Hello everyone! My name is Caroline Mifsud and I am a student in PHR 7588: Toxic Substances. For my 4 topics, I chose to study Bacillus thuringiensis, arsenic, toluene, and poison ivy. I chose these four particular topics because not only were they specifically interesting to me, but they are all clinically relevant.
In the Bacillus thuringiensis blog, you’ll learn about the role that it plays as a pesticide. Interestingly, it is pretty safe to use in terms of toxicity. You’ll learn about the mechanism of action and how it works as an insecticide.
In the arsenic blog, you’ll learn about the differences between the three types of arsenic compounds: organic, inorganic, and arsine gas. In addition, you’ll discover the variety of places that arsenic can be found. Did you know it’s commonly found in rice and even drinking water? Later, you’ll read about a research study involving rats that suggests arsenic might be considered an essential metal.
In the toluene blog, you’ll explore the many ways that one could be exposed to toluene – and why you should avoid it! There is even some genetic differences in some people who have been exposed to toluene.
Finally, you’ll learn all about poison ivy, the plant that makes us all itchy. Did you know that over 85 percent of people are allergic to this pesky plant? You’ll get to see what a rash from poison ivy looks like, as well as learn about the different remedies to use if you do come into contact with it.
Thanks for taking the time to read my blog – I hope you enjoy!
Poison ivy, also known as Toxicodendron radicans, is a poisonous plant that characteristically has three leaves – as the saying goes “leaves of three, let it be.”
The causative agent in poison ivy, urushiol, is absorbed through the skin. From there, an allergic reaction ensues, and the immune system becomes activated. The rash is usually self-limiting, and the rash will eventually clear up, often without treatment.
The causative agent of poison ivy dermatitis is a substance found on the surface of the leaves called urushiol. After coming into contact with this substance, an allergic skin reaction typically ensues. (American Skin Association, American Osteopathic College of Dermatology).
The immune system produces a protein called interleukin 33 (IL-33), which is what triggers the itching associated with poison ivy dermatitis. In addition to causing inflammation, this protein is also capable of acting on nerves. (Researchers Identify Protein That Triggers Poison Ivy Itch).
Historically, it was thought that poison ivy could be used for medical purposes and healing.
André-Ignace-Joseph Dufresnoy, a physician in the 1700’s, was very interested in the effects of poison ivy and attempted to create medicines from poison ivy to heal skin wounds and even cure paralysis. He made a distilled extract using poison ivy and prescribed it to patients to attempt to “heal them.” He claimed to have positive results, but poison ivy is not used for these purposes today.
A Japanese chemist named Rikou Majima (pictured below) was the first to identify the causative agent in poison ivy as urushiol.
Here is a picture of Rikou Majima with his students.
In most cases, the rash is self-limiting and will heal on its own within two to three weeks. Thus, treatment is not usually required. However, some treatments exist:
over the counter corticosteroid cream
calamine lotion
oatmeal baths
oral antihistamines (diphenhydramine)
soak in a cold water bath
apply a cool compress to the affected area
in some cases, your doctor may prescribe a steroid such as prednisone
Oatmeal baths can be helpful to get rid of itchiness.
Disclaimer: I do not own any of these images or videos. They have been cited with their appropriate link.
References
1. Poison ivy dermatitis—American Osteopathic College of Dermatology (AOCD). https://www.aocd.org/page/PoisonIvyDermatiti. Accessed July 21, 2019.
2. Poison ivy, sumac and oak | American Skin Association. http://www.americanskin.org/resource/poisonivy.php. Accessed July 21, 2019.
3. Poison ivy rash—Symptoms and causes. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/poison-ivy/symptoms-causes/syc-20376485. Accessed July 21, 2019.
4. Poison ivy rash—Diagnosis and treatment—Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/poison-ivy/diagnosis-treatment/drc-20376490. Accessed July 21, 2019.
5. No ill nature: The surprising history and science of poison ivy and its relatives. Science History Institute. https://www.sciencehistory.org/distillations/no-ill-nature-the-surprising-history-and-science-of-poison-ivy-and-its-relatives. Published June 2, 2013. Accessed July 21, 2019.
6. Researchers identify protein that triggers poison ivy itch. National Institute of Environmental Health Sciences. https://www.niehs.nih.gov/research/supported/sep/2017/protein-poison-ivy-itch/index.cfm. Accessed July 21, 2019.
7. U.S. Food and Drug Administration. 4 Tips to Outsmarting Poisonous Plants. https://www.youtube.com/watch?v=CEBpYdgBALg&feature=youtu.be. Accessed July 21, 2019.
8. Centers for Disease Control and Prevention (CDC). How Poison Ivy Works. https://www.youtube.com/watch?v=dgwQ1DHepOw&feature=youtu.be. Accessed July 21, 2019.
9. Mayo Clinic. Mayo Clinic Minute: How to Treat Poison Ivy Rash. https://www.youtube.com/watch?v=G5mBkVdsoEE&feature=youtu.be. Accessed July 21, 2019.
Toluene undergoes biotransformation by the cytochrome P450 enzyme CYP2E1, which is a phase 1 enzyme. Interestingly, it has been found that increased exposure to toluene results in increased CYP2E1 mRNA expression.
Absorption: occurs primarily viathe lungs, but can also occur through the skin (dermal) and through the gastrointestinal tract
Distribution: occurs through organs that are primarily composed of lipids; it is important to note that toluene can readily cross the blood brain barrier and the placenta
Metabolism: in the liver, where it is converted to benzyl alcohol and benzoic acid; metabolized by CYP2E1
Ultimately forms hippuric acid
This dissociates into anions and protons
Excess hippuric acid formation can result in metabolic acidosis, or too much acid in the body, and hypokalemia, or very low potassium levels; this is extremely dangerous
Watch this video to learn more about inhalants, including toluene.
Carcinogenicity
According to the EPA and IARC, toluene cannot be classified as a human carcinogen because of the insufficient evidence available. Therefore, more studies should be conducted to determine the carcinogenic potential of toluene in humans.
There have been many epidemiological studies conducted on the effects of toluene exposure. Here are some interesting examples:
A study in Singapore found that women exposed to toluene while working in an audio speaker factory had higher rates of spontaneous abortion compared to the control group.
A psychiatric study found that male workers who had over 12 years of toluene exposure were more likely to have intellectual impairments such as problems with concentration, learning, and memory when compared to the non-exposed control group.
A study in France examined those exposed to toluene while working in a printing plant found that many of the workers exhibited progressive changes in their color vision.
Cruz SL, Rivera-García MT, Woodward JJ. Review of toluene action: clinical evidence, animal studies and molecular targets. J Drug Alcohol Res. 2014;3. doi:10.4303/jdar/235840
Filley CM, Halliday W, Kleinschmidt-Demasters BK. The Effects of Toluene on the Central Nervous System. J Neuropathol Exp Neurol. 2004;63(1):1-12. doi:10.1093/jnen/63.1.1
Christiani DC, Mehta AJ, Yu C-L. Genetic susceptibility to occupational exposures. Occup Environ Med. 2008;65(6). doi:10.1136/oem.2007.033977
ATSDR – Medical Management Guidelines (MMGs): Toluene. https://www.atsdr.cdc.gov/mmg/mmg.asp?id=157&tid=29. Accessed June 29, 2019.
Arsenic is found in a variety of places, including rocks, soil, water, plants, animals, and the food that we eat. It can be found in its pure form, but it’s most commonly seen in combination with other chemical compounds. These compounds can be organic or inorganic.
Distribution: kidneys, liver, heart, lungs, muscle, nervous system, gastrointestinal tract, spleen, and deposits in keratin-rich areas
Metabolism: hepatic
Excretion: urine
Carcinogenicity
The International Agency for Research on Cancer (IARC) classifies arsenic and inorganic arsenic compounds as “carcinogenic to humans.” Cancer of the lung, bladder, skin, kidney, liver, and prostate is linked to arsenic exposure.
Organic arsenic compounds are less dangerous, as the IARC classifies them as “possibly carcinogenic to humans.” (Arsenic and Cancer Risk).
Mechanism of Action
From a toxicological standpoint, the trivalent and pentavalent states of arsenic are of the most concern. Each will be discussed separately.
Pentavalent arsenic MOA
Inhibition of hexokinase in glycolysis
Replacement of phosphate in the sodium pump of human erythrocytes
Uncoupler of adenosine-5′-triphosphate (ATP) via arsenolysis and subsequent depletion of ATP
Trivalent arsenic MOA
Has the ability to bind strongly to thiol groups which could result in toxicity
Inhibition of pyruvate dehydrogenase, which has downstream effects in the citric acid cycle
Arsenic impacts nearly all organ systems, including the skin, gastrointestinal, cardiovascular, neurological, genitourinary, respiratory, endocrine, and hematological systems (Acute and chronic arsenic toxicity).
If arsenic poisoning is suspected, contaminated clothes should be removed immediately. The skin should be rinsed to remove leftover arsenic that may be present. Treatment for acute arsenic poisoning includes gastric lavage, hemodialysis, and dimercaprol (British anti-Lewisite; pictured below) (Acute and chronic arsenic toxicity).
Studies have shown there is variability in genetic susceptibility to arsenic toxicity. Some genetic polymorphisms in enzymes responsible for arsenic metabolism include:
Arsenic (III) methyltransferase
Glutathione S-transferase
Methylenetetrahydrofolate reductase
Please click here to see more on the genetic polymorphisms involved in arsenic toxicity by going to page 1533, Table 2.
Some individuals possess single nucleotide polymorphisms which render them less likely to repair oxidative damage. This includes the following genes:
HOGG1
APE1
XRCC1
XRCC3
In simpler terms, individuals who have variation in these enzymes or genes can be more susceptible to arsenic toxicity if and when they encounter it.
Although it is up for debate, some studies suggest that arsenic is an essential nutrient that plays a role in methionine metabolism. Methionine (pictured below) metabolism is vital during pregnancy, lactation, and vitamin B6 deprivation (Evidence for arsenic essentiality).
Arsenic deprivation studies have demonstrated that rats deprived of arsenic had changes in their coats and growth rate compared to the control group. Some studies show that arsenic deprivation manifests similarly to vitamin B6 deficiency (Evidence for arsenic essentiality).
Disclaimer: I do not own any of these images. Each image has been cited with its corresponding link.
Ng J, Gomez-Caminero A, International Programme on Chemical Safety, eds. Arsenic and Arsenic Compounds. 2. ed. Geneva: World Health Organization; 2001.
Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. Arsenic Exposure and Toxicology: A Historical Perspective. Toxicological Sciences. 2011;123(2):305-332. doi:10.1093/toxsci/kfr184
Ratnaike RN. Acute and chronic arsenic toxicity. Postgraduate Medical Journal. 2003;79(933):391-396. doi:10.1136/pmj.79.933.391
Uthus EO. Evidence for arsenic essentiality. Environmental Geochemistry and Health. 1992;14(2):55-58. doi:10.1007/BF01783629
Vahter M. Mechanisms of arsenic biotransformation. Toxicology. 2002;181-182:211-217. doi:10.1016/S0300-483X(02)00285-8
Hughes MF. Arsenic toxicity and potential mechanisms of action. Toxicology Letters. 2002;133(1):1-16. doi:10.1016/S0378-4274(02)00084-X
Faita F, Cori L, Bianchi F, Andreassi M. Arsenic-Induced Genotoxicity and Genetic Susceptibility to Arsenic-Related Pathologies. International Journal of Environmental Research and Public Health. 2013;10(4):1527-1546. doi:10.3390/ijerph10041527
Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. Arsenic Exposure and Toxicology: A Historical Perspective. Toxicological Sciences. 2011;123(2):305-332. doi:10.1093/toxsci/kfr184
When Bt enters the body, it remains confined to the gut. While in the gut, it is broken down normally and excreted within 2-3 days. However, if Bt is absorbed through inhalation, it enters the respiratory system and is attacked via an immune response. After this immune response, it only takes about 1 day for Bt levels to markedly decrease. (Bacillus Thuringiensis General Fact Sheet).
Toxicokinetics
If Bt is consumed:
When it enters the body, it is broken down similarly to the way proteins in our diet are broken down.
After an insect ingests Bt, the spores that Bt forms are solubilized and turned into active toxins in the midgut of the insect. They subsequently bind to epithelial cell receptors and insert into the cellular membrane. Next, pores are formed, and the potassium flux across the epithelial cells changes. This leads to changes in pH, causing it to become alkaline. The high pH destroys the epithelial cells of the midgut in the insect. Eventually, they die as a result of gut paralysis and feeding inhibition. Bt is selective because the alkaline conditions under which it operates is much different than the acidic environment of the human stomach (Casarett & Doull).
This video below helps visualize how the Bt toxin works.
Target organs
In insects:
midgut, located in the alimentary canal, of the insect.
In humans and other mammals, there are little to no side effects from Bt as it has relatively low toxicity in species other than insects. Because of the low toxicity of Bt, this makes it a relatively safe insecticide to use. In some cases, Bt has been shown to cause the following symptoms (associated with acute and chronic exposure) in mammals:
skin irritation
eye irritation
allergic skin reactions
weight loss
sleep difficulties
stomach discomfort
nose irritation
throat irritation
Chronic exposure can further result in adverse immune responses.
So far, there are no known genes that render humans more susceptible to the effects of Bt. This is unsurprising as Bt is relatively nontoxic and safe for humans.
Interestingly, the genes of certain crops have been altered to make them resistant to insects by incorporating Bt genes into their genomes (Ibrahim et al). Adding the Bt genes to certain crops makes them insect-resistant and helps ensure their survival.
Historical or unique exposures
One of the most controversial historical issues associated with Bt is some people have claimed that Bt is killing monarch butterflies via pollen from transgenic crops. Many people are against the use of genetically modified crops and food products, for example, crops that are genetically altered to possess Bt genes, giving them resistance against insects. However, entomologists and other researchers have claimed that the effects on the monarch butterflies are “negligible” and the transgenic pollen does not negatively impact them (Clark et al).
In humans, there is no treatment for Bt as the digestive and/or immune system is able to handle the elimination of the toxin. Although side effects such as skin or eye irritation are limited and uncommon, they are easily managed.
Biomarkers
There is a biomarker for Bt spore germination called calcium dipicolinate (CaDPA).
The paper can be found here (Shu-shi Huang et al).
CaDPA is used to characterize the spore germination process.
This biomarker is of use in food safety.
Disclaimer: I do not own any of these images. Each image has been cited with its corresponding link.
References
Klaassen CD, Casarett LJ, Doull J, eds. Casarett and Doull’s Toxicology: The Basic Science of Poisons. 8th ed. New York: McGraw-Hill Education; 2013.
Bacillus thuringiensis (Bt) General Fact Sheet. http://npic.orst.edu/factsheets/btgen.html. Accessed May 18, 2019.
Ibrahim MA, Griko N, Junker M, Bulla LA. Bacillus thuringiensis: A genomics and proteomics perspective. Bioengineered Bugs. 2010;1(1):31-50. doi:10.4161/bbug.1.1.10519
Clarke T. Monarchs safe from Bt. Nature. September 2001. doi:10.1038/news010913-12
PubChem. Calcium dipicolinate. https://pubchem.ncbi.nlm.nih.gov/compound/9900462. Accessed May 18, 2019.
Shu-shi Huang, De Chen, Yong-qing Li. Detection of bacillus thuringiensis spore germination via CaDPA biomarker using laser tweezers raman spectroscopy. In: 2007 Quantum Electronics and Laser Science Conference. ; 2007:1-2. doi:10.1109/QELS.2007.4431273
