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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 9 HYDRAZINES AND NITRIC ACID This chapter discusses the committee’s review and evaluation of epidemiologic studies and toxicologic information on persistent human health effects that might have resulted from exposure to hydrazines and nitric acid (HNO3). This format is a departure from previous chapters in which the number of epidemiologic studies on exposure to fuels and combustion products were too numerous to include all in one chapter. US military personnel present in the Persian Gulf region during Operation Desert Storm might have been exposed to inhibited red fuming nitric acid (IRFNA) and possibly unsymmetrical dimethylhydrazine (UDMH) if it was used as rocket fuel when they were near disintegrating incoming short-range ballistic missiles, commonly known as Scuds, that dispersed uncombusted fuel, oxidizers, and combustion products (DOD 2001). Somewhat fewer than 100 Scuds were launched by Iraq; about 50 were directed at Kuwait and the remainder came down in or near Israel (DOD 2001). Many of the Scuds broke apart on re-entry, each releasing about 300 lb of residual oxidizer and 100 lb of fuel (DOD 2001). Disintegration would have had to occur less than 3 km above the ground for those chemicals not to have been dissipated by the time they reached the ground (DOD 2000). If the chemicals did reach the ground, they could potentially expose an area of 2–3 km by 100–200 m but would evaporate within a few hours (DOD 2000). The National Research Council (NRC 1998) noted that in the vicinity of a rocket launch, nitric acid would be more likely to be in the form of an aqueous aerosol than a gas. The amount of nitric acid that would result if an ignited launch were aborted would greatly exceed the amount produced if combustion proceeded. Military personnel in the vicinity of incoming Scuds reported experiencing an array of acute health effects, including burning sensations, tearing eyes, runny noses, nausea, vomiting, dizziness, sleeplessness, headaches, and blurred vision (DOD 2001). After aerial breakup of Scuds, “some cases” required medical treatment or hospitalization, but there were no instances of pulmonary edema (DOD 2000). After direct contact with several Iraqi missiles captured at a storage facility, there were two or three cases of skin burns (DOD 2001). The committee is not aware of other uses of hydrazines or nitric acid during the Gulf War that might have resulted in exposure of US military personnel. Hydrazines have similar chemical structures but they differ in their production, uses, and adverse health effects (ATSDR 1997). Symmetrical (or 1,2-) dimethylhydrazine will not be considered here, because it is not used as a rocket propellant, as are hydrazine,
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 monomethylhydrazine (MMH), and unsymmetrical (or 1,1-) dimethlyhydrazine. Although Iraq had apparently experimented with UDMH as a rocket fuel, it is more likely that kerosene was the rocket fuel used during the Gulf War (DOD 2001). Nitric acid, probably in the form of IRFNA, was used as an oxidizer for the propellant in the Scuds (DOD 2000). Metal corrosion is inhibited if a halogen compound, such as hydrogen fluoride or iodine, is added to red fuming nitric acid (RFNA) (DOD 2000). The oxidizer’s color and fuming properties result from the high concentration of nitric acid, relative to nitrogen dioxide, in the liquid (EFMA 1997). The remainder of this chapter contains the committee’s evaluation of the scientific literature on adverse, persistent health effects of hydrazines and nitric acid. It begins by reviewing toxicologic information on those chemicals, then reviews human studies related to whether persistent health effects might be associated with exposure to hydrazines and nitric acid, and finally presents the committee’s conclusions. TOXICOLOGY This section provides an overview of toxicologic information on two chemicals—UDMH and RFNA—that may have been dispersed over Gulf War veterans by disintegrating Scuds. Because toxicologic data on those chemicals are sparse, the findings on similar chemicals are also reviewed. Data on hydrazine and MMH are considered in addition to those on UDMH, and information on nitric acid in general is reviewed with the extremely limited data specifically on RFNA. For each of those sets of chemicals (hydrazines and nitric acids), the following information is presented: uses, physical and chemical properties, exposure limits recommended by national and international government bodies and organizations, toxicokinetic properties, summaries of experimental studies, and any evidence of genetic susceptibility and of interactions between the chemicals in question and other substances. The committee’s approach was to use toxicity data, primarily from experimental animal studies, for background information and as supporting evidence. Therefore, an extensive review of toxicologic studies was not appropriate here. Several organizations—for example, the Agency for Toxic Substances and Disease Registry (ATSDR 1997), the International Agency for Research on Cancer (IARC 1974, 1999a, 1999b, 1999c) the National Institute for Occupational Safety and Health (NIOSH 1976), and the National Research Council (NRC 1996, 1998, 2000)—have conducted reviews of hydrazine- and nitric acid-related compounds. The reader is referred to those sources for more detailed reviews of the toxicologic data on the compounds. Hydrazines Hydrazines contain two nitrogen atoms joined by a single covalent bond. Hydrazine, UDMH, and MMH are used as rocket propellants. Hydrazine is also used for such applications as agricultural pesticides and water treatment (IARC 1999b). UDMH is also used for chemical syntheses, as an absorbent for acid gas, and as a plant-growth control agent (NRC 2000). MMH is also used as a chemical intermediate (NRC 2000). Some physical and chemical characteristics of hydrazines are listed in Table 9.1.
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 TABLE 9.1 Chemical Identity and Selected Physical and Chemical Properties of Hydrazines and Nitric Acid Properties Hydrazine MMH UDMH Nitric Acid Synonyms Diamine, diamide, anhydrous hydrazine, hydrazine base Methylhydrazine 1,1-Dimethylhydrazine, dimazine, dimazin Aqua fortis, azotic acid, hydrogen nitrate, nitryl hydroxide; white fuming nitric acid (WFNA, 97.5% HNO3), red fuming nitric acid (RFNA, 85% HNO3), concentrated nitric acid (CNA, 68–70% HNO3) CAS registry no. 302–01–2 60–34–4 57–14–7 7697–37–2 Molecular weight 32.05 46.07 60.10 63.01 Chemical formula N2H4 CH6N2 C2H8N2 HNO3 Color Colorless Colorless Colorless Colorless, yellowish, or reddish-brown Physical state Liquid Liquid Liquid Liquid Boiling point 113.5°C 87.5°C 63.9°C 83°C (WFNA) 121°C (CNA) Melting point 2°C −52.4°C −58°C −42°C (WFNA) −38°C (monohydrate) −18°C (trihydrate) Solubility Miscible with water and methyl, ethyl, propyl, and isobutyl alcohols; insoluble in chloroform and diethyl ether Soluble in hydrocarbons; miscible with water and low-molecular-weight monohydric alcohols Miscible with water, alcohol, ether, dimethyl formamide, and hydrocarbons Miscible in water Vapor pressure 14.1 mm Hg at 25°C 49.63 mm Hg at 25°C 157 mm Hg at 25°C 57 mm Hg at 25°C (WFNA)—49 mm Hg at 20°C (CNA) Flash point 37.8°C (closed cup) −8.33°C −15°C (closed cup) Not flammable
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Properties Hydrazine MMH UDMH Nitric Acid Explosive limits 4.7–100% by volume in air Not found 2–95% by volume in air Not found Disassociation constant na na na pKa<0 Conversion factor 1 ppm=1.31 mg/m3 1 mg/m3=0.76 ppm 1 ppm=1.88 mg/m3 1 mg/m3=0.53 ppm 1 ppm=2.5 mg/m3 1 mg/m3=0.41 ppm 1 ppm=2.6 mg/m3 1 mg/m3=0.38 ppm NOTE: CAS=Chemical Abstracts Services; MMH=monomethylhydrazine; UDMH=unsymmetrical dimethylhydrazine; na=not applicable. SOURCES: ATSDR (1997), EFMA (1997), IARC (1992, 1999b), NRC (1996, 2000).
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Exposure limits and carcinogenic classifications have been recommended for hydrazines by such organizations as ACGIH, ATSDR, the US Environmental Protection Agency (EPA), IARC, NRC, and the Occupational Safety and Health Administration (OSHA). Those limits and classifications are summarized in Table 9.2. Toxicokinetics Animal studies using inhalation, dermal, and oral exposures have been conducted on the absorption, distribution, metabolism, and excretion of hydrazines. The toxicokinetics of hydrazines appears to differ among animal species (ATSDR 1997), and there are differences in the metabolic pathways of hydrazine, UDMH, and MMH (ATSDR 1997). Hydrazines are rapidly absorbed into the blood, and they and their metabolites are distributed to various tissues, such as the kidney, liver, lung, muscle, bladder, and pancreas (ATSDR 1997; Kaneo et al. 1984; Pinkerton et al. 1967). Plasma concentrations in male rats given UDMH subcutaneously at 50 mg/kg rapidly decreased after exposure, with a half-life of about 1 hour (Fiala and Kulakis 1981). UDMH was detectable in the blood of dogs within 30 sec of application (at 5–30 mmol/kg) to their shaved chests, but blood concentrations did not start to rise substantially for about 5 minutes (Smith and Clark 1971). Similar results were reported for cutaneous absorption of hydrazine (at 3–15 mmol/kg) (Smith and Clark 1972). There does not appear to be preferential accumulation in specific tissues. Hydrazines with a free amino group are able to react with endogenous alpha-keto acids, which can produce adverse health effects (ATSDR 1997). Hydrazine undergoes acetylation and can react with cellular molecules in vivo (Kaneo et al. 1984; Llewellyn et al. 1986; Preece et al. 1991). UDMH undergoes demethylation and can react with cellular molecules (Mitz et al. 1962). Evidence suggests that at least some hydrazines are metabolized by both enzymatic and nonenzymatic pathways (ATSDR 1997; Godoy et al. 1984; Tomasi et al. 1987). The metabolic process may be dose-dependent and saturable (Preece et al. 1992). Three cytochrome P450 isozymes (CYP2E1, CYP2B1, and CYP1A1/2) are involved in metabolism of hydrazine (Delaney and Timbrell 1995; Jenner and Timbrell 1994; Timbrell et al. 1982). Hydrazine has also been shown to be metabolized by another enzymatic pathway (peroxidases) and by a nonenzymatic pathway (a copper-ion-mediated pathway) (Sinha 1987). Hydrazine metabolism produces free radicals and carbonium ion intermediates that may be responsible for adverse health effects (ATSDR 1997). Koizumi et al. (1998) found that metabolism of hydrazine in humans is affected by genotypes of an isozyme of N-acetyltransferase, NAT2. Hydrazines and their metabolites are excreted in urine and in expired air (ATSDR 1997). Llewellyn et al. (1986) reported that unchanged hydrazine, acetyl hydrazine, and diacetylhydrazine were found in the urine of hydrazine-treated animals.
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 TABLE 9.2 Recommended Exposure Limits for Hydrazines and Nitric Acid Organization Chemical Type of Exposure Limit Recommended Exposure Limit Reference ACGIH Hydrazine TLV 0.01 ppm, A3, skin (adopted 1995) ACGIH 2003 UDMH TLV 0.01 ppm, A3, skin (adopted 1995) ACGIH 2003 MMH TLV 0.01 ppm, A3, skin (adopted 1995) ACGIH 2003 Nitric acid TLV 2.0 ppm (adopted 1976) ACGIH 2003 Nitric acid STEL 4.0 ppm ATSDR Hydrazine MRL 0.004 ppm (intermediate-duration inhalation exposure) ATSDR 1997 UDMH MRL 0.0002 ppm (intermediate-duration inhalation exposure) EPA Hydrazine Evaluation of carcinogenicity Probably human carcinogen (group B2) IRIS 2003 IARC Hydrazine and UDMH Evaluation of carcinogenicity Overall evaluation: possibly carcinogenic in humans (Group 2B); sufficient evidence of carcinogenicity in experimental animals; inadequate evidence in humans IARC 1999 Nitric acid (included in review of strong-inorganic-acid mists, in which exposure to sulfuric acid dominated most studies) Evaluation of carcinogenicity Overall evaluation: strong-inorganic-acid mists containing sulfuric acid are carcinogenic in humans (group 1); sufficient evidence from occupational exposures IARC 1992 NIOSH Hydrazine REL 0.03 ppm NIOSH 1997 IDLH 50 ppm MMH REL 0.04 ppm IDLH 20 ppm UDMH REL 0.06 ppm
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Organization Chemical Type of Exposure Limit Recommended Exposure Limit Reference IDLH 15 ppm NIOSH Nitric acid REL 2.0 ppm NIOSH 1994 STEL 4.0 ppm IDLH 25 ppm NRC Hydrazine SMAC 0.02 ppm (30-day exposure) NRC 1996 2000 MMH AEGL-2 0.11 ppm (8-hr exposure) UDMH 0.38 ppm (8-hr exposure) OSHA Hydrazine PEL 1.0 ppm OSHA 1997 (29 CFR 1910.1000) UDMH 0.5 ppm Nitric acid 2.0 ppm OSHA 1972 (29 CFR 1910.93) NOTE: UDMH=unsymmetrical dimethylhyrazine; MMH=monomethylhydrazine; ACGIH=American Conference of Governmental Industrial Hygienists; TWA=time-weighted average; TLV=threshold limit value (TWA for 8-hr workday and 40-hr workweek); STEL=short-term exposure limit (TWA for 15 min); A3=confirmed animal carcinogen with unknown relevance to humans; skin=potentially large contribution to exposure by cutaneous route; ATSDR=Agency for Toxic Substances and Disease Registry; EPA=US Environmental Protection Agency; IARC=International Agency for Research on Cancer; NIOSH=National Institute for Occupational Safety and Health; OSHA=Occupational Safety and Health Administration; MR=minimal risk level; REL=recommended exposure limit (TWA for 10-hr workday during 40-hr workweek); IDLH=concentration immediately dangerous to life or health; AEGL-2=acute exposure guideline level 2; SMAC=spacecraft maximum allowable concentration; PEL=permissible exposure limit (TWA for 8-hr workday during 40-hr workweek).
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Experimental Studies Experimental studies of the toxicity of hydrazines in humans and laboratory animals are summarized here. This section focuses on studies that examined chronic effects of hydrazines, particularly effects shown to persist after cessation of exposure. Epidemiologic studies assessing the adverse health effects of hydrazines are reviewed later in this chapter. On the basis of experimental data, chronic health effects of concern in relation to hydrazines are cancer and injuries to the respiratory tract, liver, and nervous and reproductive systems. Respiratory Effects MacEwen et al. (1970) exposed seven male volunteers (23–44 years old) to MMH at 90 ppm for 10 minutes by inhalation. The group consisted of smokers, former smokers, and nonsmokers. Acute effects included mild to moderate irritation of the nose, throat, and eyes; but there was no excessive lacrimation or coughing. No substantial exposure-related effects as measured with spirometry or clinical chemistry were observed during the 60 days after exposure, except for a 3–5% increase in Heinz body formation at day 7 that declined after 2 weeks. Rats and mice exposed by inhalation to UDMH at as low as 0.05 ppm for 6 months showed effects on the lungs (hyperplasia) and nasal mucosa (inflammation, hyperplasia, and dysplasia) (Haun et al. 1984; Vernot et al. 1985). Dogs subchronically exposed at 25 ppm UDMH showed lung irritation and damage, but exposure at 5 ppm did not cause those effects (Rinehart et al. 1960). No studies that assessed respiratory effects after cessation of exposure of laboratory animals to hydrazines were found. Hepatic Effects Multiple hepatic effects have been observed in laboratory animals exposed to hydrazine and UDMH by inhalation and orally. Hepatotoxic changes (fatty changes, hyperplasia, hemosiderosis, increased serum enzymes, degeneration, and pigmentation of Kupffer cells) were observed in rats, mice, dogs, and monkeys subchronically or chronically exposed by inhalation to hydrazine at 0.25–14 ppm or to UDMH at 0.05–25 ppm (Comstock et al. 1954; Haun 1977; Haun and Kinkead 1973; Haun et al. 1984; House 1964; Rinehart et al. 1960; Vernot et al. 1985; Weatherby and Yard 1955). Oral exposure to hydrazine also caused hepatotoxic effects in rats, mice, and hamsters (Biancifiori 1970; Preece et al. 1992; Wakabayashi et al. 1983; Weatherby and Yard 1955). Nervous System Effects The nervous system appears to be a target for hydrazine and UDMH. Hydrazine has been used as a chemotherapeutic agent, and some cancer patients treated with hydrazine orally at 0.2–0.7 mg/kg/day experienced neurologic effects, such as nausea, vomiting, dizziness, excitement, lethargy, and neuritis (ATSDR 1997; Ochoa et al. 1975); the side effects subsided on cessation of treatment. Nervous system effects (such as tremors, vomiting, convulsions, lethargy, and behavioral changes) have been observed in rats, mice, and dogs repeatedly exposed to hydrazine at 1 ppm or UDMH at up to 140 ppm by inhalation and acutely exposed to hydrazine at 3–15 mmol/kg or UDMH at 5–30 mmol/kg) dermally (Haun and Kinkead 1973; Rinehart et al. 1960; Smith and Clark 1971, 1972; Weeks et al. 1963). Reproductive and Developmental Effects Keller et al. (1984) conducted a teratogenicity assessment of MMH and UDMH in rats with intraperitoneal administration but reported that developmental toxicity occurred only at
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 doses that were toxic to the dams. Reproductive effects (ovarian and testicular atrophy, endometrial inflammation, endometrial cysts, and aspermatogenesis) were observed in hamsters and mice exposed by inhalation to hydrazine at 1–5 ppm (Vernot et al. 1985) and UDMH at 0.05 ppm (Haun et al. 1984). Cancer A number of animal studies have reported increases in the incidence of cancers after exposure to hydrazines (reviewed in ATSDR 1997; IARC 1999b; NRC 1996, 2000). Studies of hamsters exposed to UDMH by subcutaneous injection have had both positive findings (Ernst et al. 1987) and negative findings (Jeong and Kamino 1993). Oral exposures (by gavage or in drinking water) to UDMH or hydrazine (administered as hydrazine sulfate or isonicotinic acid hydrazide), however, have produced increased tumor rates (particularly of respiratory or hepatic tissues) in multiple strains of mice, rats, and hamsters (Bhide et al. 1976; Biancifiori 1970; Biancifiori et al. 1964, 1966; Bosan et al. 1987; Maru and Bhide 1982; Roe et al. 1967; Severi and Biancifiori 1968; Steinhoff and Mohr 1988; Toth 1969). Inhalation exposure, which would be most relevant to the Gulf War experience, has been less intensively investigated but also produced positive findings. Year-long exposure of rats and hamsters to hydrazine at 0.05, 0.25, 1.0, or 5.0 ppm for 6 hr/day, 5 days/wk followed by at least a year of observation before sacrifice led to dose-dependent increases in the incidence of lesions of the nasal epithelium (Vernot et al. 1985). Mice had slight increases in the incidence of lung adenomas in the high-dose group, but the small groups of dogs (four males and four females per dose level) showed no consistent response (Vernot et al. 1985). Inhalation exposure of rats and mice to UDMH was associated with leukemia and tumors of the lung, nasal passages, bone, pancreas, pituitary, blood vessels, liver, and thyroid (Haun et al. 1984). Chronic inhalation of MMH was not found to be carcinogenic in rats or dogs, but it did produce lung, nasal, and liver tumors in mice and nasal, renal, and adrenal tumors in hamsters (Kinkead et al. 1985). Genotoxicity Hydrazine and UDMH have been shown to be genotoxic in both in vivo and in vitro tests (reviewed in ATSDR 1997). Hydrazine and UDMH are alkylating agents and produced DNA damage in in vivo assays but had negative results in in vivo assays of unscheduled DNA synthesis, dominant lethal mutation, and gene mutation. Hydrazine and UDMH had positive results in gene-mutation assays in Salmonella typhimurium and Escherichia coli with and without activation and in Photobacterium leiognathi without activation. Mammalian cell assays had positive results for DNA alkylation, transformation, sister chromatid exchange, and unscheduled DNA synthesis without activation, and for gene mutation with and without activation. Other Health Outcomes Amyloidosis of the kidneys was observed in hamsters exposed to hydrazine by inhalation at 0.25 ppm for 6 hr/day, 5 days/wk for 1 year but not in rats, mice, or dogs experiencing the same treatment regimen (Vernot et al. 1985). No renal effects were observed in dogs exposed to UDMH by inhalation at 25 ppm (Rinehart et al. 1960) or in mice given hydrazine orally at 9.5 mg/kg/day (Steinhoff et al. 1990). Case studies have suggested that exposure to hydrazine or hydrazine derivatives is associated with systemic lupus erythematosus or a similar syndrome (Durant and Harris 1980) (Pereyo 1986), but the data are too sparse to support conclusions about an association. In addition, decreased T helper-cell counts observed in mice given UDMH by injection at 75
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 mg/kg/day are inconsistent with an autoimmune response (Frazier et al. 1991). In other studies, lymphocyte activity and DNA synthesis were suppressed by in vitro exposure to UMDH, possibly because of effects on interleukin-2 production or intracellular calcium (Bauer et al. 1990; Frazier et al. 1992). Taken together, data from laboratory animal studies fail to provide biologic plausibility of the hydrazine-induced autoimmunity suggested by human case reports. Hydrazine is a sensitizing agent. Multiple case studies have reported that dermal exposure to solutions containing up to 1% hydrazine causes contact dermatitis (reviewed in ATSDR 1997). Genetic Susceptibility Little is known about genetic susceptibility to toxic effects of hydrazines. In laboratory animals, susceptibility to hydrazines varies with species, strain, and age (ATSDR 1997; NRC 2000). Interactions No data were found on potential interactions between hydrazines and other chemicals. Nitric Acid In addition to its use as an oxidizer in explosives, nitric acid is used as a mineral acid in industrial processes (particularly in metal pickling and electroplating) and is a component in the manufacture of synthetic fertilizers (ACGIH 2003; IARC 1992; Sathiakumar et al. 1997). Some physical and chemical characteristics of nitric acid are presented in Table 9.1. Naming conventions and several of nitric acid’s properties (particularly vapor pressure, melting and boiling points, and color) depend on the proportion of nitrogen dioxide (NO2) in the nitric acid solution. Reagent grade or “concentrated” nitric acid (CNA) contains about 70% nitric acid. The fuming property is associated with yet more concentrated mixtures, which contain correspondingly less nitrogen dioxide; red fuming nitric acid (RFNA) is about 85% nitric acid, and white fuming nitric acid (WFNA) is about 97.5% nitric acid (ACGIH 2003; EFMA 1997). The designation “inhibited” for the rocket-fuel oxidizers connotes the inclusion of halogen additives (about 1% hydrogen fluoride or iodine) to suppress the corrosive properties of nitric acid on metal equipment (DOD 2000). Nitric acid is not combustible, but it is dangerously reactive with many materials (EPA 1987). The extreme corrosive potential of this strong acid has long been recognized. As summarized in Table 9.2, ACGIH adopted a TLV of 2 ppm for nitric acid in 1966 on the basis of case reports dating from 1804 and animal studies published in 1954 (Diggle and Gage 1954) (Gray et al. 1954b); this was supplemented by a short-term exposure limit (STEL) of 4 ppm in 1976. NIOSH recommended the same values in 1976, and the Occupational Safety and Health Administration (OSHA) adopted a permissible exposure limit (PEL) for nitric acid of 2 ppm. Authoritative review bodies have drawn their conclusions about nitric acid in large part on the basis of its likely mechanistic similarity to and co-occurrence in occupational mists with other strong inorganic acids (EPA 1987; IARC 1992; NIOSH 1976). Toxicokinetics Nitric acid has a corrosive effect upon contact with biological tissues. It produces oxides of nitrogen, particularly nitrogen dioxide, when it spontaneously decomposes or reacts with
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 metals or organic materials (NIOSH 1976). The deposition and toxicity of nitric acid in the respiratory tract is a function of the form of the nitric acid (vapor or aerosol); vapor or small particles penetrate more deeply into the lung. IARC (1992) noted that nitric acid is generally a vapor but that its water solubility when aerosol forms would favor upper airway deposition of larger particles that would have greater potential to alter the pH of mucus in a specific location. More recent investigations suggest that, contrary to expectation, inhaled vapor-phase nitric acid may be converted into or deposited on small particles in the humid atmosphere of the respiratory tract; this would facilitate its transport to and deposition in the deep lung (Chen and Schlesinger 1996). Detailed information on absorption, metabolic processing, tissue-specific distribution, or elimination of nitric acid was not found. Experimental Studies Experimental studies that address the toxicity of nitric acid in laboratory animals are summarized here. Epidemiologic studies assessing the adverse health effects of nitric acid are reviewed later. The primary concern of this chapter is effects of nitric acid that might persist after cessation of exposure. The immediate consequences of contact with nitric acid are severe enough for its acute effects to have led to controlling its occupational use and to additional regulation; therefore, the chronic effects and toxic mechanism of nitric acid have not been extensively investigated with contemporary protocols. On the basis of case reports and experimental data, the chronic health effects of concern for nitric acid are the residual effects of irritation of the eyes, skin, respiratory tract, and gastrointestinal tract; dental erosion; and the possibility that it is carcinogenic. Residual Effects of Corrosive Action and Irritation Occupational case reports adequately document the severe and potentially permanent dermal and ocular damage that results from contact with nitric acid, so few animal studies of these effects have been conducted. Dermal contact with concentrated nitric acid can produce burns or severe irritant (acute eczematous) dermatitis, damaging the skin’s upper and lower layers within minutes and possibly resulting in permanent scarring and impairment of function (Birmingham 1988). Aside from burns, nitric acid may stain skin yellow to brown because of the conversion of skin proteins to xanthoproteic acid (White 1934). More dilute solutions produce milder irritation and hardening of the epithelium (NIOSH 1976). Contact of the eye with nitric acid in sufficient amount or concentration can produce corneal opacification; mild injury may resolve, but severe ocular damage may persist as blindness (NIOSH 1976). Case studies of workers exposed subchronically to vapors of nitric acid have consistently reported erosion of dental enamel, a permanent effect. Most often, however, such exposure occurs in combination with other strong acids, such as sulfuric or hydrochloric acid, which actually may be more potent than nitric acid in this respect (Dettling 1935; Lynch and Bell 1947; tenBruggen Cate 1968). Similarly, the corrosive effects on the gastrointestinal tract and potentially lethal consequences observed in isolated cases of nitric acid ingestion have obviated the need for experimentation with animals on such outcomes (NIOSH 1976). In any event, this route of exposure would not be pertinent for Gulf War veterans exposed to nitric acid showering down from disintegrating Scud missiles. Somewhat more toxicologic investigation has been conducted regarding the respiratory consequences of inhaling nitric acid vapors at various concentrations. The report by Diggle and
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Reference Study Population Exposed Cases Estimated Relative Risk Rapiti et al. 1997 Italian chemical-plant workers Exposed to acid mixtures 8 1.62 (0.81–2.92)c Laryngeal Cancer Cohort Studies Ahlborg et al. 1981 Swedish metal-pickling cohort No latency 3 50.00 (10.32–146.17)b >10 years latency 3 60.00 (12.38–175.40)b Beaumont et al. 1987 Midwestern metal-pickling cohort Mortality, all acid groups 2 1.93 (0.23–6.99) Steenland et al. 1988 Incidence, all acid groups (two in “other acids”) 9 2.30 (1.05–4.36)a ≤5 years duration (one in “other acids”) 3 1.70 (0.35–4.95)a >5 years duration (one in “other acids”) 6 2.76 (1.01–6.02)a Case-Control Studies Eisen et al. 1994 Nested case-control in cohort of automobile workers exposed to machining fluids Years exposed to acid mist na 0.90 (0.66–1.22) Zemla et al. 1987 Residents of Upper Silesia, Poland Exposed to vapor (including nitric acid) 11 2.00 (1.00–3.52) Natives 2 0.57 (0.07–2.06) Immigrants 9 4.50 (2.06–8.54) De Stefani et al. 1998 Residents of Montevideo, Uruguay Exposed to strong acids (including nitric acid) 46 1.6 (0.9–2.6) 1–20 years 12 1.2 (0.6–2.5) ≥21 years 34 1.8 (1.1–3.1) Gustavsson et al. 1998 Swedish men Exposed to acid mist 4 1.31 (0.41–4.22) Esophageal Cancer Case-Control Study Parent et al. 2000 Montreal case-control study set All histologic types 15 2.2 (1.2–4.3) Exposure to sulfuric acid Nonsubstantial 12 2.0 (1.0–4.0) Substantial 3 4.1 (1.0–17.2) Squamous cell carcinoma 10 2.8 (1.2–6.1) Exposure to sulfuric acid
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Reference Study Population Exposed Cases Estimated Relative Risk Nonsubstantial 9 2.2 (1.2–6.3) Substantial 1 3.1 (0.3–28.1) Lymphopoietic Cancer Cohort Studies Mazumdar et al. 1975 Pennsylvania sheet and tin mill cohort Jobs with exposure to acid baths (containing sulfuric, hydrochloric, or phosphoric acid) Batch pickling and sheet dryers 0 — Continuous pickling and electric cleaning 0 — Stainless annealing, pickling, and processing 1 5.0 (0.13–27.85)b Coating 0 — Sheet finishing and shipping 0 — Tin finishing and shipping 3 3.00 (0.62–8.77)b Rapiti et al. 1997 Italian chemical-plant workers Exposed to acid mixtures 2 1.87 (0.33–5.88)c Non-Hodgkin’s lymphoma 1 4.17 (0.04–19.70)c Leukemia 1 1.79 (0.09–8.47)c Multiple Myeloma Case-Control Study Morris et al. 1986 Residents of four US states Self-respondents and proxies 20 1.0 (0.6–1.9) Self-respondents only 19 1.5 (0.8–2.8) Non-Cancer Health Outcomes Arteriosclerotic Heart Disease (Mortality) Cohort Study Mazumdar et al. 1975 Pennsylvania sheet and tin mill cohort (≥5 years) Jobs with exposure to acid baths (containing sulfuric, hydrochloric, or phosphoric acid) Batch pickling and sheet dryers 12 2.55 (1.15–3.88)a (p<0.01) Continuous pickling and electric cleaning 8 (vs 6.9) 1.17 Stainless annealing, pickling, and processing 16 (vs 14.0) 1.16 Coating 12 0.66 (0.35–1.20)a Sheet finishing and shipping 98 1.07 (0.86–1.29)a Tin finishing and shipping 26 1.08 (0.69–1.56)a
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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Reference Study Population Exposed Cases Estimated Relative Risk Hypertensive Heart Disease (Mortality) Cohort Study Mazumdar et al. 1975 Pennsylvania sheet and tin mill cohort (≥5 years) Jobs with exposure to acid baths (containing sulfuric, hydrochloric, or phosphoric acid) Batch pickling and sheet dryers 0 — Continuous pickling and electric cleaning 0 — Stainless annealing, pickling, and processing 1 (vs 0.5) 2.0 Coating 6 (vs 1.1) 10.83 (p<0.01) Sheet finishing and shipping 1 0.26 (0.01–1.43)a Tin finishing and shipping 0 — Vascular Lesions of CNS (Mortality) Cohort Study Mazumdar et al. 1975 Pennsylvania sheet and tin mill cohort (≥5 years) Jobs with exposure to acid baths (containing sulfuric, hydrochloric, or phosphoric acid) Batch pickling and sheet dryers 0 — Continuous pickling and electric cleaning 0 — Stainless annealing, pickling, and processing 4 (vs 3.2) 1.25 Coating 3 0.75 (0.15–2.19)b Sheet finishing and shipping 24 1.41 (0.84–1.95)a Tin finishing and shipping 4 0.74 (0.21–1.97)a Diabetes Mellitus (Mortality) Cohort Study Beaumont et al. 1987 Midwestern metal-pickling cohort All types of acid exposure 8 1.65 (0.71–3.26) NOTE: na=not available. a95% CIs were calculated with standard methods from the observed and expected numbers presented in the original paper. bRisk estimates and 95% CIs were calculated with standard methods from the observed and expected numbers presented in the original paper. c90% CIs were reported.
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Representative terms from entire chapter: