Impact of Wind Speed and Direction and Key Meteorological Parameters on Potential Pesticide Drift Mass Loadings from Sequential Aerial Applications.

Pesticide spray drift is potentially a significant source of exposure to off-target, adjacent aquatic habitats. To estimate the magnitude of pesticide drift from aerial or ground applications, regulatory agencies in North America, Europe, and elsewhere rely on spray drift models to predict spray drift deposition for risk assessments. Refined assessments should ultimately depend on best-available data for exposure modeling. However, when developing lower tier "screening" assessments designed to indicate whether further refinement is needed, regulators often make conservative assumptions with a resulting increased level of uncertainty in estimating environmental exposure or risk. In the United States, it is generally accepted that, to ensure conservative regulatory assessments, it is reasonable to assume that the wind speed might be 4.47 m/s (10 miles per hour [mph]), the relative humidity and temperature are highly conducive to drift, and the wind is blowing directly toward a receiving water for any given single spray event in a season. However, what is the probability these conditions will all co-occur for each of 4 sequential spray events spaced a week apart (common practice for insecticides)? The refined approach in the present study investigates this question using hourly meteorological data sets for 5 United States Environmental Protection Agency (USEPA) standard crop scenarios to understand how real-world data can reduce unnecessary uncertainty for sequential applications. The impact of wind speeds, temperatures, relative humidity, and wind direction at different times of day on annual drift loadings has been examined using a stepwise process for comparison with corresponding regulatory default loading estimates. The impacts on drift estimates were significant; interestingly, the time of day of the applications impacted variability more than did the selected crop scenario. When all these real-world factors were considered, estimated 30-y total drift loads ranged from 2% to 5% greater than the default estimate (2 of 30 cases due to high afternoon wind speeds) to 51% to 86% reductions (25 of 30 cases) with an overall average reduction of 63%. Integr Environ Assess Manag 2020;16:197-210. © 2019 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

The voltage-gated sodium channel Nav1.9 is required for inflammation-based urinary bladder dysfunction.

Tetrodotoxin (TTX)-resistant sodium channels are found in small diameter primary sensory neurons and are thought to be important in the maintenance of inflammatory pain. Here we examined bladder urodynamics of Nav1.9 voltage-gated sodium channel knock out (KO) mice, and the contribution of Nav1.9 to the development of inflammation-based bladder dysfunction. Basal urodynamics were not different between wildtype (WT) mice and those lacking Nav1.9. Peripheral nerve recordings from pelvic afferents in Nav1.9 KO mice revealed a lack of sensitization to intravesicularly applied prostaglandin E2 (PGE2). Consistent with this, cyclophosphamide treatment in vivo, which is associated with an enhancement of PGE2 production, evoked a reduction in bladder capacity of WT, but not Nav1.9 KO mice. We conclude that the Nav1.9 sodium channel provides an important link between inflammatory processes and changes in urodynamic properties that occur during urinary bladder inflammation.

Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors.

Neurons classified as nociceptors are dependent on nerve growth factor (NGF) during embryonic development, but a large subpopulation lose this dependence during embryonic and postnatal times and become responsive to the transforming growth factor beta family member, glial cell line-derived growth factor (GDNF). To elucidate the functional properties of GDNF-dependent nociceptors and distinguish them from nociceptors that retain NGF dependence, the cellular and physiologic properties of sensory neurons of wild-type and transgenic mice that overexpress GDNF in the skin (GDNF-OE) were analyzed using a skin, nerve, dorsal root ganglion, and spinal cord preparation, immunolabeling, and reverse transcriptase-PCR assays. Although an increase in peripheral conduction velocity of C-fibers in GDNF-OE mice was measured, other electrophysiological properties, including resting membrane potential and somal action potentials, were unchanged. We also show that isolectin B4 (IB4)-positive neurons, many of which are responsive to GDNF, exhibited significantly lower thresholds to mechanical stimulation relative to wild-type neurons. However, no change was observed in heat thresholds for the same population of cells. The increase in mechanical sensitivity was found to correlate with significant increases in acid-sensing ion channels 2A and 2B and transient receptor potential channel A1, which are thought to contribute to detection of mechanical stimuli. These data indicate that enhanced expression of GDNF in the skin can change mechanical sensitivity of IB4-positive nociceptive afferents and that this may occur through enhanced expression of specific types of channel proteins.

Relationship between the firing frequency of injured peripheral neurons and inhibition of firing by sodium channel blockers.

UNLABELLED: Animal models of neuropathic pain in which a peripheral nerve is damaged result in spontaneous activity in primary afferents that can be inhibited by intravenous administration of sodium channel blockers. Many of these compounds exhibit use-dependent block of sodium current, leading to the prediction that they should more readily inhibit neurons that fire at higher frequencies. This prediction was tested in 2 rat models of nerve injury, L5 spinal nerve section and sciatic nerve section. Sciatic nerve section produced average firing frequencies that were higher than spinal nerve section and often manifested as high-frequency bursting. Inhibition of firing by intravenous sodium channel blockers was longer lasting in this model. Within each model, higher frequency of firing did not translate into more effective block. In the spinal nerve section model, there was a robust inverse correlation between frequency and inhibition. Within the sciatic section model, only neurons that fired in rhythmic bursts were inhibited, and again, those firing at lower mean frequencies were more effectively inhibited. These results indicate that the efficacy of sodium channel blockers depends on the nature of the injury and the pattern of the resulting activity rather than simply the frequency of action potentials generated. PERSPECTIVE: This study examines the ability of frequency-dependent sodium channel blockers to inhibit spontaneous firing of injured peripheral nerves in vivo. It outlines the conditions under which inhibition is more and less effective and will provide insight into conditions under which sodium channel blockers are likely to be therapeutically useful.

Expression and localization of the Nav1.9 sodium channel in enteric neurons and in trigeminal sensory endings: implication for intestinal reflex function and orofacial pain.

The Nav1.9 sodium channel is expressed in nociceptive DRG neurons where it contributes to spontaneous pain behavior after peripheral inflammation. Here, we used a newly developed antibody to investigate the distribution of Nav1.9 in rat and mouse trigeminal ganglion (TG) nerve endings and in enteric nervous system (ENS). In TGs, Nav1.9 was expressed in the soma of small- and medium-sized, peripherin-positive neurons. Nav1.9 was present along trigeminal afferent fibers and at terminals in lip skin and dental pulp. In the ENS, Nav1.9 was detected within the soma and proximal axons of sensory, Dogiel type II, myenteric and submucosal neurons. Immunological data were correlated with the detection of persistent TTX-resistant Na(+) currents sharing similar properties in DRG, TG and myenteric neurons. Collectively, our data support a potential role of Nav1.9 in the transmission of trigeminal pain and the regulation of intestinal reflexes. Nav1.9 might therefore constitute a molecular target for therapeutic treatments of orofacial pain and gastrointestinal syndromes.

Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior.

The transmission of pain signals after injury or inflammation depends in part on increased excitability of primary sensory neurons. Nociceptive neurons express multiple subtypes of voltage-gated sodium channels (NaV1s), each of which possesses unique features that may influence primary afferent excitability. Here, we examined the contribution of NaV1.9 to nociceptive signaling by studying the electrophysiological and behavioral phenotypes of mice with a disruption of the SCN11A gene, which encodes NaV1.9. Our results confirm that NaV1.9 underlies the persistent tetrodotoxin-resistant current in small-diameter dorsal root ganglion neurons but suggest that this current contributes little to mechanical thermal responsiveness in the absence of injury or to mechanical hypersensitivity after nerve injury or inflammation. However, the expression of NaV1.9 contributes to the persistent thermal hypersensitivity and spontaneous pain behavior after peripheral inflammation. These results suggest that inflammatory mediators modify the function of NaV1.9 to maintain inflammation-induced hyperalgesia.