Specific Types of Neurotoxins 17
17.1 Metals and Metallic Compounds 339 17.1.1 Aluminum (Al) 339
17.1.2 Arsenic (As) 341 17.1.2.1 Inorganic Arsenicals 341 17.1.2.2 Organic Arsenicals 341 17.1.3 Bismuth (Bi) 341 17.1.4 Cadmium (Cd) 342 17.1.5 Gold (Au) 342 17.1.6 Lead (Pb) 342
17.1.6.1 Inorganic Lead Compounds 342 17.1.6.2 Organic Lead Compounds 343 17.1.7 Lithium (Li) 343
17.1.8 Manganese (Mn) 344 17.1.9 Mercury (Hg) 344 17.1.9.1 Elementary Mercury
and Inorganic Mercury Compounds 344 17.1.9.2 Organic Mercury Compounds 344 17.1.10 Platinum (Pt) 345
17.1.11 Thallium (Tl) 346
17.1.12 Tin (Sn) and Tin Compounds 346 17.1.12.1 Triethyltin 346
17.1.12.2 Trimethyltin 346
17.2 Non-Metallic Inorganic Neurotoxins 347 17.2.1 Phosphorus (P)
and Phosphorous Compounds 347 17.2.2 Sulfur (S) 347
17.2.2.1 Carbon Disulfide 347 17.2.3 Tellurium (Te) 347 17.3 Gases 347
17.3.1 Carbon Monoxide (CO) 347 17.3.1.1 Acute Intoxication 349 17.3.1.2 Intermittent Exposure 350 17.3.1.3 Chronic Intoxication 351
17.3.2 Cyanides and Cyanide Compounds 351 17.3.3 Hydrogen Sulfide (H2S) 352
17.3.4 Nitrous Gases and Nitrites 352 17.3.5 Oxygen (O2) 352
17.4 Industrial and Environmental Toxins 353 17.4.1 Acrylamide 353
17.4.2 Aliphatic Hydrocarbons 353 17.4.3 Halogenated Hydrocarbons 353 17.4.3.1 Methyl Chloride 353
17.4.3.2 Trichloroethylene 353
17.4.4 Chlorinated Cyclic Hydrocarbons 354 17.4.4.1 Hexachlorophene (HCP) 354 17.4.4.2 Lindane 354
17.4.5 Methyl Alcohol (Methanol) 354 17.4.6 Organophosphorus Compounds 355 17.4.7 Toxic Oil 356
17.5 Nerve Agents 356
17.6 Drugs and Pharmaceutical Products 357 17.6.1 Sedatives, Hypnotics and Analgesics 357 17.6.2 Antiprotozoal Agents 358
17.6.2.1 Chloroquine 358 17.6.2.2 Clioquinol 358
17.6.3 Cytostatics and Antituberculous Agents 359 17.6.3.1 Methotrexate 359
17.6.3.2 Vincristine, Vinblastine 359 17.6.3.3 Isoniacid 360
17.7 Biological Toxins 360 17.7.1 Plants 360
17.7.2 Animals 362 17.7.3 Microorganisms 362 17.7.3.1 Botulinum Toxin 362 17.7.3.2 Tetanospasmin 362 17.7.3.3 Diphtheria Toxin 363 17.7.3.4 Anthrax 363
Bibliography 363
References 363
17.1
Metals and Metallic Compounds
17.1.1
Aluminum (Al)
Source. Aluminum (Al) is ubiquitous in its oxi- dized form, present in air, food, and water. Its main industrial use is in the metal working industries.
Aluminum hydroxide is frequently used as an ant- acid without producing clinical symptoms. However,
clinical features attributed to aluminum intoxication have been described after chronic dialysis (see also p. 613 f) with dialysis fluid containing aluminum as well as following oral administration of phosphate- binding agents containing aluminum (McLaughlin et al. 1962; Alfrey et al. 1976; Elliott et al. 1978; Mar- tyn et al. 1989). A relationship has been hypothesized between exposure to aluminum in food and water and Alzheimer’s disease (Wisniewski et al. 1979).
The normal concentration of aluminum in the brain is ≤10 µg/l, which increases with age.
Pathogenesis. If the blood contains elevated levels of aluminum in association with a compromised blood−brain barrier (McDermott et al. 1978), the brain will also have elevated levels of aluminum (Crapper McLachlan et al. 1983). Plasma levels above 100 µg/l are potentially toxic; levels exceeding 500 µg/l are indicative of acute aluminum poisoning.
At the cellular level, aluminum is known to disrupt the slow transport of neurofilament proteins (NFP), which leads to an accumulation of NFP at the proxi- mal end of the axon (Bizzi et al. 1984; Bin and Gar- finkel 1994) and a proliferation of microfilaments in the perikaryon (Klatzo et al. 1965; Weinstein 1974).
The similarity of clinical symptoms in associa- tion with elevated levels of aluminum demonstrated in the brains of victims of dementia of Alzheimer type (Crapper McLachlan et al. 1983) has given rise to a theory that Alzheimer’s disease may be caused by an accumulation of aluminum in the brain (Martyn et al. 1989). This hypothesis has fallen out of favor.
Clinical Features. Aluminum poisoning is character- ized by progressive dementia with speech impair- ment, myoclonus, focal and/or generalized epileptic seizures, focal neurological symptoms, and loss of consciousness. An aluminum-induced degeneration of motor neurons must be distinguished from a di- alysis encephalopathy. The disease can end in death.
The differential diagnosis must include Alzheimer’s disease. Desferrioxamine is the specific chelating an- tidote.
Morphology. The morphological changes caused by aluminum intoxication are non-characteristic in H&E preparations (McLaughlin et al. 1962). Gangli- on cells are shrunken, but usually there is no clear de- cline in their numbers. Some differences can be dem- onstrated immunohistochemically: in aluminum poisoning, neurons do not react to microtubule-as- sociated protein 2 (MAP-2), β-tubulin or ubiquitin, while in Alzheimer's disease they do (Strong et al.
1991). Aluminum poisoning is also associated with proliferation of microglia and astrocytes as well as a spongiform disintegration of the neuropil in the sec- ond and third cortical layer.
Fig. 17.1a−d. Dialysis-associated encephalopathy. a Hypoglos- sal neuron with pathognomonic deeply black, fine-granular cytoplasmic inclusions in dialysis-associated encephalopathy in comparison with the brownish neuronal lipofuscin in neurons of the inferior olivary nucleus (b − silver staining; ×2000). c Laser mi- croprobe mass analysis with aluminum peak at m/z 27, confirm- ing the high aluminum content of silver-stained inclusions (peaks at m/z 104 and 106 result from silver staining). d Electron micros- copy with partly electron-dense, partly bizarre electron-lucent material of (aluminum-containing) inclusions (×40,000). The fig- ure was kindly provided by Professor Dr. E. Reusche, Lübeck
Using new variants of silver staining, Reusche described in 1991 a new effective method for the demonstration of Alzheimer changes by light- and electron microscopy (Reusche et al. 1992). The same methods allowed for the first time the demonstra- tion in ten long-term hemodialyzed patients of char- acteristic and pathognomonic aluminum-contain- ing inclusions in the cytoplasm of choroid plexus epithelia, glia, and neurons of the CNS (Reusche and Seydel 1993). Argyrophilic proteinaceous deposits of this “dialysis-associated encephalopathy” (DAE) were shown by light- and electron microscopy. They obviously result from long-standing and futile cyto- plasmic lysosomal degradation of aluminum. Simi- lar deposits could be demonstrated in peripheral or- gans as well (Reusche et al. 1996). Laser microprobe mass analysis confirmed high cellular levels of alu- minum (Fig. 17.1). The morphology is completely different from neuronal changes in Alzheimer‘s dis- ease (Reusche and Seydel 1993; Reusche 1997). The evaluation of 50 long-term hemodialyzed patients − with ingestion of aluminum-containing drugs, up to 2.5 kg “pure” aluminum − presented no increase in the incidence of Alzheimer‘s disease (Reusche et al.
2001).
17.1.2 Arsenic (As)
17.1.2.1
Inorganic Arsenicals
Source. Inorganic arsenicals are used in the manu- facture of glass (smelting industry), in the preserva- tion of wool, and as a pesticide. Intentional acute or chronic arsenic (As) poisoning often occurs in crim- inal cases (Geldmacher von Mallinckrodt 1975).
Clinical Features. Acute arsenic poisoning is char- acterized by gastrointestinal symptoms including nausea, vomiting, and diarrhea, accompanied by confusion, delirium, coma, circulatory collapse, and death. Arsenite is a strong inhibitor of the pyruvate dehydrogenase system (glycolysis) forming a stable complex with the thiol groups of the enzyme com- plex (Devlin 1997). Victims who survive develop symptoms of peripheral neuropathy with sensory defects (Le Quesne and McLeod 1977; Heaven et al.
1994). Victims of chronic arsenic poisoning exhibit symptoms of peripheral neuropathy with loss of mo- tor function, but gastrointestinal disturbances are sometimes lacking. At the same time, hyperkeratosis of the hands and feet is observed in most cases (plus so-called Mees’ lines on the fingernails). Progression of an arsenic-induced polyneuropathy can be halted by administration of water-soluble 2,3-dimercapto- propanesulfonate (DMPS).
The toxicity of arsenic is based on its capacity to uncouple mitochondrial oxidative phosphorylation.
Arsenic binds in the place of inorganic phosphate, forming arsenic analogs of high-energy phosphates, which are unstable and break down to regenerate in- organic arsenic (Vahter 1999). The pentavalent form, arsenate, is much less toxic than the trivalent form, known as arsenite.
Morphologically, the effects of arsenic poison- ing are characterized by axonal degeneration of the peripheral, large fibers (Hörtnagel and Hanin 1992), sometimes combined with segmental demyelination (Crapper McLachlan and De Boni 1980), occasion- ally presenting as a Guillain−Barré-like syndrome (Donofrio et al. 1987). No changes are apparent in the CNS.
17.1.2.2
Organic Arsenicals
Source. Organic arsenicals are used mainly in the treatment of syphilis and trypanosomiasis. Clinical- ly, poisoning by organic arsenicals produces symp- toms of encephalopathy and exfoliative dermatitis as well as peripheral neuropathy. Treatment with Brit- ish anti lewisite (BAL, =2,3-dimercaptopropanol; di- mercaprol) has proven effective. It is assumed that the clinical symptoms are caused less by the direct toxic effect than by an allergic reaction (Adams et al.
1986).
Morphologically, arsenic encephalopathy is char- acterized by pericapillary bleeding, mainly in the midbrain (hemorrhagic encephalopathy) (Hurst 1959). Sometimes the disease manifests as an acute hemorrhagic leukoencephalitis (Adams et al. 1986), which suggests an allergic pathogenesis. Finally, a Guillain−Barré-like syndrome has been attributed to treatment with melarsoprol (Gherardi et al. 1990).
17.1.3 Bismuth (Bi)
Source. Bismuth (Bi) is used to treat constipation, gastric ulcers, and indigestion following removal of the large bowel. It is also used in dental procedures and as a radiographic contrast medium.
Clinical Features. The predominant clinical features of bismuth intoxication are functional disturbances, osseous changes as well as gastrointestinal distur- bances with diarrhea and bleeding. Insoluble inor- ganic compounds are particularly neurotoxic. Brain involvement is usually characterized by mental and/
or neurological symptoms, such as anxiety, depres- sion, ataxia, tremor, dementia, memory loss, confu- sion, delirium, psychosis, and irritability. The dis- ease process may lead to coma and end in death.
Pathogenesis. The pathogenesis of bismuth poison- ing is not yet clear and sensitivity to its effects varies from individual to individual.
Morphology. Morphological changes in the nervous system typical of bismuth poisoning include a pre- dominant loss of Purkinje cells in the cerebellum and of neurons in the neocortex (laminar necrosis) and hippocampus (Liessens et al. 1978). There is also a loss of neurons and proliferation of microglia in the basal ganglia, especially the putamen (Jungreis and Schaumburg 1993). Elevated bismuth levels have been observed in the frontal cortex, basal ganglia, and cerebellar cortex (Drenckhahn and Lüllmann- Rauch 1979).
17.1.4.
Cadmium (Cd)
Source. Exposure to cadmium (Cd) is always in com- bination with zinc and − occasionally − with lead.
Today it is almost impossible to avoid exposure to cadmium since this metal is ubiquitous in the envi- ronment. Cadmium is highly toxic and has an ex- tremely long biological half-life (15−20 years), so that it accumulates within tissue. It can cause sterility and is teratogenic, carcinogenic, and may also play a role in aging (Bin and Garfinkel 1994). Cadmium does not penetrate the blood−brain barrier and thus it may be assumed that its neurotoxic effects derive secondarily from its interference with zinc metabo- lism (Jin et al. 1998).
Pathogenesis. Cadmium is thought to bind competi- tively at Ca2+-rich binding sites on the cell surface as well as to intracellular receptors (Gabbiani et al.
1967). This hypothesis is supported by the obser- vation that cadmium inhibits endothelin-binding activity (Wada et al. 1991). In nerve cells, cadmium blocks NMDA-gated channels (Reynolds and Mill- er 1988) as well as N-, L- and T-type Ca2+ channels on neurons (Gadbut et al. 1991) and glia (MacVicar 1984, 1987).
Morphology. (For review see Schröder 2000.) Cad- mium affects mainly the lung (acute intoxication:
pneumonia; chronic intoxication: emphysema). In Japan, a series of cadmium poisonings occurring be- tween 1939 and 1945 produced a clinical syndrome called “itai-itai disease,” which caused bone pain among other symptoms, apparently due to involve- ment of the spinal ganglia (Murata 1971). Cadmium- related encephalopathy has been described in a male adolescent in East India (Provias et al. 1994) with brain swelling, herniation, and perivascular edema indicating a disturbance of the blood−brain barrier.
17.1.5 Gold (Au)
Gold (Au) solutions, aurothioglucose and sodium aurothiomalate, are used to treat rheumatoid arthri- tis today (chrysotherapy). The side-effects are der- matitis, renal damage with hematuria and impaired hematopoiesis. Neurological deficits are uncom- mon and include encephalopathy, cranial neuropa- thy, myokymia and peripheral neuropathy, possibly Guillain−Barré syndrome. Psychiatric symptoms have been described in a few instances (Fam et al.
1984; Pery and Jacobsen 1984). It is unclear as to whether the neurotoxic mechanism involves a hy- persensitivity reaction, a direct toxic effect, or both.
Morphological changes in the NS have not been de- scribed.
17.1.6 Lead (Pb)
17.1.6.1
Inorganic Lead Compounds
Source. Lead accumulates in the body and reaches especially high levels in the blood, bone marrow, and soft tissues as well as in skin, muscle, and bone.
Sources of exposure are manufacturing processes re- leasing lead or lead compounds in the form of dust, smoke or steam. At one time, lead paint, lead pottery glazes, and lead pipes in water systems were major sources of lead poisoning. Today, automobile emis- sions and exposure to tetraethyl lead are the princi- pal sources of lead poisoning.
Pathogenesis. In the United States, there are 12,000−16,000 new cases and 200 deaths from lead poisoning annually. Children are particularly at risk.
Pathological lead values have been found in 10−25%
of children in slum areas (Ludwig 1977a). Lead is taken into the body through the lungs and gastroin- testinal tract. In the form of dust or vapor, metallic lead oxidizes to lead oxide. Lead concentrations in the brain are a function of blood lead levels.
The effects of lead at the cellular level are largely unknown. Absorbed lead is not metabolized and is excreted via the kidneys. An adult member of the general population will excrete lead at the rate of
<634 ng/24 h. Lead affects the blood−brain barrier and appears to have a direct toxic effect on neuronal membranes, causing impairment of the potassium pump. It also affects neurotransmitters, especially the GABA-ergic system, the latter being implicated in lead encephalopathy (Schwedenberg 1959). It is assumed (Niklowitz 1977) that lead elevates tissue Cu levels, which inhibits cell membrane adenosine
triphosphatase, thus disturbing the potassium pump and simultaneously − possibly by way of non-specif- ic membrane injury − allowing lead to reach the cell interior. This explains the ability of lead to breach the blood−brain barrier and the high risk of lead en- cephalopathy, especially in children. Recent experi- mental studies in rats have suggested that chronic prenatal and post-natal exposure to lead induces regional neurotoxicity in striatum, thalamus, and hippocampus because of increased intraneuronal (intracytoplasmic) lipid peroxidation and oxidative stress (Villeda-Hernandez et al. 2001). Moreira et al.
(2001) caution, however, that oxidative stress may not be the main neurotoxic mechanism associated with experimental low-level lead exposure in the brain.
Clinical Features (Encephalopathia Saturnina). In adults, acute lead poisoning is characterized by colic, vomiting, and diarrhea; coma and convulsions are rare. Chronic lead poisoning in adults causes toxic anemia (microcytic anemia) with constipation, gas- trocolic symptoms, and blisters and/or renal tubu- lar destruction or chronic interstitial nephropathy with headache, nausea, and impaired renal function.
Terminal chronic lead poisoning is associated with a severe organic psychosyndrome. In addition to the CNS, the PNS also suffers damage apparent in the neuromuscular syndrome, also known as lead palsy, especially prominent in the muscles of the upper limbs. In children, the clinical picture is dominated by severe brain edema with symptoms of intracra- nial pressure indicative of encephalopathy: seizures, hemiplegia, and other neurological sequelae.
The toxic mechanism has not yet been complete- ly elucidated. In victims of lead poisoning who die of acute encephalopathy, a lethal mechanism other than cerebral swelling or herniation must be impli- cated as the cause of death.
Morphology. The morphological changes caused by lead poisoning of the brain are multifarious, not uni- versal and non-specific (Krieglstein and Kuglisch 1992). Macroscopically, acute lead poisoning is rec- ognizable by signs of brain edema and hyperemia;
occasionally there is petechial bleeding in the gray and white matter; atrophy of the cerebrum and cer- ebellum has also been described (Valpey et al. 1978).
Microscopically, cases of acute lead poisoning ex- hibit signs of a disrupted blood−brain barrier with perivascular, albumin-rich exudates; in rare in- stances, edema of the white matter can cause diffuse demyelination and − in association with thinly dis- persed lymphocytic infiltrates − a multiple sclerosis- like (Schilder’s disease) picture.
Chronic lead poisoning is characterized by the proliferation of capillaries in the cerebral and cere- bellar cortices as well as a proliferation of astrocytes and microglia in the molecular layer of the cerebel-
lar cortex adjacent to microglial nodules (Pentschew 1965). The number of Purkinje cells is reduced and the granular cell layer is often atrophic. Hyalinosis of the arterioles has been described as well as Alzheim- er‘s neurofibrillary tangles (Niklowitz and Mandy- bur 1975).
The lead content of the bone marrow correlates with the presence of relatively densely packed calcar- eous deposits in the granule cell layer of the cerebel- lar cortex and pallidum (Tonge et al. 1977; Silbergeld 1983). An expression of the degree of damage to the peripheral nerves (Wallerian degeneration) is appar- ent in the central chromatolysis of the anterior horn cells (Eto and Takeuchi 1978).
17.1.6.2
Organic Lead Compounds
Source. In the 1920s, tetraethyl lead was first used as an additive to gasoline. Since the removal of lead from gasoline, the median blood lead concentrations have fallen from 0.724 µmol/l in 1978 to 0.097 µmol/
l in 1999. Exposure to lead from deteriorating lead paint in older homes continues. The Centers for Disease Control and Prevention (CDC) estimated that, in 2000, there were still 454,000 children in the United States with blood lead concentrations greater than 0.483 µmol/l (Rogan and Ware 2003). Today, lead poisoning is most frequently caused by sniffing gasoline (pp. 383 ff). Blood lead concentrations, even those below 0.483 µmol/l, are inversely and signifi- cantly associated with children’s intelligence quo- tient (IQ) scores at 3 and 5 years of age (Canfield et al. 2003).
Morphology. The morphological picture is domi- nated by cortical and cerebral atrophy with selective loss of nerve cells in the hippocampus and cerebel- lum as well as chromatolysis of the reticular nuclei of the brain stem (Kaelan et al. 1986; Valpey et al.
1978).
17.1.7 Lithium (Li)
Lithium (Li) is used therapeutically in the therapy of cyclothymic psychoses. Lithium overdose produces symptoms such as diarrhea, vomiting, and dizzi- ness as well as neurological effects such as tremor, cerebellar disturbances, truncal ataxia, broad-based ataxic gait, dyskinesia, dysarthria, and nystagmus.
Lithium impairs both intermediary and DNA metab- olism (Dempsey and Meltzer 1977). Morphologically, spongiform changes can be noted in the thalamus, midbrain, cerebellum, and spinal cord. There is also damage to cerebellar granular and Purkinje cells, gliosis in the dentate nucleus, the inferior olives, and
the red nucleus, and cytoplasmic inclusions in the neurons of cranial nerve nuclei (Peiffer 1981; Nara- moto et al. 1993).
17.1.8
Manganese (Mn)
Source. Manganese (Mn) is mined in Chile, Morocco, and Cuba. Mn is used in the production of steel and of electric batteries. Mn poisoning (manganism) has been particularly described in miners in Morocco (Rodier 1955). Mn is taken in orally (ingestion of food- stuffs or water) or by inhalation. Since Mn3+ binds to transferrin and Mn2+ binds to plasma α2-macroglob- ulin, it is also capable of penetrating the blood−brain barrier. In the brain, it accumulates in the globus pal- lidus and the substantia nigra, pars reticularis (Pei- ffer 1956; Mena 1979; Newland et al. 1989).
Clinical Features. The early phase of Mn poisoning is characterized by psychiatric symptoms such as states of agitation, disturbance of the sleep−wake cycle, af- fective instability, etc. Later symptoms include ex- tra-pyramidal disturbances resembling Parkinson’s syndrome: akinesia, dystonia, etc. (Mena 1979). The symptoms may be irreversible even after termination of exposure, and clinical symptoms do not respond to levodopa therapy (Pal et al. 1999).
Pathogenetically there is a reduction of dopamine and homovanillic acid levels in the corpus striatum (Bonilla and Diez-Ewald 1974) as well as a decline in adrenaline (Barbeau et al. 1976). Zheng et al. (1998) suggest that the mechanism of manganese neurotox- icity is alteration of brain mitochondrial aconitase activity leading to disruption of mitochondrial en- ergy production; it is not understood why it appears to be selectively toxic in the globus pallidus (Whet- sell 2002).
Morphologically, degeneration of the basal gan- glia is noted, mainly of the medial segment of the globus pallidus, with relative sparing of the substan- tia nigra (Barbeau et al. 1976; Bernheimer et al. 1973;
Yamada et al. 1986; Pal et al. 1999).
17.1.9 Mercury (Hg)
17.1.9.1
Elementary Mercury
and Inorganic Mercury Compounds
Source. Mercury (Hg) is used in thermometers, ther- mostats, Hg-based paints, etc. In medicine, Hg was applied in the past principally in the treatment of syphilis. Inorganic Hg compounds are widely used in the impregnation and preservation of wood, as
anti-corrosives in photography, and as a disinfectant (mercuric cyanide). Hg is often the vehicle of suicide or homicide, usually in the form of mercuric chloride (sublimate) (Geldmacher von Mallinckrodt 1975).
Since Hg vapor is colorless and odorless, it can be inhaled accidentally. The incidence of Hg poison- ing, however, has decreased due to improvements in precautionary measures. The use of amalgam in den- tistry has drawn criticism for being potentially toxic (Hahn et al. 1989; Boyd et al. 1991) and may cause or exacerbate degenerative diseases such as amyo- trophic lateral sclerosis or Alzheimer’s disease, but no firm proof of its toxicity has been presented (for review see Clarkson et al. 2003).
Clinical Features. Hg poisoning is characterized by affective instability, depression, erethism, ataxia, and − rarely − tremor (Ludwig 1977a, b; Kark 1994).
Early clinical symptoms are memory loss, increased excitability, insomnia, and personality changes.
Morphology. Structural changes have been described in one case with classical signs of Hg intoxication (Escourolle et al. 1977). Macroscopically, neuronal loss and glial reactions are rarely seen in the ner- vous system, but, microscopically, Hg is found in the lysosomal “dense bodies” of numerous nerve cells (Fig. 17.2a, b) as well as in peripheral nerves (Fig. 17.2c), where the metal is concentrated - even years after acute vapor exposure, on occasion of an accidental explosion (Hargreaves et al. 1988). The mechanism underlying the related neurological and psychopathological symptoms is unknown, al- though inorganic Hg has been shown to alter ADP- ribosylation of brain neuronal proteins (Palkiewicz et al. 1994) and inhibit tubulin polymerization into microtubules (Leong et al. 2002).
Pathogenesis. Due to their lipophilic properties, Hg and its non-polar compounds easily penetrate the blood−brain barrier (Chang 1980). They inhibit mi- tochondrial respiration and synaptosomes (Verity et al. 1975), which can lead to a reduction in the level of cellular oxidation of brain cells (Grundt and Bakken 1986). This metabolic failure and the injury of the cell membrane leads to an increase in the calcium content of the nerve endings (Bano and Hasan 1989), which can ultimately lead to neuronal death.
17.1.9.2
Organic Mercury Compounds
Source. Improper waste disposal or waste process- ing can result in the formation of large amounts of organic Hg compounds. Since microorganisms in water can transform inorganic compounds into or- ganic compounds (methylmercury), the ingestion of marine animals can pose a certain risk. Japanese
fishermen developed Minamata disease after eat- ing mercury-contaminated fish caught in a bay pol- luted by industrial wastes (Eto and Takeuchi 1978).
As an effective fungicide, methylmercury is used to treat wheat. Iraq experienced a widespread wave of poisoning attributable to wheat treated with meth- ylmercury, resulting in over 500 deaths (Bakir et al.
1973). In Germany, there have been alarming reports of high Hg concentrations in tuna fish.
Pathogenesis. The neurotoxicity of Hg is based on its ability to penetrate the blood−brain barrier and accumulate in neurons, with a long half-life, exceed- ing 70 days (Magos 1975). Methylmercury impairs protein synthesis by inhibiting the incorporation of amino acids into the proteins of sensory ganglia and peripheral nerves (Cavanagh and Chen 1971). Recent experiments suggest that the primary effect results from incomplete phosphorylation of uridine lead- ing to the inhibition of RNA synthesis (Sarafian and Verity 1986).
Clinical Features. The presence of acute intoxication is highlighted by gastrointestinal symptoms, where- as chronic intoxication produces both a nephritic syndrome and symptoms of nervous system involve- ment: paresthesias, fatigue, dizziness, and ataxia.
Scotomas have also been described (Ludwig 1977b).
Methylmercury can pass the placental barrier and severely impair fetal brain development (Marsh et al.
1980).
Morphology. The morphological picture is char- acterized by neuronal loss in the cerebral cortex − which is especially pronounced in the calcarine cor- tex − and in the cerebellar cortex. Cortical atrophy is sometimes even macroscopically apparent. Micro- scopically there is a spongiform disintegration of the cerebral cortex mainly affecting the second to fourth cortical layers, with massive proliferation of glial cells (Takeuchi et al. 1979). The cerebellum shows a loss of granular cells, which is especially marked in the depths of the folia. The Purkinje cells appear to be unaffected. Axon torpedoes are common. The cerebellar cortex is marked by distinct changes in the dendrites of the Purkinje cells, with antler-like and morning star-like figures (Eto and Takeuchi 1978). The basal ganglia are generally well preserved, whereas the spinal cord exhibits demyelination of the posterior white column, and, less often, of the lateral pyramidal tract.
17.1.10 Platinum (Pt)
Source. In the 1970s platinum (Pt) was first used in conjunction with cyclophosphamide in chemo-
therapy in the form of cisplatin. Intravenous appli- cation was found to induce peripheral neuropathies and hearing defects. Intravascular application in the carotid arteries produced symptoms of CNS defects (Feun et al. 1984).
Morphology. There is axonal loss in large myelinated and unmyelinated fibers together with gliosis in the anterior horns of the spinal cord (Verity et al. 1975).
Local intra-arterial injection is followed by severe
Fig. 17.2a−c. Mercury intoxication by inhaled inorganic Hg va- por. Demonstration of heavy metal granules in: a Purkinje cell, b pyramidal cell in the cerebral cortex, and c peripheral nerve from a patient with severe ataxia and tremor, who survived a boiler explosion in an amalgam distillery for 41 years . (Eosin stain, magnification a ×500; b, c ×1,000). The figures were kindly provided by Professor Dr. H. Wiethölter, Stuttgart
nerve damage, apparently caused by the direct neu- rotoxic effect of Pt (Freedman et al. 1987).
17.1.11 Thallium (Tl)
Source. Thallium (Tl) is an ubiquitous trace element in the soil and in plants (including vegetables). Me- tallic Tl is used in industry as a special alloy. Water soluble thallous salts are toxicologically important and have been used in recent decades in many types of rat and mouse poisons. Tl compounds are usually colorless, odorless, and tasteless, which accounts for their frequent use in homicides and suicides (Geldm- acher von Mallinckrodt 1975; Moeschlin 1980; Moore et al. 1993). Tl compounds are both hepatotoxic and neurotoxic.
Pathogenesis. Tl is thought to interfere with oxida- tive phosphorylation by inhibition of ATPase in the mitochondria (Melnick et al. 1976). At the same time, axonal transport is disturbed, resulting in a “dying- back” neuropathy (Cavanagh 1979). High concentra- tions of Tl may affect both energy metabolism and the antioxidant protection of cell membranes in the NS (Cavanagh 1985, 1988, 1991).
Clinical Features. In cases of acute Tl poisoning, gas- trointestinal symptoms such as diarrhea, vomiting, and convulsive stomach pains predominate. The first symptoms in chronic intoxication are pares- thesias, followed by convulsions, states of delirium, and coma. There are also peripheral deficits, extra- pyramidal and psychological disturbances (Bank 1980). The main visible symptom of chronic intoxi- cation is hair loss and changes in the fingernail beds (so-called Mees’ lines; cf. Arsenic Poisoning above) (Geldmacher von Mallinckrodt 1975).
Morphology. Macroscopically, cerebral edema is of- ten associated with disseminated hemorrhages in the white matter and cerebellum (Cavanagh et al.
1974). Microscopically, edema and necrosis can be demonstrated mainly in the subthalamic region, the substantia nigra and at the level of the corticospi- nal tracts (Ceccarelli and Clementi 1979). In addi- tion, there are primary degenerative changes in the nerve cells of the cerebral and cerebellar cortices, the hypothalamic nuclei, olivary nuclei, and the cor- pus striatum, with a conspicuously absent glial cell reaction. Peripherally there is axonal degeneration with changes typical of the “dying-back” process with chromatolytic changes in neurons in the motor cortex, substantia nigra and brain stem motor nuclei (Cavanagh et al. 1974; Kennedy and Cavanagh 1976;
Cavanagh 1985, 1991).
17.1.12
Tin (Sn) and Tin Compounds
17.1.12.1 Triethyltin
Source. Metallic tin is practically non-toxic, whereas organic tin compounds are lipid soluble, rapidly ab- sorbed, and can affect the nervous system. Organic tin compounds are used in the plastics industry and as disinfectants because of their fungicidal and in- secticidal effects. Triethyltin (TET) made headlines in 1953/54 when the drug Stalinon, which contains the active agent diethyltin diiodide with 10% TET, caused 110 deaths in France (Alajouanine et al. 1958).
The toxic dose for adults is estimated to be 70 mg of TET over a period of 8 days (Barnes and Stoner 1959).
Pathogenesis. TET-sulfate has a high affinity for my- elin (Lock and Aldridge 1975). It has a toxic effect on mitochondria, uncoupling oxidative phosphoryla- tion through inhibition of mitochondrial adenosine triphosphatase (ATPase) (Doctor and Fox 1983).
Clinical Features. Stalinon poisoning produced the following clinical features: dizziness, vomiting, head- ache, photophobia, and visual impairment as well as cerebral seizures, sensory disturbances, and loss of sphincter control. Death occurred after 4−10 days.
Morphology. The morphological hallmark of Stali- non poisoning was a pronounced cerebral edema with signs of increased intracranial pressure and herniation. Histologically, the sole finding was an edema of the white matter with spongiform degen- eration which spared most axons (Cossa et al. 1958;
Gruner 1958).
17.1.12.2 Trimethyltin
Source. Only a few cases of trimethyltin intoxication have been described (Besser et al. 1987). The main symptom was a deep depression, emotional distur- bance, forgetfulness, and loss of libido (Ross et al.
1981).
Morphology. The morphological picture was charac- terized by swollen nerve cells with eccentric, some- times pyknotic, nuclei and loss of the Nissl substance with cytoplasmic inclusions in the amygdaloid nu- cleus, in the temporal cortex, basal ganglia and the pontine nuclei (Besser et al. 1987).
17.2
Non-Metallic Inorganic Neurotoxins
17.2.1
Phosphorus (P)
and Phosphorous Compounds
Source. Today so-called white (yellow) phosphorus is only used industrially as an intermediate product in the manufacture of incendiary bombs, etc. Poisoning occurs almost exclusively in suicides and homicides.
Because white phosphorus is easily oxidized and fat soluble, it easily penetrates into the cell interior, where it impairs oxidative metabolism. The liver is the main target organ. Phosphine is a hydrogen com- pound of phosphorus (PH3) used as a pesticide.
The clinical picture of phosphorus poisoning is dominated by gastrointestinal irritation with vom- iting of luminescent stomach contents. After an in- terval of 2−3 days, a syndrome may ensue affecting the liver and kidneys (jaundice, uremia), as well as the CNS (stupor, delirium). Morphological changes in the CNS correspond to status spongiosus (spongi- form encephalopathy).
17.2.2 Sulfur (S)
17.2.2.1 Carbon Disulfide
Source. Carbon disulfide poisoning usually occurs in the handling of rubber and cellulose fibers. It primarily affects the nervous and cardiovascular systems. The main clinical features include sensory neuropathy, followed by motor weakness of distal extremities. In rare instances, acute psychosis may develop as well as neurological deficits in the sense of extrapyramidal disturbances of the Parkinsonian type (Peters et al. 1988).
Morphology. The few cases described were charac- terized by disseminated neuronal degeneration in the cerebral cortex, basal ganglia, and cerebellum.
Gliosis and demyelination of the spinal cord were also observed (Alpers and Lewy 1940).
17.2.3 Tellurium (Te)
Source. Tellurium is related to selenium and sulfur and is used in industry, where exposure occurs by inhalation of vapor containing Te. At one time, Te was used to treat leprosy, syphilis, etc.
Clinically, gastrointestinal changes, headache, fatigue, and nausea predominate. A black discolor- ation of the exposed areas of the skin is a conspicu- ous sign.
The brain tends to contain lower amounts of Te than other organs. Animal experiments have dem- onstrated severe neurotoxic properties. In humans, peripheral neuropathies (Lampert et al. 1970) and neuronal lipofuscinosis (Duckett and White 1974) have been described.
17.3 Gases
17.3.1
Carbon Monoxide (CO)
Source. Carbon monoxide (CO) is a colorless, odor- less stable gas with a density similar to that of air. CO diffuses rapidly across the alveolar capillary mem- brane and binds tightly to iron centers in hemoglo- bin and other heme proteins such as myoglobin. CO is an insidious byproduct of incomplete combustion of carbonaceous substances such as coal and gas and is generated in toxic amounts by internal combus- tion engines, fossil-fuel furnaces, and fires. Most instances of CO poisoning are accidental, but some result from attempted suicide (introduction of en- gine exhaust into the interior of the car). About 800 deaths of CO intoxication are reported in the United States per year (Ernst and Zibrak 1998; Weaver 1999).
Today, most municipal gas supplied contains no CO and cannot cause death by carbon monoxide poison- ing, but in isolated cases as a result of hypoxia/isch- emia.
Pathogenesis. (For review see Bour et al. 1967; Pan- kow 1981; Plantadosi 2002.) CO has indirect and di- rect effects on brain:
1. Indirect effects include hypotension due to pump failure of the heart: the circulation (also the brain circulation) is vasodilated by a vasodilatory ef- fect of CO.
2. Moreover an effective anemia occurs because CO causes a competitive inhibition of oxygen transport: the affinity of CO for hemoglobin is 200−250 times that of oxygen. Thus, it readily combines with hemoglobin to form carboxyhe- moglobin (CO-Hb). The normal CO-Hb level is 1−3%. Cigarette smokers increase their CO-Hb level by an average of 5% per pack smoked per day, and otherwise healthy smokers tolerate CO-Hb levels of 10% without having symptoms.
Blood saturation with CO-Hb of 60−70% is in- variably lethal. This causes an oxygen deficiency
in the heart and brain (Coburn and Forman 1987) with formation of cytotoxic brain edema. The globus pallidus is especially vulnerable (Song et al. 1983), but this can also be seen in cardiac ar- rest without CO (Garcia 1988).
This functional anemia induced by CO displace- ment of O2 from the hemoglobin molecule would normally cause a hyperdynamic circulation, as seen in the cardiac compensatory mechanism to anemia. However, CO directly depresses myocar- dial function, obviating the possibility for a fully hyperdynamic systemic circulation, with high blood pressure. The brain circulation is vasodi- lated (Komuro et al. 2001) by even 2000 ppm CO (Mendelman et al. 2002) or smaller amounts, as in smoking (Boyajian and Otis 2000). The vasodi- latory effect of CO is expected in view of its role, analogous to NO, in regulating cerebral blood flow (CBF). Indeed, in epilepsy, CO (produced by heme oxygenase) regulates CBF (Montécot et al.
1998).
Hypotension is the rule during CO poisoning, in spite of the expected cardiostimulatory effect of the functional anemia. The fall in blood pres- sure is due to depression of myocardial function by CO. This may lead to global cerebral ischemia with its anatomical distribution of necrosis with- in the brain (see above). To the extent that CO has the capability of inducing true histotoxic hypoxia (see below), one can attempt to distinguish the features within the brain due to global ischemia from those due to direct histotoxicity subsequent to CO poisoning. The distinction is problemati- cal, however, because of the capacity for global ischemia to cause, on occasion, symmetrical glo- bus pallidus necrosis (Garcia 1988) as is also seen, more characteristically, in CO poisoning.
3. In addition to indirect injury caused by the oxy- gen deficiency and global ischemia, CO has a di- rect toxic effect (Ernst and Zibrak 1998), which explains the clinical and morphological changes, above all in cases of intermittent exposure and/or a chronic course (for review see Oehmichen 2000).
The true histotoxic effect obviously is due to the high affinity of CO to iron-containing structures, i.e., hemoglobin, as well as to the globus pallidus and pars reticulata of the substantia nigra. Re- perfusion injury is caused by CO dissolved in the plasma (Yamada et al. 1986). CO causes a degra- dation of unsaturated fatty acids, which accounts for the demyelination of the white matter of the brain (Thom 1990); CO also causes oxidative stress to the cells with increased production of oxygen radicals (Thom 1992; Zhang and Pianta- dosi 1992).
Moreover, cyanide, sulfide, azide, and other agents do not have this histotoxicity in spite of being po-
tent inhibitors of mitochondrial energy production.
It is likely that transient binding to cytochromes is insufficient to cause CNS necrosis. But the inhibition of function naturally leads to apnea and immediate death. However, necrosis likely arises from a more prolonged binding with high affinity, as seen in CO poisoning.
CO is attracted to two nuclei within the brain which have a high heme iron content: the globus pal- lidus and the pars reticulata of the substantia nig- ra. These two nuclei, in spite of being anatomically distinct and somewhat removed from one another, should be considered as one for several reasons.
▬ They arise from a single embryologic nucleus which migrates upward to form the globus pal- lidus and downward to lie on the peduncular site of the substantia nigra pars compacta (the dopamine-rich portion of the substantia nigra involved in Parkinsonism). A few scattered neu- rons, termed the fields of Sano, contain large amounts of iron and are disseminated between the pars reticulata and the globus pallidus.
▬ The cytology of these two nuclei is quite similar, consisting of pauci-neuronal tissue with abun- dant neuropil. This is reflected in the name pars reticulata, denoting the reticular nervous tissue portion of the substantia nigra. In the globus pal- lidus, neuronal density is further reduced and diluted by interlacing and intersecting bundles of white matter which cross the globus pallidus.
However, the gray matter component of the sub- stantia nigra pars reticulata and of the globus pal- lidus is identical, consisting of iron-rich neurons.
In fact, the highest concentration of iron within the brain is in the globus pallidus and the pars reticulata of the substantia nigra.
▬ The globus pallidus and the pars reticulata of the substantia nigra are both susceptible to the same series of human and experimental diseases. For example, in Hallervorden−Spatz disease (neur- axonal dystrophy) there is accumulation of iron in both structures. In experimental epilepsy, the rodent brain demonstrates hypermetabolic ne- crosis in both structures (Folbergrová et al. 1985;
Ingvar et al. 1987). The globus pallidus suffers less hypermetabolic necrosis in this condition than the substantia nigra due to the dilution of its neuropil metabolism by the traversing white matter bundles, mitigating the metabolic rate in- crease and concomitant acidosis that occurs dur- ing hypermetabolism in that structure.
Although hypoxia alone cannot cause brain necro- sis in an organism with an intact, beating heart, hy- poxia does exacerbate ischemic brain damage (Mi- yamoto and Auer 2000; see pp. 275 ff). Anemia alone likewise does not cause brain damage. However, it is quite possible that the functional anemia accompa-
nying CO poisoning exacerbates the global ischemic brain damage due to cardiac failure. Superimposed upon these two interacting factors is the true, direct histotoxicity of CO on nervous tissue, due to the high and prolonged binding of CO to heme iron. It is thus the tight CO binding to heme iron, whether it be on heme iron in hemoglobin or heme iron in the mito- chondrial cytochrome systems, that causes the com- plex pathophysiological picture of CO poisoning.
17.3.1.1
Acute Intoxication
Clinical Features. The clinical picture of CO poisoning depends on the percentage of CO-Hb. Symptoms may range from headache (CO-Hb: 20%) and dizziness to nausea and stupor (CO-Hb: 30%) or unconsciousness (see Table 17.1). Cognitive sequelae lasting 1 month (Thom et al. 1995) or more (Weaver 1999) appear to occur in 25−50% of patients with loss of conscious- ness or with CO-Hb levels >25%. Incapacitation − which obviously increases the danger of continued exposure leading to death − usually occurs acutely at CO-Hb levels of 30−40%. Death is due to central respiratory and circulatory arrest (Geldmacher von Mallinckrodt 1975). The recommended treatment for acute CO poisoning is 100% normobaric oxygen, but meanwhile Weaver et al. (2002) have demonstrated that hyperbaric-oxygen therapy at 304 kPa (3 atm) absolute is superior to normobaric-oxygen therapy in reducing the incidence of delayed cognitive dys- function at 6 weeks and 12 months after acute CO poisoning (see Hampson et al. 2001). The diagnosis is confirmed by measurement of blood CO-Hb.
A delayed neurologic deterioration is usually termed
“talk and die” in the consideration of death after incidence of cerebral trauma (p. 472). However, a
similar phenomenon of delayed death can occur after cardiac arrest, and especially after CO poison- ing (Plum et al. 1962; Maxeiner 1987; Opeskin and Drummer 1994). The cause, as has long been known, is delayed white matter deterioration (Grinker 1925;
Lapresle and Fardeau 1967; Salama et al. 1986). Obvi- ously CO poisoning in these cases also causes adduct formation between myelin basic protein (MBP) and malonylaldehyde, a reactive product of lipid per- oxidation, resulting in an immunological cascade (Thom et al. 2004). MBP loses its normal cationic characteristics, and antibody recognition of MBP is altered. Immunohistochemical evidence of degraded MBP occurs in brain over days, along with influx of macrophages and CD4 lymphocytes. Lymphocytes from CO-poisoned rats subsequently exhibit an au- toreactive proliferative response to MBP, and there is a significant increase in the number of activated mi- croglia in the brain. These results demonstrate that delayed CO-mediated neuropathology is linked to an adaptive immunological response to chemically modified MBP.
Morphology. If death is sudden, the sole macroscopi- cally conspicuous feature is a bright redness of the blood and of brain sections at autopsy (Fig. 17.3a) − even after fixation in formalin (Fig. 17.3b, c). In rare cases with massive congestion, extravasation can also occur. If the acute poisoning is survived, chang- es occur which resemble those seen in global isch- emia: laminar cortical necroses, nerve cell loss in the hippocampal formation, Purkinje cell loss, and white matter necrosis. A bilateral necrosis of the glo- bus pallidus (Fig. 17.3d) and the pars reticulata of the substantia nigra are known as non-specific altera- tions. [For further details of the pallidal necrosis see Pankratz et al. (1988).] White matter deterioration in
Table 17.1. The relationship between atmospheric concentration of carbon monoxide and clinical effect. Source: Davies 1991
Atmospheric carbon monoxide (%) Clinical features
0.04 Nausea after 1−2 h
Collapse after 2 h Death after 3−4 h
0.1 Difficulty in movement
Death after 2 h
0.2 Death after 45 min
0.3 Death after 30 min
0.5 Rapid collapse
Unconsciousness and death within a few minutes
the sensed multifocal leukoencephalopathy (see also Sect. 17.3.1.2) are the morphological sequelae of a de- layed feature of CO poisoning.
17.3.1.2
Intermittent Exposure
Clinical Features. A coma lasting days or weeks in the first phase of illness may be followed by increasing clarity of consciousness. The second phase begins after 10−30 days with signs of progressive encepha- lopathy including dementia, akinesia and rigidity, and finally coma.
Morphology. The morphologic picture is character- ized by confluent foci of demyelination with swelling of oligodendrocytes and proliferation of astrocytes.
The demyelination with its patchy distribution and indistinct borders resembles the pattern of multifo- cal leukoencephalopathy; there is a continuous spec- trum up to complete demyelination (“Grinkers’ dis- ease” or “Grinker’s myelinopathy”). White matter edema is accompanied by a drop in blood pressure and increased acidosis (Brucher 1966).
Fig. 17.3a−d. Carbon monoxide poisoning. Acute intoxication:
bright redness of the dura (a) at autopsy and of the brain surface after formalin fixation (b) associated with brain swelling and (c)
redness of the frontal section. Chronic intoxication: bilateral pal- lidal necrosis as demonstrated by circles (d)
17.3.1.3
Chronic Intoxication
Clinical Features. Low levels of CO exposure can cause headache and nausea. The marked affinity of CO for Hb plus the resultant reduced expiration of CO results in an accumulation of CO-Hb in the blood, which over a period of days or weeks can pro- duce all of the symptoms of acute intoxication and, if unchecked, lead to death.
Morphology. The aforementioned hypotensive hy- poxic and ischemic necrosis and white matter inju- ries predominate.
17.3.2
Cyanides and Cyanide Compounds
Source. Deaths due to acute cyanide poisoning are relatively rare, largely owing to the restricted avail- ability of cyanide. Nevertheless, cyanide is one of the most rapidly acting poisons known and is encoun- tered today in cases of suicide or intentional killing (e.g., euthanasia/assisted suicide − Fernando and Busuttil 1991; Cina et al. 1994; for review see Muss- hoff et al. 2002). Chronic poisoning from ingestion of fruit seeds or plants containing cyanide, e.g., al- monds, is rare. Of major importance is the occur- rence of prussic acid in gas produced by the combus- tion of nitrogen-containing plastics (polyurethane, polyacrylnitrite, synthetic fibers, e.g., artificial wool or silk), which can cause mixed poisonings with CO.
A few victims of acute poisoning have survived due to intensive medical measures.
The lethal cyanide dose is relatively small and, because death is usually immediate, attempts at medical intervention are nearly always futile. The minimal lethal dose of hydrogen cyanide is 100 mg;
for sodium cyanide 150 mg and potassium cyanide 200 mg (Baselt and Cravey 1995); bitter almonds:
70 nuts for adults, 6−7 nuts for children. Hydrogen
cyanide (HCN) and its salts are characterized by the smell of bitter almonds.
Pathogenesis. Cyanide is readily soluble in lipids and diffuses rapidly. It binds to the Fe3+ in the heme group of cytochrome oxidase and thereby inhibits cellular utilization of oxygen. This results in histo- toxic anoxia at the cellular level; i.e.,“internal” suf- focation and energy failure associated with lactate production and severe metabolic acidosis (Hall and Rumack 1986; Borron and Baud 1996; Musshoff et al.
2002). Central suppression of respiration is thought to result from changes in neuronal excitability (Greer and Carter 1995). However, hypotension due to heart pump failure is a critical and necessary determinant of brain necrosis, since structural brain damage is absent without ischemia, and direct necrotizing CNS histotoxicity seems not to occur (MacMillan 1989).
Clinical Features. Cyanide intoxication is character- ized by dose-dependent impairment of neurologic function, beginning with non-specific symptoms such as headache or dizziness at one end of the spec- trum and convulsions and coma at the other. Coma and convulsions may develop within seconds. The reconstructive analysis of 27 cases of lethal poison- ing with cyanide by Vock et al. (1999) revealed that some victims had the capacity to act, especially for 5−10 min, though most victims lost consciousness within a few seconds to 1−2 min. Cardiac arrest fol- lows, depending on the concentration, almost im- mediately with all the discrete signs of suffocation (Table 17.2). The diagnosis commonly is made by toxicological examination. Cyanide levels in serum
>2.5 mg/l are associated with coma and are fatal without treatment. However, cyanide is unstable in blood and therefore cyanide levels may drop as a re- sult of degradation into less toxic components if the postmortem interval before autopsy (and the storage time of blood until examination) is too long (Ballan- tyne et al. 1974; Musshoff et al. 2002).
Table 17.2. The relationship between atmospheric concentration of hydrogen cyanide and clinical effect. Source: Davies 1991
Hydrogen cyanide (%) Clinical feature
0.004−0.005 Tolerated for 0.5−1 h
0.011−0.013 Death after 0.5−1 h
0.018 Death after 10 min
0.028 Immediate death
