Organophosphate Dichlorvos and mitochondria toxicity

[pattismith]

@Hip, @MeSci


Toxicology. 2010 Apr
Mitochondrial energy metabolism impairment and liver dysfunction following chronic exposure to dichlorvos.

Abstract
Although the effects of acute pesticide poisoning are well known but, hardly any data exists regarding the health effects after long-term low-level exposure. Major unresolved issues include the effect of moderate exposure in the absence of poisoning. The present study elucidates a possible mechanism by which chronic organophosphate exposure (dichlorvos 6 mg/kg b.wt., s.c. for 12 weeks) causes liver dysfunction. Mitochondria, a primary site of cellular energy generation and oxygen consumption represent a likely target for organophosphate poisoning. Therefore, the objective of the current study was planned with an aim to investigate the effect of chronic dichlorvos exposure on liver mitochondrial electron transport chain (ETC), mitochondrial calcium uptake and its implications on the induction of liver enzymes and liver dysfunction in rodent model. Our results indicated decreased mitochondrial electron transfer activities of cytochrome oxidase along with altered mitochondrial complexes I and II activity. This decrease in the activities of electron transport complexes in turn affected the ATP synthesis and ATP levels adversely in the mitochondria isolated from dichlorvos (DDVP) treated rat liver. Mitochondrial preparation from DDVP treated rat liver demonstrated significant increase in mitochondrial Ca(2+) uptake and increase ROS levels. The alterations in the mitochondrial calcium uptake, mitochondrial electron transfer enzyme activities and increase ROS levels in turn might have caused an increase in liver enzymes (ALT, AST and ALP). The electron micrographs of liver cells depicted morphological changes in mitochondria as well as nucleus following 12 weeks of exposure to DDVP. These studies provide an evidence of impaired mitochondrial bioenergetics which may lead to liver dysfunction after chronic exposure to dichlorvos.

 

[Valentijn]

Today is 25th anniversary of a cargo plane crash in the Netherlands which hit two large apartment buildings on the outskirts of Amsterdam. 190 liters of Dimethyl methylphosphonate (an organophosphate) was part of the cargo, though that was not made public until 6 years after the incident.

From Wikipedia:

After about a year, however, many residents and service personnel began approaching doctors with physical health complaints, which the affected patients blamed on the El Al crash. Insomnia, chronic respiratory infections, general pain and discomfort, impotence, flatulence, and bowel complaints were all reported. 67% of the affected patients were found to be infected with Mycoplasma, and suffered from symptoms similar to the Gulf War Syndrome or Chronic Fatigue Syndrome-like symptoms.

The first studies on the symptoms reported by survivors, performed by the Academisch Medisch Centrum, began in May 1998. The AMC eventually concluded that up to a dozen cases of auto-immune disorders among the survivors could be directly attributed to the crash, and health notices were distributed to doctors throughout the Netherlands requesting that extra attention be paid to symptoms of auto-immune disorder, particularly if the patient had a link with the Bijlmer crash site.

 

[Hip]

Studies in Scotland showed that farmers using organophosphate-based sheep dip have a 4 times higher prevalence of ME/CFS than the national average. Ref: 1

ME/CFS researcher Prof Peter Behan decades ago tried to bring to attention the link between organophosphates and ME/CFS, but was apparently thwarted and ridiculed by a pesticide industry.

This is what @Abha told me in a PM:

Professor Behan (who found a link between malathion (OP) and ME in his research work) did in the High Court in London (late 90s) when he defended a sheep farmer (had been in contact with sheep dip( malathion?). He lost the case and was ridiculed (as far as I remember). It seemed that the Govt/chemical companies silenced him so that no one could sue re such products.

OP = organophosphate

 

[brenda]

I was part of the sheep dip farmers class action though mine was a house spraying by a local authority to eradicate an infestation on a new tenancy but what happened was that legal aid was withdrawn so that no-one could afford to sue.

 

[Countrygirl]

We have been here before. This is a post I wrote here on Dec 16th 2009:

1. Malathion and have you beaten your wife lately

I'm sorry that I've taken sooooo long to get back to you but have spent the time in a hospital out-patient's clinic. Have just been deposited at my door by two very nice ambulance men and thought I'd better make contact straight away as it is getting late for me. Now, where were we....ah! yes Professor Behan.The bottom line is that, according to Behan's research (my notes go back a few years) the illness caused by chronic low dose OP exposure (e.g. malathion) and M.E. is identical. In The Journal of Nutrition and Environmental Medicine 1996: 6: 341-350 he says that such exposure 'in some way prepared the patients for the later development of ME'. So, all you folk who enjoyed playing in the malathion spray as children....maybe that wasn't such a good idea.

Dr Jonathon Kerr of St George's (yeep, the Dr Kerr) gives support to Behan's conclusion. In the J. of Clinical Pathology 2007 he says that he has previously reported the finding of up-regulated neuropathy target esterase (NTE) in M.E. Apparently, NTE is the main target site for OPs. and he concludes that this family of chemicals may be the 'trigger' for ME.

Malathion, according to a Dr Wayne Sinclair M.D., weakens the immune system, knocking out natural killer cells and inhibiting T-lymphocytes. According to him (Florida, I think) this causes increased susceptability to viruses, cancer and premature aging of organs.

There was a flood of information about the dangers of OPs in the British press in the mid-90s. The Daily Telegraph reported on it week after week and especially linked it to ME. In an article titled, 'The Poison that is getting in our food', journalist Christopher Booker reports that Professor Behan and his team have been increasing struck by the number of ME victims they have studied who turn out to have been exposed to OPs. 'All suffer from severe impairment of their immune system.' Linking OPs with ME is listed as a top priority. 'Evidence,' said Brooker, 'is flooding in that the ramifications of the OP disaster may extend much further than previously imagined. It not only causes damage to those in agriculture, but (through the food supply and household chemicals) among ever-increasing numbers in the population at large.' He then continues by documenting how OPs are rife and states that this 'ticking time bomb' effect could explain the explosion in the numbers of ME sufferers in the last few years.

In a later article The Telegraph states....'As evidence continues to mount that we are threatened with one of our worst public health disasters for decades through widespread poisoning from organophosphorous pesticides......' (He continues by criticising the government departments for failing to sort out the problem.)

With so many farmers falling ill with ME symptoms after repeatedly dipping sheep in OPs (does anyone think how the poor sheep feels?) the Western Morning News reported that strong links had been found between the type of dangerous chemicals used in sheep dip and the 'mysterious condition known as Yuppie Flu'

Behan, the paper says, has found evidence that farmers are at higher risk of developing severe forms of ME than any other population group. ME and organophosphate poisoning, it says, is the same complaint. Macauley, the reporter, quotes Behan as saying 'ALL HAVE SEVERE IMPAIRMENT OF THEIR IMMUNE SYSTEM. WE WERE ABLE TO SHOW THAT THEY WERE CHRONICALLY INFECTED WITH VIRUSES. THEY ALSO HAVE ABNORMAL NEURO-ENDOCRIN FUNCTION DENOTING DAMAGE TO THE HYPOTHALAMUS.....' EXPOSURE TO OPs IS NOW SHOWN TO BE A CAUSE OF LYMPHOMA.

All the above was written between 1993-1995. So what happened? Some very dirty tricks....serious ones. That is another story, which I'm too knackerered to relate at the moment and this is getting rather long...sorry folks.

Everyone (mainly farmers) were told to report to Guy's Hospital Poisons' Unit, who sent out a questionnaire. A number of farmers in my area contacted me and one sent me a copy of the questionnaire. It was disgraceful and it made it obvious that there was going to be a cover-up. Unfortunately, I no longer have a copy, but none of the questions were health-related as far as I can remember. It asked questions about the person's criminal past, tendency to violence, experience of abuse or of being the abuser (I think wife beating was mentioned!), mental illness.....that sort of thing.

Then the Royal Colleges met to discuss OP poisoning. Yes, you've guessed it...they rolled out the psychiatrists. OP poisoning was just another case of aberrant illness behaviour which would respond to CBT.

This is a huge topic......there is so much more if anyone is interested. And, of course, it is not just OPs but organochlorines as well. But ..enough for tonight.

 

[Countrygirl]

And there is this:


https://www.theguardian.com/science/2017/aug/19/sick-crew-toxic-air-planes-frequent-flyers-ill

This is part of the article from the Guardian:

Kate Leahy

Saturday 19 August 2017 09.00 BSTLast modified on Monday 21 August 2017 14.29 BST

Three years ago, Matt Bass, 34, died suddenly in his sleep. According to his father, Charlie, he had been feeling unwell for a few months. He’d lost weight, had digestive and respiratory problems, and suffered from severe fatigue. Doctors thought he might have Crohn’s disease, but were struggling to reach a diagnosis.

Matt was cabin crew for British Airways, and on the day he died had returned overnight from Accra, Ghana (by cabin crew standards, a relatively short, six-hour flight). He went for a scheduled MRI scan, hoping to get to the bottom of his ill health, then in the evening to a crew friend’s house in Slough for pizza. After a few hours, he said he needed a rest and went to lie down. When his friends couldn’t wake him, they administered CPR. An ambulance arrived and took him to A&E, where paramedics tried to revive him; but he never woke up.

When I meet Charlie Bass in a hotel lobby in Colnbrook, a small village at the end of Heathrow’s westerly operating runway, he is warm but his anger is still clear. “Matt wanted to fly for as long as Fiona, my wife, and I can remember. When he was just eight years old, he wrote to British Airways to ask about becoming a pilot. They wrote back and told him to apply when he was 18.” He smiles.

The initial postmortem did not reveal a reason for the sudden death. “The coroner’s office couldn’t tell us why Matt had died,” Charlie says. “At first we felt numb and kept asking why? We just wanted to find out what had happened.” Then two aviation experts got in touch with Charlie and Fiona. Dr Michel Mulder, a former pilot and consultant in aviation medicine, and Frank Cannon, an aviation lawyer, suggested the couple arrange a specialist secondary postmortem to look for specific toxins in Matt’s body. “We didn’t know if there would be an answer, but because of the information we had from ex-crew members who were ill, we were confident Matt’s symptoms were the same.” Desperate, they spent around £5,000 on tests; the results showed that Matt had high levels of organophosphate poisoning, one of the many effects of exposure to toxic cabin air, otherwise known as aerotoxic syndrome.

Aerotoxic syndrome is a little-known term used to describe the symptoms of exposure to contaminated air. It is a controversial diagnosis, and many in the aviation industry are adamant it doesn’t exist. But Mulder, Cannon and other campaigners believe it is responsible for long-term sickness, and even death, in a disproportionate number of people who work as cabin crew and pilots. Aerotoxic syndrome has also been cited as the reason for ill health in passengers in a number of cases. Cannon says he has more than 100 cases on his books, including two frequent fliers. Two of these cases have made headlines. Cabin crew member Warren Brady, 46, died of a heart attack as he slept during a break on a flight from Heathrow to São Paolo in June 2014; his family and friends claimed he had been suffering from severe headaches, numbness in his limbs and mood swings, all symptoms of organophosphate poisoning. Richard Westgate, 43, was a pilot who died in 2012. Before he died, he had begun legal action against his former employer, British Airways.

Angel Fleet, a website and Facebook group dedicated to the memory of cabin crew who have died. The ticker tape of names that runs across the website often lists ages at time of death – 49, 51, 34, 30, with the average being around 43. “The most frequent causes are cancer, heart problems, suicide and brain haemorrhages. All of which can be caused by toxic poisoning,” she says. Passon herself has a letter from her doctor that states she has been permanently incapacitated by aerotoxic syndrome.

Aerotoxic syndrome was so named by a small team of medical researchers in 1999. In their report, Dr Harry Hoffman, Professor Chris Winder and Jean-Christophe Balouet suggested that exposure to contaminated cabin air could result in long-term ill health, and needed further investigation. Since the 1950s, aircraft have used what’s known as the “bleed air” system to filter air through cabins. Air is sucked into the engine compressor (the cold part of the engine) before it is siphoned off into the air-conditioning units, where it mixes with the recirculated cabin air. Problems occur when the oil used to lubricate the combustion parts of the engine heat up and chemicals leak back through damaged or inefficient seals into the compressor – and from there into cabin air. Filters in the air-conditioning units are designed to remove bacteria, viruses and dust. Obvious leaks, identified by smoke or “dirty sock” smells, are known as fume events and can cause acute toxicity, with symptoms ranging from runny nose to memory loss, severe headaches, loss of balance and muscle weakness. But the constant low-level, “silent” seepages are, crew and pilots claim, just as much of a problem.

 

[pattismith]

I was myself exposed to Dichlorvos/Fenitrothion on a recurrent basis from a Dog spray insecticide (it was prohibited soon after), so I believe the more we talk about organoP toxicity, the better it is.

 

[bertiedog]

From:http://cdn.intechopen.com/pdfs/2567...cytochrome_p450_enzymes_in_vitro_a_survey.pdf

Presumably if you have various SNPs in some of these enzyme systems then it could make the problem worse of getting rid of these chemicals by our own detoxification system.

I know I have some of these SNPs specifically related to detoxification of organophosphates and in the 80s I remember that when I would put a flea spray on my Retriever which contained this chemical I would feel horrific and nearly fall over with dizziness. It was pretty immediate and not dissimilar to the effect I get if I eat any MSG which of course is a different process (breaking down an amine where again I have problems).


"Cytochrome P450 enzymes (CYPs) are active in the metabolism of wide variety of xenobiotics. The investigation of the contributions of human CYPs in pesticides metabolism, especially insecticides, is still growing. One of the background tools to facilitate this task is by sorting the contribution of each human CYP isoform in the metabolism of pesticides. This paper attempts to provide a comprehensive literature survey on the role of human hepatic CYPs such as human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5 and CYP3A7 in pesticides biotransformation in vitro as well as to sort the reactions mediated. Based on relevant publications identified by searching databases from 1995 through 2011, more than 400 metabolic reactions were reported to be mediated at least in part by human CYPs in vitro. Some information on older papers was obtained from previous literature surveys compiled by Hodgson 2001 & 2003. Finally, we give brief insight into potential modulations and consequences of human CYP genes – pesticides interactions. "

Pam

 

[pattismith]

Today is 25th anniversary of a cargo plane crash in the Netherlands which hit two large apartment buildings on the outskirts of Amsterdam. 190 liters of Dimethyl methylphosphonate (an organophosphate) was part of the cargo, though that was not made public until 6 years after the incident.

From Wikipedia:

Thank you Valentijn, I didn't know this horrific accident;

It is unclear in the wikipedia page if the health issues of the survivors were a result of the deplete uranium contamination or the organophosphate...

Interestingly, deplete uranium weapons were heavily used in Gulf war...

https://southfront.org/depleted-uranium-radioactive-contamination-iraq-overview/

an extract:

• "Pathological Studies of DU Effects on Human Health

Dr. Huda Ammash- Professor of Molecular Biology in the College of Science in University of Baghdad, 1998, presented a paper on the mechanisms of toxicity induced by free radicals resulting from irradiation with DU and ionization of the atmosphere in Iraq [42] [43]. This paper pinpointed the need for DU toxicity studies on enzymes (SOD), Caralase, hydrogenates and Glyceraldehydes Dehydrogenates levels. She also presented the multi aborative cases on the DNA level where out of 50 studied cases, 29 cases were found with DNA abnormalities (with no hereditary evidence). Other multi aborative cases investigating the toxoplasmosis effect showed that out of 130 cases, over 65% more were infected than those recorded in 1989.

Muhammed, Z.T. et al, 2002, [44] published a paper about the effects of DU radiation on the human immune system enzyme. A group of (26) Iraqi veterans who were exposed to DU radiation with (43) control individuals were all subjected to tests for Adenosine DA Amines (ADN) enzyme activity. Results indicated mean activity of the enzyme of the exposed individuals of (0.184 ±0.016) U/gm protein, while the unexposed individual’s enzyme activity (0.291 ±0.022) U/gm protein.

ADA enzyme activity in the exposed individuals were found to be significantly lower than the control group. P<0.05 significant correlation coefficient was found between ADA activity as an important immune enzyme and related clinical signs and symptoms related to defective cellular immune functions.

Ammash, H., Alwan, L. and Marouf, B.A.,2002, published a paper (in Arabic) [45] about the results of Genetic hematological analysis for a group of individuals who live in DU contaminated areas in Southern Iraq. Blood tests for the (47) individuals who lived in Basra contaminated areas and other (30) individuals as a control group who lived in Baghdad. The research included other clinical and correlated factors."

 

[mariovitali]

CC @Jesse2233

Environmental pollutants directly affect the liver X receptor alpha activity: Kinetic and thermodynamic characterization of binding.


Liver X receptor is a ligand-activated transcription factor, which is mainly involved in cholesterol homeostasis, bile acid and triglycerides metabolism, and, as recently discovered, in the glucose metabolism by direct regulation of liver glucokinase. Its modulation by exogenous factors, such as drugs, industrial by-products, and chemicals is documented. Owing to the abundance of these synthetic molecules in the environment, and to the established target role of this receptor, a number of representative compounds of phthalate, organophosphate and fibrate classes were tested as ligands/modulators of human liver X receptor, using an integrated approach, combining an in silico molecular docking technique with an optical SPR biosensor binding study. The compounds of interest were predicted and proved to target the oxysterols-binding site of human LXRα with measurable binding kinetic constants and with affinities ranging between 4.3 × 10(-7) and 4.3 × 10(-8)M. Additionally, non-cytotoxic concentration of these chemicals induced relevant changes in the LXRα gene expression levels and other target genes (SREBP-1c and LGK) in human liver hepatocellular carcinoma cell line (HepG2), as demonstrated by q-RT-PCR.

https://www.ncbi.nlm.nih.gov/pubmed/25869557