Classification of EDCs based on Danish criteria
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-partners-with-ehs-for-digital-advertising-representation-20210416",title:"IntechOpen Partners with EHS for Digital Advertising Representation"},{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"}]},book:{item:{type:"book",id:"2261",leadTitle:null,fullTitle:"Entrepreneurship - Born, Made and Educated",title:"Entrepreneurship",subtitle:"Born, Made and Educated",reviewType:"peer-reviewed",abstract:"Entrepreneurship has a tremendous impact on the economic development of a country. 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This lifelong infection suggests that herpesviruses have critical features to evade immunosurveillance. The knowledge about herpesvirus molecular genetics has been critical to design new therapies based on Herpes simplex vectors.
\r\n\r\n\tThis book summarizes the main aspects of Herpesviruses infection, the key molecular mechanisms associated to latency and reactivation, mechanism related to immune evasion, immunosuppression and cellular stress, the contribution of herpesvirus (Herpes simplex type 1, Human herpevirus 6) to the neurodegenerative disease and autoimmunity, development of new drugs and vaccines against Herpesviruses, and development of gene therapy against cancer based on herpes simplex vectors.
\r\n\t
The incidence of diabetes and associated metabolic disorders has tripled over recent decades and continues to rise at an alarming rate. Currently, 382 million individuals worldwide are estimated to have diabetes and this number is believed to increase to 592 million by 2035 [1]; the vast majority of the cases is type 2 diabetes mellitus (T2DM).
Taking into account the number of patients impacted by T2DM and its long-term consequences in terms of morbidity, mortality and economic costs, there is considerable interest in understanding the contribution of non-traditional risk factors to the diabetes epidemic, especially concerning environmental chemicals and particularly endocrine-disrupting chemicals (EDCs).
Researches addressing the role of environmental chemicals in the development of metabolic disorders, like obesity and T2DM, have rapidly expanded. Epidemiological and experimental evidence suggest an association between exposure to EDCs and T2DM, especially since the exposure to chemicals increased massively in the last decade.
In this chapter we tried to elucidate the following issues: (1) the concept of EDCs; (2) human exposure to EDCs; (3) particular concepts related to EDCs; (4) mechanisms of EDCs action involved in the development of T2DM; (5) evidence of T2DM in animal models; (6) epidemiological data linking EDCs exposure to T2DM and (7) challenges in EDCs research.
Originally articulated in the early 1990s by Colbron [2], the theory of
Various attempts to set up a scientific definition of an EDC have been made. Today is generally wide acceptance of using the WHO definition [6], which is similar with the EU definition [7]: „
EDCs interfere and disrupt physiological hormonal balance inducing adverse effects on human health through different mechanisms including direct interaction with hormone receptors, competition on binding and transport proteins or interference with hormone metabolism (blocking or inducing the synthesis of the hormones). Starting from this definition there are clearly two requirements for a substance to be defined as an EDCs, namely the demonstration of an adverse effect and an endocrine disruption mode-of-action. Additionally, the definition implies proof of causality between the observed adverse effect and the endocrine disruption mode-of-action.
It is important to underline that the definition of EDC includes the term “adverse” which was considered as a key criterion to differentiate a genuine EDC from a mere endocrine modulator (that elicits an adaptative reversible response in endocrine homeostasis). According to WHO the term “adversity” means: “
This definition is not covering the potential or indicates EDC. A potential (or suspected) EDC may alter function(s) of the endocrine system and consequently may cause adverse health effects, while a substance with indication of endocrine disrupting properties (called indicated EDC) might be expected to lead to endocrine disruption in an intact organism, or its progeny, or (sub)populations.
The need for an expansion of the general term to potential EDCs is reflected on the new Guidance document on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption (OECD 2011) [9]: “
Recently, the Endocrine Society published a statement of principles on endocrine disruptors [10] in which another definition of an EDC has been proposed:
A wide variety of chemicals act as EDCs. The Endocrine Disruption Exchange List (TEDX) to date lists almost 1000 endocrine disruptors [11]. The group of EDCs is highly heterogeneous and includes synthetic chemicals used as industrial solvents/lubricants and their by-products (persistent organic pollutants – POPs, dioxins like 2,3,7,8-tetrachlorodibenzo-p-dioxin – TCDD), plastics (bisphenol A – BPA), pesticides (as dichlorodiphenyltrichloroethane – DDT), plasticizers (phthalates like diethylhexyl phthalate – DEHP), heavy metals (arsenic, cadmium), tributyl tin (TBT), fungicides (vinclozolin) and pharmaceutical agents (diethylstilbestrol – DES). POPs comprise a broad class of organohalides, including polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs) and organochlorine pesticides.
However, one should keep in mind that there is also a large number of EDCs of natural origin occurring in plants consumed as food and also some secondary metabolites from fungi that may contaminate food. Examples of EDCs with oestrogenic activity are present in soy (e.g. genistein and daidzein), mycotoxins in cereals (e.g. zearalenone), goitrogens in cabbage (with the potential to inhibit iodine uptake) and glycirrhizine in liquorice (with the potential to disturb the mineralocorticoid system) [12].
EDCs are widely dispersed in the environment. Some are persistent, having long half-lives [13], while others are rapidly degraded in the environment or human body or may be present for only short periods of time but at critical periods of development, considered windows of susceptibility.
The effects of EDCs are observed especially on sensitive groups (foetus and child), based on their susceptibility to hormonal effects [14]. Therefore, for these groups the adverse effects may occur at concentrations that are far below levels that would be considered harmful in the adult [15]
Of a special concern are EDCs such as phthalates [16], PBBs [17] and BPA, detected in pregnant women, fetuses and newborns, taking into account that exposure occuring early in pregnancy can have short-term health effects, while exposure later or during early childhood may induce cognitive and developmental deficiencies [18].
Published studies illustrate that
Actually, is considered that
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t|
• | \n\t\t\t• • On a case-by-case basis, • In special cases, categorization or QSAR approaches may provide the necessary data in combination with • Reliable and good quality evidence from human cases or epidemiological studies | \n\t\t
\n\t\t\t\t | \n\t\t|
• or • | \n\t\t\t• • • In some cases, read across, chemical categorization and/or QSAR approaches may provide the necessary data in combination with • Good quality epidemiological studies showing associations between exposure and adverse human health effects related to endocrine systems. | \n\t\t
\n\t\t\t\t | \n\t\t|
• | \n\t\t\t• • QSAR, read-across, chemical categorization, ADME information (OECD, CF level 2) • System biology methods indicating associations between the substance and adverse human health effects related to endocrine systems. | \n\t\t
Classification of EDCs based on Danish criteria
Many other chemicals have also been implicated in promoting toxicity for multiple generations, including BPA [24] or pesticides [25], but in these cases the multigenerational effects involved direct exposures, therefore are not considered transgenerational because they are not transmitted solely through the germ cells. Only effects appearing in the F3 generation are considered to be truly transgenerational [26].
There are multiple classifications of EDCs, based on their mechanisms of action (on enzymes, transport proteins or receptors), the pathways modulated (e.g., xenoestrogens/antiestrogens, xenoandrogens/antiandrogens), or the biological outcomes (simulation or inhibition) [27]. However, the best classification is the Danish criteria, based on available data (
Environmental human exposure occurs through a variety of routes and varies widely around the world. Food ingestion represents the major route by which people are exposed to EDCs. For example, diet is thought to account for up to 90% of a person’s POPs body burden [31]. Taking into account that these pollutants are accumulated particularly in highly rank predators, like fish, in Sweden, consumption of fatty fish from the Baltic Sea is the major source of POPs, but also dairy products and meat contain these pollutants [32]. Also contaminated ground water is a major exposure source to inorganic arsenic in the general adult population in several regions, notably Bangladesh and India [33,34].
Regarding BPA exposure, small amounts of BPA can migrate from polymers to food or water, especially when heated. The human consumption of BPA from epoxy-lined food cans alone is estimated to be about 6.6 μg per person per day [35]. BPA has been found in concentrations of 1–10 ng/ml in serum of pregnant women, in the amniotic fluid of their fetus, and in cord serum taken at birth [36]. Moreover, BPA concentrations up to 100 ng/g were reported in placenta [37], but also in breast adipose tissue, taking into account its lipophilicity.
With the increase in household products containing pollutants and the decrease in the quality of building ventilation, indoor air has become a significant source of EDCs exposure, via inhalation [38]. Published studies [39,40] suggest that contaminated house dust may be the major source of PBBs body burden (up to 82%).
Other routes of exposure include the dermal contact (e.g. parabens or triclosan), via lactation or infants fed formula (especially for phytoestrogens as genistein or BHA). A published study [41] reported that urinary concentrations of genistein and daidzein were about 500-fold higher in infants fed with soy formula compared with those fed cow’s milk formula.
For decades, two major interrelated concepts are particularly addressed regarding EDCs: the low dose effect and non-monotonous dose–response relationships (e.g. “inverted U-shapes” of the dose–response curve).
Like hormones, some of EDCs act at low or very low doses, other variable, therefore their blood levels are not reflecting the real activity [42].
The traditional toxicological endpoints are not sufficient to preclude the adverse outcome. Therefore for the endocrine-sensitive endpoints it was suggested to set the NOAEL (no observed adverse effect level) or the LOAEL (lowest observed adverse effect level) from traditional toxicological studies or even below the range of human exposures, as the highest dose in experiments designed to test EDCs. For example, low-dose effects of BPA should be investigated in rodents exposed to 400 µg/kg bw/day BPA or lower, because this concentration produces levels of unconjugated BPA in the range of human blood concentrations [43]; this level is incomparable lower with the classical developmental studies, where LOAEL corresponds to 50 mg/kg bw/day [44]. Actually, most effects were seen at doses below 50 μg/kg [43], so even lower concentration than those normally detected in humans may induce adverse effects.
The effect of EDCs also depends on the type of tissue and the expression of hormone receptors on those cells, therefore the effect is considered to be tissue specific. Taking into account that some EDCs can exhibit different potencies on different receptors isoforms (e.g ERα or ERβ), the effect is also receptor-selective.
A well-known example is related to methyl-and propylparaben.
By comparison with native hormones, EDCs exhibits lower affinity for hormone receptors, with some exceptions, such as TBT, which is the most potent agonist of retinoid-X-receptor and PPARγ (peroxisome proliferator activating receptor subtype gamma) in the low nanomolar range [49].
The shape of the dose-response curve for EDCs does not follow the usual dose-response curve. The curve can have a sigmoidal shape (relationship between dose and effect occure based on the saturability of the receptors), but in general EDCs do act via a non-monotonic dose-response relationship [43]. In this case, the slope of the curve changes sign somewhere within the range of the examined doses. In other words, some effects can be seen at very low doses, while slightly higher doses can show no effects and then, at high doses, some different types of effects may be found.
For example, hypoglycaemic or hyperglycaemic effects of TCDD (tetrachlorodibenzo-p-dioxin) observed in animal models are dose-dependent. Repeated low-dose of TCDD (500 ng/kg p.o.) reduced glucokinase gene expression in mice [50], while higher dosage (12.8 µg/kg TCDD p.o) induced a significantly reduction of serum glucose levels [51]. Moreover, a higher dose of TCDD (116 µg/kg i.p.) impaired insulin-stimulated glucose uptake in mice [52].
Another example is BPA. On isolated pancreatic islets of Langerhans BPA induced an increase of insulin content following an inverted U-shape dose response curve, with a significant effect observed at 1 nM and 10 nM BPA compared to vehicle. Higher concentrations of BPA (1 µM) produced no increase in insulin content [53].
A similar non-monotonic behaviour is exhibited by BPA in animal studies where treatment with high dosage (BPA 100 µg/kg bw/day) twice per day for 4 days increased pancreatic insulin content, produced hyperinsulinemia, and induced insulin resistance in adult male mice [54] while sustained exposure of pregnant mouse dams to lower levels of BPA (10 µg/kg bw/day) from gestation day 9–16 impaired glucose tolerance, increased plasma insulin, triglycerides and leptin concentrations, thus revealing the ability of BPA to alter pancreatic function and metabolic parameters [55].
Also PBBs, especially PBDE-153 (polybrominated diphenyl ether) showed an inverted U-shaped association with metabolic syndrome in epidemiological study in humans [56].
So, the most important effects of EDCs observed in animal models are those that occur at low doses, similar with the level of human environmental exposure, therefore only these toxicological data should be corroborated with epidemiological studies.
We also should note that for the assessment of EDCs effects, the assumption of an experimental threshold (like a NOAEL) is questionable. A first reason is related to the lack of adversity for some endpoints investigated (e.g., uterotrophic assay). A second reason is connected with the difficulties to establish it. According to Blair et al. [57], a threshold could be established in the absence of endogenous hormone at some life stage, if the endogenous hormone induces no adverse effect or if there is effective homeostatic control. Even if a threshold does exist, for a certain endpoint, taking into account the population variability and the connection with already ongoing biological process (EDCs exhibit additive effects), the threshold will not be observable.
In addition to the classical pathway modulated by EDCs (as interaction with aryl hydrocarbon receptor (AhR) or nuclear hormone receptors, in particular estrogens, androgens and thyroid receptors), it was observed that EDCs exhibit the capacity to modulate signalling pathways involved in energy regulation, in general, and glucose homeostasis in particular. EDCs can decrease insulin sensitivity, impair β-cell insulin production, impair cellular insulin action or alter the intermediary metabolism. All these mechanisms contribute to the pathogenesis of T2DM. Experimental data revealed that one EDC acts on different levels and receptors, therefore the ultimate effect on insulin action may be the result of all pathways involved (Table 2).
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t(+)ERα via ERK1/2 | \n\t\t\t|
(+) ER-GPR30 | \n\t | \n|
| \n | \n|
| \n||
Potent antagonist of PPARγ (-) PDI | \n\t||
\n\t\t \n\t\t | \n\t(+) AhR | \n\t|
(+) MAPK1/2 (+) CaMK2 | \n\t(-) IRS-1 phosphorylation | \n|
(-)Akt phosphorilation | \n\tInsulin resistance | \n|
| \n | \n
Example of EDC that acts on multiple pathways
Legend: (+) activate; (-) inhibit;
Interestingly, some EDCs such as TCDD [58], PCBs [59], inorganic arsenic [60] or cadmium [61] that modulate β-cell function, may also play a role in type 1 diabetes mellitus, as a result of β-cell destruction or dysfunction as well as promotion of β-cell death.
The following mechanisms of action can explain the development of T2DM: (1) activation of aryl hydrocarbon receptor (AhR) or interaction with estrogenic receptors (ERs); (2) β-cell dysfunction and impairment of insulin secretion; (3) impairment of cellular insulin action and (4) alteration of the intermediary metabolism.
EDCs can exhibit their metabolic effects through the classical pathways, such as the activation of AhR or the interaction with ERs. It is well known that AhRs are involved in the glucose homeostasis [50], therefore activation of AhR or its heterodimerization partner, called ARNT (AhR nuclear translocator) by EDCs could interfere with glucose uptake. Gunton et al. [62] revealed that abnormal ARNT expression causes impaired insulin release in human islets, but it is unclear if this effect is a cause or a consequence of T2DM.
PCBs [63] or PBDE [64] reduce primary hepatocyte glycogen levels and impair gluconeogenesis due to a specific down regulation of phosphoenolpyruvate carboxykinase (PEPCK) expression, a central regulator of gluconeogenesis. The alteration of PEPCK expression was proportional to activation of the AhR, suggesting a direct correlation between AhR activation and perturbation in intermediary metabolism.
PCBs (especially PCB-77) also impaired glucose homeostasis through another AhR-dependent mechanism, associated with an adipose-specific increase in TNF-α (tumor necrosis factor-α) expression and interleukin-6 (IL-6) levels [65, 66]. In addition to its effects on TNF-α and IL-6, PCB-77 also increases expression of MCP-1 (monocyte chemoattractant protein-1), an adipocyte-secreted molecule with inflammatory function that contributes to global insulin sensitivity [67].
The implication of estrogenic receptors (especially ERα) in the pancreatic β-cell insulin content is confirmed by BPA studies. At physiologically relevant doses, BPA increases pancreatic β-cell insulin content, the effect being mediated by ERα activation via extracellular regulated kinase1/2 (ERK1/2) [53]. ERα is also implicated in β-cell survival [68], regulates the glucose transporter (GLUT4) in skeletal muscle [69] and insulin sensitivity in the liver [70]
Also the non-classical membrane G protein related estrogen-receptor (ER-GPR30), expressed in pancreatic islets is involved in the effects of estrogens on glucose metabolism, its deficiency inducing hyperglycemia, impaired glucose tolerance, and elevated blood pressure [71]. GPR30 activation by several EDCs, e.g. BPA could partly contribute to the increase of insulin after BPA exposure [72]
Taking into account their reduced capacity to fight against chronic oxidative stress and the lack of detoxification mechanisms, β-cells are the perfect target for EDCs that disrupt their structure and function or promote death.
Oxidative stress is the mechanism implicated in T2DM induced by exposure to inorganic arsenic. At relatively low concentrations arsenic-induced oxidative stress produces impairment of glucose-stimulated insulin secretion [73], while exposure to high concentrations results in irreversible damage (including oxidative damage) to β-cells followed by apoptosis or necrosis [74]. Actually, the mechanism behind arsenic-induced oxidative stress is more complex. Chronic exposure to relative low concentration of arsenite (1–2 μM) produced an adaptive response, activating the transcription factor NF-E2–related factor 2 (Nrf2). Even if Nrf2 is generally considered a protective cellular component that induces antioxidant / detoxification enzymes [73], in this case Nrf2 activation that diminishes the reactive oxygen species (ROS) have a negative impact on insulin secretion. In normal cells, ROS signals produced during glucose metabolism increase the insulin secretion [75], thefore arsenic Nrf2-mediated response appears to play an important role in reduced glucose-stimulated insulin secretion. Inorganic arsenic also promotes β-cell apoptosis via induction of endoplasmic reticulum stress, but this mechanism is poorly studied and necessitates further investigations [76].
Regarding the interference and impairment of insulin secretion, different examples can be provided, especially taking into account that insulin secretion is a calcium-dependent process. On isolated pancreatic β-cells BPA at low concentration (10-9 M) increases the phosphorylation of CREB (transcription factor cyclic adenosine monophosphate-response element-binding protein) via an alternative mechanism, involving a non-classical membrane estrogen receptor [77], which provokes the closure of K+/ATP channels. As a result the plasma membrane depolarizes, opening the L-type voltage-dependent calcium channels and increasing intracellular calcium ion levels [Ca2+]i and triggering insulin secretion [78].
Also abnormal levels of [Ca2+]i and the impairment of insulin secretion were observed on isolated islet cells exposed to TBT and are associated with the disruption of protein-kinase A activity [79].
PCB treatment of RINm5F cells resulted in a rapid increase of [Ca2+]i as a result of Ca2+/calmodulin-dependent kinase II (CaMK2) and mitogen-activated protein kinase 1 and 2 (MAPK 1 and 2) activation [80]. In addition, RINm5F cells exposed to inorganic arsenic (III) exhibited a reduction of insulin secretion as a result of decreased calcium-dependent calpain-10 activity, a pathway that triggers insulin exocytosis [81]. Arsenic also reduces the β-cell line proliferation in a dose-dependent manner, as an indirect consequence of the decrease in insulin secretion.
Taking into account that insulin signalling mechanisms are described in detail elsewhere [82], we present only a short analysis of the insulin signalling cascade in order to provide some insights into how EDCs might modulate insulin action.
Insulin acts on target cells and stimulates glucose uptake via membrane –bound tertrametric insulin receptor (IR) with tyrosine kinase activity. Binding to extracellular α-subunits of IR leads to activation of tyrosine kinase. Once the tyrosine kinase of IR is activated, it promotes autophosphorylation of the β subunit, where phosphorylation of three tyrosine residues (Tyr-1158, Tyr-1162, and Tyr-1163) is required for amplification of the kinase activity. Then tyrosine kinase phosphorylates the insulin receptor substrate proteins (IRS 1 and 2) and phosphotyrosine residues on IRS proteins become targets for the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase).
The activated PI3-kinase generates higher levels of phosphotidylinositides, such as phosphatidyl-inositol-3,4-bisphosphate (PIP2) and phosphatidyl-inositol-3,4,5-trisphosphate (PIP3), which bind to the phosphoinositidedependent kinase-1 (PDK1). PDK1 can directly phosphorylate all protein kinase C (PKCs).
Downstream from PI3-kinase, activation of Akt (protein kinase B) produces its effects, including those on gene transcription as well as glucose uptake through the translocation of facilitative glucose transporter 4 (GLUT4) to the cell membrane.
Each step in this signaling cascade is a potential target for EDCs. EDCs interact and impair the cellular insulin effect acting at different levels: on IRS, PI3-kinase, Akt, PDK or PKC or through associated mechanisms. Some examples are included in figure 1.
A schematic illustration of EDCs interference on insulin signaling pathways. Arrows represent an activation process; X represent an inhibition process
For example, TCDD, arsenic or PCB alter IRS activity (especially IRS-1 phosphorylation) through different mechanisms: TCDD increasing MAPK (mitogen-activated protein kinase) activity and JNK (c-Jun N-terminal kinase) activity [83], arsenic decreasing p70-S6-kinase activity [84] and PCBs increasing CaMK2 and MAPK 1 and 2 activity [80].
Other EDCs act on insulin-stimulated Akt phosphorylation. Akt phosphorylation is attenuated by PCB-77 [65] or BPA [55]. Arsenic (III) exposure was also associated with suppression of AkT phosphorylation and glucose uptake in 3T3-L1 adipocytes, causing an insulin resistant phenotype [85,86].
BPA acts not only on Akt phosphorylation, but also stimulates tyrosine phosphorylation via PI3-kinase, the global effect being the impairment of IRS activity [87].
Additional studies have demonstrated that TCDD [83], BPA [88] or DEHP [89] are modulating the insulin signalling cascade by down-regulation of the insulin receptors or acting on plasma membrane GLUT4 level and antagonizing insulin action [90].
Also, cadmium induces impaired glucose tolerance by down-regulating GLUT4 expression in adipocytes [91].
Inorganic arsenic (III) inhibits PDK-1 activity, thus suppressing PDK-1-catalyzed phosphorylation of PKB/Akt and p-PKB/Akt–mediated translocation of GLUT4 transporters to the plasma membrane [85,92].
In addition to direct effects on the insulin signalling cascade, EDCs alter the intermediary metabolism, mainly the gluconeogenesis. TCDD [63], or PCBs [93] have been shown to down-regulate the expression of phosphoenolpyruvate carboxykinase (PEPCK), reducing its activity and inducing hypoglicemia. In the case of PCBs, the suppression of hepatic PEPCK expression was proportional to activation of the AhR, suggesting a direct correlation between AhR activation and perturbation of the intermediary metabolism.
Alternative mechanisms are implicated in the development of T2DM, such as inflammation or oxidative stress. For example, PCB-77 has been shown to promote expression of IL-6 and TNF-α, leading to impaired insulin signalling in endothelial cells [64]. In addition to its effects on TNF-α and IL-6, PCB-77 also increases expression of MCP-1, adipocyte-secreted molecule that contributes to global insulin sensitivity [66].
BPA augments secretion of IL-6 and TNF-α, but simultaneously inhibits the release of adiponectin in human adipose tissue explants [94]. The suppression of adiponectin release could promote insulin resistance and increase the risk of developing the metabolic syndrome. The same outcome is expected based on elevated IL-6 levels.
We should highlight the strong correlation between increased TNFα production and insulin resistance [95]. TNFα affects insulin resistance by downregulating the glucose transporter, interfering with IR phosphorylation and signaling, and by inhibiting transcription factors that affect insulin sensitivity.
Some EDCs are acting on other nuclear receptors involved in fat metabolism and regulation of glucose uptake, like PPARs (peroxisome proliferator-activated receptors), especially on PPARγ which are involved in the regulation of adipocyte differentiation, production of adipokines or insulin responsiveness [96]. By antagonizing PPARγ, EDCs significantly inhibit the release of adiponectin that has insulin-sensitizing effects, as it enhances inhibition of hepatic glucose output as well as glucose uptake and utilization in fat and muscle tissues. So, adiponectin levels are correlated with insulin sensitivity, therefore supressing its biological effects affects glucose homeostasis.
For example, BPA at 0.1 and 1 nM doses is a potent antagonist of PPARγ, which suppresses adiponectin release in human adipose tissue explants [97]. In the same time, BPA influences adiponectin level via another mechanism that implies binding to protein disulfide isomerase (PDI), a critical player in the retention of adiponectin in cells [98]
Interestingly,
Other EDCs such as phthalates (DEHP) act as potent agonists of PPARα or PPARγ. In rodent models, PPARα appears to mediate high-dose DEHP-induced body weight loss [101], but these effects can not be extrapolated to humans, taking into account that the levels required to activate human PPARα are almost three times higher than the concentrations required to activate mouse PPARα, and the maximum-fold induction is less for human PPARα than for mouse PPARα [102].
In conclusion, the investigation of insulin signaling pathways may explain how EDCs modulate insulin action, especially in the case of exposure to singular compound; however, in the context of accidental or occupational exposures, humans are exposed to mixtures of compounds and this complicates understanding the global biological effects. For example, if different compounds are acting through the same pathway, but at different points, co-exposure is likely to have additive or synergistic effects that promote the development of insulin resistance and T2DM. Moreover, points of pathway convergence (e.g., IRS) might be the perfect target of drug intervention to treat environmentally-mediated diabetes.
There are enough published data in animal models that investigated the correlation between EDCs exposure and T2DM. This correlation between exposure in the animal models and alterations in glucose homeostasis, including hyperglycemia and glucose intolerance is crucial, taking into account that epidemiological studies fail to establish a causality.
A number of examples are given below.
Repeated low dose of TCDD (500 ng/kg bw), administered orally, reduced glucokinase gene expression, predicting a rise in blood glucose levels on C57BL/6 mice [103], while in diabetic rats, a higher dose of 12.8 µg/kg bw TCDD had significantly reduced serum glucose levels by day 8 of treatment [51]. Moreover, a single but high dose of TCDD (116 µg/kg bw i.p.) impaired insulin-stimulated glucose uptake in C57BL/6 and DBA/2J mice [52].
Administration of 75 µg/kg bw DEHP for 14 days reduced insulin levels and raised serum glucose levels in exposed female Wistar Kyoto rats [104]. Almost similar results were obtained on male rats treated for a longer period (21 days) with diet supplemented with 2% (w/w) of DEHP [105].
Male mice treated orally with 0.5-50 µg/kg bw TBT for 45 days demonstrated hepatic steatosis, hyperinsulinemia, hyperleptinemia and a reduction in hepatic adiponectin levels, in a dose-dependent fashion, confirming PPARγ stimulation observed
Similar results were obtained in adult Sprague-Dawley rats exposed for 28 days to crude salmon oil containing POPs [107]. The animals developed insulin resistance syndrome, abdominal obesity and hepatosteatosis, the contribution of POPs to insulin resistance being confirmed also by the same authors in cultured adipocytes. These findings are important since POPs are accumulating in the lipid fraction of fish, and fish consumption represents the main source of POP exposure to humans.
Also coplanar PCBs (e.g. PCB-77 and PCB-126), at dosage of 50 mg/kg orally, impaired glucose homeostasis in lean C57BL/6 mice and mitigate beneficial effects of weight loss on glucose homeostasis in obese mice [66], while inorganic arsenic (III) administered in the drinking water for 20 weeks, at doses of 25 or 50 ppm As/kg bw/day, impaired glucose tolerance in C57BL/6 mice in a dose-dependent manner [108].
In the animal studies mentioned before, not just blood glucose levels were investigated, but other markers of insulin regulation, such as HOMA-IR, pancreatic production of NO, SOD and CAT activity, in order to reflect the magnitude of the global disturbance. While most studies have demonstrated perturbations in insulin action, some of them have shown improved glucose tolerance or even hypoglycaemia. Acute exposure of adult male mice to high dosage of BPA (100 µg/kg bw/day) produced a rapid hyperinsulinemia based on significant increase in β-cell insulin content, as a direct result of BPA estrogenic properties [109], while sustained exposure to lower dosage (10 µg /kg bw/day) impaired glucose tolerance and reduced the hypoglycaemic effect of insulin, through a compensatory peripheral insulin resistance [54]. These results are easily correlated with non-monotonic dose response curve exhibited
Taking into account that EDCs alter glucose homeostasis and endocrine pancreatic function not just in adult animals but also during pregnancy or in offspring, these effects were also investigated in pregnant animals. For example, prenatal exposure to high dosage of diisobutyl phthalate (600 mg/kg bw/day) from gestation Day 7 to Day 21 reduced plasma leptin and insulin levels in male and female offspring, complementary to sexual distrurbance [110]. Maternal glucose intolerance was observed in pregnant mice exposed to inorganic arsenic (V) at dosage of 9.6 mg/kg bw, this explaining the neural tube defects induced by arsenate [111].
In conclusion, all these examples regarding
There is growing concern in the scientific community that EDCs may be contributing to the high incidence of diabetes, particularly in young people.
Epidemiological studies (as occupational or population-based studies) but also disasters tried to link, at least partially, the environmental exposure to EDCs with the development of T2DM.
We collected and compiled from a comprehensive scientific literature the most relevant epidemiological studies concerning the T2DM and exposure to EDCs like TCDD, arsenic, phthalates or BPA.
Disasters such as Seveso accident or exposure of military personnel during the Vietnam War and follow-up studies have suggested a link between TCDD exposure and a higher incidence of diabetes [112, 113, 114]. Other cross-sectional studies [115, 116] did not revealed such correlation, while longitudinal studies that have been conducted are inconsistent [117].
Some poisoning cases reported during late 1970s have involved contaminated rice oil with PCBs. PCB exposure was associated with an increased prevalence of diabetes in women [118]. Other prospective studies on PCB153 showed a positive association with T2DM, but taking into account the variation across studies, it did not allow a metaanalysis. For example, five studies used different diagnostic strategies and several approaches to address serum lipid levels [119]. In addition, the age varied between cohorts from 18 to 30 years [119] to 70 years [120] while gender was also inconsistent, exclusively female in one study [121], exclusively male in another [119] and mixed in the remaining studies [120; 122, 123]. The temporal and geographic variation among the studies induced significant differences in the exposure assessment especially on duration of exposures or on the composition of the mixtures. However, other variables must be considered in the interpretation of PCBs studies, such as the use of PCB153 as a surrogate for total PCBs or the lack of data regarding kinetics of different PCBs (especially on accumulation) that influence their current serum levels.
A closer evaluation of the cohorts described before revealed the non-monotonic exposure-response relationships exhibited by PCBs: the risk of diabetes was significantly increased with small increases within the lower ranges of PCBs concentrations, but only slightly increased with significant increases in concentrations of PCBs. This non-monotonic relationship exhibited by PCBs in cohorts was also observed in brominated flame retardants studies, like those conducted on PBDE-153 [124], but not in BPA cohorts, where BPA urinary levels were associated with diabetes incidence in a dose-dependent manner [125].
Evaluation of studies conducted on EDCs (PCBs or TCDD) reveal that many of them focused specific populations (e.g. occupational studies or exposure through industrial accidents or disasters), so they might not reflect the actual risk of the general population. However, recent investigations were done on representative sampling of the US population, using data from the National Health and Nutrition Examination Survey (NHANES). For example, Lee et al. [126] reported strong and highly significant associations, among participants in the NAHNES study, between serum concentrations of POPs and the HOMA-IR insulin resistance values, after correction for age, sex, BMI, and waist circumference.
\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t \n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t
\n\t\t\t | \n\t\t\n\t | ||||
Cross-sectional [male 225 nonsmokers 209 smokers] | \n\t\tSelf-report | \n\t\tIncreased urinary As in nonsmoking diabetics | \n\t\tn.r. | \n\t\tNonsmokers: 5.59 (diabetics) vs. 4.7 (nondiabetics) μg As/L Smokers: 7.27 (diabetics) vs. 5.41 (nondiabetics) μg As/L (urine) | \n\t\t127 | \n\t
Cross-sectional [n=11,319] | \n\t\tSelf-report prior to baseline | \n\t\tadjOR=1.24 (0.82- 1.87) | \n\t\t0.1–864 | \n\t\t41–92 (Q3) vs. 0.1–8 (Q1) μg As/L drinking water, CEI | \n\t\t128 | \n\t
Case–control [n=144 female] | \n\t\tFasting blood glucose, OGTT | \n\t\tIncreased As in urine from diabetics | \n\t\tn.r. | \n\t\t4.13 (diabetics) vs. 1.48 (nondiabetics) μg As/L in urine | \n\t\t129 | \n\t
Retrospective [41,282male 38,722 female] | \n\t\tDeath certificate | \n\t\tMale SMR =1.28 (1.18-1.37) Female SMR =1.27 (1.19- 1.35) | \n\t\t1.27–11.98 | \n\t\t6 counties vs. state μg As/L (drinking water) | \n\t\t130 | \n\t
Case–control [n=87] | \n\t\tNot reported | \n\t\tRR=0.87 (0.5- 1.53) | \n\t\tn.r. | \n\t\t75th vs. 25th percentile μg As/L (urine) | \n\t\t131 | \n\t
Retrospective [n=1,074 deaths] | \n\t\tDeath certificate | \n\t\tRR=1.6 (0.36- 7.16) | \n\t\tn.r. | \n\t\tResidence time within 1.6 km (1 mi): ≥ 10 years vs. < 1 year | \n\t\t132 | \n\t
Cross-sectional [n=235] | \n\t\tHospital records | \n\t\tRR=1.098 (0.98- 1.231) | \n\t\t16–272 | \n\t\t21–272 (range) vs. 16–38 (range) μg As/L (drinking water) | \n\t\t133 | \n\t
Case–control [n=117] | \n\t\tNot reported | \n\t\tRR=1.09 (0.79- 1.49) | \n\t\tn.r. | \n\t\t75th vs. 25th percentile μg As/mL (plasma) | \n\t\t134 | \n\t
Cross-sectional [n=1,185] | \n\t\tSelf-report | \n\t\tadjOR=1.02 (0.49 - 2.15) | \n\t\t0–2,389 | \n\t\t> 10 vs. < 2 μg As/L (well-water) | \n135 | \n
Cross-sectional [n=788] | \n\tFasting blood glucose, self-report, medication | \n\tadjOR=3.58 (1.18- 10.83) | \n\t- | \n\t18 (≥ 80th) vs. 3.5 (≤ 20th percentile) μg As/L (urine) | \n\t136 | \n
Cross-sectional [n=1,279] | \n\tFasting blood glucose, self-report, medication | \n\tadjOR=2.60 (1.12 - 6.03) | \n\t- | \n\t7.4 (80th) vs. 1.6 (20th percentile) μg As/L (urine) | \n\t137 | \n
Cross-sectional [n=795] | \n\tFasting blood glucose, self-report, medication | \n\tadjOR=1.15 (0.53 - 2.50) | \n\t- | \n\t12 (≥ 80th) vs. 2.7 ( ≤ 20th percentile) μg As/L (urine, not adjusted for creatinine) | \n\t138 | \n
\n\t\t | \n\t\n\t\t | \n\t\n\t\t \n\t\t | \n\t\n\t\t | \n\t\n\t\t | \n\t\n\t\t | \n
\n\t\t | \n|||||
Cross-sectional [n=11,319] | \n\tSelf-report prior to baseline | \n\tadjOR=1.11 (0.73- 1.69) | \n\t0.1–864 | \n\t176.2–864 (Q5) vs. 0.1–8 (Q1) μg As/L drinking water, CEI | \n\t134 | \n
Cross-sectional [n=891] | \n\tSelf-report, OGTT, treatment history | \n\tadjOR=10.05 (1.3-77.9) | \n\t700–930 | \n\t≥ 15 vs. 0 ppm-year drinking water, CEI | \n\t141 | \n
Case–control [n=235] | \n\tGlucose, blood | \n\tOR=2.95 (0.954, - 9.279) | \n\t3–875 | \n\t218.1 μg As/L vs. 11.3 μg As/L(mean) | \n\t140 | \n
Cross-sectional [n=1,107] | \n\tSelf-report, OGTT, glucosuria | \n\tadjPR=5.2 (2.5- 10.5) | \n\t10–2,100 | \n\tKeratosis vs. non-keratosis | \n\t141 | \n
Retrospective [n=19,536] | \n\tDeath certificate | \n\tSMR=1.46 (1.28- 1.67) | \n\t250–1,140 | \n\tBlackfoot endemic region vs. national reference | \n\t142 | \n
Prospective [n=446] | \n\tFasting blood glucose, OGTT | \n\tRR=2.1 (1.1- 4.2) | \n\t700–930 | \n\t≥ 17 vs. < 17 mg/L-year As (drinking water, CEI) | \n\t143 | \n
Cross-sectional [n=706,314] | \n\tInsurance claims | \n\tadjOR=2.69 (2.65- 2.73) | \n\t350–1,140 | \n\tEndemic vs. non-endemic region | \n\t144 | \n
Association between arsenic and diabetes
Abbreviations: 95% CI – confidence interval 95%; adjOR-adjusted odds ratio; adjPR-adjusted prevalence ratio; As-arsenic; CEI, cumulative exposure index; OGTT-oral glucose tolerance test; Q-quintile; RR-relative risk; SMR-standardized mortality ratios; n.r. – not reported
The correlation between the level of arsenic in drinking water and the incidence of T2DM was extensively investigated. The published cohorts were categorized based on the level of exposure (table 3) in order to identify the correlation between exposure and critical endpoints. In addition to diabetes, epidemiological studies have associated exposure to arsenic with other measures of disturbed glucose homeostasis, such as glucose tolerance or metabolic syndrome.
Preliminary analysis on the existing human data provide limited support for an association between arsenic and diabetes in populations exposed to relatively high levels (≥ 150 μg As/L in drinking water), but the evidence is insufficient to conclude that exposure to low to moderate level is associated with diabetes. However, a major gap is obvious. The measurement of arsenic in drinking water supplies, which was often used to assess arsenic exposure, is not appropriate to calculate the internal dose, taking into account individual variation in arsenic uptake and metabolism. Also, individual information on the duration and timing of exposure, which is critical, especially for estimating cumulative exposure, are missing.
Regarding phthalates, cohort studies were mainly focused on correlation between exposure and obesity and less on T2DM. However, those found were done on representative sampling of the US population, using data from NHANES. For example, Stahlhut et al. [145] investigated 1,292 adult US male participants in the NHANES 1999–2002 and revealed that urinary concentrations of three phthalate metabolites (mono-n-butyl phthalate, monobenzyl phthalate and monoethylphthalate) were associated with increased insulin resistance, assessed by HOMA-IR. In addition, phthalates levels were associated with increased waist circumference. A similar association between urinary phthalate metabolite concentrations, body mass index and waist circumference was found in another cross-sectional study of NHANES data [146]. However, considering the methodological limitations of the existing data, there is no sufficient evidence to conclude there is a correlation between phthalates and diabetes or obesity.
The epidemiological data on BPA and T2DM is less consistent compared with POPs, but is growing. There are two cross-sectional analyses of NHANES data 2003-2008 that reported a positive associations of BPA exposure (median 2.5 and 1.8 µg/l) with self-reported diagnosis of diabetes [125, 147]. However, these analyses have an important weakness that limits their value: the use of a single spot urine sample collected concurrent with the information on diagnosis of diabetes. The single spot sample reflects only recent BPA exposure, so cannot be extrapolated to longer period (like years or decades) which is relevant for the development of diabetes. Other large cross-sectional studies on BPA in China provide conflicting data [148,149].
A closer evaluation of all epidemiological studies on EDCs reveals some weaknesses, such as the assessment of one compound as a surrogate for total mixture (in case of PCBs), the lack of data regarding kinetics, especially on accumulation in lipid-rich tissues (in case of POPs), limited type of biological material used for direct measurement EDCs (serum or urine) or environmental measurement which is not appropriate to calculate the internal dose (in case of As). Other caveats must be considered in the interpretation of studies, such as heterogeneity in the definition of diabetes or insulin resistance.
There are a number of challenges limiting our understanding of the impact of EDCs on T2DM related to the physical properties of EDCs: the selection of experimental models to assess effects on glucose homeostasis or coexisting risk factors on the exposed individuals included in the epidemiological studies.
The thousands of chemicals released into the environment create the real scenario of human co-exposure and an enormous analytical challenge in the assessment. Sometimes the physical properties of EDCs such as lipophilicity contribute to their accumulation and persistence in human tissues, even after the exposure has terminated. In this case biomonitoring is the key for the assessment of EDCs. Regarding the types of sample used in analysis, these must be expanded beyond urine and serum to lipid-rich organs (e.g., POPs are accumulated in brain and adipose tissue) as well as tissues relevant to
Although environmental and tissue levels of certain EDCs (e.g., PCBs) have declined in some countries in response to EU regulations, they remain of concern in other countries, and uncertainty still exists regarding future trends.
Another important challenge is related with the lack of clear structure-function relationships that excludes a possible
The experimental design is further complicated by non-monotonic dose response correlation, multiple mechanisms of action for a single compound, potential additive, synergistic or antagonistic effects observed during co-exposure or the lack of adversity for some endpoints defined in OECD guideline (e.g. uterotrophic assay).
The main gaps of epidemiological studies were already addressed. Still other factors like geographic and temporal variation among the studies can induce differences in the exposure assessment, especially on the composition of chemical mixtures (especially for POPs) and duration of exposure.
Also inter-individual variation, transgenerational effects or predisposing factors (such as obesity or a family history of diabetes) may influence the metabolic effects observed in the epidemiological studies.
More studies are necessary to establish the exact mechanisms through which EDCs determine impairments of glucose homeostasis; these studies are imperatively important in order to impose international guidelines that will lead to a reduction of the incidence of T2DM cases induced by chemical exposure.
The work has been performed under the Young Investigator Grant (28344/04.11.2013) supported by UMF Carol Davila
A pesticide is any substance which is used to prevent, destroy or repel any pest from causing any damage. The term pest represents any living organism that may cause harm to human in respect to food competition, destruction of property and spread of disease. Pests include insects, rodents, microbes, fungi and weeds (unwanted plants), etc. of agricultural, medical and veterinary importance, and therefore, a pesticide can be an insecticide, an insect and plant growth regulator, a fungicide, an herbicide, a molluscicide, and an algaecide, etc. based on the target pest organism.
The major site of action for most pesticides are the nervous and endocrine systems and, therefore, are also potentially toxic to human with serious direct or indirect adverse health effects. Human beings are exposed to pesticides directly or indirectly. Direct exposure occurs during pesticide application process in agriculture, public health and livestock, and fumigation while indirect exposure involves ingestion of contaminated food and water, and inhalation of pesticides droplets from the drift. Children are more susceptible to pesticides than adults due to their physical makeup, behavior and physiology, and exposure to very low levels at early developmental stages can cause adverse health effects. Codex Alimentarius committee and the Pesticide Data Program of the United States Department of Agriculture have established pesticide maximum residue limits in edible food which must be followed to avoid any health risks.
Pesticide exposures have been linked to the elevated incidence of human diseases such as cancers, Alzheimer, Parkinson, amyotrophic lateral sclerosis, asthma, bronchitis, infertility, birth defects, attention deficit hyperactivity disorder, autism, diabetes, and obesity, respiratory diseases, organ diseases and system failures. People who are exposed to pesticides are at a greater risk to develop various cancers including non-Hodgkin lymphoma (NHL), leukemia, brain tumors, and cancers of the breast, prostate, lung, stomach, colorectal, liver, and the urinary bladder.
Pesticides cause genetic and epigenetic changes by involving various processes at cellular levels. Pesticides may be involved in endocrine disruption and induction of inflammatory signals which result in production of reactive oxygen species (ROS) causing oxidative stress. ROS disrupt the cellular functions of mitochondria and endoplasmic reticulum.
This chapter covers different types, importance and modes of action of pesticides. Human exposure to pesticides and pesticide residues in food are also discussed. Finally, the impacts of pesticide exposure on human health with focus on the major chronic health effects (neurotoxic, genotoxic and carcinogenic, and reproductive effects) and recent findings regarding health effects associated with exposure to common types of pesticides, i.e., organochlorines, organophosphates, carbamates, pyrethroids and neonicotinoids insecticides, fungicides and herbicides are discussed.
Pesticides can be classified based on chemical classes, functional groups, mode of action, and toxicity. The active ingredients of most pesticides are either organic (contain carbon) or inorganic (minerals e.g. copper sulfate, ferrous sulfate, copper, lime, sulfur, etc.). Organic pesticides are hydrophobic and more complex than those of inorganic pesticides. Organic pesticides can be natural (produced from naturally available sources) or synthetic (artificially produced by chemical synthesis in factories). The major types of pesticides used in agriculture, forestry, landscape, medical and veterinary sectors are listed in Table 1.
Type of pesticide | Active ingredient | Target pests |
---|---|---|
Insecticides | Natural and synthetic | Insect (6-legged) pests of agricultural, forestry, landscape, medical and veterinary importance |
Miticides/acaricides | Natural and synthetic | Mites (8-legged) pests of agricultural, forest, landscape, medical and veterinary importance |
Fungicides | Natural and synthetic | Fungal diseases (molds, mildews, rust) of agricultural, forestry and landscape importance |
Herbicides | Natural and synthetic | Unwanted plants (weeds) of agricultural and landscape importance |
Insect growth regulators | Synthetic | Disrupt the growth and reproduction of insect pests. IGR are species or genus specific. |
Pheromones | Natural and synthetic | Attract and trap male insects and are often species-specific. |
Plant growth regulators | Synthetic | Alter plants growth, e.g., induce or delay flowering |
Algaecides | Natural and synthetic | Algae growing on different surfaces, e.g., patios |
Molluscicides | Natural and synthetic | Slugs and snails of agricultural, forestry and landscape importance |
Biopesticides | Natural | Can be insecticides, fungicides or herbicides |
Antimicrobials | Synthetic | Microbes (mostly bacteria) of medical and veterinary importance |
Rodenticides | Natural and synthetic | Rodents (mice, rats) in agriculture, landscape, building, storages and hospitals |
Treated seeds | Synthetic | Seeds coated with an insecticide or fungicide or both to prevent damage from soil insect pests and fungus diseases |
Wood preservatives | Synthetic | Pesticides to protect wood from insect pests, fungus and other diseases |
Minimum risk pesticides | Natural and synthetic | Any pesticides which have been proven safe for human and are exempt from registration by any regulatory authorities |
Major types of pesticides used in agriculture, forestry, landscape, medical and veterinary sectors. (adopted from: National Pesticides Information Center at http://npic.orst.edu/ingred/ptype/index.html).
Pesticides are sold as formulated products. Pesticide formulations are a combination of one or more active ingredients (a.i.) and several inert ingredients. Active ingredients control the pests. The inert ingredients help in solubility and stability of the product. A ULV (Ultra Low Volume) formulation need specialized spray equipment and the Ready-to-Use formulations are already diluted and are appropriate for indoor or small areas, for example, aerosols (A), granules (G), and most baits (B) [1].
Most liquid formulations are diluted with water according to the label directions. The three main types of liquid formulations are solutions, suspensions, and emulsions. A true solution is a mixture that cannot be separated by a filter or other mechanical means while a suspension is an even mixture of very small solid particles throughout a liquid and an emulsion is a mixture of droplets of one liquid in another liquid. Common Liquid Formulations are Emulsifiable Concentrate (E or EC), Solutions (S, CS), Emulsions in Water (EW), Flowables (F, L, or SC), Microencapsulated Pesticides (M or ME) and Aerosol (A).
In dry formulations the active ingredient is on the surface of a solid carrier, such as talc, clay, or ground corncobs. Common solid formulations include Granules (G), Wettable Powders (WP or W), Soluble Powder (SP or S), Water-Dispersible Granules (WDG) or Dry Flowables (DF Water-Soluble Bags/Packages (WSB) and Baits (B).
The United Nations population division estimates 9.7 billion people by the year 2050 and to feed them, the Food and Agriculture Organization (FAO) of the United Nations estimates that an 80% increase in food production is necessary. This increase in production will come from an increase in yields of crops as well as a decrease of damage to crops due to pests. There are approximately 9000 species of insects/mites (14% loss), 50,000 species of plant pathogens (13% loss) and 8000 weeds species (13% loss) worldwide [2]. Without pesticide application the pest losses to fruits, vegetables and cereals would reach 78%, 54% and 32%, respectively. Pesticides are, therefore, indispensable in agricultural production and there will be a need for pesticide based pest control and food security in the future. Pesticides are also used to control vector-born infectious diseases such as Zika virus, Lyme disease, and rabies, household pests like cockroaches, bed bugs, and as repellents etc. More than 1000 active ingredients are used in pesticides around the world to ensure food safety and prevention from pests and the highest amount (~45%) is spent on herbicides followed by insecticides, fungicides, and other types of pesticides.
Human beings get exposed to pesticides either actively through occupational exposure or passively through non-occupational exposure. Pesticides occupational exposure may occur during manufacturing, transportation, sale, and application process including exterminators. For example, in an incident of occupational exposure, 2800 workers were poisoned during malathion spray for malaria vector control in Pakistan [3]. Parents working in agriculture industry usually take pesticide contaminated clothing, equipment home, which has been associated with the development of cancers in their children.
Non-occupational exposure may include pesticides residues ingestion with contaminated food and water and inhalation of pesticides droplets from the air through drift from point of release or fumigation. Human beings are also exposed to residual indoor sprays and outdoor fogging of insecticides applied against insect pests of public health importance and homeowners exposed to structural pest control pesticides. Additionally, treatment of ectoparasites in pets, e.g. fleas, is also a source of exposure, especially for children.
Exposure through the intact skin (dermal exposure) is the most common route and may occur as a result of a splash, spill, or spray drift, during mixing, loading, disposing, and/or cleaning of application equipment especially when proper protective equipment are not used. Dermal absorption can be influenced by the amount/concentration, duration of exposure and temperature/humidity. Absorption is high through groin areas, the eyes and ear canal. Liquid formulations (e.g., emulsifiable concentrates) are readily absorbed through the skin compared to the solid formulations (e.g., powders, dusts, and granules).
Accidental ingestion of pesticides (oral exposure) occurs by drinking from unlabeled containers when pesticides are stored in food/drink container, water stored in pesticide-contaminated bottles, eating or smoking while, or after handling pesticides or through application equipment or pesticide residues in food and water. Inhalation of pesticides (respiratory exposure) may occur due to application of fumigants (which change into toxic gas after coming in contact with moisture in air) or presence of fine droplets in air (particle or vapor drift) after application of pesticides. Pesticides can enter blood stream after absorption through lungs.
Pesticides are distributed throughout the human body through the bloodstream and are excreted through urine, skin, and exhaled into air after metabolism. These pathways also determine the toxicity of any pesticide. Pesticides recognized as persistent organic pollutant (POP) are fat soluble and are easily accumulated within the human fat-tissues, breast milk, and maternal blood placenta.
The amount of risk from pesticide exposure depends on the toxicity and the exposure to the pesticide. Toxicity is a measure of how harmful or poisonous a pesticide is (causing sickness or other unwanted effects), while exposure is a measure of the contact (duration) with a pesticide. Toxicity of a pesticide is measured as lethal dose (LD50). The LD50 value is the statistical estimate of a pesticide (mg/kg of body weight) which will kill 50% of the test animals within a stated period of time (24 hours to 7 days). The LD50 value also depends on the route of entry of a pesticide; oral LD50 for oral ingestion, dermal LD50 for skin contact exposure and Lethal Concentration (LC50) for inhalation of fumigants and pesticide vapors.
A short term exposure or exposure to a single dose will cause acute toxicity with its health effects. Chronic toxicity results from repeated exposure to a pesticide over a longer period of time from several months to years. Hazard symbols, signal words and color on the primary display panel of a pesticide label are based on their dermal toxicity.
Insecticides Resistance Action Committee (IRAC) has classified insecticides into 32 groups based on their mode/site of action, in addition, there are 5 other types of insecticides with unknown modes of action. Most commonly used insecticides work at different sites in the nervous system of insects. Insecticides target the same sites of action in human nervous system and cause toxicity with adverse health effects. Carbamate (group 1A) and Organophosphate (OP) (group 1B) insecticides inhibit the enzyme Acetyl Choline Esterase (AChE) and cause hyper-excitation. AChE terminates the action of the excitatory neurotransmitter acetylcholine at the nerve synapses. Examples of pesticides inhibiting AChE include dichlorvos, malathion, phorate, carbaryl, carbofuran, etc. Cyclodiene organochlorine insecticides (OC) (group 2A) and phenylpyrazoles (group 2B) block the gamma amino butyric acid (GABA)-activated chloride channel causing hyper-excitation and convulsions. GABA is the major inhibitory neurotransmitter in insects. Examples of insecticides inhibiting GABA include endosulfan and fipronil. Synthetic pyrethroids and natural pyrethrins (group 3A) and DDT (group 3B) keep sodium channels open causing hyper-excitation and, in some cases, nerve blockage. Sodium channels are involved in the propagation of action potentials along nerve axons. Examples include deltamethrin and permethrin. Neonicotinoid insecticides (group 4A) bind to the acetylcholine site on nicotinic acetylcholine receptor (nAChRs) causing a range of symptoms from hyper-excitation to lethargy and paralysis. Examples include acetamiprid, clothianidin, imidacloprid, thiacloprid and thiamethoxam. Other groups of insecticides that work on nervous system includes those which allosterically activate nAChRs (e.g. spinetoram, spinosad) or glutamate-gated chloride channels (GluCls) (e.g. abamectin, emamectin benzoate), or allosterically inhibit the GABA-activated chloride channel and cause paralysis (e.g. broflanilide and fluxametamide). Glutamate is an important inhibitory neurotransmitter in insects. Other insecticides will block the nAChR ion channel or sodium channels, e.g. indoxacarb, cause nervous system shutdown and paralysis.
Fungicides inhibit fungal growth by interfering with critical cellular processes. Fungicide resistance action committee (FRAC) classify fungicides and bactericides into 50 groups based on the site of action. Within each group, there are target sites, which are the specific enzymes to which the fungicides bind. The different known target sites include nucleic acids metabolism, cytoskeleton and motor protein, respiration, amino acids and protein synthesis, signal transduction, lipid synthesis or transport/membrane integrity or function, sterol biosynthesis in membranes, cell wall biosynthesis, melanin synthesis in cell wall and host plant defense induction. Some fungicides and herbicides are considered endocrine disrupting pesticides.
Herbicides are pesticides that inhibit or interrupt normal plant growth and development. Herbicides are widely used in agriculture, landscape industry, and non-crop areas for weed management. Herbicides resistance action committee (HRAC) has classified herbicides into 27 groups. These include: growth regulators (synthetic auxins; auxin transport inhibitors), seedling growth inhibitors, photosynthetic inhibitors, amino acid synthesis inhibitors, lipid synthesis inhibitors, cell membrane disrupters, pigment inhibitors.
Growth regulator herbicides consist of the synthetic auxin and auxin transport inhibitory compounds and the most commonly used synthetic auxins include 2,4-
‘Pesticide residue’ means any specified substance in food, agricultural commodities, or animal feed resulting from the use of pesticides. The term also includes any derivatives of a pesticide, such as conversion products, metabolites, reaction products, and impurities considered to be toxic. Application of pesticides during the production or storage of agricultural commodities result in pesticide residues in food (fruits, vegetables, grain, meat, etc). Pesticide residues are also found in the drinking water. Pesticide residues can build up to harmful levels through bio-accumulation and bio-magnification within the food chain.
WHO, in collaboration with FAO performs pesticide risk assessment to humans, both through direct exposure and through residues in food. The WHO core assessment group on pesticide residues review toxicological data and establish the acceptable daily intakes (ADIs) and acute reference doses (ARfDs) of pesticide residues for different commodities through a lifetime of food consumption. The ADIs are amount of pesticide residues which will not result in adverse health effects. Codex Alimentarius Commission (the intergovernmental standards-setting body for food) establishes maximum residue limits (MRLs) for pesticides in food based on ADIs.
The MRL depends on the crop it is used on, and the same pesticide active ingredient may have different MRL values when used on different crops. Extraneous maximum residue limit (EMRL) refers to the maximum permitted limit of residues of mostly POP pesticides, which were previously used as pesticides but not registered any more, and residues arising from environmental contamination (including previous agricultural use) or residues from uses of these pesticides other than for agricultural purpose, e.g. DDT, Aldrin, etc.
There are several reports of pesticide residues detected on food exceeding the MRL values. For example, in India, vegetable samples were tested for the presence of OC, OP and pyrethroid insecticides, and 15.3% samples exceeded the MRL. In two Brazilian pesticide residue monitoring programs less than 3% of the samples had residue levels above the MRL. Pesticide residues were detected in 34% of samples of cereal grains collected throughout Poland and 3% samples contained residues over the maximum limit. A study from Maule Region (Talca, Chile) found pesticide residues on the fruits and vegetables schoolchildren brought as snack [5].
The pesticide residues detected in fruits and vegetables from Lithuania had multiple pesticides; 9 residues in grapes and tea, 5-9 residues in orange, mandarins, lemons, peaches, pears and 3-5 residues in pomegranates, plums, cucumbers, tomatoes and strawberries, and found that 2.6% samples exceeded the MRL values [6]. In a European Union study 14–23% of the samples had detectable residues of more than one active ingredient where 3.0–5.5% samples had residues levels above the MRL [7]. Exposure to multiple pesticide residues could be due to intake from a single food item containing multiple residues or from several food items each containing one or more residues. The combined toxic effects of two or more compounds can be independent, additive or synergistic.
Both recreational and medicinal cannabis samples contained high levels of residual pesticides and pesticides not legally allowed to be used on cannabis products in Oregon. Medicinal cannabis products were found to have mean levels of residual pesticides that were 3-12 times higher than recreational products, and 9 of the 50 pesticides identified were classified highly or extremely hazardous by the WHO [8].
Pesticide residues have been found in surface, groundwater and potable water samples from India [9]. Pesticide residues levels in river water and in drinking water samples in Turkey were significantly high compared with guideline values set by Turkey, EU and WHO as hazardous to human health [10]. Higher concentrations of pesticides in ambient air were recorded from potato farm sites in Prince Edward Island, Canada, Taihu Lake region of China and Kaweah Reservoir, CA, USA. A total of 87 pesticides were identified in the household dust samples from the rural Yakima Valley of Washington state, 47 of these have evidence of neurotoxicity included in the EPA list [11].
The short-term acute adverse effects pesticide exposure on human health are stinging eyes, rashes, blisters, skin irritations, blindness, nausea, dizziness, diarrhea and death. Exposure to pesticides in agricultural work can cause serious risks to the respiratory system causing chronic cough, dyspnea, wheezing and expectoration, decreased lung capacity, asthma, and bronchitis. These respiratory problems were found in workers in flower crops in Ethiopia, coffee plantations in Brazil and banana plantations in Costa Rica. In banana farming in Rio Grande do Norte (Brazil), the use of pesticides was related to the symptoms of burning in the throat and lungs, airway congestion, cramps, skin peeling, diarrhea, headache, chest pain, weakness, cough and skin irritation.
In banana production region of the Ribeira Valley (Brazil), workers (majority males, low schooling, mean age 39.6 years and 13.8 years of working time) had moderate obstructive disorder (10.0%) and mild obstructive disorder (13.3%) with decreased FEV1 (forced expiratory volume in 1 second) and FEV1/FVC (the ratio between forced expiratory volume in the first second and forced vital capacity and is very important for the detection of obstructive disorders). Similarly, exposures to mixtures (pollutants and pesticides) in children with asthma in California were also associated with reduced lung function measures FEV1 and FVC [12].
Many studies have found positive associations with pesticide exposure and children’s respiratory and allergic effects such as asthma, wheezing, coughs, acute respiratory infections, hay fever, rhinitis, eczema, chronic phlegm, and lung function impairments. A study of school-age children with asthma in the agricultural community of Yakima Valley (Washington State) found that increase in exposures to OP insecticides was related with increase in LTE4 levels which was associated with a higher risk of asthma morbidity [13]. The neonicotinoid insecticides (e.g. imidacloprid, nitenpyram) are nicotinic receptors agonists and their exposure cause nausea, vomiting, muscle weakness, respiratory effects, headache, lethargy, and tachycardia.
The long-term chronic adverse effects of pesticides exposure are cancers, birth defects, reproductive harm, neurological and developmental toxicity, immunotoxicity, and disruption of the endocrine system. The chronic effects of pesticides on human can be categorized into three major groups; neurotoxic effects, genotoxic and carcinogenic effects, and reproductive effects.
Neurotoxicity can be defined as any adverse effect on the central or peripheral nervous system caused by chemical, biological or physical agents. A developing nervous system in children (during replication, migration, differentiation, myelination of neurons, and synapse formation) is more susceptible to neurotoxic chemicals including pesticides. Chemicals (pesticides) can cause neuronal cell death by disruption of the cytoskeleton, induction of oxidative stress, calcium overload, or by damaging mitochondria. Most of the synthetic insecticides, some fungicides and herbicides, currently in use are neurotoxicants.
Pesticide molecules are small and lipophilic in nature, and can enter from blood to brain and then in neurons, glial cells and brain micro vessels. Pesticides can disrupt blood-brain barrier receptors in the central nervous system which enhance chronic toxicity and affect the receptor-mediated transcytosis. Neuronal cells are more susceptible to oxidative stress due to their high polyunsaturated fat content in the myelin sheaths, low anti-oxidative capabilities, enzymatic systems with transient metals that aid in the production of free radicals, and demand for high oxygen and glucose metabolism rate.
OPs and carbamates bind to and phosphorylate/carbamalate the AChE which causes accumulation of acetylcholine at cholinergic synapses causing overstimulation of muscarinic and nicotinic cholinergic receptors. Neuropsychiatric disorders, such as anxiety and depression, are observed in patients with acute and long-term poisoning from OPs. OPs may also cause an intermediate syndrome and OP-induced delayed polyneuropathy (OPIDP) 1-3 weeks after a single exposure. In carbamates, the AChE inhibition is reversible and acute intoxication is generally resolved within a few hours.
The OP insecticides can disturb the function of mitochondria by inducing oxidative stress in central nervous system through critical depletion of mitochondrial energy, the activation of proteolytic enzymes, and DNA fragmentation leading to apoptosis. The dysfunction of mitochondria and oxidative stress is responsible for several neurological diseases, including Parkinson’s disease, seizure, cognitive dysfunction, attention and memory deficits, dementia, depression, and Alzheimer’s disease. OP triggered induction of a xanthine oxidase may play a role in cognitive impairment.
In a study, increased inhibition of cholinesterase enzyme with increased exposure to OP insecticides was confirmed in both occupationally exposed (OE) and environmentally exposed (EE) groups of people. The OP exposure, mainly in the EE group, was associated with a diminished neuropsychological performance; general mental status, language, memory, attention, executive function, praxis and psychomotricity.
Acute poisoning due to exposure to OP (particularly chlorpyrifos) was reported with higher prevalence of peripheral polyneuropathy, and deterioration of cognitive functions (verbal fluency, and visual and auditory memory) was observed in agricultural workers and in inhabitants of rural agricultural areas. Exposure to OP insecticides in rural schoolchildren was associated with a lower processing speed in children and an IQ lower than expected for their age.
Exposure to type I pyrethroids cause tremor syndrome (behavioral arousal, aggressive sparring, increased startle response, and fine body tremor progressing to whole-body tremor, and prostration) while type II pyrethroids exposure cause salivation syndrome (profuse salivation, coarse tremor progressing to choreoatetosis, and clonic seizure). The poisoned cerebral cortex affect learning, memory, emotions, and movement. Pyrethroids exposure has been positively associated with hearing loss in U.S. adolescents. Pyrethroids exposure induced Tau protein malfunction which may be the mechanism underlying cognitive impairment. Paraquat, triazine and pyrazole (herbicides) through oxidative stress, raised influx of calcium and the stimulation of nitrogen oxide species, and aggravated Aβ amyloidogenesis cause cognitive impairment.
Exposure to endocrine disrupting chemicals (EDCs) including many pesticides can disrupt maternal thyroid imbalance which can result in permanent and lifelong neurodevelopmental consequences for their children, including attention-deficit disorder, autism spectrum disorder, and cognitive and behavioral dysfunction. Workers of fruit and seed export companies in a rural area of Santiago exposed to methyl bromide (CH3Br, a fumigant) had increased concentration of CH3Br in blood after application which resulted in a higher frequency of insomnia, headaches, paresthesias, mood swings, memory loss, and decreased concentration [14].
Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons of the nigrostriatal pathway and the formation of alpha-synuclein (α-syn)-containing Lewy bodies. Dieldrin (OC) is selectively toxic to dopaminergic cells, disrupts striatal dopamine activity, and may promote α-syn aggregation while ziram (dithiocarbamate fungicide) increases the probability of synaptic vesicle release by dysregulation of the ubiquitin signaling system and increases excitability in both aminergic and glutamatergic neurons leading to PD.
A genotoxic agent can be a physical, chemical or biological agent that can interact with the genetic material (DNA) causing alterations, damage or ruptures, and those that interfere with enzymatic processes of repair, genesis or polymerization of proteins involved in chromosome segregation. These alterations could lead to impaired embryonic development or be the initial steps in the development of cancer. Pesticides exposure can cause genomic damage. Genetic damage caused by pesticides is broadly classified into three classes; (i) Pre-mutagenic damage like DNA strand breaks and DNA adducts (ii) gene mutations like insertion, deletion, inversion and translocation (iii) chromosomal aberrations, including loss or gain of whole chromosome (aneuploidy), deletion or breaks (clastogenicity), and chromosomal rearrangements.
Farmers exposed to pesticide mixtures in Greece had possible clastogenic (chromosome breakage cause mutation) and aneugenic (abnormal number of chromosomes) effect of pesticides on the genetic material. DNA methylation changes in the placenta were significantly associated with the maternal plasma concentrations of OCs in early pregnancy causing prenatal toxicity. OPs affect DNA methylation, induce the AChE gene expression and activate the NMDA glutamate receptors resulting in calcium influx in the post-synaptic neurons leading to degeneration.
Genetic damage has been reported from exposure to malathion (OP), carbofuran (carbamate), triflumuron (Insect growth regulator), imidacloprid, acetamiprid and thiamethoxam (neonicotinoid insecticides), pentachlorophenol (OC), Emamectin benzoate (used in agriculture, household, and veterinary medicine), and tembotrione (novel post-emergence herbicide) (Table 2).
WHO Hazard Class | Band color | Signal word | Dermal LD50 (mg/Kg) | |
---|---|---|---|---|
Solid formulation | Liquid formulation | |||
Class Ia Extremely Hazardous | Red | VERY TOXIC | <10 | <40 |
Class Ib Highly Hazardous | Red | TOXIC | 10–100 | 40–400 |
Class II Moderately Hazardous | Yellow | HARMFUL | 100-1000 | 400-4000 |
Class III Slightly Hazardous | Blue | CAUTION | >1000 | >4000 |
Class U Products unlikely to present a hazard | Green |
Pesticides hazard classification by FAO.
Cancer is characterized by an uncontrolled cell growth with limitless replication, resistance to apoptosis, alteration of growth factors (GFs), resistance to chemotherapy, metastasis and angiogenesis. Cancer develops as a result of multi-factorial complex interactions of genetic and lifestyle factors including, diet, stress, physical and biological agents, infections, and exposure to the hazardous chemical substances. Pesticides exposure acts as a stimulant to cancer and chronic low-dose is considered one of the important risk factors for the increasing cancer incidence. Table 3 presents a list of pesticides suggesting carcinogenicity in different types of studies.
Type of cancer | ToP | Name of pesticide | Type of study | Reference |
---|---|---|---|---|
Non-Hodgkin lymphoma (NHL)and Hodgkin lymphoma (HL) | OC | P,p’-DDT | Case control | [15] |
P,p’-DDE | Agricultural health | [16] | ||
HCH | Case control | |||
MoC | Nonachlor/trans-nonachlor hexachlorobenzene | Blood Agricultural health | ||
OC | Mirex | Case control | ||
Chlordane | Case control | |||
Lindane | Case control | |||
OP | Malathion | Case control | [17] | |
Diazinon | ||||
Terbufos | Case control | [18] | ||
Dimethoate chlorpyrifos | Agricultural health | [15] | ||
PYR | Permethrin | Case control | [16] | |
NPYR | Pyrethrum | Agricultural health | [17] | |
PHE | 2,4-D | Case control | [19] | |
Mecoprop | Epidemiological | [20] | ||
CHL | Dichlorprop | Case control | [21] | |
BNZ | Dicamba | Case control | [20] | |
GLY | Glyphosate | Case control | [16] | |
Breast | OC | Pp\'-DDT | Histopathology | [22] |
Pp\'-DDD | Histopathology | [23] | ||
P,p′-DDE | ||||
β-HCH | Histopathology | [24] | ||
Heptachlor | ||||
Hexachlorobenzene | ||||
OP | Chlorpyrifos | MCF-7 breast cancer cells | [25] | |
Malathion | ||||
Terbufos | Case control/MCF-7/MCF-10F | [26] | ||
Diazinon | ||||
Dimethoate | ||||
PYR | Flucythrinate | AutoDock Vina 1.1.1 | [27] | |
Fluvalinate | ||||
Bifenthrin | ||||
Cyhalothrin | ||||
Cypermethrin | ||||
NEO | Thiacloprid imidacloprid | Hs578t cells | [28] | |
PTH | Captan | Agricultural health | [29] | |
GLY | Glyphosate | Case control | [30] | |
Prostate | OC | Pp\'-DDT Lindane | Case-control | [31] |
Endosulfan | Human prostate cancer PC3 and DU145 cell | [32] | ||
OB | Methyl bromide | Agricultural health | [33] | |
OP | Chlorpyrifos | Prostate epithelial lines | [34] | |
Dimethoate | Agricultural health | [35] | ||
Malathion Carbaryl | Case-control | [31] | ||
PYR | λ-Cyhalothrin | Prostate epithelial lines | [34] | |
Bifenthrin | PC3 human | [36] | ||
Deltamethrin | Prostate cancer cell | [37] | ||
QUI | Dichlone | Case control | [31] | |
IMI | Prochloraz | PC-3 prostate cancer cells | [38] | |
DIC | Vinclozolin | |||
MoV | M2 | |||
CHL | 2,4-D | Case control | [31] | |
2,4-DB | Histopathology | [39] | ||
2,4,5-T | ||||
CHP | Picloram | Histopathology | [39] | |
ORG | Cacodylic acid | Case control | [31] | |
TRI | Simazine Atrazine | RM1 cells | [40] | |
Mo2 | 2, 4-dichlorophenol (DCP) | Case control | [31] | |
MoD | Dinoseb amine | |||
GLY | Glyphosate | Prostate epithelial lines | [34] | |
Lung cancer | OP | Diazinon | Epidemiological | [41] |
PYT | Cypermethrin | Lewis lung cancer cells | [42] | |
αCH | Acetochlor | Agricultural health | [43] | |
TRI | Atrazine | |||
Bladder | IMZ | Imazethapyr imazaquin | Agricultural health | [44] |
Hepatocellular carcinoma | OC | Pp\'-DDT | Serum levels | [45] |
Pp\'-DDE | Toxicological | [46] | ||
OC | Endosulfan | Human liver carcinoma cells (HepG2) | [47] | |
CAR | Carbaryl | Toxicological | [46] | |
BEZ | Fluopyram | Female rat | [48]] | |
BED | Carbendazim | Toxicological | [46] | |
BEN | Dicamba | Agricultural health | [49] | |
αCH | Acetochlor | Human liver carcinoma cells (HepG2) | [47] | |
Stomach | TRI | Atrazine | Agricultural health | [50] |
Thyroid | OP | Malathion | Agricultural health | [51] |
TRZ | Penconazole | Agricultural health | [52] | |
TRI | Atrazine | Agricultural health | [53] | |
Amitrole | Nthy-ori-3-1 cell | [54] | ||
Ovarian | OC | Pp\'-DDT | Blood | [55] |
Pp\'-DDE | ||||
β-HCH | ||||
Endosulfan | ||||
OP | Diazinon | Agricultural health | [51] | |
PYR | λ-Cyhalothrin | BG-1 ovarian cancer cells | [56] | |
Cypermethrin | ||||
Cyprodinil | ||||
HYD | Fenhexamid | Mouse model with transplanted BG-1 cells | [56] | |
Colorectal | OC | Pp\'-DDE | [57] | |
Endosulfan | ||||
OP | Chlorpyrifos | Human colorectal adenocarcinoma H508 cells | [58] | |
CAR | Aldicarb | |||
αCH | Acetochlor | Agricultural health | [51] | |
Brain | OP | Dichlorvos | Male albino Wistar rats | [59] |
List of Pesticides Suggesting Carcinogenicity in different types of studies.
ToP, type of pesticide; OC, organochlorine insecticide; MoC, metabolites of chlordane; OP, organophosphate insecticide; PYT, pyrethroid insecticide; NPYT, natural pyrethroid insecticide; PHC, phenoxy-carboxylate herbicide; CHL, chlorophenoxy herbicide; BEN, benzoate herbicide; GLY, glycine herbicide; NEO, neonicotinoid insecticide; PHT, phthalimide fungicide; OB, organobromine insecticide; QUI, quinone algicide; IMI, imidazole fungicide; DIC, dicarboximide fungicide; MoV, metabolite of vinclozolin; CHP, chlorinated pyridine herbicide; ORG, organoarsenic herbicide; TRI, triazine herbicides; Mo2, metabolite of 2,4-D; Mod, metabolite of dinoseb dinitrophenol herbicide; αCH, α-chloroacetamides herbicide; IMZ, imidazolinones herbicides; CAR, carbamate insecticide/nematicide; BEZ, benzamide, pyramide fungicide; BED, benzimidazole fungicide; TRZ, triazole fungicide; HYD, hydroxyanilides fungicides.
Non-Hodgkin lymphoma (NHL) is a diverse group malignancies and its incidence has increased worldwide. Patients with immune dysfunction are at a high risk to develop NHL. Studies have reported an elevated risk of NHL with exposure to several classes of pesticides. Terbufos (OP nematicide), dimethoate, malathion and chlorpyrifos (OP insecticide), and 2,4-D and dichlorprop (chlorophenoxy herbicides) have been associated with significant risk of developing HL.
Leukemia has been associated with occupational exposure with a higher risk in livestock farmers and golf course superintendents. The risk of chronic myelocytic leukemia (CML) and acute myeloblastic leukemia (AML) was found to be higher in women. Children whose parents used garden and indoor insecticides, or whose mothers had been exposed while pregnant had increased rates of all types of leukemia. Children living on farms and those exposed to household pesticides have increased risk of leukemia. Association between occupational exposure to pesticides and chronic lymphocytic leukemia (CLL) has been reported from Spain. A nationwide study in France showed a moderate increase in incidence of childhood AL in municipalities where viticulture is common.
Brain tumors are the most common solid tumors in children and the leading cause of cancer-related mortality during childhood. A positive association has been reported between parental occupational, prenatal or residential exposure, living on a farm, mothers living on farms, rural activity and childhood brain tumors. Increased risk for primitive neuroectodermal tumors (PNETs) was associated with maternal exposure living on pig or poultry farms. Exposure to pyrethroid formulations used to control mosquitoes and cockroaches at home also increase the risk of brain tumors.
Breast cancer is the leading cause of cancer-related deaths among women. About 650 pesticides out of the 800 used worldwide can affect the functioning of the endocrine system and are called endocrine disrupting pesticides (EDPs). EDPs have the potential ability to act as tumor promoters and increasing risk of breast cancer. All women diagnosed with breast cancer between 1995 and 2005 in the city of Arica (geographic area that received massive aerial applications of malathion in 1980) were 5.7 times more likely to suffer from breast cancer compared to women diagnosed during the same period in the city of Iquique, Chile [14]. Several chemical classes of insecticides, fungicides and herbicides have been associated with breast cancer in women (Table 3).
Prostate cancer is the second most common cancer in men globally, and accounts for 7% of all cancers. More than 95% of cases of prostate cancer are androgen-dependent. The higher incidence of prostate cancer, at least in part, has been associated with the hormone disrupting pesticides and consistent positive associations between prostate cancer and pesticide exposure have been reported.
Hepatocellular carcinoma (HCC) is the 6th most common cancer, and the 4th most common cause of cancer-related mortality. The major risk factors include hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, aflatoxin contaminated foods, obesity, smoking and type 2 diabetes besides pesticides. Pesticides exposure has been associated with increased risk of developing HCC.
EDCs are emerging as one of the leading risks and are recognized as serious and urgent threats to public health. In laboratory studies, EDCs are reported to shorten gestation, alter intrauterine growth, and disrupt metabolic programming. Prenatal exposure to EDCs can affect fetal neurodevelopment through disruption of peroxisome proliferator activated receptors, mainly estrogen receptors, and thyroid hormone receptors.
Failure of testosterone production in Leydig cells leads to failure of testosterone-bound androgen receptor-mediated gene transcription necessary for spermatogenesis. Many studies have shown that various pesticides decrease testosterone levels. Testosterone is required for the final stages of sperm maturation, so a decrease in intra-testicular testosterone is likely to impair fertility. Vinclozolin (fungicide) and chlorpyrifos (OP) can reduce testosterone production. Exposure to higher concentrations of OP and dialkyl phosphates (metabolites of OPs), p,p’-DDE, fenvalerate and atrazine (chlorotriazine herbicide) have been consistently associated with lower semen quality (sperm concentration, motility, and morphology).
A study of male children from a village of cashew plantations, where endosulfan (OC, EDC) had been aerially sprayed for more than 20 years, showed a delay in sexual maturity and an alteration in sex hormone synthesis. Endosulfan, in exposed mothers, can move via trans-placental route and breast feeding to children. Exposure during critical periods of development might contribute to decline conception rates and increased incidence of female reproductive disorders, such as altered cyclicity, endometriosis, fetal growth retardation, and pregnancy loss [60].
A high incidence of spontaneous abortions 81.02 / 1000 live newborns was reported in Valparaíso Region (agricultural area) compared to 9.5 /1000 live newborns in the rest of Chile. A 28% incidence of congenital malformations in live newborns was reported in the O’Higgins Region (agricultural area) compared to only 15% of cases in non-agricultural in Chile [14].
Pesticides are used in managing pests of agricultural and public health importance, and their use will continue in future because of food security and vector control. Additionally, pesticides are used at home in fumigation for structural pests and to mitigate household pest using aerosols or sprays. It is difficult to eliminate pesticides in the near future, but they should be used with care and caution. Most pesticides are potentially toxic to human beings resulting in severe health consequences including cancers.
Epidemiological evidence suggests that there is an increased incidence of different diseases including leukemia, lymphoma, and several other types of cancers in farmers, and those who are associated with application of pesticides. There is also evidence that parental exposure, as well as, exposure in early life or adolescence could increase the longer-term risks.
Since animal studies are problematic, expensive and often generate ethical problems, cell cultures are increasingly used as a model of research. Correctly conducted and properly selected, the cell culture is an excellent experimental model reflecting human exposure to different xenobiotics through all relevant routes. The cell cultures are also becoming more widely used to study the effect of pesticides on the human body at a molecular level, which is necessary to understand the hazards and determine the level of exposure.
Some pesticides (OCs) are no longer used worldwide due to their persistence and toxicity. However, their residues or metabolites are still found in food and water samples. The use of OPs and carbamate insecticides has been reduced since the arrival of newer chemistries in different parts of the world but most of them are still use around the world.
The workplace safety standards and proper pesticide management and storage must be implemented to reduce the risks posed to human health. Pesticide users should be aware of their risks and proper handling, as well as must use personal protective equipment which are effective in reducing damage to human health. To ensure healthy childhood growth, efforts should be made to develop comprehensive pesticides risk mitigation strategies and interventions to reduce children’s exposure.
It is critical to achieve sustainable development in agricultural systems. Newer approaches in pest management have been developed which should be encouraged. For example, RNA interference- (RNAi-) based pesticides are emerging as a promising new biorational control strategy [61] and steam treatment at temperature of 150.56°C can kill 93.99% of nematode 97.49% of bacteria [62].
Future research need in the context of minimizing the impact on human health due to exposure to pesticides include an urgent need to eliminate the use of carcinogenic pesticides and to develop environmentally sound integrated pest management (IPM) strategies that use the minimum amount of pesticides. Such IPM strategies should aim at reducing the pesticides residues on food products and pesticides-free water and air.
The author acknowledges the financial support by the Sultan Qaboos University, Muscat, Oman. This work was funded through an Internal Grant # IG/AGR/CROP/18/02.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'By accessing the website at www.intechopen.com you are agreeing to be bound by these Terms of Service, all applicable laws and regulations, and agree that you are responsible for compliance with any applicable local laws. Use and/or access to this site is based on full agreement and compliance of these Terms. All materials contained on this website are protected by applicable copyright and trademark laws.
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\n\nAny use of the above terminology, or other words in the singular, plural, capitalization and/or he/she or they, are taken as interchangeable.
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\n\nWe employ the use of cookies. By using the IntechOpen website you consent to the use of cookies in accordance with IntechOpen’s Privacy Policy. Most modern day interactive websites use cookies to enable the retrieval of user details for each visit. On our site, cookies are predominantly used to enable functionality and ease of use for those visiting the site.
\n\nIn no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
\n\nIntechopen.com website content and services are provided on an "AS IS" and an "AS AVAILABLE" basis. Material appearing on www.intechopen.com could include minor technical, typographical, or photographic errors. IntechOpen may make changes to any material contained on its website at any time without notice.
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\n\nThese Terms and Conditions are governed by and construed in accordance with the laws of the United Kingdom and you irrevocably submit to the exclusive jurisdiction of the courts in London, United Kingdom.
\n\nCroatian version of Terms and Conditions available here
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