Hydrazine Toxicology

Etiology

Hydrazine and its derivatives have numerous industrial, military, and medical applications.[3][5] Due to its high heat of combustion and highly exothermic reaction in the presence of oxygen, German scientists first developed hydrazine as the principal component of rocket fuel during World War II.[6] Postwar, hydrazines became widely adopted as a powerful and reliable propellant with liquid properties like water.[7] From the 1970s to today, they can be found in thruster fuel for spacecraft and as a propellant for missiles.

Because hydrazines possess strong reducing properties, they are commonly used as a starting or intermediate reactant during the production of foaming or blowing agents for plastic production, agricultural products (plant-growth regulators, herbicides, fungicides, insecticides), and polymers.[8] It is also used as an oxygen scavenger to prevent corrosion in boiler water and water-heating systems. 

Naturally occurring hydrazines are rare and can be found as mycotoxins in the Gyromitra and Agaricus species of mushrooms. The Gyromitra mushrooms contain the toxin gyromitrin (n-methyl-N-formyl hydrazone) and undergo hydrolysis to the principal toxic compound monomethylhydrazine (MMH), which is responsible for seizures in severe poisoning. Small amounts of hydrazine have been reported in tobacco; however, there have been no documented toxicities from human exposures.[9]

Epidemiology

Epidemiological studies of the consequences of exposure to hydrazine can be divided into acute and chronic exposures.

Acute Exposure

Acute exposures have been documented since 1965 and were primarily associated with military occupational exposures to hydrazine.

Frierson et al described 2 cases where young men were exposed to vapors of hydrazine mixed with unsymmetrical dimethyl hydrazine (UDMH). Both were treated with pyridoxine with rapid improvement of their symptoms.[10] 

Reid et al described a young sailor who accidentally ingested liquid hydrazine while working in the ship’s engine room.[11] Sotaniemi et al 1971 described a fatal accidental exposure to a machine worker with chronic repeated exposures for six months.[12] 

Kirklin et al described a case of a man exposed to a hydrazine industrial explosion and went into a coma that responded to pyridoxine.[13] 

Harati and Niakin describe a case of a young man who accidentally ingested a mouthful of liquid hydrazine.[14] 

Dhennin et al described a chemical technician exposed to a UDMH industrial explosion.[15] Kao et al 2007 described a case of a fighter jet technician that experienced hepatic injury after exposure to a hydrazine fuel leak.[16] 

Binyamin et al 2018 described a case of an aircraft technician who developed elevated creatine phosphokinase (CPK) levels after exposure to hydrazine vapor. 

Dermal exposures are mostly linked to occupational injuries through the gold-plating industry, chicken feed additives, herbicides, or steam power plants.[17][18][19]

Chronic Exposure

Chronic exposures have been further studied in epidemiological studies for various reasons, but mainly to determine the carcinogenicity of hydrazine. Unfortunately, many epidemiological studies on hydrazine were confounded by concomitant exposure to other chemicals, making direct correlations difficult.[20][21][22][23] 

Wald et al studied 427 men exposed to varying levels of hydrazine, among other chemicals, in a hydrazine manufacturing plant.[24] He concluded that the overall number of deaths in the hydrazine-exposed group was lower than expected, and mortality rates from lung and all types of cancer were similar to expected values.[24] Roe et al had previously examined 423 of these same individuals in 1978. They also determined that occupational exposures to hydrazine were not significantly associated with a greatly increased cancer incidence.[25] 

Contassot et al described 130 men exposed to hydrazine at various levels over six months. They showed a statistically significant higher incidence of cancer in the high-exposure group (>1 ppm), which was reduced when skin cancers were excluded.[26] Morris et al followed up with 95% of the workers initially evaluated by Wald et al (1984) and Roe et al (1978) 10 years after their initial evaluation. They determined that there was also no all-cause mortality increase from occupational exposure to hydrazine.[27] 

Ritz et al 2006 performed an epidemiological study of 6107 aerospace workers exposed to varying amounts of hydrazine for at least 2 years and showed an increased risk of lung cancer mortality, increased incidence of colon and rectal cancers, and a possible dose-response association with pancreatic cancer. This study also had patients that developed leukemias, lymphomas, and kidney cancers; however, the numbers of exposed individuals were too small to show significance.[22] Common criticisms of this study are that there were many other chemicals the workers may have been exposed to.[20] 

Zhao et al 2005 examined the same group and founder a higher incidence of lung cancers and melanoma with a possible higher incidence of esophageal cancer, stomach cancer, non-Hodgkin lymphoma, and leukemias; however, they concluded that it was most likely attributed to mineral oil exposure. In addition, they found a higher incidence of kidney cancers which they attributed to trichloroethylene exposure.[28] 

Krishnadasan et al 2007 also evaluated the same cohort of aerospace workers and found a higher incidence of prostate cancer; however, they attributed it to trichloroethylene exposure.[23]

The World Health Organization (WHO) in 1987 described populations with potentially high occupational exposures as workers at facilities producing hydrazine itself and/or its salts and derivatives, propulsion testing facilities, rocket launching sites, and locations where aircraft using hydrazine as an emergency fuel are assembled or refueled.[26] 

The Agency for Toxic Substances and Disease Registry (ATSDR) in 1997 stated that human exposures to hydrazine and 1,1-dimethylhydrazine occur mainly in the workplace or the vicinity of aerospace or industrial facilities or hazardous waste sites.

Pathophysiology

Hydrazine's pathophysiology depends on the route of exposure and the system it affects.

Inhalation exposure causes direct pulmonary injury due to the caustic nature of hydrazine and may also lead to an increased incidence of lung cancer.[22] In animal studies, hydrazine inhalational injuries have been shown to cause pulmonary edema and localized bronchial mucosal damage.[29] Importantly, there have been reports of inhalation injury causing systemic effects such as neurotoxicity and hepatotoxicity.[30]

The pathophysiology of dermatological injury of hydrazine toxicity is mostly derived from animal studies and a few human case reports. Hydrazine can cause contact dermatitis or caustic injury.[31][17][18] This is due to hydrazine's strong alkali properties and can cause liquefactive necrosis similar to other alkali-caustic burns.[29][32] There are 2 cases of people developing systemic symptoms from dermal exposure, including neurotoxicity and hepatotoxicity; however, these were exposures to industrial explosions, so there was likely a combination of dermal and inhalational exposures.[13][15] 

Ingested oral exposure to hydrazines has the potential to cause systemic symptoms, mostly secondary to taking medications that have hydrazine as a metabolite. Asymptomatic patients taking isoniazid (INH) at therapeutic doses (300 mg/day) for two weeks showed elevated levels of hydrazine in their blood and plasma.[26][33] There have also been acute oral exposures to hydrazine through ingestion of hydrazine-containing fuel, which produced systemic symptoms including neurotoxicity, specifically seizures, loss of consciousness, altered mental status, agitation, nystagmus, and peripheral neuropathy.[11][14]

Hydrazine's neurotoxicity occurs from disrupting the equilibrium between gamma-aminobutyric acid (GABA) and glutamate (the human body's primary inhibitory and excitatory neurotransmitters, respectively). Through various mechanisms, hydrazine-containing compounds inhibit pyridoxine (vitamin B6) and its downstream metabolite, pyridoxal 5' phosphate (P5P), the essential cofactor for glutamic acid decarboxylase and GABA synthesis, resulting in reduced GABA levels and subsequent clinical effects of seizures. Hydrazine metabolites are found in INH and gyromitrin mycotoxin (from the gyromitra mushroom species).

Isoniazid toxicity stems from several mechanisms of its downstream metabolites. INH hydrazine, 1,1-dimethylhydrazine, and hydrazones directly inhibit the enzyme pyridoxine phosphokinase by complexing its essential cofactor, pyridoxine.[26] Thus, pyridoxine cannot convert to P5P, the catalysis for the enzyme glutamic acid decarboxylase, in effect inhibiting the conversion of glutamate to GABA. INH hydrazines also directly bind with pyridoxal phosphate to form a hydrazone complex that is renally excreted. Through these mechanisms, hydrazine and its derivatives cause a functional pyridoxine deficiency resulting in the depletion of GABA and an excess of glutamate, leading to refractory seizures.[26]

Additionally, in animal studies, hydrazine has been shown to affect the urea cycle by increasing the activity of argininosuccinase and inhibiting ornithine-ketoacid transaminase, leading to hyperammonemia which can contribute to its neurotoxicity.[34][29] 

Secondary to these mechanisms, hydrazine-induced neurotoxicity can present as any of the following: twitching, hyperreflexia, clonic movements, restlessness, violent behavior, altered mental status, ataxia, paresthesias, lethargy, seizures, and coma.[32] 

Similarly, hydrazine's hepatotoxicity is mainly known from isoniazid toxicity. Hydrazines metabolized from isoniazid by direct hydrolyzation or metabolism by N-acetyltransferase type 2 to acetylhydrazine are oxidized by CYPE1 to reactive metabolites that induce oxidative stress and alter lipid metabolism, causing hepatotoxicity.[35] This leads to focal hepatic necrosis, cell degeneration, and fatty liver.[32]

Gyromitrin compounds from the Gyromitra species of mushrooms are metabolized to monomethylhydrazine and inhibit the conversion of glutamate to GABA by similar mechanisms.[35]

Hydrazine's hemotoxicity is known through in vitro studies with human red blood cells. This showed the development of hemolytic anemia, methemoglobinemia, and Heinz body formation.[29] It is hypothesized that hydrazine and its derivatives cause denaturing of hemoglobin, which destroys red blood cells.[29]

Toxicokinetics

The toxicokinetics of hydrazines are not fully characterized and are largely unknown, as there are no human studies evaluating exposures to hydrazine through inhalation, cutaneous, or oral routes. Animal studies on oral, inhalational, and dermal exposures suggest that hydrazines are rapidly absorbed into the blood and readily distributed to tissues without preferential accumulation at any specific site.[3] 

Tissue levels of hydrazine and 1,1-dimethylhydrazine generally reach maximal values within 1 hour and are undetectable after 24 hours. In vivo and in vitro studies indicate that hydrazines are metabolized through several enzymatic and nonenzymatic pathways.[36] Free radicals and carbonium ion intermediates formed during the hydrazine metabolism may be associated with the adverse health effects produced during exposures.[3] Limited animal studies suggest that hydrazine is excreted primarily in the urine and air exhalation.[37] 

A. Absorption

There are no studies regarding human absorption after oral, inhalation, or dermal hydrazine exposure.

Oral Exposure

Of note, isoniazid (INH), an antituberculosis drug, is metabolized into hydrazine and its derivatives. Patients taking INH were found to have elevated levels of hydrazine in their blood plasma.[33] A single animal study (Preece et al 1992) examining oral absorption of hydrazine in rats suggests that at least 19 to 46% of administered oral dose (2.9 - 81 mg/kg) is absorbed, based on excreted urine levels of hydrazine and its metabolites over 24 hours. However, the actual amount of absorption by the gastrointestinal tract is most likely higher, as 24 hours may have been too short of a period. 

Inhalational Exposure

A single animal study (Llewellyn et al 1986) investigated the absorption of hydrazine in lungs where rats were exposed to 10 to 500 ppm of hydrazine for 1 hour.[3] Based on the excreted urine levels of hydrazine and its metabolites at 48 hours, the absorption was suggested to be 8.4 to 29.5%.[3] However, the actual absorption in the lungs may be higher, as a large portion of the administered dose may be retained in the body tissue or excreted by fecal or pulmonary routes. 

Dermal Exposure

Toxicokinetic studies on hydrazine dermal exposures are limited to 2 animal studies on dogs examining monomethylhydrazine (MMH) and 1,1-dimethylhydrazine (UDMH).[38][39] Graded doses of MMH and UDMH were administered to a 300-cm area of the dog's chest. MMH and UDMH were detectable in the blood within 30 seconds of initial application indicating rapid absorption.[39][38] Peak levels of both MMH and UDMH were found 1 hour after initial exposure.[38][39] 

Of note, MMH was found to cause a reddish discoloration of the skin within 5 minutes of application, which progressed to purple and light grey, and was associated with swelling.[39] As opposed to UDMH, which caused a slight initial reddening of the skin that quickly dissipated and no visible local skin damage.[38][39]

B. Distribution

There are no studies regarding the distribution of hydrazine in humans after oral, inhalation, or dermal exposures. Furthermore, no current studies are available regarding the distribution of hydrazine in animals after inhalation or dermal exposures.

Oral Exposure

A single animal study examines the distribution and metabolism of ingested hydrazine in rats. After a single dose of 2.9-81 mg/kg hydrazine, peak plasma and liver hydrazine levels occurred at 30 minutes.[36] The authors found that liver concentrations of hydrazine did not increase proportionally with higher doses, suggesting saturation.[36]

C. Metabolism

Hydrazine is metabolized through several enzymatic and nonenzymatic pathways. However, studies show that the pathways involved and metabolites formed during the metabolism of hydrazines are not dependent on the route of exposure. 

Metabolism of INH occurs by either direct hydrolysis of INH or by hydrolysis of its metabolite, acetylhydrazine.[33] Slow acetylators were found to have higher plasma concentrations of hydrazine than fast acetylators after chronic dosing but not after a single dose. Animal studies by Llewellyn et al suggest that hydrazine undergoes acetylation to acetyl hydrazine and diacetyl hydrazine, then excreted in the urine.[40] In addition, animal studies show that hydrazine is rapidly metabolized by cytochrome P-450 but also forms free radicals, which may be an important mechanism of hydrazine toxicity.[41][40]

D. Excretion

No studies have been reported on human excretion after oral, inhalation, or dermal exposure to hydrazines.

Oral Exposure

A single animal study by Preece et al found that at least 19 to 46% of the hydrazine administered was found in the urine of rats.[3] Additionally, hydrazine has also been detected in the urine of patients receiving INH.[33] 

Inhalation Exposure

Unchanged hydrazine, acetyl hydrazine, and diacetyl hydrazine were recovered in the urine of rats inhaling hydrazine after 48 hours from administration.[3] (Llewellyn et al 1986)  

Dermal Exposure

The animal studies performed by Smith and Clark et al on dermal exposure of hydrazine and 1,1-dimethylhydrazine reported detection in the urine at about 3 and 5 hours, respectively.[38][39]

History and Physical

To recognize hydrazine toxicity, it is essential to be familiar with occupational and environmental risk factors known to be commonly exposed to hydrazine and its derivatives. The occupations most commonly exposed to hydrazine are facilities producing or storing rocket fuels, such as propulsion testing facilities, rocket launching sites, aerospace facilities, hazardous waste sites, and military installations.[26] 

A medical history of concurrent tuberculosis may include isoniazid (INH), which metabolizes into hydrazine. Mushroom foragers may be exposed to the false morel, Gyromitra, which contains the mycotoxin gyromitrin that metabolizes into monomethylhydrazine (MMH).

Hydrazine toxicity can occur through inhalation and oral and dermal exposures. Exposures may be categorized as acute (<14 days), intermediate (15 to 364 days), and chronic (>365 days).[26] Chronic exposure to hydrazine can lead to similar symptoms in the acute setting but also includes additional carcinogenic risk.[22][25][24] Hydrazine has been associated with various cancers, including lung, lymphopoietic, liver, colorectal, and skin cancers.[26]

Dermal exposure has been mostly linked to occupational injuries through the gold-plating industry, chicken feed additives, herbicides, or steam power plants. [17][18][19] Skin irritation and caustic liquefactive necrosis may occur within 1 hour. Hydrazine sulfate has been reported to cause contact dermatitis, suggesting it is a sensitizing agent.[29][42][43][18][17] Chronic dermal exposure by a factory worker in a steam power station has also been linked to the development of multiple basal cell carcinomas in a case report.[19] 

Acute inhalational hydrazine exposure has been associated with pulmonary edema and pleural effusions.[29] Exposed individuals to hydrazine and 1,1-dimethylhydrazine vapors exhibited symptoms of dyspnea, sore throat, burning sensation of the face and nasal mucosa, and chest tightness.[29] This may progress to delayed pulmonary edema with pleural effusions and death. Hydrazine has also been associated with an ammonia-like odor.[32] Respiratory arrest in toxic inhalational exposures may be more attributed to hydrazine's neurotoxic and convulsive effects. 

Neurotoxicity from acute exposures to hydrazine, monomethylhydrazine (MMH), and 1,1-dimethylhydrazine (UDMH) may range from central nervous system (CNS) depression to seizures.[11] Hydrazine has been found to induce seizures at high doses but CNS depression at low doses. The CNS depression described in human exposures has been reported to last up to 3 days. In contrast, the alkyl derivatives of hydrazine, MMH, and UDMH induce primarily neuroexcitatory effects and tonic-clonic seizures, with MMH being more potent than UDMH. Other neuroexcitatory effects include twitching, hyperreflexia, and clonus.[29]

Hydrazine and its derivatives may cause hemolytic anemia and methemoglobinemia. MMH has been described as having the most severe hemotoxic effects.[29] 

Hydrazine exposure has been shown to cause an elevation in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 5 hours and lasting up to 1 week, with resolution after 4 to 5 weeks.[4] Focal hepatic necrosis and fatty liver degeneration have been described in chronic exposures.[44][45] In humans, there has been a case of an inhalation injury of a machinist exposed to hydrazine hydrate once a week for 6 months, which proved fatal; the patient presented with hepatorenal failure and died secondary to complications from pneumonia.[12] An aircraft technician also had an acute inhalation exposure (<10 minutes) that caused transient hepatotoxicity.[16] 

Chronic exposure to hydrazine can lead to similar symptoms in the acute setting but also includes additional carcinogenic risk.[22][25][24] A study of chronic inhalation exposure to hydrazine in aerospace workers also showed an increased risk of lung cancer mortality.[22] Prior studies with intermediate-to-chronic inhalation injury in a hydrazine-manufacturing plant did not show a statistically significant increase in lung cancer mortality due to the small sample sizes.[24][21] Hydrazine has been associated with various cancers, including lung, lymphopoietic, liver, colorectal, and skin cancers.[26] 

Evaluation

Oral ingestions of hydrazine may cause caustic injury and liquefactive necrosis due to its alkali properties.[14][11] If the patient exhibits any 2 of these 3 symptoms—drooling, stridor, or vomiting—the patient should be evaluated by endoscopy to assess the extent of the esophageal and gastric injury.[46] Airway protection may be needed if there is extensive edema and caustic injury to the oropharynx and the inability to tolerate secretions. 

The patient's mental status may range from CNS depression to CNS excitation, and seizures refractory to standard treatment with benzodiazepines, barbituates, and propofol may occur. Fingerstick blood glucose level should be obtained as hydrazine is associated with hypoglycemia.[47] 

The pulmonary exam and chest radiography may show signs of pleural effusion to pulmonary edema. Blood gas oximetry may show methemoglobinemia. A complete blood count may show hemolytic anemia, and a blood smear may show Heinz bodies.[29] The basic metabolic panel may show rhabdomyolysis, and liver function testing may range from transient transaminitis to fulminant hepatic failure.[45] Prolonged hepatic injury has been seen to last up to 1 week and resolves in patients surviving the initial exposure after 4 or 5 weeks.[16]

Chronic exposures to hydrazine in the occupational setting should also be evaluated for certain cancers, as hydrazine is carcinogenic. Cancers of the colon, skin, nasal epithelium, lung, and liver have all been described but may be confounded due to exposures to other toxins in these studies.[48][22] Hydrazine exposure has also been associated with basal cell carcinoma.[19]

Treatment / Management

Treatment of hydrazine exposures involves decontamination, supportive care, and administration of pyridoxine for neurological sequelae, especially seizures. Patients should be removed from the site of exposure to a minimum of 75 feet away. Full decontamination, including removing all clothing and copious irrigation of exposed skin and/or eyes with water for a minimum of 15 minutes.[29] (A1)

First responders and emergency medical services at the site of hydrazine exposure should wear Level A personal protective equipment against vapors, skin, and eyes. Caustic burns to the skin should be treated similarly to soft tissue injuries and may require special management at a burn center.[13](B3)

Inhalational exposures to hydrazine are managed by supportive care, including supplemental oxygen and close airway observation. Delayed pulmonary edema may occur, and observation for 24 to 48 hours may be required. 

Oral ingestions of hydrazines may cause caustic injury to the upper airway and gastrointestinal tract; thus, activated charcoal is not recommended in this situation. Since hydrazines are rapidly absorbed when ingested, activated charcoal administered after arrival to the emergency department may be futile. Early activated charcoal decontamination is recommended for acute isoniazid and gyromitra ingestions.[35]

Hydrazine neurotoxicity ranging from coma and seizures has been treated successfully with pyridoxine.[13][49] In INH-induced seizures, adults are given 1 g of IV pyridoxine for each gram of INH ingested, with a maximum dose of 5 g. If the amount ingested is unknown, 5 g of IV pyridoxine may be given empirically. Pediatric dosing is 70 mg/kg of IV pyridoxine with a maximum of 5 g.[35][50][35] (B3)

For the actively seizing patient, pyridoxine may be given 0.5 g/min until the cessation of seizure or the maximum dose is reached. After seizure control, the remainder of the dose may be infused over 4 to 6 hours to maintain pyridoxine concentrations while INH is eliminated.[50] Repeat dosing is indicated if the patient has CNS depression or non-convulsive status epileptics. For hydrazine, MMH, and UDMH poisonings, using the same dosage as INH poisoning is reasonable. The dosing of pyridoxine for hydrazine toxicity has varied from 200 mg intravenous with 400 mg intramuscular to 10 grams intravenously.[13][51] Benzodiazepines and barbituates should also be used to stop seizure activity rapidly.(B3)

Methemoglobinemia should be treated with standard treatment with methylene blue.

Differential Diagnosis

Pulmonary irritants

• Phosgene
• Chlorine
• Ammonia
• Ethylene oxide
• Chloramine

Hepatotoxicity

• Amantia mushrooms

Alkali Caustic Burns

• Sodium hydroxide
• Potassium hydroxide
• Sodium hypochlorite
• Ammonia

Seizures

• Status epilepticus of unknown origin
• Severe hyponatremia
• Substance-induced
• Sedative-hypnotic withdrawal
• Hypoxic syncope
• Anti-NMDA receptor encephalitis

CNS depression/coma

• Sedative-hypnotic intoxication
• Opioid intoxication
• Hepatic encephalopathy 
• Hypoglycemia
• Cerebrovascular accident

Prognosis

The prognosis for hydrazine toxicity depends on the dose and route of exposure. There have only been 2 reported cases of death from direct hydrazine toxicity.[45][12] Most exposure cases show rapid improvement in neurologic symptoms and eventual improvement of hepatic injury.[29] There have been cases of persistent neuropathy and hepatic injury.[15] This excludes the prognosis of isoniazid or other medications with hydrazine metabolites.

Complications

Pulmonary toxicity: Mucosal irritation, pleural effusion, delayed pulmonary edema

Neurotoxicity: CNS depression, coma, clonus, refractory seizures

Cutaneous toxicity: Dermatitis and liquefactive necrosis

Hepatoxicity: Fulminant hepatic failure[29]

Nephrotoxicity: Rhabdomyolysis[45]

Hemotoxicity: Methemoglobinemia and hemolytic anemia

Possible long-term sequelae are secondary to the potential carcinogenic nature of hydrazine exposure. These include lung, lymphopoietic, skin, colorectal, and liver cancers.[22][48][19]