Gulf War and Health Volume 10: Update of Health Effects of Serving in the Gulf War, 2016 (2016) / Chapter Skim
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5 Animal Studies
5 Animal Studies
Pages 217-238
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From page 217... ...
Volumes 4 and 8 of the Gulf War and Health series were concerned only with associations between being deployed to the Persian Gulf region during the war and the prevalence of health outcomes in deployed vs nondeployed veterans; the two volumes did not examine specific toxicant exposures and thus animal studies were not considered in them. Based on the premise that different populations of Gulf War veterans inevitably experienced multiple and variable chemical exposures, in this chapter, the committee focuses its review on animal toxicology studies that used multiple exposures which were generally considered to be relevant to those exposures 217
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From page 218... ...
In addition, some animal studies have examined potential effects of Gulf War toxicants on the reproductive system, the musculoskeletal system, and the immune system as veterans have complained of adverse health effects related to those systems. There are some challenges in the interpretation of animal study data for the purposes of elucidating Gulf War illness.
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From page 219... ...
and multiple different stress paradigms have not replicated those initial findings. Rats exposed to pole climbing avoidance stress plus tritiated PB to assess its blood–brain barrier permeability, showed no radioactivity in brain micropunches and cryosections (Amourette et al., 2009)
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From page 220... ...
Thus, PB did not exacerbate the effects of stress on either performance measures or on levels of stress hormones. A mouse model of Gulf War illness was used to study effects on phospholipid metabolism following coadministration of 2mg/kg PB and 200 mg/kg permethrin intraperitoneal for 10 days followed by up to a 150-day observation period (Abdullah et al., 2011)
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From page 221... ...
Summary of Brain Effects Inconsistent results on the permeability of the blood–brain barrier and associated effects to certain combinations of toxic exposures, but not others, give weak support for the hypothesis that stress-induced damage to the blood–brain barrier is a cause for symptoms of Gulf War illness. Three studies showed increased permeability (Abdel-Rahman et al., 2002, 2004; Freidman et al., 1996)
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From page 222... ...
Several studies have evaluated the effect of Gulf War–related toxicants and aspects of motor function likely based on numerous reports of fatigue in Gulf War illness. Executive Function Learning In general, only two different paradigms of learning have been examined in response to Gulf War illness–related toxicants.
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From page 223... ...
Following combined exposures to PB, DEET, and permethrin alone or in conjunction with restraint stress, no deficits were reported in novel object recognition memory, suggesting no deficits in shortterm memory (Parihar et al., 2013)
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From page 224... ...
Combined exposures of both male and female mice to PB, permethrin, DEET, and restraint stress resulted in more time spent in the perimeter in the 15-minute open field test (Abdullah et al., 2012) ; however, the differences tend to be about 5 seconds or less, raising questions about their biological significance.
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From page 225... ...
Motor Function Most animal studies have evaluated motor function in terms of locomotor activity (ambulation, rearing) and aspects of motor or sensorimotor function.
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From page 226... ...
Based on the available studies, it is not clear that lower levels of Gulf War toxicants that may mirror Gulf War veteran exposures alter fine motor functions in the absence of more overt toxicity. Summary of Behavioral Effects The committee finds that it is difficult to arrive at any generalities regarding the behavioral studies discussed in this section for the following reasons: 1.
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From page 227... ...
No data was provided on body weight or other indicators of systemic toxicity. The studies in mice suggest a potential mechanism for muscle injury following combined exposures to chemicals and stress designed to mirror those exposures reported by Gulf War veterans.
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From page 228... ...
CONCLUSIONS Animal studies have suggested physiological alterations in response to the toxicant exposures that Gulf War veterans might have experienced while deployed. However, animal studies have typically examined isolated symptoms of Gulf War illness rather than the symptom clusters that are reported by veterans.
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From page 229... ...
, areas where no disruption of the blood–brain barrier was observed Amourette PB + stress No evidence of increased blood–brain et al., 2009 Two 5-day periods of daily exposure to 1.5 mg/kg 3H-PB with barrier permeability to PB with stress Rats and without stress of pole climbing avoidance Friedman PB + stress Evidence of increased blood–brain et al., 1996 Daily ip injections of 0.5 or 1.0 mg/kg of PB with or without barrier permeability to PB with stress Mice stress of two 4-min forced swim sessions Grauer PB + stress Evidence of decreased blood–brain et al., 2000 Stress by two 4-min forced swim sessions or 5 min with feet barrier permeability to PB with stress Mice in ice water and then treated with saline, 0.4 mg/kg PB or 0.2 mg/kg physostigmine im or ip Kant et al., PB + stress No evidence of increased blood–brain 2001 Treated with 200 μl of saline, 25 mg/ml PB, or 20 mg/ml barrier permeability to PB with stress Rats physostigmine, administered by osmotic minipump, with and without avoidance/escape stress, or yoked stress Lallement PB + stress Evidence of decreased blood–brain et al., 1998 Exposure to saline or 0.2 mg/kg PB with or without stress: barrier permeability in response to PB Guinea low (24.3–25.9°C for 2 hrs) ; medium (38.4–39.6°C for 2 hrs)
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From page 230... ...
, then PB, then restraint tube (60 min) Song et al., PB + paraoxon Paraoxon increased the number of 2004 Treatment: 30 mg/kg PB by gavage 50 min before 100 μg/kg leaky capillaries in the brain of young Rats paraoxon im rats but not older rats Tian et al., PB + stress No evidence of increased PB toxicity 2002 1: Controls, no stress or PB or increased blood–brain barrier Rats 2: no stress, 30 mg/kg PB permeability to PB with stress 3: stress and saline 4: stress and 30 mg/kg PB Stress: forced run on a treadmill after, before, or before and after PB treatment; or forced swimming before or after PB treatment Brain Metabolism and Histopathology Abdel- DEET + permethrin Evidence of diffuse neuronal Rahman All conditions applied dermally cell death in cerebral cortex, et al., 2001 1: Control: 70% ethanol hippocampus, and cerebellum for all Rats 2: 40 mg/kg DEET in ethanol three exposures 3: 0.13 mg/kg permethrin in ethanol 4: DEET + permethrin in ethanol 7 d per week for 60 d
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From page 231... ...
indicating peroxisomal and lysosomal dysfunction Buchholz PB + permethrin No evidence of harmful synergistic et al., 1997 1: PB 7.75 mg/kg in food effect of PB and permethrin on Rats 2: PB +14C-permethrin 4.75 μg/kg ip central nervous system 3: Controls, plain food for 10 days Husain and PB + sarin + stress Little evidence that exercise increased Somani, 1: Controls the effects of PB or sarin on 2004 2: 0.01 mg/kg/d sarin sc for weeks 5 and 6 butyrcholinesterase, AChE, neurotoxic Mice 3: exercise on treadmill daily for 10 weeks with increasing esterase in plasma or brain speed and time 4: sarin + exercise 5: 1.2 mg/kg/d PB orally for weeks 5 and 6 6: PB + exercise 7: PB + sarin 8: PB + sarin + exercise Animals sacrificed 24 hrs after last treatment Kant et al., PB + stress No evidence that PB exacerbated the 2001 Treated with 200 μl of saline, 25 mg/ml PB, or 20 mg/ml effects of stress. PB decreased blood Rats physostigmine administered by osmotic minipump at a rate AChE by half, but had no effect on of 1.5 or 1.2 mg/kg/d, with and without avoidance or escape cortical brain AChE and no effect on stress, or yoked stress blood corticosterone levels elevated by stress continued
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From page 232... ...
; activity or sleep architecture 2: 500 μg/kg/d PB by miniosmotic pump or sterile saline 21 months Executive Function Abdullah DEET + PB + permethrin + stress Evidence of possible beneficial effects et al., 2012 Control: water, and topical 70% ethanol of PB in water maze performance but Mice Treatment: 1.3 mg/kg PB in water; 0.13 mg/kg permethrin and deficits on a rotating rod 40 mg/kg DEET dermally; and 5 min of restraint stress; 28 days. 42-d observation period Hattiangady DEET + PB + peermethrin + stress Evidence that treatment impaired et al., 2014 Treatment group: 40 mg/kg/d DEET dermally + 0.13 mg/kg/d place recognition memory and caused Rats permethrin dermally + 1.3 mg/kg/d PB by gavage + 5 min/d novel object recognition memory restraint stress; for 4 weeks dysfunction Testing conducted 3 months after exposure Kant et al., PB + physostigmine + stress No evidence of effect of PB or 2001 Treated with 200 μl of saline, 25 mg/ml PB, or 20 mg/ml physostigmine and stress on working Rats physostigmine administered by osmotic minipump; with and memory without avoidance or escape stress, or yoked stress
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From page 233... ...
neuropathology associated with PB Testing at 18-d and 5-months postexposure and permethrin Anxiety and Mood-Related Behaviors Abdullah PB + permethrin Evidence of decreased anxiety-like et al., 2011 Single dose of 2 mg/kg PB and/or 200 mg/kg Per in DMSO, behavior in rats exposed to PB and Mice or DMSO only, ip for 10 d permethrin at 15 days postexposure, 115-d observation period but increased anxiety-like behavior at 30 days Abdullah DEET + PB + permethrin + stress Evidence of increased anxiety-like et al., 2012 Control: water, and topical 70% ethanol behavior Mice Treatment: 1.3 mg/kg PB in water; 0.13 mg/kg permethrin and 40 mg/kg DEET dermally; and 5 min of restraint stress; 28 days 42-d observation period Hattiangady DEET + PB + permethrin + stress No evidence of effect on anxiety-like et al., 2014 Treatment group: 40 mg/kg/d DEET dermally + 0.13 mg/kg/d behavior; evidence for depressionRats permethrin dermally + 1.3 mg/kg/d PB by gavage + 5 min/d type behavior restraint stress For 4 weeks; testing conducted 3 months after exposure continued
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From page 234... ...
Testing on days 15–199 Parihar DEET + PB + permethrin + stress Evidence of increased anxiety-like et al., 2013 1: control vehicle and handling daily behavior in rats exposed to PB, Rats 2: 40 mg/kg/d DEET and 0.13 mg/kg/d permethrin dermally, DEET, permethrin, and stress and 1.3 mg/kg/d PB by gavage; 3: DEET + PB + permethrin + stress (restraint stress 5 min/d) 4: control group 4 weeks Scremin PB + sarin No evidence of effects of PB or sarin et al., 2003 1: PB 80 mg/L in drinking water on avoidance behavior at 16 weeks Rats 2: sarin 62.5 μg/kg 3 times/week sc 3: PB + sarin 3 weeks; assessed at 2, 4, or 16 weeks after treatment Servatius PB + neostigmine + interleukin Evidence that PB potentiated auditory and Beck, PB: 0.1 or 1.0 mg/kg ip startle responses in the presence of 2005 Neostigmine: 0.016 mg/kg ip odors associated with stressors Rats Interleukin: 1 or 3μg/kg ip Testing on days 2 and 15 Motor Function Abdullah PB + permethrin Evidence of reduction in locomotor et al., 2011 Single dose of 2 mg/kg PB and/or 200 mg/kg permethrin in activity 30 days postexposure Mice DMSO, or DMSO only, ip for 10 d, 115-d observation period Abou- DEET + PB + permethrin Evidence that PB increased beam Donia 1: 1.3 mg/kg PB for days 30-45 walk latency, but not other measures et al., 2001 2: 40 mg/kg/d DEET dermally of motor function Rats 3: 0.13 mg/kg/d permethrin dermally 4: DEET + permethrin 5: DEET + PB 6: permethrin + PB 7: DEET + permethrin +PB 45 days
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From page 235... ...
but no effect on other restraint stress behaviors (open field test) For 4 weeks; testing conducted 3 months postexposure Hoy et al., DEET + PB + permethrin Evidence of reduced locomotor 2000a 1: 10 mg/kg PB by gavage speed in male rats exposed to PB + Rats 2: 50, 200, or 500 mg/kg DEET by gavage permethrin and DEET + permethrin 3: 15, 30, or 60 mg/kg permethrin ip 4: 100 mg/kg DEET + 5 mg/kg PB 5: 15 mg/kg permethrin + 5 mg/kg PB 6: 100 mg/kg DEET + 15 mg/kg permethrin Testing conducted 30 min after last treatment Hoy et al., DEET + PB + permethrin Evidence of reduced locomotor speed 2000b 1: 7.5 mg/kg PB by gavage with PB + DEET Rats 2: 200 mg/kg DEET by gavage 3: 60 mg/kg permethrin ip 4: 3.75 mg/kg PB + 30 mg/kg permethrin 5: 3.75 mg/kg PB + 100 mg/kg DEET 6: 2.5 mg/kg PB + 20 mg/kg permethrin + 67 mg/kg DEET 7: 100 mg/kg DEET + 30 mg/kg permethrin Daily for 7 days; testing conducted 24 hrs after last treatment Mach Stress + sarin Evidence of decreased locomotor et al., 2008 Shaker stress 90 min/d for 7 days activity Mice 6.4 μg/kg/d sarin on days 4-6 Tests conducted on days 5 and 7, and 21 days after exposure continued
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From page 236... ...
Mice 2: 1.2 mg/kg PB orally for weeks 5 and 6 3: PB + stress exercise daily for 10 weeks Sacrificed 24 hrs after last treatment Somani PB + stress Evidence of effects on skeletal muscle et al., 2000 1: sedentary control (changes in muscle respiration) Mice 2: stress exercise daily for 10 weeks 3: PB 1.2 mg/kg orally for weeks 5 and 6 4: PB + stress Sacrificed 24 hrs after last treatment Stevens PB + vaccines; No evidence of effects on muscle et al., 2006 1: 500 μg/kg/d PB days 15–44 function Marmosets 2: vaccines at 20% of human dose days 0-51 3: vaccines + PB Animals sacrificed 18 months after first vaccinations Immune System Abdullah PB + permethrin Evidence of long-term immune effects et al., 2011 Single dose of 2 mg/kg PB and/or 200 mg/kg permethrin in Mice DMSO, or DMSO only, ip for 10 d, 115-d observation period Griffiths PB + vaccines Little evidence of immune system et al., 2006 1: 10 vaccines at 20% of human dose scheduled the same as impairment Marmosets service members, and 500 μg/kg/d PB between days 15 and 44 2: vaccines and saline Hornby PB + vaccines Little evidence of immune system et al., 2006 1: 500 μg/kg/d PB on days 15 and 44 impairment Marmosets 2: vaccines at 20% of human dose between days 0-51 3: vaccines + PB
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From page 237... ...
noted in Rats days 1–14 treated animals during treatment 30 or 60 days; animals sacrificed 8 and 12 weeks postexposure but indices returned to normal after cessation of treatment Nutter PB + permethrin No evidence of effects on pain et al., 2013 Treatment: 2.6 mg/kg/d permethrin dermally; behavior or activity measures Rats 120 mg/kg chlorpyrifos sc every 14 days; 13 mg/kg/d PB by gavage on days 1–14 30 or 60 days; animals sacrificed 8 and 12 weeks postexposure NOTE: AChE = acetylcholinesterase; DEET = N,N-diethyl-meta-toluamide; DMSO = dimethyl sulfoxide; im = intramuscular; ip = intraperitoneal; JP-8 = jet propellant 8; PB = pyridostigmine bromide; sc = subcutaneous.
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