The reason for this is that pancreatic islet cells show an extremely weak level of antioxidant enzymes. In addition, it has been reported that organophosphate compounds increase lipid peroxidation, glutathione breakdown and a significant change in the enzymatic antioxidant protection systems. This indicates a significant induction of oxidative damage in the pancreatic tissue. It has been proven that oxidative stress is important in the development of insulin resistance and ß-cell dysfunction due to its ability to activate stress-sensitive signaling pathways (Rezg et al., 2010). Furthermore, current experimental studies have shown that the organophosphate chlorpyrifos leads to excessive weight gain, hyperlipidemia and hyperinsulinemia in adult rats that were neonatally exposed to this pesticide (Starling et al., 2014).

Pancreatic ß-cells contain muscarinic acetylcholine receptors, which are involved in the glucose-dependent production of insulin. Organophosphates are known inhibitors of acetylcholinesterase. Therefore, exposure to sufficiently high levels of organophosphate compounds leads to an accumulation of acetylcholine. This can potentially lead to a 15th

Overstimulation and a possible down-regulation of its receptors lead and reduce the insulin production. In addition, prolonged stimulation by acetylcholine can reduce the sensitivity of the ß-cells to glucose. Organophosphate compounds are also strong prooxidants. NADH (nicotinamide adenine dinucleotide hydrogen) and NADPH (nicotinic acid amide adenine dinucleotide phosphate) are involved in the recycling process of oxidized cellular antioxidants. Glucose-6-phosphate dehydrogenase catalyzes the first step of the pentose phosphate pathway, the most important function of which is the reduction of NAD (nicotinamide adenine dinucleotide) and NADP (nicotinamide adenine dinucleotide phosphate). These enzymes require glucose as a substrate for their activation. For this reason, there may be a sustained decrease in glucose with chronic exposure to organophosphate compounds with subsequent insulin depletion (Rafaat et al., 2012).

Acute pancreatitis is a well-known complication of organophosphate poisoning. The cause can be excessive cholinergic stimulation within the pancreas and ductal hypertension. Furthermore, organophosphate compounds are known to trigger the formation of laughing gas, which is assumed to be involved in the destruction of ß-cells. The hyperglycemia that occurs in organophosphate poisoning can possibly be caused by this injury to the pancreatic ß-cells. It is also believed that the hyperglycemic condition triggered by organophosphate compounds can affect the effector sites in the adrenal medulla. Consequently, this leads to hypersecretion of adrenaline. This promotes glycogenolysis in the hepatocytes and skeletal muscle cells. It also plays a key role in the pathogenesis of insulin resistance due to the inhibition of glucose transport in skeletal muscles by disrupting the insulin signaling pathway. In addition, it promotes lipolysis, which contributes to the accumulation of free fatty acids. In addition, an increased content of free fatty acids has an inhibiting effect on insulin signaling and glycogen synthesis (Rafaat et al., 2012).

park et al. (2019) examined the association between pesticide exposures and the prevalence of diabetes in a rural population in Korea. Data for this cross-sectional study was taken from the Korea Farmers Cohort study, which included 2,559 participants in the baseline survey between November 2005 and January 2008. After the admission, a clinical examination followed, which also included a blood sample. The data obtained were assessed on the basis of diabetes diagnosis, demographics and pesticide exposures. The authors found that exposure to pesticides is associated with diabetes. The association was stronger in overweight or obese individuals than in those of normal weight. A high BMI (> 25) can increase the risk of developing diabetes when exposed to pesticides. The authors also found that the prevalence of diabetes was higher among study participants who were ever farmers or who have ever used any pesticide compared to those who did not use pesticides (Park et al., 2019).

Over 80 million adults (prevalence of 9% to 10%) live with diabetes mellitus in India. About 90% of them have type 2 diabetes. The rates are just as high in the South Asian diaspora population. Including those who live in the UK.South Asians living in the UK have a two to three times higher rate of type 2 diabetes than European fair skinned populations. Diabetes mellitus develops in South Asian Indians at lower body weight, blood lipid levels and age than in other ethnic groups. Previously known risk factors, including genetics, cannot explain this increased vulnerability. One possible explanation is that South Asians are exposed to higher exposure to organochlorine pesticides, which has been linked to diabetes mellitus in European, American and Korean populations (Daniels et al., 2018).

Daniels et al. (2018) compared the concentrations of organochlorine pesticides in South Asian immigrants and European fair-skinned people who lived in London for their study. To investigate whether diabetes mellitus is positively linked to organochlorine pesticides in South Asian immigrants. 120 South Asians of Tamil or Telugu descent and 72 fair-skinned Europeans were included in the study. Of the study participants of South Asian descent, 24 had diabetes and the remaining 96 were chosen as controls. Then blood samples, biometric and clinical data as well as survey data were collected from all participants. The plasma levels of p, p'-dichlorodiphenyldichloroethene (p, p'-DDE), p, p'-dichlorodiphenyltrichloroethane (p, p'-DDT), ß-hexachlorhexane (ß-HCH) and polychlorinated biphenyl-118 were determined by means of gas chromatography Mass spectrometry analyzed. Subsequently, significantly higher concentrations were found in South Asian immigrants compared to the European fair-skinned people who lived in West London. The authors were able to show that the participants with ancestry from Tamil had approximately three to nine times higher levels of organochlorine pesticides and the study participants from Telugu had 9 to 30 times higher levels of organochlorine pesticides compared to the European fair-skinned people. The probability of exposure to p, p'-DDE above the 50th percentile was significantly higher in the South Asian diabetes cases than in the controls (OR: 7.00; 95% CI: 2.22-22.06). It was also found that the probability of exposure to ß-HCH above the 50th percentile was significantly higher in the diabetes cases of Tamil origin than in the controls (OR: 9.35; 95% CI: 2.43-35 , 97) was. The results show that South Asian immigrants have a higher body exposure to organochlorine pesticides than European fair-skinned people. For this reason, diabetes mellitus has been associated with higher p, p'-DDE and ß-HCH concentrations in these populations. The authors recommend carrying out additional long-term studies with South Asian populations (Daniels et al., 2018).

The South Asian population has been exposed to organochlorine pesticides for longer periods of time and at higher concentrations than the population in Western Europe, where these compounds were largely banned in the 1970s and 1980s. Following the signing of the Stockholm Convention in 2006, uncontrolled spraying of organochlorine pesticides for the control of vector-borne diseases as well as for agricultural purposes continued in India. India is currently still the top producer and consumer of organochlorine pesticides. This country also has one of the world's highest levels of breast milk for these pesticides, including DDT and the HCHs. In contrast to other Asian nations such as China, the levels of DDT and the HCHs in India have not decreased since the introduction of stronger regulations. Dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethene (DDE) are stored in body fat for a long time and are resistant to metabolism. They can have a half-life of 2 or 6 to 7 years in human plasma. The organochlorine pesticide ß-HCH also has a long half-life of 7 years in humans. Because of this, these organochlorine pesticides persist in the bodies of South Asian immigrants for many years after they emigrated (Daniels et al., 2018).

In Thailand, the diabetes rate among people over the age of 18 increased dramatically from 6.9% in 2009 to 8.9% (4.8 million sufferers) in 2014. For this reason, Juntarawijit and Juntarawijit (2018) carried out a population-based case-control study among residents in the “Bang Rakam District” of Phitsanulok Province, Thailand. Lifelong pesticide exposure data and other relevant data were collected from 866 participants with diabetes mellitus and 1,021 healthy controls. The authors found that the prevalence of diabetes was positively associated with exposure to all types of pesticides, including insecticides, herbicides, fungicides, rodenticides, and molluscicides. The exposure to rodenticides was statistically significant (OR: 1.35; 95% CI: 1.04 -1.76). Statistically significant odds ratios were determined for three insecticides among the 35 pesticides examined. These included the organochlorine pesticide endosulfan (OR: 1.40; 95% CI: 1.01-1.95), the organophosphate Mevinphos (OR: 2.22; 95% CI: 1.17-4.19) and the carbamate Carbaryl / Sevin (OR: 1.50; 95% CI: 1.02-2.19) and the fungicide Benlat (OR: 2.08; 95% CI: 1.03-4.20). Thus, the results suggest that the presence of diabetes among Thai farmers is linked to pesticide exposure. Furthermore, the data collected here shows that the rate of personal protective equipment used was less than 30% and 41% of users did not change their clothes immediately after spraying pesticides. In addition, especially rural Thais tend to eat little protein in their diet and instead consume a large amount of vegetables. In addition, they often have a poor level of education and socio-economic status. These are all confirmed risk factors for diabetes (Juntarawijit and Juntarawijit, 2018).

Starling et al. (2014) used data from the “Agricultural Health Study” for their study. This is a large, prospective cohort study of pesticide applicators and their spouses in Iowa and North Carolina. Among the 13,637 women of the farmers who personally mixed or applied pesticides, five specific pesticides were identified as being linked to incident diabetes during a 10-year follow-up period. These included the three organophosphates fonofos (hazard ratio2 (HR): 1.56, 95% CI 1.11-2.19), phorate (HR: 1.57, 95% CI: 1.14-2.16) and parathion (HR: 1.61, 95% CI : 1.05-2.46). Furthermore, the organochlorine pesticides were dieldrin (HR: 1.99, 95% CI: 1.12-3.54) and the herbicide 2,4,5-T / 2,4,5-TP (HR: 1.59 , 95% CI: 1.00-2.51) positively associated with newly onset diabetes. Thus, the results of this study show that certain organophosphates and organochlorine pesticides can potentially increase the risk of diabetes (Starling et al., 2014).

The organophosphate malathion is one of the most widely used insecticides worldwide. The Environmental Protection Agency (EPA) estimates that malathion is used in excess of £ 30 million annually. It is used for a wide variety of crops, especially cotton and rice. In Egypt, malathion is used extensively in agriculture, veterinary medicine, medical offices, and public health. The reasons for this are the low price and the low acute toxic effects on mammals (Rafaat et al., 2012). Because of this, Rafaat checked et al. (2012) investigated the relationship between chronic exposure to malathion and insulin resistance in Egyptian farmers in a comparative cross-sectional study. The study included 98 non-diabetic farmers who had been exposed to agricultural insecticides while working in the fields. The length of the exposure period was 15 to 20 years. All farmers were male, with a mean age of 39 ± 12 years. 90 male administrative employees of the Zagazig University Clinic who had no diabetes and whose age was appropriate were selected as controls. Family history for diabetes was recorded. Furthermore, the blood pressure, height, weight, waist circumference and body mass index (BMI) were determined for all participants. In addition, blood samples were taken in order to be able to determine the malathion concentration, the fasting blood sugar and fasting insulin levels for the calculation of the homeostatic model evaluation for insulin resistance (HOMA-IR). The results of Rafaat et al. (2012) show that 24.5% of farmers had a positive history of diabetes. In addition, statistically significant differences in the mean values ​​of the fasting blood sugar level, fasting insulin level and HOMA-IRs were observed between the exposed group of farmers and the control group. Exposed farmers had mean values ​​for the HOMA-IR above the accepted normal values. Furthermore, the authors found statistically significantly higher mean values ​​of the malathion blood concentration in the exposed farmers compared with the individuals in the control group. The reason for this may be that malathion can activate the hepatic glycogen phosphorylase enzyme that triggers glycogenolysis. It also stimulates phosphoenolpyruvate carboxykinase, which is responsible for gluconeogenesis (the generation of glucose from other organic molecules) (Rafaat et al., 2012).

It is known that obesity has a positive correlation with insulin resistance, because increased secretion of free fatty acids, inflammatory cytokines and decreased secretion of adiponectin are involved in mediated insulin resistance. The size of the waist circumference seems to be more important than the BMI in the development of insulin resistance. A waist circumference of over 96 cm is said to be more likely to promote insulin resistance. In this study, there was a strong positive correlation between the increase in the concentration of malathion in the blood and the increase in waist circumference and body mass index (Pearson correlation coefficient of 0.510 and 0.831, respectively).One explanation for this is that most insecticides are lipophilic and people with a high BMI are likely to have higher levels of insecticides in their bodies than people with a low BMI and the same exposure. The results of this study lead to the assumption that chronic exposure to the organophosphate malathion can trigger insulin resistance in exposed, non-diabetic farmers. This effect even seems to increase with increasing waist circumference (Rafaat et al., 2012).

Montgomery et al. (2008) wanted to find out whether there is a connection between lifetime exposure to certain pesticides used in agriculture and the incidence of diabetes among pesticide users. 33,457 licensed pesticide applicators who were also registered in the “Agricultural Health Study” took part in the study. The participants themselves reported incidental diabetes in a follow-up interview after five years (1999-2003). At that time, there were 1,176 diabetics and 30,611 non-diabetics who were included in the analysis. The study participants reported on lifetime exposure and covariate information at registration from 1993 to 1997. Using logistic regression, the authors determined seven specific pesticides (aldrin, chlordane, heptachlor, dichlorvos, trichlorfon, alachlor and cyanazine) for which the probabilities of diabetes incidence were both increased with each use, as well as with the cumulative days of use. Applicants who used the organochlorine pesticides aldrin, chlordane and heptachlor for more than 100 days in their lifetime had a 51%, 63% and 94% increased chance of developing diabetes, respectively. This leads to the assumption that long-term exposure to certain pesticides, especially organochlorine and organophosphate insecticides, may be associated with an increased risk of diabetes (Montgomery et al., 2008).

3.3 Cancer

Cancer is a leading cause of morbidity and mortality worldwide. While there were 14 million new cancer cases and 8 million deaths in 2012, according to GLOBOCAN (Global Cancer Statistics) there were already an estimated 18.1 million new cases of cancer and 9.6 million cancer-related deaths worldwide in 2018 record (Bray et al., 2018; Fidler et al., 2018). The number of new cancer cases and cancer-related deaths is expected to rise to 22 million and 13 million annually in 2030 (Fidler et al., 2018). Combined for both sexes, lung cancer was the most frequently diagnosed cancer in 2018, accounting for 11.6% of all new cancer cases. In addition, this cancer is the most common cause of cancer-related death, accounting for 18.4% of all cancer deaths. In terms of incidence, female breast cancer (11.6%), prostate cancer (7.1%) and colon cancer (6.1%) follow. In terms of mortality, lung cancer is closely followed by colon cancer (9.2%), stomach cancer (8.2%) and liver cancer (8.2%). It is believed that in 2018, for both sexes combined, half of all cancer cases and more than half of all cancer deaths in the world occurred in Asia. One of the reasons for this is that around 60% of the world's population live there. Europe accounts for 23.4% of all cancer cases and 20.3% of all cancer-related deaths, even if this part of the world is only 9% of the world's population. America ranks behind Europe with 21% of global incidence and 14.4% of global mortality (Bray et al., 2018).

The increasing trend in cancer incidence in the last 50 to 60 years is, among other things, the result of the growth and aging of the population, but also the consequence of social, economic and lifestyle-related changes. However, the increase in cancer incidence can not only be attributed to these factors, but also to the spread of carcinogenic substances in the professional and general environment (Fidler et al., 2018; Parrón et al., 2014). An increasing body of epidemiological, molecular biological and toxicological evidence has shown that exposure to various environmental pollutants, including pesticides used in agriculture, commercially and in the home or garden, is associated with increasing incidence of cancer. Exposure to certain pesticides, along with other chemical exposures, lifestyle factors, and genetic factors, can increase cancer risk (Alavanja et al., 2013; Parrón et al., 2014). The risk of developing cancer does not only exist in people who apply pesticides, but under certain conditions also in those who are in the vicinity of the pesticide application (Alavanja et al., 2013).

The International Agency for Research on Cancer (IARC) has reviewed the carcinogenicity of various pesticides. Of these, lindane and pentachlorophenol were assigned to group 1 and thus classified as carcinogenic. The insecticides dichlorodiphenyltrichloroethane (DDT), aldrin, dieldrin, diazinon, malathion and the herbicide glyphosate are placed in group 2A and are therefore probably carcinogenic for humans. Parathion, chlordane, 2,4,6-trichlorophenol (TCP), chlordecone, heptachlor, hexachlorocylcohexane (HCH), hexachlorobenzene (HCB), mirex and toxaphene belong to group 2B and are possibly carcinogenic to humans. Endrin and methoxychlor, which were classified in group 3, cannot be classified with regard to a carcinogenic effect in humans (Guyton et al., 2015; Adnan et al., 2018).

Pesticides are likely to cause cancer through a number of different mechanisms, although these have not yet been fully understood. The risk of cancer does not appear to be limited to a functional group of pesticides (e.g. insecticides) or the chemical class (e.g. organochlorine pesticides). Direct genotoxicity is believed to be an important mechanism for promoting cancer. However, non-genotoxic mechanisms also appear to be involved in this process. The genetic susceptibility to the carcinogenic effects of some pesticides can also be an important part of the disease mechanism (Alavanja et al., 2013).

The three most common types of cancer in adults (lung, breast and prostate cancer) and childhood leukemia, which is the most common cancer in children, are described in more detail below, and the relationship to exposure to pesticides is explained.

3.3.1 Lung Cancer

Globally, lung cancer is the most common cancer with 2.1 million new cases and the leading cause of death from cancer with approximately 1.8 million deaths in 2018. This means that about 1 in 5 cancer deaths (18.4%) occur Lung cancer (Bray et al., 2018). By 2035, the number of deaths from lung cancer is expected to rise to 3 million worldwide. The reasons for this increase include the aging of the population in industrialized countries, an increasing prevalence of cigarette consumption and higher life expectancy in less developed countries (Didkowska et al., 2016).

Lung cancer does not become clinically visible until it has reached an advanced stage. More than 75% of lung cancer cases are diagnosed when the disease has progressed or has metastasized. Since only 1 in 10 lung cancer patients survives the next 5 years, the prognosis for the disease is very poor (Shankar et al., 2019). Lung cancer is particularly common in North America (especially dark-skinned people) and New Zealand (especially Maori). The disease often affects people in the UK, Europe and Australia as well. In contrast, the disease is most rarely diagnosed in West and East Africa. The age at diagnosis is rarely less than 40 years. On the other hand, an increase in the incidence can be observed with increasing age. Lung cancer is diagnosed on average between the ages of 65 and 70 years. It can also be observed that lung cancer is more common in the lower than the upper classes of society. The reason for this is possibly the more frequent cigarette consumption in the lower social classes (Aigner et al., 2016a).

Lung cancer development is a multifactorial process (Luqman et al., 2014). In western countries, more than 85% of all lung cancer cases result from the consumption of cigarettes (Alavanja and Bonner, 2012). However, the incidence of lung cancer in non-smokers is also increasing, suggesting that lung cancer in non-smokers is caused by genetic, familial and social factors, as well as various environmental risk factors such as lifestyle, diet and occupational exposure. Epidemiological evidence shows a connection between lung cancer and exposure to non-occupational and occupational pollutants. The main occupational exposures occur with workers who are involved in the smelting and refining of metals, the production of pesticides, pigments, dyes, glass, semiconductors, wood / cotton products and various pharmaceutical substances (Luqman et al., 2014). The non-occupational exposures mostly occur through passive smoking, pollution of the outside air and living near industrial emission sources, asbestos, pollution of the inside air, arsenic and chlorinated by-products in drinking water, dioxins and electromagnetic fields (Luqman et al., 2014; Shankar et al., 2019). In addition, there is clear evidence that exposure to harmful pesticides or aflatoxins in the home or work environment can promote the development of cancer. Agricultural and public health workers can be exposed to harmful pesticides during handling, dilution and application. During use, exposure mainly takes place via the skin and the respiratory tract (Shankar et al., 2019).

Compared to the general population, farmers smoke less and usually develop lung cancer significantly less often (Alavanja and Bonner, 2012). Nonetheless, increasing mortality from lung cancer has been reported among licensed pesticide applicators.In light of this, there is a possibility that exposure to certain pesticides may increase the risk of lung cancer in farmers (Bonner et al., 2016).

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1 The odds ratio is used as a comparative measure in case-control studies and cross-sectional studies. A comparison is made between cases that suffer from the disease to be examined and controls that are not affected by the disease. There is a retrospective recording. In order to be able to conclude that the observed effect is statistically significant, the confidence interval must also be taken into account. The odds ratio is calculated using the following formula (ressing et al., 2010):

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2 The hazard ratio is a quotient of the hazards of two groups. It shows how much higher the death rate in one group is compared to the death rate in the other group. It serves as a descriptive measure to be able to compare the survival times between two different groups (Zwiener et al., 2011).

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