Biological effects of inhaled hydraulic fracturing sand dust. VI. Cardiovascular effects.

Hydraulic fracturing is used to access oil and natural gas reserves. This process involves the high-pressure injection of fluid to fracture shale. Fracking fluid contains approximately 95% water, chemicals and 4.5% fracking sand. Workers may be exposed to fracking sand dust (FSD) during the manipulation of the sand, and negative health consequences could occur if FSD is inhaled. In the absence of any information about its potential toxicity, a comprehensive rat animal model study (see Fedan et al., 2020) was designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems. The goal of this study was to assess the effects of inhalation of one FSD, i.e., FSD 8, on factors and tissues that affect cardiovascular function. Male rats were exposed to 10 or 30 mg/m3 FSD (6 h/d for 4 d) by whole body inhalation, with measurements made 1, 7 or 27 d post-exposure. One day following exposure to 10 mg/m3 FSD the sensitivity to phenylephrine-induced vasoconstriction in tail arteries in vitro was increased. FSD exposure at both doses resulted in decreases in heart rate (HR), HR variability, and blood pressure in vivo. FSD induced changes in hydrogen peroxide concentrations and transcript levels for pro-inflammatory factors in heart tissues. In kidney, expression of proteins indicative of injury and remodeling was reduced after FSD exposure. When analyzed using regression analysis, changes in proteins involved in repair and remodeling were correlated. Thus, it appears that inhalation of FSD does have some prolonged effects on cardiovascular, and, possibly, renal function. The findings also provide information regarding potential mechanisms that may lead to these changes, and biomarkers that could be examined to monitor physiological changes that could be indicative of impending cardiovascular dysfunction.

Transcriptional Pathways Altered in Response to Vibration in a Model of Hand-Arm Vibration Syndrome.

OBJECTIVE: The aim of this study was to use an established model of vibration-induced injury to assess frequency-dependent changes in transcript expression in skin, artery, and nerve tissues. METHODS: Transcript expression in tissues from control and vibration-exposed rats (4 h/day for 10 days at 62.5, 125, or 250 Hz; 49 m/s, rms) was measured. Transcripts affected by vibration were used in bioinformatics analyses to identify molecular- and disease-related pathways associated with exposure to vibration. RESULTS: Analyses revealed that cancer-related pathways showed frequency-dependent changes in activation or inhibition. Most notably, the breast-related cancer-1 pathway was affected. Other pathways associated with breast cancer type 1 susceptibility protein related signaling, or associated with cancer and cell cycle/cell survivability were also affected. CONCLUSION: Occupational exposure to vibration may result in DNA damage and alterations in cell signaling pathways that have significant effects on cellular division.

Long-term daily vibration exposure alters current perception threshold (CPT) sensitivity and myelinated axons in a rat-tail model of vibration-induced injury.

Repeated exposure to hand-transmitted vibration through the use of powered hand tools may result in pain and progressive reductions in tactile sensitivity. The goal of the present study was to use an established animal model of vibration-induced injury to characterize changes in sensory nerve function and cellular mechanisms associated with these alterations. Sensory nerve function was assessed weekly using the current perception threshold test and tail-flick analgesia test in male Sprague-Dawley rats exposed to 28 d of tail vibration. After 28 d of exposure, Aß fiber sensitivity was reduced. This reduction in sensitivity was partly attributed to structural disruption of myelin. In addition, the decrease in sensitivity was also associated with a reduction in myelin basic protein and 2',3'- cyclic nucleotide phosphodiasterase (CNPase) staining in tail nerves, and an increase in circulating calcitonin gene-related peptide (CGRP) concentrations. Changes in Aß fiber sensitivity and CGRP concentrations may serve as early markers of vibration-induced injury in peripheral nerves. It is conceivable that these markers may be utilized to monitor sensorineural alterations in workers exposed to vibration to potentially prevent additional injury.

The effects of repetitive vibration on sensorineural function: biomarkers of sensorineural injury in an animal model of metabolic syndrome.

Exposure to hand-transmitted vibration in the work-place can result in the loss of sensation and pain in workers. These effects may be exacerbated by pre-existing conditions such as diabetes or the presence of primary Raynaud's phenomena. The goal of these studies was to use an established model of vibration-induced injury in Zucker rats. Lean Zucker rats have a normal metabolic profile, while obese Zucker rats display symptoms of metabolic disorder or Type II diabetes. This study examined the effects of vibration in obese and lean rats. Zucker rats were exposed to 4h of vibration for 10 consecutive days at a frequency of 125 Hz and acceleration of 49 m/s(2) for 10 consecutive days. Sensory function was checked using transcutaneous electrical stimulation on days 1, 5 and 9 of the exposure. Once the study was complete the ventral tail nerves, dorsal root ganglia and spinal cord were dissected, and levels of various transcripts involved in sensorineural dysfunction were measured. Sensorineural dysfunction was assessed using transcutaneous electrical stimulation. Obese Zucker rats displayed very few changes in sensorineural function. However they did display significant changes in transcript levels for factors involved in synapse formation, peripheral nerve remodeling, and inflammation. The changes in transcript levels suggested that obese Zucker rats had some level of sensory nerve injury prior to exposure, and that exposure to vibration activated pathways involved in injury and re-innervation.

Recovery of vascular function after exposure to a single bout of segmental vibration.

Work rotation schedules may be used to reduce the negative effects of vibration on vascular function. This study determined how long it takes vascular function to recover after a single exposure to vibration in rats (125 Hz, acceleration 5 g). The responsiveness of rat-tail arteries to the vasoconstricting factor UK14304, an α2C-adrenoreceptor agonist, and the vasodilating factor acetylcholine (ACh) were measured ex vivo 1, 2, 7, or 9 d after exposure to a single bout of vibration. Vasoconstriction induced by UK14304 returned to control levels after 1 d of recovery. However, re-dilation induced by ACh did not return to baseline until after 9 d of recovery. Exposure to vibration exerted prolonged effects on peripheral vascular function, and altered vascular responses to a subsequent exposure. To optimize the positive results of work rotation schedules, it is suggested that studies assessing recovery of vascular function after exposure to a single bout of vibration be performed in humans.

The effects of impact vibration on peripheral blood vessels and nerves.

Research regarding the risk of developing hand-arm vibration syndrome after exposure to impact vibration has produced conflicting results. This study used an established animal model of vibration-induced dysfunction to determine how exposure to impact vibration affects peripheral blood vessels and nerves. The tails of male rats were exposed to a single bout of impact vibration (15 min exposure, at a dominant frequency of 30 Hz and an unweighted acceleration of approximately 345 m/s(2)) generated by a riveting hammer. Responsiveness of the ventral tail artery to adrenoreceptor-mediated vasoconstriction and acetylcholine-mediated re-dilation was measured ex vivo. Ventral tail nerves and nerve endings in the skin were assessed using morphological and immunohistochemical techniques. Impact vibration did not alter vascular responsiveness to any factors or affect trunk nerves. However, 4 days following exposure there was an increase in protein-gene product (PGP) 9.5 staining around hair follicles. A single exposure to impact vibration, with the exposure characteristics described above, affects peripheral nerves but not blood vessels.

Characterization of frequency-dependent responses of the vascular system to repetitive vibration.

OBJECTIVE: Occupational exposure to hand-transmitted vibration can result in damage to nerves and sensory loss. The goal of this study was to assess the frequency-dependent effects of repeated bouts of vibration on sensory nerve function and associated changes in nerves. METHODS: The tails of rats were exposed to vibration at 62.5, 125, or 250 Hz (constant acceleration of 49 m/s2) for 10 days. The effects on sensory nerve function, nerve morphology, and transcript expression in ventral tail nerves were measured. RESULTS: Vibration at all frequencies had effects on nerve function and physiology. However, the effects tended to be more prominent with exposure at 250 Hz. CONCLUSION: Exposure to vibration has detrimental effects on sensory nerve function and physiology. However, many of these changes are more prominent at 250-Hz exposure than at lower frequencies.

Acute effects of COREXIT EC9500A on cardiovascular functions in rats.

These studies characterized cardiovascular responses after an acute inhalation exposure to COREXIT EC9500A, the oil dispersant used in the Deepwater Horizon oil spill. Male Sprague-Dawley rats underwent a single 5-h inhalation exposure to COREXIT EC9500A (average exposure level 27.12 mg/m(3)) or air. On d 1 and 7 following the exposure, rats were implanted with indwelling catheters and changes in heart rate and blood pressure were assessed in response to increasing levels of adrenoreceptor agonists. A separate group of rats was euthanized at the same time points, ventral tail arteries were dissected, and vascular tone along with dose-dependent responses to vasoconstricting and dilating factors were assessed in vitro. Agonist-induced dose-dependent increases in heart rate and blood pressure were greater in COREXIT EC9500A-exposed than in air-exposed rats at 1 d but not 7 d after the exposure. COREXIT EC9500A exposure also induced a rise in basal tone and reduced responsiveness of tail arteries to acetylcholine-induced vasodilation at 1 d but not 7 d following the exposure. These findings demonstrate that an acute exposure to COREXIT EC9500A exerts transient effects on cardiovascular and peripheral vascular functions.

Characterization of frequency-dependent responses of the vascular system to repetitive vibration.

OBJECTIVE: The current frequency weighting proposed in the International Standards Organization-5349 standard may underestimate the risk of injury associated with exposure to vibration >100 Hz. The goal of this study was to assess the frequency-dependent responses of the peripheral vascular system to repeated bouts of vibration. METHODS: The effects of exposure to vibration at 62.5, 125, or 250 Hz (constant acceleration of 49 m/s2) on vascular morphology, oxidative stress, inflammation, and gene expression were examined in the ventral tail artery of rats. RESULTS: Vascular responses indicative of dysfunction (eg, remodeling and oxidative activity) became more pronounced as the frequency of the exposure increased. CONCLUSION: Exposure to vibration frequencies that induce the greatest stress and strain on the tail (ie, >100 Hz) result in vascular changes indicative of dysfunction.

Vibration disrupts vascular function in a model of metabolic syndrome.

Vibration-induced white finger (VWF) is a disorder seen in workers exposed to hand-transmitted vibration, and is characterized by cold-induced vasospasms and finger blanching. Because overweight people with metabolic syndrome are pre-disposed to developing peripheral vascular disorders, it has been suggested that they also may be at greater risk of developing VWF if exposed to occupational vibration. We used an animal model of metabolic syndrome, the obese Zucker rat, to determine if metabolic syndrome alters vascular responses to vibration. Tails of lean and obese Zucker rats were exposed to vibration (125 Hz, 49 m/s(2) r.m.s.) or control conditions for 4 h/d for 10 d. Ventral tail arteries were collected and assessed for changes in gene expression, levels of reactive oxygen species (ROS) and for responsiveness to vasomodulating factors. Vibration exposure generally reduced the sensitivity of arteries to acetylcholine (ACh)-induced vasodilation. This decrease in sensitivity was most apparent in obese rats. Vibration also induced reductions in vascular nitric oxide concentrations and increases in vascular concentrations of ROS in obese rats. These results indicate that vibration interferes with endothelial-mediated vasodilation, and that metabolic syndrome exacerbates these effects. These findings are consistent with idea that workers with metabolic syndrome have an increased risk of developing VWF.