This Blog will expand your knowledge on Toxic Substances!!!
Glyphosate Tin Carbon Tetrachloride Tobacco
I chose to investigate these toxic substances because they seem very interesting. These substances for some workers and professionals are utilized in their everyday life and learning more in-depth about their importance as well as their other properties are important. These substances while effective in one area can be harmful or in some cases lethal in other and knowing their chemical effects as well as their therapeutic effects can be very important when these substances cause severe toxicity. One the next couple of pages, you will learn noteworthy components of each substance.
Tobacco plants (Nicotiana tabacum and Nicotiana rustica) found mostly in South America, derive an alkaloid called Nicotine, which is main addictive agent in tobacco products.
Tobacco products can be taken in by smoking cigarettes, chewing tobacco, holding moist snuff in mouth, inhaling dry snuff via nose, inhaling smoke from a waterpipe and inhaling vapour from an electronic cigarette.
It can be hard to distinguish effects of nicotine compared to other many toxic substances these products contain.
Mechanism of Action (BMJ, 2014):
Nicotine is a amine that is tertiary including a pyridine and pyrrolidine ring, which joins to nicotinic cholinergic receptors (nAChRs), causing the discharge of dopamine and other neurotransmitter including noradrenaline (norepinephrine), acetylcholine, serotonin, gamma-aminobutyric acid, glutamate and endorphins.
Constant cigarette smoking decreases brain monoamine oxidase A and B activity, this causes higher amount of monoaminergic neurotransmitters such as dopamine and noradrenaline in synapses, increasing the nicotine effects and giving addiction.
Reoccurring exposure to nicotine, tolerance starts building with higher number of nAChR binding locations in brain, believed to constitute up-regulation in reaction to nicotine-mediated desensitization of receptors.
Signs and Symptoms of Nicotine, begins at 3:02:(Audiopedia, 2014)
Figure 1 (Schep, 2009):
This table depicts the signs and symptoms of severe nicotinic and nicotinic-like alkaloids exposure.
Treatment (basicfirstaid.ca):
Wash affected areas of the skin with soap and water for 15 minutes.
Put some sugar under the tongue.
Drink Plenty of water or eat a tablespoon of honey.
Induce vomiting or let the person have activated charcoal to eliminate the poison from the body.
Mouth-to-mouth resuscitation or CPR in case the persona has difficulty breathing.
Perform oral suction in case of severe drooling or salivation.
Oxygen and artificial ventilation when the person has seizures or coma.
Perform Gastric lavage.
Toxicokinetics (Schep, 2009):
Nicotine is mainly absorbed through all routes of the exposure including gastrointestinal, dermal, intranasal, and inhalation routes.
Nicotine has a increased degree of first-pass metabolism with 70-75% being metabolized pre-systemically.
Nicotine is rapidly and widely distributed throughout most of the body with volume of distribution of 1-3L/kg.
After intravenous dosing, Nicotine can also distribute to the GI tract, hinting enterohepatic circulation or passive diffusion.
Nicotine is mainly metabolized by the liver with the making of many metabolites which includes cotinine up to 70-80% of times.
It is mainly excreted in the urine with terminal half-life averaging 2 hours, and there might be variability depending on the individual which could range from 1-4 hours.
Carcinogenicity: (BMJ, 2014)
Nicotine is not a direct carcinogen, there is no evidence that medicinal nicotine is carcinogenic.
Sources:
Drug and Therapeutics Bulletin. Republished: Nicotine and health. BMJ. 2014 Nov 26;349:2014.7.0264rep. doi: 10.1136/bmj.2014.7.0264rep. PMID: 25428425.
Carbon tetrachloride can evaporate into the air or leach into groundwater from its disposal in landfills.
People can also be exposed to carbon tetrachloride in air and from accidental releases from production and uses.
Carbon tetrachloride is a contaminant of indoor air; the sources that cause exposure are building materials or products as well as cleaning agents utilized in the home.
Drinking contaminated water can also expose individuals to carbon tetrachloride.
Almost all of the Carbon tetrachloride is eliminated from the body unaltered. However, there might be some of it altered to other chemicals (chloroform, hexachloroethane, and carbon dioxide) before leaving the body. Chloroform and hexachloroethane can themselves cause dangerous conditions.
Mechanism of Action: (cdc.gov)
Carbon tetrachloride oral exposure has been linked to have adverse effects on the liver. Most importantly damage of the smooth and rough endoplasmic reticulum and its connection to enzyme activities, protein synthesis inhibition, fat accumulating resulting from inability to secrete triglycerides, centrilobular necrosis and ultimately fibrosis and necrosis.
Regenerative proliferation is proof of hepatic injury caused carbon tetrachloride ingestion, originally affecting the peri-portal zone and spreads in dose-dependent response to the perivenous-to-midlobular zones.
In rats 7,970 mg/kg of carbon tetrachloride was exposed and showed a peak increase in ALT serum levels at 24 hours and AST levels at 48 hours as well as increased activity of DNA-synthesizing enzymes, thymidine kinase and thymidylate synthetase was also seen at 48-72 hours.
These led to the conclusion of initial leakage of enzymes from ruined hepatocytes trailed by cell regeneration.
This figure depicts the carbon tetrachloride interaction with the lipids and its consequences.
Toxicokinetics: (cdc.gov)
Carbon tetrachloride is easily absorbed from the gastrointestinal and respiratory tracts with gradual absorption through the skin.
Carbon tetrachloride is distributed to all major organs with elevated concentrations in the fat, liver, bone marrow, adrenals, blood, brain, spinal cord and kidneys.
When carbon tetrachloride is absorbed, it is metabolized by cytochrome P-450 enzymes with the making of the trichloromethyl radical.
This metabolism of the trichloromethyl radical can aerobically form phosgene. When left in the absence of free oxygen trichloromethyl radical can go through reactions to make chloroform, hexachloroethane, or carbon monoxide, and bind straight to lipids, proteins, and deoxyribonucleic acid (DNA).
Carbon tetrachloride is excreted mainly in expired air with initial elimination half-life of 1-3 hours and in the feces meanwhile very low amounts are expelled in the urine.
This figure represents physiologically based pharmacokinetic model for a exploratory chemical substance, it is absorbed by the skin by inhalation, ingestion, metabolized in the liver and excreted in the urine or by exhalation.
Populations Unusually Susceptible: (cdc.gov)
Individuals who are average to heavy drinkers are at notably higher risk of liver and/or kidney injury after ingestion or inhalation of carbon tetrachloride.
Professional exposure to isopropanol has been linked to noticeably increase the hepatic or renal toxicity of carbon tetrachloride in men and women.
Essential exposure to alcohol and ketones can occur in professional settings or in the use of household products containing chemicals.
Mixed function oxygenase (MFO) inducers drugs like phenobarbital, pentobarbital, and phenylbutazone can greatly increase the toxicity of carbon tetrachloride by increasing its biotransformation to reactive, cytotoxic metabolites.
Exposure to insecticides such as DDT, chlordecone, or mirex, or to industrial chemical such as PCBs or PBBs as all of these chemicals are MFO inducers have shown to increase the hepatotoxicity of carbon tetrachloride.
Hepatic ATP levels can impact the final outcome of toxicity as low levels tend to block recovery mechanisms.
Carcinogenicity: (cdc.gov)
International Agency for Research on Cancer (IARC) has categorized carbon tetrachloride in Group 2B, possibly carcinogenic to humans.
Carbon tetrachloride being converted to reactive metabolites that sticks to nuclear protein, lipids, and DNA may be applicable to better understand carbon tetrachloride carcinogenicity.
Hepatic carcinogenicity has been seen in lab rodents after chronic-duration inhalation or oral exposure to carbon tetrachloride.
Biomarkers: (cdc.gov)
Elevated bilirubin levels following exposures has been seen in humans and reduced serum levels of produced liver proteins.
Elevations in serum levels of enzymes, alkaline phosphatase and gamma-glutamyl transferase set free from ruined hepatocytes have been confirmed in occupational exposures more than 1 ppm enduring months to years.
Liver-type arginase (ARG) is a sensitive biomarker for severe exposure to carbon tetrachloride and ascribe its design of appearance in serum because it is a cytosolic enzyme and its tiny molecular weight compared to other enzyme biomarkers.
Lipid peroxidation, elevated erythrocyte membrane cholesterol/phospholipid ration as well as reduced erythrocyte ATPase activity were all linked with the start of carbon tetrachloride-induced liver cirrhosis.
Signs and Symptoms: (cdc.gov)
Headache
Dizziness
Sleepiness
Nausea and vomiting
Jaundice
Swollen and tender liver
Elevated serum enzymes = hepatocellular injury
Hypertension
Pulmonary edema
Dyspepsia
Gastrointestinal pain
Giddiness
lethargy
Stupor
Treatment: (cdc.gov)
Consultation of medical toxicologists and poison control centers
Tin is found mainly in cassiterite (SnO2) from which it is reduced with coal in a reverberatory furnace. Tin’s world supply is largely exported from Malaysia, Bolivia, Indonesia, the Republic of Congo, Thailand, and Nigeria. United States being the main consumers has some deposits in Alaska and California, but produces none. Some important alloys that utilize tin are Type metal, fusible metal, bell metal, Babbitt metal, white metal, pewter, bronze, phosphor bronze, soft solder and die casting alloy (Schäfer, 1984).
Certain Organotins: Triphenyltin, tributylin, dibutyltin and dioctyltin cause Thymic atrophy by reducing the number of cortical thymocytes which decreases thymus weight. T-cell mediated responses are crushed with prolonged exposure. Thymocytes that are loss appears to cause suppression of proliferation of immature thymocytes with apoptosis of mature thymocytes at higher dosage. In thymocyte cell direct effects on thymus as both cytotoxicity and apoptosis has been seen when exposed to di-or-tributyltin and triphenyltin. Supression of DNA and protein synthesis can also be caused by cytotoxicity of butyltin compounds in thymocyte. The start of apoptosis causes an increase in cytosolic ionized calcium concentration as a result of intracellular calcium stores as well as interference of calcium transport at the cell membrane. This dysregulation of calcium level has direct effects on energy metabolism of mitochondria causes uncontrolled production of reaction oxygen species, liberating of cytochrome C to the cytosol and apoptosis (Agency of Toxic Substance and Disease Registry).
Toxicokinetics on Tin and Tin compounds lack persuading evidence for expert Physiologically based pharmacokinetic model. There has been no estimates on absorption of inhaled inorganic or organotin compounds. Animal studies imply that redox state and number of alkyl moieties influence gastrointestinal absorption of tin compounds. No information on the distribution of specific inorganic or organotin compounds in humans. Quantitative estimates of rates of elimination rates of absorbed tin in human is not yet made available. Animals studies have shown that elimination rates differ with chemical across species for the tin compound of interest (Agency of Toxic Substance and Disease Registry).
Image source can be found here. Page 172. This figure depicts the tin level distribution in the Human Tissues with Bone having the highest Wet weight.
Biomarker:
There are no model that would support quantitative estimates of exposure to tin and tin compounds on the basis of blood or urine levels of tin or a specific organotin or metabolite. Further research on this can help test the prevalence and magnitude of exposure in an at-risk population (Agency of Toxic Substance and Disease Registry).
Populations that are Susceptible:
No Specific population has been observed that is unusually susceptible to the effects of exposure to organotin compounds or tin and tin compounds. Although studies have suggested that inorganic tin affects the metabolism of various essential trace elements. For example, zinc absorption is reduced when dietary tin levels are high than those in normal diets this reduces growth and reduces plasma copper levels and leads to anemia. As a result, children or adults who intake diets already poor in these mineral may have higher risks of developing signs of lack of zinc or copper if their dietary tin is excessive like in a canned food based diet. It is vital to remember that >90% of tin-lined cans used for food today are coated with lacquer (Agency of Toxic Substance and Disease Registry).
Symptoms, Exposure and Treatment
Resources:
Schäfer SG. Tin–a toxic heavy metal? A review of the literature. Regulatory toxicology and pharmacology. 03/1984;4(1):57-69. doi: 10.1016/0273-2300(84)90006-0.
Glyphosate [N-(phosphonomethyl) glycine] is the widely utilized herbicide in the world. It is known for efficiently destroying weeds at low cost as well as its perceived low toxicity, rapid absorption by plants, and slow evolution of glyphosate resistance in weeds. In 2011, it received 5.5 billion dollars in sales and a global demand of approximately half a million tonnes per year. It is adopted in soybean, corn, cotton, canola and sugarbeet due to its effectiveness in glyphosate-resistant crops combining with its broad spectrum of control at a relatively cheap cost.
Glyphosate is a non-selective, systemic, post emergence herbicide which inhibits enzyme 5-enolphyruvylshikimate-3-phosphate synthase (ESPS) in the shikimate pathway, which produces aromatic amino acids utilized for the production of proteins and plays a key role in the production of secondary metabolite; lignin. This inhibition restricts the shikimate pathway causing uncontrolled carbon flow and depletes compounds needed for carbon fixation, this ruins organisms metabolism.
Glyphosate is easily absorbed through the gastrointestinal tract; not lot of glyphosate gets absorbed through the skin and is assumed to get easily absorbed through the respiratory tract.
Glyphosate does not get gathered up in any specific organ or tissues but is easily distributed by the blood.
Glyphosate does not go through significant metabolism in mammals; less than 1% is metabolized to aminomethylphosphonic acid (AMPA).
2/3 of an oral dose is excreted in the feces as parent compound that is unabsorbed. Almost all the glyphosate is quickly excreted in urine as parent compound.
Figure 1: (cdc.gov) Image source can be found here
Pgs.: A-12 – A-14.
Summary: This figure depicts the most sensitive endpoint being gastrointestinal die to its oral chronic-duration of laboratory animals to glyphosate. Inflammation of gastric squamous mucosa was observed in female but not male rats. Even though salivary gland cytoplasmic changes were eminent in rats, theses changes were only of little or mild severity and are not considered adverse effects.
Biomarkers (cdc.gov):
Glyphosate and its metabolite AMPA have been found in blood and urine, but most absorbed glyphosate is easily excreted as parent compound and urine is usually considered to be a stronger biomarker of exposure because level of detection is lower than blood. Best quantification would require immediate analysis of blood and urine within hours of exposure.
Treatment (Bradberry, 2004):
Gastric lavage is an option for someone who has ingested life-threatening amount of a concentrated glyphosate formulation within 1 hour.
Appropriate use of crystalloids, colloids and blood products can be used to treat hypotension and fluid loss.
Most severe poisoning likely requires intubation and mechanical ventilation.
Sodium bicarbonate can be used for significant acidosis.
Electrocardiogram should be performed in all symptomatic cases.
Skin contamination can be managed by removal of contaminated clothing and washing with soap and water.
Eye contamination should be managed with sufficient irrigation.
Resources:
1.) Bai SH, Ogbourne SM. Glyphosate: environmental contamination, toxicity and potential risks to human health via food contamination. Environ Sci Pollut Res Int. 2016 Oct;23(19):18988-9001. doi: 10.1007/s11356-016-7425-3. Epub 2016 Aug 19. PMID: 27541149.
2.)Heap I, Duke SO. Overview of glyphosate-resistant weeds worldwide. Pest Manag Sci. 2018 May;74(5):1040-1049. doi: 10.1002/ps.4760. Epub 2017 Nov 29. PMID: 29024306.
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