For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

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Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

Accurate pesticide use data are essential when studying the environmental and public health impacts of pesticide use. Since the mid-1990s, significant changes have occurred in when and how glyphosate herbicides are applied, and there has been a dramatic increase in the total volume applied. Data on glyphosate applications were collected from multiple sources and integrated into a dataset spanning agricultural, non-agricultural, and total glyphosate use from 1974–2014 in the United States, and from 1994–2014 globally. Since 1974 in the U.S., over 1.6 billion kilograms of glyphosate active ingredient have been applied, or 19 % of estimated global use of glyphosate (8.6 billion kilograms). Globally, glyphosate use has risen almost 15-fold since so-called “Roundup Ready,” genetically engineered glyphosate-tolerant crops were introduced in 1996. Two-thirds of the total volume of glyphosate applied in the U.S. from 1974 to 2014 has been sprayed in just the last 10 years. The corresponding share globally is 72 %. In 2014, farmers sprayed enough glyphosate to apply ~1.0 kg/ha (0.8 pound/acre) on every hectare of U.S.-cultivated cropland and nearly 0.53 kg/ha (0.47 pounds/acre) on all cropland worldwide. Genetically engineered herbicide-tolerant crops now account for about 56 % of global glyphosate use. In the U.S., no pesticide has come remotely close to such intensive and widespread use. This is likely the case globally, but published global pesticide use data are sparse. Glyphosate will likely remain the most widely applied pesticide worldwide for years to come, and interest will grow in quantifying ecological and human health impacts. Accurate, accessible time-series data on glyphosate use will accelerate research progress.

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Trends in glyphosate herbicide use in the United States and globally

The industrialization of the agricultural sector has increased the chemical burden on natural ecosystems. Pesticides are agrochemicals used in agricultural lands, public health programs and urban green areas in order to protect plants and humans from various diseases. However, due to their known ability to cause a large number of negative health and environmental effects, their side effects can be an important environmental health risk factor. The urgent need for a more sustainable and ecological approach has produced many innovative ideas, among them agriculture reforms and food production implementing sustainable practice evolving to food sovereignty. It is more obvious than ever that the society needs the implementation of a new agricultural concept regarding food production which is safer for man and the environment, and to this end, steps such as the declaration of Nyeleni have been taken.

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Chemical Pesticides and Human Health: The Urgent Need for a New Concept in Agriculture.

The broad-spectrum herbicide glyphosate (common trade name “Roundup”) was first sold to farmers in 1974. Since the late 1970s, the volume of glyphosate-based herbicides (GBHs) applied has increased approximately 100-fold. Further increases in the volume applied are likely due to more and higher rates of application in response to the widespread emergence of glyphosate-resistant weeds and new, pre-harvest, dessicant use patterns. GBHs were developed to replace or reduce reliance on herbicides causing well-documented problems associated with drift and crop damage, slipping efficacy, and human health risks. Initial industry toxicity testing suggested that GBHs posed relatively low risks to non-target species, including mammals, leading regulatory authorities worldwide to set high acceptable exposure limits. To accommodate changes in GBH use patterns associated with genetically engineered, herbicide-tolerant crops, regulators have dramatically increased tolerance levels in maize, oilseed (soybeans and canola), and alfalfa crops and related livestock feeds. Animal and epidemiology studies published in the last decade, however, point to the need for a fresh look at glyphosate toxicity. Furthermore, the World Health Organization’s International Agency for Research on Cancer recently concluded that glyphosate is “probably carcinogenic to humans.” In response to changing GBH use patterns and advances in scientific understanding of their potential hazards, we have produced a Statement of Concern drawing on emerging science relevant to the safety of GBHs. Our Statement of Concern considers current published literature describing GBH uses, mechanisms of action, toxicity in laboratory animals, and epidemiological studies. It also examines the derivation of current human safety standards. We conclude that: (1) GBHs are the most heavily applied herbicide in the world and usage continues to rise; (2) Worldwide, GBHs often contaminate drinking water sources, precipitation, and air, especially in agricultural regions; (3) The half-life of glyphosate in water and soil is longer than previously recognized; (4) Glyphosate and its metabolites are widely present in the global soybean supply; (5) Human exposures to GBHs are rising; (6) Glyphosate is now authoritatively classified as a probable human carcinogen; (7) Regulatory estimates of tolerable daily intakes for glyphosate in the United States and European Union are based on outdated science. We offer a series of recommendations related to the need for new investments in epidemiological studies, biomonitoring, and toxicology studies that draw on the principles of endocrinology to determine whether the effects of GBHs are due to endocrine disrupting activities. We suggest that common commercial formulations of GBHs should be prioritized for inclusion in government-led toxicology testing programs such as the U.S. National Toxicology Program, as well as for biomonitoring as conducted by the U.S. Centers for Disease Control and Prevention.

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Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement

Environmental and health effects of the herbicide glyphosate.

https://www.gmoseralini.org/wp-content/uploads/2013/01/Gasnieral.TOX_2009.pdf

Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines.

https://www.csus.edu/indiv/m/merlinos/pdf/seralini2012.pdf

Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize

https://www.gmoseralini.org/wp-content/uploads/2013/01/Clairal_ToxInVitro_2012-1.pdf

A glyphosate-based herbicide induces necrosis and apoptosis in mature rat testicular cells in vitro, and testosterone decrease at lower levels.

The health effects of a Roundup-tolerant NK603 genetically modified (GM) maize(from 11% in the diet), cultivated with or without Roundup application and Roundupalone (from 0.1 ppb of the full pesticide containing glyphosate and adjuvants) indrinking water, were evaluated for 2 years in rats. This study constitutes afollow-up investigation of a 90-day feeding study conducted by Monsanto in orderto obtain commercial release of this GMO, employing the same rat strain andanalyzing biochemical parameters on the same number of animals per group as ourinvestigation. Our research represents the first chronic study on thesesubstances, in which all observations including tumors are reportedchronologically. Thus, it was not designed as a carcinogenicity study. We reportthe major findings with 34 organs observed and 56 parameters analyzed at 11 timepoints for most organs. Biochemical analyses confirmed very significant chronic kidney deficiencies, forall treatments and both sexes; 76% of the altered parameters were kidney-related.In treated males, liver congestions and necrosis were 2.5 to 5.5 times higher.Marked and severe nephropathies were also generally 1.3 to 2.3 times greater. Infemales, all treatment groups showed a two- to threefold increase in mortality,and deaths were earlier. This difference was also evident in three male groups fedwith GM maize. All results were hormone- and sex-dependent, and the pathologicalprofiles were comparable. Females developed large mammary tumors more frequentlyand before controls; the pituitary was the second most disabled organ; the sexhormonal balance was modified by consumption of GM maize and Roundup treatments.Males presented up to four times more large palpable tumors starting 600 daysearlier than in the control group, in which only one tumor was noted. Theseresults may be explained by not only the non-linear endocrine-disrupting effectsof Roundup but also by the overexpression of the EPSPS transgene or othermutational effects in the GM maize and their metabolic consequences. Our findings imply that long-term (2 year) feeding trials need to be conducted tothoroughly evaluate the safety of GM foods and pesticides in their full commercialformulations.

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Republished Study: Long-Term Toxicity of a Roundup Herbicide and a Roundup-tolerant Genetically Modified Maize

Purpose: We reviewed 19 studies of mammals fed with commercialized genetically modified soybean and maize which represent, per trait and plant, more than 80% of all environmental genetically modified organisms (GMOs) cultivated on a large scale, after they were modified to tolerate or produce a pesticide. We have also obtained the raw data of 90-day-long rat tests following court actions or official requests. The data obtained include biochemical blood and urine parameters of mammals eating GMOs with numerous organ weights and histopathology findings. Methods: We have thoroughly reviewed these tests from a statistical and a biological point of view. Some of these tests used controversial protocols which are discussed and statistically significant results that were considered as not being biologically meaningful by regulatory authorities, thus raising the question of their interpretations. Results: Several convergent data appear to indicate liver and kidney problems as end points of GMO diet effects in the above-mentioned experiments. This was confirmed by our meta-analysis of all the in vivo studies published, which revealed that the kidneys were particularly affected, concentrating 43.5% of all disrupted parameters in males, whereas the liver was more specifically disrupted in females (30.8% of all disrupted parameters). Conclusions: The 90-day-long tests are insufficient to evaluate chronic toxicity, and the signs highlighted in the kidneys and livers could be the onset of chronic diseases. However, no minimal length for the tests is yet obligatory for any of the GMOs cultivated on a large scale, and this is socially unacceptable in terms of consumer health protection. We are suggesting that the studies should be improved and prolonged, as well as being made compulsory, and that the sexual hormones should be assessed too, and moreover, reproductive and multigenerational studies ought to be conducted too.

https://www.gmoseralini.org/wp-content/uploads/2012/11/Seralini2011.pdf

Emilie Clair

Papers

Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines.

Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize

A glyphosate-based herbicide induces necrosis and apoptosis in mature rat testicular cells in vitro, and testosterone decrease at lower levels.

Republished Study: Long-Term Toxicity of a Roundup Herbicide and a Roundup-tolerant Genetically Modified Maize

Genetically modified crops safety assessments: present limits and possible improvements