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Hello everyone my name is Kwabina Larbi and I am a student in the Masters of Translational Pharmacology Program at The Ohio State University. This is my final blog entry and it covers some of the topics we discussed throughout the semester. We were asked to create a blog post on pesticides, metals, solvent, and plants and animal toxicity. Below is a brief summary of my blog entry.

Pesticide toxicity: Nicotine is what I talked about in this post. Nicotine is a highly addictive chemical compound present in the tobacco plant. Nicotine is well known to have serious systemic side effects on the peripheral and central nervous systems. I talked about the source, biotransformation, toxicokinetic, carcinogenicity, mechanism of action, target organ(s), signs and symptoms of toxicity, genetic susceptibility or heritable traits, historic or unique exposure, biomarkers, and treatment of nicotine. To read more about my nicotine blog entry, click on this link: https://u.osu.edu/larbi-7/2021/05/25/pesticide-blog-nicotine/

Metal toxicity: For my metal toxicity, I wrote about lead (Pb). During my research on lead, I found out lead poisoning, for the most part, is asymptomatic. The vast majority of cases, therefore, go undiagnosed and untreated. I talked about the source, biotransformation, toxicokinetic, carcinogenicity, mechanism of action, target organ(s), and symptoms of toxicity, genetic susceptibility or heritable traits, historic or unique exposure, biomarkers, deficiency and treatment of lead toxicity. Click on this link to read more about my lead blog entry: https://u.osu.edu/larbi-7/metal-blog-entry-leadpb/

Solvent toxicity: In the solvent category, my choice was diethylene glycol. Diethylene glycol is an important industrial chemical that, when managed appropriately, has numerous safe uses. The following components were discussed: source/uses, toxicokinetic, carcinogenicity, mechanism of action, target organ(s), Signs and symptoms of toxicity, biomarkers, Historical or unique exposures, and treatment of diethylene glycol toxicity. Read more about my diethylene blog by following this link: https://u.osu.edu/larbi-7/2021/07/06/diethylene-glycol-blog-entry/

Plant and animal toxicity: So, for this blog, I chose plant toxicity and the plant I wrote about was foxglove. This was an interesting choice because ingestion of any parts of the foxglove plant can result in severe poisoning. Yet, the plant is extracted to produce a very powerful cardiac medicine called digoxin. In this blog, I included a video that shows how digoxin is extracted from the leaves. To read more about my blog on foxglove, click on this link: https://u.osu.edu/larbi-7/2021/07/28/foxglove-blog-entry/

Foxglove is an herbaceous biennial or short-lived plant with flowers arranged in a terminal elongated cluster; flowers are typically purple, but some species may have pink, yellow, or white flowers. Due to the presence of the cardiac glycosides, mostly digitoxin, foxglove leaves are poisonous to human and may be fatal if ingested.¹

Source of image.

The table below is the classification of foxglove.

This film describes the chemical composition and medicinal properties of the common foxglove (Digitalis purpurea), and shows how digoxin is extracted from the leaves of the white Danubian foxglove (Digitalis Lanata).

• Source/uses

Withering an English physician, used digitalis for a wide variety of ailments, including anasarca (generalized edema), epilepsy, hydrothorax (fluid in the pleural cavities), ovarian dropsy, and phthisis pulmonalis (probably tuberculosis). Today, foxglove leaves are extracted to yield digoxin, a cardiac glycoside.⁴

• Mechanism of Action (if known)

The main mechanism of action of foxglove (digitalis) is on the sodium-potassium ATPase of the myocyte. It reversibly inhibits the ATPase resulting in increased intracellular sodium levels. The build-up of intracellular sodium leads to a shift of sodium extracellularly through another channel in exchange for calcium ions. This influx of intracellular calcium assists with myocyte contractility.³

• Signs and symptoms of toxicity

Foxglove plants contain toxic cardiac glycosides. Ingestion of any parts of the plant can result in severe poisoning. Symptoms include nausea, headache, skin irritation and diarrhea. In severe cases it can lead to visual and perceptual disturbances and heart and kidney problems.²

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• Treatments

Treatment involves early recognition and the administration of antibodies specifically against digoxin also known as Fab fragments. Empiric treatment consists of 10 vials of Fab fragments for adults and five vials for children.

Activated charcoal can be considered in the treatment of acute ingestion within two hours. Further treatment is supportive.³

References

1. Negroni, M. S., Marengo, A., Caruso, D., Tayar, A., Rubiolo, P., Giavarini, F., Persampieri, S., Sangiovanni, E., Davanzo, F., Carugo, S., Colombo, M. L., & Dell’Agli, M. (2019). A Case Report of Accidental Intoxication following Ingestion of Foxglove Confused with Borage: High Digoxinemia without Major Complications. Case Reports in Cardiology, 2019, 1–6. https://doi.org/10.1155/2019/9707428
2. https://www.woodlandtrust.org.uk/blog/2020/07/uk-poisonous-plants/
3. Rehman R, Hai O. Digitalis Toxicity. [Updated 2021 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459165/
4. Digitalis: The flower, the drug, the poison. American Association for the Advancement of Science. (n.d.). https://www.aaas.org/digitalis-flower-drug-poison.

Diethylene glycol (DEG) is a clear, colorless, practically odorless, viscous, hygroscopic liquid with a sweetish taste.¹

Source of image.                                                  Source of image.

Source/Uses: DEG is used as a component of multiple different products including antifreeze preparations, cosmetics, lubricants, brake fluids, wallpaper strippers, heating/cooling fuel and as a plasticizer.²

Toxicokinetic:

DEG is rapidly absorbed and distributed within the body following ingestion. Metabolism occurs principally in the liver and both the parent and the metabolite, 2-hydroxyethoxyacetic acid (HEAA), are renally eliminated rapidly.¹

Metabolism of diethylene glycol in rats and humans. Source of image. 

Carcinogenicity:

There is no evidence of a direct carcinogenic effect of diethylene glycol.

Mechanism of action:

Although the mechanism of toxicity is not clearly understood, research suggests that the DEG metabolite, HEAA, is the major contributor to renal and neurological toxicities.¹

Target organ(s):

The target organs for acute DEG toxicity are the kidney, liver, and nervous system.³

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Signs and symptoms of toxicity:

There are three phases of DEG poisoning.

• Phase one is characterized by GI symptoms, inebriation and the development of a metabolic acidosis.
• Phase two is characterized by renal failure.
• Patients develop a variety of neurologic complications in phase three. The mortality rate remains high despite aggressive therapy.¹

Treatment:

Initial treatment consists of appropriate airway management and attention to acid-base abnormalities. Prompt use of fomepizole or ethanol is important in preventing the formation of the toxic metabolite HEAA; hemodialysis can also be critical, and assisted ventilation may be required.¹

Biomarkers:

A case-control study in 2006 to characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens concluded Diglycolic acid is associated with human DEG poisoning and may be a biomarker for poisoning.⁴

Historical or unique exposures:

The first mass poisoning was the sulfanilamide-Massengil disaster in the United States in 1937.  There have subsequently been a dozen additional epidemics involving numerous cases, and many deaths.²

The table below is the summary of major diethylene glycol mass poisoning incidences.

References:

1. Schep LJ, Slaughter RJ, Temple WA, Beasley DM. Diethylene glycol poisoning. Clin Toxicol (Phila). 2009 Jul;47(6):525-35. doi: 10.1080/15563650903086444. Erratum in: Clin Toxicol (Phila). 2009 Sep;47(8):840. PMID: 19586352.
2. Diethylene Glycol Poisoning · California Poison Control System (CPCS). California Poison Control System (CPCS). (2018, September 20). https://calpoison.org/news/diethylene-glycol-poisoning.
3. Besenhofer, L. M., Adegboyega, P. A., Bartels, M., Filary, M. J., Perala, A. W., McLaren, M. C., & McMartin, K. E. (2010). Inhibition of Metabolism of Diethylene Glycol Prevents Target Organ Toxicity in Rats. Toxicological Sciences, 117(1), 25–35. https://doi.org/10.1093/toxsci/kfq167
4. Schier JG, Hunt DR, Perala A, McMartin KE, Bartels MJ, Lewis LS, McGeehin MA, Flanders WD. Characterizing concentrations of diethylene glycol and suspected metabolites in human serum, urine, and cerebrospinal fluid samples from the Panama DEG mass poisoning. Clin Toxicol (Phila). 2013 Dec;51(10):923-9. doi: 10.3109/15563650.2013.850504. Epub 2013 Nov 25. PMID: 24266434; PMCID: PMC4547770.

Nicotine is considered a health hazard because it causes human addiction to tobacco and is also the major toxic component presented in tobacco wastes. Nicotine has been designated as a Toxic Release Inventory chemical by the U.S. Environmental Protection Agency since 1994 (Wang et al.)

For a brief introduction on what nicotine is, view video here

Structure:

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Source: According to Food and Drug Administration, “nicotine is a highly addictive chemical compound present in the tobacco plant. Tobacco products, including cigarettes, cigars, smokeless tobacco, hookah tobacco, and most e-cigarettes, contain nicotine”

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Biotransformation: In research from Wang et al. (2012), Nicotine can be transformed by bacteria into hydroxylated-pyridine intermediates, which are important precursors for the chemical synthesis of valuable drugs and insecticides. Such biotransformation could be a useful approach to utilize tobacco and its wastes.

Toxicokinetic: Nicotine like any other drug passes in four different phases namely Absorption, Distribution, Metabolism and Elimination. Nicotine is absorbed via the lung, oral and nasal mucosa, skin, and gastrointestinal (GI) tract. Nicotine has an apparent volume of distribution in adults of 1.7–3.0 l kg−1.Nicotine is extensively metabolized by first pass metabolism in the liver. Nicotine and its metabolites are rapidly excreted in the urine ((Holloway, 2014).

Carcinogenicity:  A study conducted by Sanner and Grimsrud (2014) suggests at present it is not possible to draw any conclusion with regard to the potential carcinogenic effect of long-term treatment with nicotine. The authors also said tobacco products contain various amounts of carcinogenic substances, such as polycyclic hydrocarbons (PAH) and TSNA, which undoubtedly play an important role in cancer development.

Mechanism of action: According to (Chaturvedi et al., 2015) Nicotine acts via 3 major mechanisms. These mechanisms produce physiological and pathological effects on a variety of organ systems. The three mechanisms are Ganglionic transmission, Nicotinic acetylcholine receptors (nAChRs) on chromaffin cells via catecholamines and Central nervous system (CNS) stimulation of nAChRs.

View video of mechanism of action here

Target organ(s): Nicotine is well known to have serious systemic side effects (Chaturvedi et al., 2015). Target organs are the peripheral and central nervous systems which include nerves outside the brain, and the brain and spinal cord respectively.

Source of image

Signs and symptoms of toxicity: Despite the fact that smokers regularly inhale small quantities of nicotine in tobacco smoke, nicotine in pure form is extremely toxic to mammals and is considered a Class I (most dangerous) poison. Nicotine is particularly hazardous because it penetrates skin, eyes, and mucous membranes readily both inhalation and dermal contact may result in death. Ingestion is slightly less hazardous due to the effective detoxifying action of the liver⁷

Image source found here

Genetic susceptibility or heritable traits: There have been major advances in understanding the role of genetics in nicotine dependence. The condition is clearly heritable and has been found to be associated with a large number of individual genetic polymorphisms (MacKillop et al., 2010).

Historical or unique exposures: There were 557 cases of exposure to nicotine-containing substances reported to the California Poison Control System in 2004. The vast majority (85%) involved children aged 5 years and younger. Recreational tobacco products (cigarettes, chewing tobacco, etc.) were involved in 481 cases (86%), pharmaceutical preparations (patches, gum, lozenges) in 72 cases (13%) and nicotine-containing plants in 4 cases (1%)⁹

Treatment: Early decontamination of potentially dangerous ingestions with oral activated charcoal may be beneficial, but might be difficult to achieve due to the common presence of gastrointestinal symptoms and the risk of seizures and coma. No specific antidote exists and treatment consists of symptomatic and supportive care (Nicotine Poisoning, n.d.)

Biomarkers: The most widely used biomarker of nicotine intake is cotinine, which may be measured in blood, urine, saliva, hair, or nails (Benowitz, 2009)

References

1.National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 89594, Nicotine. Retrieved May 22, 2021 from https://pubchem.ncbi.nlm.nih.gov/compound/Nicotine..

 2.Wang, S., Huang, H., Xie, K. et al. Identification of nicotine biotransformation intermediates by Agrobacterium tumefaciens strain S33 suggests a novel nicotine degradation pathway. Appl Microbiol Biotechnol 95, 1567–1578 (2012). https://doi.org/10.1007/s00253-012-4007-2

3.Mishra, A., Chaturvedi, P., Datta, S., Sinukumar, S., Joshi, P., & Garg, A. (2015). Harmful effects of nicotine. Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology, 36(1), 24–31. https://doi.org/10.4103/0971-5851.151771

4.Holloway, A. (2014). Nicotine. Encyclopedia of Toxicology, 514–516. https://doi.org/10.1016/b978-0-12-386454-3.00521-2

5.Benowitz, N. L., Hukkanen, J., & Jacob, P., 3rd (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handbook of experimental pharmacology, (192), 29–60. https://doi.org/10.1007/978-3-540-69248-5_2

6.Sanner, T., & Grimsrud, T. K. (2015). Nicotine: Carcinogenicity and Effects on Response to Cancer Treatment – A Review. Frontiers in Oncology, 5. https://doi.org/10.3389/fonc.2015.00196

7.Landscape IPM. Botanical Insecticides ” Landscape IPM. (n.d.). https://landscapeipm.tamu.edu/types-of-pest-control/chemical-control/organic/botanical/.

8.https://www.fda.gov/tobacco-products/health-information/nicotine-addictive-chemical-tobacco-products

9.Nicotine Poisoning. (n.d.-b). California Poison Control System (CPCS). https://calpoison.org/news/nicotine-poisoning

10.Mackillop, J., Obasi, E., Amlung, M. T., McGeary, J. E., & Knopik, V. S. (2010). The Role of Genetics in Nicotine Dependence: Mapping the Pathways from Genome to Syndrome. Current cardiovascular risk reports, 4(6), 446–453. https://doi.org/10.1007/s12170-010-0132-6