**2. Physical and chemical properties and stages of intoxication**

#### **2.1. Organophosphorus**

which, combined with influence of the book "Silent Spring", and accumulated evidence on the effects of pesticides, culminated in banning of the use of DDT in the United States in 1972.

The 1970s and 1980s saw the introduction of more selective pesticides. In the 1990s, research activities concentrated on finding new members of existing pesticides that were even more selective. Besides, pesticides with new chemical groups emerged. During this period, safer chemicals arose. In addition, Integrated Pest Management (IPM) systems, came into play – these systems used crop production methods that attracted predators or parasites that attacked pests and timed pesticide applications to coincide with the most susceptible period of the pest's

However, IPM or related methods did not eliminate the need for pesticides. These chemicals ensure the production of adequate quantities of high quality pest-free crops, which is impor‐ tant for food supply, prevents human diseases transmitted by insect or rodent vectors, and

The best pesticide policies need to reconcile environmental concerns with economic realities – pest management is mandatory, and farmers must survive economically. A number of studies have described the problems that not using pesticides would cause. Without pesticides, food production would be lower, and larger cultivated farm areas would be necessary to produce the same amount of food, which would impact the wildlife habitat. More frequent cultivation of the fields would be increase soil loss due to erosion, too. Knutson et al. [7] have pictured the U.S. society without pesticides: agricultural production would decrease, food prices would rise, farmers would be less competitive in global markets, and U.S. exports would

Despite their benefits, pesticides can be hazardous to both humans and the environment. Countless chemicals are environmentally stable, prone to bioaccumulation, and toxic [6]. Because some pesticides can persist in the environment, they can remain there for years. Environmental contamination or occupational use can expose the general population to pesticides residues, including physical and biological degradation products present in the air,

Less than 1% of the total amount of pesticides applied for weed and pest control reach the target pests. A large quantity of pesticides is lost via spray drift, off-target deposition, run-off, and photodegradation, for instance, which can have undesirable effects on some species, communities, or ecosystems as a whole, as well as on the humans [10]. Another relevant factor is that low concentrations of many chemicals may not elicit acute detectable effects in organ‐ isms, but they may induce other damage, like genetic disorders and physiological alterations,

There are various ways to group pesticides, including classification based on the pests they control. Some example, insecticides combat insect growth or survival, herbicides act against plants, weeds, and grasses, rodenticides tight against rats and other rodents, avicides act against bird populations, fungicides attack fungi, and nematicides combat nematodes [12]. The

Thereafter, other countries discontinued the use of DDT, as well [5].

life cycle, thereby reducing the amount of applied pesticides [2].

positively impacts public health [6].

196 Toxicology Studies - Cells, Drugs and Environment

drop, leading to many job losses [8].

which reduce life span in the long run [11].

water, and food [9].

Organic compounds containing phosphorus, the so called organophosphorus compounds (OP), have found application as pesticides and war gases since their synthesis, in 1937 [14]. OP contain carbon and derive from phosphorous acid. Their primary structure may vary depend‐ ing on whether they bear sulfur (S) or oxygen (O) double binds. X is a group of the general structure that separates when the compound binds to acetylcholinesterase (AChE). On the basis of the variations in their general structure, it is possible to subdivide these compounds into phosphates, phosphorothioates, phosphoramidates, and phosphonate, for example. The structural difference between these compounds results in peculiar characteristics regarding OP metabolism and toxicity. Some representatives of this class of pesticides are Diazinon, Malathion, and Paration [15].

The skin, conjunctiva, gastrointestinal tract, and lungs rapidly absorb most OP compounds. Cytochrome P450 isozymes metabolize these chemicals in the liver, which sometimes gener‐ ates metabolites that are more toxic than the parent compounds [16]. One example is the oxon form, which may bind to cholinesterase or undergo hydrolysis to a dialkyl phosphate and a hydrolyzed organic moiety specific to the pesticide [14]. Most OP are polar and hence water soluble. Their metabolites arise 12 to 48 h after exposure. However, a few compounds, such as dichlofenthion, possess high partition coefficients, which culminates in long-lasting symp‐ toms [17].

These pesticides can reversibly or irreversibly stablish covalent bonds with the serine residue in the active site of acetyl cholinesterase, to prevent the natural function of this enzyme in the catabolism of neurotransmitters [14]. The formation of complexes between acetylcholinester‐ ase enzymes and organophosphates leads to phosphorylation and deactivation, and the neurotransmitter acetylcholine consequently accumulates in the synaptic cleft. The accumu‐ lation of large amounts of acetylcholine stimulates and exhausts cholinergic synapses due to the excessive cholinergic activity produced by these agents [18]. The cholinesterase-bound phosphate group can lose the o,o-dialkyl groups or undergo hydrolysis, to regenerate the active enzyme. This process occurs not only in insects, but also in humans and the wildlife [14].

The main symptoms of pesticides intoxication can be differentiated into syndromes like the muscarinic syndrome, in which the action of acetylcholine on the smooth muscle, heart, and exocrine glands increases bronchial secretion, tearing, and sweating; disrupts the gastrointes‐ tinal tone to cause nausea, vomiting, and diarrhea; and elicits urinary incontinence, broncho‐ spasm, miosis, and bradycardia. Another example is the nicotine syndrome, in which acetylcholine accumulates at the motor nerve endings in the autonomic ganglia and causes tremors, spasms, hypertonicity, hyperreflexia, paralysis, or muscle weakness and stimulates the sympathetic autonomic ganglia, to promote tachycardia, pallor, hyperglycemia, and hypertension. Additional effects on the central nervous system (CNS) include anxiety, headache, dizziness, ataxia, sleep and memory disorders seizures, tremors, respiratory depression, and coma. Some OP still have teratogenic potential and mutagenic effects. Laboratory diagnosis of this syndrome involves determination of cholinesterase activity [19].

To treat poisoning with OP, it is necessary to maintain vital functions and assess cholinesterase levels in the red cells and pseudocholinesterase levels in the plasma, before therapy. It is important to avoid the use of parasympathomimetic agents, which may increase the anticho‐ linesterase activity. Treatment should start with atropine, which acts as a competitive mus‐ carinic anticholinergic agent, together with pralidoxime, until complete control of the symptoms. After atropinization, administration of furosemide prevents pulmonary conges‐ tion, whereas administration of benzodiazepines controls seizures [20].

#### **2.2. Carbamates**

Carbamates insecticides produce clinical signs and symptoms of cholinergic excess that resemble the signs elicited by organophosphate toxicity, except that the effects are more reversible and less severe [14]. The mechanisms underlying carbamates poisoning involve carbamylation of the active site of acetylcholinesterase, which inactivate this essential enzyme in the nervous system of humans and other animal species [21]. The reaction of carbamates with acetylcholinesterase is similar to the reaction of OP with the same enzyme. However, reactivation of the carbamylated enzyme by hydrolysis is faster as compared with reactivation of the phosphorylated enzyme, with reversal of inhibition typically occurring half an hour or less after exposure [22]. Nevertheless, reports on cases of neuropathy after poisoning exist [23].

Organisms readily absorb carbamates through the lungs, gastrointestinal tract, and skin. Fortunately, carbamates poorly penetrate the blood-brain barrier. Therefore, they affect brain cholinesterases activity minimally and promote fewer CNS symptoms as compared with organophosphates. In addition, the spontaneous in vivo hydrolysis of the carbamate-choli‐ nesterase complex contributes to less severe and less enduring symptoms.

The main symptoms of carbamates intoxication are miosis, salivation, sweating, tearing, rhinorrhea, behavioral change, abdominal pain, vomiting, diarrhea, urinary incontinence, bronchospasm, dyspnea, hypoxemia, bradycardia, bronchial secretions, pulmonary edema, respiratory failure, drop in body temperature, incoordination, lip tingling, tremors, and seizures. Less common symptoms include muscle spasms, twitching, muscle weakness (including respiratory muscles), paralysis, tachycardia, and hypertension [24].

The treatment of carbamates intoxication includes maintenance of vital functions. It is crucial to avoid the use of parasympathomimetic agents, because they may increase the anticholines‐ terase activity. Treatment should start with atropine, followed by administration of furose‐ mide, only if necessary. If poisoning is due to pure carbamates only, it is not necessary to administrate pralidoxime, except in cases that these carbamates are associated with OPs [15].

#### **2.3. Organochlorines**

the excessive cholinergic activity produced by these agents [18]. The cholinesterase-bound phosphate group can lose the o,o-dialkyl groups or undergo hydrolysis, to regenerate the active enzyme. This process occurs not only in insects, but also in humans and the wildlife [14].

The main symptoms of pesticides intoxication can be differentiated into syndromes like the muscarinic syndrome, in which the action of acetylcholine on the smooth muscle, heart, and exocrine glands increases bronchial secretion, tearing, and sweating; disrupts the gastrointes‐ tinal tone to cause nausea, vomiting, and diarrhea; and elicits urinary incontinence, broncho‐ spasm, miosis, and bradycardia. Another example is the nicotine syndrome, in which acetylcholine accumulates at the motor nerve endings in the autonomic ganglia and causes tremors, spasms, hypertonicity, hyperreflexia, paralysis, or muscle weakness and stimulates the sympathetic autonomic ganglia, to promote tachycardia, pallor, hyperglycemia, and hypertension. Additional effects on the central nervous system (CNS) include anxiety, headache, dizziness, ataxia, sleep and memory disorders seizures, tremors, respiratory depression, and coma. Some OP still have teratogenic potential and mutagenic effects. Laboratory diagnosis of this syndrome involves determination of cholinesterase activity [19].

To treat poisoning with OP, it is necessary to maintain vital functions and assess cholinesterase levels in the red cells and pseudocholinesterase levels in the plasma, before therapy. It is important to avoid the use of parasympathomimetic agents, which may increase the anticho‐ linesterase activity. Treatment should start with atropine, which acts as a competitive mus‐ carinic anticholinergic agent, together with pralidoxime, until complete control of the symptoms. After atropinization, administration of furosemide prevents pulmonary conges‐

Carbamates insecticides produce clinical signs and symptoms of cholinergic excess that resemble the signs elicited by organophosphate toxicity, except that the effects are more reversible and less severe [14]. The mechanisms underlying carbamates poisoning involve carbamylation of the active site of acetylcholinesterase, which inactivate this essential enzyme in the nervous system of humans and other animal species [21]. The reaction of carbamates with acetylcholinesterase is similar to the reaction of OP with the same enzyme. However, reactivation of the carbamylated enzyme by hydrolysis is faster as compared with reactivation of the phosphorylated enzyme, with reversal of inhibition typically occurring half an hour or less after exposure [22]. Nevertheless, reports on cases of neuropathy after poisoning exist [23].

Organisms readily absorb carbamates through the lungs, gastrointestinal tract, and skin. Fortunately, carbamates poorly penetrate the blood-brain barrier. Therefore, they affect brain cholinesterases activity minimally and promote fewer CNS symptoms as compared with organophosphates. In addition, the spontaneous in vivo hydrolysis of the carbamate-choli‐

The main symptoms of carbamates intoxication are miosis, salivation, sweating, tearing, rhinorrhea, behavioral change, abdominal pain, vomiting, diarrhea, urinary incontinence, bronchospasm, dyspnea, hypoxemia, bradycardia, bronchial secretions, pulmonary edema,

nesterase complex contributes to less severe and less enduring symptoms.

tion, whereas administration of benzodiazepines controls seizures [20].

**2.2. Carbamates**

198 Toxicology Studies - Cells, Drugs and Environment

Organochlorine is used mainly as insecticides. Human body burden due to organochlorine pesticides results from the universal presence of these contaminants in the environment. This constitutes a major public health concern; indeed, organochlorines have been linked with cancer, asthma, diabetes, and growth disorders in children [25]. Organochlorine pesticides include cyclodienes, hexachlorocyclohexane isomers, and DDT and its analogues (e.g., DDE, methoxyclor, and dicofol) [14].

Exposure to organochlorines occurs via ingestion of contaminated food or water, inhalation of vapor, and absorption through the skin. Occupational and other domiciliary exposures are also possible. Dietary exposure results in bioaccumulation of these chemicals in the human body [26].

Organochlorines have similar structure – they all contain a cyclodiene ring. The lungs, gastrointestinal tract, and skin can absorb all these compounds. In addition, although the organism absorbs approximately 10% of the applied dose, lipid solvents increase dermal penetration [15], thereby raising the risk of intoxication in the case of workers who apply these products in crops without proper protective equipment.

The accumulation of organochlorine compounds is a result of their chemical structure and their physical properties such as polarity and solubility. These fat-soluble compounds persist in both the body and the environment. Consequently, researchers and regulatory agencies have banned several organochlorines [14].

The main symptoms of organichlorines intoxication are dizziness, headache, anorexia, nausea, vomiting, malaise, dermatitis, diarrhea, apprehension, excitement, irritability, gait disorders, excessive sweating, altered reflexes, muscle weakness, tremors, spasms, mental confusion, anxiety, seizures, coma, and death. The carcinogenicity of this class of compound is assigned to polychlorocyclodiene compounds that form epoxides during their biotransformation. Because organochlorines have long half-life, these levels in the serum constitute a marker of exposure to these pesticides [15].

To treat organochlorines intoxication, it is necessary to maintain the vital functions, administer diazepam and phenobarbital by slow injection, to control seizures, and to monitor the airways closely. Lorazepam constitutes an alternative to diazepam. Ion exchange resins can also be administered orally. Arrhythmias that damage the myocardium rarely occur. Lidocaine is the treatment of choice [27].

## **2.4. Pyrethrins and pyrethroids**

Pyrethrins and pyrethroids function mainly as iseticides. Pyrethrins are natural compounds originating from the plant *Chrysanthemum cinerariaefolium*. They comprise active agents (pyrethrins I-VI), but pyrethrins I and II are the most active. These compounds decompose rapidly in the presence of light, but synthetic production of pyrethroids around 1950 overcame some disadvantages of natural pyrethrins [15].

Crude pyrethrum is a dermal and respiratory allergen, probably due it is to non-insecticidal ingredients. Contact dermatitis and allergic respiratory reactions (rhinitis and asthma) have occurred after exposure to this compound [28].

Both pyrethrins and pyrethroids bear an acid moiety, a central ester bond, and an alcohol moiety in their structure. This class of compounds typically exists as stereoisomers (*trans* and *cis*) for a total of eight different stereoenantiomers. In adittion, they comprise two main groups, Type I and Type II, which bear a cyano group in the alpha position or not, respectively [29].

After absorption, rapid pyrethroids distribution occurs in the organism. Therein, these compounds undergo biotransformation via two mechanisms: hydrolysis of the ester linkage by carboxylesterases and oxidation of the alcohol moiety by cytochromes P450 [30]. Pyrethroids exert the same mechanism of action in insects and mammals. Both pyrethrins and pyrethroids have insecticide potential because they can disrupt the muscular system and alter the normal functioning of voltage-dependent sodium channels. Sodium channels play an important role in the cell-to-cell communication, which is vital for the function of more excitable cells involved in the action potential that the excitable cells can propagate in the CNS. Pyrethroids bind to the α-subunit of the sodium channel that is left open for a longer time, to increase membrane permeability to sodium. Consequently, these compounds cause paralysis, especially in flying insects, known as knockdown. The specific interaction of pyrethroids with the sodium channel shows both the activation and inactivation properties of the sodium channel, making the hyperexcited cells [31]. After interaction of moderate levels of pyrethroids with the sodium channel, the cell can continue to operate in an abnormal state of hyperexcitability. The amplitude of the sodium current remains unchanged until the level of hyperexcitability overwhelms the maintenance of the activity of the sodium channel. This culminates in depolarization and blocks conduction of the action potential until the situation in the cell becomes unsustainable [31].

The toxicodynamics of pyrethroids may also include other mechanisms such as antagonism of gamma-aminobutyric acid (GABA), stimulation of chloride channels modulated by protein kinase, modulation of nicotinic cholinergic transmission, increased release of noradrenaline, and deregulation of calcium homeostasis. Authors have also proposed that pyrethroids act on the voltage-sensitive chloride channels as well as on the voltagedependent calcium channels [31].

Diagnosis can be difficult because acute pyrethroid poisoning can be mistaken for OP intoxi‐ cation. Pyrethroid poisoning symptoms are: tremors, spasms, incoordination, prostration, drooling, irregular movements of the limbs, tonic and clonic convulsions, and hypersensitivity to stimuli. It can also cause skin irritation and tingling due to hyperactivity of cutaneous sensory nerve fibers. Eye miosis also occurs due to exposure [32].

Because exposure to pyrethroids does not usually prompt systemic effects, most patients only require decontamination of the skin and eyes, besides basic maintenance of the vital functions. Paresthesia usually subsides within 12-24 h, which dismisses direct treatment. If severe skin irritation occurs, application of DL-α-tocopherol acetate (Vitamin E) should alternate this problem. Gastric lavage is discarded in case of ingestion, because solvents present in many formulations may increase the risk of aspiration pneumonia. Ingestion of a potentially toxic amount requires administration of activated charcoal within one hour of the event [32].

#### **2.5. Triazines**

**2.4. Pyrethrins and pyrethroids**

200 Toxicology Studies - Cells, Drugs and Environment

becomes unsustainable [31].

dependent calcium channels [31].

some disadvantages of natural pyrethrins [15].

occurred after exposure to this compound [28].

Pyrethrins and pyrethroids function mainly as iseticides. Pyrethrins are natural compounds originating from the plant *Chrysanthemum cinerariaefolium*. They comprise active agents (pyrethrins I-VI), but pyrethrins I and II are the most active. These compounds decompose rapidly in the presence of light, but synthetic production of pyrethroids around 1950 overcame

Crude pyrethrum is a dermal and respiratory allergen, probably due it is to non-insecticidal ingredients. Contact dermatitis and allergic respiratory reactions (rhinitis and asthma) have

Both pyrethrins and pyrethroids bear an acid moiety, a central ester bond, and an alcohol moiety in their structure. This class of compounds typically exists as stereoisomers (*trans* and *cis*) for a total of eight different stereoenantiomers. In adittion, they comprise two main groups, Type I and Type II, which bear a cyano group in the alpha position or not, respectively [29].

After absorption, rapid pyrethroids distribution occurs in the organism. Therein, these compounds undergo biotransformation via two mechanisms: hydrolysis of the ester linkage by carboxylesterases and oxidation of the alcohol moiety by cytochromes P450 [30]. Pyrethroids exert the same mechanism of action in insects and mammals. Both pyrethrins and pyrethroids have insecticide potential because they can disrupt the muscular system and alter the normal functioning of voltage-dependent sodium channels. Sodium channels play an important role in the cell-to-cell communication, which is vital for the function of more excitable cells involved in the action potential that the excitable cells can propagate in the CNS. Pyrethroids bind to the α-subunit of the sodium channel that is left open for a longer time, to increase membrane permeability to sodium. Consequently, these compounds cause paralysis, especially in flying insects, known as knockdown. The specific interaction of pyrethroids with the sodium channel shows both the activation and inactivation properties of the sodium channel, making the hyperexcited cells [31]. After interaction of moderate levels of pyrethroids with the sodium channel, the cell can continue to operate in an abnormal state of hyperexcitability. The amplitude of the sodium current remains unchanged until the level of hyperexcitability overwhelms the maintenance of the activity of the sodium channel. This culminates in depolarization and blocks conduction of the action potential until the situation in the cell

The toxicodynamics of pyrethroids may also include other mechanisms such as antagonism of gamma-aminobutyric acid (GABA), stimulation of chloride channels modulated by protein kinase, modulation of nicotinic cholinergic transmission, increased release of noradrenaline, and deregulation of calcium homeostasis. Authors have also proposed that pyrethroids act on the voltage-sensitive chloride channels as well as on the voltage-

Diagnosis can be difficult because acute pyrethroid poisoning can be mistaken for OP intoxi‐ cation. Pyrethroid poisoning symptoms are: tremors, spasms, incoordination, prostration, drooling, irregular movements of the limbs, tonic and clonic convulsions, and hypersensitivity Triazines are effective and inexpensive compounds that have found application as herbicides. They combat a wide spectrum of weeds by inhibiting photosynthesis and the electron transport chain in plants. Physiological and molecular changes due to accumulation of these compounds in organisms remain unclear. Human exposure to triazines has been associated with carcino‐ genicity and endocrine disruption, but these effects are still debatable [33]. The chemical structures of triazine herbicides correspond to permutations of the alkyl substituted 2,4 diamines of chlorotriazine [14].

After absorption, these compounds undergo conjugation with glutathione or simply dealky‐ lation. The chlorine group of the triazine structure is replaced with the free-SH group of glutathione, the terminal peptide is cleaved, and the cysteine moiety is N-acetylated. The mercapturate residues and the dealkylation metabolites are subsequently excreted in the urine [14]. Triazines have low acute oral and dermal toxicity. Chronic toxicity studies have primarily indicated reduced body weight gain [16].

Atrazine is the often most studied triazine herbicide. Authors have investigated their carci‐ nogenic potential in mice and rats. Tumor incidence did not augment in mice, whereas atrazine appeared to increase the incidence of mammary carcinoma in Sprague-Dawley rats [34, 35].

Reports of human poisoning by this class of compounds are rare. When they happen, irritation at the site of contamination such as the skin, eyes, nose, and TGI occurs. Triazines may be carcinogenic and teratogenic, but there is still no evidence that this is really the case. Contam‐ ination with atrazine may also cause sensory motor polyneuropathy [15, 33].

Because exposure to triazines usually causes local irritation, in most cases it is only necessary to decontaminate the site exposed to the substance, besides offering basic life support [15].

#### **2.6. Phenoxy derivatives**

The structures of phenoxy derivatives bear an aliphatic carboxylic acid moiety attached to a chloride or methyl-substituted aromatic ring. The commonest phenoxy herbicides are 2,4 dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). A combi‐ nation of these two herbicides in equal proportions affords Agent Orange, a product applied in the jungles of Vietnam, Laos, and Cambodia during the Vietnam War. Manufacture of phenoxy herbicides often requires co-formulation with ioxynil and/or bromoxynil, which are generally more toxic than the herbicides. Moreover, other more toxic substances can emerge during the fabrication of some of these herbicides at excessively high temperatures, such as at chlorinated dibenzo dioxin and chlorinated dibenzo furan [36]. Because 2,4,5-T contains the highly toxic and persistent 2,3,7,8-tetrachlorodibenzeno-*p*-dioxin along with other chlorinated dioxins and furans, regulatory agencies have banned it for most applications [14].

Phenoxy salts and esters rapidly dissociate or hydrolyze in vivo, so the toxicity of the derivative will depend mainly on the acid form of the pesticide. Individuals and species vary substantially in terms of phenoxy herbicides elimination. The biological half-life of herbicides in humans reportedly varies from 12 to 72 h [36], but long half-lives occur at large doses and after prolonged exposure [28].

The gastrointestinal tract absorbs phenoxy derivatives. The lungs absorb them less, their cutaneous absorption is minimal, and fat does not store them. Phenoxy derivatives exhibit a variety of mechanisms of toxicity including dose-dependent cell membrane damage, uncoupling of oxidative phosphorylation, and disruption of acetylcoenzyme A metabolism [36]. Phenoxy acids and esters are moderately irritating to the skin, eyes, and the respiratory, gastrointestinal, and mucous membranes. Their toxicity on the CNS is dose-dependent. These derivatives disrupt the blood-brain barrier and the neuronal membrane transport mechanisms, and damage to the intracellular membrane results in uncoupling of oxidative phosphorylation [36]. In addition, prolonged inhalation of these herbicides may cause burning sensation in the nasopharynx and dizziness. Some recent studies have examined female exposure to herbicides and assessed effects such as spontaneous abortion, birth defects, and infertility, among others [28].

Intoxication by this class of compounds is uncommon, but when they occur they can cause serious sequelae. The main symptoms are nausea, dizziness, vomiting, burning in the mouth, constipation, abdominal pain, numbness, diarrhea, gastrointestinal bleeding, gastrointestinal fluid loss, vasodilation and/or direct toxicity due to grafting hypotension, ECG alterations like ventricular or supraventricular tachycardia and, on rare occasions, sinus bradycardia. In more severe cases, agitation, confusion, weakness, paralysis, coma, and death by ventricular fibrillation can occur, and chances of survival are small. Other disrupted functions comprise changes in the NCS [36]. Some compounds of this class (e.g., 2,4,5-T) can also produce carcinogenic and teratogenic effects as well as hepatotoxicity. As for metabolic acidosis, clinical signs such as hyperthermia (due to uncoupling of oxidative phosphorylation), renal failure, increased aspartate aminotransferase and alanine and lactate dehydrogenase, thrombocyto‐ penia, hemolytic anemia, and hypocalcemia activities can arise [36].

In general, treatment of phenoxy derivatives poisoning includes maintenance of the vital functions. If the poisoning is due to ingestion, administration of activated charcoal is necessary for adsorption of the compounds, provided that intoxication occurred within an hour. Systemic poisoning calls for hemodialysis, but other effective purification methods exist, like alkalini‐ zation of the urine flow and increase of urine volume to facilitate excretion. To control seizures, administration of benzodiazepines is mandatory [36].

### **2.7. Dipyridyl derivatives**

phenoxy herbicides often requires co-formulation with ioxynil and/or bromoxynil, which are generally more toxic than the herbicides. Moreover, other more toxic substances can emerge during the fabrication of some of these herbicides at excessively high temperatures, such as at chlorinated dibenzo dioxin and chlorinated dibenzo furan [36]. Because 2,4,5-T contains the highly toxic and persistent 2,3,7,8-tetrachlorodibenzeno-*p*-dioxin along with other chlorinated

Phenoxy salts and esters rapidly dissociate or hydrolyze in vivo, so the toxicity of the derivative will depend mainly on the acid form of the pesticide. Individuals and species vary substantially in terms of phenoxy herbicides elimination. The biological half-life of herbicides in humans reportedly varies from 12 to 72 h [36], but long half-lives occur at large doses and after

The gastrointestinal tract absorbs phenoxy derivatives. The lungs absorb them less, their cutaneous absorption is minimal, and fat does not store them. Phenoxy derivatives exhibit a variety of mechanisms of toxicity including dose-dependent cell membrane damage, uncoupling of oxidative phosphorylation, and disruption of acetylcoenzyme A metabolism [36]. Phenoxy acids and esters are moderately irritating to the skin, eyes, and the respiratory, gastrointestinal, and mucous membranes. Their toxicity on the CNS is dose-dependent. These derivatives disrupt the blood-brain barrier and the neuronal membrane transport mechanisms, and damage to the intracellular membrane results in uncoupling of oxidative phosphorylation [36]. In addition, prolonged inhalation of these herbicides may cause burning sensation in the nasopharynx and dizziness. Some recent studies have examined female exposure to herbicides and assessed effects such as

Intoxication by this class of compounds is uncommon, but when they occur they can cause serious sequelae. The main symptoms are nausea, dizziness, vomiting, burning in the mouth, constipation, abdominal pain, numbness, diarrhea, gastrointestinal bleeding, gastrointestinal fluid loss, vasodilation and/or direct toxicity due to grafting hypotension, ECG alterations like ventricular or supraventricular tachycardia and, on rare occasions, sinus bradycardia. In more severe cases, agitation, confusion, weakness, paralysis, coma, and death by ventricular fibrillation can occur, and chances of survival are small. Other disrupted functions comprise changes in the NCS [36]. Some compounds of this class (e.g., 2,4,5-T) can also produce carcinogenic and teratogenic effects as well as hepatotoxicity. As for metabolic acidosis, clinical signs such as hyperthermia (due to uncoupling of oxidative phosphorylation), renal failure, increased aspartate aminotransferase and alanine and lactate dehydrogenase, thrombocyto‐

In general, treatment of phenoxy derivatives poisoning includes maintenance of the vital functions. If the poisoning is due to ingestion, administration of activated charcoal is necessary for adsorption of the compounds, provided that intoxication occurred within an hour. Systemic poisoning calls for hemodialysis, but other effective purification methods exist, like alkalini‐ zation of the urine flow and increase of urine volume to facilitate excretion. To control seizures,

dioxins and furans, regulatory agencies have banned it for most applications [14].

spontaneous abortion, birth defects, and infertility, among others [28].

penia, hemolytic anemia, and hypocalcemia activities can arise [36].

administration of benzodiazepines is mandatory [36].

prolonged exposure [28].

202 Toxicology Studies - Cells, Drugs and Environment

The dipyridyl compounds paraquat and diquat are non-selective contact herbicides that have found wide application in agriculture and industries. They help to control weeds. However, these compounds are highly toxic and managing poisoning with these substances requires a great skill and knowledge of proper management procedures [28].

Paraquat (1,1'-dimethyl-4,4'-dipyridylium) is a dipyridylium quaternary ammonium com‐ pound related to diquat and morfamquat. The latter product is the least toxic but also the least effective herbicide [15]. Their biotransformation produces free radicals, with consequent lipid peroxidation and cell injury [37].

Paraquat causes aggressive tissue damage in the lungs, kidney, and liver. The major target organ of paraquat poisoning is the lung, which consists of the most lethal and the least treatable manifestation of toxicity. Reactive oxygen species (ROS) play a crucial role in paraquat induced pulmonary injury, characterized by edema hemorrhage and hypoxemia, as well as infiltration of inflammatory cells [28, 38].

The other representative of this class is diquat (1,1'-ethylene-2,2'-bipyridilium), which causes fewer poisoning events than paraquat, the reason why reports on human toxicity and animal experimental data are less extensive for diquat than paraquat. The mechanisms of paraquat and diquat toxicity are similar: radicals destroy lipid membranes. After absorption, diquat does not selectively concentrate in the lung tissue, but it exerts severe toxic effects on the CNS, an event that is not typical in the case of paraquat [28]. The kidney is the main excretory pathway for absorbed diquat. Renal damage is therefore an important feature of diquat poisoning [15, 28].

A very interesting action against poisoning by diquat and paraquat is the addition of an emetic agent in their formulations, wherein the additive acts rapidly in the body and causes the individual to regurgitate the pesticide before it performs its toxic action [38 - 40]. The main poisoning symptoms are dehydration resulting from vomiting. The high oxidative stress elicited by these herbicides causes necrosis in the gastrointestinal tract, kidney tubules, liver, and lung; in the latter case, respiratory failure and pulmonary fibrosis may occur. Ingestion of large amounts of these compounds leads to death within two to three weeks, a result of acute renal failure, hepatitis, and especially respiratory failure caused by pulmonary inflammation and fibrosis. In addition to the systemic effects, these compounds are very harmful to the skin and may cause severe burns [38, 41].

The treatment of poisoning with dipyridyl derivatives includes maintenance of the vital functions, minimization of the absorption of the compound more cathartic (activated charcoal), acceleration of excretion (forced diuresis, hemodialysis, or hemoperfusion), abatement of the effects on the affected tissue, and fluid replacement. Topical lesions should be treated with topical silver sulfadiazine, combined with systemic antibiotics [41]. An addition method to recognize paraquat poisoning is to test the urine with sodium dithionite [42].

#### **2.8. Glycine derivatives**

Two representatives of this class are glyphosate (N-phosphonomethyl glycine) and glufosinate (N-phosphonomethyl homoalanine), marketed primarily as the isopropylamine salt (glypho‐ sate) or ammonium salt (glufosinate). Both substances are broad-spectrum nonselective systemic herbicides with application in for post-emergent control of annual and perennial plants. Although both compounds contain a P=O moiety, they are not organophosphates, but organophosphonates, and they do not inhibit AChE [36].

Glyphosate, which contains phosphorus, is a herbicide used in 75% of all the genetically modified crops (GMCs), which tolerate high concentrations of this compound [36, 43]. Glyphosate inhibits an enzyme in the biosynthesis of tryptophan, phenylalanine, and tyrosine, present in plants, fungi, and bacteria, but not in animals or humans. [44]. However, according to literature reports, glyphosate can enter living organisms, including humans, where it exerts various toxic effects [45].

One pathway of glyphosate metabolism involves formation of aminomethylphosphonic acid (AMPA) by action of glyphosate oxidoreductase; AMPA is also the metabolite that emerges in humans [36]. Knowledge of the toxicokinetics of glyphosate derives mainly from animal studies and the similar patterns of absorption, metabolism, and eliminations in humans [46]. Rats absorb only 30% glyphosate after oral administration [36]. Glyphosate plasma concen‐ trations peak at 1-2 h, and declined thereafter, with distributions to the intestine, colon, kidney, and bones [47].

The mechanisms of toxicity of glyphosate formulations are complicated [36]. The most widely used glyphosate product is Roundup®, formulated as a concentrate containing 41% glypho‐ sate [16]. Some in vitro studies have suggested that, at high concentrations of glyphosate, its metabolites and impurities may reduce acetylcholinesterase (AChE) activity [48], although no evidence for significant AChE inhibition in mammals in vivo exists [36]. A study published in the *Archives of Toxicology* by Koller and colleagues showed increased in nuclear aberrations after exposure to glyphosate concentrations between 10 and 20 mg/L, which indicated DNA damage [49]. In adition, in vitro tests using isolated rat liver mitochondria showed that glyphosate uncoupled the electron transport chain [50].

Glufosinate inhibits the synthesis of glutamine in plants, and plant death occurs as a conse‐ quence of the increased ammonia levels [16]. Glufosinate supress the activity of glutamine synthetase and glutamate decarboxylase, reducing glutamic acid levels and elicits various types of moderate-to-severe CNS toxicities [51]. Given the differences in the biochemical and metabolic pathways of plants and mammals, glufosinate ammonium formulations are minimally toxic to humans [52]. However, ingestion of the undiluted form can cause grave outcomes such as seizures, respiratory arrest, coma, and disturbance of consciousness, which appear after a latent period of 4 – 60 h [53]. No work has reported that this compound induces genotoxic or carcinogenic effects or that impacts reproduction and fertilization [16].

The effects of this class of compounds range from irritation upon local contact (skin, GI), to hypotension, development of acute renal failure with oliguria, and severe hypoxia and death [54].

The treatment of glycine derivatives poisoning includes maintenance of the vital functions. Hemodialysis is crucial to reduce the amount of toxins normally excreted by the kidney, thereby preventing the impacts on this organ [54].

#### **2.9. Dithiocarbamates**

**2.8. Glycine derivatives**

204 Toxicology Studies - Cells, Drugs and Environment

various toxic effects [45].

and bones [47].

and death [54].

organophosphonates, and they do not inhibit AChE [36].

glyphosate uncoupled the electron transport chain [50].

Two representatives of this class are glyphosate (N-phosphonomethyl glycine) and glufosinate (N-phosphonomethyl homoalanine), marketed primarily as the isopropylamine salt (glypho‐ sate) or ammonium salt (glufosinate). Both substances are broad-spectrum nonselective systemic herbicides with application in for post-emergent control of annual and perennial plants. Although both compounds contain a P=O moiety, they are not organophosphates, but

Glyphosate, which contains phosphorus, is a herbicide used in 75% of all the genetically modified crops (GMCs), which tolerate high concentrations of this compound [36, 43]. Glyphosate inhibits an enzyme in the biosynthesis of tryptophan, phenylalanine, and tyrosine, present in plants, fungi, and bacteria, but not in animals or humans. [44]. However, according to literature reports, glyphosate can enter living organisms, including humans, where it exerts

One pathway of glyphosate metabolism involves formation of aminomethylphosphonic acid (AMPA) by action of glyphosate oxidoreductase; AMPA is also the metabolite that emerges in humans [36]. Knowledge of the toxicokinetics of glyphosate derives mainly from animal studies and the similar patterns of absorption, metabolism, and eliminations in humans [46]. Rats absorb only 30% glyphosate after oral administration [36]. Glyphosate plasma concen‐ trations peak at 1-2 h, and declined thereafter, with distributions to the intestine, colon, kidney,

The mechanisms of toxicity of glyphosate formulations are complicated [36]. The most widely used glyphosate product is Roundup®, formulated as a concentrate containing 41% glypho‐ sate [16]. Some in vitro studies have suggested that, at high concentrations of glyphosate, its metabolites and impurities may reduce acetylcholinesterase (AChE) activity [48], although no evidence for significant AChE inhibition in mammals in vivo exists [36]. A study published in the *Archives of Toxicology* by Koller and colleagues showed increased in nuclear aberrations after exposure to glyphosate concentrations between 10 and 20 mg/L, which indicated DNA damage [49]. In adition, in vitro tests using isolated rat liver mitochondria showed that

Glufosinate inhibits the synthesis of glutamine in plants, and plant death occurs as a conse‐ quence of the increased ammonia levels [16]. Glufosinate supress the activity of glutamine synthetase and glutamate decarboxylase, reducing glutamic acid levels and elicits various types of moderate-to-severe CNS toxicities [51]. Given the differences in the biochemical and metabolic pathways of plants and mammals, glufosinate ammonium formulations are minimally toxic to humans [52]. However, ingestion of the undiluted form can cause grave outcomes such as seizures, respiratory arrest, coma, and disturbance of consciousness, which appear after a latent period of 4 – 60 h [53]. No work has reported that this compound induces

genotoxic or carcinogenic effects or that impacts reproduction and fertilization [16].

The effects of this class of compounds range from irritation upon local contact (skin, GI), to hypotension, development of acute renal failure with oliguria, and severe hypoxia Dithiocarbamates comprise two groups: [1] dimethyldithiocarbamate and [2] ethylenebisdi‐ thiocarbamate, depending on which metal cation is present in the chemical structure. The nomenclature of various compounds of this class is related to the association of the metal cations; e. g., maneb (manganese), and zineb and ziram (zinc) [16, 50].

The slow absorption of these compounds means that they have low acute oral and dermal toxicity. On the other hand, chronic exposure to dithiocarbamates leads to adverse effects due to contact with dithiocarbamate acid or metal ligand [16].

The metabolite that arises from dithiocarbamates biotransformation is ethylenethiourea (ETU), which induces thyroid cancer and modifies thyroid hormones. Moreover, dithiocarbamates and disulfiram have similar structures, and both can inhibit acetaldehyde dehydrogenase, the enzyme that converts acetaldehyde into acetic acid [55].

Although these products are little toxicity to humans, they are potential precursors of ethyle‐ nethiourea, which has carcinogenic and teratogenic action.

There is no specific treatment for poisoning with this class of compounds, so only maintenance of vital functions and minimization of their absorption (activated charcoal) are necessary.

#### **2.10. Others**

Others classes of pesticides exist, including the chloroacetanilide commonly used in agricul‐ ture. A number of chloroacetanilides, like alachlor, acetochlor, metolachlor, and propachlor are carcinogenic [56]. The metabolism of chloroacetanilides most likely proceeds via conjuga‐ tion with glutathione, as judged from the amount of glutathione-related metabolites in the urine of rats treated with these herbicides. [57]. However, the predicted differences between humans and rats in terms of disposition together with the lower rates of alachlor metabolism in human nasal microsomes have led scientists to question the human relevance of chloroa‐ cetanilide olfactory carcinogenicity [58].

Benzimidazoles are another important class of pesticides. They are commonly used as veterinary medicines (anthelmintics) and pesticides. They inhibit microtubule formation when they bind to free β-tubulin monomers at the colchicine-binding site [59].

Regarding new technologies, nanopesticides or nanoplant protection products represent an emerging technological development. In relation to pesticide use, these technologies could offer a range of benefits including increased efficacy and durability, and they use of smaller amounts of active ingredients [60]. Nanopesticides "involve either very small particles of a pesticide active ingredient (ai) or other small engineered structures with useful pesticidal properties" [61]. Nanoformulations combine several surfactants, polymers (organic), and metal nanoparticles (inorganic) in the nanometer size range [62].



**Physical and Chemical**

**Exposition**

**Toxicokinetics** Rapidly absorbed and

Covalent bonds with the

Muscarinic syndrome

Maintenance of vital

functions and cholinesterase

levels. It is important to avoid

the use of

206 Toxicology Studies - Cells, Drugs and Environment

parasympathomimetic

agents20.

and nicotine syndrome,

serine residue in the active

site of acetyl cholinesterase

resulting of excess

acetylcholine in the

synaptic cleft19.

(reversibly or

irreversibly)14.

metabolized by P450

isozymes in oxom

form, more toxic than

the parent

compounds16.

**Toxicodynamics**

**Signs and Symptoms**

**Treatment**

**Properties**

Organic compounds containing

phosphorus15. The properties

Skin, conjunctiva,

gastrointestinal

tract, and lungs16.

vary with the size and structure.

In general are more soluble in

organic solvents 65.

The carbamate is an ester

derivative14. A wide range of

melting points (50 to 150oC) is

Lungs,

Readily absorbed by

Carbamylation of the active

Miosis, salivation,

Maintenance of vital

functions and cholinesterase

levels. It is important to avoid

the use of

parasympathomimetic

agents24.

sweating, tearing,

rhinorrhea, behavioral

change, abdominal pain,

vomiting, diarrhea24.

Dizziness, headache,

Maintenance of vital

functions and administer

diazepam and phenobarbital

to control seizures, and to

monitor the airways

closely27.

anorexia, nausea,

vomiting, malaise,

dermatitis, diarrhea,

muscle weakness,

tremors, spasms, mental

confusion, anxiety15.

Tremors, spasms,

incoordination,

Decontamination of the skin

and eyes, besides basic

maintenance of the vital

prostration, drooling,

irregular movements of

the limbs, tonic and

functions32.

clonic convulsions, and

organisms with

site of

acetylcholinesterase22.

exception the bloodbrain barrier22.

gastrointestinal

tract, and skin22.

found for these compounds and

the majority have low vapor

pressures and poor volatiliry at

usual temperatures 21.

They all contain a cyclodiene

The organism absorbs

approximately 10% of

Endocrine disrupters and

growth disorders in

children25.

the applied dose, but

the lipid solvents

increase the

accumulation15.

ring. Fat-soluble compounds

persist in both the body and the

Lungs,

gastrointestinal

tract, and skin26.

environment15. The majority of

organochlorines are sparingly

soluble and semivolatile 66.

Both bear an acid moiety, a

central ester bond, and an alcohol

moiety in their structure29.

Skin, lungs and

After absorption, are

They can disrupt the

muscular system and alter

the normal functioning of

voltage-dependent sodium

channels. This interaction

rapidly distributed in

the organism and

undergo

biotransformation by

gastrointestinal28.

Generally, have been low vapor

pressures, low Henry's law

constants, and large octanol/

Pyrethrins and

Pyrethroids

**Organochlorines**

**Carbamates**

**Organophosphorus**

Impact of Pesticides on Environmental and Human Health http://dx.doi.org/10.5772/59710 207


Recently, some studies have reported on the nanomaterial-induced perturbation of different cell death pathways. In the majority of the cases, the key to understanding the toxicity of nanomaterials is that their smaller size as compared with cells and cellular organelles allows them to penetrate these basic biological structures and disrupt their normal function [63]. Thus, advances in research into the mechanism of action of nanopesticides will allow better predic‐ tion of the consequences of human exposure to these materials.

All these compounds are among more than 1000 active ingredients that are marketed as insecticide, herbicide, and fungicide. However, with the news pest resistance and need to hygienic controls the quantities of the formulations have been increased constantly [64].

Ass seen above, pesticides currently used over the world are numerous and have various chemical and physico-chemical properties [21]. Nevertheless, is already known that long-term contact to pesticides can harm human life and can disturb the function of different organs in the body, including nervous, endocrine, immune, reproductive, renal, cardiovascular, respiratory systems, and chronic diseases, including cancer, Parkinson, Alzheimer, multiple sclerosis, diabetes [64].
