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Dimethylaminopropionitrile

• General
  • The propionitriles, a family of compounds containing the basic structures: X - CH₂ - CH₂ - CN, have a wide variety of toxic effects that depend on the identity of the X moiety (14). Two compounds, b,b-iminodipropionitrile (5) and dimethylaminopropionitrile (DMAPN)(14), have neurotoxic properties. The neurotoxic effects of DMAPN were first identified during an epidemic of urinary dysfunction and polyneuropathy that occurred when workers in polyurethane foam manufacturing plants were exposed to the compound in 1976 and 1977 (1,7-10,14).
  • DMAPN (Table) is a water-soluble liquid with an amine-type odor (14). It is colorless, but becomes yellow on exposure to air. DMAPN is synthesized from acrylonitrile and dimethylamine. Before its toxicity was identified, DMAPN was a component in a catalyst used for the manufacture of polyurethane foam.
  • Physical properties of DMAPN

    Molecular weight	98.15
    Boiling point	174.5 °C
    Freezing point	-44.3 °C
    Vapor pressure	1 mm Hg
    Specific gravity	0.8715
    Heat of vaporization at 1 atm	394 BTU/kg

• General Toxicology
  • DMAPN may be absorbed through the skin, respiratory system or gastrointestinal tract (14). Its metabolism varies among species. Rats excrete about 44% of administered DMAPN unchanged in the urine, while in mice the figure is only 6% (12,13). b-aminopropionitrile, cyanoacetic acid, and thiocyanate are urinary metabolites. Cyanide is also a metabolic byproduct (2). Metabolism of DMAPN probably occurs via a cytochrome P450-dependent mixed-function oxidase system. DMAPN, unlike other propionitriles, does not inhibit lysyl oxidase (19). DMAPN may inhibit the action of several glycolytic enzymes (3) but does not inhibit monoamine oxidase activity (18).
  • Animal studies
    
    • Acute (single dose). The LD50 in rats is 2.6 ml/kg given orally and 0.5 to 1.0 ml/kg after intraperitoneal administration (14). Via skin penetration, the LD50 in rabbits is 1.4 ml/kg. After a single large dose, DMAPN produces irritability and then generalized, stimulus-sensitive, clonic movements. Death occurs after 5 to 10 minutes during tonic status epilepticus. If status epilepticus is prevented by sedation, then the LD50 is doubled.
      
    • Short Term. Direct contact with DMAPN results in erythema and induration of the skin, and surface injury to the cornea (14,15). Doses of 175 to 700 mg/kg are followed by weight loss, reduced water consumption, urinary retention, and bladder wall injury (6,13). The bladder wall pathology includes edema, petechial hemorrhage, and inflammation. Bladder function normalizes two days after short term exposure to DMAPN is eliminated. DMAPN also produces systemic autonomic dysfunction (4). Heart rate and blood pressure cease to respond to stress for 2 hours after treatment of rats with DMAPN. This effect may be due to central actions of DMAPN since heart rate responded normally to systemically administered atropine and propranalol.
      
    • Prolonged Exposure Prolonged exposure of rats to DMAPN produces swelling of nerve terminals (14). Animals that received 0.5% DMAPN in drinking water for 2 to 9 months developed abnormally enlarged motor nerve terminals, containing disordered neurofilaments. Systemic effects of chronic DMAPN exposure include brown pigmentation of the skin, tail and teeth similar to that in aged rats and a 50% shortened life span. DMAPN does not produce the changes of osteolathyrism that result from exposure to other propionitriles (11).
  • Toxic mechanisms: The most common syndrome associated with DMAPN intoxication is urological and results from a flaccid urinary bladder. DMAPN and its metabolites may have a direct toxic effect on the bladder wall. An underlying neuropathy probably also plays a role in the bladder dysfunction, and produces sensory loss, involving the sacral dermatomes and distal extremities, and some distal weakness. In humans and animals exposed to DMAPN, distal axons are enlarged with accumulations of neurofilaments similar to those found in proximal axons after intoxication by b,b-iminodipropionitrile. Humans also show evidence of a loss of small and large axons. The toxic syndrome is often reversible with many of its manifestations reduced or eliminated in the years since the usage of DMAPN was eliminated.
• Human epidemiology
  • Several months after DMAPN was introduced into the manufacturing process of polyurethane foams many exposed workers developed a characteristic syndrome (1,7-10,14).
  • DMAPN was the major component of a catalyst (15) that was introduced into several workplaces several months before the onset of symptoms of urinary and sexual dysfunction in many exposed people. A second compound dimethylaminoethylether (DMAEE) was also used in the catalyst (16). However, DMAEE was used without associated neurologic symptoms, in the absence of DMAPN, in similar industrial processes and concentrations, before and after the epidemic.
    
  • During the months of exposure to DMAPN its concentration in the manufacturing process was progressively increased (0.5 to 2.0%). The prevalence of urologic symptoms increased during this period, being highest in early 1978, just before the utilization of DMAPN was terminated. The latency between first exposure to DMAPN and the onset of symptoms varied inversely with the concentrations or amounts used. When DMAPN was first introduced and used in the lowest amounts (in mid-1977), workers were exposed for several months before noting urinary symptoms. Later, when use of DMAPN was at its peak (early 1978), several workers became symptomatic within one to four days of employment. No workers with new symptoms were identified after the use of DMAPN was discontinued. Most affected workers reported that their symptoms began to abate shortly (days to weeks) after DMAPN was removed from the workplace.
    
  • Airborne spread of DMAPN probably played a major role in the epidemic (14). In one factory the highest incidence of symptoms occurred among those workers who worked in a room where hot freshly produced foam was processed. Within that room there was no difference in the incidence of the clinical syndrome between workers who had skin contact with the foam of high DMAPN content, and those who handled foam with little or no DMAPN. Further, some workers with the most severe symptoms had no skin contact with the foam. The highest levels of organic vapors in factory air samples were in the areas with a high incidence of affected workers. No data are available regarding the air levels of DMAPN during its industrial use. High concentrations (11 mg/M3) were found in the air of a warehouse where foam, produced 2 months previously, was stored. DMAPN was detectable, at much lower concentrations (0.11 mg/M) in a manufacturing plant one week after all use was discontinued (17). In a laboratory test simulating manufacturing conditions, DMAPN was detected as a reaction off-gas, and also extractable from the cured foam. Although it seems likely that DMAPN intoxication resulted from inhalation, absorption through the skin from contaminated clothes cannot be ruled out.
• Clinical
  • Initial symptoms were usually urinary hesitancy and abdominal discomfort. Many workers then noted a decreased urinary stream, reduced frequency of urination and urinary incontinence. In severely affected patients a Credé or Valsalva maneuver was necessary to initiate urination. Other systems became involved over time. Sexual function was impaired by difficulty initiating or maintaining an erection. Paresthesias and numbness appeared, first in the feet, and then in the hands and more proximally in the legs. Other symptoms related to DMAPN included insomnia and feelings of tiredness and weakness.
  • Neurologic examinations showed a characteristic pattern of sensory loss in the more severely affected workers (14). Pricking pain, temperature, and light touch sensations were diminished in a symmetric distribution confined to the lower sacral dermatomes, and the distal legs and hands. Vibratory sensation was diminished only in the feet. Muscle strength was decreased distally in the arms and legs. Tendon reflexes were generally preserved, but ankle jerks were often sluggish. Cranial nerve and cerebellar testing was intact. Autonomic functions, such as pupillary reflexes and response of pulse and blood pressure to changes in position, were normal.
    
  • The prognosis for recovery was generally good (14). Three months after exposure to DMAPN was eliminated, only 13% of workers in one plant still had symptoms. All patients with residual symptoms had urinary dysfunction. Half also had sexual dysfunction. After 10 years at least one worker had persistent urinary and sexual complaints (Pestronk, unpublished observations). People with persistence of symptoms tended to be older and have more seniority at work. It is not clear whether persistence of symptoms was due to age or length and severity of exposure.
    
• Laboratory
  • Routine hematological and blood chemistry tests on affected workers showed no consistent abnormalities.
  • Cerebrospinal fluid from one severely affected worker was normal.
  • Imaging: Intravenous pyelograms, performed several weeks after DMAPN exposure was eliminated, a time when symptoms were abating, revealed significant post-void residual urine in 28% of symptomatic workers. Cystometrograms in some patients showed flaccid neurogenic bladders with residual urine volumes up to one liter.
• Nerve conduction studies
  • Mild abnormalities in severely affected patients.
  • Sacral nerve latencies were prolonged in three patients.
  • Motor nerve conduction studies were normal except for mild slowing and reduced amplitudes of compound muscle action potentials in several severely affected patients.
  • Sensory potentials had small amplitudes with slightly prolonged terminal latency. All measurements returned to normal 5 months after exposure to DMAPN was eliminated.
• Pathology on the effects of DMAPN in humans
  • Available from one severely affected 38 year-old male, who was otherwise in good health (14).
  • The gastrocnemius muscle showed mild denervation, including small angular muscle fibers and fiber type grouping. An increased number of muscle fibers with internal nuclei, a non-specific finding, was also noted.
  • In the sural nerve, findings often associated with axonal degeneration included Wallerian degeneration and collagen pockets surrounded by Schwann cell cytoplasm. There was a mild reduction in the number of myelinated (5,400/mm2) and unmyelinated (21,000/mm2) axons. There was no evidence of demyelination or axonal regeneration. On ultrastructural examination, occasional axons showed swellings with central cores of axoplasm containing disordered neurofilaments surrounded by an accumulation of densely packed particulate organelles, including mitochondria, membrane bound vesicles of smooth endoplasmic reticulum, and dense bodies. These swellings resembled reactive swellings in interrupted axons, and the terminal swellings in DMAPN treated rats and in axons regenerating after acrylamide intoxication. Myelin sheaths were not seen around these swellings suggesting that they had either displaced the myelin sheath, or arisen in unmyelinated fibers.

DMAPN: Muscle & Nerve Pathology

Acute denervation: Small angular muscle fibers

Gomori trichrome stain

Chronic denervation with reinnervation: Fiber type grouping

Axon loss: Large & Small

Ultraterminal sprout with Swelling

Axon loss with collagen pockets

Axon swelling: Contains central cores of axoplasm with disordered neurofilaments surrounded by an accumulation of densely packed particulate organelles, including mitochondria, membrane bound vesicles of smooth endoplasmic reticulum, and dense bodies.