8. EFFECTS ON HUMANS 8.1 Poisoning incidents 8.1.1 Oral exposure There are a very large number of clinical reports of poisonings arising from ingestion of nitrobenzene (Dodd, 1891; Hogarth, 1912; Zuccola, 1919; Scott & Hanzlik, 1920; Wright-Smith, 1929; Fullerton, 1930; Leader, 1932; Carter, 1936; Wirtschafter & Wolpaw, 1944; Chambers & O’Neill, 1945; Chapman & Fox, 1945; Nabarro, 1948; Parkes & Neill, 1953; Myślak et al., 1971; Harrison, 1977; Schimel- man et al., 1978). In a literature review that was by no means compre- hensive, Von Oettingen (1941) listed 44 published case reports that appeared between 1862 and 1936. One reason for this high incidence of poisonings arose from the fact that, following its discovery, nitro- benzene was thought to be a cheap substitute for oil of bitter almonds and was used in perfume (e.g., soaps) and in sweets; in many countries, it was handled freely under the name “oil of mirbane.” The initial symptoms of nitrobenzene poisoning, which may be delayed for up to 12 h after ingesting the poison, are those of gastric irritation (e.g., nausea and vomiting). Methaemoglobinaemia, indicated by cyanosis, which is normally unaccompanied by respiratory distress, usually develops in a few hours, but in some cases it may be apparent within an hour. In severe poisoning, usually suicidal, but rarely accidental, neurological symptoms, namely progressive drowsiness and coma, lead to death from respiratory failure, as in the case discussed by Chambers & O’Neill (1945). These symptoms are ascribed to cerebral anoxia as well as a possible direct action of nitrobenzene on the nervous system. In severe poisoning, after ingestion but not, as a rule, after inhalation, haemolytic anaemia may also occur on or about the fifth day (Nabarro, 1948). Nitrobenzene has been ingested as an abortifacient in doses of 15– 100 g up to 400 g. In a review by Spinner (1917), 7 of 16 women died and only 1 aborted; 1 recovered after ingesting, it was claimed, 400 g of the poison. In a later review by Von Oettingen (1941), many more 141 EHC 230: Nitrobenzene literature reports of fatalities arising from nitrobenzene’s use as a presumed abortifacient were cited. Several relatively recent reports of poisoning by the oral route are detailed below. A 21-year-old man was thought to have taken about 30–40 ml of a nitrobenzene-containing dye used in screen printing about 30 min before admission to hospital. He was reported to have peripheral and central cyanosis; pupils were normal size, heartbeat was 160 beats per minute, blood pressure was 80/54 mmHg and respiration was 28 per minute. Blood samples were dark brown. After 1 h of positive-pressure ventilation, gastric lavage and intravenous fluids, the patient became conscious and well oriented, with a decrease in heart rate and an increase in blood pressure. Serum methaemoglobin was 4.29 g/dl. A slow intravenous infusion of ascorbic acid was started, and methylene blue was injected intravenously; after 35 min, the colour of the patient changed dramatically from brownish-blue to pink. After a second injection of methylene blue and a transfusion of packed red blood cells, methaemoglobin was 0.6 g/dl. A peripheral blood smear revealed evidence of haemolytic anaemia, but there was no evidence of occult blood in the urine. The patient was discharged on the fifth day of admission (Kumar et al., 1990). A 33-year-old man injected 4 ml of India ink into a median cubital vein with suicidal intent. He was hospitalized in good general condition 10 h after the injection. Abnormal laboratory test results were leukocytosis, a methaemoglobin level of 36.9% (normal range 1.5%) and a free haemoglobin level of 74 nmol/litre (normal range <25 nmol/litre). The presence of nitrobenzene in blood and urine was demonstrated. Intravenous administration of vitamin C and tolonium chloride plus forced diuresis led to an improvement in cyanosis and a fall in the methaemoglobin concentration. Repeated increases in the concentration of aminobenzene were successfully treated by haemo- dialysis (Ewert et al., 1998). A review of published reports does not provide any consistent indication of the likely acute toxicity of nitrobenzene in humans. Some reports reported recovery after massive doses of nitrobenzene in amounts of as much as 400 g, whereas other studies indicated that nitrobenzene is much more toxic (Dodd, 1891; Spinner, 1917; 142 Effects on Humans Walterskirchen, 1939; Wirtshafter & Wolpaw, 1944; Moeschlin, 1965). Von Oettingen (1941) cited results of incidents in which oral intakes of about 4 ml caused deaths, 8–15 drops caused toxic effects and 20 drops were fatal. In a fairly detailed clinical report given by Moeschlin (1965), a 23-year-old florist swallowed 1–2 ml of nitrobenzene (suspended in a little water) to procure an abortion and was at “the point of death” when admitted to hospital 3 h later. Polson & Tattersall (1969) claimed that even 12 ml reported by Parkes & Neill (1953) was probably on the high side; they claimed that a toxic dose of the order of 15 drops, as reported by Smith & Fiddes (1955), was likely. The lethal dose has been claimed to be as little as 1 ml (Thienes & Haley, 1955). A more recent detailed report more reliably indicated that about 5–10 ml of nitrobenzene (near 200 mg/kg of body weight) could be fatal in the absence of medical intervention (Myślak et al., 1971). Myślak et al. (1971) estimated that, following ingestion of about 4.3–11 g of nitrobenzene, the initial level of methaemoglobin was 82% at about 90 min after ingestion, accompanied by severe symptoms, including unconciousness, cyanosis, circulatory insufficiency and rapid and shallow breathing. 8.1.2 Dermal exposure Cases of severe and nearly lethal toxic effects after dermal expo- sure to aniline-based dyes were reported as early as 1886; the incident involved 10 infants in a maternity ward exposed to dye-stamped diapers (Gosselin et al., 1984). Between 1886 and 1959, there were numerous further reports of babies with a cyanotic syndrome arising from the use of laundered hospital diapers freshly stamped with an identifying mark using ink dissolved in aniline or nitrobenzene; the most recent published observation of an outbreak of methaemo- globinaemia in a number of babies was by Ramsay & Harvey (1959). The other common dermal poisonings arose in persons wearing freshly dyed shoes. The resulting condition was often termed “nitro- benzene poisoning,” even though exposures may have been to nitro- benzene or aniline (Von Oettingen, 1941; Gosselin et al., 1984). A poisoning episode involving 17 men at a US army camp was traced to the wearing of newly dyed shoes or puttees; the shoe dye contained nitrobenzene (Stifel, 1919). The soldiers experienced headache, nausea, dizziness and general malaise and were cyanosed. Cyanosis and ill-effects of nitrobenzene, including methaemoglobinaemia, were 143 EHC 230: Nitrobenzene also demonstrated when two volunteer soldiers wore boots that had been saturated with a nitrobenzene-containing dye for 6 h. Nine cases of poisoning by shoe dye were reported by Muehl- berger (1925). Here, also, cyanosis of sudden onset was the outstand- ing feature. The poisoning was ascribed to aniline solvent in six cases, nitrobenzene in the remainder. Poisonings including fatalities have also occurred when nitro- benzene was spilt on clothing (Stifel, 1919); most such reports indicate that it is absorbed with great rapidity and can rapidly cause severe intoxication (Moeschlin, 1965). 8.1.3 Inhalation exposure No reports of fatalities after exposure to nitrobenzene by inhala- tion were retrieved, but poisoning by inhalation can be severe (Simpson, 1965). Children may be particularly susceptible to poisoning by inhalation. Twins aged 3 weeks slept on a mattress that had been treated with a disinfectant intended to kill bed bugs. The fluid had been applied only to the edges of the mattress but was sufficient to produce an odour that had given the mother an intense headache half an hour before putting the babies to bed for 11 h. The bodies of the infants were not in contact with the poison. The next morning both had lead-coloured fingernails and toenails and were of ashen hue. It was subsequently shown that the disinfectant contained nitrobenzene. Blood analysis showed the presence of methaemoglobin. They recovered after about 8 days (Stevens, 1928). Zeligs (1929) described the case of a 2-month-old child who was put to sleep in a crib several feet away from the mother’s bed, the mattress of which had been treated with nitrobenzene for bed bugs. Within an hour, the child became blue and cried all night. Next morn- ing, the cyanosis had deepened and she vomited. There was complete recovery after 4 days. Sanders (1920) reported poisoning of a man (marked cyanosis) who wore newly dyed shoes when visiting a theatre for the afternoon, where he sat in an ill-ventilated place; the report did not rule out direct 144 Effects on Humans dermal absorption of nitrobenzene, in addition to the inhalation exposure. Several other anecdotal reports even include ill-effects from the vapours arising from the use of “almond”-glycerine soap in a warm bath. 8.2 Occupational exposure Von Oettingen (1941) listed 14 reports published between 1862 and 1939 regarding industrial poisonings, stating that there were many other reports as well. More than 50% of the workers of a nitrobenzene plant reported spells of cyanosis, 20% showed pallor and subicteric coloration, 33% suffered from abnormal congestion of the pharynx and 45% experienced intermittent headache (Heim de Balsac et al., 1930). Severe methaemoglobinaemia was reported in a 47-year-old woman who was occupationally exposed to nitrobenzene at unmea- sured levels for 17 months (Ikeda & Kita, 1964).