Glyphosate and neurological outcomes: A systematic literature review of animal studies.

Studies of nervous system effects of glyphosate, a widely used herbicide, have not been critically examined. The aim of this paper was to systematically review glyphosate-induced neurotoxicity literature to determine its usefulness in regulatory decision-making. The review was restricted to mammalian studies of behavior, neuropathology, and neuropharmacology; in vitro and other biochemical studies were considered supplementary information. Glyphosate formulation studies were also considered, despite uncertainties regarding toxicities of the formulated products; no studies used a formulation vehicle as the control. Inclusion criteria were developed a priori to ensure consistent evaluation of studies, and in vivo investigations were also ranked using ToxRTool software to determine reliability. There were 27 in vivo studies (open literature and available regulatory reports), but 11 studies were considered unreliable (mostly due to critical methodological deficiencies). There were only seven acceptable investigations on glyphosate alone. Studies differed in terms of dosing scenarios, experimental designs, test species, and commercial product. Limitations included using only one dose and/or one test time, small sample sizes, limited data presentation, and/or overtly toxic doses. While motor activity was the most consistently affected endpoint (10 of 12 studies), there were considerable differences in outcomes. In six investigations, there were no marked neuropathological changes in the central or peripheral nervous system. Other neurological effects were less consistent, and some outcomes were less convincing due to influences including high variability and small effect sizes. Taken together, these studies do not demonstrate a consistent impact of glyphosate on the structure or function of the mammalian nervous system.

The Irwin Test and Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents.

The modified Irwin procedure or functional observational battery (FOB) can be used to achieve several goals. New chemical entities (NCEs) can be behaviorally screened for nervous system effects at a variety of doses to identify potential therapeutic uses and in the selection of appropriate doses for subsequent assays. NCEs can also be evaluated in the behavioral battery and compared with reference standards to assess liabilities in a new compound class, with an estimated therapeutic index being suggested by the doses used in comparison to therapeutic doses. For the assessment of neurotoxicology, the FOB is often used. The differences between the two assays are subtle. The procedures used are essentially the same, but when considering neurotoxicology, the FOB is often conducted using GLP guidelines, with more animals being used per group, and doses that are low enough to determine a no effect level and high enough to induce marked nervous system behaviors. © 2018 by John Wiley & Sons, Inc.

Neurotoxicological and thyroid evaluations of rats developmentally exposed to tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tris(2-chloro-2-ethyl)phosphate (TCEP).

Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tris(2-chloro-2-ethyl)phosphate (TCEP) are organophosphorous flame retardants with widespread usage and human exposures through food, inhalation, and dust ingestion. They have been detected in human tissues including urine and breast milk. Reports of disrupted neural growth in vitro, abnormal development in larval zebrafish, and altered thyroid hormones in several species have raised concern for neurodevelopmental toxicity. This is especially the case for TDCIPP, which is more potent and has more activity in those assays than does TCEP. We evaluated the potential for developmental neurotoxicity of TDCIPP and TCEP in a mammalian model. Pregnant Long-Evans rats were administered TDCIPP (15, 50, or 150 mg/kg/day) or TCEP (12, 40, 90 mg/kg/day) via oral gavage from gestational day 10 to weaning. Corn oil was the vehicle control in both studies. Body weight and righting reflex development were monitored in all pups. A subset of offspring at culling and weaning, and dams at weaning, were sacrificed for serum and organ collection for measurement of brain, liver, and thyroid weights, serum thyroid levels, and serum and brain acetylcholinesterase activities. Brain weights were also measured in a group of adult TDCIPP-treated offspring. One male and one female from each litter were allocated for behavioral testing at several ages: standard locomotor activity (preweaning, postweaning, adults), locomotor activity including a lighting change mid-way (postweaning, adults), elevated zero maze (postweaning, adults), functional observational battery (FOB; postweaning, adults), and Morris water maze (place learning, reference and working memory; adults). Neither chemical produced changes in maternal body weight or serum thyroid hormones, but relative liver weight was increased at the high doses of both TDCIPP and TCEP. In offspring, there were no effects on viability, litter size, or birth weight. With TDCIPP, absolute liver weights were lower at weaning and weight gain was lower in the high-dose offspring until about two months of age. Thyroid hormones and brain weights were not altered and acetylcholinesterase (both brain and serum) was not inhibited by either chemical. TDCIPP-treated offspring showed slight differences in floating in the water maze, hindlimb grip strength, and altered activity habituation, whereas TCEP-treated rats showed differences in quadrant time (probe) and middle-zone preference in the water maze. Regarding these few changes, the effects were minimal, mostly not related to dose, and did not appear treatment-related or biologically significant. Overall, these data do not support the potential for thyrotoxicity or developmental neurotoxicity produced by TDCIPP or TCEP.