Tetrodotoxin

Source

Tetrodotoxin is most commonly known to be found in certain water-dwelling creatures like the infamous and delicious puffer fish. It has been found that certain bacteria create tetrodotoxin for the fish to use as a defense mechanism (Magarlamov, 2017).

 

Biotransformation

Biotransformation of tetrodotoxin is still under investigation and is not well understood in mammals, including humans (Bane et al., 2014)

 

Toxicokinetics

An interesting study by Matsumoto et al looked at how tetrodotoxin travels through and damages the liver of a puffer fish injected with its own toxin (Matsumoto et al., 2008). This apparently occurs in a few short hours (Matsumoto et al., 2008). In the human, the toxin is absorbed through first pass metabolism, as it’s usually ingested. It remains mostly unchanged while it wreaks havoc on the body until it is excreted in the urine by the kidneys.

 

Carcinogenicity

Due to its sudden and major effects, there is very little information about its carcinogenicity, as that would require prolonged exposure to the toxin. Most people are not being exposed to tetrodotoxin on that regular of a basis.

 

Mechanism of Action

Tetrodotoxin works by interfering with sodium channel functions through blocking these channels (Bane et al., 2014). This accounts for its neurotoxic effects as it interrupts proper neuron actional potential functions.

Check out a neat summary video of tetrodotoxin and its mechanism here.

 

Target organ(s)

The main target organ of tetrodotoxin is the brain. This toxin is a neurotoxin, but it can also suppress the respiratory system (Kotipoyina et al., 2021)

 

Signs and symptoms of toxicity

Kotipoyina et al (2021) have a great list referenced in their article about the four grades of tetrodotoxin poisoning. It reads as follows:

“There are 4 grades of poisoning base on a scale created by Fukuda and Tani in 1941:

• Grade 1: Paresthesias and perioral numbness, with or without gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea)
• Grade 2: Facial numbness, slurred speech, early motor paralysis, and incoordination, but with normal reflexes
• Grade 3: Generalized flaccid paralysis, aphonia, respiratory failure, and fixed/dilated pupils (in a conscious patient)
• Grade 4: Severe respiratory failure with hypoxia, bradycardia, hypotension, cardiac dysrhythmias, and unconsciousness”

 

Genetic susceptibility or heritable traits

None seem to be present.

 

Historical or unique exposures

Tetrodotoxin is thought to be one of the ingredients used in an old Hatian Voodoo ritual that has been used to create a Zombi. Much like our modern walking dead zombies, the Zombi was thought to be a person’s body that was brought back from the dead, only without the person’s original soul. These Zombis were sometimes used as slaves and servants with no will and ambition of the original soul. Considering their ritual powders and potions had a whole batch of different neurotoxins like tetrodotoxin and others, it’s no wonder the people that went through the rituals came out as a shell of their former selves. Check out some of the links below about Zombis and zombies.

Clairvius Narcisse, The Man Who Was A Zombie.

How pufferfish can cause “zombification.”

How Zombies Work.

 

Treatments

Tetrodotoxin does not have an existing antidote. Any treatments are strictly symptom-based treatments and treatments intended to remove as much of the toxin as possible from the body (Kotipoyina et al., 2021).

 

Biomarkers

Biomarkers include tetrodotoxin in the blood and urine of afflicted individuals (Bane et al., 2014).

 

References and other interesting articles

Bane, V., Lehane, M., Dikshit, M., O’Riordan, A., & Furey, A. (2014). Tetrodotoxin: Chemistry, Toxicity, Source, Distribution and Detection. Toxins, 6(2), 693–755. https://doi.org/10.3390/toxins6020693

Chau et al. – 2011—On the origins and biosynthesis of tetrodotoxin.pdf. (n.d.).

Chau, R., Kalaitzis, J. A., & Neilan, B. A. (2011). On the origins and biosynthesis of tetrodotoxin. Aquatic Toxicology, 104(1–2), 61–72. https://doi.org/10.1016/j.aquatox.2011.04.001

Clairvius Narcisse, The Man Who Was A Zombie. (2013, March 4). Stranger Dimensions. https://www.strangerdimensions.com/2013/03/04/clairvius-narcisse-the-man-who-was-a-zombie/

How pufferfish can cause “zombification.” (n.d.). Retrieved July 26, 2021, from https://www.environment.sa.gov.au/goodliving/posts/2017/10/pufferfish-zombies

How Zombies Work. (2005, October 28). HowStuffWorks. https://science.howstuffworks.com/science-vs-myth/strange-creatures/zombie.htm

Kotipoyina, H., Kong, E., & Warrington, S. (2021). Tetrodotoxin Toxicity. StatPearls. https://www.statpearls.com/articlelibrary/viewarticle/30383/

Magarlamov, T. Yu., Melnikova, D. I., & Chernyshev, A. V. (2017). Tetrodotoxin-Producing Bacteria: Detection, Distribution and Migration of the Toxin in Aquatic Systems. Toxins, 9(5), 166. https://doi.org/10.3390/toxins9050166

Matsumoto et al. – 2008—Pharmacokinetics of tetrodotoxin in puffer fish Ta.pdf. (n.d.).

Matsumoto, T., Nagashima, Y., Kusuhara, H., Ishizaki, S., Shimakura, K., & Shiomi, K. (2008). Pharmacokinetics of tetrodotoxin in puffer fish Takifugu rubripes by a single administration technique. Toxicon, 51(6), 1051–1059. https://doi.org/10.1016/j.toxicon.2008.01.007

Mechanism of Action – The Chemistry of Tetrodotoxin. (n.d.). Retrieved July 26, 2021, from https://sites.tufts.edu/tetrodotoxin/mechanism/

PubChem. (n.d.). Tetrodotoxin. Retrieved July 26, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/11174599

Tetrodotoxin. (n.d.). Retrieved July 26, 2021, from https://go.drugbank.com/drugs/DB05232

Tetrodotoxin: Biotoxin | NIOSH | CDC. (2021, July 9). https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750019.html

Source

Toluene is an incredibly common solvent and chemical for manufacturing and industry across the industrialized world. It can be found in simple household items like paint, nail varnish, various glues, fragrance sprays, gasoline, cigarette smoke, and more (Toluene.Pdf, n.d.). In nature, this substance can be found in crude oil and one specific tree known as the tolu tree (“Toluene,” 2018).

 

Biotransformation

Toluene can be oxidized into the metabolites o-cresol and p-cresol (Blazevic et al., 2019). Phenol hydroxylase has been studied to determine if it can be used in microorganisms to transform toluene into catechols, which would make metabolites of toluene that are useful in industry (Blazevic et al., 2019).

Toxicokinetics

This graphic from the ToxGuideTM for Toluene has a quick summarization of toluene’s toxicokinetics.

 

Absorption occurs primarily through the respiratory tract, as this is the main source of exposure for people (Air Quality Guidelines – Second Edition Chapter 5.14 Toluene, 2000). Once in the body, toluene distributes to many organs and tissues including the kidneys, the brain, and adipose tissue (Air Quality Guidelines – Second Edition Chapter 5.14 Toluene, 2000). In the brain it gathers in the hippocampus and cerebral cortex, leading to neurological and cognitive dysfunction (Air Quality Guidelines – Second Edition Chapter 5.14 Toluene, 2000). Metoblism through enzymes like cytochrome P-450 and alcohol dehydrogenase occur to produce metabolites that interact with compounds like glycine to create chemical compounds that are excreted through the urine (Air Quality Guidelines – Second Edition Chapter 5.14 Toluene, 2000).

The breakdown of metabolism of absorbed toluene is as follows:

70-80% – Benzoic acid

7-20% – Toluene

(Air Quality Guidelines – Second Edition Chapter 5.14 Toluene, 2000)

Carcinogenicity

Several sources indicate that toluene is not a carcinogen (Toluene | Medical Management Guidelines | Toxic Substance Portal | ATSDR, n.d.; Toluene.Pdf, n.d.; Toxguide-56.Pdf, n.d.). Though more testing needs done, other sources suspect that there is a carcinogen risk to toluene (McMichael, 1988) and toluene diisocyanate (Doe & Hoffmann, 1995).

Mechanism of Action (if known)

Toluene’s mechanism of action is a tough one to pinpoint, as it alters many neurochemical pathways. It is thought to effect all of the following:

Dopamine: Increase in whole brain and striatum dopamine levels or a blockage of dopamine receptors. The real effect is still under investigation.

Serotonin: Increased levels in the medulla, cerebellum, and midbrain.

Norepinephrine: Increased levels in the medulla and midbrain.

Acetylcholine: Increased levels in the striatum and whole brain.

These and other neurochemical tests can be found referencecd in the article titled “Neurotoxicity and Mechanism of Toluene Abuse” (Eisenberg, 2003)

Target organ(s)

The main target organs of toluene are found in the CNS. As mentioned earlier, toluene tends to gather within the hippocampus and cortex of the brain.

Signs and symptoms of toxicity

Exposure can come from inhaling toluene fumes in industrial workplace and other workplace settings that use toluene products in a poor ventilation setting (Toluene – Overview | Occupational Safety and Health Administration, n.d.). Symptoms can appear at exposure levels that are below the safety threshold (Toluene – Overview | Occupational Safety and Health Administration, n.d.).

These symptoms may manifest as follows:

• Loss of appetite
• Nausea
• Memory loss
• Weakness/tiredness
• Dizzy sensations/disorientation
• Confusion

(Toxguide-56.Pdf, n.d.)

Genetic susceptibility or heritable traits

It is thought that a mutation in human leucocyte antigen genes may cause some people to be more likely to develop toluene diisocyanate-induced asthma when their coworkers without this mutation do not develop this asthma (Mapp et al., 2000). There are other enetic factors that are suspected to play a role in why only a certain amount of people develop severe and long-term reactions to toluene and toluene diisocyyanate exposure.

Below is an interesting abstract from the paper titled Influence of genetic factors on toluene diisocyanate-related symptoms: evidence from a cross-sectional study” that addresses some of the suspected gene mutations (Broberg et al., 2008).

“Abstract

Background: Toluene diisocyanate (TDI) is a highly reactive compound used in the production of, e.g., polyurethane foams and paints. TDI is known to cause respiratory symptoms and diseases. Because TDI causes symptoms in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility.

Methods: Workers (N = 132) exposed to TDI and a non-exposed group (N = 114) were analyzed for genotype (metabolising genes: CYP1A1*2A, CYP1A1*2B, GSTM1*O, GSTM3*B, GSTP1 I105V, GSTP1 A114V, GSTT1*O, MPO -463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, SULT1A1 R213H; immune-related genes: CCL5 -403, HLA-DQB1*05, TNF -308, TNF -863) and symptoms of the eyes, upper and lower airways (based on structured interviews).

Results: For three polymorphisms: CYP1A1*2A, CYP1A1*2B, and TNF -308 there was a pattern consistent with interaction between genotype and TDI exposure status for the majority of symptoms investigated, although it did reach statistical significance only for some symptoms: among TDI-exposed workers, the CYP1A1 variant carriers had increased risk (CYP1A1*2A and eye symptoms: variant carriers OR 2.0 95% CI 0.68–6.1, p-value for interaction 0.048; CYP1A1*2B and wheeze: IV carriers OR = 12, 1.4–110, p-value for interaction 0.057). TDI-exposed individuals with TNF-308 A were protected against the majority of symptoms, but it did not reach statistical significance. In the non-exposed group, however, TNF -308 A carriers showed higher risk of the majority of symptoms (eye symptoms: variant carriers OR = 2.8, 1.1– 7.1, p-value for interaction 0.12; dry cough OR = 2.2, 0.69–7.2, p-value for interaction 0.036). Individuals with SULT1A1 213H had reduced risk both in the exposed and non-exposed groups. Other polymorphisms, showed associations to certain symptoms: among TDI-exposed,NAT1*10 carriers had a higher risk of eye symptoms and CCL5 -403 AG+AA as well as HLA-DQB1 *05 carriers displayed increased risk of symptoms of the lower airways. GSTM1, GSTM3 and GSTP1 only displayed effects on symptoms of the lower airways in the non-exposed group.

Conclusion: Specific gene-TDI interactions for symptoms of the eyes and lower airways appear to exist. The results suggest different mechanisms for TDI- and non-TDI-related symptoms of the eyes and lower airways.”

Historical or unique exposures

As this is a fairly common chemical in industry and manufacturing, it is strange that no unique and historical exposures come to the forefront when searching for them. Most cases of toluene exposure come off as standard and normal inhalation cases with CNS problems.

Treatments

Prehospital care includes standard treatments including oxygen administration and removal of tight clothing (Toluene Toxicity Treatment & Management, 2019). Once at the hospital, treatment involves decontamination, ABC checks, and respiratory aid through oxygen and inhalers as needed (Toluene | Medical Management Guidelines | Toxic Substance Portal | ATSDR, n.d.). For eye exposure, eyes should be flushed and for ingestion, activated charcoal should be administered (Toluene | Medical Management Guidelines | Toxic Substance Portal | ATSDR, n.d.).

Biomarkers

Toluene, itself, can be found in the urine of exposed individuals (Toxguide-56.Pdf, n.d.). Ortho-cresol is a metabolite that can also be found in the urine of exposed individuals (Toxguide-56.Pdf, n.d.). These are the two main biomarkers.

References

Air Quality Guidelines—Second Edition Chapter 5.14 Toluene. (2000). Retrieved July 6, 2021, from https://www.euro.who.int/__data/assets/pdf_file/0020/123068/AQG2ndEd_5_14Toluene.PDF

Blazevic, A., Albu, M., Mitsche, S., Rittmann, S. K.-M. R., Habler, G., & Milojevic, T. (2019). Biotransformation of Scheelite CaWO4 by the Extreme Thermoacidophile Metallosphaera sedula: Tungsten–Microbial Interface. Frontiers in Microbiology, 10. https://doi.org/10.3389/fmicb.2019.01492

Broberg, K., Tinnerberg, H., Axmon, A., Warholm, M., Rannug, A., & Littorin, M. (2008). Influence of genetic factors on toluene diisocyanate-related symptoms: Evidence from a cross-sectional study. Environmental Health, 7, 15. https://doi.org/10.1186/1476-069X-7-15

Doe, J. E., & Hoffmann, H. D. (1995). Toluene Diisocyanate: An Assessment of Carcinogenic Risk Following Oral and Inhalation Exposure. Toxicology and Industrial Health, 11(1), 13–32. https://doi.org/10.1177/074823379501100102

Eisenberg, D. P. (2003). Neurotoxicity and Mechanism of Toluene Abuse. 10.

Mapp, Beghè, Balboni, Zamorani, Padoan, Jovine, Baricordi, & Fabbri. (2000). Association between HLA genes and susceptibility to toluene diisocyanate-induced asthma. Clinical & Experimental Allergy, 30(5), 651–656. https://doi.org/10.1046/j.1365-2222.2000.00807.x

McMichael, A. J. (1988). Carcinogenicity of benzene, toluene and xylene: Epidemiological and experimental evidence. IARC Scientific Publications, 85, 3–18.

Toluene. (2018, July 10). ChemicalSafetyFacts.Org. https://www.chemicalsafetyfacts.org/toluene/

Toluene | Medical Management Guidelines | Toxic Substance Portal | ATSDR. (n.d.). Retrieved July 6, 2021, from https://wwwn.cdc.gov/TSP/MMG/MMGDetails.aspx?mmgid=157&toxid=29

Toluene Toxicity Treatment & Management: Prehospital Care, Emergency Department Care, Consultations. (2019). https://emedicine.medscape.com/article/818939-treatment

Toluene—Overview | Occupational Safety and Health Administration. (n.d.). Retrieved July 6, 2021, from https://www.osha.gov/toluene

Toluene.pdf. (n.d.). Retrieved July 6, 2021, from https://www.epa.gov/sites/production/files/2016-09/documents/toluene.pdf

Toxguide-56.pdf. (n.d.). Retrieved July 6, 2021, from https://www.atsdr.cdc.gov/toxguides/toxguide-56.pdf

 

Tungsten (Wolfram) – A Relatively Safe Metal

 

 

Source

Tungsten is a metal that can be found in nature in mineral forms such as in wolframite ((TOXICOLOGICAL,n.d.), (tungsten | Uses, Properties, & Facts, n.d.)) It is most often found in heavy-metal-based industrial settings. It can be alloyed with a number of metals, including nickel, steel, and cobalt, to produce useful mechanical elements, hardened metals, and even lead bullet substitutes ((TOXICOLOGICAL,n.d.), (tungsten | Uses, Properties, & Facts, n.d.)).

 

Biotransformation

Tungsten does not appear to undergo biotransformation within humans. It is relatively stable as a metal element. Something that is interesting is that there are bacteria that can biotransform tungsten-containing sheelite minerals to produce soluble tungsten (Blazevic, 2019). The article exploring this can be found here.

 

Toxicokinetics

Tungsten is a metal that is not readily absorbed by the human body. The majority of tungsten that enters the GI tract is rapidly expelled through waste organs like the kidneys and colon quickly (TOXICOLOGICAL,n.d.). Even the small amount of tungsten that maintains itself in the blood stream is readily expelled from the body (TOXICOLOGICAL,n.d.). It appears that inhalation exposure to tungsten dust is one of the biggest absorption points for this metal (TOXICOLOGICAL,n.d.). The tungsten dust may play a role in lung aggravation, tumor formation, and diffuse pulmonary fibrosis ((TOXICOLOGICAL,n.d.), Technical Fact Sheet – Tungsten , 2015)).

Carcinogenicity

Tungsten is suspected of causing lung cancer, if only from chronic lung irritation, inflammation, and effects from the alloys (TOXICOLOGICAL,n.d.). A study by a Laulicht and team in 2015 managed to find evidences suggesting tungsten can affect tumor-related genes localized to the lung.

 

Mechanism of Action (if known)

Due to its low body-absorption, there is not much known about the mechanism of action for tungsten. Recent studies have started to look into this, but so far not much has been found, as this element isn’t a high human health risk, so priority for understanding it is also low. There are evidences to suggest that tungsten and molybdenum share mechanistic pathways (TOXICOLOGICAL,n.d.).

 

Target organ(s)

Due to tungsten’s rapid removal from the body, one target organ is thought to be the kidney, as the kidney receives excessive exposure to tungsten while removing the metal from the body. The other main target organ is the lung, as this is where the majority of exposure occurs in the form of inhaled tungsten dust.

 

Signs and symptoms of toxicity

Signs and symptoms of toxicity can include general irritations of the mucous membranes and skin, feeling unwell, kidney problems, neural symptoms, seizures, coma, and even death in extremely high concentrations. You can find three decent sources describing tungsten poisoning symptoms here, here, and here.

 

Genetic susceptibility or heritable traits

There are no known genetic or heritable traits associated with adverse reactions to tungsten outside of an allergic reaction that may actually be a reaction to the other metals or salts in the tungsten mixture .(Allergic Reaction , n.d.). This worry is also addressed in an interesting blog about tungsten rings.

It should be noted that an inherent lack of good judgement, though not heritable, can lead to a higher susceptibility for a person to experience tungsten poisoning, as you will see in the next section.

 

Historical or unique exposures

Interestingly, one 19-year-old French fellow serving in the artillery regiment became one of the first documented tungsten poisoning cases. How? Well, by drinking alcohol out of toasty tungsten-containing a gun barrel. How else?  A quick overview on this fellow and his case can be found in this abstract by Marquet et al (1997). Apparently this fellow started feeling ill within the hour and then had a seizure and fell into a coma before medical staff realized his blood levels of tungsten were outrageously high. The bullets being used in his gun did, in fact, contain tungsten. It’s not noted if the hot alcohol helped cause a scenario in which excess tungsten entered his blood or not or if there was just so much tungsten residue in his gun that it overwhelmed his system. Moral of the story, don’t shot gun a beer from a shot gun…

Cheers!

 

Treatments

Treatments for tungsten poisoning include symptomatic treatment and hemodialysis if the poisonings is bad enough. Other treatments include supplemental oxygen and anti-convulsive medications. These recommendations and information on tungsten poisoning can be found here. A video about what hemodialysis is can be found here.

Biomarkers

Tungsten is its own biomarker. Due to its remarkable stability and lack of biotransformation in the human body, blood, urine, fecal, hair, and nail samples can all be tested for the metal. These routes were all tested in our favorite French drinking buddy mentioned earlier and can be found discussed in the same abstract found here.

Essentiality and deficiency (specific to metals)

It’s pretty clear that tungsten probably isn’t essential for human life. If it were, it wouldn’t be so readily passed through the human body. One study suggests that mice treated with tungsten in their diet had less arterial plaque formations than mice who weren’t given tungsten (Schröder, 2006). So, although it’s not an essential metal, it at least shows a potential health benefit. Having a deficiency in tungsten doesn’t appear to cause any detriment.

 

 

 

References

Allergic Reaction to Tungsten. (n.d.). Retrieved June 15, 2021, from https://healthfully.com/550872-allergic-reaction-to-tungsten.html

Blazevic, A., Albu, M., Mitsche, S., Rittmann, S. K.-M. R., Habler, G., & Milojevic, T. (2019). Biotransformation of Scheelite CaWO4 by the Extreme Thermoacidophile Metallosphaera sedula: Tungsten–Microbial Interface. Frontiers in Microbiology, 10. https://doi.org/10.3389/fmicb.2019.01492

Doi:10.1016/j.freeradbiomed.2006.03.026 | Elsevier Enhanced Reader. (n.d.). https://doi.org/10.1016/j.freeradbiomed.2006.03.026

Fresenius Medical Care. (2017, June 23). Understanding hemodialysis. https://www.youtube.com/watch?v=CX8uI4NVLYw

Laulicht, F., Brocato, J., Cartularo, L., Vaughan, J., Wu, F., Kluz, T., Sun, H., Oksuz, B. A., Shen, S., Paena, M., Medici, S., Zoroddu, M. A., & Costa, M. (2015). Tungsten-induced carcinogenesis in human bronchial epithelial cells. Toxicology and Applied Pharmacology, 288(1), 33–39. https://doi.org/10.1016/j.taap.2015.07.003

Marquet et al., 1997  P. Marquet, B. François, H. Lotfi, et al. J. Forensic. Sci. May;, 42 (3) (1997), pp. 527-530

PubChem. (n.d.). Tungsten. Retrieved June 14, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/23964

Schröder, K., Vecchione, C., Jung, O., Schreiber, J. G., Shiri-Sverdlov, R., van Gorp, P. J., Busse, R., & Brandes, R. P. (2006). Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet. Free Radical Biology and Medicine, 41(9), 1353–1360. https://doi.org/10.1016/j.freeradbiomed.2006.03.026

Technical Fact Sheet – Tungsten. (2015). 6.

TOXICOLOGICAL PROFILE FOR TUNGSTEN. (n.d.). 203.

Tungsten | Uses, Properties, & Facts. (n.d.). Encyclopedia Britannica. Retrieved June 15, 2021, from https://www.britannica.com/science/tungsten-chemical-element

Tungsten Poisoning. Symptoms of tungsten poisoning. (n.d.). Retrieved June 15, 2021, from https://patient.info/doctor/tungsten-poisoning

Diafenthiuron

A pesticide with a concerning lack of human health information.

Source

Diafenthiuron is a pesticide created from alterations in the base thiourea structure. These alterations include modifications of the nitrogen atoms, including the addition of an ether group that contains dual aromatic rings on one nitrogen atom, as well as a a tert-butyl group on the other nitrogen atom.

 

While thioureas are used and found in many aspects of industry, from inks to plastics to certain medicines, sources of Diafenthiuron exposure generally aren’t so prevalent. Occupational exposure seems to be the main source of human contact with this synthesized pesticide, specifically in impoverished farming areas in countries that do not have Diafenthiuron on a national chemical ban list. More on that later. One can speculate that the prevalence of countries banning this pesticide could be the reason behind a gaping chiasm in the literature where research on this pesticide should be.

Biotransformation

What we do know about the biotransformation of this pesticide can be found in the era of grunge and flannel, also known as the 1990s. During the early years of this decade, while the rest of the world was contemplating Y2K, researcher Franz J. Ruder and team were diving headfirst into researching the mechanisms behind Diafenthiuron’s action in certain plant-eating pests. In their studies, they discovered that it isn’t Diafenthiuron that’s the killer compound, rather the sun-light-induced metabolite that is produced and then absorbed by the bugs’ bodies (Ruder, 1991). To get this metabolite, Diafenthiuron has to shave off its sulfur atom and two hydrogen atoms like a bad 80’s mullet to produce a carbodiimide product affectionately called CGA 140408 (Ruder, 1991). So, how is this biotransformation? Well, it’s not. However! It has also been discovered that the liver enzyme cytochrome P450 can also cause Diafenthiuron to lose its sulfur group and form its CGA 140408 product, which then wreaks havoc on the body.

More will be discussed on CGA 140408 and it’s mechanism of action in another section.

Toxicokinetics

So, since science knows what the active product is once Diafenthiuron sheds its sulfur group, science knows what sort of toxicity it’ll produce in the human population, right? Yes! But also… no. You see, tests have been performed in insects, which can react to compounds drastically differently than humans. Small mammals are an option, but they don’t always react the same way as we would. And asking a group of random civilians to take a good, long sniff of a potentially fatal compound isn’t exactly ethical. When it comes to direct human research involving pesticide exposure, the more ethical way is to wait until an accidental catastrophe happens involving that pesticide, and studying the patients as they roll in. Fortunately, any sampling for this is small, because several European countries, including the country that makes Diafenthiuron, have a ban on the product. There is a brief news article that mentions this ban that you can read here.

Exactly two results were found in Pubmed when the search terms “toxicokinetics” and “Diafenthiuron” were entered in the search field. Neither result provided desired information. It would seem the mechanism of action and which bugs are affected the worst by this pesticide make up the majority of the research on this compound. There is one source from the United Kingdom that explicitly states Diafenthiuron has a low toxicity in mammals, though finding research to back that up is near impossible.

Carcinogenicity

There is currently no data to be found regarding whether or not Diafenthiuron is a carcinogen or not. A search in Pubmed with the terms “carcinogenicity” and “Diafenthiuron” yielded zero results. Considering this pesticide has been around for well over 30 years, it is concerning to not have studies examining long-term health effects and cancer risk.

Mechanism of Action

Abstract from Ruder, 1991:

“The thiourea diafenthiuron (CGA 106630) is a novel insecticide/acaricide. The present paper is concerned with the molecular mechanism underlying its action. So far, we have not found any direct target for diafenthiuron itself to explain its toxic effect. Since it is known that diafenthiuron is rapidly desulfurated abiotically to the pesticidal carbodiide CGA 140408 in the presence of sunlight and singlet oxygen, CGA 140408 is probably the toxic agent mediating the in vivo action of diafenthiuron. Indeed, CGA 140408 is one of the major in vivo products of diafenthiuron in Calliphora. Furthermore, there is evidence that cytochrome P450 mediates this desulfuration, biotically, since diafenthiuron binds to cytochrome P450 as a substrate in rat liver microsomes. None of the known molecular targets of current commercial insecticides are affected by either diafenthiuron or CGA 140408 (e.g., acetylcholinesterase, sodium channel, acetylcholine receptor, chitin synthesis). Further, we cannot confirm a proposed octopaminergic action of CGA 140408. However, we have been able to demonstrate that CGA 140408, but not diafenthiuron, is a potent in vitro inhibitor of mitochondrial respiration in rat liver and Calliphora flight muscles. It selectively blocks the coupling site in a time-dependent manner which is different from the action of other pesticides. The resemblance in the chemical structure to the well-known mitochondrial inhibitor dicyclohexylcarbodiimide suggests that CGA 140408 inhibits mitochondrial ATPase. Further experimental details are reported in a forthcoming paper. “

Ruder and team did, indeed,  follow up this study with another article that contained more experimental details. In it they discuss how they discovered two main regions affected by Diafenthiuron’s metabolite CGA 140408. These regions include mitochondrial ATPase’s F0 moiety and a protein called porin. The alteration of action for these two regions lead to obstructed ATP synthesis and transport, and overall decrease of mitochondrial respiration. This affects all tissues that come into contact with this pesticide metabolite, and leads to the classical slow decline in activity before death observed in many of the test insects. No ATP means no cellular energy, which means the cells and body can’t function, which leads to death.

 

Target organ

Due to Diafenthiuron’s mechanism of action, it is not per say an organ that is the target, rather an organelle -mitochondria- that is a target. As mentioned earlier, CGA 140408 targets binding sites involved in mitochondrial ATP processes.

From the minor bits of research out there, it seems that this drug is not target-specific to any one organ, but adversely affects the cells of the organs and tissues it comes in contact with. In a study by Riaz-ul-Haq and team, they looked at hematological, serum, and elemental molecule differences between control and Diafenthiuron-exposed fish over short and long term durations (2018). Fish were used as they aren’t the primary animal target of Diafenthiuron exposure, but like with any pesticide, Diafenthiuron can easily make its way into waterways. It was discovered that the exposed fish had different concentrations or many blood cells, serum proteins, and elemental molecules. This study also noted that the fish began to act differently after a few days of low Diafenthiuron exposure. They began sluggish and slow. Considering the blood and serum is where the compound circulates, it makes sense that blood cell counts and proteins would be adversely affected from exposure to a tissue non-discriminant, mitochondrial-targeting compound.

Signs and symptoms of toxicity

So, due to the limited research on human health effects of this compound, it may be suspected that the signs and symptoms of Diafenthiuron poisoning are unknown, right? Wrong! Or at least, they are known only thanks to a few news articles covering the same breaking story from India, 2017. What is this news story you ask? Well, remember earlier the talk about waiting for an accidental human catastrophe to occur for studying potentially lethal compounds? Well…Over the course of 2017, many farmers in rural India used the Swiss-produced pesticide, Polo which contains the active ingredient Diafenthiuron. This story and its details can be found through articles published by PAN India (2020) and Public Eye (n.d.) According to PAN India, of the 55 cases of Diafenthiuorn poisoning that were recorded by public advocacy agencies that year, it was found that only 41 of those cases lived. Those that lived reported a variety of symptoms including coma, neurological dysfunctions, muscular dysfunction, breathing difficulties, and even temporary blindness, according to PAN India (2020).

Genetic susceptibility or heritable traits

There is currently no research on the interactions of genetics and Diafenthiuron exposure.

Historical or unique exposures

As mentioned in the section Signs and symptoms of toxicity, in 2017 India had its share of historical Diafenthiuron exposures. The PAN India article notes that some of the reported symptoms continued to be presented into 2020 for those who were poisoned by the pesticide. This occurrence seems to be a focal point in determining what level of responsibility a manufacturer has with regards to the safety of the consumer, especially when it comes to a chemical that is banned for use in the manufacturer’s own country.

Treatments

Current lacking research and country-wide bans on this pesticide suggests that there is no standardized methods of treatment for Diafenthiuron poisoning. A news article by PAN India confirms that “no antidote is available in case of poisoning” for Diafenthiuron, which was a key legal point regarding whether or not the pesticide’s Swiss manufacturer should be legally held at fault for the poisonings. Considering a few countries with poor farming populations, like India and Pakistan, have not banned this pesticide and continue to actively use it, this is a serious problem. Those who are poisoned by Diafenthiuron exposure have to undergo general medical care and observation while their loved ones hope and pray they can recover. Either banning this pesticide entirely or doing more research on it to create a standard treatment should be the next logical step.

Biomarkers

It is thought that an increase in red blood cells may be a potential, all be it poor, biomarker for Diafenthiouron exposure (Riaz-ul-Haq, 2018). They suspect that increased stress from this pollutant may lead to an increased need for oxygen, especially considering ATP processing would be decreased and stress-inducing. It was also found that certain liver-produced proteins like albumin and globulin were decreased, showing that liver function is likely impaired. However, this study has not been replicated, and no other studies seem to examine non-insect species and biomarker interactions.