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Off topic: Roundup may be source of many medical problem increases - April 2013

Lethality of Roundup 'Weedkiller' Extends Beyond Plants To Humans, Study Suggests

Lethality of Roundup 'Weedkiller' Extends Beyond Plants To Humans, Study Suggests

A shocking new study finds that glyphosate, the active ingredient in Roundup herbicide, "...may be the most biologically disruptive chemical in our environment," capable of contributing to a wide range of fatal human diseases.

A new report published in the journal Entropy links the active ingredient in Roundup herbicide known as glyphosate with a wide range of fatal diseases.i

Glyphosate is the world's most popular herbicide and is designed to kill all but genetically modified "Roundup Ready" plants, such as GM corn, soy, beet, cottonseed and canola.  Over 180 million pounds of the chemical are now applied to US soils each year,ii and while agrichemical manufacturers and government regulators have considered it 'relatively safe,' an expanding body of biomedical research indicates that it may cause over 30 distinct adverse health effects in exposed populations at far lower concentrations than used in agricultural applications.

The new report, authored by Stephanie Seneff, a research scientist at the Massachusetts Institute of Technology, and Anthony Samsel, a retired science consultant from Arthur D. Little, Inc., brings to the forefront concerns voiced by an outspoken minority that Roundup and related glyphosate herbicide formulations are contributing to diseases as far-ranging as inflammatory bowel disease, anorexia, cystic fibrosis, cancer, Alzheimer's and Parkinson's disease, and infertility.   In fact, the authors propose that glyphosate, contrary to being essentially nontoxic, "...may be the most biologically disruptive chemical in our environment."

The researchers identified the inhibition and/or disruption of cytochrome P450 (CYP) enzymes as a hitherto overlooked mechanism of toxicity associated with glyphosate exposure in mammals.

CYP enzymes are essential for detoxifying xenobiotic chemicals from the body. Glyphosate therefore enhances the damaging effects of other food borne chemical residues and environmental toxins.  The researchers also showed how interference with CYP enzymes acts synergistically with disruption of the biosynthesis of aromatic amino acids by gut bacteria (e.g. tryptophan), as well as impairment in serum sulfate transport, a critical biological system for cellular detoxification (e.g. transulfuration pathway which detoxifies metals).

These effect, according to the researchers, can contribute to causing or worsening "...most of the diseases and conditions associated with a Western diet which include gastrointestinal disorders, obesity, diabetes, heart disease, depression, autism, infertility, cancer and Alzheimer's disease."

This new report may help to explain why over 30 adverse health effects associated with Roundup herbicide exposure have been identified in the peer-reviewed and published literature so far. The full report in PDF form can be obtained here. Please help us spread this information, as well as our Roundup Toxicity Research and GMO Research pages, by sharing them with other concerned individuals and groups.

Glyphosate's Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases
Entropy 2013, 15, 1416-1463; doi:10.3390/el5041416
Anthony Samsel  and Stephanie Seneff 2'*
1 Independent Scientist and Consultant, Deerfield, NH 03037, USA; E-Mail: anthonysamsel at acoustictracks.net
2 Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA
* Author to whom correspondence should be addressed; E-Mail: Seneff at csail.mit.edu; Tel.: +1-617-253-0451; Fax: +1-617-258-8642.
Received: 15 January 2013; in revised form: 10 April 2013 /Accepted: 10 April 2013 / Published: 18 April 2013

Abstract: Glyphosate, the active ingredient in Roundup®, is the most popular herbicide used worldwide. The industry asserts it is minimally toxic to humans, but here we argue otherwise. Residues are found in the main foods of the Western diet, comprised primarily of sugar, corn, soy and wheat. Glyphosate's inhibition of cytochrome P450 (CYP) enzymes is an overlooked component of its toxicity to mammals. CYP enzymes play crucial roles in biology, one of which is to detoxify xenobiotics. Thus, glyphosate enhances the damaging effects of other food borne chemical residues and environmental toxins. Negative impact on the body is insidious and manifests slowly over time as inflammation damages cellular systems throughout the body. Here, we show how interference with CYP enzymes acts synergistically with disruption of the biosynthesis of aromatic amino acids by gut bacteria, as well as impairment in serum sulfate transport. Consequences are most of the diseases and conditions associated with a Western diet, which include gastrointestinal disorders, obesity, diabetes, heart disease, depression, autism, infertility, cancer and Alzheimer's disease. We explain the documented effects of glyphosate and its ability to induce disease, and we show that glyphosate is the "textbook example" of exogenous semiotic entropy: the disruption of homeostasis by environmental toxins.

{Just the titles ofmost sections of the long study}
2. Glyphosate's Pathological Effects: Controlled Studies
3. Gut Dysbiosis, Autism and Colitis
4. Sulfate Transport Impairment and Phenol Synthesis
5. Evidence that Glyphosate Inhibits CYP Enzymes
6. The Path to Obesity
7. The Path to Inflammatory Bowel Disease and Anorexia Nervosa
8. Cytochrome P450 Enzymes

The cytochrome P450 (CYP) enzymes are a diverse, ancient class of enzymes that date back to three billion years ago, and play an important role in plant, animal, and microbial biology 161. These enzymes participate in oxidation, peroxidation and reduction of compounds ranging from pharmaceutical drugs to environmental chemicals to endogenous bioactive molecules 123. There are at least 18 distinct CYP families in humans, which are classified as a series of numerical "CYP" classes. In humans, CYP1, CYP2, CYP3, and CYP4 P450 enzymes in the liver are essential for detoxification of many xenobiotics 162. Members of the CYP5 and CYP7 classes are essential for the formation of water-soluble bile acids from cholesterol in the liver. Bile acids act as powerful detergents to aid in the digestion of fats, and also provide a pathway for disposal of oxysterols. A loss-of-function mutation in CYP7B1 leads to liver failure in children, associated with high serum levels of oxysterols 163.
Both cholesterol and vitamin D3 = synthesis and degradation depend upon various CYP enzymes. At least seven CYP enzymes have a role in converting acetate into sterols. Lanosterol 14a-desmethylase (CYP51A1) is pivotal in cholesterol synthesis. Two CYP enzymes in the liver catalyze 25-hydroxylation of vitamin D3 = to its active form, and two other CYP enzymes catalyze the breakdown of vitamin D3 = in the liver 164,165.
There is a growing epidemic of vitamin D deficiency in the United States. In a study on serum 25-hydroxyvitamin D levels obtained from the National Health and Nutrition Examination Survey (NHANES) data, it was found that vitamin D3 = levels fell sharply in the interval from 2001 to 2004 compared to the interval from 1988 through 1994 166. While this problem is in part due to overaggressive sun avoidance practices, glyphosate's interference with CYP proteins may play a role in disrupting vitamin D3 = activation in the liver.
Several CYP enzymes participate in steroid synthesis. Cytochrome P450 oxidoreductase deficiency (POR) is a newly described disorder of steroidogenesis 167. Five crucial lipid hormones, aldosterone, androstenedione, cortisol, corticosterone and dehydroepiandrosterone (DHEA), are produced in the adrenal glands, testes and ovaries, and in the adrenal cortex. All steroid hormones are produced from cholesterol by these CYP enzymes, contained within the inner mitochondrial membrane. The lipophilic nature of these steroids allows them to diffuse across the lipid bilayers. CYP19A1 (aromatase), whose inhibition has been confirmed in association with glyphosate 109,110 converts androgenic precursors into estrogen. Suppressed aromatase synthesis has been found in the brain in association with autism 168, leading to the "super-male" profile associated with this condition 169.
CYP26A1 catabolizes retinoic acid; hence, its suppression would lead to excess retinoic acid bioavailability. CYP26A1 is induced by retinoic acid during neural differentiation, and its action leads to the degradation of retinoic acid, a necessary step towards maturation of the developing neurons 114. The aryl hydrocarbon receptor (Ahr) gene induces CYP1B expression, leading to degradation of retinoic acid. Ahr-knockout mice accumulate excess retinoic acid in the liver 170. Thus, if liver CYP1B expression were disrupted by glyphosate, it would lead to excess retinoic acid. Retinoic acid suppresses the synthesis of cholesterol sulfate, a crucial step in bile acid synthesis 171; thus, excess retinoic acid in the liver should lead to impaired synthesis of bile acids and impaired fat metabolism.
Mutations in CYP7A1 are associated with high serum LDL and high hepatic cholesterol content, along with deficient bile acid excretion 172. Human CYP7B1 mutations lead to both defects in bile acid synthesis and spastic paraplegia, involving impaired myelin sheath in the spinal cord and uncontrolled movement disorders. The drug, clopidogrel (Plavix), administered to suppress life-threatening stent thrombosis following cardiovascular surgery, depends upon a liver CYP enzyme, CYP2C19, to transform it into an activated metabolite. Patients with a loss-of-function mutation in this CYP enzyme have significant risk of an adverse event following surgery 173,174.
Glyphosate from food sources or as a contaminant in water would be likely to reach the liver in high concentrations through direct transport from the digestive system via the hepatic portal vein. It could be anticipated that glyphosate would disrupt many of the diverse CYP enzymes that are bioactive in the liver, involved in cholesterol synthesis and metabolism, vitamin D3 = synthesis and metabolism, the detoxification of xenobiotics, and regulation of retinoic acid.
Glyphosate would also be expected to travel throughout the blood stream, disrupting any CYP enzymes it comes in contact with. Of particular concern are the two that regulate blood clotting (thromboxane A2 synthase: CYP5A1) and hemorrhaging (prostacyclin synthase: CYP8A1). CYP5A1 stimulates platelet aggregation, whereas CYP8A1 inhibits platelet aggregation. The elderly often face instabilities in hemorrhaging and clotting leading to Disseminated Intravascular Coagulation (DIC) and life-threatening destabilization of the blood 175, which could be due to impaired function of these two enzymes.

9. Glyphosate's Potential Role in eNOS Dysfunction
10. Involvement of the Brain
10.1. Serotonin, Mood Disorders, and Autism
10.2. Ammonia, Autism and Alzheimer's Disease.
10.3. A Role for Zinc Deficiency.
10.4. Methylation Impairment
10.5. Molecular Mimicry and Multiple Sclerosis
10.6. Dopamine and Parkinson's Disease
11. Other Adverse Health Effects
11.1. Liver Disease
11.2. Development and Fertility
11.3. Cancer
11.4.Cachexia (muscle wasting).
12. Glyphosate in Food Sources

Following its successful commercial introduction in 1974 in the U.S., glyphosate has now become the dominant herbicide worldwide 6. In large part this is due to its perceived lack of toxicity in humans. Since becoming generic in 2000, the dramatic drop in cost has encouraged global use of the generic version. Today, it is estimated that 90% of the transgenic crops grown worldwide are glyphosate resistant. The rapidly growing problem of glyphosate-resistant weeds is reflected in steady increases in the use of glyphosate on crops.
Table 1. Estimated range for glyphosate usage in agriculture in the U.S. as a function of year. Range is estimated in units of millions of pounds. These data were obtained from the EPA 272.
Glyphosate usage for the USA (Range in millions of pounds)
Year 2001                    2003 2005 2007
Range 85-90                 128-133 155-160 180-185
Today, Americans spray more than 100 million pounds of Roundup®, the most popular among Monsanto's chemicals, on their yards and farms every year. According to the most recent statistics from the U.S. Environmental Protection Agency (EPA) 272, the U.S. currently represents 25% of the total world market on herbicide usage. Glyphosate, first registered for use in 1974, has been the most common herbicide used in the United States since 2001, and the amount of glyphosate usage has increased steadily since then, as shown in Table 1. In 2007, the most recent year for which such numbers are available, the U.S. used an estimated 180 to 185 million pounds of glyphosate, more than doubling the amount used just six years before.
The Western diet is a delivery system for toxic chemicals used in industrial agriculture. The diet consists primarily of processed foods based on corn, wheat, soy and sugar, consumed in high quantities. Chemical residues of insecticides, fungicides and herbicides like glyphosate contaminate the entire diet. Over the last decade, there has been widespread adoption in the U.S. of Roundup Ready® (RR) crops, particularly for the major productions of soy, beet sugar, and corn that supply the processed food industry. The recent alarming rise in type-2 diabetes has been attributed to excess intake of high fructose corn syrup, which has increased to unprecedented levels in the last decade 273. This refined sugar is now usually derived from glyphosate-exposed GM corn. GM cotton is also increasingly being used as a source for cottonseed oil, widely present in processed foods such as potato chips, due to its low cost. A recent comparison between glyphosate-sensitive and glyphosate-resistant soybean crops revealed that the resistant plants took up much higher levels of glyphosate into their leaves 274. A corollary is that these plants would be expected to yield much higher glyphosate concentrations in derived food sources, compared to their non-GMO counterparts.
Confined animal feeding operations (CAFOs) are used to produce dietary animal protein for a mostly non-agrarian population 275. Cows, pigs, sheep, goats, chickens and even farm-raised fish and shrimp are fed a diet primarily of genetically engineered grains and forage materials laced with herbicide. As a consequence, animal products like, eggs, butter, cheese and milk are also contaminated with these residues. The highest levels of glyphosate are found in grain and sugar crops. The herbicide is not only used with RR crops, but also, as previously mentioned, it is used as a preharvest desiccant on sugar cane, wheat and also RR sugar beets, canola, and cottonseed for oils, among others.
It is difficult to get information on actual amounts of glyphosate present in foods, due to the perception that it is nontoxic to humans 1,6. The USDA Pesticide Data Program (PDP) is a voluntary program which randomly monitors agricultural chemical residues in the food supply. A search of the most recent data for 2010, published in May 2012, found statistics for the most popular agricultural chemicals except for glyphosate and glufosinate, another organophosphate. Residue data for the most popular herbicide on the planet were not available, but, interestingly, information on atrazine and other herbicides were readily available. Communication with USDA revealed that no data were available due to lack of monitoring. However, in 2013, for the first time, the USDA will be releasing a small amount of data for glyphosate residues only in soy. Lack of program funding was cited as the reason for this lack of data.
Recently, residue levels have been on the rise, due to higher rates and frequency of application, which in turn is due to increasing weed resistance. This has led the chemical and biotech industry to demand approvals for higher residue standards. In 1999 both the European Union (EU) and the UK raised the maximal glyphosate levels allowed in soy for industry from 0.1 ppm to 20 ppm. Both the USA and Argentina supply glyphosate-laden grains to European markets, so one could expect to find similar levels in the U.S.
The European Union's current standard for glyphosate in lentils is 0.1 mg/kg but a new industry proposal seeks to raise the standard by more than 100 times to 10 mg/kg or even 15 mg/kg 276. This is not due to safety considerations, but rather to levels that are anticipated, following usage of the herbicide as a preharvest desiccant. The action will ignore the possible effects to public health. The effects of animal health from ingestion of glyphosate residues have also been ignored. Current standards for residues in feed and forage materials are totally out of line with those of humans. Tolerances for animal grass and corn forage are 300 and 400 ppm respectively. It is apparent that the EPA standard is being ignored on a global scale for industry at the expense of public health and the environment.

13. Discussion
Glyphosate is today the most popular herbicide in use in agricultural practices in the U.S., and, increasingly, throughout the world. Its usage rate has accelerated significantly in the last decade due mainly to two factors: (1) the patent expiration in 2000 led to greatly reduced cost, and (2) the adoption of genetically modified crops that are resistant to its toxic effects allows for higher exposure with little loss in harvest yield. The notion that glyphosate has minimal toxicity in humans, widely popularized by Monsanto, has prevented farmers from using caution in their application of this chemical to their crops.
The recent rise in the rates of autism diagnoses in the United States is a cause for alarm. We have recently proposed that autism can be characterized as a chronic low-grade encephalopathy, where the cascade of events taking place in the brain is a process that enables the renewal of severely depleted sulfate supplies to the brain 277. We identified a dysbiosis in the gut as a source of ammonia that initiates the encephalytic response, and we proposed glyphosate as one of the many environmental toxins that might be responsible for the dysbiosis and for sulfate depletion. A review of the literature on glyphosate has confirmed our suspicions that glyphosate might play a role, and, further, have led us to believe that glyphosate may be the most significant environmental toxin contributing to autism. While it is pervasive in our food supply, the fact that it is deemed by most regulators to be nontoxic makes it especially insidious. The key pathological biological effects of glyphosate -- disruption of the gut bacteria, impairment of sulfate transport, and interference with CYP enzyme activity—can easily explain the features that are characteristic of autism.
The term "developmental immunotoxicity" has been coined to describe permanent modifications to the immune function that take place early in life, leading to later development of allergies, asthma, and autoimmune diseases 278-280. These authors have argued that prenatal and/or early life exposure to environmental toxins can lead to a phenotype that includes a hyperinflammatory response and disruption of cytokine networks, and they propose that an increased exposure to environmental toxins early in life may contribute to the increased incidence of these conditions observed today. It is significant that these problems often occur in association with autism 281.
Contrary to the current widely-held misconception that glyphosate is relatively harmless to humans, the available evidence shows that glyphosate may rather be the most important factor in the development of multiple chronic diseases and conditions that have become prevalent in Westernized societies. In addition to autism, these include gastrointestinal issues such as inflammatory bowel disease, chronic diarrhea, colitis and Crohn's disease, obesity, cardiovascular disease, depression, cancer, cachexia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ALS, among others. While glyphosate is obviously not the only environmental toxin to contribute to these diseases and conditions, glyphosate's ability to disrupt the gut bacteria, to impair serum transport of sulfate and phosphate, and to interfere with CYP enzymes, logically progresses to this multitude of diseased states, through well-established biological processes. And glyphosate's disruption of the body's ability to detoxify other environmental toxins leads to synergistic enhancement of toxicity. While genetics surely play a role in susceptibility, genetics may rather influence which of these conditions develops in the context of glyphosate exposure, rather than whether any of these conditions develops.
We have explained the logical sequence of events leading to serotonin deficiency and subsequent pathologies, following glyphosate's disruption of tryptophan synthesis by gut bacteria 10,29, and its further sequestration into macrophages that infiltrate the intestinal tissues in order to detoxify lipopolysaccharides released from pathogenic bacteria, whose overgrowth is induced by glyphosate 35. Sulfate depletion arises in the gut, both because of impaired transport of free sulfate in the bloodstream and impaired sulfate synthesis by eNOS 63,64. Disruption of gut bacteria, exposure to toxic phenolic compounds necessary to enable sulfate transport, and deficient sulfate supply to the mucopolysaccharides in the gut all contribute to the leaky gut syndrome that is a common feature in autism 51. The evidence shows that glyphosate can interfere with development through its suppression of aromatase synthesis 110 and through its interference with the breakdown of retinoic acid 113 and its interference with CDKs and sulfate supplies. Glyphosate could also be a factor in the current epidemic in vitamin D3 deficiency 166 through its disruption of the CYP enzymes that activate this hormone in the liver 164,165. The kosmotropic property of the glyphosate molecule combined with its disruption of CYP enzymes in the blood stream can lead to excess thrombosis and hemorrhaging, common problems today among the elderly.

We propose that glyphosate's disruption of the synthesis of sulfate by the CYP orphan enzyme, eNOS, leads to widespread deficiencies in cholesterol and sulfate in the blood stream and all the tissues. We have previously described how disruption of eNOS' synthesis of sulfate would lead to diabetes and cardiovascular disease 177. Glyphosate's induction of excess synthesis of ammonia in the gut, combined with depletion of zinc through impaired absorption, depletion of serotonin through dysbiosis of its substrate, tryptophan, depletion of dopamine through impaired synthesis of its substrate, tyrosine, depletion of vitamin D3, due to impairments in the CYP enzyme responsible for its activation, and depletion of sulfate through interference with its synthesis, can all lead to a multitude of pathologies in the brain, including autism, Alzheimer's disease, ADHD, Parkinson's disease, multiple sclerosis and ALS.
There is a substantial alignment among countries, worldwide, with low or decreasing birth rates, emerging obesity problems, and an increasing glyphosate burden. Given the arguments presented here, it is plausible that glyphosate is causal in these trends. It may also be possible to demonstrate strong correlations between glyphosate usage and both autism and breast cancer. Formal epidemiological studies should be conducted to look at these issues more closely.
In our opinion, it is imperative that governments around the globe unite in investing significant research funds to support independent studies evaluating the long-term effects of glyphosate. Other researchers should try to reproduce the results obtained in 9 showing tumorigenesis and premature death in rats with life-long exposure to glyphosate. The study on the gut microbiome of chickens 35 needs to be reproduced in other species, and the gene array study on E. coli 39 needs to be reproduced for other common gut bacteria. The novel idea that glyphosate disrupts sulfate transport through its kosmotropic effects, as predicted given biophysical laws, needs to be verified in specific studies among a variety of species. This could be done by comparing the levels of free sulfate in the blood under conditions of glyphosate exposure against controls. The study on glyphosate's effects on bees 126 should be reproduced by other researchers, along with further studies examining the impact of prior exposure to glyphosate on bees' resistance to pesticides. More refined and economical methods for detecting glyphosate in the food supply, such as in 0,283, and in the water supply 284, need to be developed, and then applied to a variety of different food items. Most critical in our view are the vegetable oils derived from GM crops ? canola oil, soybean oil, corn oil, and cottonseed oil, as well as soy-derived protein, beet sugar, and high fructose corn syrup - ingredients that are pervasive in processed foods. Glyphosate is likely also present in meat, eggs, cheese, and other dairy products derived from animals fed glyphosate-contaminated grass, alfalfa, corn, and soy 285,286.
14. Conclusion
This paper presents an exhaustive review of the toxic effects of the herbicide, glyphosate, the active ingredient in Roundup®, in humans, and demonstrates how glyphosate's adverse effects on the gut microbiota, in conjunction with its established ability to inhibit the activity of cytochrome P450 enzymes, and its likely impairment of sulfate transport, can remarkably explain a great number of the diseases and conditions that are prevalent in the modern industrialized world. Its effects are insidious, because the long-term effects are often not immediately apparent. The pathologies to which glyphosate could plausibly contribute, through its known biosemiotic effects, include inflammatory bowel disease, obesity, depression, ADHD, autism, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, cancer, cachexia, infertility, and developmental malformations. Glyphosate works synergistically with other factors, such as insufficient sun exposure, dietary deficiencies in critical nutrients such as sulfur and zinc, and synergistic exposure to other xenobiotics whose detoxification is impaired by glyphosate. Given the known toxic effects of glyphosate reviewed here and the plausibility that they are negatively impacting health worldwide, it is imperative for more independent research to take place to validate the ideas presented here, and to take immediate action, if they are verified, to drastically curtail the use of glyphosate in agriculture. Glyphosate is likely to be pervasive in our food supply, and, contrary to being essentially nontoxic, it may in fact be the most biologically disruptive chemical in our environment.

 

See also Web

  • Glyphosate: A Trajectory of Human Misery April 2013 Green Medical Information
    In 1999, the EU and UK, where no GM crops are currently grown for human consumption, increased the limit for soy from 0.1 parts per million to 20 ppm—a 200-fold increase!
  • Why We Must Fight To Label GMOs May 2013, Green Medical Information
    conventional corn has 437 times more calcium, 56 times more magnesium, and 7 times more manganese than GM corn.
    Tests show organ damage to animals at .1ppm of glyphosate in water; GM corn has 13 ppm.
    Formaldehyde is toxic in ingestion to animals at .97 ppm; GM corn has 200X that.

     

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