Gage (1954) of exposure to nitric acid for an unspecified period at 25 ppm (63 mg/m3) as a no-observed-effect level (NOEL) in rats was first cited by ACGIH when proposing the current TLV of 2 ppm in 1964 and has since served as a primary piece of toxicologic data supporting regulatory levels for nitric acid; the original article, however, provided no detail about the conduct of the assay (NIOSH 1976).

The other long-referenced body of information about the toxicologic effects of inhaling nitric acid (and RFNA in particular) is a series of studies by Gray et al. (1952, 1954a, 1954b). Rats exposed to RFNA (nitrogen dioxide at 9–14 ppm, nitric acid concentration not stated) showed widespread inflammation of the airways, especially of the upper portion, immediately after exposure for 40–96 hours; several weeks later, much of the inflammation had abated, but all lungs examined were reported to have localized areas of “emphysema”. The extent and persistence of those effects were not functions of duration of exposure (Gray et al. 1952). Acute 30-minute exposures of male rats to nitrogen dioxide alone, RFNA (8–17% nitrogen dioxide), or WFNA (0.1–0.4% nitrogen dioxide) produced lethal concentrations (LC50s) of 174 ppm, 310 ppm, and 334 ppm, respectively; burns were observed on the animals, but pulmonary edema was the cause of death (Gray et al. 1954b). Those findings have been interpreted as suggesting that the nitrogen dioxide with which nitric acid coexists may be the primary toxic constituent of the vapor mixtures (ACGIH 2003; NIOSH 1976). Chronic exposure of 30 mice, 90 rats, and 10 guinea pigs to RFNA at 4 ppm for 4 hr/day, 5 days/wk for up to 6 months produced no pathologic changes compared with control animals (Gray et al. 1954a).

There have been several studies of nitric acid’s effect on isolated animal tissues (Greenberg et al. 1971; Pham-Huu-Chanh et al. 1966; Preziosi and Ciabattoni 1987). Nitric acid has been used to produce animal models of human obstructive airway disease (Greenberg et al. 1971; Mink et al. 1984; Peters and Hyatt 1986; Totten and Moran 1961).

More recently, nitric acid has been one of several components of ambient air pollution investigated in chamber studies. Nitric acid alone was found to penetrate far more deeply into the lung than might have been expected given its anticipated solubility in the mucus of the upper respiratory tract, perhaps as a result of being converted from vapor to particle form (Schlesinger et al. 1994, 1995). Nitric acid also impaired macrophage secretion of superoxide and tumor necosis factor alpha, and this has implications for pulmonary immunocompetence (Schlesinger et al. 1994, 1995) Unlike acid sulfates which can produce hyperreactivity, nitric acid tended to produce hyporeactivity (Schlesinger et al. 1994, 1995).


Considerable attention has been addressed to the possibility that nitric acid, like other strong inorganic acids, might contribute to the development of lung or laryngeal cancer in workers exposed to acid mists (IARC 1992). Those acids often occur in combination, and sulfuric acid has been considered the compound most likely to be responsible for any such effect, but they could share a mechanism of toxic action. Soskolne et al. (1989) reviewed the existing information to evaluate whether acids are likely to cause chronic effects, particularly cancer. They focused on the sulfuric acid literature, but asserted that the chronic tissue irritation associated with acid exposure and the perturbations of cellular functioning arising from pH extremes are plausible mechanisms of genotoxic and carcinogenic activity. Swenberg and Beauchamp (1997) concurred that a carcinogenic mechanism of action was feasible but concluded that the evidence from experimental animals neither strongly supports nor refutes the induction of cancer by inorganic acid mists.

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