Toxicology is a branch of pharmacology concerned with the study of adverse effects of chemical, biological and physical agents on biological systems to establish the extent of damage. Determination of relationship between dose levels and its effects on the living organisms attain great significance in clinical studies. The Journal of Toxicology is an open access, peer-reviewed international journal that publishes studies including Environmental toxicology, Chemical toxicology, Industrial toxicology, Toxicogenomics, Reproductive toxicology, etc.

Toxic Effects of Pesticides

Use of glyphosate-based herbicides (GBHs) increased ∼100-fold from 1974 to 2014. Additional increases are expected due to widespread emergence of glyphosate-resistant weeds, increased application of GBHs, and preharvest uses of GBHs as desiccants. Current safety assessments rely heavily on studies conducted over 30 years ago. We have considered information on GBH use, exposures, mechanisms of action, toxicity and epidemiology. Human exposures to glyphosate are rising, and a number of in vitro and in vivo studies challenge the basis for the current safety assessment of glyphosate and GBHs. We conclude that current safety standards for GBHs are outdated and may fail to protect public health or the environment. To improve safety standards, the following are urgently needed: (1) human biomonitoring for glyphosate and its metabolites; (2) prioritisation of glyphosate and GBHs for hazard assessments, including toxicological studies that use state-of-the-art approaches; (3) epidemiological studies, especially of occupationally exposed agricultural workers, pregnant women and their children and (4) evaluations of GBHs in commercially used formulations, recognising that herbicide mixtures likely have effects that are not predicted by studying glyphosate alone.

https://jech.bmj.com/content/jech/71/6/613.full.pdf

Is it time to reassess current safety standards for glyphosate-based herbicides?

Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Initially patented as a metal ion chelator, glyphosate rapidly jumped to a leading position as an active ingredient of commercial pesticides from the 1970s when Monsanto discovered its herbicidal activities. The herbicidal mode of action of glyphosate is primarily to inhibit the shikimic acid pathway,[2] causing a shortage of aromatic amino acids. Since this biochemical pathway does not exist in vertebrates, it is generally assumed that glyphosate is safe for mammals, including humans.[8] As a consequence, GBH are used in private gardens, city parks and along roads and railway lines, as well as within an agricultural context on food and feed crops. All these diverse applications of GBH have resulted in escalating levels of human exposure and thus body burden.

Glyphosate is an aminophosphonic analog of glycine. The fact that glycine and other amino acids like glutamate function as neurotransmitters and play a crucial role in brain function, makes the potential neurotoxic effects of glyphosate a matter of concern.[5] The potential of glyphosate to act as a neurotoxin is further supported by its structural similarity to the glutamate receptor agonist 2-amino-3-phosphonopropionic acid. Indeed, GBH exposure induces glutamate excitotoxicity through L-VDCC and NMDA receptor activation in immature rat hippocampus, by reducing glutamate uptake and metabolism within glial cells, and by increasing glutamate release in the synaptic cleft.[3] However, the lack of esterase inhibition by glyphosate (the neurotoxic mechanism of most organophosphate compounds), was considered by regulatory authorities as sufficient grounds to avoid having to undertake a complete assessment of glyphosate's neurological effects.[6]

The most recent reevaluation of the acceptable daily intake (ADI) for glyphosate within the European Union (EU) conducted by the German regulatory agency (BfR), states that this has been determined by scrutiny of approximately 450 regulatory toxicological studies and 900 publications from the scientific literature.[4] Based on the review of all these investigations, the BfR concluded that the “no observed adverse effect level” of glyphosate was in the region of 30-50 mg/kg body weight (bw) per day in rats and the ADI was thus calculated at 0.5 mg/kg bw/day, which constitutes a recommended increase from the current 0.3 mg/kg bw/day. However, these glyphosate ADI values have previously been challenged as review of the same studies and especially extending to feeding studies in animals other than rats, suggested that the current ADI of 0.3 mg/kg bw/day was at least three times higher than what the data suggest should be the case.[1] Nevertheless, with a review of such a relatively large number of studies by the official regulatory authorities, the assessment of the toxicological effects of glyphosate is being considered as complete. The notional strength of glyphosate's safety profile has also resulted in it being neglected in some national wide-scale toxicity testing schemes such as the U.S. Environmental Protection Agency (EPA) ToxCast program.

However, a debate continues as to the soundness of this BfR-led assessment as the studies taken into account were performed with an experimental design adapted to the study of poisoning effects based on the principle of “the dose makes the poison”; that is, the higher the dose the greater the poisoning effect. Of major concern is that none of the studies referred to incorporated testing principles derived from a contemporary understanding of (neuro) endocrinology or developmental epigenetics.

In the classic theory of toxicology, as applied for the study of glyphosate toxicity at a regulatory level, a nontoxic threshold is evidenced by decreasing the level of exposure and assuming that toxic effects observed are a linear response to the dose. Lower doses corresponding to environmental exposures are assumed to be safe and are not tested. However, in contrast to a classical poison, an endocrine disruptive chemical (EDC) will alter the functioning of hormonal systems and induce adverse effects at various dosage levels. Such EDC effects will, in some cases, occur in a nonlinear (non-monotonic) manner at environmentally relevant levels of exposure and will not be observed at higher doses. In addition and not surprisingly, EDC effects can be sex-specific in nature. Such nonmonotonic and sex-specific EDC effects have been extensively described for common pollutants.[7] Although nonmonotonic and sex-specific effects have been reported in many cases with GBH, the regulatory authorities considered these as false positive outcomes rather than a suggestion of potential EDC effects.[4]

Major endpoints of toxicity such as neurodevelopmental, reproductive, and transgenerational effects in humans still needs to be investigated at the glyphosate ADI and other concentrations reflective of human levels of exposure. Given its increasing wide-scale use and consequent rise in exposure, we urgently call for greater research efforts on the toxicology of glyphosate and its commercial herbicide formulations, as well as pesticide neurodevelopmental effects in general. Furthermore, pesticide combinatorial (additive or synergistic) effects remain a poorly investigated subject and area of concern that needs to be addressed. Such studies are particularly relevant to the brain since it is physiologically dependent on neurosteroids, making it potentially very sensitive to endocrine disruptive compounds.

Glyphosate, pathways to modern diseases III: Manganese, neurological diseases, and associated pathologies.

http://digitalcommons.sacredheart.edu/cgi/viewcontent.cgi?article=1105&context=bio_fac

Glyphosate induces neurotoxicity in zebrafish.

One of the most controversial societal issues today, regarding pesticide registration in the European Union (EU) may be the case surrounding re-registration of the active herbicide ingredient glyphosate. Shortly before the announcement of the conflicting views regarding the carcinogenicity status of this regulated agrochemical by EU Agencies, the European Food Safety Authority (EFSA) and the European Chemicals Agency (ECHA) on the one hand, and the International Agency for Research on Cancer (IARC) on the other hand, the Cancer Assessment Review Committee of the US Environmental Protection Agency (US EPA) also published re-evaluations. The US EPA assessment classified glyphosate into Group E, “not likely to be carcinogenic to humans”. Similar positions were reached by EFSA and ECHA, assessing glyphosate as “unlikely to pose a carcinogenic hazard to humans” and “not classified as a carcinogen”, respectively. A strongly opposing evaluation has previously been reached by IARC by classifying glyphosate into Group 2A, “probably carcinogenic to humans”. IARC identified potential cancer hazards in this case, but did not estimate the level of risk it may present, which was taken into consideration by opposing agencies. Multiple effects of glyphosate have been reported, of which carcinogenic effects are only one component. Formulated glyphosate products – especially with polyethoxylated tallowamine and related compounds – have been shown to cause stronger cytotoxic or endocrine disrupting effects than the active ingredient glyphosate alone. Questions related to hazards and corresponding risks identified in relation to this active ingredient and its formulated herbicide preparations divide scientific circles and official health and environmental authorities and organizations, and touch upon fundamental aspects of risk assessment and product regulation. The decision has to consider both hazard-based (IARC) and risk-based analysis (EFSA); the former may not be suitable to calculate practical significances, and the latter being challenged if exposure estimations are uncertain in light of new data on residue levels. The results of current analytical surveys on surface water are particularly worrisome. In turn, the precautionary principle appears to be the optimal approach in this case for regulation in the EU.

/pdf/re-registration-challenges-of-glyphosate-in-the-european-tqquh2yxxx.pdf

Re-registration Challenges of Glyphosate in the European Union

Effect of glyphosate on the sperm quality of zebrafish Danio rerio

Use of trehalose in the semen cryopreservation of Amazonian catfish Leiarius marmoratus.

Reproductive effects caused by the exposure to environmentally relevant dosages of atrazine on wild animals are poorly understood. This study evaluated the effects of three dosages of atrazine on sperm parameters of adult Calomys laucha males. Adult mice were orally exposed to dosages of 0 (water and vehicle control), 0.1, 1, and 10 mg/kg of animal weight for a 21-day period. Following exposure, analyses were performed to determine sperm motility parameters, plasma membrane integrity and fluidity, mitochondrial functionality, acrosome integrity, DNA damage, lipid peroxidation, and production of reactive oxygen species (ROS) in the sperm samples. Total and progressive motility were reduced in all dosages in comparison to control groups. Membrane integrity and mitochondrial functionality of sperm were reduced in all dosages, and the sperm membrane fluidity increased in the higher dosages of atrazine (1 and 10 mg/kg), in comparison with the vehicle control. A decrease in the acrosome integrity was noted at 10 mg/kg of atrazine, compared to the control groups. The integrity of DNA, ROS generation, and lipid peroxidation of sperm showed no significant differences when compared with the control groups. These results suggest that exposure to low dosages of atrazine can affect sperm parameters of Calomys laucha and therefore reduce the reproductive capacity of wild rodent species.

Low atrazine dosages reduce sperm quality of Calomys laucha mice

The study of embryological development of reproductive organs is an important tool for understanding the particularities of the equine species. Also it is important for increasing knowledge about the development of antral follicles that can be used for  in vitro  production of embryos. This study aimed to describe the morphological changes of fetal equine ovaries occurring during gestational development. It was used equine fetuses from a slaughterhouse. After slaughter, it was performed the measurement of cefalococcigea distance to calculate the gestational age (days of pregnancy - DP). Afterwards, the ovaries were grossly evaluated, removed and fixed. Then, they were histologically assessed by hematoxylin-eosin and PAS techniques. It was used 19 fetuses aged 50 to 269 days of gestation, distributed in 9 groups divided according to DP. In the grossly evaluation, it was observed differences between the volume of the ovaries according to gestational age, being observed bigger/larger ovarian volume between 210 days to 269 DP. During the histological evaluation, it was observed a simple cuboidal epithelium and a distinction between the cortical and medullary layers in fetal ovaries from 50-89 DP. The main characteristics identified were: the morphological distinction between the cortical and medullary layers in equine fetal ovaries; the ovigerous cords emerged in the interval between 150 and 179 DP; the cortex initiated as a thin layer with an increased amount of connective tissue rich in blood vessels by the 210 DP, structural uniformity acquired in the medular region by the 150 DP, showing similar cells in size and blood vessels of larger caliber. From this stage, the cells in this region had decreased in size and dense connective tissue bundles, which made this zone partially divided.

/pdf/estudo-de-ovarios-fetais-equinos-uma-abordagem-histologica-x55ap3vwro.pdf

Alessandra Cardoso da Silva

Papers

Effect of glyphosate on the sperm quality of zebrafish Danio rerio

Use of trehalose in the semen cryopreservation of Amazonian catfish Leiarius marmoratus.

Low atrazine dosages reduce sperm quality of Calomys laucha mice

Estudo de ovários fetais equinos: uma abordagem histológica