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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants 4 Hydrogen Fluoride This chapter summarizes the relevant epidemiologic and toxicologic studies of hydrogen fluoride. It presents selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation-exposure levels from the National Research Council and other agencies. The committee considered all that information in its evaluation of the U.S. Navy’s 1-h, 24-h, and 90-day exposure guidance levels for hydrogen fluoride. The committee’s recommendations for hydrogen fluoride exposure levels are provided at the end of this chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill the remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES Hydrogen fluoride is a corrosive, colorless gas that may fume in air (Budavari et al. 1989). Odor thresholds have been reported to range from 0.04 to 3 ppm (HSDB 2008). Like hydrogen chloride, hydrogen fluoride is highly soluble in water. Hydrofluoric acid is the term used to describe aqueous solutions of hydrogen fluoride. Selected physical and chemical properties are shown in Table 4-1. OCCURRENCE AND USE Hydrogen fluoride is used primarily to produce aluminum fluoride, synthetic cryolite, fluoropolymers, and chlorofluorocarbons (Lindahl and Mahmood 2005). It is also used in inorganic fluoride production, uranium enrichment, and fluorine production. Fluoride is found in some foods and beverages, particularly fish, seafood, gelatin, and tea; and many public water sources are fluoridated
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants TABLE 4-1 Physical and Chemical Properties of Hydrogen Fluoride Synonyms Anhydrous hydrofluoric acid CAS registry number 7664-39-3 Molecular formula HF Molecular weight 20.01 Boiling point 19.51°C Melting point −83.55°C Flash point NA Explosive limits NA Specific gravity 1.002 at 0°C/4°C Vapor pressure 917 mmHg at 25°C Solubility Very soluble in water and alcohol; slightly soluble in ether; soluble in many organic solvents Conversion factors 1 ppm = 0.82 mg/m3; 1 mg/m3 = 1.22 ppm Abbreviation: NA, not available or not applicable. Sources: Budavari et al. (1989) and HSDB (2008). (ATSDR 2003). Ambient air concentrations of hydrogen fluoride are typically below the detection limit, although concentrations may be higher near industrial facilities that use or produce hydrogen fluoride (ATSDR 2003). Hydrogen fluoride has been measured on board submarines. NRC (1988) listed hydrogen fluoride as a potential contaminant of submarine air and reported a concentration of 0.3 ppm. No information was provided on sampling protocol, location, operations, or duration. Trials conducted on three nuclear-powered attack submarines did not detect hydrogen fluoride; the level of detection was about 3 ppb (Hagar 2008). Whether the reported results are representative of the submarine fleet is not known; few details were provided about the conditions on the submarines when the samples were taken. No other exposure data were located. Hydrogen fluoride emissions aboard submarines are thought to arise from decomposition of halogenated hydrocarbons and refrigerants (Hagar 2008). SUMMARY OF TOXICITY Hydrogen fluoride and its aqueous solutions present an acute hazard by inhalation or dermal exposure. The primary target of airborne gaseous hydrogen fluoride is the respiratory tract; however, injury to distant organs may also occur because of absorption of substantial amounts of fluoride. Acute effects of hydrofluoric acid include damage to skin and lungs, including severe burns, and sys-
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants temic effects, such as cardiac arrhythmias and acute renal failure (see, for example, Sanz-Gallén et al. 2001; Björnhagen et al. 2003; Horton et al. 2004; Holstege et al. 2005; Mitsui et al. 2007; Vohra et al. 2008). Some of the systemic effects may be due to depletion of calcium and magnesium or hyperkalemia. The critical effects of inhalation exposure to hydrogen fluoride are respiratory tract irritation and the induction of respiratory disease. Respiratory tract irritation is documented in animal models and has been observed in controlled human exposure studies. Marked sensory irritation can occur at exposures greater than 3 ppm for 1 h (Lund et al. 1997). Prolonged respiratory tract effects can occur after short-term exposure. To evaluate longer-term exposures or systemic effects, the total fluoride intake from all exposure routes (inhalation, dermal, and ingestion) must be considered (EPA 1988; NRC 2006). Chronic exposure to hydrogen fluoride (with particulate fluorides) in the aluminum industry is associated with increased risk of asthma (Taiwo et al. 2006). The literature on the systemic toxicity of fluoride is voluminous and is not addressed in full detail here. NRC (2006) recently reviewed fluoride toxicity with an emphasis on chronic toxicity. Fluoride-induced effects include hormonal disturbances; renal damage; reproductive toxicity; skeletal changes, including fluorosis; and possible genotoxicity and cancer. Effects in Humans Accidental Exposures Several case reports of death after acute accidental exposure to hydrogen fluoride are available and have been extensively reviewed by ATSDR (2003) and NRC (2004). Most of the reports stem from accidents involving spills of hydrofluoric acid. Because of its high volatility, inhalation exposure to hydrogen fluoride results from spills of hydrofluoric acid. The degree to which hydrofluoric acid-induced burns or dermal absorption of fluoride may have contributed to the death is not known. Nonetheless, the case reports indicate that lung injury, including pulmonary edema (with or without hemorrhage), is common after such accidents. An informative case report describes the delayed and prolonged chemical pneumonitis that developed in a woman after use of large amounts of 8% hydrofluoric acid as a cleaner in an unventilated bathroom (Bennion and Franzblau 1997). Airborne hydrogen fluoride concentrations were unknown. Symptoms developed slowly in the days after the exposure and eventually necessitated oxygen therapy (100% O2; 10 cm H2O peak end-expiratory pressure) because of hypoxemia. Chest radiography indicated a lung infiltrate, and signs included diffuse rhonchi and wheezing in both lungs. Another case report describes a woman who used 8-9% hydrofluoric acid as a cleaner in a ventilated bathroom (Franzblau and Sahakian 2003). It was estimated that hydrogen fluoride in the bathroom may have exceeded 170 ppm.
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants She developed breathing problems, such as persistent wheezing and difficulty taking a deep breath, over the 1-2 months after exposure. Examination at that time revealed a mild obstructive pattern. Several months after the exposure, she was diagnosed with reactive airways dysfunction syndrome (RADS); her intermittent wheezing on exertion persisted for at least 3 years. An industrial accident in Texas in 1987 resulted in the release of 24,000 kg of hydrogen fluoride and about 3,000 kg of isobutane over a small community (population, 41,000; Wing et al. 1991). The airborne hydrogen fluoride concentration 1 h after the accident was reported to be 10 ppm; 2 h after the accident, concentrations were “minimal.” The report indicates that air sampling was performed at those times but provides no information on the analytic methods used to determine hydrogen fluoride concentrations. A total of 939 people sought emergency care; common symptoms were eye irritation, throat irritation (burning), headache, and shortness of breath. Of those who sought care, 94 were hospitalized. Forced expiratory volume in 1 s (FEV1) was less than 80% of predicted in one-third of the people who sought medical care and were not hospitalized compared with half the people who were hospitalized. A follow-up study revealed that respiratory symptoms persisted in some people for at least 2 years, although much reduced (Dayal et al. 1992). The degree to which psychologic factors influenced the symptoms is unknown, but it is thought that the symptoms could not be explained entirely on the basis of psychologic stress (Dayal et al. 1994). In summary, respiratory tract injury appears to be the predominant response to accidental exposure to hydrogen fluoride. Respiratory tract effects include irritation, airway obstruction (as assessed with FEV1), and airway inflammation. Upper airway symptoms may have occurred in some situations and gone unreported because they were overshadowed by the lower airway effects. There are suggestions that long-term respiratory tract effects may occur after exposure to hydrogen fluoride at high concentrations as indicated by the development of RADS in one subject and the presence of persistent respiratory symptoms in the general population after the release of hydrogen fluoride during an industrial accident. The studies indicate that the respiratory tract may be a critical target of hydrogen fluoride in the general population but do not provide information on concentration-response relationships. Fluoride ion is rapidly and efficiently absorbed into the circulation after inhalation of hydrogen fluoride or airborne fluorides as indicated by increased blood or urinary fluoride concentrations (see, for example, Collings et al. 1951, 1952; Largent et al. 1951). Therefore, the possibility of systemic fluoride-induced injury after accidental exposure to hydrogen fluoride is important to consider. Little information is available on systemic effects after accidental inhalation exposure to fluoride, but accidental ingestion has been followed by itching, rash, gastrointestinal symptoms, and numbing or tingling of extremities or the face (reviewed by NRC 2006).
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants Experimental Studies Upper Airway Irritation There are several published controlled studies of short-term inhalation exposure to hydrogen fluoride in humans (Table 4-2). The exposure durations in the studies spanned from 1 min to 6 h/day for multiple days. All studies report upper airway irritation as the predominant symptom. The degree of upper airway irritation was reported as intolerable at 122 ppm for more than 1 min, marked at 61 ppm for several minutes, and mild at 32 ppm for several minutes (Machle et al. 1934). Lund et al. (1997) described a 1-h exposure with exercise at low concentration (0.2-0.7 ppm), intermediate concentration (0.9-2.9 ppm), and high concentration (3.1-6.3 ppm). Exercise consisted of a fixed workload of 75 W on a bicycle ergometer for the last 15 min of exposure. There were no air-exposed control subjects, but baseline reporting of symptoms was conducted for all subjects before exposure. Subjects were men, 21-44 years old; persons with asthma or recent respiratory tract infection were excluded from the study, but the study group did include people with “hay fever.” Symptoms, including upper airway (nose or throat) itching and soreness, were reported during exposure on a scale of 0-5 (1 was very mild, and 5 was severe). More detail was not provided on the scaling; the authors report ratings of 1-3 as representing a “low” degree of irritation and greater than 3 as representing a “high” degree of irritation. It seems reasonable to assume that low corresponds to mild irritation and high corresponds to moderate to marked irritation. In the low-concentration group, four of nine subjects reported mild upper airway irritation. In the intermediate-concentration group, six of seven reported mild irritation. In the high-concentration group, three of seven reported moderate to severe irritation, and the other four reported mild irritation. Thus, a clear concentration-response relationship was observed in the study. Only mild irritation was reported at concentrations as high as 2.9 ppm, whereas marked irritation was reported in some subjects at concentrations as low as 3.1 ppm. Thus, 3 ppm appears to reflect the demarcation between minimal and marked irritation, at least as determined by the small number of subjects in this study. In a later study with high concentration (4.0-4.8 ppm), six of 10 subjects reported mild irritation, and one of 10 reported marked irritation (Lund et al. 2002)—essentially the same response pattern observed in their earlier study (Lund et al. 1997). There were no air-exposed control subjects, but baseline reporting of symptoms was conducted for all subjects before exposure. Largent (1961) performed a study with multiple 6-h exposures to hydrogen fluoride 5 days/week for a total of 10-50 exposures. Again, upper airway irritation was experienced. One subject exposed at 1.4 ppm reported no symptoms, and all five subjects exposed at 2.6-4.7 ppm reported the perception of
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants TABLE 4-2 Effects of Hydrogen Fluoride in Controlled Human Studies Concentration (ppm) Duration Subjects and Effects Reference 32, 61,122 1 to several min Two healthy subjects, smoking status unknown Maximum tolerable level (1 min) at 122 ppm; marked conjunctival, nasal, and large airway irritation at 61 ppm (several minutes); mild conjunctival, nasal, and large airway irritation at 32 ppm (several minutes); sour taste detected at all concentrations Machle et al. 1934 1.4, 2.6-4.7 6 h/day 5 days/week 10-50 days Five healthy subject, smoking status unknown No reported airway irritation in one subject exposed at average of 1.4 ppm; slight cutaneous (facial), ocular, and nasal irritation in all subjects at average concentration of 2.6-4.7 ppm daily for a total of 10-50 days; cutaneous erythema frequent (requiring face-cream application); increased symptoms in one subject who developed an upper respiratory tract infection during the protocol Largent 1961 0.2-6.3 1 h (with exercise) Twenty healthy, nonsmoking men (21-44 years old); persons with airway infection or history of asthma excluded; three exposure groups (low, 0.2-0.7 ppm; middle, 0.9-2.9 ppm; high, 3.1-6.3 ppm); symptom scores reported as “low,” presumably mild (1-3 on scale of 0-5), and “high,” presumably moderate to marked (>3 on scale of 0-5). Lund et al. 1997 Mild upper airway irritation was reported in four of nine subjects in low-concentration group, six of seven in middle concentration group, four of seven in high-concentration group; moderate to severe upper airway irritation reported in three of seven in high-concentration group; mild lower airway irritation reported in two of seven and moderate to severe irritation in one of seven in high-concentration group; eye irritation (mild) reported in two subjects in each concentration group
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants Concentration (ppm) Duration Subjects and Effects Reference 0.2-6.3 1 h (with exercise) Nineteen healthy, nonsmoking men (21-44 years old); persons with airway infection or history of asthma excluded; three exposure groups (low, 0.2-0.7 ppm; middle, 0.9-2.9 ppm; high, 3.1-6.3 ppm). Lund et al. 1999 Publication presumably provides BAL results in subjects described in Lund et al. (1997); BAL performed 24 h after exposure; percentage of lymphocytes increased in both bronchial and bronchoalveolar portions of BAL with no apparent concentration-response relationship; increases appeared to be present in middle-and high-concentration groups; no observed changes in any other cell type; myeloperoxidase increased in bronchial portion of BAL with no apparent concentration-response relationship 4.0-4.8 1 h (with exercise) Ten healthy, nonsmoking men (21-44 years old); persons with airway infection or history of asthma excluded; all exposed at 4.0-4.8 ppm for 1 h with exercise; nasal irritation symptoms reported as “low,” presumably mild (1-3 on scale of 0-5), and “high,” presumably moderate to marked (>3 on a scale of 0-5). Lund et al. 2002 Mild irritation reported by six of 10 and marked irritation by one of 10 subjects; nasal lavage performed immediately and 90 min after exposure; lavage neutrophil count and lavage proteins (TNF-α, PGE2, LTB4, peptide LT) significantly increased; symptom score and lavage neutrophil counts correlated with each other 4.0-4.8 1 h (with exercise) Ten healthy, nonsmoking men (21-44 years old); persons with airway infection or history of asthma excluded; all exposed at 4.0-4.8 ppm for 1 h with exercise; nasal symptomology not measured; BAL performed 2 h after exposure Lund et al. 2005 No increase observed in differential cell count or in numerous mediators (interleukins, myeloperoxidase, eicosanoids, others); several significantly decreased. Abbreviations: BAL, bronchoalveolar lavage; LTB4, leukotriene B4; PGE2, prostaglandin E2; TNF-α, tumor-necrosis factor-alpha; peptide LT, peptide leukotriene.
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants slight irritation. One subject developed an “upper airway cold” during the protocol, at which time exposure at 3.4 ppm produced “considerable discomfort.” All subjects completed the multiple-exposure regimen—an indication that the degree of irritation was not sufficient to cause withdrawal from the study. Although a quantitative scaling of symptoms was not reported, comparison of the data with the symptoms reported in the studies of Lund et al. (1997, 2002) suggests that repeated exposure to hydrogen fluoride does not result in exacerbation of the irritation response and may actually lead to some degree of habituation. In summary, symptoms of upper airway irritation were uniformly reported in clinical studies. The threshold for mild irritation may be 0.5 ppm or less in some people. Given that the studies used small numbers of subjects, the database suggests that a significant fraction of subjects experience moderate to marked irritation at concentrations over 3 ppm but only mild irritation at lower concentrations. Lower Airway Irritation Lower airway irritation has been reported in human subjects exposed to hydrogen fluoride but is generally of less magnitude than upper airway irritation. In the intermediate-concentration group (0.9-2.9 ppm) of the study of Lund et al. (1997), one of seven subjects reported mild lower airway irritation (chest tightness and soreness, coughing, expectoration, or wheezing) during the 1-h exposure (compared with six of seven reporting mild upper airway irritation). In the high-concentration group (3.1-6.3 ppm), two of seven reported mild lower air-way symptoms, and one of seven reported moderate to marked lower airway symptoms compared with three of seven reporting upper airway symptoms of this degree. A concentration-response relationship may be apparent, but the changes in the lower airway symptoms did not achieve statistical significance, and this led the study authors to conclude that lower airway symptoms were not reported to a significant degree in relation to exposure to hydrogen fluoride. The study design included forced expiration to assess lower airway physiologic changes. No consistent change was observed in forced vital capacity (FVC) or FEV1. Thus, mild symptoms of lower airway irritation occur at exposures as high as 2.9 ppm, and more marked symptoms may occur in some people exposed at higher concentrations, but such changes occurred in the absence of alterations in airway function as assessed by forced expiration. Airway Inflammation Hydrogen fluoride exposure for 1 h results in airway inflammation as assessed by increases in inflammatory cells in nasal lavage or bronchoalveolar lavage (BAL) fluid. Exposure at 4.4 ppm for 1 h (range, 4.0-4.8) results in a significant increase in nasal lavage neutrophils and proinflammatory mediators,
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants including tumor-necrosis factor-alpha, prostaglandin E2, and leukotriene B4 (Lund et al. 2002). Although hydrogen fluoride clearly induced upper airway inflammation, the exposure was not debilitating, nor would any long-term effects be expected to result from a response of this nature. Exposure to hydrogen fluoride for 1 h also results in inflammatory cell changes in the lower airways as assessed by BAL (Lund et al. 1999). A significant correlation between increases in BAL lymphocyte numbers (but not neutrophil or eosinophil numbers) and increased exposure concentrations was observed 24 h after exposure (Lund et al. 1999, which involved the same subjects described in Lund et al. 1997). It is difficult to discern precisely the concentration-response relationships from the data presented, but apparently no alteration occurred in the low-concentration (0.2-0.7 ppm) group; increases in BAL lymphocyte number occurred only in the intermediate (0.9-2.9 ppm) and high (3.1-6.3 ppm) groups. The changes were observed 24 h but not 2 h after the 1-h exposure (Lund et al. 1999, 2005). Although lavage neutrophil numbers were not significantly increased, a slight increase in the myeloperoxidase content in the bronchial portion of the BAL fluid was observed; this suggests that subtle recruitment or activation of neutrophils occurred. The absence of an overt increase in neutrophils or overt symptoms suggests that the responses would not result in short-term or long-term health impairment. Other Irritation Effects Cutaneous irritation and ocular irritation have been reported in subjects exposed to hydrogen fluoride. In the study of Machle et al. (1934), two subjects exposed to hydrogen fluoride at 32 ppm or higher for several minutes reported cutaneous, ocular, and respiratory tract irritation. Ocular irritation was reported during 1-h exposures in the study of Lund et al. (1997), but the degree of ocular irritation was less than that of upper airway irritation. Largent (1961) used multiple 6-h exposures and found that cutaneous irritation was experienced at 2.6-4.7 ppm. Subjects applied cream to alleviate symptoms. Cutaneous erythema was common in the five subjects although reported to be without discomfort. One subject experienced peeling of the skin in the third week of exposure. It should be noted that the sour, pungent taste of hydrogen fluoride can be detected during exposure at above 3 ppm. Amoore and Hautala (1983) reported the odor threshold at below 1 ppm. Systemic Effects Exposure to hydrogen fluoride or other airborne fluorides may result in absorption of fluoride ion (see, for example, Collings et al. 1951, 1952; Largent et al. 1951; Waldbott and Lee 1978); thus, the potential for fluoride-induced systemic effects should be considered. For example, given a ventilation rate of
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants 15 m3/day (EPA 1997) for a 70-kg man and 100% deposition and absorption, a 1-h exposure to hydrogen fluoride at 3 ppm results in systemic absorption of 1.5 mg of fluoride (0.02 mg/kg).1 Few experimental studies involving human exposure to hydrogen fluoride or inhaled fluorides are available; experimental studies and case reports involving ingestion of fluoride have reported antithyroid effects (0.03-0.14 mg/kg-day for 20-245 days; Galletti and Joyet 1958) and hypersensitivity or reduced tolerance to fluoride (0.02 mg/kg-day for short-term exposures; Grimbergen 1974; Waldbott 1956, 1958). One study reported a threshold of hydrogen fluoride for the light-adaptive reflex2 of 0.04 ppm (Sadilova et al. 1965) in three subjects exposed to hydrogen fluoride at 0.02, 0.04, or 0.07 ppm (exposure duration not available), but it is difficult to evaluate the underlying experimental work (Smith and Hodge 1979), and the toxicologic relevance of the response is unknown (ATSDR 2003). The absorbed doses at those exposures are likely to be so low that it is difficult to attribute the neurologic effect to absorbed fluoride itself. Occupational and Epidemiologic Studies A variety of occupational and epidemiologic studies of airborne and ingested fluoride have been conducted; many of them have been reviewed by NRC (2006) and ATSDR (2003). The following paragraphs discuss respiratory symptoms (asthma), renal damage, endocrine effects, increased risk of bone fracture, and bone and joint pain (skeletal fluorosis). In the workplace, exposure to hydrogen fluoride rarely occurs in the absence of exposure to other particulates (such as calcium fluoride [CaF2] or sodium aluminum fluoride [Na3AlF6]) or gaseous fluoride-containing materials (such as tetrafluorosilane [SiF4]); this confounds interpretation of the results with respect to the effects of hydrogen fluoride. That is particularly true of possible effects of systemic fluoride absorption because the source of the fluoride is not known with certainty. Many studies of worker health in the aluminum industry have found an association between occupational exposure to fluoride in aluminum “potrooms” and respiratory disease or asthma (see, for example, Kaltreider et al. 1972; Soyseth and Kongerud 1992; Kongerud et al. 1994). Most studies, however, did not reveal potential etiologic agents. In aluminum potrooms, workers are exposed to particulate fluoride, gaseous fluoride (presumably hydrogen fluoride), sulfur dioxide, and other irritants. A recent study of the health of workers in the aluminum industry suggests that exposure to airborne fluorides is associated with an increased incidence of asthma (Taiwo et al. 2006). Analysis of records on 1 The calculation is as follows: (15 m3/day)(1 day/24 h)(3 ppm)(0.82 mg/m3 per ppm)(19/20 mg fluoride per mg hydrogen fluoride) = 1.5 mg of fluoride for 1-h exposure, assuming 100% absorption. 2 The light-adaptive reflex is defined as reflex changes in ocular sensitivity to light based on dark adaptation. It is measured as a marker of neurologic effects.
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants 12,000 workers (about 10% of whom worked in potrooms) found an increased risk of asthma in workers exposed to gaseous fluoride at 0.27 ± 0.53 ppm (mean ± SD) for an average of 16 ± 10.8 years. The study included only people who had a new diagnosis of asthma after two or more asthma-free years in the workplace; thus, anyone who developed occupationally related asthma in the first 2 years of employment was excluded. The average age of the potroom workers was 43.7 ± 10.1 years. Using a multivariate generalized linear model relating the natural logarithm of predicted asthma rate, the authors concluded that asthma risk was significantly associated with exposure to hydrogen fluoride and current smoking but not to other contaminants in the workplace, such as particulate fluoride and sulfur dioxide. The relative risk for development of asthma was estimated by the model to be 1.18 per 0.1 mg/m3 change in hydrogen fluoride (95% confidence interval [CI], 1.09-1.3), which corresponds to a relative risk of 1.18 per 0.12 ppm. Although documentation of an association does not indicate cause and effect, a 1-h exposure to hydrogen fluoride does cause increased BAL lymphocytes (Lund et al. 1999), and persistent respiratory symptoms were reported in the general community after exposure to hydrogen fluoride in an industrial accident (Wing et al. 1991). Those facts raise concern that the increased incidence of asthma in potroom workers may reflect a response to hydrogen fluoride. It is important to note that the presence of high dust concentrations and other irritants and occasional short-term (15-min) high-exposure excursions to hydrogen fluoride may have contributed to the response (Taiwo et al. 2006). Waldbott and Lee (1978) reported a case of systemic fluoride toxicity from repeated exposures to hydrogen fluoride gas in the alkylation unit of an oil company. Estimated exposures over the worker’s 10 years of employment were often above 3 ppm, on the basis of odor detection, and were thought to have been very high (25-200 ppm) during some procedures. Chronic symptoms included reduction in pulmonary function, gastrointestinal problems, and severe back and leg pains. Fluoride measured in bone 10 years after the maximal exposures was significantly above normal. Given a hydrogen fluoride concentration of 3 ppm, an 8-h workday, a ventilation rate of 15 m3/day, and complete absorption, the worker’s minimum systemic fluoride dose was 8 mg/day, averaged over the entire week, or about 0.08 mg/kg-day for his reported weight of 230 lb (105 kg).3 Derryberry et al. (1963) reported a significantly higher frequency of albuminuria in a group of workers exposed to airborne fluoride in a phosphate-fertilizer plant than in nonexposed controls (12.2% vs 4.5%) and suggested a relationship between fluoride excretion and renal function. Urinary fluoride excretion averaged 4.6 mg/L (range, 2.1-14.7 mg/L) in the exposed group and 1.15 mg/L (range, 0.15-3.2 mg/L) in the controls. Two studies of aluminum potroom workers did not yield similar findings (reviewed by Hodge and Smith 1977). 3 The calculation is as follows: (15 m3/day)(1 day/24 h)(3 ppm)(0.82 mg/m3 per ppm)(19/20 mg fluoride per mg hydrogen fluoride)(8 h/day)(5/7) = 8 mg/day, assuming 100% absorption and dose averaged over the entire week.
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants 1991), 25% mortality was observed in male rats exposed to hydrogen fluoride at 10 ppm. Neither mortality nor histologic lesions were observed at 0.1 or 1 ppm for 90 days, but it is not clear that the critical regions of the nose were examined (Placke and Griffin 1991; Rosenholtz et al. 1963). On the basis of body-weight reductions, the study authors considered 1 ppm to represent a NOAEL. The subchronic animal exposure study of Stokinger (1949) included only a small number of animals, and complete histopathologic evaluation was not performed, so use of the results is problematic. In that study, one of five dogs exposed to hydrogen fluoride at 8.6 ppm 6 h/day, 5 days/week for 10 weeks exhibited focal pulmonary hemorrhage that was observable during necropsy, but no histologic examinations of the nose or lungs were included. Thus, the committee considered the animal studies as inadequate for establishing a CEGL. If a human NOAEL were derived from the animal NOAEL of 1 ppm by applying an interspecies uncertainty factor of 3-10, the resulting value would not differ markedly from a NOAEL derived from occupational epidemiology in which a relative risk of asthma for hydrogen fluoride of 1.18 per 0.12 ppm was estimated. Given the weaknesses of the animal database and the weight that human data should receive for risk assessment, it is appropriate to base the 90-day CEGL on the human occupational epidemiologic data. Because the other agents in the workplace (such as particulate fluorides and sulfur dioxide) and the short-term high-exposure excursions may have contributed to the asthma risk in the workers, the relative risk for hydrogen fluoride of 1.18 per 0.12 ppm may overestimate the health risk. Therefore, 0.12 ppm is a reasonable point of departure for CEGL derivation. A concentration-time extrapolation of the data is problematic; workers in the study of Taiwo et al. (2006) were exposed 8 h/day, 5 days/week for at least 2 years compared with submariners’ exposure 24 h/day for 90-day durations. The two scenarios may represent similar exposure concentrations on an annualized basis; therefore, a concentration-time extrapolation is not proposed. The worker population in the epidemiologic study most likely included people who had rhinitis or were otherwise sensitive, so an interindividual uncertainty factor is not suggested here. Although the occupational epidemiologic study of Taiwo et al. (2006) was well performed, uncertainties are associated with using this study, particularly the uncertainty introduced by excluding people who had a new diagnosis of asthma within 2 years of beginning work. On the basis of that uncertainty and the difficulty of extrapolating a typical 5 days/week occupational exposure to the submarine setting, a database uncertainty factor of 3 was applied. The resulting 90-d CEGL is 0.04 ppm. Sensory irritation is not expected at this exposure level on the basis of the 1-h and multiple 6-h human studies by Lund et al. (1997) and Largent (1961). The proposed 90-d CEGL of 0.04 ppm most likely protects against systemic fluoride-induced toxicity if airborne hydrogen fluoride is the only important source of fluoride exposure. At a ventilation rate of 15 m3/day, it corresponds to a total absorbed dose of 0.5 mg/day (0.007 mg/kg-day for a 70-kg person). However, for systemic effects, it is necessary to consider fluoride exposure from all sources (EPA 1988; NRC 2006). Furthermore, it is necessary to
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants consider effects that could occur within a 90-day exposure and long-term effects due to cumulative exposures, of which 90-day exposures on a submarine would be a part. Health end points that require long-term exposure or accumulation of fluoride include effects on bones (increased risk of fracture and of skeletal fluorosis). Other effects (such as endocrine effects) do not necessarily require accumulation or long-term exposure but may depend on current physiologic fluoride concentrations. In particular, subchronic thyroid effects have been reported in animals—an indication that altered concentrations of thyroid hormones do not necessarily require long exposure. Impaired glucose tolerance and male reproductive effects have also been reported in animals exposed to fluoride for 28-100 days. Table 4-8 summarizes systemic fluoride effects and corresponding estimated intakes in humans. For most end points, systemic effects in generally healthy people have been reported in situations corresponding to estimated average chronic intakes of around 0.05 mg/kg-day or higher. Long-term fluoride exposure would include exposure to airborne and ingested fluoride on board a submarine and on shore. Table 4-9 summarizes the estimated average fluoride intake (by source and total from all sources) based on information provided to the committee by the U.S. Navy (LCDR D. Martin, U.S. Navy, personal commun., July 8, 2008). The proposed 90-d CEGL of 0.04 ppm based on chronic respiratory effects would lead to a systemic fluoride intake of 0.5 mg/day (0.007 mg/kg-day) at an inhalation rate of 15 m3/day (EPA 1997) and an average body weight of 70 kg. That value would correspond to an estimated average total systemic fluoride intake (from all sources) of 0.023 or 0.026 mg/kg-day for normal or high activity levels, respectively (Table 4-9). That estimated total daily fluoride intake is less than 0.05 mg/kg-day, the lowest dose associated with the potential for fluoride-induced systemic toxicity (Table 4-8). Persons who have fluoridated water on shore will have total systemic fluoride intakes on board a submarine that will be lower than those on shore. TABLE 4-8 Summary of Systemic Effects in Humans Associated with Chronic Intake of Fluoride from All Sources Effects Estimated NOAEL (mg/kg-day) Typical Fluoride Intake Associated with Effects (mg/kg-day) Endocrine effects 0.01-0.03 0.05 Increased risk of bone fracture NA ~0.05 Skeletal fluorosis (stage II) NA 0.05 Reduced testosterone concentrations <0.03 0.05 NA, not available.
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants TABLE 4-9 Estimated Fluoride Intakes (mg/kg-day) for Specified Exposure Situationsa Source of Fluoride Exposure On Board Submarine On Shore Drinking water (normal activity) 0.0024b Fluoridated source:c Nonfluoridated source:c 0.0173 0.0024 Drinking water (high activity)d 0.005 Fluoridated source: Nonfluoridated source: 0.05 0.005 Food and beveragese 0.0114 0.0114 Pesticidesf 0.0007 0.0007 Toothpasteg 0.0014 0.0014 Air 0.007h 0.0006 Totals: Normal activity 0.023 Fluoridated source: Nonfluoridated source: 0.031 0.017 High activity 0.026 Fluoridated source: Nonfluoridated source: 0.064 0.019 aBased on NRC (2006) estimates for U.S. adults 20-49 years old unless otherwise indicated. bAssumes that drinking water on submarine is primarily from reverse-osmosis unit. Purified water is expected to have low fluoride concentrations (<0.15 mg/L; NRC 2006). cDrinking water on shore could be from fluoridated sources (around 1 mg/L) or non-fluoridated sources (defined as <0.7 mg/L; assumed here to be ≤0.5 mg/L). Two types of sources are considered separately. dAssumes a drinking-water intake of 50 mL/kg of body weight per day (Table 2-4, NRC 2006) and fluoride concentrations of 1 mg/L (fluoridated source) or 0.1 mg/L (on board submarine or nonfluoridated source on shore). eFood on board submarine includes fresh and frozen ingredients, canned soups and vegetables, and canned fruits and fruit juices. Commercial beverages (such as soft drinks and bottled tea) are available. Tea, coffee, and Kool-Aid are available. Tea is prepared from tea bags. This diet is considered comparable with average diet of adults in United States with respect to fluoride intake. fExposure to fluoride from pesticides is considered typical for adults in United States. gToothpaste use and inadvertent ingestion of toothpaste are considered typical for adults in United States. hBased on proposed 90-d CEGL of 0.04 ppm, inhalation rate of 15 m3/day, and average body weight of 70 kg. DATA ADEQUACY AND RESEARCH NEEDS NRC (2006) identified a number of research needs regarding fluoride toxicology for various health end points. In particular, nearly all human studies require improved characterization of fluoride exposure, including individual fluoride intake. There are very few subchronic or short-term studies of humans with any route of exposure. There have been occupational studies and studies of ex-
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Emergency and Continuous Exposure Guidance Level for Selected Submarine Contaminants posures to airborne fluoride from coal combustion in China, but most of the literature on effects in humans comes from ingestion exposures, primarily to fluoride in drinking water. Although many health end points (such as effects on bones) require long-term exposure or accumulation of fluoride, others (such as endocrine effects, low tolerance or hypersensitivity, and asthma) do not. A critical research need for animal studies would be a 90-day continuous-inhalation bioassay for hydrogen fluoride. Studies that use multiple 90-day exposures that mimic the exposure of the submarine crew may be needed to examine fully the potential for the induction of asthma. A species appropriate for examination of induction of allergic airway disease and measures of airway function would be critical for such a study. REFERENCES Aardema, M.J., and T. Tsutsui. 1995. Sodium fluoride-induced chromosome aberrations in different cell cycle stages. Mutat. Res. 331(1):171-172. Aardema, M.J., D.P. Gibson, and R.A. LeBoeuf. 1989. Sodium fluoride-induced chromosome aberrations in different stages of the cell cycle: A proposed mechanism. Mutat. Res. 223(2):191-203. ACGIH (American Conference of Governmental Industrial Hygienists). 2005. Threshold Limit Values (TLVs) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs) for 2005. American Conference of Governmental Hygienists, Cincinnati, OH. Alarie, Y. 1973. Sensory irritation by airborne chemicals. CRC Crit. Rev. Toxicol. 2(3):299-363. Alexeeff, G.V., D.C. Lewis, and N.L. Ragle. 1993. Estimation of potential health effects from acute exposure to hydrogen fluoride using a “benchmark dose” approach. Risk Anal. 13(1):63-69. Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3(6):272-290. Ando, M., M. Tadano, S. Yamamoto, K. Tamura, S. Asanuma, T. Watanabe, T. Kondo, S. Sakurai, R. Ji, C. Liang, X. Chen, Z. Hong, and S. Cao. 2001. Health effects of fluoride pollution caused by coal burning. Sci. Total Environ. 271(1-3):107-116. Araibi, A.A., W.H. Yousif, and O.S. Al-Dewachi. 1989. Effect of high fluoride on the reproductive performance of the male rat. J. Biol. Sci. Res. 20(1):19-30. ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile for Fluorides, Hydrogen Fluoride, and Fluorine. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. September 2003 [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp11-p.pdf [accessed Mar. 27, 2009]. ATSDR (Agency for Toxic Substances and Disease Registry). 2008. ATSDR Minimal Risk Levels (MRLs). U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA. December 2008 [online]. Available: http://www.atsdr.cdc.gov/mrls/pdfs/atsdr_mrls_december_2008.pdf [accessed Mar. 27, 2009].
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