toxicity

Styrene Toxicity

What is Styrene?

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Styrene’s chemical structure

Styrene > Polymerization > Polystyrene Graphic

Polystyrene plastic chemical structure

Styrene is a colorless, clear liquid. It has a sweet smell and can be found in nature as well as manufactured. Styrene was originally found in the oriental sweetgum tree (levant styrax). It can also be found in common foods and beverages, such as strawberries, coffee, cinnamon, peanuts, and tobacco. Manufactured styrene has a wide range of uses and is a component of many goods, including: polystyrene, fiberglass, packaging materials, electrical insulation, home insulation, drinking cups and food packaging, rubber, and carpet backing.

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Uses of styrene

How Does Styrene’s Biotransformation Lead to Carcinogenicity?

The main method of styrene exposure is inhalation. A small amount of styrene is ingested or absorbed through dermal contact. Styrene is extensively metabolized by the body enzymes into other chemicals that are excreted through urine.

FIGURE 3-1. Primary metabolic pathways of styrene.

Metabolic action is required for carcinogenicity and toxicity. In the photo below, the metabolites from styrene bond to the DNA base guanine and cause carcinogenic effects.

Image result for styrene toxicity

 

What is Known of Styrene’s Toxicokinetics and Mechanism of Action?

Not much is known about styrene’s mechanism of action or toxicokinetics. Styrene can be oxidized by many CYP450 isozymes, so activation and deactivation of styrene can vary based on tissue type. It is metabolized in mice in the liver and lungs. Styrene-7,8-oxide is a metabolite of styrene that is genotoxic and can travel by blood in humans. This indicates that it can cause tumor growth in locations other than where it is formed. The tumorigenic response of styrene is dependent on the balance between the rate of activation and rate of detoxification, though information on these rates in humans is not available.

What are the Known Target Organs of Styrene?

  • Lymphohematopoietic system
  • Esophagus
  • Pancreas
  • Kidney
  • Lungs

Signs and Symptoms of Styrene Toxicity

Acute:

  • Mucus membrane irritation
  • Eye irritation
  • Gastrointestinal effects
  • Metallic taste
  • Drowsiness
  • Vertigo
  • Slight muscular weakness

Chronic:

  • Central nervous system effects
    • changes in color vision
    • feeling “drunk”
    • impaired learning
    • headache
    • fatigue
    • weakness
    • depression
    • dysfunction
  • Hearing loss
  • Peripheral neuropathy
  • Dermatitis and blistered skin
  • Liver effects
    • increased serum bile acid
    • enhanced plasma enzyme activity
  • Reproductive effects
    • decreased births
    • increased spontaneous abortions
    • Sperm damage
  • “Reasonably anticipated to be a human carcinogen” by The Department of Health and Human Services National Toxicology Program
    • Lymphohematopoietic cancers
      • Leukemia
      • Lymphoma
    • Pancreatic tumors
    • Esophageal tumors

Is There Genetic Susceptibility to Styrene?

There is some evidence that workers exposed to styrene that have the GSTT1 null genotype have an increase in micronucleated binucleated cells (MNBD). This suggests that styrene has genotoxic effects on exposed workers that is potentiated by the GSTT1 gene deletion.

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572017000500727

Areas where GSTT1-null genotype are found

History of Styrene

In 1839, German apothecary Eduard Simon isolated styrene from the sap of the oriental sweetgum tree. He called it Styrol. After exposure to light, air, or heat, Styrol hardened into a rubber-like material he called Styroloxyd, now known as polystyrene.

What Treatments are Available for Styrene Toxicity?

The only treatment for styrene toxicity is treating the effects and symptoms of exposure and avoiding re-exposure to styrene. This includes monitoring for styrene-related cancers and tumors.

References

1. Agency for Toxic Substances and Disease Registry (ATSDR). 2010. Toxicological profile for Styrene. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.

2.DHHS/National Toxicology Program; Report on Carcinogens, Fourteenth Edition: Styrene (November 2016). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Styrene (100-42-5) is listed as reasonably anticipated to be a human carcinogen. http://ntp.niehs.nih.gov/pubhealth/roc/index-1.html

3. Migliore L1, Naccarati A, Coppedè F, Bergamaschi E, De Palma G, Voho A, Manini P, Järventaus H, Mutti A, Norppa H, Hirvonen A. Cytogenetic biomarkers, urinary metabolites and metabolic gene polymorphisms in workers exposed to styrene. 2006 Feb;16(2):87-99.

4. https://www.epa.gov/sites/production/files/2016-09/documents/styrene.pdf

Video 1: https://www.youtube.com/watch?v=iIR1WcxP6RU

Photo 1: https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+171

Photo 2 and 3: https://styrene.org/about-styrene/qa/

Photo 4: https://www.intechopen.com/books/household-hazardous-waste-management/polystyrene-as-hazardous-household-waste

 

 

 

Bismuth: Heavy Metal Toxicity

What is Bismuth and Where is it Found?

Image 1: A bismuth crystal and bismuth’s periodic table information.5

Bismuth (Bi) is a heavy metal with an atomic number of 83 and an atomic mass of 208.9804 atomic mass units (amu).1 Naturally occurring bismuth is very rare, found as bismuthimite and bismite ores.1 Bismuth is commercially produced as a by-product of lead, copper, tin, silver, and gold ore refining. Most bismuth is mined in Peru, Mexico, Bolivia, Japan, and Canada. Elemental bismuth is nontoxic, but bismuth salts can cause toxicity.2

Bismuth salts are relatively insoluble, so environmental and occupational exposure is low. Most toxic exposure to bismuth is from consumption, usually from medicinal use.1

Video 1: How to make bismuth crystals using a bismuth ingot. While not related to bismuth toxicity, this video is an interesting look into some of the properties of bismuth.9

What are the Medicinal Uses of Bismuth?

Bismuth salts are used for a variety of gastrointestinal disorders. Antacids, such as bismuth subnitrate, bismuth subcarbonate, and bismuth subgallate, are used for diarrhea, flatulence, intestinal cramping, constipation, and dyspepsia. Colloidal bismuth subcitrate (CBS), bismuth subsalicylate (Pepto-Bismol®), and bismuth citrate mixed with ranitidine (Tritec®) are used to treat peptic ulcers and gastritis associated with an Helicobacter pylori infection. Bismuth is also used in surgical packing and pastes used for ileostomies and colostomies.3

Table 1: Medicinal products that contain bismuth in the US.6

 

Image 2: Pepto-Bismol is a commonly used and recognized medication made with a bismuth salt.7

What are the Toxicokinetics of Bismuth?

Due to bismuth compounds being relatively insoluble, they are generally poorly absorbed, ~0.2%.1 90% of ingested bismuth is excreted in urine, so the highest concentration of bismuth is found in the kidneys. The elimination half-life is around 21 days.1

What is Bismuth’s Mechanism of Action?

The exact mechanism of action of bismuth is relatively unknown due to lack of data. Large doses of bismuth compounds lead to acute renal injury. The tubular epithelium is the primary site of toxicity, with bismuth leading to the degeneration of renal tubular cells and the production of bismuth-protein nuclear inclusion bodies.1 A large dose of CBS can cause reversible damage to the proximal tubules.1

Chronic bismuth toxicity tends to lead to more neurotoxic and behavioral effects, indicating the accumulation of bismuth in lysosomes and in the reticular, hypothalamic, oculomotor, hypoglossal, and Purkinje cells. Bismuth appears to be distributed by axonal transport.1

Is Bismuth Carcinogenic?

There is no evidence that bismuth is carcinogenic.4

What Organs are Targeted by Bismuth?1

  1. Kidneys
  2. Brain
  3. Liver
  4. Bones

What are the Signs of Bismuth Toxicity?

Bismuth toxicity has acute and chronic clinical features.1

  • Acute toxicity signs include:
    • abdominal pain
    • oliguria
    • acute tubular necrosis
    • renal failure
  • Chronic toxicity signs include:
    • progressive diffuse encephalopathy
    • behavior changes
      • apathy
      • irritability
      • poor concentration
      • poor short-term memory
      • visual hallucinations
    • movement disorders
      • myoclonus
      • ataxia
      • tremors
    • pigmentation of the skin and oral mucosa
    • seizures
    • coma
    • death

Image 3: Encephalopathy with ataxia from chronic bismuth toxicity.8

What Treatment is Available for Bismuth Toxicity?

The main treatment for bismuth toxicity is to discontinue bismuth intake. Chelation therapy can be done using dimercaprol to reduce the concentration of bismuth in the kidneys and liver and increase renal elimination of bismuth. Dimercaprol is the only chelator that can lower the levels of bismuth in brain tissue.1

Is Bismuth an Essential Nutrient? Can Humans be Deficient in Bismuth?

There is no evidence that bismuth is an essential nutrient. Since bismuth is rarely found in the environment, most people that do not take bismuth containing medications are not exposed to bismuth and suffer no negative consequences from their bismuth deficiency.4

References

  1. Tokar EJ, Boyd WA, Freedman JH, Waalkes MP. Toxic Effects of Metals. In: Klaassen CD. eds. Casarett and Doull’s Toxicology: The Basic Science of Poisons, Eighth Edition New York, NY: McGraw-Hill; 2013. http://accesspharmacy.mhmedical.com.proxy.lib.ohio-state.edu/content.aspx?bookid=958&sectionid=53483748. Accessed June 08, 2019.
  2. Bismuth (UK PID). (2019). Retrieved from http://www.inchem.org/documents/ukpids/ukpids/ukpid49.htm
  3. Reynolds, P., Abalos, K., Hopp, J., & Williams, M. (2012). Bismuth Toxicity: A Rare Cause of Neurologic Dysfunction. International Journal Of Clinical Medicine, 03(01), 46-48. doi: 10.4236/ijcm.2012.31010
  4. Gordon, M., Abrams, R., Rubin, D., Barr, W., & Correa, D. (1995). Bismuth subsalicylate toxicity as a cause of prolonged encephalopathy with myoclonus. Movement Disorders, 10(2), 220-222. doi: 10.1002/mds.870100215
  5. Pictures, stories, and facts about the element Bismuth in the Periodic Table. (2019). Retrieved from https://periodictable.com/Elements/083/index.html
  6. Bismuth toxicity. (2019). Retrieved from http://environmentalhealthrisk.blogspot.com/2010/03/bismuth-toxicity.html
  7. Pepto Bismol Chewable Tablets for Nausea, Heartburn, Indigestion, Upset Stomach, and Diarrhea Relief, Original Flavor 12 ct – Walmart.com. (2019). Retrieved from https://www.walmart.com/ip/Pepto-Bismol-Chewable-Tablets-for-Nausea-Heartburn-Indigestion-Upset-Stomach-and-Diarrhea-Relief-Original-Flavor-12-ct/17325219?athcpid=17325219&athpgid=athenaItemPage&athcgid=null&athznid=PWVUB&athieid=v0&athstid=CS020&athguid=7abbc081-359-16b3f310189f30&athena=true
  8. Siram R, Botta R, Kashikunte C, Pal PK, Yadav R. Chronic encephalopathy with ataxia, myoclonus, and auditory neuropathy: A case of bismuth poisoning. Neurol India 2017;65:186-7
  9. How to Make Bismuth Crystals. (2019). Retrieved from https://www.youtube.com/watch?v=v8KYZHMkTHw

Bipyridyl Compounds

What are Bipyridyl Compounds?

Bipyridyl compounds, most notably paraquat and diquat, are commercial herbicides. Paraquat and diquat are bis-quarternary ammonium compounds that each contain a bipyridyl ring and are divalent cations associated with anions; chloride for paraquat and bromide for diquat.¹ Paraquat is the more toxic of these compounds, and has one of the highest acute toxicities of herbicides.² However, both compounds are inactivated by clay soils and ultraviolet light, so there is little risk of chronic exposure. Most toxic events involving bipyridyl compounds are due to accidental or intentional ingestion.¹

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Figure 1: Chemical structures of Paraquat and Diquat, two well known bipyridyl compound herbicides²

What are the Toxicokinetics of Bipyridyl Compounds?

Only a small amount of data is available on the pharmacokinetics/toxicokinetics of bipyridyl compounds. From one Sri Lankan population analysis on paraquat, there appears to be a clearance of 1.17 L/h, a volume of distribution of 2.4 L/kg, and a half-life of 87 hours.¹ Peak plasma concentration in humans is thought to be around 4 hours.¹ The toxicity of paraquat depends greatly on the species, route of exposure, and concentration of solution. Rats appear to have a higher tolerance to paraquat than other species, including humans.² There is also a difference in absorption between species; rats only absorb 1-5% of an oral dose where dogs (and presumably humans) absorb around 45-65% of an oral dose.¹

The intraperitoneal route is the most toxic, followed by the oral route. Absorption and inhalation rarely cause toxicity.² Bipyridyl compounds are excreted through urine, with a large amount of the dose eliminated in the first few hours after ingestion, unchanged. This elimination starts to slow as renal damage occurs and renal function deteriorates.¹ There are several organs that act as reservoirs for paraquat, including the lungs and skeletal muscles. This has resulted in paraquat being found in the urine up to three months after ingestion.¹

What is the Mechanism of Action of Bipyridyl Compounds?

Paraquat is toxic to living organisms due to a process called redox cycling. This is when a drug enters a cell, undergoes a reduction followed by reoxidation. Paraquat is reduced to form free radicals, which are then reoxidized and for a cation and a superoxide anion.

Image not available.

Figure 2: Proposed mechanisms of toxicity for paraquat. 1. Intracellular redox cycling results in the oxidation of NADPH, which leads to cellular depletion, augmented by the detoxification of hydrogen peroxide from the glutathione peroxidase/reductase enzyme system to regenerate GSH, 4. 2. Generation of superoxide anion and hydroxy radicals would initiate lipid peroxidation, 3, and lead to cell death.²

Once absorbed, paraquat accumulates in the lungs and kidneys. Paraquat accumulates in the lungs and causes free radical damage in the alveolar epithelium. This is followed by edema, infiltration of inflammatory cells, and death due to anoxia.² If a person survives this initial phase, there will be proliferation of fibroblasts in the lungs, causing intensive fibrosis leading to progressive loss of lung function.² Similar damage occurs in the renal tissue, leading to reduced renal function.

What Concerns are There Other than Acute Toxicity?

There are no other major toxicological concerns for bipyridyl compounds other than those related to the acute systemic effects of exposure. Bipyridyl compounds have little to no genotoxic activity, no carcionogenic activity, no teratogenic activity, no effects on fertility, and are only fetotoxic at maternal toxic doses.²

Target Organs

Bipyridyl compounds have systemic effects, affecting several organs and systems, including²:

    • epithelium
    • cornea
    • liver
    • kidneys
    • lining of GI tract
    • lining of respiratory tract

The lungs are the primary target organ of paraquat in humans and some other animal species due to the uptake and accumulation of paraquat in type I and II alveolar epithelial cells and Clara cells.¹

respclara1.jpg (73595 bytes)

Figure 3: Clara cells in a histology of lung tissue³

What are Signs and Symptoms of Toxicity?

    • Shortly after ingestion²
      • nausea
      • vomiting
      • abdominal pain
      • diarrhea
    • 48-72 hours after exposure¹²
      • oliguria
      • jaundice
      • cough
        • productive and blood-stained
      • dyspnea
        • due to adult respiratory distress syndrome
        • bronchopneumonia
      • tachypnea
      • pulmonary edema
      • convulsions
      • coma

What Are Treatment Options?

The main treatment for bipyridyl compound poisoning is focused on prevention of absorption from the GI tract, prevention of accumulation in the lungs, use of free radical scavengers, and prevention of lung fibrosis.² Removal of the ingested poison by purging or absorption is the most effective treatment.² Treatment is largely ineffective due to the paraquat reservoirs in the body, leading to poor prognosis for critically ill patients. Once the compound has been absorbed, supportive care and keeping the patient comfortable is the only course of treatment.¹

References

1. Eddleston, M. Bipyridyl Herbicides. Clinical Toxicology 2000, 38, 123-128. DOI 10.1007/978-3-319-20790-2_100-1. https://link.springer.com/content/pdf/10.1007/978-3-319-20790-2_100-1.pdf

2.Klaassen, C.D., Ed. (2013). Casarett and Doull’s Toxicology: The Basic Science of Poisons . 8th Edition, McGraw-Hill. https://accesspharmacy-mhmedical-com.proxy.lib.ohio-state.edu/content.aspx?bookid=958&sectionid=53483747

3.https://inside.ucumberlands.edu/academics/biology/faculty/kuss/courses/Histology/histology02/histo/clara.htm