Assessment of Exposure-Response Functions for Rocket-Emission Toxicants (1998)

NITRIC acid (HNO₃) is a colorless, photochemically stable gas in the atmosphere (EPA 1993). It is highly soluble in water to form an aqueous HNO₃ solution. Fuming HNO₃ is concentrated nitric acid that contains dissolved NO₂. Fuming nitric acid is a yellow-to-red fuming liquid with an acrid, suffocating odor. Because it is so volatile, HNO₃ gas at normal atmospheric concentrations does not condense into an aerosol. However, aerosols of aqueous HNO₃ are readily formed by passing clean air over reagent-grade aqueous HNO₃ (Koenig et al. 1989a). Due to the high aqueous vapor content of rocket-exhaust clouds, HNO₃ would likely exist in the aerosol form inside the clouds.

HNO₃ is widely used by a number of industries. In the chemical industry, it is used for the manufacture of metallic nitrates, sulfuric acid, aqua regia, arsenic acid and derivatives, nitrous acid and nitrites, oxalic acid, phthalic acid, and so forth. HNO₃ is used for the manufacture of trinitrophenol, trinitrotoluene, nitroglycerin, and various dyes and pharmaceuticals. Much of the NO and NO₂ emitted to the atmosphere from air-pollution sources is converted to HNO₃. EPA (1993) compiled measurements of average concentrations of HNO₃ in the continental United States; those ranged from 0.5 to 3 µg/m³ for 13 rural sites and from 1.1 to 2.7 µg/m³ for 5 urban sites. A 9-day average concentration of HNO₃ for Claremont, CA was 11 µg/m³ (4.4 ppb) (Wolff et al. 1991). Daily averages can be as high as 60 µg/m³ (26 ppb) and hourly averages as high as 200 µg/m³ (80 ppb) (EPA 1982; Lioy and Lippmann 1986; Lippmann 1989a,b). HNO₃ is produced at very low concentrations in rocket emissions from the combustion of hydrazine and N₂O₄ under normal launch conditions but at significant concentrations when a launch is aborted after ignition for rockets using liquid propellants.

The disposition of HNO₃ is not easily determined. It reacts immediately with respiratory mucous membranes after inhalation and does not appear to be absorbed after oral administration (Gosselin et al. 1984). Instead, it causes erosion of the gastrointestinal (GI) mucosal membranes, which produces severe GI distress. Following inhalation exposure, some HNO₃ might decompose to other nitrogen oxides, which might be absorbed by the bloodstream (EPA 1993) (see Appendix E).

The toxicity of HNO₃ is predominately associated with the extremely corrosive nature of this strong acid. In addition, it is an excellent oxidizing agent and reacts immediately with any tissue to cause such effects as skin burns, eye irritation, coughing, dyspnea, and pulmonary edema. Delayed toxicity, possibly as a result of the decomposition of HNO₃ to

other nitrogen oxides, could produce methemoglobinemia, but no documentation exists to support that hypothesis (EPA 1993). Respiratory disorders, including pulmonary edema, can occur several hours after an acute exposure and are probably related to inflammation resulting from cellular necrosis in lung tissues. Alveolar type II cells and cell hyperplasia of alveoli are primary cellular responses in the deep lung in animals treated with HNO₃ by instillation (1% solution). Bronchiolitis and alveolitis are associated with instillation of 1% HNO₃ in rats. There are no data concerning the developmental or reproductive effects of HNO₃ (EPA 1993).

Very little is known about the effects of HNO₃ vapor on animals or humans, and no long-term studies have been reported. An aqueous aerosol of HNO₃ can be generated by passing clean air over reagent-grade aqueous HNO₃ solution. Exposures to this aerosol should approximate the exposures of military and civilian populations to the combustion clouds that are produced by rocket emissions at ground level. Some information is known about the effect of HNO₃ gas on human respiratory function. The reported experimental exposures to HNO₃ as an aerosol or as a gas have been generally for short durations (40 min to 4 hr) that approximate the potential exposure duration for individuals in the vicinity of a launch.

There is no doubt that very high exposure concentrations of HNO₃ are lethal to humans. ''Rapidly progressive pulmonary edema of delayed onset" was observed after an exposure (10-15 min) of three young healthy men to fumes from an explosion of a tank that contained approximately 1,736 liters (L) of 66% HNO₃ (Hajela et al. 1990). The onset of "respiratory difficulties" occurred approximately 4-6 hr after the accident; all died within 24 hr of the exposure.

In a study with humans, exposure of 12 nonsmoking subjects with mild asthma for 3 min to an "acid fog" that was 30 milliosmolar (mOsm) at pH 2 significantly increased specific airway resistance (Balmes et al. 1989). The approximate concentration of HNO₃ in those studies was very high, 40 mg/m³ (15 ppm). Subjects inhaled the aerosols through a mouthpiece from an ultrasonic nebulizer. Bronchoconstriction was correlated with acidity of the fog, not the nature of the acid, since fogs

made up of either HNO₃ or H₂SO₄ or both showed equally potent effects. These studies showed that very short exposures to high concentrations of HNO₃ can cause moderate-to-severe effects in sensitive humans.

Aris et al. (1993) conducted an excellent study to determine the effects of HNO₃ gas, not aerosol, in healthy humans. They designed the study to reflect the conditions of exposure that might occur in dry weather. The test subjects (eight males and two females) were exposed to HNO₃ at 500 µg/m³ (0.2 ppm) in a 2.5 × 2.5 × 2.4 meter chamber for 4 hr during moderate exercise. Eighteen hours later the subjects underwent bronchoscopy, which included bronchial lavage and bronchial biopsy to evaluate biochemical and morphological changes. The study was done carefully and a number of end points were examined, including pulmonary function. None of the assessments of respiratory toxicity showed any effects from HNO₃ gas in the 10 subjects. Therefore, a human no-observed-effect level (NOEL) for HNO₃ can be established as 0.2 ppm for 4 hr.

Other investigators have tested lower concentrations of HNO₃ on human subjects. Becker et al. (1992) showed that a 200-µg/m³ (0.08 ppm) exposure for 2 hr produced no adverse respiratory effects in nine human subjects. That concentration was chosen to represent a concentration of HNO₃ that was higher than those observed in ambient air (EPA 1993); ambient concentrations ranged from 0.1 to 20 ppb. Later, Becker et al. (1996) used the same exposure concentration and duration, but did not observe any adverse effects as judged by bronchoalveolar lavage and pulmonary-function tests. None of the biochemical measures, such as protein levels, lactate dehydrogenase (LDH), and fibronectin, changed as a result of the exposure. The investigators observed a surprising increase in the phagocytic activity of alveolar macrophages from exposed individuals, but that was not believed to be an adverse effect. Therefore, no toxic effects occurred in humans exposed to HNO₃ for 2 hr at 0.08 ppm.

The use of a 0.2-ppm NOEL for healthy humans exposed to HNO₃ based on the study of Aris et al. (1993) appears appropriate. However, the studies of Koenig et al. (1989a,b) indicate that individuals with asthma might be more sensitive than those without. In these studies, adolescent asthmatic subjects (six males and nine females) with exercise-induced bronchospasm were exposed via a rubber mouthpiece with nose clips to HNO₃ aerosol at a concentration of 0.05 ppm (130 µg/m³). Respiratory function was measured at the end of the exposure. The expo-

sure at 0.05 ppm for 40 min (30 min at rest followed by a 10-min moderate exercise period) produced a decrease in forced expiratory volume (FEV) of 4% and an increase in respiratory resistance of 23% (Koenig et al. 1989a). The authors concluded that individuals with asthma represent a population group that might be exquisitely more sensitive to the effects of HNO₃ than healthy individuals.

However, another study of allergic adolescents selected by the same criteria (Koenig et al. 1989b) showed no effect at the same exposure concentration of HNO₃ for 45 min with 2 15-min moderate exercise periods and a 15-min rest period between exercise periods. The results of that study are different from those of the previous investigation in that no changes in respiratory function were produced, despite the increased period of exercise during the exposure. However, the exercise rate, measured as volume of air expired per minute, was slightly lower in the second study (Koenig et al. 1989b), 25 L/min, than in the first study (Koenig et al. 1989a), 32 L/ min. The authors attempted to explain the lack of an effect in the second study by emphasizing that the two studies were conducted during different parts of the calendar year. However, it is difficult to rationalize why testing in summer months would produce effects and testing in winter months would not produce effects in a well-controlled study, because cold-induced bronchospasm often occurs in those with asthma. The subcommittee concludes that, although the results of the two human studies appear to be contradictory, exposure to HNO₃ at 0.05 ppm for 40 to 45 min might cause respiratory problems in certain sensitive subgroups such as in asthmatic individuals. That low exposure concentration and duration can be used to establish a NOEL for the subgroup of asthmatic individuals in the general population.

Table F-1 summarizes the quantitative exposure-response data for humans exposed to HNO₃ via inhalation.

Only a few studies have been conducted in which animals have been exposed to HNO₃ via inhalation. HNO₃ was administered via instillation in a number of studies, but that protocol represents an artificial method of administering HNO₃ directly to the respiratory tract. Although the method provides a good determination of the toxicities of

HNO₃ to tissues along the respiratory tract, the relevance of that method of administration is certainly questionable for human exposures to clouds of combustion products that contain HNO₃. Thus, installation studies will not be used to evaluate inhalation exposure-response levels in this report. Therefore, only two studies are listed in Table F-1, and both of those studies exposed sheep and rats to HNO ₃ vapor.

Abraham et al. (1982) exposed seven healthy sheep and seven allergic sheep to HNO₃ vapor at 1.6 ppm for 4 hr. The seven allergic sheep used in this study were characterized by their response (bronchospasm) to inhalation of a 1:20 dilution of Ascaris suum extract antigen. The animals had a mean pulmonary flow resistance of 1.4 ± 0.7 cm of H₂O/mL of lipopolysaccharide (LPS) before the antigen challenge, and 5.8 ± 4.1 cm of H₂O/mL of LPS after the challenge. Two of the healthy sheep had large increases in air reactivity after HNO₃ exposure; increases of over 100% in specific airway resistance of the lung occurred after carbachol challenge. Effects in the allergic sheep were more pronounced than in the nonallergic sheep. Nadziejko et al. (1992) observed a reduction in the ability of macrophages to generate a burst of superoxide in rats exposed to vapors of HNO₃ at 0.25 ppm for 4 hr.

The work of Abraham et al. (1982) with sheep and the studies of Nadziejko et al. (1992) with rats established the respiratory toxicity of HNO ₃ vapor exposures in animals. These studies show that 1.6 ppm is the lowest-observable-effect level (LOEL) for decreased pulmonary resistance in sheep and 0.25 ppm is the LOEL for reduction in respiratory burst of macrophages in rats. The reduction in respiratory burst of macrophages in rats is probably not an appropriate end point for setting a no-effect human exposure level, especially if uncertainty factors are applied to that level (see "Evaluation of Toxicity Information"), because reduction in macrophage function is not necessarily predictive of an adverse response in animals or humans. Conversely, HNO₃ administration to sheep caused increased pulmonary resistance, and the subcommittee considers that a moderate adverse effect. In the sheep study, allergic sheep were slightly more sensitive to HNO₃ exposures than healthy sheep.

Table F-2 summarizes established inhalation exposure limits for HNO ₃. ACGIH set the Threshold Limit Value (TLV) time-weighted average

(TWA) for HNO₃ at 2 ppm to be intermediate between the TLV for hydrogen chloride (5 ppm, ceiling) and the TLV for sulfuric acid (0.25 ppm). The TLV-short-term exposure limit is twice the TLV-TWA value.

Effects from exposures to HNO₃ can range from severe to mild, depending on exposure concentration; however, the relation between exposure concentration, duration, and severity of effect has not been quantified. Inhalation of aerosols or vapors of HNO₃ can produce severe edema and result in death in humans, but the exposure concentrations associated with death are very high and have not been measured. Mild effects resulting from exposure to HNO₃ include temporary nasal and eye irritation, which are common responses to acids. Other mild effects could include the reduction of respiratory burst of macrophages that have been observed in animals. Moderate effects include reductions in respiratory function, sometimes associated with bronchoconstriction. Those effects have been demonstrated almost exclusively in sensitive human populations (those with asthma). The data on HNO₃ toxicity are too few to allow estimation of a dose-response function for any health end point. Some data might be used to estimate exposure concentrations and dura-

tions at which no adverse health effects would be expected in exposed human populations.

If the study on rats by Nadziejko et al. (1992) were used to estimate a no-effect level for humans, applying an uncertainty factor of 10 to estimate a NOEL from a LOEL and an uncertainty factor of 10 to estimate effects in humans from effects in rats would yield a no-effect level of 0.0025 ppm in humans. However, as is demonstrated by the work of Aris et al. (1993), that level is far below the no-effect level for healthy humans. The subcommittee concludes, therefore, that changes in macrophage function in rats caused by this chemical are not an appropriate end point for predicting no-effect levels for the respiratory effects of HNO₃ in humans.

If a LOEL-to-NOEL uncertainty factor of 10 and an animal-to-human uncertainty factor of 10 are applied to the 1.6 ppm effect level for a 4-hr exposure of sheep from the work of Abraham et al. (1982), a value of 0.016 ppm is predicted to be a no-effect level in humans. That value is more than a factor of 10 below the observed no-effect level in human studies and would be more conservative than necessary to protect healthy humans.

The study by Aris et al. (1993) identified a NOEL for exposure of healthy humans to HNO₃ at 0.2 ppm for a period of 4 hr. To establish a NOEL for periods of 1 hr or less, Haber's rule is used to extrapolate from 0.2 ppm at 4 hr to a NOEL of 1.0 ppm (0.8 ppm rounded up) for a period of 1 hr or less. Haber's rule states that the biological effects of some types of inhalation toxicants are related to the total cumulative exposure, that is the time-weighted-average concentration multiplied by the duration of exposure. Given that acute HNO₃-induced inhalation toxicity results from the corrosive or acidic nature of the compound in the respiratory tract, Haber's rule is expected to apply to this compound over relatively short exposure durations. The subcommittee considers that exposure concentration to be a ceiling value, because toxicity can be observed in humans at concentrations about 15 times higher than 0.2 ppm for a short period. In addition, concentrations substantially higher that 1.0 ppm might produce decreased pulmonary resistance in humans, effects similar to those seen at 1.6 ppm in sheep.

The studies with human asthmatic subjects have shown that this portion of the population might be more sensitive to HNO₃ than healthy individuals. As discussed above, the two studies by Koenig et al. (1989a,b) provide somewhat different results but suggest that some

asthmatic individuals under some conditions might experience a mild, reversible increase in respiratory resistance when exposed to HNO₃ at concentrations as low as 0.05 ppm. Therefore, the subcommittee believes that 0.05 ppm should be considered a ceiling value for HNO₃ exposure of humans with compromised respiratory function.

It is obvious from the discussion above that a major research need for HNO₃ is to establish exposure-response information in animals or humans. The concentrations that produce no effects in humans are well founded, but an important gap exists in the exposure-response data between the 0.2-ppm NOEL and the 15-ppm concentration that produces bronchoconstriction. In addition, including sensitive individuals (e.g., with asthma) in the same experiment would be valuable in defining their relative sensitivity. A carefully performed study on experimental animals that includes a wide range of doses and functional, as well as histopathological, end points could be used to establish an exposure-response function for this chemical.

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