seralini

Is it Time to Include Inactive Ingredients in Chemical Safety Testing?

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The answer to that question is an unequivocal and very loud YES. For generations, the industrial chemical companies, whether they be pharmaceutical, agricultural, energy or from other sectors, have maintained that only certain ingredients in their products must be measured and accounted for – the so-called ‘active ingredients’. The adjuvants, those chemical compounds that dilute, preserve or in some way maximize the delivery of the primary chemical, are considered inert or inactive by regulatory agencies. As a result, and much to the benefit of the chemical manufacturers, those adjuvants fall outside the purview of testing and regulation. That is, not only are most of these chemicals not identified in the primary product, but they are not tested for safety – ever.  Only the active ingredients are tested, singly, and never with the entire chemical cocktail that is the product itself.

As one might suspect, the inactive ingredients are far from inactive, either when tested alone or when combined with the active ingredients. In chemistry when compounds interact, it is not always a simple, linear, one to one relationship; sometimes 1+1 = 10 or more. That is the case with adjuvants. Indeed, that is their function – to maximize the strength of the active ingredients, and so, by definition and by design, failing to test adjuvant safety represents the height of scientific dishonesty.

Slowly and despite the chemical industry’s promulgations to the contrary, independent scientists are demonstrating just how active, inactive ingredients really are. In the field of agricultural chemical safety testing, one lab stands out – the Seralini Lab in France. Over the last several years, researchers from the Seralini Lab have conducted and released a series of controversial studies on agricultural chemical safety. Here are just a few that we have covered on Hormones Matter: Controversy, GMO Research and Women’s Health and Inert Ingredients in Glyphosate Herbicides are Toxic Too.

Adjuvants Matter

Just recently, the Seralini Lab published another damning set of experiments showing just how toxic the cocktail of chemicals found in common, presumed safe, pesticides, herbicides and fungicides really are. The study: Major Pesticides are More Toxic to Human Cells than their Declared Active Principles, demonstrates clearly the egregious inanity of testing only manufacturer declared active chemicals.

In the present study, researchers measured the toxicity of nine common, commercially and consumer available formulations, three from each category, pesticides, herbicides and fungicides, against three types of human cells, embryonic-kidney (HEK293), placental (JEG3), and young adult liver (HEPG2).  What they found was striking. Eight of the 9 formulations tested were several hundred to several thousand times more toxic than the active chemical alone and at levels significantly less than currently allowed by regulatory standards and used commercially. The single formulation that was not more toxic than declared, contained no adjuvants.

Fungicides were found to be the most toxic chemical formulations at levels 300-600 times lower than currently accepted agricultural dilutions. Next in line was Roundup, one of the most heavily marketed and used herbicides, worldwide. Roundup toxicity ranged from twice to 10 times that of the other herbicide and pesticides and its total formulation was 125X more toxic than its declared active chemical, glyphosate.The placental cells were most sensitive to the toxins, followed by embryonic and liver cells, respectively.

Mechanisms of Toxicity

The most common mechanisms of toxicity were cell membrane disruption and the interruption of mitochondrial respiration rather than an immediate initiation of cell death or apoptosis. The authors note that apoptosis was difficult to measure because cell-death occurred via a necrotic progression rather than an immediate apoptosis reaction. This is important for a number of reasons.

The job the adjuvant is to maximize the insect, fungal or weed killing properties of the active ingredient. Seralini’s work shows us that these adjuvants work as designed, even in human cells. They maximize the killing properties of the active ingredients by weakening cell membranes (all the better to absorb the poison intracellularly and leak cell contents out into the extracellular space) and disrupting mitochondrial respiration (impaired energy and nutrient processing, make surviving the toxin that much more difficult).

Adjuvants increase toxicity by specific mechanisms that call into question, not only, their absence in testing, but the nature of toxicology testing in general. Specifically, these adjuvants evoke cell injury versus cell death. They increase the permeability of the cell wall and decrease mitochondrial respiration. These mechanisms evoke complex and chronic health conditions that are difficult quantify in standard dose-response toxicology curves with humans. Here is it is not the dose per se that increases death rate, even though higher doses would expedite the process, but the time lapse required between the exposure and the necrotic reactions in cells to reach critical mass to be clinically relevant. Imagine a slow and painful death versus the immediate and easily recognizable death.

In lower organisms like bugs, weeds and fungi, where mass is smaller, life cycles are shorter and chemistry simpler, the time frame is quicker, the injuries are more obvious and death more expedited. A standard dose response curve may appear appropriate because with the expedited time frame of the organisms life cycle e.g. the critical mass of necrotic cells can be reached more quickly to initiate death.

In contrast, however, those same deleterious mechanisms activated in higher animals and humans, would not be so easily detected, within the short time frame generally allocated for these types of studies. Initiating mitochondrial dysfunction in humans and large animals would be unrecognizable at first, and perhaps chronically, making connecting the dots between exposure to these toxic chemicals and ill health particularly difficult. When the mechanisms action of the poison evokes a process that is time dependent, larger doses appear safe, at least in the short term and with lower organisms.

In humans, the effects of the formulation would also be dispersed across multiple tissues and organs systems but how and where the toxins wreak the most havoc would be inconsistent and dependent on other factors such as previous exposures, genetic predispositions, other illnesses, medications or stressors that would modulate the current exposure. All factors that are not accounted for in toxicology in general, but especially in toxicology studies that ignore all but the manufacturer’s declared active principle – the active ingredients.

Final Thoughts

Any toxicology study that purports product safety but does not test the entire chemical formulation, adjuvants and other presumed inactive ingredients included, should be thrown out. Simple, dose-response curves are inadequate for all but most preliminary investigations. Long term studies must be conducted to evaluate the onset of disease and cumulative exposure effects, including endocrine disruption. Finally, Seralini points out, that his research is among the first to test the safety of these chemicals in human cells. This is beyond unconscionable, particularly considering these products have been on the market for decades. Regulatory agencies must test product safety against human cells. Otherwise, why even bother.

Controversy, GMO Research & Women’s Health

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If you’ve been on the internet at all over the last several weeks, you’ve likely come across these pictures- the white rats with grotesquely large mammary tumors warning of the dangers of GMO foods. A controversial and not yet even officially published study out of France on the Long term toxicity of Roundup herbicide and a Roundup-tolerant genetically modified maize is responsible.

In this 2 year study (compared to the 90-120 days for most previous protocols) researchers purportedly demonstrated the ill-effects of glyphosate (active ingredient in Roundup herbicide) and its adjuvants (putatively inactive ingredients that enhance the absorption, distribution or metabolism of the active ingredient), but also inadvertently, and despite the rampant criticism of the study, may have identified a mechanism of action for the growth of these tumors; a disruption of the estrogen pathway perhaps linked to primary kidney and liver damage. Moreover, and again perhaps inadvertently, the research points to a possible player in the development of fibroid type tumors.

How GMO Research is Conducted

There is great debate over the safety of herbicide rendered or engineered, genetically modified organisms (GMO) within the food and water supply. Studies on the side of industry, suggest no major ill-effects, while those on the side of environmentalist indicate differently.  Research design likely contributes to the disparate findings. Much research to date has been short-term (90-120 days) and/or has limited the analysis to testing or manipulating only the active ingredient in the herbicide (glyphosate) and not the variety adjuvants found in the total herbicide formulation and that would be dispersed into the natural environment (food, water) post herbicide use.

The current study sought to remedy some of those short-comings and approximate what humans might be exposed to with current regulatory standards in place and in an ‘natural environment’ where exposure rates and types would necessarily vary. (Whether lab rats can approximate human physiology or the lab can be considered a ‘natural environment’  are debates for another day).

The Seralini GMO Study

Using healthy male and female Sprague-Dawley rats, the researchers evaluated the long-term (two years), across a life-span effects, of eating Roundup treated foods (maize) and water with Roundup residue at levels below the currently parts per billion standard and consistent with what humans might be exposed to in the current environment. Control rats were fed non-GMO diets and the test rats were fed varying levels of GM maize (11%, 22% and 33% of the total diet) and water with Roundup – well below the approved levels found in the environment.

Tumors, Toxicity, Death and the GM Diet

Compared to control rats fed a non-GM diet, those fed the GM-maize and Roundup water, died five times sooner and developed huge tumors, often greater than 25% of their body weight and requiring euthanasia to reduce suffering. There were distinct differences between the male and female treated animals. The females died more quickly and developed primarily mammary tumors, followed by a lower percentage of pituitary tumors and kidney and liver toxicity. While the males, demonstrated more severe kidney and liver disease along with skin tumors. The females were more susceptible to the Roundup in the water and both groups were equally susceptible to both the lower and higher percentage (11% and 33%) exposure to GM food, suggesting a threshold effect for disease initiation rather than a cumulative or additive effect.

Endocrine Disruption

The endocrine effects were also telling and pointed to sex-dependent differences in the tumor and disease expression. The ratio of testosterone to estradiol was disrupted in both males and females. Males in the highest Roundup treatment group (33% of total feed maize), demonstrated double the levels of circulating estradiol (see Evolution or Extinction of Men for details on male endocrine disruption) when compared to the control group. Whereas the exposed females showed increased testosterone levels.

Potential Fibroid Connection

The explosive growth of tumors in the female treated rats is notable both because of the large size and location of the tumors (mammary and pituitary) but more so perhaps because of the nature and physiology of the tumors themselves. In all but two cases, the tumors were non-cancerous, non-infective or non-metastatic.  The tumors were benign adenomas and fibroadenomas, those commonly found in human women as they age (also common in this strain of lab rat as it ages). Fibroadenomas are comprised of fibrous and glandular tissue located in the breast. Fibroids are similar in tissue composition, but are found in the uterus.  In the present study, fibroadenomas were found in the mammary tissue and adenomas in the pituitary gland. There was no mention of uterine fibroids or adenomas in other female reproductive regions. Similarly, although, the authors make no such claim regarding the expression of fibroid type tumors, relative to hormone changes and concurrent liver dysfunction (where the enzymes and proteins involved in the hormone regulation reside), I surmise that perhaps there is a connection there as well.  It is conceivable that the combined insult of aging and environmental toxins on liver function alters hormone pathways sufficiently to promote this type of tumor growth.

Controversy and Criticism

As this study was released both pro- and anti-GMO factions got their pants in a bunch. On the anti-GMO side, this study represented proof-positive that GMO foods were bad. The results of this study, and in particular, the pictures of the tumor-ridden rats went viral on the internet. On the pro-GMO side, the criticism was as swift as it was vitriolic, with claims ranging from poor methodology, to outright scientific fraud.  I suspect the truth lay somewhere in between.

My Take

Releasing to press first. This merited all sorts of criticism, most of which has no bearing on the actual study but does suggest a less than forthright approach to media relations. However, given the politics surrounding this topic, one can understand this PR approach.

Sprague-Dawley rats are prone to tumors. Yes, they are and as they age, tumors become more frequent. But here we have a little pot and kettle action going on. Sprague-Dawley and other outbred strains of rats and mice, all have predilections for certain diseases and tumors, but are nevertheless what is used in all industry supported (even the studies supporting the safety of GMO) and academic research. The choice of lab rat/mice is important, but even within specific strains there is huge variability. Nullifying the study because the researchers used the same strain of lab rats that other researchers also use, is a weak criticism at best and more than a little disingenuous. Perhaps a better criticism would be the use of lab rats in general to extrapolate human physiology.

Sprague-Dawley rats are prone to tumors as they age. Well guys, so are women. By the time a woman reaches age 50, upwards of 70% of women have fibroid type tumors. And frankly, aging, whether in animals or humans, increases disease expression. Our bodies just don’t work as well when we are older. Simply measuring the effects of a toxin for a short period of time in youthful animals does not, in any way, mirror the real life of the animal or a human, where effects are cumulative over time and sometimes even multiplicative and synergistic.

The study was too long and the control rats were dying too. Life is longer than adolescence. If one wants to evaluate how a treatment or toxin affects an organism over time and as it ages, one has to evaluate across that life span. This study compared tumor progression, disease and death rates between the non-GM controls and the GM fed groups, across the rodent’s life span, which is about 2+/- years. As the rodents aged, both groups developed tumors and some died, but there were more tumors and earlier deaths in the experimental group.

Failure to observe or measure is not synonymous with non-existence. Neglecting to measure a particular toxin or analyte, a specific symptom or disease process, or failing to evaluate long term effects does not mean that the toxin, analyte, symptom or disease process in question did not happen or does not exist. It simply means that you chose not to measure it. So claiming that a 3-month study in youthful rodents nullifies results from a longer study, regardless of any other methodological issues with either study, is an utterly false, and more than a little dishonest argument.

The dose response-curve was not linear. Damn it, how dare our complex physiology not conform to the simplicity of linear statistics. A common dose-response reaction is highly linear, where a small dose elicits a similarly small response and a larger dose increase the response size. This is not case when dealing with endocrine disruptors. Hormone systems are complex and highly non-linear. Hormone reactions occur at extremely low doses and often interact synergistically with other factors and respond differently over time and with cumulative exposures. This was the case in the current study.

In spite of the flaws with this study and contrary to the criticism, the Seralini study represents one of the only, if not the only, long term evaluation of the effects of Roundup and GM feeding on health. Long term studies, even in rodents, are not common place. They should be.

The next long term study (and there should be many more) should include different strains of rodent, measure additional hormones and steroidogenic proteins altered with liver disease and if they want to be really ingenious, look at the estrogen, androgen and progesterone receptor densities in the tumors.

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