Hi everyone-

How’s your pandemic going? I’m keeping busy and healthy so no complaints here 🙂 Why did I choose cannabis? Well, a few years ago I thought it would be interesting to see if cannabis could be of medical use to veterinary patients so I started to educate myself. I’ll admit right off that I’ve learned enough about cannabis to also have a practice called Nevada Veterinary Cannabis, but I have not done anything with it yet. I’m admittedly a bit biased, I suppose.

Back to the blog…in this case, I’m going to look at the toxicological effects of Δ⁹-tetrahydrocannabinol or THC which is the primary psychoactive component of the cannabis plant. We’ll not have time to discuss synthetic cannabinoids which are an entirely different toxicological issue, but here is some information on synthetic cannabinoids.

Cannabis is a complex plant with over 400 chemical entities of which more than 60 of them are cannabinoid compounds, some of them with opposing effects.

What is THC? In this case, we’ll focus on the 2 main ways for humans to ingest THC (ingestion or inhalation).

Image from

What is the mechanism of action of THC?

Sources of THC will vary (as will other components present) if it is plant-derived, meaning it contains not only THC, but also the other cannabinoids, terpenes and phytochemicals; or if it is a pharmaceutical formulation.

Marinol (an example of a pharmacological formulation of tetrahydrocannabinol):

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Marinol package insert: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018651s021lbl.pdf

THC is widely available in my area. Here’s an image from today from Google:

The onset of action of THC between the different routes of ingestion (inhalation versus oral) differ:

Both the above images from: https://thesunlightexperiment.com/blog/how-is-thc-metabolized

Here’s a nice and recent summary of the toxicokinetics of cannabinoids:

The toxic effects of cannabinoids are secondary to overstimulation of the endocannabinoid system by exogenous cannabinoids. This immoderate stimulation of the endocannabinoid system leads to the aforementioned erratic neurotransmitter modulation that can lead to toxicity. The absorption kinetics of cannabinoids and THC depends on the exposure route, with inhalation reaching peak serum concentrations in less than thirty minutes, and ingestion peaking in concentration at around 2 to 4 hours (or longer) after consumption. Duration of toxicity secondary to inhalation and ingestion lasts approximately 2 to 6 hours and 8 to 12 hours, respectively. THC’s volume of distribution is approximately 3 liters per kilogram, and after exposure eventually collects in fat due to its high lipid solubility. Chronic exposures lead to increased accumulation in fat.

THC crosses the placenta and can accumulate in significantly elevated concentrations in breast milk. The hepatic cytochrome p450 system primarily metabolizes THC to many metabolites, mostly inactive. THC’s main active metabolite is 11-hydroxy-delta-9-tetrahydrocannabinol which is further broken down to numerous inactive metabolites, including 11-nor-delta-9-tetrahydrocannabinol-carboxylic acid (THC-COOH), which is detectable in urine, as excretion is through both feces and urine over the course of hours to days, with more prolonged elimination depending on the chronicity of use. The toxicokinetics of synthetic cannabinoids are less predictable as the specifically abused compound may vary, and adulteration is not uncommon.

In looking at carcinogenicity of THC, here’s what the CDC website states:

Also:

In conclusion, while both tobacco and cannabis smoke have similar properties chemically, their pharmacological activities differ greatly. Components of cannabis smoke minimize some carcinogenic pathways whereas tobacco smoke enhances some. Both types of smoke contain carcinogens and particulate matter that promotes inflammatory immune responses that may enhance the carcinogenic effects of the smoke. However, cannabis typically down-regulates immunologically-generated free radical production by promoting a Th2 immune cytokine profile. Furthermore, THC inhibits the enzyme necessary to activate some of the carcinogens found in smoke. In contrast, tobacco smoke increases the likelihood of carcinogenesis by overcoming normal cellular checkpoint protective mechanisms through the activity of respiratory epithelial cell nicotine receptors. Cannabinoids receptors have not been reported in respiratory epithelial cells (in skin they prevent cancer), and hence the DNA damage checkpoint mechanism should remain intact after prolonged cannabis exposure. Furthermore, nicotine promotes tumor angiogenesis whereas cannabis inhibits it. It is possible that as the cannabis-consuming population ages, the long-term consequences of smoking cannabis may become more similar to what is observed with tobacco. However, current knowledge does not suggest that cannabis smoke will have a carcinogenic potential comparable to that resulting from exposure to tobacco smoke.

It should be noted that with the development of vaporizers, that use the respiratory route for the delivery of carcinogen-free cannabis vapors, the carcinogenic potential of smoked cannabis has been largely eliminated.

Information on carcinogenicity associated with ingestion of THC was not located.

The target organs for THC would be those within the endocannabinoid system (ECS):

 

Toxicity, from what I have read, is typically associated with the ingestion of excessive amounts of THC.

Here’s an interesting article from the Los Angeles County Public Health Department website:

From a WHO 2018 meeting:

Here’s something interesting that I learned about why some individuals have an aversion response to THC:

Historical use of THC:

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From what I can find, one of the earliest medicinal uses of THC was reported approximately 1700 BC:

Treatment for THC intoxication:

MANAGEMENT:

The management of cannabis (marijuana) intoxication consists of supportive care. Because of the differences in toxic manifestations the management differs significantly by age.

Children — Children with cannabis (marijuana) exposure are much more likely to demonstrate severe or life-threatening toxicity consisting of excessive and purposeless motor activity (hyperkinesis) or deep coma. Consultation with a regional poison control center and a medical toxicologist is encouraged for all symptomatic exposures.

Central nervous system depression — Severe central nervous system (CNS) depression from marijuana exposure is unique to the pediatric population and can present with profound depression, lethargy, and coma.

Treatment is supportive and consists of the following measures:

●Maintain airway, breathing, and circulation. Patients with lethargy and coma should receive supplemental oxygen, assessment and support of airway and breathing, and vascular access. Patients with apnea or at risk for aspiration should undergo rapid sequence endotracheal intubation and receive assisted ventilation.

●Measure rapid blood glucose to exclude hypoglycemia.

●Administer naloxone to patients presenting with features of opioid intoxication. Naloxone will not reverse coma due to cannabis toxicity.

The duration of coma is typically one to two days. Full recovery is expected.

Seizures — Seizures have rarely been described after cannabis intoxication in children and may be associated with coingestants (eg, cocaine). Initial treatment of toxin-associated seizures consists of benzodiazepines (eg, lorazepam or midazolam). If seizures persist despite multiple doses of benzodiazepines, then treatment for status epilepticus caused by toxins, as described in the table, is warranted.

Dysphoria — Dysphoria is not a common presentation in pediatric marijuana exposure. However, if symptoms of marked anxiety or agitation develop, benzodiazepines (eg, lorazepam) are frequently effective and have a low adverse effect profile.

Adolescents and adults

Mild intoxication — Mild intoxication with dysphoria is a common presentation in either naïve or chronic marijuana users after ingestion or inhalation of a high-potency product such as an edible or concentrate. Most patients can be managed with a dimly lit room, reassurance, and decreased stimulation. Short-acting benzodiazepines (eg, lorazepam) can be helpful in controlling symptoms of anxiety and have a low side effect profile.

Severe intoxication — Severe physiologic effects are rare after cannabis use and their presence should prompt the clinician to consider coingestion of other recreational drugs, including cocaine, amphetamines, and phencyclidine, or coexisting mental illness.

Marked agitation or combativeness not responsive to reassurance and benzodiazepines may necessitate the use of other medications, depending upon the cause, and is rarely encountered with intoxication from cannabis alone. The approach to sedation of the acutely agitated or violent adult is discussed in detail separately.

Chest pain — Chest pain in association with cannabis use should be managed according to etiology as follows:

●Acute coronary syndrome – Substernal squeezing chest pain suggestive of myocardial ischemia or infarction may occur rarely in association with cannabis use. Patients complaining of chest pain suggestive of coronary insufficiency should be evaluated for acute coronary syndrome and treated accordingly. 

●Pneumothorax or pneumomediastinum – Inhalation and breathholding during cannabis use may cause a pneumothorax or pneumomediastinum with sharp, pleuritic chest pain and subcutaneous crepitus. Management of a pneumothorax depends upon its size and includes oxygen administration and, if necessary, evacuation with needle decompression or chest tube insertion.

No specific treatment is necessary for uncomplicated pneumomediastinum.

●Asthma exacerbation – Cannabis use may cause chest tightness with bronchospasm and wheezing. Standard therapy for status asthmaticus should be provided.

Gastrointestinal decontamination — We suggest that patients who ingest cannabis (marijuana) not undergo gastrointestinal decontamination with activated charcoal (AC). After ingestion, most symptoms are delayed up to three hours, which limits the efficacy of AC. Also, the clinical effects of cannabis ingestion are often limited and good outcomes occur with supportive care alone. In addition, in children, clinical toxicity may include rapid onset of altered mental status or vomiting, which may raise the risk of aspiration if AC is administered.

There is no role for gastrointestinal decontamination after toxicity caused by inhaled cannabis.

Cannabis hyperemesis syndrome — Cannabis hyperemesis syndrome is typically seen with chronic marijuana use but can be seen with acute or acute on chronic use. Patients may complain of abdominal pain, vomiting, or nausea that is typically relieved by hot showers. Acute treatment consists of symptomatic care including intravenous fluid hydration, antiemetics (eg, ondansetron), and benzodiazepines. Cessation of marijuana use is also recommended.

Limited observational evidence (case reports and case series) also suggests that topical capsaicin cream (supplied in concentrations of 0.025 to 0.1 percent) applied once in a thin film over the abdomen may improve acute severe abdominal pain and emesis in patients not responsive to ondansetron or benzodiazepines. Evidence is lacking to determine if capsaicin cream has a role for the treatment of chronic symptoms.

In addition, case reports have documented the successful use of haloperidol to abort severe episodes of hyperemesis not responsive to fluid hydration and administration of antiemetics, and benzodiazepines. In one instance, hospital admission was avoided after administration of 5 mg of haloperidol intravenously. However, more evidence is needed to evaluate the safety and efficacy of this therapy including the indications, dose, and route of administration.

DISPOSITION:

Disposition is determined by several factors including patient age, social circumstances, duration of toxicity, and type of symptoms as follows:

●Children – The duration of symptoms after acute marijuana exposure in children can vary from four to 48 hours depending upon the dose ingested. Patients with persistent vomiting, altered mental status, or excessive, purposeless motor activity (hyperkinesis) warrant hospital admission.

Patients who remain asymptomatic or become asymptomatic following exploratory ingestion of legally acquired cannabis products may be discharged after a brief observation period (eg, four to six hours after ingestion).

Ingestion of illicit marijuana or intentional exposure of a child warrants involvement of a child abuse team, when possible, and should be reported to child protection services.

●Adolescents and adults – Most symptoms after acute marijuana use in adults and adolescents resolve within a few hours and will not require hospital admission.

Hospital admission may rarely be needed for prolonged delirium or agitation requiring repeated doses of benzodiazepines or antipsychotics. These patients should also be screened for substance use disorder, mood disorders, and, if needed, undergo psychiatric consultation and appropriate referrals to substance-use treatment programs.

The disposition for patients with complications of marijuana use depends upon the degree of illness and response to therapy. Patients with proven myocardial infarction or pneumothorax requiring chest tube thoracostomy warrant hospital admission to an appropriate level of care.

Biomarkers and testing:

Testing for tetrahydrocannabinol metabolites can be performed using blood, plasma, urine, oral fluid, hair, sweat, or breath.

Here’s some interesting test results from a 2017 NHTSA Report to Congress:

 

Here’s a good infographic that summarizes urine testing for THC metabolites:

There is also some information on ways to potentially interfere with testing:

So, overall, this was an interesting bit of reading today and I feel a bit more prepared to discuss THC in a regulatory and testing situation now.

Hi everyone…how’s your summer going?

Here’s why I chose dimethyl sulfoxide…when I was around 14 years old, we had a pet German Shepherd dog that had severe hip dysplasia resulting in some symptoms of arthritis. This was in the early 1980’s prior to the development of safe and effective osteoarthritis medications and supplements for dogs as we have now. One of the topical therapies that was applied to our family pet dog was DMSO or dimethyl sulfoxide and me, being the young, eager “I want to be a veterinarian when I grow up” kid that I was, I was the one that was chosen to apply the DMSO to the family pet, so I chose this solvent because I have personal experience with it.

Work-life balance update: Well, I still have to take my nanotoxicology and air pollution quiz today, so let’s just say I’m still working on this. I don’t think I’m efficient enough to take more than one class at a time…I’m amazed that people can take multiple classes and work!

OK, back to dimethyl sulfoxide. Let’s start with the basics, what is dimethyl sulfoxide (DMSO)?

This is an entertaining video:

Here’s a good summary from PubChem:

Dimethyl Sulfoxide may have anti-inflammatory, antioxidant and analgesic activities. Dimethyl Sulfoxide also readily penetrates cellular membranes. The membrane-penetrating ability of dimethyl sulfoxide may enhance diffusion of other substances through the skin. For this reason, mixtures of idoxuridine and dimethyl sulfoxide have been used for topical treatment of herpes zoster in the United Kingdom.

and

Dimethyl Sulfoxide is a highly polar organic liquid that is used widely as a chemical solvent and a free radical scavenger. It shows a range of pharmacological activity including analgesia and anti-inflammation. Because of its ability to penetrate biological membranes, it is used as a vehicle for topical application of pharmaceuticals. It is also used to protect cells and tissue during cryopreservation and has been used to treat extravasation damage caused by anthracycline-based chemotherapy.

 

 

It appears that given the reported medical, laboratory and industrial uses for dimethyl sulfoxide, exposure to this substance would be predominantly dermal. The CDC reports that exposure routes include inhalation, skin absorption, ingestion, skin and/or eye contact. A pharmaceutical grade of DMSO is available as a liquid formulation that would be used for intravesicular instillation for cases of interstitial cystitis. A pharmaceutical grade DMSO product is used as an antidote that is applied topically as part of the therapy for extravasation of chemotherapeutic agents (the DMSO is thought to have free-radical scavenging properties as well as the ability to help absorb the extravasated agent). DMSO is not to be used for intravenous or intramuscular injection.

Image from:

DMSO is available online in both a gel and a liquid form for intentional application to the skin:

Image from:

That makes sense. I definitely recall this being a dermal exposure for me as well.

Although the mechanism by which DMSO enhances skin permeability is not fully understood, it has been suggested that it (1) removes much of the lipid matrix of the stratum corneum, making holes on artificial shunts in the penetration barrier; (2) alters keratin configuration to change protein structure; and (3) functions as a swelling agent (Williams and Berry, 2004).

I found this fascinating video from 1980 that shows how cavalierly we treated topical solvents at that time. I used to apply topical dimethyl sulfoxide to my dog using no personal protective equipment and that smell of garlic and taste of oysters that is mentioned in the video is the experience that I recall having. Interesting. So once that DMSO was absorbed, I wonder what the potential toxicological effects of that solvent were.

Potential toxicological effects of dimethyl sulfoxide (DMSO) in humans:

From:

Dimethyl sulfoxide (DMSO) is produced both naturally as part of the sulfur cycle and it is also produced for industry. Natural DMSO occurs by the atmospheric oxidation of dimethyl sulfide (DMS) that is produced by phytoplankton and is found in small quantities. The industrial production of DMSO uses lignin, a complex structural plant polymer that is obtained from the conversion of wood chips into paper (using a process called Kraft processing). DMSO was initially synthesized by Alexander Zaytsev in 1866.

From:

Dimethyl sulfoxide (DMSO) biotransformation after dermal application in both humans and miniature pigs was evaluated in this 1971 article here:

Dimethyl sulfoxide toxicokinetics information from the European Chemicals Agency website:

• The acute inhalation toxicity of DMSO in rats has been investigated in studies compliant with OECD guidelines and also in non-guideline studies. For the oral and dermal routes, only non-guideline studies are available.
• DMSO is of low acute toxicity. In non-guideline studies, LD50 in rats are generally higher than 20,000 mg/kg bw and 40,000 mg/kg bw by the oral and dermal routes, respectively. In an acute inhalation study performed following the OECD guideline # 403, the 4h-LC50 in rats was higher than 5330 mg/m3.

As an aside, the European Chemicals Agency website appears to be a very comprehensive resource for these substances.

Dimethyl sulfoxide (DMSO) has three concentration-dependent mechanisms of action on the cell membrane; as summarized by this article:

Dimethyl sulfoxide target organ(s):

Eyes:

This study showed some changes in the eyes of dogs (predominantly) and pigs, rabbits and rats to a lesser degree. Ocular toxicity has not been reported in humans with the appropriate use of dimethyl sulfoxide.

Respiratory system:

This study discusses a dose-dependent inhibitory effect on lung ventilation and hypoxic responsiveness in mice. This repeat exposure inhalational study of DMSO in rats failed to show any significant effects other than a slight increase in serum urea nitrogen in the high dose group.

Liver:

The FDA toxicological data for class 3 solvents appendix states that:

This peer-reviewed article discusses a systematic review of the studies that have been done to evaluate adverse reactions to dimethyl sulfoxide in humans, and in this article, gastrointestinal and skin reactions were most common and did not require therapy.

I’d personally experienced the abnormal taste sensation of garlic or oysters after applying over the counter DMSO using a cotton ball (no gloves) to my own family pet, so of course I was curious to see what the association of that was (and there was not much to be found so far). From Wikipedia:

The perceived garlic taste upon skin contact with DMSO may be due to nonolfactory activation of TRPA1 receptors in trigeminal ganglia.

Dimethyl sulfoxide signs and symptoms of toxicity:

• DMSO is able to easily penetrate the skin, so substances dissolved in or dissolved by this solvent could result in intoxication.
• Nausea and vomiting are the most commonly reported gastrointestinal symptoms.
• Application of dimethyl sulfoxide (in a variety of methods) can result in a local burning sensation or, less commonly, peripheral edema or an allergic reaction.

Dimethyl sulfoxide historical or unique exposures:

This part was fascinating because I vaguely recall this episode (I lived in Los Angeles at the time), but it involves the case of a woman named Gloria Ramirez (aka “the Toxic Woman”) and media reports that hospital workers became ill with symptoms of respiratory distress and collapse while working on her in the emergency room. One of the emergency room personnel reported that

…at that point several people saw an oily sheen covering Ramirez’s body, and some noticed a fruity, garlicky odor that they thought was coming from her mouth.

To obtain blood for analysis, a registered nurse named Susan Kane swabbed Ramirez’s right arm with rubbing alcohol, inserted a catheter, and attached a syringe. And that’s when the frenetic yet orderly routine of the emergency room began to break down. As the syringe filled, Kane noticed a chemical smell to the blood. Kane handed the syringe to Welch and leaned closer to the dying woman to try to trace the odor’s source. Welch sniffed the syringe and smelled something, too: I thought it would smell like chemotherapy, the way the blood smells putrid when people are taking some of those drugs. Instead, Welch says, it smelled like ammonia.

The Wikipedia link has some interesting information.

In the above case, it is suspected that the dimethyl sulfoxide that was being self-administered by the patient oxidized to dimethyl sulfone and then formed dimethyl sulfate.

Dimethyl sulfate is a volatile and toxic substance that is suspected to be the cause of the symptoms shown by the emergency room personnel.

Here are the symptoms from the above mentioned table:

Dimethyl sulfoxide exposure treatment recommendations for most exposures involve washing to remove the contamination according to the CDC:

Dimethyl sulfoxide biomarkers:

So overall, dimethyl sulfoxide does appear to be a low toxicity and friendly solvent but I did not find as much information regarding the mechanism of action on the taste sensation that the exposure to DMSO results in.

Here’s what I learned between last time I did a blog entry and today:

1. I’m much too slow to blog for a living.
2. I didn’t think I’d like blogging, but this part is kind of interesting.
3. I’m not at all concerned about my historical dimethyl sulfoxide exposure given the lack of associated carcinogenesis findings.

Have a good summer out there and stay safe 🙂 I don’t see anything in my reading for this blog entry that makes me want to add dimethyl sulfoxide to my recommended therapies nor will I be placing any orders for the rose-scented aloe vera DMSO gel above.

 

 

 

 

Hey. Thanks for stopping by. I hope everyone is healthy and safe out there.

I’m in my 5th week of being back in school and in addition to learning about the myriad of substances out there in the world that can be toxic to you or the environment, I’m also learning how to manage my study time. What worked for me in the past definitely does not work in the online learning environment but I’ll adapt 🙂 That’s one of my learning discoveries this week…management of study time. I tend to be a procrastinator (old news) but the amount of reading for PHR 7588/Toxic Substances while reasonable for this class, is not something that should be done on a Monday (this was a lesson I only needed to teach myself one time).

But enough about me. Let’s get back to an essential, yet potentially toxic metal, cobalt.

Cobalt is an essential trace element that is required for normal functioning of the mammalian body and it is not produced by the body. Cobalamin (also called vitamin B12 or cyanocobalamin) is a cobalt-containing molecule that is required for the production of red blood cells. Cobalamin is synthesized by bacteria or archaea by microbial fermentation. Good dietary sources of vitamin B12 include milk, eggs and meat and individuals with gastrointestinal absorption issues, some vegetarians and some elderly people can become deficient in this element.

Image from: https://pernicious-anaemia-society.org/conference/the-cobalamin-b12-conference/

Cobalt is found in the environment and is typically sourced as a by-product of copper mining.

Where cobalt is mined: https://www.americanexperiment.org/2018/09/wall-street-journal-mining-cobalt-congo-still-dirty-dangerous/

According to Department of the Interior data from 2020, the following states have the largest cobalt reserves: “Alaska, California, Idaho, Maine, Michigan, Minnesota, Missouri, Montana, North Carolina, New Mexico, Oregon, Pennsylvania, Puerto Rico and Tennessee.” from https://catalog.data.gov/dataset/cobalt-deposits-in-the-united-states

Cobalt is found in the environment, so mammalian exposure could be from food, water or air at low levels. Higher exposure to cobalt (via dust inhalation or skin contact, occasionally ingestion) can occur in some industries where metal grinding or cobalt containing metal production occurs or sporadically in some individuals. Cobalt is also a component of medical implants (such as hip replacement surgery). Cobalt is also a component of some blue pigments. Radioactive cobalt (cobalt 60) has medical uses in cancer radiation therapy. https://semspub.epa.gov/work/HQ/174482.pdf 

Here are some ways that cobalt can enter the body:

From: https://apcz.umk.pl/czasopisma/index.php/EQ/article/view/EQ.2019.016/17600

Here’s a sample of the color cobalt from Pantone:

From: https://www.pantone.com/color-finder/19-4037-TCX

Individuals employed in the cobalt industry are at risk for developing a condition called “hard metal lung disease” (also known as “hard metal pneumoconiosis”) which is a rare condition that results in permanent lung damage. As a result of this disease association, the Occupational Safety and Health Administration has set limits to reduce the level of acceptable levels of cobalt in the air. Additional information at: https://www.osha.gov/dts/sltc/methods/inorganic/id213/id213.html

Here’s an interesting article from Brazil (2016) that is a case series for Hard Metal Lung Disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344095/

Cobalt can result in skin irritation or allergy. Cobalt was declared the Contact Allergen of the Year by the American Contact Dermatitis Society in 2016.

Image from: https://dermnetnz.org/topics/allergy-to-cobalt/

The toxicokinetics of cobalt have been studied and the form of the cobalt-containing compound affects the absorption of cobalt. Differences in oral absorption of cobalt in rodents and humans have been reported. For instance, from C&D:

Less than 5% of an oral dose of cobalt oxide is absorbed, whereas about 30% of an oral dose of cobalt chloride is absorbed in rodents. Oral absorption of cobalt varies widely in humans, and it is estimated to be between 5% and 45%. Increasing doses of cobalt results in a decreasing proportional absorption, so increased cobalt levels tend not to cause significant accumulation. Absorption of inhaled cobalt compounds appears to be relatively effective in humans and animals.

Cobalt is considered by the International Agency for Research on Cancer (IARC) to be a Group 2A (probably carcinogenic to humans) or 2B (possibly carcinogenic to humans) depending on the form (cobalt metal with or without tungsten carbide and cobalt salts).

https://oem.bmj.com/content/58/10/619

Cobalt can have toxic effects on the mitochondrial enzyme system (it inhibits aerobic metabolism), it can interfere with protein synthesis (cobalt displaces magnesium from cofactor enzyme site) and it can have effect on cell membrane lipid movement (by binding to these molecules). More can be found here: https://www.sciencedirect.com/science/article/abs/pii/S0005273620300754

As well as here: https://pubmed.ncbi.nlm.nih.gov/22732165/

Target organ/organs for cobalt poisoning include the cardiovascular system, the endocrine system, the hematologic system, the pulmonary system, effects on the nervous system, the renal system, the dermatological system as well as the reproductive system. There is quite a bit online about cobalt poisoning related to metal-on-metal prosthetic hip implants and some of the side effects that can result from this condition (called arthroplasty cobaltism). This is a particularly interesting syndrome that results in symptoms of heart disease, hypothyroidism, polycythemia and effects on both the peripheral and nervous system.

Signs/symptoms of cobalt poisoning can include the following:

From: https://www.sciencedirect.com/science/article/pii/S2451993620300104

Cobalt cardiomyopathy in hip arthroplasty article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728440/

Here’s an image from an echocardiogram showing the depressed systolic function of the left ventricle:

From: https://www.nejm.org/doi/10.1056/NEJMcps1213196

There may be a genetic differences in an individual’s ability to metabolize and detoxify metals, including cobalt.

From: https://www.sciencedirect.com/science/article/pii/S0753332218374407

The most interesting historical aspect I found regarding cobalt poisoning is a syndrome called “beer drinker’s cardiomyopathy”. This was a historical issue in the 1960’s in Nebraska and Quebec where cobalt was added to beer to restore and stabilize the foam that can be destroyed by agents used to clean glassware. This syndrome was characterized by some differences from a typical alcoholic cardiomyopathy (the acute cobalt cardiomyopathy that resulted from this syndrome tended to show an abrupt onset of biventricular heart failure, pericardial effusion as well  as polycythemia).

One of the implicated brands:

From: https://www.macleans.ca/general/of-meat-beer-disease-and-death/

Quebec historical article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1923410/?page=2

Nebraska historical article: https://www.amjmed.com/article/0002-9343(72)90136-2/pdf

Cobalt effects on heart: https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.116.003604

Cobalt could potentially be used as an athletic (in both humans, and race horses) performance enhancing substance, by increasing the production of red blood cells (the hypoxia that can be caused by cobalt results in a compensatory increase in red blood cell production).

From: https://esc.rutgers.edu/wp-content/uploads/2019/01/Evaluation-of-Cobalt-as-a-Performance-Enhancing-Drug-in-Fit-Standardbred-Racehorses.pdf

From: https://www.cobaltinstitute.org/cobalt-and-red-blood-cells.html

Treatment of cobalt poisoning depends on the body system involved and the degree of exposure but if there is an acute cobalt intoxication, then decontamination of the patient should be performed as well as aggressive medical management. Gastric decontamination methods have not been studied but if radiopaque solid forms of cobalt are noted in the gastrointestinal tract, whole-bowel irrigation can be considered. After any remaining cobalt has been irrigated from the gastrointestinal tract, then chelation therapy can be considered. Chelators, such as CaNa2EDTA and NAC can be used to enhance urinary or fecal elimination of cobalt based on a single human case report and several animal studies. Sulfur-containing proteins (NAC, L-histidine and L-cysteine) are administered to reduce mortality by reducing the tissue cobalt burden and tissue injury in the liver and spleen. For arthroplasty cobaltism, revision of the surgery is also an important part of therapy. Specific cardiac therapy for cobalt cardiomyopathy would be appropriate. Thiamine should be administered as well.

Are there any biomarkers are ways to measure cobalt concentration in the body?

From: https://www.mctlaw.com/joint-replacement/cobalt-chromium-poisoning/

Cobalt is excreted primarily via the urine, with a lesser extent in the feces, so urine cobalt testing is available.

Here’s an example of a US laboratory that performs urine cobalt testing: https://www.labcorp.com/tests/071514/cobalt-urine

Blood testing is also available (appears to be in combination with chromium): https://www.labcorp.com/tests/738770/chromium-and-cobalt-whole-blood

It appears that the testing is the easy part, but the interpretation of these results can be difficult because of a variable elimination pattern in the urine. Cobalt is present in the urine after inhalation, and can be rapidly found in the urine after exposure, but if there is a prolonged exposure to cobalt, the elimination of cobalt is reduced in rate. Vitamin supplementation or a diet high in vitamin B12 can also affect the blood or urine cobalt test results. The toxic level of cobalt appears to be not well-defined and can vary whether there is an acute exposure or a chronic lower level exposure.

References and resources:

Fang, H., Kang, J., & Zhang, D. (2017). Microbial production of vitamin B₁₂: a review and future perspectives. Microbial cell factories, 16(1), 15. https://doi.org/10.1186/s12934-017-0631-y.

 

 

 

Hi and thanks for visiting. Join me on a journey of middle-aged distance learning about toxic substances as well as technology.

For my first ever blog post, I’ll introduce you to Bacillus thuringiensis (Bt). Bt is a soil-dwelling bacterium that is used as a microbial pesticide/insecticide. Briefly, this microbe holds appeal as an insecticide because it is selectively toxic to certain insects and not mammals. This strain of bacteria was discovered in the Free State of Thuringia in central Germany in 1915.

Structure discussion here (discuss microscopic findings)

EM of Bt

Google Map image

Back to our topic, Bacillus thuringiensis (Bt). If, like me, this was a new word to you, I’ve attached a link with pronunciation of this microorganism.

https://youtu.be/q9pixg7-SXY

The main benefit of using a biopesticide such as Bt is the select toxicity of this agent to certain insects (predominantly worms and caterpillars, not beneficial insects such as ladybugs, earthworms and honey bees) and not off-target mammalian species due to the mechanism of action. Here’s an interesting website from some other school that discusses this.

How to control invasive pests while protecting pollinators and other beneficial insects

Here’s a video that not only provides a great summary of how Bt works, it also makes the microbe look adorable.

Link: Summary of Bt

Bt would be used topically on plants as a pesticide (insecticide), but it can also be incorporated in plants using genetic modification. Plants, such as corn, cotton, potato and tobacco can be genetically modified to produce the Bt insecticidal Cry/Cyt proteins.

Genetically engineered (modified) crops (Bacillus thuringiensis crops) and the world controversy on their safety

Bt containing products are available over-the-counter as well as online and do not require specialized personal protective equipment or training to use.

Link: https://www.bonide.com/products/garden-naturals/view/802/thuricide-bt-conc

Toxicokinetics of Bt if ingested or inhaled by mammalian species:

Mammal ingestion: Bt remains in the digestive system and it is not absorbed systemically into the body when ingested. The Bt bacteria does not reproduce inside the body of the mammal that has ingested it. The Cry/Cyt protein that is produced by Bt is digested in the acidic gastric fluid of mammals (versus this protein being soluble in the alkaline solution in the midgut of sensitive insects).

Link to pH of gastric fluid discussion: Safety and Advantages of Bacillus thuringiensis-Protected Plants to Control Insect Pests

Mammal inhalation:  When inhaled, Bt can be absorbed via the lungs, blood and lymphatic system and the kidneys but is then removed by the immune system resulting in a decrease in Bt levels systemically within one day. Link: http://npic.orst.edu/factsheets/BTgen.pdf

Carcinogenicity of Bt: This substance has been studied in humans, and was not noted to be associated with an increased risk of cancer. http://npic.orst.edu/factsheets/BTgen.pdf

Mechanism of Action of Cry/Cyt toxin that is produced by Bt: The feeding insect ingests the Bt bacterium and once inside the insect, the crystallized Cry/Cyt toxin is digested and processed to produce an endotoxin. This endotoxin binds to epithelial cell receptors in the midgut of the insect digestive system and results in pore formation. This alters potassium flux across these damaged cells as well as an increase in intracellular pH. The midgut epithelial cells are destroyed by pH and osmotic lysis leading to starvation and septicemia of the insect. Here’s a nice (silent) video that goes over the mechanism of action in detail: Bt toxin method of action

This is an in-depth article that discusses the mode of action of Bt in lysing the midgut epithelial cells of the insect.  Mode of action of Bacillus thuringiensis Cry and Cyt toxins and their potential for insect control

Target organ(s):
Insects: in the midgut of the digestive (alimentary) system of the insect.
Humans:

• Gastrointestinal system if ingested
• Respiratory system if inhaled
• Skin if topical exposure

Signs and symptoms of toxicity:
Insects-starvation, death.

Link: http://www.bt.ucsd.edu/how_bt_work.html

Humans: Given the insect specificity of the method of action of Bt, this substance is considered to be of low toxicity to mammals. Some potential symptoms that may be reported by individuals that are exposed to a Bt-containing insecticide include:

• Eye irritation
• Skin irritation
• Rarely, people with hay fever reported symptoms such as difficulty with sleep and concentration, stomach upset, nose and throat irritation but seasonal (pollen) factors may contribute to this report
• Farm workers with exposure of > 4 month duration may develop an immune response and potential skin allergies

http://npic.orst.edu/factsheets/BTgen.pdf

Genetic susceptibility or heritable traits:

Human genetic susceptibility not reported.

Insects are developing some mutations that provide some resistance to Cry proteins, so interventions to reduce the development of resistance to this pesticide are being researched.

Resistance to Bacillus thuringiensis Mediated by an ABC Transporter Mutation Increases Susceptibility to Toxins from Other Bacteria in an Invasive Insect

Historical or unique exposures reported: A historical concern about using Bt crops and monarch butterflies was noted historically but a peer-reviewed study showed

“that monarch butterflies exposed to Bt corn in the environment are not subjected to any significant risk.”

https://www.inspection.gc.ca/plant-health/plants-with-novel-traits/general-public/monarch-butterflies/eng/1338140112942/1338140224895

“Pharming” Fate and Effects in Soil of Cry Proteins from Bacillus thuringiensis: Influence of Physicochemical and Biological Characteristics of Soil

Treatment:

• Human ingestion exposure:
• Human inhalational exposure:
• Human dermal exposure:

Fact sheet: General Fact Sheet

Biomarkers: Since this substance is digested in the mammalian digestive tract a biomarker could not be found, but there is a method (biomarker called CaDPA) to observe germination of spores of  Bacillus thuringiensis. The utility of this evaluation would be in food safety/public health settings.

Detection of Bacillus thuringiensis Spore Germination via CaDPA Biomarker Using Laser Tweezers Raman Spectroscopy

Whole Genome Sequence of Bacillus Thuringiensis ATCC 10792 and Improved Discrimination of Bacillus Thuringiensis From Bacillus Cereus Group Based on Novel Biomarkers

In summary, I found that I have learned quite a bit about toxic substances over the past few weeks and I’m excited to be participating.

Stacy

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