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Toxicity From The Giant Silkworm Moth (Lonomia Obliqua)

 

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What is the Giant Silkworm Moth?

The giant silkworm moths are members of the Saturniidae family. They range in size from medium to very large moths, they have hairy, stubby bodies and feathery antennae. A female’s antenna can be a feathery or a thin filament. These moths only live a few weeks because they do not feed as they have a little or absent mouthpart. Many species of this family have prominent eyespots and decorated with bright colors.

75 different species of Lonomia Obliqua live in North America north of Mexico and about 16 species live in Missouri including luna, imperial, rosy maple, royal moths, and more.

Lonomia Obliqua larvae are fairly large and rounded with tubercles and spines or hairs. These hairs can cause skin irritation or sting. The larvae or caterpillar stage corresponds with the spring and summer months and this is of concern because this increases the chances of contact with humans.

History and Exposure

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Exposure to Giant silkworm moth larvae (caterpillars) and their bristles can cause a variety of symptoms ranging “from mild discomfort to systemic bleeding” (3).  The earliest records of exposure to lepidopteran caterpillars date back to 1912 in Brazil and were described by Zoroastro Alvarenga. Interactions with Lonomia Obliqua occur mostly through the skin on the upper limbs of children and rural workers. There has shown to be a higher incidence of accidents with Lonomia Obliqua in the spring and summer months, which is the time they are in the caterpillar stage, as stated earlier.

Route of Administration and Effects 

Giant silkworm larvae can release its toxins with anticoagulant properties through its bristles and if it comes into contact with the skin it can cause leukocytosis, anemia, bruising, hematuria, hematoma, vomiting, nausea, headache, a burning sensation at the site, swelling, redness, and pain. Clinically, fibrin degradation products increase, coagulation factor levels decrease, and clotting time increases. However, exposure does not cause a decrease in platelets as usually seen in coagulopathies.

Skin contact symptoms

  • Pain, redness and swelling
  • Burning sensation at the site of contact
  • Headache and nausea
  • Vomiting
  • Hematoma and hematuria
  • Bruising
  • Anemia
  • Leukocytosis

Additional clinical signs following skin contact

  • Increased clotting time
  • Increase in fibrin degradation products
  • Decrease in coagulation factor levels

It is important to note that more severe cases of poison from Lonomia Obliqua have been studied in relatively recent times, and more surprising findings have come to light. Experimental findings have led researchers to believe that the venom released from Lonomia Obliqua larvae damages the blood-brain barrier.  Renal failure has also been reported.

Mechanism of action

Systemic vascular and inflammatory disorders can be stimulated by the venom of Lonomia Obliqua. By increasing intravascular thrombin ( a protein that causes blood clotting) concentration and disrupts endothelial cell monolayers, leading to hemorrhagic conditions and few leukocytes in test animals (5).L. Obliqua is thought to indirectly cause an up-regulation of several genes involved in the amplification and generation of the clinical manifestations listed above. There is evidence that supports that Obliqua venom has bioactive peptides that change the migratory characteristics of different cell types.

Cell migration involves molecules on cells itself, and in the extracellular matrix, and L. Obliqua venom seems to interfere with both which can influence cell migration and blood vessel permeability. an important part of cell migration is coordinated by the Rho family GTPases. Rac1 promotes or initiates actin assembly which is involved in cell to extracellular matrix adhesion and cell to cell adhesion. When certain RhoGTPases regulators (Rho GAP 21, Rho GEF 12) are modified by LOBE (L.Obliqua Bristle extract), this may cause activation Rac1 and cause an increase in cell membrane protrusion. This makes all of the previously mentioned molecules good biomarkers in the clinical setting.

Currently, the only known treatment for L. Obliqua envenomation is Lonomia Antivenom (LAV).

References:

(1) http://www.naturenorth.com/spring/bug/silkmoth/Fsilk2.html Accessed July 27th, 2020

(2) http://web.b.ebscohost.com.proxy.lib.ohio-state.edu/ehost/pdfviewer/pdfviewer?vid=2&sid=1ddac6a9-86ce-4b27-8281-ced3b1fb6fb9%40pdc-v-sessmgr05 Accessed July 27th, 2o2o

(3) https://www-sciencedirect-com.proxy.lib.ohio-state.edu/science/article/pii/S0041010104003198 Accessed July 27th, 2020

(4) https://onnaturemagazine.com/butterfly-and-moth-guide.html Accessed July 27th, 2020

(5) https://www-sciencedirect-com.proxy.lib.ohio-state.edu/science/article/pii/S0041010119300601 Accessed July 28th, 2020

Carbon Disulfide Toxicity

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Sources and Exposures of Carbon Disulfide

Carbon disulfide is not a naturally occurring constituent of the surrounding environment. In fact, it was discovered in a laboratory in the year 1796 (3). Carbon disulfide is used in the industrial production of materials such as rayon, which is a man-made fiber made from wood and other agricultural material. It is important to note that carbon disulfide was widely used to vulcanize rubber or melt to extreme heats to improve elasticity. It is no longer used for this purpose but still has a variety of industrial applications. The primary route of exposure of carbon disulfide to humans is inhalation. If industrial workers or people in a community surrounding industrial plants that use carbon disulfide are exposed to the substance, it can cause deleterious effects, especially if in large amounts.

The opening image is of a book that tells a story of “an epidemic of mental cases that struck a rayon plant in Delaware” (4). Unfortunately, toxicities of some substances are unknown until occupational exposures, for example, cause an outbreak of similar symptoms in a large number of people.

 

Mechanism of Action (How it Works)

Target Organs/Systems

Carbon disulfide toxicity is shown to interfere in the metabolism in different organ systems in the human body. This includes:

  • The CNS
  • Respiratory system
  • Cardiovascular system
  • GI system
  • Ocular/Ophthalmic
  • Dermal

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Mechanism of Action

The mechanism of action for carbon disulfide is not fully understood just yet, however it is thought that it forms metabolites like dithiocarbamates and possibly other derivatives that can have severe effects on human organs as pictured in the figure above.

Acute Exposures of Carbon Disulfide

Adverse effects after acute toxic exposure seem to have an immediate onset. Local irritation can progress to concentration-dependent neurological symptoms. Dizziness, nausea, delusions, hallucinations, mania, and blurred vision are some of the symptoms following acute exposure.

Chronic Exposures of Carbon Disulfide

Chronic exposures can look much like acute exposures but at reduced levels of exposure. Chronic exposures may cause

  • Permanent peripheral and central nervous system damage
  • Atherosclerotic like manifestations
  • ECG abnormalities
  • Kidney damage
  • Liver degeneration
  • Hearing loss
  • Sexual dysfunction
  • Retinal microaneurysm
  • Visual disturbances
  • Gastrointestinal disturbances

It is thought that chronic exposures may be more detrimental for children due to the possibility of longer latency periods of toxic substances in younger individuals.

Sings and Symptoms

Lab test include chest radiography, electrocardiogram, blood chemistry, and arterial blood gasses where the presence can be detected.

Clinical signs

  • Skin irritation
  • Eye irritation
  • CNS depression
  • Psychiatric manifestations (delirium and psychosis)
  • CNS Motor abnormalities (parkinsonism; poorly reversible)
  • Atherosclerosis
  • Reproductive adverse events

Carcinogenicity

According to the Agency for Toxic Substances and Disease Registration, “ A carcinogenicity classification for carbon disulfide has not been established by the Department of Health and Human Services, The International Association for Research on Cancer, or the U.S. EPA” ( 1)

Treatments

There is no antidote for carbon disulfide, however, if a person experiences a severe acute inhalation exposure of carbon disulfide and when present in a hospital setting, the staff will make sure to:

  1. Decontaminate the patient and area to prevent any further exposure and exacerbation of symptoms.
  2. Remember ABC’s

Evaluate and support the

    • Airways
    • Breathing
    • Circulation
  1. If exposure was from inhalations, administer oxygen via mask if the patient complains of respiratory problems. In the presence of bronchospasms, treat patients with an aerosolized bronchodilator like albuterol.

 

References:

  1. https://www.atsdr.cdc.gov/MMG/MMG.asp?id=470&tid=84 Accessed July 7th, 2020
  2. https://accessmedicine.mhmedical.com/content.aspx?bookid=391&sectionid=42069857 Accessed July 7th, 2020
  3. https://www.ncbi.nlm.nih.gov/books/NBK208282/ Accessed July 7th, 2020
  4. https://undark.org/2017/06/09/viscose-rayon-occupational-health/ Accessed July 7th, 2020
  5. https://pubs.rsc.org/en/content/articlelanding/2017/cs/c6cs00585c#!divAbstract Accessed July 7th, 2020

Metal Toxicities : Beryllium

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Background and Exposure (1) :

Beryllium occurs in nature, but most exposures to beryllium that cause disease are related to beryllium processing. Beryllium is a strategic and critical material for many industries resulting in occupational exposures. It is widely used despite the high cost because it performs better than alternatives in some situations (2). The major source of its emission into the environment is through the combustion of fossil fuels (primarily coal), which releases beryllium-containing particulates and fly ash into the atmosphere. Toxic exposures can result in symptoms similar to pneumonia or bronchitis. Beryllium is not crucial for humans and in fact one of the most toxic elements we know.

Biotransformation and Mechanism of Action (2):

Target Organs (8):

  • Lungs:
    • Chronic beryllium disease is characterized as an immunologically mediated granulomatous lung disease in humans and appears to be the result of direct chemical toxicity and foreign-body-type reactions in rats.
  • Skeletal system:
    • Rickets in young animals appeared to be the result of the binding of phosphate to beryllium in the gut.
  • Skin, liver, spleen, lymph nodes, myocardium, skeletal muscles, kidney, bone, and salivary glands may exhibit granulomas, similar to those of the lungs.

Target Organ MoA and Effects: The lungs

The primary exposure pathway for beryllium is inhalation, but beryllium is not well absorbed by any route. The major toxicological effects of beryllium are on the lung (3). Beryllium interacts with the antigen-presenting cells in the lungs. Beryllium peptide associated with the major histocompatibility (MHC) class II molecule is recognized by the T-cell receptor with the help of CD4+ molecules. This interaction triggers CD4+ T lymphocyte activation and proliferation.

Beryllium and its compounds are not biotransformed however, soluble beryllium salts are converted to less soluble forms in the lung.  About half of inhaled beryllium is cleared in ∼2 weeks. The remainder is cleared slowly and the residual becomes fixed in the lung (granulomata) (3).

In general, inhalation exposure to beryllium results in long-term storage of appreciable amounts of beryllium in lung tissue, particularly in pulmonary lymph nodes, and in the skeleton, which is the ultimate site of beryllium storage.

 

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Toxicokinetics in Humans (2):

The most common health effects associated with overexposure to beryllium in the workplace include beryllium sensitization, chronic beryllium disease (CBD), and lung cancer (4).

May cause skin reactions such as:

  • Edematous
  • Erythematous
  • Papulovesicular dermatitis

May also cause:

  • Conjunctivitis in occupationally exposed workers.
  • Gingivitis in persons with dental implants made from alloys including beryllium.
  • Granulomatous necrotic changes and ulcerations caused by skin penetration by insoluble beryllium salts.

*These pathological changes are due to delayed allergic hypersensitivity, which has been proven in-vitro and in-vivo.

Inhalation exposure may cause irritation in:

  • Skin
  • Eyes
  • Nose
  • Throat
  • Upper and lower airway inflammation
  • Pulmonary edema
  • Chemical pneumonitis

*The pathogenesis of inflammatory changes is probably connected with the acidity of beryllium salts

Systemic effects

There are acute systemic effects, following acute exposure, reported in studies with animals that resulted in death. Chronic systemic effects include chronic Beryllium disease (CBD) which includes pulmonary granulomatosis and Berylliosis. Other Chronic systemic effects include

  • Cardiovascular effects (severe cases of chronic beryllium disease can result in right ventricle hypertrophy),
  • Endocrine system effects ( In a study of workers at a plant manufacturing fluorescent lamps, 1 of 17 workers exposed to beryllium who died from chronic beryllium disease had marked hyperemia and vacuolization in the histology of adrenal glands)

Carcinogenic Effects:

The International Agency for Research on Cancer (IARC) classified beryllium as a group 1 carcinogen. IARC 2001, noted that 1. the epidemiological data generally showed increases in observed lung cancers at most of the beryllium processing plants, 2. these increases were generally associated with high exposure levels that occurred before 1950, and 3. the highest risk of lung cancer occurred in individuals with acute beryllium disease. Beryllium is recognized as a known carcinogen in many other health organizations across the world.

Biomarkers (2):

BLTP:

The beryllium blood lymphocyte proliferation test (BLTP) is used as a medical surveillance tool for the assessment of persons at risk for developing clinical and subclinical CBD however, we have to consider its negative result is not the evidence for the absence of beryllium exposure.

Inflammation markers:

For the assessment of CBD progression, some nonspecific inflammation markers (cytokines) or basic fibroblast growth factor (bFGF) have been used.

Genetics:

Blood biomarkers of CBD susceptibility include class II major histocompatibility complex (MHC) genes: HLA-DP, HLA-DR.

Signs and Symptoms (5):

Patient-reported symptoms:

  • Nonproductive cough
  • Fatigue
  • Exertional dyspnea
  • Weight loss
  • Fever
  • Myalgia

Clinical Signs in radiograph findings:

  • Nodular diffuse infiltrates
  • Diffusely linear infiltrates
  • Hilar adenopathy in 30-40%

Treatments (2):

  • Remove affected workers from exposure to beryllium (however, no epidemiological studies have examined whether removal from exposure brings changes to the clinical course).
  • Systemic glucocorticosteroid (GCS) use in improving the symptoms and/or pulmonary function.
  • Immunosuppressive agents such as methotrexate and cyclosporine may be used in individuals nonresponding to GCS.
  • Supportive therapy including oxygen, bronchodilators, and immunization against respiratory pathogens.

 

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References:

(1) https://www.cancer.gov/about-cancer/causes-prevention/risk/substances/beryllium#:~:text=Hand%2Dto%2Dmouth%20exposures%20and,fly%20ash%20into%20the%20atmosphere. Accessed June 16th, 2020

(2) https://www.sciencedirect.com/science/article/pii/B9780123694133500768 Accessed June 16th, 2020

(3) https://www.sciencedirect.com/science/article/pii/B9780123864543008204 Accessed June 16th, 2020

(4) https://www.osha.gov/SLTC/beryllium/healtheffects.html#:~:text=The%20most%20common%20health%20effects,CBD)%2C%20and%20lung%20cancer. Accessed June 16th, 2020

(5) https://www.youtube.com/watch?v=CdYOYFDunsM Accessed June 16th, 2020

(6) https://www.jimmunol.org/content/196/1/22 Accessed June 16th, 2020

(7) https://www.livescience.com/28641-beryllium.html Accessed June 16th, 2020

(8) https://rais.ornl.gov/tox/profiles/beryllium.html#t2 Accessed June 16th, 2020

Pesticides: Mirex and Chlordecone

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Background and overview

Mirex. Animal studies demonstrate that mirex may result in a variety of toxic reactions in populations that are exposed. The organs affected are the thyroid, liver, selected developmental endpoints, and kidneys. Mirex may cause decreased hepatobiliary function and decreased glycogen storage. Glomerulosclerosis and proteinuria have been observed in the kidneys. If exposure occurs during a specific time period after birth, ocular lesions including cataracts in the eyes of the young. An increase in cystic follicles has been seen in the thyroid. There has been evidence of decreased fertility and developmental toxicity after exposure to the pesticide. Mirex results in testicular atrophy and reproductive failure. Included in the developmental effects in fetuses are cardiovascular disturbances, visceral anomalies, cataracts, increased stillbirths, and increased resorptions. In animals m,irex is a carcinogen in liver cells.

Chlordecone: Primary targets of chlordecone are the kidney, liver, reproductive system, nervous system, selected developmental endpoints, and the endocrine system. Humans exposed to chlordecone while working show toxicity in the reproductive system, the nervous system, and the liver. In high exposure cases, tremors, anxiety or irritability, blurring of vision, headache, and increased cerebrospinal fluid pressure we indicated. “Reproductive toxicity consisted of decreased sperm and sperm motility” (U.S. Department of Health and Human Services, May 2019).

Mechanism of Action:

The mechanism of action by which mirex is transferred into the systemic circulation is not yet known. It is a highly stable compound, that is also lipophilic and resistant to metabolism. It is readily absorbed by fat and can be accumulated in tissues. Mirex demonstrates a very high potential for accumulation in tissues because it is readily absorbed in tissues.

The mechanism of action by which chlordecone is absorbed into the systemic circulation is not yet known either. It is thought that it is transported in the plasms differently from other organochlorine compounds because it is mainly distributed to the liver instead of fat tissue. In vivo and In vitro studies in human, rat, and pig plasma show that chlordecone is mostly bound to albumin and HD, high-density lipoproteins.

Studies have attempted to outline the mechanism mirex and chlordecone use to inhibit hepatobiliary excretion. At high levels, the two agents depress ATPase activity. Moderate to high doses can also decrease cellular energy utilization and subsequently inhibiting biliary secretions. There are other possible explanations for the hepatotoxicity that mirex and chlordecone cause but are other body systems affected by their toxic effects.

Neurotoxicity has been demonstrated from mirex and chlordecone but there is no known mechanism of action. However, some studies show that chlordecone does not appear to act through a mechanism similar to other chlorinated hydrocarbons insecticides and demonstrates a different neurotoxicity profile. Chlordecone mainly causes tremors and hyperexcitability, with convulsions, and doesn’t act at the GABA receptor in mammals. The tremors induced by chlordecone appear to be started in the central nervous system above the level of the spinal cord.

Mechanisms underlying many of the adverse effects of chlordecone on reproductive function may be related to the estrogenic properties of chlordecone (U.S. Department of Health and Human Services, May 2019). Findings show that Chlordecone binds to estrogen receptors and causes translocation of the receptor. It has also been indicated in tumor suppression and developmental toxicity.

Mirex is absorbed from the digestive tract in animals, the majority of excretion via feces, with the fecal mirex unabsorbed. Widely distributed throughout the body with long retention time in the body. Mirex can also be excreted in human milk. Chlordecone is absorbed via oral routes and via inhalation.it is readily absorbed in the GI tract of humans and widely distributes throughout the body with higher concentrations in the liver. The agent is metabolized to chlordecone alcohol, which is excreted in the bile along with the parent substance. It is also excreted in saliva and mother milk.

Radiolabeling experiments demonstrate that mirex is not metabolized by humans, rodents, cows, or minipigs. It is believed that the suspected metabolite may have arisen as a result of bacterial action in the lower gut or feces (U.S. Department of Health and Human Services, May 2019)

Besides the biomarkers already mentioned, there is a lack of information about mirex and chlordecone biomarkers because their mechanism of action is still mostly unknown.

Signs and symptoms:

Studies assessing Mirex and Chlordecone test for diabetes, cancers, development, and reproductive endpoints. Clinical signs of Mirex include(1):

  •  cataracts
  • cardiac dysrhythmias
  • lesions of the lens
  • histopathologic effects on reproductive organs and decreased fertility
  • adaptive changes to the liver and decreased hepatobiliary function, histopathological lesions, and decreased glycogen storage
  • Increases in glomerulosclerosis and proteinuria in kidneys
  • carcinogenicity in the liver

Clinical signs and symptoms of Chlordecone include but, like Mirex, are not limited to (1):

  • hepatomegaly
  • evidence of increased microsomal enzyme activity
  • mild inflammatory changes
  • fatty degeneration
  • selected kidney lesions in rats
  • increased weight, depletion of epinephrine, hyperplasia, loss of adrenal lipid, and histopathologic lesions in the adrenal gland
  • tremors,
  • unfounded anxiety or irritability,
  • blurring of vision,
  • headache
  • increases in cerebrospinal fluid pressure
  • decreases in sperm count and motility
  • increased stillbirths
  • decreased postnatal viability
  • delayed skeletal ossification
  • selected anomalies and malformations
  • subtle neurological changes

Treatments:

Although treatments and pretreatments are under assessment for symptoms of Mirex and Chlordecone toxicities, they are still being explored and certain treatments have been known to exacerbate tremors(3).

References:

https://www.atsdr.cdc.gov/toxprofiles/tp66.pdf (1)

https://www.rt.com/news/440765-french-indies-cancer-pesticide/ (2)

https://www.atsdr.cdc.gov/toxprofiles/mirex_and_chlordecone_addendum.pdf (3)