Nitrobenzene exposure

Nitrobenzene reacts with red blood cells in the body to produce methemoglobin. If you have recently been exposed to nitrobenzene, the levels of methemoglobin in your blood will be elevated. This level can be measured. However, many toxic chemicals produce methemoglobin, and this method does not give specific information about nitrobenzene exposure. 

In cases of long-term exposure to nitrobenzene, the presence of its breakdown products, p-nitrophenol and p-aminophenol, in the urine is an indication of nitrobenzene exposure. These tests require special equipment and cannot be routinely done in a doctor s office. The results of these tests cannot be used to determine the level of nitrobenzene exposure or if harmful health effects can be expected to occur. 

Strain and species differences in response to nitrobenzene exposure were demonstrated by Medinsky and Irons (1985). At an exposure level of 125 ppm nitrobenzene, there was a 40% rate of lethality in Sprague-Dawley (CD) rats and morbidity necessitating early sacrifice of all B6C3F1 mice. Fischer-344 rats, however, tolerated this level for 2 weeks without any adverse clinical signs. The relevance of these findings to human exposure is not known. 

Differences in species and possibly strain susceptibility to the renal effects of nitrobenzene exposure may exist, but their relevance to the potential renal effects in humans is not clear. The occurrence of renal effects in male rats, but not female rats or mice of either sex, in response to exposure to chemical toxicants is not unique to nitrobenzene. These differences have also been found with exposure to 1,4-dichlorobenzene, isophorone, and unleaded gasoline (Charbonneau and Swenberg 1988) and have been attributed to the production of high concentrations of the protein alpha- 2 i -globulin in the kidneys of male rats, but not in female rats, mice, or humans. These observations suggest that the severe renal effects observed in male rats exposed to nitrobenzene will probably not occur in exposed humans. 

Liver effects have been reported in both humans and animals exposed to nitrobenzene. Hepatic enlargement and tenderness, jaundice, and altered serum chemistries were reported in a 47-year-old woman who had been occupationally exposed to nitrobenzene for 17 months (Ikeda and Kita 1964). The authors considered these changes to be related to increased destruction of hemoglobin and enlargement of the spleen. Liver effects observed in animals following nitrobenzene exposure are hepatocyte necrosis in rats (Medinsky and Irons 1985) and increased liver weight, hepatocyte hyperplasia, and multinucleated hepatocytes in mice (Hamm 1984). Hepatic effects have not been reported in oral studies. Dermal painting studies in mice resulted in diffuse necrosis in the outer two- thirds of the lobules of the liver (Shimkin 1939). 

Neurological Effects. Neurotoxic symptoms reported in humans after inhalation exposure to nitrobenzene have included headache, confusion, vertigo and nausea (Ikeda and Kita 1964) effects in orally exposed persons have also included those symptoms as well as apnea and coma (Carter 1936 Leader 1932 Myslak et al. 1971). Studies in animals exposed via inhalation have shown morphological damage to the hindbrain (cerebellar peduncle) (Medinsky and Irons 1985). Damage to the brainstem, cerebellum and fourth ventricle was observed in orally exposed animals. Thus, it is possible that similar neurological changes may occur in humans as a result of nitrobenzene exposure. 

Epidemiological and Human Dosimetry Studies. No epidemiological studies were located regarding human health effects from nitrobenzene exposure. Studies of occupationally exposed populations would probably provide useful information. Areas of major interest would include methemoglobin levels, effects on reproductive function, immunological status, and neurobehavioral function. 

Biomarkers of Exposure and Effect. The presence of p-nitrophenol in urine serves as a satisfactory biomarker of nitrobenzene exposure. Because nitrobenzene metabolites, nitrosobenzene and phenylhydroxylamine, bind to hemoglobin in the blood of rats and mice, the presence of these hemoglobin adducts in human blood may also serve as biomarkers of nitrobenzene exposure. More information on this possibility would be useful. 

Comparative Toxicokinetics. Species and strain differences in response to nitrobenzene exposure have been noted in inhalation studies using mice and rats. The reason for these differences and the toxicokinetics involved are not understood. Additional toxicokinetic studies in species other than rodents and attempts to estimate the sensitivity of humans relative to these test species would be valuable aids in interpreting the results of available toxicity studies and in understanding individual differences noted in response to nitrobenzene exposure. 

As a source of nitrobenzene exposure of humans, soil appears to rank a distant third in terms of its contribution. Nelson and Hites (1980) reported 8 ppm in the soil of a former dye manufacturing site along the Buffalo River, but failed to detect nitrobenzene in river sediments, as noted above. The presence of nitrobenzene in the soils of abandoned hazardous waste sites is inferred by its presence in the atmosphere above several sites (Harkov et al. 1985 LaRegina et al. 1986). Nitrobenzene was detected in soil/sediment samples at 4 of 862 hazardous waste sites at a geometric mean concentration of 1,000 pg/kg (CLPSD 1988). No further data on nitrobenzene levels released to soils were located. 

GC and HPLC methods, not fully investigated, may be used for qualitative monitoring. It may be noted that exposure to certain chemicals, such as parathion, may also produce p-nitrophenol as a urinary metabolite. A screening test for nitrobenzene exposure may be performed by monitoring methe-moglobin in the blood. 

Strong acids and strong alkaUes can severely bum the skin, chromium compounds can produce skin rashes, and repeated exposure to solvents causes removal of natural oils from the skin. Infection is always a concern for damaged skin. Absorption through the skin is possible for materials that are appreciably soluble iu both water and oil, eg, nitrobenzene, aniline, and tetraethyllead. Other materials can be absorbed if first dissolved iu extremely good solvents, eg, dimethyl sulfoxide. Subcutaneous iujection can occur accidentally by direct exposure of the circulatory system to a chemical by means of a cut or scratch or iuadvertent penetration of the skin with a hypodermic needle. 

The average exposure value of nitrobenzene (see RartThree) (maximum authorised concentration for 8h). Does the presence of an open receptacle in a poorly ventilated room comply with regulations ... 

General considerations. Nitroaromatic compounds, such as nitro-furans and nitrobenzenes are commercially important chemicals used as drugs, food additives or synthetic intermediates. Since there is widespread human exposure to these chemicals, their metabolism has been studied extensively. Nitroaromatic compounds are reduced by both hepatic cytosol and microsomes. The microsomal activity... 

DNB and 1,3,5-TNB are nitrobenzene compounds that are structurally similar. The only difference in structure between 1,3-DNB and 1,3,5-TNB is the presence of an additional nitro group in 1,3,5- TNB. There is no information on 1,3,5-TNB exposure by the inhalation route. There is also very little information regarding inhalation exposure to 1,3-DNB. 

Another early symptom of exposure to 1,3-DNB is cyanosis due to oxygen deprivation because of the presence of methemoglobin in the blood. These changes are also not specific for 1,3-DNB and may be produced by other nitrobenzene compounds and dinitrobenzene isomers. Therefore, cyanosis is not a good biomarker for 1,3-DNB exposure. 

With regard to human health effects of 1,3-DNB, the few available studies involved acute-duration occupational exposure to 1,3-DNB by the inhalation and dermal routes, a case of accidental ingestion of a nitrobenzene dye, and a case of an experimenter who self-applied 1,3-DNB dermally for research purposes. No information was located on intermediate-or chronic-duration exposures in humans by any route. No information is available regarding immunologic, developmental, reproductive, genotoxic, or cancer effects in humans by any route of exposure. 

Exposure. Exposure to 1,3-DNB is currently measured indirectly by determining levels of methemoglobin in the blood (Donovan 1990). However, increased methemoglobin formation is not a specific response to 1,3-DNB exposure and may occur after exposure to other nitrobenzene compounds such as the other two isomers of dinitrobenzene. Determination of methemoglobin levels is widely used and is a reliable detection method. Very few methods are available for direct evaluation of 1,3-DNB levels, and they are not extensively used, probably because of the relatively rapid rate of conversion of 1,3-DNB to its degradation products (Cossum and Rickert 1985). Preliminary data suggested that the formation of adducts of 1,3,5-TNB with tissue DNA and/or with blood proteins may be useful as markers for exposure to 1,3,5-TNB (Reddy et al. 1991). Further research with both 1,3-DNB and 1,3,5-TNB in the area of adduct formation could provide valuable additional information. 

Effect. Cyanosis is also an early symptom of exposure to 1,3-DNB (Okubo and Shigeta 1982) and is a result of oxygen deprivation due to the presence of methemoglobin in the blood. However, it is not specific and may occur after exposure to other nitrobenzene compounds or other non-related chemicals. 

Fletcher JS, McFarlane JC, Pfieeger T, et al. 1990. Influence of root exposure concentration on the fate of nitrobenzene soybeam. Chemosphere 20 513-523. 

Ingestion of alcohol aggravates the toxic effects of nitrobenzene. In general, higher ambient temperatures increase susceptibility to cyanosis from exposure to methemoglobin-forming agents." p-Nitrophenol and p-aminophenol are metabolites of nitrobenzene, and their presence in the urine is an indication of exposure."... 

Pendergrass SM An approach for estimating workplace exposure to o-toluidine, aniline, and nitrobenzene. Am Ind Hyg Assoc J 55 733-737, 1994... 

Vanillic acid has been prepared from vanillin in small amounts by action of moist air, exposure to sunlight and nitrobenzene, reaction with soil bacleria," ozone, and by caustic fusion. High yields of vanillic acid have been obtained from vanillin by con-... 

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