Death as a Drug Side Effect in FAERS: Is Glyphosate Contamination a Factor?

Stephanie Seneff, Nancy Swanson, Chen Li, Gerald Koenig
2015 Agricultural Sciences  
An analysis of selected datasets from the FDA's drug Adverse Event Reporting System (FAERS) leads us to hypothesize that glyphosate contamination in both food and drugs is a major contributor to chronic and acute kidney failure respectively. In chronic kidney failure, glyphosate-induced pancreatitis results in the release of trypsin, causing a leaky vasculature. The albumin-bound glyphosate escapes into the tissues, protecting the circulatory system and kidneys but resulting in multiple
more » ... in multiple symptoms related to skin, gut, brain, bones, lungs, etc. The rare and poorly understood acute kidney failure response reported for protamine sulfate and Trasylol ® is strikingly similar to that associated with glyphosate poisoning. Both drugs are derived from biological tissues that are plausibly contaminated with glyphosate. These drugs protect from haemorrhage, which leads to retention of glyphosate in the vasculature, are followed by circulatory collapse and a high likelihood of death as an outcome. We support our argument by comparing symptom profiles of selected subsets of FAERS with those related to glyphosate poisoning, anomalous reactions to protamine sulfate, and conditions showing strong statistical time-trend correlations with glyphosate. S. Seneff et al. 1473 is extremely high. An estimate from data in 1994 suggested that adverse reactions were between the fourth and sixth leading cause of death [2] . The US Food and Drug Administration's (FDA's) Adverse Event Reporting System (FAERS) database is a large collection of drug side effect reports dating back to 2004. While it contains a wealth of information, it is difficult to tease out from the data the cause-and-effect relationships. This is mainly because most of the entries contain multiple drugs and multiple side effects, and some of the drugs are long-term maintenance drugs that may be irrelevant to the event. Furthermore, many of the side effects mentioned are likely preconditions such as diabetes or heart disease, which are probably provided to give additional useful information about the patient, but unfortunately they contribute noise to the task of sorting out cause-and-effect relationships. Given these caveats, we report here on our attempts to critically analyze a specific subset of FAERS, focusing on an important side effect that is undeniably not a precondition: death. Doctors must be able to rely on pharmaceutical purity of drugs. When dealing with complex, unanticipated and inexplicable patient responses to pharmaceutical drugs, doctors need to be aware that the response may not be due to the drug itself, but rather to an inadvertently included contaminant. When drugs are contaminated with unknown harmful ingredients, it may take time for doctors to realize this and recognize the underlying problem. Analyzing drug side effects statistically is one way to begin to explore the possibility of drug contaminations. In this paper, we offer an explanation for an unusual and acute, life-threatening, adverse reaction to certain biological drugs derived from animal products that we believe may be due to unintended contaminants. Our broadly specified goals are to establish which drugs are most strongly linked to death as an outcome, as well as which other symptoms co-occur with death, and then to try to explain our results by linking them to previous studies in the research literature. Our quest has yielded a most surprising hypothesis: certain biological drugs may carry a high risk of death due to contamination with glyphosate, the active ingredient in the pervasive herbicide, Roundup ® . Furthermore, we believe we have identified a class of patients suffering from chronic kidney disease who statistically and collectively exhibit a profile of symptoms that can be explained as a consequence of chronic exposure to glyphosate in the ingested food and water. Our hypothesis is based, in part, on the increasing amounts of glyphosate found in food, air [3] [4], rain [3] [5], groundwater [5], surface water [4]-[6], soil [5], seawater [7], human serum [8] and urine [9], and even in samples of marijuana [10]. Formal testing of the suspected drugs and ingested foods for glyphosate contamination can and should be done to validate our hypothesis. We gathered as our first set all the data in FAERS where DEATH was mentioned as a side effect. We then identified the top ten other side effects co-occurring with death. We constructed a second, larger subset of the database by extracting all the entries where at least one of these side effects was mentioned (with or without death). This gives us a contextualized larger population with key symptoms associated with DEATH as a side effect. We then used a formal, mathematical procedure to obtain a short list of drugs most strongly linked to death within this subset population. This allowed us to compare the pooled subsets of our database with and without these particular drugs, and to see which other symptoms occur most frequently in association with the 9 drug classes we identified as potential "High-Death-Association drugs" (HDA DRUGS). The list of HDA DRUGS was surprising. One noteworthy aspect is that many of them were biologicals derived from animal tissues, such as bovine lung or sturgeon testes, or from blood. This led to the realization that contaminants could be present due to the animals' exposure to certain toxic chemicals. Since we were aware that glyphosate is pervasive in our environment today, we formulated the hypothesis that severe reactions to these biological drugs could be due to contamination with glyphosate. Exploration of the research literature led us to specific papers where lists of side effects were provided for conditions we suspected to be relevant to our hypothesis. We could then systematically compare the side effects associated with our candidate HDA DRUGS and the reactions reported in these papers. Manufacturers of drugs are aware that unintended contamination through the manufacturing process is a serious issue. Flaum summarized the situation aptly in a review article on this subject: "In fact, the types of contaminants, their relative hazard to human health, the sources of contamination, and the methods for prevention and detection of such contamination are so varied and numerous as almost to defy compilation" ([11], p. 1). For example, in March of 2015, a subsidiary of Johnson & Johnson agreed to pay $25 million in damages due to the discovery of nickel and cadmium contamination in liquid Tylenol ® products intended for infants. This is not an isolated occurrence, as a Reuters' press release concerning this story reported: "There were far-reaching multiple recalls from 2008 to 2010 involving hundreds of millions of bottles and packages of consumer brands such as S. Seneff et al. 1474 Tylenol, Motrin, Rolaids, Benadryl and other products due to faulty manufacturing" [12] . The single drug most strongly linked to death in the FAERS database is Trasylol ® , a serine protease inhibitor extracted from bovine lung that is used to protect from haemorrhage during open heart surgery. Red blood cells and protamine sulfate, used to neutralize heparin, were also strongly linked to death in our data analysis. A paper published in 1987 [13] brought the exciting news that aprotinin (Trasylol ® ) administered during cardiac surgery could reduce the need for transfusions by a factor of eight. Aprotinin was approved by the FDA in 1993 to reduce blood loss during coronary-artery bypass grafting [14] . Aprotinin was widely adopted for this purpose over the following years, but by 2008 it was becoming clear that aprotinin could cause an acute reaction terminating in kidney failure and death [15]-[18]. The FDA took action that year to remove aprotinin from the market, but it was later reinstated. In an observational study published in 2006, involving 4374 patients, use of aprotinin was associated with twice the risk of renal failure requiring dialysis, a 55% increase in the risk of myocardial infarction or heart failure, and a 181% increase in risk of stroke or encephalopathy [15] . Strikingly, this increased risk was not found in association with tranexamic acid or aminocaprioc acid, two other drugs used similarly to prevent haemorrhage. An analysis of 8548 patients published in 2008 found a lack of a dose-response relationship between aprotinin and renal failure [19] , which can be explained by varying levels of glyphosate contamination in the administered drug. In 2008, Fergusson et al. [20] compared aprotinin with another antifibrinolytic agent, aminocaproic acid, and found a greater than 50% relative increase for death within the first month linked to aprotinin. The abstract concluded with these harsh words: "Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery". In contradiction, a meta-analysis of 211 randomized controlled trials published in 2004 showed no risk of renal failure or death [21] , but this was representing early data before the large increase in the potential of glyphosate contamination. A much later study from 2011 found nearly a 4-fold increase in odds of death one year later for patients administered aprotinin compared to no aprotinin use [22] . So it appears that the risk of death following aprotinin administration is increasing over time, in step with the increased contamination of glyphosate in animal feed. The Environmental Protection Agency (EPA) currently allows between 100 -300 ppm of glyphosate residues in livestock feed [23] . In 2014, Kruger et al. reported finding 30 ppb of glyphosate residues in bovine lung tissue [9] . Protamine sulfate was the third most strongly associated with death, after "red blood cells" and Trasylol ® . In a case study on protamine sulfate, a rare, unexplained, anomalous reaction was identified that matched well with the symptoms linked to death. We again hypothesized that glyphosate contamination might explain the acute reaction. Protamine sulfate is administered as an antidote to heparin therapy following surgery, to inactivate the heparin and protect from haemorrhage. It was originally isolated from the sperm of salmon and sturgeon, but is now produced primarily through recombinant biotechnology. Like aprotinin, protamine sulfate has also been found to produce an inexplicable acute response in rare cases, manifested as a drop in blood pressure, pulmonary hypertension and noncardiac pulmonary oedema with cardiopulmonary collapse [24] . The severity of the reaction is not dose-related. Holland et al. reported in 1984 on four unusual cases of an anomalous reaction to protamine sulfate [25] . These four represented only 0.2% of the patient pool exposed to the drug in their population, but their reaction was uniquely different from the usual anaphylaxis due to an antibody-mediated response, well recognized as a risk factor in association with this drug. While protamine sulfate was known to sometimes evoke an allergic reaction, an autoimmune reaction was ruled out for these four cases. Symptoms involved a drop in blood pressure within the first hour following administration associated with profound vascular damage with pulmonary oedema or total vascular collapse. Mortality is high at 30%, with survivors suffering significant morbidity. What is striking to us is that intravenous administration of glyphosate salts to piglets induced a very similar reaction, with a precipitous drop in blood pressure within the first hour and high mortality rate [26] . These symptoms are also remarkably similar to those of acute glyphosate poisoning. We therefore identified a set of symptoms linked to glyphosate exposure following suicide attempts [27] , and showed that these symptoms were over-represented in our death-related dataset. A very fruitful avenue of exploration was to look specifically at the side effects related to kidney failure, which was the number two (after PAIN) side effect coincident with DEATH. Kidney failure is reaching epi-
doi:10.4236/as.2015.612143 fatcat:k4dkkuq64bfipkqkdgfuo25quu