Arsenic intoxication in the rhesus monkey

An arsenic compound was fed to adolescent and infant rhesus monkeys. Severe symptoms of subacute arsenic poisoning were observed in the adolescent monkeys at high dosage levels. Chronic arsenic intoxication could not be induced in young monkeys. The deaths that occurred were sudden, with few symptoms to characterise the poisoning and the diagnosis of arsenic poisoning could be based only on the high tissue arsenic levels. Large amounts of arsenic were administered to some monkeys over a 12-month period without inducing clinical or pathological effect, and without accumulation of arsenic in the tissues. There is no evidence to indicate that delayed arsenic poisoning is a reality.     

Different clinical features of amitraz poisoning in children

OBJECTIVE: To evaluate clinical experience of amitraz poisoning in children. METHODS: In this study, the clinical and laboratory features of amitraz poisoning in 14 children are presented and compared with previous studies. RESULTS: This study revealed that clinical manifestations of poisoning by oral and dermal routes appeared within 30-150 min, and that central nervous system (CNS) depression, which is the most important sign, improved within 6-24 hours and other signs within 24-72 hours. Unlike the findings in other studies, three severe cases in our study had reversible mydriasis and one of them required resuscitation because of cardiopulmonary arrest occurring as a result of serious respiratory depression. In addition, hepatic function test levels had increased in these three cases, and aspiration pneumonitis existed because of emesis in two of them. CONCLUSION: There is little information in the literature about dermal poisoning. The signs and symptoms of dermal poisoning were relatively mild compared with oral poisoning, and there were no topical signs. The classical signs of alpha2-adrenergic stimulation such as marked sinusal bradycardia and mydriasis as reported in many poisoning cases of animals have not been reported before our three severe cases among children.     

Thiamin (vitamin B1) effects on lead intoxication and deposition of lead in tissues: Therapeutic potential

The purpose of this study was to evaluate the effects of thiamin on lead (Pb) poisoning in cattle. Fifteen Holstein male calves were divided into three groups: Group I served as controls, Group II calves were dosed orally with 5 mg Pb acetate/day/kg of body wt, and Group III calves were dosed similarly with Pb and with 100 mg/day/calf of thiamin hydrochloride, subcutaneously. Calves were treated daily for 20 days. None of the control or Pb plus thiamin-treated calves showed clinical signs of poisoning and no deaths occurred. However, four of five Pb-treated calves showed signs of Pb poisoning and two died during the study. Tissues from both groups receiving Pb contained significantly higher (p < 0.01) concentrations of Pb than tissues from control calves. However, tissues from calves receiving Pb plus thiamin contained 2 to 10 times less Pb than tissues from calves receiving only Pb. The Pb concentrations in liver, kidney, and blood from thiamin-treated calves remained below confirmatory levels associated with Pb poisoning; while Pb concentrations in the same tissues from calves dosed only with Pb were within the range considered diagnostic of Pb poisoning. On the other hand, δ-aminolevulinic acid dehydratase activity in erythrocytes was decreased 70% from pretreatment levels in both groups receiving Pb. Thus, thiamin appeared to have no protective effect on the ability of Pb to inhibit this enzyme. But in the tissues analyzed, thiamin interacted with Pb in some way to prevent tissue accumulation, thus preventing clinical signs and death. These results suggest that therapeutic doses of thiamin may be of value in the prevention and treatment of Pb poisoning in cattle, and in other animals or humans exposed to high environmental levels of Pb.     

Food poisoning due to methamidophos-contaminated vegetables

BACKGROUND: Organophosphate poisoning is well known for its characteristic symptoms and signs, but food poisoning caused by pesticide-contaminated food is seldom reported. CASE REPORT: We report three incidents of food poisoning that resulted from exposure to the organophosphate insecticide methamidophos in vegetables. These outbreaks caused a cholinergic syndrome in 4 patients. The cholinergic overactivity led as to suspect organophosphate food poisoning. All patients recovered well following appropriate therapy. The clinical diagnosis of organophosphate poisoning was confirmed by reduced levels of erythrocytes and plasma cholinesterase and the presence of methamidophos in the vegetable leftovers. The implicated vegetables and levels of methamidophos were: Ipomoea batatas 255 ppm, Gynura bicolor 110 ppm, and red cabbage 26.3 ppm. Since methamidophos is normally applied to vegetables during planting, improper selection and/or overuse of pesticide or improper harvest times may explain the occurrence of these high residue levels of methamidophos.     

Toxicology of selenium: a review

The concentration of selenium in soil, water, or minerals is site specific. World or regional averages are of little practical value. In one report from the front range area of Colorado, average selenium concentrations in bodies of standing water were from 0.3 to 15.8 micrograms Se per liter of water. In some aquatic organisms there is a strong correlation between the Se content of the water ant that of the body tissues; in others no such correlation obtains. Some organisms bioaccumulate Se by factors as high as 1300 to 3800. In most fish the amount of Se in the flesh seems to depend on the amount in the food taken in; there are exceptions, however. Aquatic organisms from seleniferous regions bioconcentrate selenium so as to reach total body levels of 60 micrograms Se per gram or up to 100 micrograms Se per gram of liver. There seems to be no evidence for "biomagnification" of selenium by aquatic organisms. Selenium exerts a strong protective action against the poisoning effects of many heavy metals (lead, cadmium, arsenic, and mercury, for example) and of some organic toxicants (paraquat, for example) in birds, mammals, and man. Data on man are sketchy. Selenium is released into the environment from the burning of coal. No identifiable hazard to man or to plants and animals useful to man can, at this time, be attributed to this source. Selenium is poisonous to man and animal in large amounts. It is a necessary micronutrient for many animals in small amounts; it may also be a needed micronutrient for man, but the data are sparse. The usual American diet contains adequate selenium for human health. Occupational selenium poisoning is mostly accidental and rare.     

Chronic Arsenic Poisoning Following Ayurvedic Medication

Background

Ayurveda, Indian traditional system of medicine, is practiced commonly in South East Asia and in many parts of the world. Many ayurvedic drugs contain heavy metals and may lead to metal toxicity. Of these, chronic lead poisoning is the most common. Chronic arsenic poisoning following the use of ayurvedic medication, though reported, is rare.

Case Reports

We describe three patients who presented with features of chronic arsenic poisoning following prolonged ayurvedic medication use. The diagnosis of chronic arsenic poisoning was confirmed by high arsenic levels in the blood, urine, hair, and nails in all the three patients and in ayurvedic drug in two patients. The ayurvedic medication was discontinued and treatment with d-penicillamine started. At 6 months after treatment, blood arsenic levels returned to normal with clinical recovery in all of them.

Conclusion

Arsenic poisoning following ayurvedic medication is much less common than lead poisoning, though mineral ayurvedic medicines may lead to it. We used d-penicillamine as chelator and all of them recovered. Whether withdrawal of medication alone or d-penicillamine also played a role in recovery is unclear and needs to be assessed.     

Amitraz poisoning in children

Amitraz is an acaricide and insecticide indicated for the treatment of generalized demodicosis in dogs and for the control of ticks and mites in cattle and sheep. There is little information available in the human literature about the toxicology of the product. In this study, the clinical and laboratory features of amitraz poisoning in 11 children are presented. The age range of the patients was 2-1/2 to 6 years. Accidental ingestion of an improperly stored liquid pesticide was determined in all patients. Unconsciousness (100%), drowsiness (100%), and myosis (84%) were the most common abnormal signs; 45%, 27%, and 18% of patients had bradycardia, respiratory insufficiency, and hypotension, respectively. All of the patients were treated with atropine, gastric lavage, activated charcoal, and supportive care. Although the patients had a prompt response to therapy, three patients required multiple doses of atropine during a 24-h period. This study revealed that clinical poisoning by oral route emerged within 30-90 min and that central nervous system (CNS) depression, which is the most important sign, resolved within 8-1/2-14 h. All cases were discharged.     

Selenium toxicity in sheep grazing reclaimed phosphate mining sites

Phosphate mining operations in southeastern Idaho have exposed selenium (Se) that was originally sequestered in the subsurface. Sheep grazing in these areas have died as a result of high Se concentrations in forage and water. This study was designed to monitor the health status of sheep grazing in a natural environment with known elevated levels of Se. A total of 72 Columbia x Suffolk sheep were divided into 3 treatment groups that included control (Con), low selenium (LoSe) and high selenium (HiSe). The baseline phase of the study was conducted in an area with normal background Se levels in forage and water, and was grazed for 3 w by all sheep groups. The sheep then were moved onto reclaimed mine areas to begin the 4-w exposure phase. This was followed by a 2-w depuration phase where sheep again received normal Se levels in forage and water. The Con group was held on areas with normal Se levels of forage (< 0.32 ppm Se dw) and water (< 1.70 ppb Se). The LoSe group was held in an area of elevated forage Se (< 13.0 ppm Se dw) and normal Se levels in their water (< 1.70 ppb Se) during the exposure phase. The HiSe group was held on mining areas with elevated Se forage (< 49.0 ppm Se dw) and drinking water (340 to 415 ppb Se). Whole blood and serum levels in the HiSe group peaked at 1.32 and 0.99 ppm mean Se, respectively. The LoSe group had mean whole blood and serum Se levels of 0.75 ppm on day 42 and 0.32 ppm on day 35 respectively. The Con group maintained low Se levels in both whole blood and serum that ranged from 0.05 to 0.14 ppm and 0.06 to 0.13 ppm respectively. The Se exposure in the HiSe group was estimated 0.26 mg Se/kg body weight/d. One sheep in the HiSe group died and was diagnosed with Se toxicosis based on clinical signs, histopathology and tissue Se levels. Se in liver (3.90 ppm), kidney (1.90 ppm) and skeletal muscle (0.70 ppm) were indicative of high to toxic Se exposure. Two other sheep necropsied after the exposure phase also had Se concentrations in liver, kidney and skeletal muscle representative of high or toxic Se exposure (5.50, 3.50 and 1.10 ppm Se), but these sheep had no gross or histopathological signs of illness. More research is needed on the toxicology of Se in sheep grazing natural settings.     

Acetylcholinesterase prophylaxis against organophosphate poisoning. Quantitative correlation between protection and blood-enzyme level in mice

Fetal bovine serum acetylcholinesterase (FBS-AChE, EC 3.1.1.7) was titrated, both in vitro and in vivo, with a highly toxic anti-ChE organophosphate, 7-(methylethoxyphosphinyloxy)-1-methyl-quinolinium iodie (MEPQ). Approximately 1:1 stoichiometry was obtained for the sequestration of MEPQ by FBS-AChE in mice. A quantitative, linear correlation was demonstrated between blood-AChE levels and the protection afforded by exogenously administered AChE in mice when challenged with anti-ChE MEPQ. The results presented in this report demonstrate that such prophylactic measures are indeed sufficient to protect animals against poisoning by as high as an 8 x LD50 dose of organophosphate without the administration of any supportive drug. Despite the relatively large toxic dose, most of the mice that survived the challenge did not show any classical clinical signs of severe anti-ChE poisoning. MEPQ may be considered a suitable model compound for studying the quantitative aspects of the scavenger prophylactic approach described here.     

Carbon monoxide poisoning: a review epidemiology, pathophysiology, clinical findings, and treatment options including hyperbaric oxygen therapy

Carbon monoxide (CO) poisoning is the leading cause of poisoning deaths (accidental and intentional) in the United States. While confirmation of CO poisoning is easily obtained via assessment of carboxyhemoglobin (COHgb) levels, evaluation of the severity of intoxication is both difficult and inconsistent. Acute intoxication most commonly results in neurologic dysfunction and/or myocardial injury. Delayed neurologic sequelae are observed in approximately 10% of patients. New information from clinical observations and animal research has prompted a re-evaluation of the clinical assessment of the severity of CO intoxication and its resultant pathophysiology. Patients at the extremes of age (the very young and the elderly), those with pre-existing cardiovascular and/or pulmonary disease, as well as pregnancy are at increased risk. Once the diagnosis of CO poisoning has been established, treatment with 100% O2 is indicated. Based on the body of clinical, basic and scientific information currently available, patients who manifest signs of serious intoxication (i.e., unconsciousness or altered neurologic function, cardiac or hemodynamic instability) should be considered candidates for hyperbaric oxygen therapy (HBO) in addition to other appropriate supportive and intensive care. Any patient who has suffered an interval of unconsciousness, regardless of the patient's clinical exam on arrival, warrants HBO therapy. Treatment plans based on any specific COHgb level are not well founded.     

Symptoms and implications of selenium toxicity in fish: the Belews Lake case example

Belews Lake, North Carolina was contaminated by selenium in wastewater from a coal-fired power plant during the mid-1970s, and toxic impacts to the resident fish community (20 species) were studied for over two decades. Symptoms of chronic selenium poisoning in Belews Lake fish included, (1) telangiectasia (swelling) of gill lamellae; (2) elevated lymphocytes; (3) reduced hematocrit and hemoglobin (anemia); (4) corneal cataracts; (5) exopthalmus (popeye); (6) pathological alterations in liver, kidney, heart, and ovary (e.g. vacuolization of parenchymal hepatocytes, intracapillary proliferative glomerulonephritis, severe pericarditis and myocarditis, necrotic and ruptured mature egg follicles); (7) reproductive failure (reduced production of viable eggs due to ovarian pathology, and post-hatch mortality due to bioaccumulation of selenium in eggs); and (8) teratogenic deformities of the spine, head, mouth, and fins. Important principles of selenium cycling and toxicity were documented in the Belews Lake studies. Selenium poisoning in fish can be 'invisible', because, the primary point of impact is the egg, which receives selenium from the female's diet (whether consumed in organic or inorganic forms), and stores it until hatching, whereupon it is metabolized by the developing fish. If concentrations in eggs are great enough (about 10 microg/g or greater) biochemical functions may be disrupted, and teratogenic deformity and death may occur. Adult fish can survive and appear healthy despite the fact that extensive reproductive failure is occurring--19 of the 20 species in Belews Lake were eliminated as a result of this insidious mode of toxicity. Bioaccumulation in aquatic food chains causes otherwise harmless concentrations of selenium to reach toxic levels, and the selenium in contaminated sediments can be cycled into food chains for decades. The lessons learned from Belews Lake provide information useful for protecting aquatic ecosystems as new selenium issues emerge.     

A review of the epidemiologic literature on the role of environmental arsenic exposure and cardiovascular diseases

Cardiovascular disease is the leading cause of mortality worldwide. Arsenic is a ubiquitous metalloid in the crust of the earth. Chronic arsenic poisoning is becoming an emerging epidemic in Asia. Epidemiological studies have shown that chronic arsenic poisoning through ingestion of arsenic-contaminated water is associated with various cardiovascular diseases in dose-response relationships. These cardiovascular disorders include carotid atherosclerosis detected by ultrasonography, impaired microcirculation, prolonged QT interval and increased QT dispersion in electrocardiography, and clinical outcomes such as hypertension, blackfoot disease (a unique peripheral vascular disease endemic in southwestern Taiwan), coronary artery disease and cerebral infarction. Chronic arsenic poisoning is an independent risk factor for cardiovascular disease. The adverse cardiovascular effects of long-term arsenic exposure may be persistent and/or irreversible. Arsenic-induced cardiovascular diseases in human population may result from the interaction among genetic, environment and nutritional factors. The major adverse cardiovascular effect of chronic arsenic poisoning has been established qualitatively and quantitatively in the high arsenic exposure areas, but the low-dose effect of arsenic on cardiovascular diseases remains to be explored. Cardiovascular death is the major cause of mortality worldwide, and a small increased risk may imply a large quantity of excess mortality.     

Lead poisoning in cattle and buffalo near primary lead-zinc smelter in India

Varying degrees of lead (Pb) poisoning was recorded in cows and buffaloes near a primary lead-zinc smelter in India. Affected animals had history of clinical signs characterized by head pressing, violent movement, blindness and salivation. These animals revealed considerably high lead levels in blood (1.43 +/- 0.07 ppm) and milk (0.75 +/- 0.19 ppm). Animals from the same place without the history of clinical signs suggestive of Pb poisoning recorded lower blood Pb levels than the affected animals; however, their blood Pb was higher than that reported for cattle in rural and urban areas of India. Affected animals also carried high levels of cadmium (Cd) in blood (0.11 +/- 0.01 ppm) and milk (0.05 +/- 0.01 ppm). These values were considerably higher than those for rural cattle in India. The findings indicated varying degrees of exposure of animals to Pb and Cd in the vicinity of the smelter.     

Plasma concentrations of cardiac glycosides in digitalis intoxication

Summary Using the method of Löwenstein and Corrill modified by the authors the relationship between measured plasma digitalis concentrations and symptoms and signs of toxicity was studied in cases of suicide and accidental poisoning. Direct relationship could not be detected between plasma levels and clinical symptoms. Severe toxic symptoms occured only in the presence of high levels. Nevertheless, patients with high plasma levels may be symptom-free. Parallelism was observed between a fall in the digitalis level and the disappearance of clinical symptoms.Supported by the National Committee of Technical Development.     

Photokeratitis and other phototoxic effects on the cornea and conjunctiva

Except when sleeping, the cornea and interpalpebral conjunctiva are exposed to the ambient environment, both natural and man-made. Levels of solar ultraviolet irradiance reaching the eye may exceed the damage threshold under a number of circumstances. The consequences of overexposure may be acute after a latent period, sequelae to an acute exposure, or long-term chronic effects. Previously derived action spectra for photokeratitis and photoconjunctivitis due to incoherent ultraviolet are presented. These reveal interspecies similarities for the levels of radiant energy reaching each tissue. The initial in vivo (clinical) signs of photokeratitis are due to lost or damaged epithelial cells with other signs produced by this primary response. The conjunctival signs include injection and chemosis. Chronic exposure to solar ultraviolet is a factor in climatic droplet keratopathy and pterygium. Phototoxic compounds or their by-products potentially can reach the cornea from the air, via the tears or aqueous humor, or from the limbal capillaries. However, the human cornea appears to be much less susceptible to the influence of phototoxic agents than the skin.     

Comparative toxicities of the naturally occurring nitrile 1-cyano-3,4-epithiobutane and the synthetic nitrile n-valeronitrile in rats: differences in target organs, metabolism and toxic mechanisms

Toxic but sublethal oral doses of 125 mg/kg (1.1 mmol/kg) of the cruciferous nitrile, 1-cyano-3,4-epithiobutane (CEB), or 175 mg/kg (2.1 mmol/kg) of its synthetic saturated analogue, n-valeronitrile (VN), were given by gavage to male CDF (F-344/CrlBr) rats once daily for 1, 2 or 3 days, in order to compare target tissues and to observe structure-activity relationships between the nitriles. CEB-induced changes included degeneration and necrosis of the pars recta of the renal proximal tubules, ulceration and necrosis in the forestomach, a mild increase (4.5-fold) in daily urinary thiocyanate (SCN-) excretion (only in rats treated for 3 days) and 1.5- to 2.4-fold increases in hepatic and pancreatic non-protein thiol (RSH) concentrations (in all CEB-treated groups). In VN-treated rats, there were no consistent histological changes but 95- to 170-fold increases in daily urinary SCN- excretion, delayed clinical signs of cyanide toxicity and minimal effects on tissue RSH concentrations. These results indicate different toxic mechanisms for VN and CEB. The nephrotoxic effects of CEB were very similar to those of 1-cyano-2-hydroxy-3,4-epithiobutane, suggesting a role for the epithio group in the nephrotoxicity of these nitriles. The relatively low SCN- excretion in CEB-treated rats also suggested that cyanide played only a minimal role in CEB toxicity, while the high SCN- excretion, clinical signs of cyanide poisoning and lack of histological changes imply a greater role for metabolically-derived cyanide in VN toxicity. The enhancement of tissue RSH by CEB treatment with indications of enhanced tissue glutathione concentrations suggested the involvement of glutathione in the detoxication of CEB and/or its reactive metabolites.     

Comparison of selected skin decontaminant products and regimens against VX in domestic swine

An anesthetized domestic swine model was used to compare the efficacy and cross-contamination potential of selected skin decontaminant products and regimens against the chemical warfare agent, VX. Animals topically exposed to 2x, 3x or 5x LD(50) VX showed typical signs of organophosphate nerve agent poisoning, including miosis, salivation, mastication, dysrhythmias, and respiratory distress prior to death. Animals were exposed to 5x LD(50) VX and then decontaminated 45 min later with the reactive skin decontamination lotion (RSDL), Fuller's earth (FE), 0.5% hypochlorite, or soapy water. Survival was 100% when the reactive skin decontamination lotion or FE was utilized, although 50% of Fuller's earth-decontaminated animals exhibited serious signs of VX poisoning. Decontamination of VX-treated animals with 0.5% hypochlorite was less effective but also increased survival. Soapy water was ineffective in preventing lethality. Blood cholinesterase levels were not predictive of clinical outcome in decontaminated animals. The potential of "decontaminated" VX in open wounds to cause poisoning was assessed by vigorously mixing 5x LD(50) VX with the test decontaminants for 5 min and then placing the mixture onto a full-thickness skin wound. Soapy water was ineffective in preventing lethality. Although treatment with dry Fuller's earth prevented death and all signs of organophosphate poisoning, a significant proportion of treated animals decontaminated with Fuller's earth in aqueous suspension exhibited serious signs of organophosphate poisoning, suggesting that live agent may be desorbed from Fuller's earth when it is exposed to a liquid environment. Animals treated with reactive skin decontamination lotion or 0.5% hypochlorite-VX mixtures showed no signs of organophosphate poisoning during the 6- h test period.     

Synthetic seleno-organic compound with glutathione peroxidase-like activity in the chick

The glutathione peroxidase activity catalyzed by the seleno-organic anti-inflammatory drug Ebselen (registered under the trademark of the Natterman Corp. Cologne, FRG) [PZ51, 2-phenyl-1,2-benzisoselenazol-3(2H)on], as measured by NADPH oxidation, was inhibited in vitro by the selenium-dependent glutathione peroxidase (SeGSHpx) inhibitors aurothioglucose and D-(-)penicillamine HCl. Vitamin E- and selenium-deficient chicks were given 0, 80 or 320 ppm PZ51 in diets devoid of vitamin E and supplemented with low levels of sodium selenite (0.04 ppm selenium added to the basal diet containing ca. 0.015 ppm selenium) when a small number of chicks (ca. 13%) had exudative diathesis (ED). By 24 hr, the high PZ51 dose (320 ppm) delayed the onset of ED compared to untreated controls. Similarly, vitamin E-deficient chicks fed diets containing 0, 80, 160, 320, 640 or 1280 ppm PZ51 and supplemented with 0.04 ppm selenium showed ED in inverse proportion to log PZ51 dose. Plasma and liver post-mitochondrial supernatant samples from these chicks also exhibited log-linear relationships between dietary PZ51 level and selenium content or SeGSHpx-like activity. The amount of SeGSHpx-like activity for chicks given PZ51 above that determined for untreated chicks was extractable into ethanol, indicating that those PZ51-associated increases were not due to protein-bound selenium or SeGSHpx. This suggests that selenium from PZ51 was not available to support synthesis of SeGSHpx. Dietary PZ51 (1280 ppm) or selenium (0.1 ppm) alone or in combination decreased the acute lethalities of nitrofurantoin or paraquat in vitamin E-adequate chicks. The results indicate that SeGSHpx-like activity in selenium-deficient chicks is increased by oral administration of PZ51, which appears to mimic the true enzyme by affording protection against clinical signs of selenium deficiency (i.e. ED) and pro-oxidant drug lethality.     

A novel approach to assessing percutaneous VX poisoning in the conscious guinea-pig

Nerve agents like VX (S-2-diisopropylaminoethyl-O-ethyl-methylphosphonothiolate) are potent irreversible acetylcholinesterase (AChE) inhibitors. Following percutaneous nerve agent exposure there is a slower rate of absorption, later onset and longer duration of signs of poisoning. Relatively little is known about the physiological effects of percutaneously applied nerve agent in unanaesthetised laboratory animals. Heart rate (ECG), brain electrical activity (EEG), body temperature, locomotor activity and clinical signs were monitored following percutaneous application of VX to conscious guinea-pigs.A fall in heart rate (bradycardia) preceded incapacitation following the highest VX dose, and occurred in the absence of incapacitation at the lower doses. Following the highest dose of VX (0.592 mg kg(-1)) three out of four animals died within 24 h. The lower two doses of VX (0.296 and 0.148 mg kg(-1)), produced extended periods of bradycardia in the absence of observable signs of poisoning. Bradycardia preceded, or occurred in the absence of, a temperature decrease; seizure-like EEG changes were not observed at any of the VX doses tested. Acetylcholinesterase activity was significantly inhibited in the blood and most brain areas at 48 h. There were significant dose-related decreases in body weight at 24 and 48 h following VX. This preliminary study suggests that decreased heart rate may be an early sign of the toxic effects of VX, whereas temperature and observable clinical signs are not good early indicators of percutaneous VX poisoning in this animal model. Future studies will use this model to assess the benefit of administering medical countermeasures in response to a defined decrease in heart rate.