Glyphosate and Cancer
Date Added to website 4th May 2014
A review of new research
ISIS Report 26/03/14
New research shows that the low levels of glyphosate found in human urine can promote the growth of human breast cancer cells, confirming the carcinogenic potential of the herbicide known since the 1980s Dr Mae Wan Ho
A fully referenced version of this article is posted on ISIS members website
http://www.i-sis.org.uk/Glyphosate_and_Cancer.php
GM and herbicide cancer warning suppressed in retracted study
Among the unsettling results of the Séralini study [1], which almost certainly lie behind its notorious retraction by the journal editor a year after it was published ([2] Retracting Seralini Study Violates Science & Ethics, SiS 61), are cancers in rats fed GM maize and/or exposed to Roundup. Although the word 'cancer' was never used by the authors, they recorded three 'metastases' (i.e., cancers) - two in females and one in a male - plus two kidney Wilm's tumours in male rats, which had to be euthanized a year early because the cancerous tumours grew to more than 25 % of body size. This makes a total of at least 5 cancers in the treatment groups, in addition to the excess of grotesquely large tumours, premature deaths, pituitary, kidney, liver, and other pathologies compared with the controls. The cancer cases certainly should not be ignored, and to make sure this important paper is not erased from public record, it is now freely available and permanently registered on thesparc [3] a floating knowledge archive for the survival of people and planet. The findings are especially important in the light of new research and indeed, previous research on the carcinogenic potential of glyphosate (and GM food).
Glyphosate promotes growth of human breast cancer cells at minute concentrations
A research team in Thailand led by Jutamaad Satayavivad at the Center of Excellence on Environmental Health and Toxicology, Ministry of Education, and The Chulabhorn Graduate Institute in Bangkok, published a paper [4] in the very same Journal from which the Séralini study was retracted. They found that glyphosate at minute concentrations enhanced the proliferation of human hormone-dependent breast cancer T47D cells, but not hormone-independent breast cancer MDA-MB231 cells. Their detailed experiments showed that glyphosate mimics the action of oestrogen, and uses the same molecular pathways as the natural hormone to promote proliferation of the cancer cells. They also found that glyphosate had synergistic effects in enhancing breast cancer cell growth in combination with genistein, a common phytoestrogen in soybean.
Glyphosate at concentrations between 10-12 and 10-6 M (0.169 ng/L to 0.169 mg/L) boosted the proliferation of T47D cells by 15 to 30 %, about half as effectively as the most potent oestrogen, 17 b-estradiol (E2).
The same low concentrations of glyphosate induced the activation of oestrogen response element (ERE) - a specific DNA sequence promoting gene expression with high affinity for the oestrogen receptor (ER) that binds oestrogen - thereby activating gene expression in response to oestrogen. Furthermore, this activation was inhibited by an oestrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs.
The highest oestrogen mimicking effect was at 10-9M or 0.169 mg/L and the effect was half that of oestrogen, the most potent growth-promoter in hormone-dependent breast cancer cells. ICI 182780, a specific inhibitor of oestrogen at 1 nM reduced the proliferative effects of both glyphosate and E2. At 10 nM it completely inhibited the growth enhancing effects of glyphosate, suggesting that glyphosate acts via the oestrogen receptor ER.
T47D-KBluc cells, with stably transfected triplet oestrogen response element (ERE) promoter–luciferase reporter gene construct, when treated with glyphosate at the concentration range of 10-12 to 10-6 M, proliferated at 5-13 fold of the controls without glyphosate or E2, less than half that induced by oestrogen.
That is not all. Glyphosate-based herbicides are widely used for soybean cultivation (especially for Roundup Ready GM soybean); and the researchers also found an additive oestrogenic effect between glyphosate and genistein, a soybean phytoestrogen.
Genistein phytoestrogen is a major isoflavone in soybean. With a structure similar to E2, it acts like oestrogen via the ER pathways. At concentrations ranging between 10-9 and 10-4M, genistein produced concentration-dependent proliferation effects in T47D cells (104 to 170 % of controls). Genistein also stimulated ERE-gene transcription activity at the concentration range of 10-11 to 10-6M, to 5-25 fold the activity of controls.
The concentration ranges of glyphosate and genistein inducing ERE activity more than 10 fold of control are individually 10-11 to 10-9M and 10-7 to 10-5 M respectively. Glyphosate residues in soybean were found in the range of 0.1-5.6mg/g, while genistein were in the range of 0.01-1.2 mg/g. As mentioned earlier, glyphosate concentrations in human urine could be 1.8 x 10-8 to 1.4 x10-6 M. Using these concentrations as a guide, the interaction range between the two oestrogenic mimics were set at genistein 10-7 to 10-5 M, and glyphosate 10-11 to 10-9; the concentrations were varied with a fixed ratio of both compounds. The results showed significant enhancement of ERE activation in the combination of 10-10 glyphosate with 10-6M genistein and 10-9 M glyphosate with 10-5M genistein. At 10-7M genistein and 10-9M glyphosate, cell proliferation was increased to 169 % of control, where individually, the promotion was 145 %.
The important new finding is that glyphosate mimics oestrogen activity at minute concentrations; it may be inhibitory for oestrogen at high conentrations (while other toxicities also come into effect. Nonlinear concentration dependence is characteristic of environmental pollutants with endocrine disrupting effects (see [1]).
Glyphosate in humans and animals within the range with carcinogenic potential
The lab findings indicate that low, environmentally relevant concentrations of glyphosate have oestrogen-like activity. Glyphosate concentrations between 1.8 x 10-8 to 1.4 x10-6 M were found in human urine in the United States [5]. Analysis of urine samples of 182 subjects from 18 European countries [6] found that 80 (43.9 %) have glyphosate, with a mean of 0.21 mg/L (> 10-12M) and a maximum of 1.82 mg/L (10-11M). AMPA (aminomethylphosphonic acid), the main metabolite of glyphosate, was present in 65 (35.71 %), with a mean of 0.18 mg/L and a maximum of 2.63mg/L. Malta, Latvia and UK have the highest values of glyphosate, Croatia, Belgium and Malta have the highest levels of AMPA. Glyphosate and AMPA do not correlate very well, probably dependent on the precise amounts of glyphosate and residue in people's diet.
A new study led by Monika Krüger at University of Leipzig finds glyphosate residues in livestock, wild life and humans in Germany and Denmark at average concentrations of 9-5.4 mg/L in urine, and 35 mg/kg cow tissues, including intestine, liver, muscles spleen and kidney [7]. Human urine samples average 5.4 + 11.5 mg/L (range 0.01 to 40 mg/L); those on predominantly organic food have significantly lower levels compared to those on conventional foods, and individuals with chronic diseases have significantly higher levels than healthy individuals. Cow urine samples average 35 + 50 mg/L (range 0 to 164 mg/L). Germany cow urine samples have significantly lower values than those of Danish cows, and cows from GM-Free areas also have significantly lower concentrations of glyphosate than cows under conventional husbandry. The tissues of cows from slaughter houses have average glyphosate concentrations of 20 + 26 mg/kg (range 4.7 to 108 mg/kg). Rabbit urine samples average 12.5 + 12.1 mg/L (range 3.17 to 42 mg/L); significantly higher than in those of hares.
Carcinogenic potential of glyphosate known since the 1980s
The carcinogenic potential of glyphosate has been known since the 1980s. An excellent review on glyphosate toxicity written by Caroline Cox of Northwest Coalition for Alternatives to Pesticides, Eugene, Oregon in the US published in 1995 showed that most if not all the toxic effects of glyphosate had already been demonstrated in laboratory studies [7]. Glyphosate was not only acutely toxic to animals and human beings; subchronic studies showed that feeding glyphosate to animals for three months caused "reduced weight gain, diarrhea, and salivary gland lesion." Lifetime feeding caused "excess growth and death of liver cells, cataracts and lens degeneration, and increase in the frequency of thyroid, pancreas and liver tumors." Also documented were effects on fertility: reduced sperm counts in males and lengthening of the oestrus cycle in females.
But the public were kept in the dark through a litany of outright fraud committed by testing companies working for the corporations, deception, and half-truths.
On carcinogenicity, Cox wrote [8]: "The potential of glyphosate to cause cancer has been a controversial subject since the first lifetime feeding studies were analyzed in the early 1980s. The first study (1979-1981) found an increase in testicular interstitial tumors in male rats at the highest dose tested (30 mg/kg of body weight per day) [9], as well as an increase in the frequency of a thyroid cancer in females [10]. The second study (completed in 1983) found dose-related increases in the frequency of a rare kidney tumor in male mice [11]. The most recent study (1988-1990) found an increase in the number of pancreas and liver tumors in male rats together with an increase of the same thyroid cancer found in the 1983 study in females [12]."
But the US Environment Protection Agency (EPA) explained all that away. Cox continued [8]: "All of these increases in tumor incidence are "not considered compound-related" [12] according to EPA. In each case, different reasons are given for this conclusion. For the testicular tumors, EPA accepted the interpretation of an industry pathologist who said that the incidence in treated groups (12 percent) was similar to those observed in other control (not glyphosate-fed) rat feeding studies (4.5 percent) [13]. [This is a blatant, illicit use of controls.] For the thyroid cancer, EPA stated that it was not possible to consistently distinguish between cancers and tumors of this type, so that the incidences of the two should be considered together [a questionable manipulation of data]. The combined data are not statistically significant [10]. For the kidney tumors, the registrants reexamined slides of kidney tissue, finding an additional tumor in untreated mice so that statistical significance was lost. This was despite a memo from EPA's pathologist stating that the lesion in question was not really a tumor [11] [and hence amounts to a falsification of data]. For the pancreatic tumors, EPA stated that there was no dose-related trend and no progression to malignancy [this is frequently the case in endocrine disrupting chemicals]. For the liver tumors and the thyroid tumors, EPA stated that pairwise comparisons between treated and untreated animals were not statistically significant and there was no progression to malignancy [12]." (Comments between square brackets added).
EPA concluded that glyphosate should be classified as Group E [13], "evidence of non-carcinogenicity for humans." They added that this classification "is based on the available evidence at the time of evaluation and should not be interpreted as a definitive conclusion that the agent will not be a carcinogen under any circumstances."
The EPA authorities went against the advice of their own scientists, as Cox revealed [8]. An EPA statistician wrote in a memo concerning one of the carcinogenicity studies [13], "Viewpoint is a key issue. Our viewpoint is one of protecting the public health when we see suspicious data." Unfortunately, EPA has not taken that viewpoint in its assessment of glyphosate's cancer-causing potential.
Epidemiological evidence that pesticides are associated with cancer risks
Studies dating back to the 1980s have indicated that despite the low overall mortality rate from heart disease, cancers of the lung, oesophagus, bladder and colon, farmers in many countries appear to have higher rates for Hodgkin's disease, leukaemia, multiple myeloma, non-Hodgkin's lymphoma, and cancers of the lip, stomach, prostate, skin, brain, and connectives tissue compared with the general population. The strongest links of cancers in agricultural workers are to herbicides [14]. In 1993, the National Cancer Institute Bethesda Maryland in the US launched a large prospective cohort study in North Carolina and Iowa on people most likely to be exposed to pesticides - farmers and pesticide applicators – identified when they applied for a pesticide applicator license and undergo training and testing [15].
The 10-year Agricultural Health Study (1993-2003) was recently summarized to the press as the EPA proposes new safety rules for farm pesticide use [16]: "Current medical research suggests that while farmers are generally healthier than the general U.S. population, they may have higher rates of some cancers, including leukemia, myeloma, non-Hodgkin lymphoma, and cancers of the lip, stomach, skin, brain, and prostate." This finding is no different from when the Study began.
The supreme irony is that the EPA has set new standards that drastically increase the amounts of glyphosate allowed [17]: in oilseed crops such as flax, soybeans and canola, it is doubled from 20 ppm to 40 ppm, while in food crops, it is multiplied 30-fold, from 200 ppm to 6 000 ppm. So although pesticides as a group is acknowledged to be carcinogenic, glyphosate is still considered a non-carcinogen by the EPA, the same as in 1985 [13]. But since 1994, the first year that GM crops were commercially grown, the use of glyphosate herbicides has gone up enormously, with regulatory authorities putting up the allowable levels to track the upward trajectory [18].
By 2007, glyphosate is the most commonly used pesticide in the agricultural sector, and second most commonly used in homes and garden as well as industry/commercial/ government sectors [19]. In other words, its use has become pervasive; and everyone in whatever sector will be exposed to it, through air, water and food as recent measurements in Europe confirms (see above). Not surprisingly, it has proven difficult to link individual pesticides with specific cancers in the Agricultural Health Study, least of all to glyphosate, given that dozens of pesticides are typically used, and the general population probably as much exposed to glyphosate-herbicides and herbicide residues as farmers and agricultural workers.
A review published in 2012 (ahead of EPA's decision to increase allowable glyphosate levels) [20] "found no consistent pattern of positive associations indicating a causal relationship between total cancer (in adults or children) or any site-specific cancer and exposure to glyphosate." The lead author of the review has served as a paid consultant to Monsanto Company, and the research was supported by the Monsanto Company. Actually, there have been studies aimed at glyphosate in particular that found increased risks to specific cancers, which were explained away in the review.
A Swedish study of 910 cancer cases and 1016 controls found a significant excess of non-Hodgkin lymphoma (NHL) associated with the phenoxy herbicide 2-methyl-4-chlorphenoxyactice acid (MCPA) OR (odds ratio) 2.1, and with glyphosate OR 2.02 [21]. This confirmed the team's earlier pooled analysis of two case control studies - one on NHL and another on hairy cell leukemia, a rare subtype of NHL- consisting of 515 cases and 1141 controls [22]. Increased risks were found for subjects exposed to herbicides OR 1.75, insecticides OR1.43, fungicides OR 3.11, impregnating agents OR 1.48. Among herbicides, significant associations were found for glyphosate OR 3.04, and 4-chloro-2-methyl phenoxyacetic acid (MCPA) OR 2.62.
In another study, associations between glyphosate exposure and cancer incidence was examined in a prospective cohort of 57 311 licensed pesticide applicators (mostly male middle-aged) in Iowa and North Carolina (part of the Agricultural Health Study). There was no association with all cancers, but there was increased risk for melanoma (OR 1.8) adjusted for age, which decreased to OR 1.6 adjusted for age, demographic and lifestyle factors, and other pesticides. Adjusted risk estimates for colon, rectum kidney and bladder cancers were elevated by 30 to 60 % but not statistically significant. However, there was more than 2-fold risk of multiple myeloma (OR 2.1) associated with ever-use of glyphosate [23].
The situation is best summed up in a 2013 review with lead author Michael Alavanja who also led the Agricultural Health Study [19]: "A growing number of well-designed epidemiological and molecular studies provide substantial evidence that the pesticides used in agricultural, commercial, and home and garden applications are associated with excess cancer risk….The literature does strongly suggest that the public health problem is real." They strongly recommend reducing the use of pesticides as the best measure to counteract the problem, a recommendation that some countries in Europe such as Sweden and Denmark have already adopted since the late 1990s. Instead of reducing pesticide use, the US EPA has increased allowable glyphosate limits yet again, and by 30-fold [17].
The carcinogenicity of glyphosate is among the latest avalanche of damning evidence that makes a ban on glyphosate all the more compelling. Sri Lanka is the second country in the world to ban glyphosate after El Salvador. Having rejected GMOs back in 2003, it has now banned glyphosate [24] on the strength of a study by Sri Lanka's own scientists [25] implicating glyphosate in an epidemic of deadly chronic kidney disease that has struck Sri Lanka and other poor farming countries [26] (see [27] Sri Lanka Bans Glyphosate for Deadly Kidney Disease Epidemic, SiS 62). Glyphosate is already implicated in the marked deterioration of the health status of the US population [28]. The incidence of diseases and adverse conditions that have gone up in parallel with the increase in GM crops and the use of glyphosate herbicide since 1994 (first year of commercialization of GM crops) include thyroid cancer, liver and bile duct cancer, obesity, high blood pressure, hospitalizations for acute kidney injury, diabetes, and end stage renal disease. It is also a prime suspect in the rise of human male infertility worldwide [29] (Glyphosate/Roundup and Human Male Infertility, SiS 62), and implicated in coeliac sprue, an autoimmune gluten intolerance bowel disease [30]. A recent test on 31 samples of GM glyphosate-tolerant soybean found average glyphosate level of 3.26mg/kg and average AMPA level of 5.74mg/kg [31], at the high end of oestrogenic concentrations reported here, which could easily account for the levels present in human urine [5-7]. Glyphosate is well-known for its toxicities to cells and animals including livestock, crops and soil, and lethality to amphibians; it is also harmful to other wildlife [32] (Ban GMOs Now, ISIS special report).
The full extent of glyphosate's eco-toxicity has emerged in new experiments. At concentrations of several parts per million, Roundup is lethal to the neotropical fish Piaractus mesopotamicus, a native to Brazil and Paraguay of considerable ecological and commercial value [33]. Exposure of the freshwater fish Channa punctatus t0 similar concentrations of Roundup caused oxidative stress, lipid peroxidation and DNA damage in blood and gill cells [34].
As the retracted Séralini study [1] and other research cited here make clear, the toxicities of glyphosate/Roundup are independent of and in addition to the toxicities of the GMOs, which is why a ban on both GMOs and glyphosate is in order.