Commercial formulations of pesticides are invariably not single ingredients. Instead they are cocktails of chemicals, composed of a designated pesticidal "active principle" and "other ingredients," ...with the latter collectively also known as "adjuvants." These include surfactants, antifoaming agents, dyes, etc. Some adjuvants are added to influence the absorption and stability of the active principle and thus promote its pesticidal action. Currently, the health risk assessment of pesticides in the European Union and in the United States focuses almost exclusively on the stated active principle. Nonetheless, adjuvants can also be toxic in their own right with numerous negative health effects having been reported in humans and on the environment. Despite the known toxicity of adjuvants, they are regulated differently from active principles, with their toxic effects being generally ignored. Adjuvants are not subject to an acceptable daily intake, and they are not included in the health risk assessment of dietary exposures to pesticide residues. Here, we illustrate this gap in risk assessment by reference to glyphosate, the most used pesticide active ingredient. We also investigate the case of neonicotinoid insecticides, which are strongly suspected to be involved in bee and bumblebee colony collapse disorder. Authors of studies sometimes use the name of the active principle (for example glyphosate) when they are testing a commercial formulation containing multiple (active principle plus adjuvant) ingredients. This results in confusion in the scientific literature and within regulatory circles and leads to a misrepresentation of the safety profile of commercial pesticides. Urgent action is needed to lift the veil on the presence of adjuvants in food and human bodily fluids, as well as in the environment (such as in air, water, and soil) and to characterize their toxicological properties. This must be accompanied by regulatory precautionary measures to protect the environment and general human population from some toxic adjuvants that are currently missing from risk assessments.
Evidence is growing that human exposures to pesticides are contributing in a myriad of complex ways to chronic disease. Regulatory and public health agencies have struggled for years with the ...definition of acceptable exposure thresholds. At the same time, scientists are trying to design studies so that a chemical is delivered at ‘environmentally relevant levels.’ The aim of this review is to: (1) explain the many factors that must be taken into account in determining environmentally relevant levels or doses; (2) improve the ability to properly translate results from laboratory studies into human-health risk assessment; (3) enhance opportunities to compare results across studies using different experimental designs, organisms and routes of exposure. We found that confusion over the relationship between concentrations, dosing levels, regulatory thresholds and ‘safe’ exposure levels is common. We provide recommendations to scientists and authors, peer reviewers and journal editors in the hope of advancing understanding of how to design, carry out, interpret and explain the real-world significance of both old and new lines of scientific inquiry.
The safety profile of the herbicide glyphosate and its commercial formulations is controversial. Reviews have been published by individuals who are consultants and employees of companies ...commercializing glyphosate-based herbicides in support of glyphosate's reapproval by regulatory agencies. These authors conclude that glyphosate is safe at levels below regulatory permissible limits. In contrast, reviews conducted by academic scientists independent of industry report toxic effects below regulatory limits, as well as shortcomings of the current regulatory evaluation of risks associated with glyphosate exposures. Two authors in particular (Samsel and Seneff) have published a series of commentaries proposing that long-term exposure to glyphosate is responsible for many chronic diseases (including cancers, diabetes, neuropathies, obesity, asthma, infections, osteoporosis, infertility, and birth defects). The aim of this review is to examine the evidential basis for these claimed negative health effects and the mechanisms that are alleged to be at their basis. We found that these authors inappropriately employ a deductive reasoning approach based on syllogism. We found that their conclusions are not supported by the available scientific evidence. Thus, the mechanisms and vast range of conditions proposed to result from glyphosate toxicity presented by Samsel and Seneff in their commentaries are at best unsubstantiated theories, speculations, or simply incorrect. This misrepresentation of glyphosate's toxicity misleads the public, the scientific community, and regulators. Although evidence exists that glyphosate-based herbicides are toxic below regulatory set safety limits, the arguments of Samsel and Seneff largely serve to distract rather than to give a rational direction to much needed future research investigating the toxicity of these pesticides, especially at levels of ingestion that are typical for human populations.
The herbicide active ingredient glyphosate can affect the growth of microorganisms, which rely on the shikimate pathway for aromatic amino acid biosynthesis. However, it is uncertain whether ...glyphosate exposure could lead to perturbations in the population of human gut microbiota. We have addressed this knowledge gap by analysing publicly available datasets to provide new insights into possible effects of glyphosate on the human gut microbiome. Comparison of the abundance of the shikimate pathway in 734 paired metagenomes and metatranscriptomes indicated that most gut bacteria do not possess a complete shikimate pathway, and that this pathway is mostly transcriptionally inactive in the human gut microbiome. This suggests that gut bacteria are mostly aromatic amino acid auxotrophs and thus relatively resistant to a potential growth inhibition by glyphosate. As glyphosate blocking of the shikimate pathway is via inhibition of EPSPS, we classified E. coli EPSPS enzyme homologues as class I (sensitive to glyphosate) and class II (resistant to glyphosate). Among 44 subspecies reference genomes, accounting for 72% of the total assigned microbial abundance in 2144 human faecal metagenomes, 9 subspecies have class II EPSPS. The study of publicly available gut metagenomes also indicated that glyphosate might be degraded by some Proteobacteria in the human gut microbiome using the carbon–phosphorus lyase pathway. Overall, there is limited experimental evidence available for the effects of glyphosate on the human gut microbiome. Further investigations using more advanced molecular profiling techniques are needed to ascertain whether glyphosate and glyphosate-based herbicides can alter the function of the gut microbiome with consequent health implications.
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•It is debated whether glyphosate can perturb the human gut microbiota•Gut microbiome EPSPS enzymes are predicted to be sensitive to glyphosate•Shikimate pathway is mostly transcriptionally inactive in the human gut microbiome•Most gut microbiome bacteria do not possess a complete shikimate pathway•Investigations using more advanced techniques such as metabolomics are needed
► From 1h of Roundup exposure Leydig cells are reacting. ► Within 24–48h Roundup is toxic from 0.05%, by contrast to glyphosate alone. ► Glyphosate alone from 0.005% induces membrane degradation in ...Sertoli cells first. ► Glyphosate induces apoptosis in germ cells or in Sertoli/germ cells co-cultures. ► Roundup has an impact at very low environmental doses on isolated testicular cells.
The major herbicide used worldwide, Roundup, is a glyphosate-based pesticide with adjuvants. Glyphosate, its active ingredient in plants and its main metabolite (AMPA) are among the first contaminants of surface waters. Roundup is being used increasingly in particular on genetically modified plants grown for food and feed that contain its residues. Here we tested glyphosate and its formulation on mature rat fresh testicular cells from 1 to 10000ppm, thus from the range in some human urine and in environment to agricultural levels. We show that from 1 to 48h of Roundup exposure Leydig cells are damaged. Within 24–48h this formulation is also toxic on the other cells, mainly by necrosis, by contrast to glyphosate alone which is essentially toxic on Sertoli cells. Later, it also induces apoptosis at higher doses in germ cells and in Sertoli/germ cells co-cultures. At lower non toxic concentrations of Roundup and glyphosate (1ppm), the main endocrine disruption is a testosterone decrease by 35%. The pesticide has thus an endocrine impact at very low environmental doses, but only a high contamination appears to provoke an acute rat testicular toxicity. This does not anticipate the chronic toxicity which is insufficiently tested, and only with glyphosate in regulatory tests.
We describe a comprehensive repository describing a collection of data from a range of studies investigating the molecular mechanisms of toxicity of glyphosate, the glyphosate-based herbicide ...commercial formulation Roundup, and a mixture of glyphosate and 5 other most frequently used pesticides (azoxystrobin, boscalid, chlorpyrifos, imidacloprid and thiabendazole) present as residues in food products in Europe. The data were obtained by analysing tissues from rats exposed to the pesticides for 90 days via drinking water. The administration of the mixture of six pesticides was chosen to mimic a possible human exposure scenario. We compared conventional methods used in regulatory toxicity studies to evaluate the safety of pesticide exposure (gross pathology, serum biochemistry) to new molecular profiling methods encompassing the analysis of the caecum and blood metabolome, liver transcriptome, liver DNA methylation, liver small RNA profiles, and caecum metagenome of the exposed animals. Altogether, these investigations provided in-depth molecular profiling in laboratory animals exposed to pesticides revealing metabolic perturbations that would remain undetected by standard regulatory biochemical measures. Our results highlight how multi-omics phenotyping can be used to improve the predictability of health risk assessment from exposure to toxic chemicals to better protect public health.
Pesticides are recognised as a key threat to pollinators, impacting their health in many ways. One route through which pesticides can affect pollinators like bumblebees is through the gut microbiome, ...with knock-on effects on their immune system and parasite resistance. We tested the impacts of a high acute oral dose of glyphosate on the gut microbiome of the buff tailed bumblebee (Bombus terrestris), and glyphosate's interaction with the gut parasite (Crithidia bombi). We used a fully crossed design measuring bee mortality, parasite intensity and the bacterial composition in the gut microbiome estimated from the relative abundance of 16S rRNA amplicons. We found no impact of either glyphosate, C. bombi, or their combination on any metric, including bacterial composition. This result differs from studies on honeybees, which have consistently found an impact of glyphosate on gut bacterial composition. This is potentially explained by the use of an acute exposure, rather than a chronic exposure, and the difference in test species. Since A. mellifera is used as a model species to represent pollinators more broadly in risk assessment, our results highlight that caution is needed in extrapolating gut microbiome results from A. mellifera to other bee species.
The toxicology of herbicides, which are currently in use is under-explored. One highly used but under investigated herbicide is pendimethalin. Here we mined high-throughput data from the US National ...Toxicology Program (NTP) to identify whether pendimethalin possesses an estrogenic capability in human cells. We also evaluated effects of pendimethalin and its reference commercial formulated herbicide Stomp Aqua on the transcriptome profile of three human mammary epithelial cell lines, cancerous MCF-7 and non-cancerous MCF-10 A and MCF-12 A to see whether this compound could have endocrine disrupting effects and if co-formulants present in the commercial formulation could amplify its toxicity.
The data mined from the US NTP database suggests that pendimethalin activates estrogen receptors at a concentration of approximately 10?M. MCF-7, MCF-10A and MCF-12A cells were exposed to 10 ?M pendimethalin and Stomp Aqua at an equivalent concentration. Transcriptome analysis showed changes in gene expression patterns implying that pendimethalin affected ubiquitin-mediated proteolysis and the function of the spliceosome. The formulated pendimethalin product Stomp Aqua gave comparable effects suggesting pendimethalin was responsible for the observed transcriptome alterations. Given the lack of information on the exposure to this pesticide, our study prompts the need for biomonitoring studies, especially under occupational use scenarios, to understand if low level exposure to pendimethalin could have endocrine disrupting effects on populations exposed to this compound. A deeper understanding of the exposure and mechanisms of action of this endocrine-disrupting pesticide is needed.
Background We investigated daily blood pressure (BP) changes during fasting periods ranging from 4 to 41 (10.0±3.8) days in a cohort of 1610 subjects, including 920 normotensive, 313 hypertensive ...nonmedicated, and 377 hypertensive medicated individuals. Methods and Results Subjects underwent a multidisciplinary fasting program with a daily intake of ≈250 kcal. Weight and stress scores decreased during fasting, and the well-being index increased, documenting a good tolerability. BP mean values decreased from 126.2±18.6/81.4±11.0 to 119.7±15.9/77.6±9.8 mm Hg (mean change, -6.5/3.8 mm Hg). BP changes were larger for hypertensive nonmedicated subjects (>140/90 mm Hg) and reduced by 16.7/8.8 mm Hg. This reduction reached 24.7/13.1 mm Hg for hypertensive nonmedicated subjects (n=76) with the highest BP (>160/100 mm Hg). In the normotensive group, BP decreased moderately by 3.0/1.9 mm Hg. Interestingly, we documented an increase of 6.3/2.2 mm Hg in a subgroup of 69 female subjects with BP <100/60 mm Hg. In the hypertensive medicated group, although BP decreased from 134.6/86.0 to 127.3/81.3 mm Hg, medication was stopped in 23.6% of the subjects, whereas dosage was reduced in 43.5% and remained unchanged in 19.4%. The decrease in BP was larger in subjects fasting longer. Baseline metabolic parameters, such as body mass index and glucose levels, as well as age, can be used to predict the amplitude of the BP decrease during fasting with a machine learning model. Conclusions Long-term fasting tends to decrease BP in subjects with elevated BP values. This effect persisted during the 4 days of stepwise food reintroduction, even when subjects stopped their antihypertensive medication. Registration URL: https://www.drks.de/drks_web/; Unique identifier: DRKS00010111.
Background: There is a growing consensus that fasting-induced ketosis has beneficial effects on human physiology. Despite these compelling benefits, fasting-induced ketosis raises concerns in some ...clinicians because it is often inappropriately compared with the pathologic uncontrolled ketone production in diabetic ketoacidosis. The determinants of the inter-individual differences in the intensity of ketosis during long-term fasting is unknown. Methods: We monitored daily variations in fasting ketonemia, as well as ketonuria, which is less invasive, in a large cohort of 1610 subjects, fasting between 4 and 21 days with the Buchinger Wilhelmi program, minimally supplemented with ~75–250 kcal (daily fruit juice, vegetable soup, and honey). Results: Ketonuria was detected in more than 95% of fasting subjects from day 4 onwards. Subjects consuming only soups, without fruit juice or honey, exhibited reduced caloric intake (72 kcal instead of 236 kcal) and carbohydrate intake (15.6 g instead of 56.5 g), leading to more intense ketonuria. Participants with high ketonuria were, in the majority, males, young, had a higher body weight, and had lower HDL-C and urea values. They had a larger decrease in blood glucose, glycated haemoglobin levels, body weight, and waist circumference. Furthermore, in the high-ketonuria group, a larger increase in blood uric acid concentration was observed. Conclusion: Our study showed that long-term fasting triggered ketosis, never reaching pathological levels, and that ketosis is influenced by age, gender, health, and the level of physical activity. Furthermore, it is modulated but not suppressed by minimal carbohydrate intake. Our study paves the way for better understanding how supplementation can modulate the therapeutic effects and tolerability of long-term fasting.
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