Herbicide Poisoning

Overview

Herbicides are substances that are used to kill or control the growth of unwanted plants Plants Cell Types: Eukaryotic versus Prokaryotic.

• Herbicides are classified as pesticides, defined by the U.S. Environmental Protection Agency (EPA) as any substance intended for preventing, destroying, or repelling any pest. 
• The term “pesticides” also applies to fungicides, rodenticides, bactericides, and insecticides Insecticides Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. Trypanosoma cruzi/Chagas disease.
• In the past few decades, the production and use of modern herbicides have increased faster than for any other class of pesticides: 
  • > 2× that of insecticides Insecticides Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. Trypanosoma cruzi/Chagas disease
  • > 3× that of fungicides
• Human effects of herbicides are caused by the:
  • Method of application ( skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions exposure Exposure ABCDE Assessment is the most common)
  • Mode of action

Paraquat Poisoning

Etiology

Paraquat:

• 1st nonselective contact herbicide (a bipyridyl compound)
• Rapidly acting herbicide, causing limited injury in spray or dermal exposure Exposure ABCDE Assessment, but highly fatal in accidental or intentional ingestion
• Leading cause of fatal poisoning in many parts of Asia ASIA Spinal Cord Injuries, Pacific nations, and the Americas
• 1 of only 2 pesticides still used in the United States that are banned in the European Union, China, and Brazil

Rules in the United States:

• For “restricted commercial use”
• Safety features to reduce toxicity Toxicity Dosage Calculation:
  • Blue coloration/dye to keep it from being confused with beverages
  • Sharp odor
  • Agent added to cause vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia if ingested

Pathophysiology

• Mechanism of toxicity Toxicity Dosage Calculation: reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Nonalcoholic Fatty Liver Disease are formed → nicotinamide adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids dinucleotide phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes ( NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway) depletion and lipid peroxidation Lipid peroxidation Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. Drug-induced Liver Injury → cellular damage → mitochondrial damage Mitochondrial Damage Cell Injury and Death → apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
• Within hours to days, multiorgan failure can occur, as paraquat is distributed to other tissues within 6 hours of ingestion.
• Target tissues (have high oxygen and energy requirements): lung, kidney, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, heart

Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor

• After ingestion → immediate pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and swelling Swelling Inflammation of the mouth and throat Throat The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy 
• Followed by:
  • Oropharyngeal ulcerations: “paraquat tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy”
  • Abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics/ vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea (may be bloody)
  • GI bleeding
• Pulmonary:
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea (from pulmonary edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema)
  • Hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis (from hemorrhage) 
  • Can progress to pulmonary fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans over days to weeks
  • Severity of lung involvement correlates with outcome.
• Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
• People with large ingestions of paraquat (> 30 mL of 20%–24% paraquat formulation) are not likely to survive.

Diagnosis

• Mainly clinical by known exposure Exposure ABCDE Assessment and symptoms
• Laboratory testing:
  • Urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat dithionite test: 
    • Confirms exposure Exposure ABCDE Assessment
    • Survival is expected if test is negative.
  • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products paraquat
• Additional tests:
  • Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes and renal function:
    • Fast rate of increase in creatinine points to a poor outcome.
    • An increase > 4.3 μmol/L per hour in 6 hours = increased mortality Mortality All deaths reported in a given population. Measures of Health Status
  • Blood gas:
    • Alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis initially due to vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis, both respiratory and metabolic, follows (due to pulmonary edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury, and hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension).
  • Lactic acid: High levels correlate with poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas.
  • Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests:
    • Check for lung injuries.
    • Check for mediastinal involvement ( mediastinitis Mediastinitis Mediastinitis refers to an infection or inflammation involving the mediastinum (a region in the thoracic cavity containing the heart, thymus gland, portions of the esophagus, and trachea). Acute mediastinitis can be caused by bacterial infection due to direct contamination, hematogenous or lymphatic spread, or extension of infection from nearby structures. Mediastinitis, pneumomediastinum Pneumomediastinum Mediastinitis).

Management

• Resuscitation Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome and supportive care:
  • IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids 
  • Intubation Intubation Peritonsillar Abscess
  • Excessive oxygen administration should be avoided because it may worsen paraquat toxicity Toxicity Dosage Calculation. 
• Decontamination:
  • Remove all contaminated clothing.
  • Wash all areas of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions.
  • Flush eyes if contact occurs.
  • Activated charcoal Charcoal An amorphous form of carbon prepared from the incomplete combustion of animal or vegetable matter, e.g., wood. The activated form of charcoal is used in the treatment of poisoning. Antidotes of Common Poisonings (AC)
  • Nasogastric suction Nasogastric suction Metabolic Alkalosis with gastric lavage may be considered for ingestions that present at < 1 hour. 
• Hemodialysis Hemodialysis Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. Crush Syndrome/hemoperfusion for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with acute renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome, large doses, or pulmonary edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
• No proven antidote Antidote An antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications. Antidotes of Common Poisonings exists for paraquat poisoning but patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with systemic toxicity Toxicity Dosage Calculation may benefit from:
  • High-dose glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
  • Acetylcysteine

Agent Orange Exposure

Etiology

Agent Orange:

• A tactical herbicide (a defoliant) used by the U.S. military in the Vietnam War to eliminate forest cover and crops
• Chemical was transported in storage drums with orange stripe/band. 
•  60% of herbicides used in the Vietnam War

Pathophysiology

• Main ingredients: 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)
• Has trace 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD):
  • By-product of herbicide production
  • Toxic even in small amounts
  • Can last in natural environment for years
  • Dangerous to humans—classified as a human carcinogen
  • A common exposure Exposure ABCDE Assessment is by ingestion, as it accumulates in the food chain (most likely in fish FISH A type of in situ hybridization in which target sequences are stained with fluorescent dye so their location and size can be determined using fluorescence microscopy. This staining is sufficiently distinct that the hybridization signal can be seen both in metaphase spreads and in interphase nuclei. Chromosome Testing, which are regulated in the United States).
• Effects of TCCD are mediated via aryl hydrocarbon receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (AhR) signaling pathway (which modulates gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics expression):
  • Induces cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury 1A1 (CYP1A1)
  • Disrupts normal hormone signaling pathways
  • Causes reproductive and developmental defects
  • Leads to immunotoxicity
  • Leads to liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy toxicity Toxicity Dosage Calculation
  • Contributes to tumorigenesis

Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor

Acute:

• Darkening of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
• Severe acne-like skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions disease called chloracne
• Muscular dysfunction
• Hormone disruption
• Birth defects due to parental exposure Exposure ABCDE Assessment

Chronic:

• Long-lasting impacts on pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care:
  • Miscarriages
  • Abnormal fetal development
  • Craniofacial deformities 
  • Extremity deformities 
• Type 2 Type 2 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease
• Heart disease
• Amyloid light-chain ( AL AL Amyloidosis) amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis
• Parkinson’s disease
• Neuropathy Neuropathy Leprosy
• Porphyria cutanea tarda Porphyria cutanea tarda An autosomal dominant or acquired porphyria due to a deficiency of uroporphyrinogen decarboxylase in the liver. It is characterized by photosensitivity and cutaneous lesions with little or no neurologic symptoms. Type I is the acquired form and is strongly associated with liver diseases and hepatic toxicities caused by alcohol or estrogenic steroids. Type II is the familial form. Porphyrias
• Carcinogenic:
  • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
  • Lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
  • Soft tissue Soft Tissue Soft Tissue Abscess sarcoma
  • Non-Hodgkin lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum (NHL)
  • Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma
  • Chronic B-cell leukemias
  • Prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer

Diagnosis and management

• Diagnosis is clinical, based on exposure Exposure ABCDE Assessment and symptoms.
• Laboratory testing for liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy function is indicated.
• Adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or “brite” adipose tissue, which is a transitional form. Adipose Tissue: Histology and blood serum analyzed for the presence of TCDD are not routinely recommended due to being expensive and time-consuming.
• Workup of long-term effects depends on presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor.
• Management:
  • Decontamination and removal of exposure Exposure ABCDE Assessment
  • No antidote Antidote An antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications. Antidotes of Common Poisonings exists.
  • Supportive care for symptoms

Glyphosate Toxicity

Etiology

Glyphosate:

• N-(Phosphonomethyl) glycine Glycine A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. Synthesis of Nonessential Amino Acids: most common brand name is “Round-Up”
• First used as an herbicide in 1971
• Classified as nonselective herbicide
• Applied directly to plant foliage
• Widely used in agriculture, forestry, industrial weed control, lawn, garden, and aquatic environments

Pathophysiology

• Inhibits enolpyruvylshikimate-3-phosphate synthase (EPSP), blocking the synthesis Synthesis Polymerase Chain Reaction (PCR) of aromatic amino acids Aromatic amino acids Amino acids containing an aromatic side chain. Basics of Amino Acids (e.g., tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids and phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids) → ↓ plant growth
• In humans, toxicity Toxicity Dosage Calculation of glyphosate is due to uncoupling of mitochondrial oxidative phosphorylation Oxidative phosphorylation Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. Electron Transport Chain (ETC).
• Relatively low toxicity Toxicity Dosage Calculation in mammals, with majority of toxicity Toxicity Dosage Calculation (in large doses) due to suicide Suicide Suicide is one of the leading causes of death worldwide. Patients with chronic medical conditions or psychiatric disorders are at increased risk of suicidal ideation, attempt, and/or completion. The patient assessment of suicide risk is very important as it may help to prevent a serious suicide attempt, which may result in death. Suicide attempts

Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor

Mild to moderate toxicity Toxicity Dosage Calculation:

• Dermal exposure Exposure ABCDE Assessment: eye and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions irritation
• Inhalation exposure Exposure ABCDE Assessment: oral/nasal discomfort, tingling Tingling Posterior Cord Syndrome, and throat Throat The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy irritation
• Ingestion:
  • Erosion Erosion Partial-thickness loss of the epidermis Generalized and Localized Rashes of the GI tract
  • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
  • GI hemorrhage

Severe toxicity Toxicity Dosage Calculation:

• Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
• Dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration
• Pneumonitis Pneumonitis Human Herpesvirus 6 and 7
• Dysrhythmias
• Altered level of consciousness Altered Level of Consciousness Intracerebral Hemorrhage
• Hepatic dysfunction
• Oliguria Oliguria Decreased urine output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0. 5 or 1 ml/kg/hr depending on the age. Renal Potassium Regulation, renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome, acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis, and hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
• Death

Diagnosis and management

• Diagnosis is clinical, from exposure Exposure ABCDE Assessment and presenting symptoms.
• Glyphosate measurement in blood or urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat can be done but is not necessary.
• Management:
  • Aggressive supportive therapy
  • Decontamination: Gastric lavage can be administered or AC can be given if patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship without buccal irritation or burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns present < 1 hour after ingestion.
• Hemodialysis Hemodialysis Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. Crush Syndrome and IV lipid emulsion have been used for severe toxicity Toxicity Dosage Calculation. 
• No known specific antidote Antidote An antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications. Antidotes of Common Poisonings

Organophosphate Toxicity

Etiology

Organophosphates:

• Irreversible cholinesterase Cholinesterase Liver Function Tests inhibitors
• Examples of organophosphate (OP) chemicals:
  • Herbicides: tribufos (DEF), merphos
  • Insecticides Insecticides Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. Trypanosoma cruzi/Chagas disease: malathion Malathion A wide spectrum aliphatic organophosphate insecticide widely used for both domestic and commercial agricultural purposes. Cholinomimetic Drugs, parathion Parathion A highly toxic cholinesterase inhibitor that is used as an acaricide and as an insecticide. Insecticide Poisoning, diazinon Diazinon A poisonous bipyridylium compound used as contact herbicide. Contact with concentrated solutions causes irritation of the skin, cracking and shedding of the nails, and delayed healing of cuts and wounds. Insecticide Poisoning, fenthion Fenthion Potent cholinesterase inhibitor used as an insecticide and acaricide. Insecticide Poisoning, dichlorvos Dichlorvos An organophosphorus insecticide that inhibits acetylcholinesterase. Insecticide Poisoning, chlorpyrifos, ethion
  • Nerve gases: soman, sarin Sarin An organophosphorus ester compound that produces potent and irreversible inhibition of cholinesterase. It is toxic to the nervous system and is a chemical warfare agent. Cholinomimetic Drugs, tabun, VX
  • Ophthalmic agents: echothiophate, isoflurophate Isoflurophate A diisopropyl-fluorophosphate which is an irreversible cholinesterase inhibitor used to investigate the nervous system. Cholinomimetic Drugs
  • Anthelminthics: trichlorfon
  • Industrial chemical (plasticizer): tricresyl phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes

Pathophysiology

• Inhibits the cholinesterase Cholinesterase Liver Function Tests enzyme in the synaptic cleft Synaptic cleft Synapses and Neurotransmission
• Irreversible phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing of acetylcholinesterase (AChE) leading to inhibition of the AChE, which is present in:
  • Parasympathetic and sympathetic ganglia
  • Parasympathetic muscarinic terminal junctions
  • Sympathetic fibers located in sweat glands Sweat glands Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. Soft Tissue Abscess
  • Nicotinic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors at the skeletal neuromuscular junction Neuromuscular junction The synapse between a neuron and a muscle. Skeletal Muscle Contraction
• Persistently ↑ acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS levels due to AChE inhibition leads to ↑ neurotransmitter signaling.

Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor

• Presents as a cholinergic toxidrome Toxidrome A toxidrome describes a group of signs, symptoms, and/or characteristic effects associated with exposure to a particular substance or class of substances. General Principles of Toxidromes
• Pinpoint pupils
• Sweating, salivation
• Bronchoconstriction
• Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia 
• Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
• CNS stimulation then depression
• Muscle fasciculations Fasciculations Involuntary contraction of the muscle fibers innervated by a motor unit. Fasciculations may be visualized as a muscle twitch or dimpling under the skin, but usually do not generate sufficient force to move a limb. They may represent a benign condition or occur as a manifestation of motor neuron disease or peripheral nervous system diseases. Polyneuropathy, weakness, paralysis
• Death from respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure

Diagnosis

• Primarily a clinical diagnosis based on history and examination
• Some organophosphorus agents have a distinct petroleum or garlic-like odor.
• Can be confirmed by measurement of cholinesterase Cholinesterase Liver Function Tests activity:
  • RBC AChE and plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cholinesterase Cholinesterase Liver Function Tests (PChE) or butyrylcholinesterase (BuChE) levels can both be used.
  • Acetylcholinesterase is a more useful marker of organophosphate poisoning.

Management

• Airway Airway ABCDE Assessment, breathing, and circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment (ABC) assessment
• Decontamination:
  • Removal of clothes, irrigation or washing of exposed areas
  • AC (within an hour of ingestion)
  • PPE: Use neoprene gloves and gowns, as hydrocarbons can penetrate nonpolar substances such as latex and vinyl.
  • Charcoal Charcoal An amorphous form of carbon prepared from the incomplete combustion of animal or vegetable matter, e.g., wood. The activated form of charcoal is used in the treatment of poisoning. Antidotes of Common Poisonings cartridge masks for respiratory protection
  • Irrigate the eyes of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who have had ocular exposure Exposure ABCDE Assessment.
• Supportive care: 
  • IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids
  • Intubation Intubation Peritonsillar Abscess:
    • Avoid succinylcholine Succinylcholine A quaternary skeletal muscle relaxant usually used in the form of its bromide, chloride, or iodide. It is a depolarizing relaxant, acting in about 30 seconds and with a duration of effect averaging three to five minutes. Succinylcholine is used in surgical, anesthetic, and other procedures in which a brief period of muscle relaxation is called for. Cholinomimetic Drugs because it is metabolized by AChE.
    • May be necessary in cases of respiratory distress due to laryngospasm Laryngospasm Hypoparathyroidism, bronchospasm Bronchospasm Asthma Drugs, bronchorrhea, or seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
• Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures: Give benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines.
• Antidotal therapy:
  • Atropine Atropine An alkaloid, originally from atropa belladonna, but found in other plants, mainly solanaceae. Hyoscyamine is the 3(s)-endo isomer of atropine. Anticholinergic Drugs: 
    • Binds to muscarinic receptors Muscarinic Receptors Asthma Drugs, temporarily blocking them and reducing cholinergic effect(s)
    • Dosing titrated to clearance of respiratory secretions and cessation of bronchoconstriction
  • Pralidoxime Pralidoxime Various salts of a quaternary ammonium oxime that reconstitute inactivated acetylcholinesterase, especially at the neuromuscular junction, and may cause neuromuscular blockade. They are used as antidotes to organophosphorus poisoning as chlorides, iodides, methanesulfonates (mesylates), or other salts. General Principles of Toxidromes (2-PAM): 
    • Effective in both muscarinic and nicotinic effects
    • Reactivates AChE but has a transient inhibitory effect on the enzyme, so should be given in conjunction with atropine Atropine An alkaloid, originally from atropa belladonna, but found in other plants, mainly solanaceae. Hyoscyamine is the 3(s)-endo isomer of atropine. Anticholinergic Drugs

Mnemonics

SLUDGE BBB BBB Specialized non-fenestrated tightly-joined endothelial cells with tight junctions that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. Nervous System: Histology (muscarinic effects):

• Salivation
• Lacrimation (crying is key feature)
• Urination
• Defecation ( diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea)
• GI cramping (distress)
• Emesis
• Bronchospasm
• Bronchorrhea
• Bradycardia

DUMBELS (muscarinic effects):

• Defecation
• Urination
• Miosis
• Bronchorrhea/ bronchospasm Bronchospasm Asthma Drugs/ bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias
• Emesis
• Lacrimation
• Salivation

Clinical Relevance

• Toxidrome Toxidrome A toxidrome describes a group of signs, symptoms, and/or characteristic effects associated with exposure to a particular substance or class of substances. General Principles of Toxidromes: group of clinical signs and symptoms associated with toxic ingestion or exposure Exposure ABCDE Assessment. There are 5 traditional toxidromes Toxidromes A toxidrome is a group of clinical signs and symptoms associated with a toxic ingestion or exposure. There are 5 traditional toxidromes: anticholinergic, cholinergic, opioid, sympathomimetic, and sedative-hypnotic. General Principles of Toxidromes: anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs, cholinergic, opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation, sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs, and sedative-hypnotic. Toxidromes Toxidromes A toxidrome is a group of clinical signs and symptoms associated with a toxic ingestion or exposure. There are 5 traditional toxidromes: anticholinergic, cholinergic, opioid, sympathomimetic, and sedative-hypnotic. General Principles of Toxidromes often arise from ingestion of overdose amounts, accumulation of medications with resultant elevated serum levels, adverse drug reactions, or interactions between ≥ 2 medications.  Diagnosis is by clinical findings based on medication and exposure Exposure ABCDE Assessment history and physical examination.
• Insecticide poisoning Insecticide Poisoning Insecticides are chemical substances used to kill or control insects, to improve crop yields, and to prevent diseases. Human exposures to insecticides can be by direct contact, inhalation, or ingestion. Important insecticides that can affect humans include organochlorines (dichlorodiphenyltrichloroethane (DDT)), organophosphates (malathion and parathion), and carbamates (carbaryl, propoxur, aldicarb, and methomyl). Insecticide Poisoning: Insecticides Insecticides Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. Trypanosoma cruzi/Chagas disease are chemical substances used to kill or control insects. Important insecticides Insecticides Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. Trypanosoma cruzi/Chagas disease include dichlorodiphenyltrichloroethane Dichlorodiphenyltrichloroethane A polychlorinated pesticide that is resistant to destruction by light and oxidation. Its unusual stability has resulted in difficulties in residue removal from water, soil, and foodstuffs. This substance may reasonably be anticipated to be a carcinogen: fourth annual report on carcinogens. Insecticide Poisoning ( DDT DDT A polychlorinated pesticide that is resistant to destruction by light and oxidation. Its unusual stability has resulted in difficulties in residue removal from water, soil, and foodstuffs. This substance may reasonably be anticipated to be a carcinogen: fourth annual report on carcinogens. Insecticide Poisoning), organophosphates, and carbamates. Exposure Exposure ABCDE Assessment to DDT DDT A polychlorinated pesticide that is resistant to destruction by light and oxidation. Its unusual stability has resulted in difficulties in residue removal from water, soil, and foodstuffs. This substance may reasonably be anticipated to be a carcinogen: fourth annual report on carcinogens. Insecticide Poisoning results in neurotoxicity and endocrine disruption. Organophosphates and carbamates produce cholinergic effects by inhibiting AChE. Organophosphates bind BIND Hyperbilirubinemia of the Newborn the enzyme irreversibly, while carbamates inhibit the enzyme for < 24 hours. Diagnosis is by history and clinical findings. Management involves decontamination, supportive care, and symptom control. For cholinergic toxidrome Toxidrome A toxidrome describes a group of signs, symptoms, and/or characteristic effects associated with exposure to a particular substance or class of substances. General Principles of Toxidromes, atropine Atropine An alkaloid, originally from atropa belladonna, but found in other plants, mainly solanaceae. Hyoscyamine is the 3(s)-endo isomer of atropine. Anticholinergic Drugs and pralidoxime Pralidoxime Various salts of a quaternary ammonium oxime that reconstitute inactivated acetylcholinesterase, especially at the neuromuscular junction, and may cause neuromuscular blockade. They are used as antidotes to organophosphorus poisoning as chlorides, iodides, methanesulfonates (mesylates), or other salts. General Principles of Toxidromes are given to reverse the effects of cholinergic excess.
• Caustic ingestion Caustic Ingestion Caustic agents are acidic or alkaline substances that damage tissues severely if ingested. Alkali ingestion typically damages the esophagus via liquefactive necrosis, whereas acids cause more severe gastric injury leading to coagulative necrosis. Caustic Ingestion (Cleaning Products): Acidic or alkaline substances Alkaline Substances Caustic Ingestion (Cleaning Products) damage tissues severely if ingested. Alkali ingestion typically damages the esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus: Anatomy. Acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance cause more severe gastric injury. In large amounts and high concentrations, caustic ingestion Caustic Ingestion Caustic agents are acidic or alkaline substances that damage tissues severely if ingested. Alkali ingestion typically damages the esophagus via liquefactive necrosis, whereas acids cause more severe gastric injury leading to coagulative necrosis. Caustic Ingestion (Cleaning Products) also leads to severe injuries such as shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock, abdominal rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon, respiratory distress, and/or altered mental status Altered Mental Status Sepsis in Children. Diagnosis is by laboratory tests, abdominal and chest imaging, and endoscopy Endoscopy Procedures of applying endoscopes for disease diagnosis and treatment. Endoscopy involves passing an optical instrument through a small incision in the skin i.e., percutaneous; or through a natural orifice and along natural body pathways such as the digestive tract; and/or through an incision in the wall of a tubular structure or organ, i.e. Transluminal, to examine or perform surgery on the interior parts of the body. Gastroesophageal Reflux Disease (GERD). Management involves stabilizing the patient, decontamination, and supportive therapy. Severe injury may require surgery.