Common chemicals causing diabetes; mechanism: melatonin mimic

Posted on 22 Jan 2017

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Will you be poisoned by pesticides today? 

Synthetic chemicals commonly found in insecticides and garden products bind to the receptors that govern our biological clocks, University at Buffalo researchers have found. The research suggests that exposure to these insecticides adversely affects melatonin receptor signaling, creating a higher risk for metabolic diseases such as diabetes.
Published online on Dec. 27 in Chemical Research in Toxicology, the research combined a big data approach, using computer modeling on millions of chemicals, with standard wet-laboratory experiments. It was funded by a grant from the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

Disruptions in human circadian rhythms are known to put people at higher risk for diabetes and other metabolic diseases but the mechanism involved is not well-understood.

“This is the first report demonstrating how environmental chemicals found in household products interact with human melatonin receptors,” said Margarita L. Dubocovich, PhD, senior author on the paper and SUNY Distinguished Professor in the Department of Pharmacology and Toxicology and senior associate dean for diversity and inclusion in the Jacobs School of Medicine and Biomedical Sciences at UB.

“No one was thinking that the melatonin system was affected by these compounds, but that’s what our research shows,” she said.

The current research focuses on two chemicals, carbaryl, the third most widely used insecticide in the U.S. but which is illegal in several countries, and carbofuran, the most toxic carbamate insecticide, which has been banned for applications on food crops for human consumption since 2009. It is still used in many countries, including Mexico and traces persist in food, plants and wildlife.

“We found that both insecticides are structurally similar to melatonin and that both showed affinity for the melatonin, MT2 receptors, that can potentially affect glucose homeostasis and insulin secretion,” said Marina Popevska-Gorevski, co-author, now a scientist with Boehringer Ingelheim Pharmaceuticals, who worked in Dubocovich’s lab while earning her master’s degree at UB. “That means that exposure to them could put people at higher risk for diabetes and also affect sleeping patterns.”

The results suggest that there is a need to assess environmental chemicals for their ability to disrupt circadian activity, something which is not currently being considered by federal regulators. The UB researchers are developing a rapid bioassay that might be able to assess environmental chemicals for this kind of activity.

The work is part of a larger effort by Dubocovich and her colleagues at UB to develop their Chem2Risk pipeline, combining UB’s expertise in computational biology and melatonin receptor pharmacology.

“Our approach seamlessly integrates the screening of environmental chemicals through computer simulation, in vitro and in vivo techniques to gauge the risk these chemicals present for various disease end points,” explained Raj Rajnarayanan, PhD, lead author and assistant professor of pharmacology and toxicology at UB.

The UB database contains about four million chemicals reported to have some level of toxicity. “From those, we identified hundreds of thousands of compounds that had readily available chemical structures so that we could study them,” Rajnarayanan explained. After grouping the chemicals in clusters according to their similarity, they found several with functional groups similar to melatonin.

Using predictive computational modeling and in vitro experiments with cells that express human melatonin receptors, they found that carbamates selectively interact with a melatonin receptor. That interaction can disrupt melatonin signaling and alter important regulatory processes in the body.

“By directly interacting with melatonin receptors in the brain and peripheral tissues, environmental chemicals, such as carbaryl, may disrupt key physiological processes leading to misaligned circadian rhythms, sleep patterns, and altered metabolic functions increasing the risk for chronic diseases such as diabetes and metabolic disorders,” said Dubocovich.

For example, she explained, there is a fine balance between the release of insulin and glucose in the pancreas at very specific times of day, but if that balance becomes disrupted over a long period of time, there is a higher risk of developing diabetes.

Dubocovich is an internationally renowned authority on the brain hormone melatonin and how melatonin receptors are regulated. Her work has significantly boosted the scientific understanding of how melatonin impacts circadian rhythms and human health in general, including sleep disorders, metabolic disease and drug addiction.

Popovska-Gorevski presented preliminary findings on this work at the 2014 Experimental Biology meeting in San Diego, receiving a Best Abstract Award from the Toxicology Division of the American Society for Pharmaceutical and Experimental Therapeutics and a Best Poster Award from the Upstate New York Pharmacology Society.

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This is worth reading as well:

The insecticide carbaryl, … has been associated with such a large number of health problems. From acute toxicity, suppression of immune system functions, and behavioral problems to cancer, genetic damage, and reproductive problems in both males and females, carbaryl’s adverse effects span an enormous range.

Carbaryl (1-naphthyl methyl carbamate) is one of the three most commonly used insecticides in the United States with an estimated annual use of between 10 and 15 million pounds. … It is a broad-spectrum insecticide and is registered for use on more than 100 different crops, animals, ornamental plants, and indoor areas. … It has been registered in the U.S. since 1958. Previously manufactured by Union Carbide, the primary U.S. manufacturer is now Rhone Poulenc Agricultural Company; many of its carbaryl-containing products are marketed under the brand name Sevin.

Carbaryl is a carbamate insecticide. Like all members of this chemical family, it inhibits the action of an enzyme that is an essential component of insect, fish, bird, and mammal nervous systems. The enzyme, acetyl cholinesterase (AChE), controls the chemical reaction that transforms acetylcholine into choline after acetylcholine has been used to transmit nerve impulses across the junctions between nerves. Without functioning AChE, acetylcholine accumulates and prevents the smooth transmission of nerve impulses. This causes loss of normal muscle control, and ultimately death. The AChE inhibition is said to be reversible because the carbaryl disassociates from the AChE within several hours. This happens even if death has already occurred. … 

Given that carbaryl’s primary mode of action disturbs the nervous system, it is not surprising that researchers have measured a variety of neurological and behavioral effects of carbaryl exposure. Case reports of human exposures tell some compelling stories. For example, a professor of medicine at a New England university reported that his twice daily applications of a commercial tick powder with active ingredient carbaryl to his cat had dramatic effects on the cat’s personality. The pet, who had never been much of a hunter, began attacking large numbers of birds and mice. The professor’s personality underwent a parallel change (in spite of the gloves and mask he wore while dusting the cat) and he was described as being in a “continual rage.” Ending the tick powder treatments brought an end to the aggressive behavior in both doctor and cat within a week. 

Two other reports describe patients with a neurological condition called delayed peripheral neuropathy following carbaryl exposure. This condition, normally associated with certain organophosphates and not carbamates like carbaryl, causes nerve degeneration and paralysis of arms or legs several weeks after exposure. …

People are exposed to carbaryl through using the insecticide in homes and gardens, consuming residues on food, drinking contaminated water, being contaminated due to drift from nearby applications, and working with carbaryl. …

Effects on Nontarget Species

A wide variety of animals, plants, and bacteria are adversely affected by carbaryl. Not only acute toxicity, but many different kinds of chronic effects have been documented in bees, beneficial insects, fish, birds, earthworms, frogs, crop plants, nitrogen-fixing bacteria, and other species. Some effects occur at surprisingly low doses. …

Synergy

The anti-ulcer drug Tagamet (cimetidine) has been shown to inhibit the breakdown of carbaryl in both laboratory animals and humans. This means that people exposed to both cimetidine and carbaryl will have longer and more pronounced symptoms. For example, a man who was exposed to six home treatments of a carbaryl-containing insecticide and who was also taking cimetidine suffered from headaches, memory loss, muscle weakness and cramps, anorexia, weight loss, and sleep apnea for a seven month period. Some neurological symptoms persisted for over a year. The acute and chronic toxicity of niridazole, a drug used to treat schistosomiasis, is also enhanced by carbaryl exposure.

The common insecticide synergist piperonyl butoxide increases carbaryl toxicity. In fish, acute toxicity of a carbaryl-piperonyl butoxide mixture was over 100 times that of carbaryl alone. In addition, carbaryl increases the acute toxicity of the phenoxy herbicide 2,4-D, the insecticides rotenone (a botanical) and dieldrin (an organochlorine) as well as the wood preservative pentachlorophenol.72 Sublethal effects of the organophosphate insecticide phenthoate are also synergized by carbaryl in fish, including AChE inhibition73 and both morphological and behavioral changes.74 While the toxicity of combinations of chemicals is rarely studied, the ability of carbaryl to interact with a large number of chemical classes is striking.

Manufacturing

One of the intermediaries used in the manufacture of carbaryl is the highly reactive compound methyl isocyanate (MIC). On December 3, 1984 a toxic cloud containing MIC and other reaction products escaped from a tank in a Union Carbide plant in Bhopal, India that manufactured carbaryl and aldicarb (another carbamate insecticide). Between 2500 and 5000 people died as a result of the accident, and up to 200,000 people were injured. Injuries included respiratory problems, eye damage, fetal and newborn deaths, suppression of the immune system, and changes in blood chemistry. A smaller, but similar accident occurred the following year at Union Carbide’s aldicarb and carbaryl plant in Institute, West Virginia and 135 people were hospitalized.
Secret “Inert” Ingredients 
Most carbaryl-containing pesticide products contain “inert” ingredients whose identity EPA and the pesticide industry claim are trade secrets. There is little publicly available information about most of these “inerts.” Some carbaryl formulations contain crystalline silica as an “inert” and others contain petroleum oils.  EPA has listed petroleum hydrocarbons as an inert with high priority for testing because some petroleum products are suspected or known carcinogens.

Crystalline silica causes the chronic lung disease silicosis and the International Agency for Research on Cancer has classified crystalline silica as having “limited evidence of carcinogenicity in humans” and “sufficient evidence of carcinogenicity” in animals. Silica was responsible for what has been called “America’s worst industrial disaster” during the 1930s when over 700 workers died of silicosis after working on a tunneling project for Union Carbide in West Virginia.

Other “inerts” in carbaryl formulations also pose toxicological problems. For example, exposure of prawns to sublethal concentrations of a commercial formulation of carbaryl caused more AChE inhibition than did exposure to carbaryl alone. The researchers believe that the emulsifier in the commercial formulation is responsible for the enhanced toxicity.

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How do you avoid carbaryl, the third most widely used insecticide in the U.S., and carbofuran, the most toxic carbamate insecticide, which is still used in many countries, including Mexico? The MSDS from Bayer on carbaryl says it can be inhaled, invested and absorbed through the skin. Advice for exposure:

Symptoms: Temporary blurred vision due to contraction of the pupils (miosis) following contact with the eyes., Bradycardia, Low blood pressure,
Salivation, Bronchial hypersecretion, Vomiting, Diarrhoea, Sweating, Muscular fasciculation, Spasm, Breathing difficulties, Respiratory paralysis, Somnolence, Coma, Respiratory failure, Hypothermia, Convulsions, Nausea

Monitor: respiratory, cardiac and central nervous system. Monitor: blood picture. Monitor: red blood cell and plasma cholinesterase. ECG – monitoring (Electrocardiogram). Oxygen or artificial respiration if needed. Keep respiratory tract clear. In case of ingestion gastric lavage should be considered in cases of significant ingestions only within the first 2 hours. However, the application of activated charcoal and sodium sulphate is always advisable. The following antidote is generally accepted: atropine. Before antidote is administered, either clear symptoms of poisoning have to be present or the cholinesterase activity is inhibited to below 30% of normal. In case of convulsions, a benzodiazepine (e.g. diazepam) should be given according to standard regimens. Contraindications: oximes (pralidoxime, obidoxime).
Do not use oximes such as 2-PAM unless organophosphate intoxication is suspected. Watch for pulmonary edema, which may develop in serious cases of poisoning even after 24-48 hours. At first sign of pulmonary edema, the patient should be placed in an oxygen tent and treated symptomatically. Contraindications: derivatives of morphine.

Somnolence is a state of strong desire for sleep, or sleeping for unusually long periods. Interesting given that we now know carbaryl mimics melatonin.
Muscle fasciculation means small, involuntary muscle twitches. It can happen to any muscle in the body, including the tongue.

Intermittent unexplained symptoms in myself include: trouble sleeping, jittery heart, arrhythmia, nerves in arms falling asleep in the night, nausea and dizziness in the evening and long term tinnitus. 

I still have the ringing in my ears, but I haven’t had many of these symptoms since I moved away from agricultural fields. 

Post a comment if you have any tips on detecting, deactivating or avoiding this common man made toxin. 

Posted in: Biology, Health