Glyphosate is the active ingredient in the herbicide formulations most commonly used on genetically engineered (GE) crops. For nearly a decade, glyphosate has been far and away the most widely and heavily used pesticide in the US and globally.

In 2015, US farmers and ranchers applied enough glyphosate to spray about three-quarters of a pound of active ingredient on every acre of cultivated cropland in the country. Globally, close to half a pound may have been applied in 2015 on every acre of cultivated cropland on the planet.^[1],[2]

Levels of glyphosate and its primary breakdown product AMPA are rising in soil, water, food, and the atmosphere. People are being exposed through multiple sources. For these reasons, it is crucial that safety thresholds applicable to glyphosate-based herbicides (GBH) be founded on the very best science possible.

Regrettably, this is clearly not now the case.

A number of studies support the concern that glyphosate is harmful.”^[3] Another key consideration is that glyphosate is usually applied in a commercial formulation called Roundup®. The adjuvants are so-called “inert” ingredients and are used in Roundup® herbicides to improve the stability and penetration of glyphosate into plant, human, and animal cells.^[4] They may present safety concerns of their own.

In this article, we point out the following:

• There is increasing evidence that glyphosate and GBH are toxic and/or damaging to human health via different mechanisms, depending on the amount of exposure;
• Multiple factors are driving GBH use upward: increased planting of GE, Roundup Ready® crops; the need for higher rates and greater number of applications to combat resistance of weeds; and, new uses for GBH such as for habitat restoration, crop desiccation to accelerate harvest operations, backyard and local neighborhood use by schools, businesses, and government;
• Some of the published reports that claim that wide margins of safety exist rely on studies that are outdated, not designed to detect subtle cellular, metabolic, or genetic changes, and/or are of limited relevance to human health outcomes; and
• Human exposure is unmonitored but common, as suggested by the fact that glyphosate has been found in the urine of both rural and urban people, as well as in the breast milk of urban mothers.

TOXICITY

Glyphosate and GBH are toxic

There exists an extensive scientific literature documenting doses at which glyphosate, either alone or in combination with adjuvants and surfactants, has been shown to be harmful. Its effects include endocrine disruption,^[5] alteration of populations of gut microbes,^[6] reproductive harm,^[7] DNA damage,^[8] liver damage,^{[9],[10],[11],[12]} kidney damage,^[13],[14] and cancer promotion.^[15] Glyphosate also inhibits the action of CYP2C9,^[16] an enzyme in the human liver responsible for the breakdown of a pro-inflammatory omega-6 fatty acid (arachidonic acid), as well as over 100 drugs commonly used in the clinical setting, such as certain blood thinners.^[17]

Glyphosate has also been found to cause oxidative damage in the liver of pregnant rats and their fetuses.^[18] Damage has also been caused to brain cells, specifically cells from a part of the brain called the substantia nigra^[19],[20] which is involved in the etiology of Parkinson’s disease.

Liver damage was also observed in rats fed small, environmentally relevant doses of GBH over both 3-month and 2-year periods.^{[21],[22],[23]} The changes observable at 3 months, the standard time used for sub-chronic safety screening, were interpreted as clinically irrelevant, but longer exposures revealed an apparent worsening of these changes.^[24]

Glyphosate is an endocrine disruptor, meaning that it mimics or modifies the effects of hormones. For example, in placental cell cultures it reduces the activity of the enzyme aromatase, which is responsible for the synthesis of estrogen.^[25] Rats fed glyphosate during puberty show changes in testicular morphology.^[26]
One mechanism whereby glyphosate disrupts development was elucidated in Argentina after government agencies reported high levels of reproductive abnormalities in vertebrates in agricultural regions where glyphosate is extensively used.^[27]

Glyphosate also alters cell division by affecting a mechanism universal to living cells.^[28],[29] This could adversely impact development in several ways.
Glyphosate induces growth of breast cancer cells in the laboratory.^[30] Epidemiological studies have consistently correlated glyphosate exposure to cancer, particularly non-Hodgkin’s Lymphoma (NHL). Of the four such studies identified by the International Agency for Research on Cancer (IARC) panel, three reported a statistically significant increase in the incidence of NHL in farmers exposed to glyphosate.^[31],[32]

Glyphosate is a known chelator,^[33] which means that it binds tightly to metal ions. These metal ions include nutrient minerals such as iron, copper, zinc, manganese, and calcium. Research suggests that there are few differences in mineral content between GE and non-GE plants.^[34] But that study does not address the question of whether glyphosate residues present in plant material might make these nutrients unavailable to animals. Cows fed a diet containing glyphosate were found to have lower levels of copper, selenium, zinc, cobalt, and manganese in their bloodstreams.^[35] It is not known whether these lowered levels affected the health of these cows, or whether a similar phenomenon could be occurring in humans. If indeed mineral bioavailability is altered in the human GI tract by the presence of glyphosate residues, clinical syndromes could be triggered and associated with a number of health problems.

Teams of international scientists are assessing the possible human health impacts of glyphosate use and exposures in tropical regions with hard (metal containing) drinking water. For over 10 years now, the World Health Organization has invested heavily in identifying the causes behind hundreds of thousands of cases of often-lethal chronic kidney disease among otherwise healthy male farm workers. Evidence is mounting that some of the cases were triggered by ingestion of chelated glyphosate via drinking water, which then became lodged in the kidneys. Because of the bond to a metal ion, the kidney apparently may not be able to normally metabolize and secrete the glyphosate, triggering damage to the kidney and the progression to disease.

A 2009 review concluded that there was not enough information available to determine whether glyphosate is safe for humans.^[36] The extensive published literature cited above, as well as the IARC’s recent findings of the probable carcinogenicity of glyphosate, have since raised additional concerns regarding its safety.

Glyphosate is patented as an antibiotic.^[37],[38] Its main mechanism of action involves interference with the enzyme EPSP synthase, which is present in many bacteria.^[39] In spite of what we now understand to be a crucial role of beneficial bacteria in human health,^[40] the EPA has not evaluated the possible disruption in the human GI tract as a result of exposure to GBH.^[41]

INCREASED USE

The Use of GBH Continues to Increase

Before GE crops became widespread, farmers used Roundup® to eliminate weeds only prior to planting, because the crops themselves would have been destroyed by it; while fields were idle (i.e., summer fallow fields); or, after harvest to clean up any surviving weeds.

Now GE soybeans, corn, cotton, canola, sugarbeets, and alfalfa can be “Roundup Ready®” which means that they can be, and are, sprayed with GBHs during the growing season. Plants sprayed late in the growing season can take glyphosate up into their stems, leaves, and seeds,^[42] making it impossible to remove residues before consumption.

GBH is also sprayed on several non-GE crops (sugarcane, cereal crops, orchards, and others), usually just before planting, or right before harvest in order to dry leaves and hasten ripening and harvest. In some cases, GBHs also can apparently improve yields.^[43] As a result, foods labeled “non-GMO” can contain high levels of glyphosate and adjuvants used in conjunction with glyphosate. This agricultural practice increases our cumulative exposure to both glyphosate, its major metabolite AMPA, and the adjuvants and surfactants in commercial formulations.

More than half of the GBH used in the US are applied by farmers on our food crops.^[44] In addition, GBHs are widely available to: (a) the public for use in and around the home, (b) local businesses and governments for use around buildings, parking lots, transmission lines, around schools, in parks and other public places, and by agencies attempting to eradicate non-native plants.^[45] These uses contribute to ambient levels in the environment, drinking water, and food, and hence also add to each individual’s daily dose of glyphosate.

AVAILABLE STUDIES CAN NOT “SETTLE” THE DEBATE

Existing Assessments Are Not Reassuring

Numerous studies and literature reviews performed by the companies that manufacture GBHs attempt to reassure the public of their safety.^{[46],[47],[48],[49],[50]} However, there are several problems with them:

• They were commonly written by scientists hired by the herbicide manufacturing industry, or who worked in firms specializing in public relations for that industry;
• A careful analysis of the way in which safe levels were determined revealed significant errors.^[51]
• They did not take into account the many adjuvants and surfactants present in all commercial formulations of glyphosate.^[52] Farmers never use glyphosate alone. Adjuvants are needed for glyphosate to penetrate into plants in order to kill them. Some adjuvants are more toxic than glyphosate, but are nevertheless considered inert ingredients.^[53] Thus, the substances present in the adjuvant mixture to which humans are exposed could promote adverse health effects in their own right or in conjunction with glyphosate.
• Conclusions were mainly based on studies assessing acute toxic effects to rodents, mainly death and organ damage. They neglected more subtle endocrine (hormone system) effects, nervous system disruptions, long-term liver and kidney damage, immune dysfunction that could lead to autoimmunity and/or allergy, metabolic diseases (diabetes, thyroid), dysbiosis, depression or dementia, and learning and behavioral issues such as difficulty with speech and social behavior.
• They did not fully account for variation in susceptibility to chemical-induced health problems across the human population.

Studies have not asked the right questions

The ideal study would be a multi-generation, full lifespan, mammalian feeding study with control and several treatment groups. A wide range of reproductive, developmental, metabolic, and pathological endpoints would be monitored. To gain confidence that the observed impacts and associated safety levels are correct, such studies need to be done with at least three different types of experimental animals, and replicated until there is agreement on both the most sensitive endpoints, and the lowest doses at which adverse impacts are observed.

Because glyphosate is an endocrine disruptor (see above), future studies should incorporate testing principles from endocrinology (e.g. hormone dosage). Moreover, both glyphosate alone and formulated GBHs must be tested at environmentally relevant levels, to sort out the contribution of glyphosate to any toxic effects versus the contribution of the adjuvants and surfactants.

More biomonitoring of human fluids for glyphosate and its breakdown products should also be performed. Glyphosate’s effects on the general population need to be investigated by conducting properly designed epidemiological studies. While several epidemiological studies have concluded there is a link between glyphosate exposure and cancer, others have reported negative results.

Based on the current pervasiveness of GBH in the environment, the possibility that any given “control group” is contaminated by glyphosate residues cannot be ruled out. In a study performed in 2007,^[54] for example, similar levels of glyphosate were found in farm household members and non-farm household members. Conversely, glyphosate concentrations reported as occupational exposures may be, at least in part, due to background environmental exposure. These observations imply that future epidemiological studies should incorporate monitoring of human fluids for glyphosate (and adjuvants), rather than rely on indirect estimates of exposure.
The closest we can come to full life-cycle mammalian feeding studies are either studies that use a higher level of glyphosate than is found in our environment (including our food and our neighborhoods) and studies that use intermediate end-points instead of diseases. For example, one can measure metabolic disturbances that are known to underlie many diseases, such as precancerous changes, immune dysfunction, and oxidative stress. However, no GBH feeding studies using these parameters as biomarkers have been conducted to date.

The one peer-reviewed, long-term toxicity study published thus far on the effects of GBH Roundup®, and of eating Roundup Ready® GE corn event NK603, is Séralini et al., originally published in Food and Chemical Toxicology.^[55] This controversial paper has been dissected by dozens of regulatory bodies, expert groups, and research teams. While constructive suggestions have been made regarding how larger sample sizes would have increased the power of the study to detect health impacts, there have been no serious questions raised about the validity of the basic pathological findings.
The Roundup® used for this study was tested at three different doses. Liver and kidney toxicity were observed at levels well below the regulatory threshold set for glyphosate alone.^[56]

Séralini et al. presents clear evidence regarding the toxicity of both NK603 corn and Roundup® herbicide in Sprague-Dawley rats and also reports, as secondary observations, the increased mortality and tumor incidence observed in the study animals by the researchers.^[57] Because this study was not undertaken as a carcinogenesis study, and because – after thoroughly evaluating the manuscript and all of the raw data it was based on – the Editor-in-Chief of Food and Chemical Toxicology found its results “inconclusive,” follow-up studies are urgently needed.

Some individuals are more vulnerable than others

It is only in recent years that scientists have begun to study and understand aspects of gene structure and function that influence our ability to cope with harmful chemicals. Such studies make it clear that certain individuals can be at much higher risks than others. For example, individuals with an altered version of the aldehyde dehydrogenase enzyme have been shown to experience enhanced pesticides effects that are associated with Parkinson’s disease.^[58]

CONCLUSION

Glyphosate has been found in human urine and breast milk

In one study of Europeans, glyphosate was detectable in the urine of most of the study’s participants.^[59] In another study of US citizens, it was detected in 3 out of 10 samples of breast milk.^[60]   Studies indicate that glyphosate can be readily identified in the human body, and thereby attest to how thoroughly populations are exposed to this compound through water, food, and/or the environment.

Studies show that 23% of an oral dose of glyphosate is absorbed. Once absorbed, it diffuses quickly into body tissues, and then is eliminated at a rate of about 50% every 16 hours. This means that after 24 hours, more than 25% of the initial absorbed dose is still in the body;^[61] it can therefore build up if one continues to ingest it.

As we likely ingest some glyphosate every day, glyphosate is probably present at some level in our bodies all the time.^[62] We know from studies in goats that levels in liver and kidneys tend to be higher than in fat or muscle.^[63] Accumulated glyphosate has also been found in other livestock (pigs, cattle), which may not only negatively impact their health, but also act as yet another source of human exposure through meat consumption.^[64]

Note that the above paragraph concerns the effects of glyphosate alone and not in combination with adjuvants. Some researchers find that Roundup® is much more toxic than glyphosate, possibly due to enhanced absorption into cells.^[65],[66]
In the US and Europe, exposure to glyphosate is common^[67] and elicits little official concern, as evidenced by the fact that the EPA raised acceptable levels of glyphosate in several crops in 2011 at the request of manufacturers.^[68]

Exercising Appropriate Caution

In 2015, the World Health Organization’s cancer agency reported that glyphosate is a probable human carcinogen.^[69],[70] This report from a highly respected international organization challenges conventional wisdom regarding glyphosate safety. Also in 2015, researchers demonstrated in rat experiments that extremely small doses of Roundup®, well below regulatory limits, can be harmful to kidneys and liver.^[71],[72] And yet consumers generally have no way of knowing where, how, and how extensively they are exposed to glyphosate.
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