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5
Formaldehyde

This chapter summarizes the relevant epidemiologic and toxicologic studies on formaldehyde. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are also presented. The subcommittee considered all of that information in its evaluation of the Navy’s current and proposed 1-hour (h), 24-h, and 90-day exposure guidance levels for formaldehyde. The subcommittee’s recommendations for formaldehyde exposure levels are provided at the conclusion of this chapter along with a discussion of the adequacy of the data for defining those levels and the research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Formaldehyde is a flammable, colorless gas at room temperature and has a pungent, suffocating odor (Budavari et al. 1989). Odor thresholds ranging from 0.5 to 1.0 parts per million (ppm) (ATSDR 1999) and 0.06 to 0.5 ppm (Gerberich et al. 1994) have been reported. Formaldehyde reacts readily with many substances and polymerizes easily, making it one of the world’s most important industrial chemicals (Gerberich et al. 1994). Selected chemical and physical properties are listed in Table 5-1.

OCCURRENCE AND USE

Formaldehyde is an important industrial chemical because of its versatility as a chemical intermediate (Gerberich et al. 1994). It primarily is used in the production of urea-formaldehyde, phenol-formaldehyde, and



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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 5 Formaldehyde This chapter summarizes the relevant epidemiologic and toxicologic studies on formaldehyde. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are also presented. The subcommittee considered all of that information in its evaluation of the Navy’s current and proposed 1-hour (h), 24-h, and 90-day exposure guidance levels for formaldehyde. The subcommittee’s recommendations for formaldehyde exposure levels are provided at the conclusion of this chapter along with a discussion of the adequacy of the data for defining those levels and the research needed to fill the remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES Formaldehyde is a flammable, colorless gas at room temperature and has a pungent, suffocating odor (Budavari et al. 1989). Odor thresholds ranging from 0.5 to 1.0 parts per million (ppm) (ATSDR 1999) and 0.06 to 0.5 ppm (Gerberich et al. 1994) have been reported. Formaldehyde reacts readily with many substances and polymerizes easily, making it one of the world’s most important industrial chemicals (Gerberich et al. 1994). Selected chemical and physical properties are listed in Table 5-1. OCCURRENCE AND USE Formaldehyde is an important industrial chemical because of its versatility as a chemical intermediate (Gerberich et al. 1994). It primarily is used in the production of urea-formaldehyde, phenol-formaldehyde, and

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants TABLE 5-1 Physical and Chemical Properties of Formaldehydea Synonyms and trade names Formic aldehyde, methanal, methyl aldehyde, methylene oxide, oxomethane, oxymethylene CAS registry number 50-00-0 Molecular formula HCHO Molecular weight 30.03 Boiling point –19.5°C Melting point –92°C Flash point 83°C (closed cup) Explosive limits 7% to 73% Specific gravity 1.067 with respect to air Vapor pressure 3,890 mmHg at 25°C Solubility Very soluble in water; soluble in alcohol and ether Conversion factors 1 ppm = 1.23 mg/m3; 1 mg/m3 = 0.81 ppm aFlash point and explosive limits from ACGIH (2001), vapor pressure from HSDB (2003), and all other data from Budavari et al. (1989). Abbreviations: mg/m3, milligrams per cubic meter; mmHg, millimeters of mercury; ppm, parts per million. melamine-formaldehyde resins, which are used as adhesives in the production of particle board, fiber board, and plywood. Formaldehyde is also used in the manufacture of plastics, insulation, fertilizers, fungicides, biocides, corrosion inhibitors, embalming fluids, disinfectants, and household cleaners, and it is used in the textile industry in the production of permanent press and fire-retardant fabrics. Formaldehyde occurs naturally in the environment and is emitted from vegetation, forest fires, and animal wastes (ATSDR 1999). It is a natural component of fruits and other foods and is an essential intermediate in human metabolism (IARC 1995; ATSDR 1999). Although naturally occurring, formaldehyde also enters the environment from many anthropogenic sources. In fact, combustion sources, such as power plants, incinerators, refineries, wood stoves, kerosene heaters, and cigarettes, are typically the largest contributors of formaldehyde emitted to the environment (ATSDR 1999). Other sources of formaldehyde emissions include motor vehicles, construction materials, textiles, paper, and cosmetics. Formaldehyde has been monitored in both ambient and indoor air; concentrations are typically higher in indoor air (ATSDR 1999). Ambient measurements in urban and rural areas in the United States indicate a range

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants of 1 to 68 parts per billion (ppb) (ATSDR 1999). Kelly et al. (1994) reported a median concentration of 2.5 ppb after a survey of 58 locations. Indoor concentrations of formaldehyde are highly dependent on building construction (ATSDR 1999). For example, a range of 20 to 800 ppb was found in mobile homes, homes containing urea-formaldehyde foam insulation, and homes where residents had reported adverse symptoms. Average concentrations at 76 ppb and 50 ppb were reported in newer homes and older conventional homes, respectively. Although emissions from pressed-wood products might be the largest contributors of formaldehyde in indoor air, ATSDR (1999) noted that 10-25% of exposures might result from environmental tobacco smoke. Sources of formaldehyde on submarines include high-temperature paints, motor varnishes, diesel generators, and cigarette smoke (Crawl 2003). A few measurements of formaldehyde have been made on board submarines. Raymer et al. (1994) reported the results of air sampling conducted over 6 h during the missions of two submarines. Sampling indicated formaldehyde concentrations at 24 ppb and 8.1 ppb in the fan rooms, 17 ppb and 9.0 ppb in the engine rooms, and 24 ppb and 6.9 ppb in the galleys of two submarines. A similar sampling exercise (two submarines, three locations, and a sampling duration of 6 h) was reported by Holdren et al. (1995). Formaldehyde concentrations ranged from 5.1 to 20.2 ppb on the two submarines. The subcommittee notes that the results presented by Raymer et al. (1994) and Holdren et al. (1995) represent one-time sampling events on four submarines. Whether the reported concentrations are representative of the submarine fleet is not known, particularly as few details were provided about the conditions on the submarines when the samples were taken. SUMMARY OF TOXICITY Formaldehyde is one of the most well-studied chemicals used today, and its toxic effects have been the subject of several comprehensive reviews (NRC 1981; NRC 1994; IARC 1995; Paustenbach et al. 1997; ATSDR 1999; ACGIH 2001; Health Canada 2001; Bender 2002; WHO 2002; Liteplo and Meek 2003; NAC 2003). This review relies on those documents, which conclude that irritation of the eyes and upper respiratory tract is the primary human health effect of concern for setting exposure limits for both acute and chronic inhalation exposures to formaldehyde. Formaldehyde irritation does not appear to follow Haber’s law (concentration [C] ×

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants exposure time [t] = response [k]) for extrapolating between short-term and long-term toxicity levels. Generally, concentrations that do not produce short-term sensory irritation also do not produce sensory irritation after repeated exposure. Accommodation to low concentrations that cause short-term irritation has been reported; in such cases, irritation subsides with exposure duration. Risk of cancer and other chronic health effects appears to be negligible at concentrations that do not produce chronic irritation and overt target tissue damage. Formaldehyde is widely used in industry, agriculture, and commercial products, and a wealth of clinical toxicology and epidemiologic data are available from workplace, community, and controlled exposures. Thus, the subcommittee placed more emphasis on reviewing adverse health effects in humans than in animals. Effects in Humans Accidental Exposures No reports of deaths in humans resulting from inhaled formaldehyde were mentioned in the literature, and only a few case reports of accidental inhalation exposures resulting in human intoxication were found in the reviews consulted (IARC 1995; ATSDR 1999; ACGIH 2001; Health Canada 2001; WHO 2002; Liteplo and Meek 2003; NAC 2003). Effects of formaldehyde at high but unreported concentrations include tracheobronchitis and spasms and edema of the larynx (ACGIH 2001). Pulmonary edema, inflammation, and pneumonia occurred after exposure to airborne formaldehyde at concentrations of 50 to 100 ppm (ACGIH 2001). Allergic reactions and asthma-like conditions also have been reported following occupational exposures. Experimental Studies A number of controlled-exposure studies have been conducted in human volunteers. These studies are generally short-term (for example, 90 minutes [min] or less), but unlike occupational studies, they are not confounded by simultaneous exposures to other chemicals that might affect the reports of irritation attributed to formaldehyde. Some controlled chamber studies have focused on potentially more sensitive individuals, such as asthmatic individuals, nonsmokers, and people who previously have re-

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants sponded adversely to formaldehyde. Other studies have examined the consequences of continuous versus discontinuous formaldehyde exposures and exercise during exposures. Thus, data from 22 clinical studies involving over 500 subjects form the most reliable basis for estimating health-protective short-term exposure levels for airborne formaldehyde (see Table 5-2). As summarized by NAC (2003), the most sensitive end point identified in the study literature is ocular and upper respiratory tract irritation. A concentration of 1 ppm appears to be the approximate threshold between complaints of symptoms ranging from none to mild to moderate with no clear concentration-response relationship or increase in complaints among exposed subjects compared with controls (subjects exposed to clean air) and definite symptoms of discomfort in a number of exposed subjects. For example, a controlled study in asthmatic subjects (Harving et al. 1990) found no association between subjective ratings of sensory irritation and increasing formaldehyde exposures at concentrations of 0, 0.01, 0.1, and 0.69 ppm. The “clean air” control groups in the chamber studies are important for distinguishing between the background occurrence of irritation symptoms in subjects and the effects related to formaldehyde exposures. IARC (1995) noted irritation thresholds of 0.5-1 ppm in those studies. NAC (2003) identified 0.9 ppm as the highest exposure concentration at which the responses of subjects whose eyes were sensitive to formaldehyde were not significantly different from controls. Even at 3 ppm, however, the majority of subjects reported only mild (typically defined as present but not annoying) to moderate (annoying) irritation. In only one study at that concentration did any subject rate the eye irritation as severe (1 of 180 subjects) (Sauder et al. 1987; NAC 2003). Although many studies do not report the ranges of individual irritation scores, the small variation in scores indicates that a score of severe is very unlikely. In the study with the subject reporting severe eye irritation (Sauder et al. 1987), “severe” was defined by the investigators as debilitating, but scoring depended on the interpretations of the participants, who rated their own symptoms. In that study, 22% of subjects exposed to clean air reported eye irritation, and 33% reported nose or throat irritation. The overall difference between the eye-irritation responses to exposure at 3 ppm and exposure to clean air was not statistically significant until 1 h into the exposure. In addition to the person who reported severe eye irritation, another person reported no irritation, and according to group means, the rest of the subjects rated their eye irritation as mild (defined as present but not annoying) at 1 h and at 180 min. At 120 min, one of the subjects may have reported eye irritation as between mild and moderate. All subjects in the Sauder et al. (1987) study were clinically diagnosed with asthma, and the

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants subject who reported severe eye irritation was a female who remained in the chamber for the full 3 h of the study and successfully completed the spirometry measurements at 15, 30, 60, 120, and 180 min during the study period. Spirometry measurements showed little change in forced expiratory volume at 1 second (FEV1). Thus, this subject appears to be an outlier, and it is doubtful whether the severe eye irritation reported was actually debilitating. Many of the controlled inhalation studies included potentially sensitive individuals. These studies either excluded less sensitive individuals (for example, those without complaints of eye irritation at 1.3-2.2 ppm or smokers) or focused on potentially sensitive individuals (for example, asthmatic individuals and those with formaldehyde-related contact dermatitis or previous formaldehyde sensitivity) (see Table 5-2). As summarized by NAC (2003), Bender (2002), and Paustenbach et al. (1997), the results of those studies indicate that sensitive individuals might experience moderate ocular irritation at 1 ppm. Below 3 ppm, formaldehyde appears to be largely scrubbed in the upper airways, because asthmatic individuals (who normally react to mid- and lower-respiratory airway irritants) engaging in moderate exercise showed no decrements in several pulmonary function parameters when exposed at up to 3 ppm. Thus, asthmatic individuals exposed to airborne formaldehyde at exposure concentrations at or below 3 ppm do not appear to be at greater risk of suffering airway dysfunction than nonasthmatic individuals. In addition, the short-term chamber studies indicate that adaptation or accommodation to irritation can develop with time. Changes in pulmonary function (described as mild and reversible changes in FEV1 and midexpiratory flow) can occur in individuals sensitized to formaldehyde at concentrations approaching 2 ppm (Bender 2002). Only five studies investigated the effects of airborne concentrations above 3 ppm (see Table 5-2). One study noted severe irritation symptoms at 5 ppm; however, another study reported no complaints of ocular irritation at 8 ppm in four out of five subjects. Mild lacrimation was noted at 13.8 ppm in another study, but adaptation occurred within 30 min. A concentration of formaldehyde at 20 ppm was described as objectionable. Occupational and Epidemiologic Studies Occupational and epidemiologic studies involve longer, more continuous exposure durations and a greater number of subjects but are less controlled for simultaneous exposures to other substances, such as irritants, solvents, or particulates. Many of these investigations suffer from uncertain

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants exposure concentrations (Paustenbach et al. 1997; ATSDR 1999; ACGIH 2001; Bender 2002). Some of the occupational studies also involved exposures to formaldehyde in particulates because paraformaldehyde or powered resins were being used. The mean airborne concentrations of formaldehyde reported in many of these studies do not adequately represent peak excursions, which would be more likely to be associated with adverse health effects. In several studies, documentation of health complaints relied on self-reporting and recall via surveys. Thus, these studies are useful as supporting evidence with regard to limits for sensory irritation and pulmonary function, particularly over longer exposure periods, but they lack the precision of the controlled inhalation studies. Studies of occupational formaldehyde exposures involve workers in the manufacture of formaldehyde, formaldehyde-based resins, and other chemical products; wood products and paper; textiles and garments; and metal products and mineral wool. Some studies involve workers exposed to formaldehyde used in their occupational settings, which included mortuaries, hospitals, and laboratories. In general, studies in workers associate irritation with lower concentrations of formaldehyde than those reported in the controlled human studies. Eye irritation has been reported in occupational studies at concentrations as low as 0.01 ppm, although ACGIH (2001) notes that those exposures occurred in association with other chemicals that may have been acting synergistically. Most studies reported increased eye, nose, or throat irritation beginning at about 0.3 ppm and above (Paustenbach et al. 1997; ACGIH 2001). As found in the experimental chamber studies, exposure concentrations at about 1 ppm and above result in more consistent reports of eye and mucous membrane irritation in major percentages of workers, such as 40-50%. Some level of background irritation is apparent in workers and the general population, and irritation is often reported by control subjects in studies evaluating the effects of formaldehyde exposure. A study of workers exposed to formaldehyde from particle board or molded product found that 21% of workers exposed to workplace concentrations at 0.4-1 ppm reported sore throat as compared with 8% of those exposed at 0.05-0.4 ppm (Horvath et al. 1988). In the control group of that same study, sore throat occurred in 4% of workers, which was not statistically different from the percentage of workers experiencing sore throat exposed at 0.05-0.4 ppm. The control group also had occurrences of nose irritation in 2% of subjects and burning or watering eyes in 9% of subjects. In a study of funeral workers (Holness and Nethercott 1989), half of the exposed workers reported eye irritation at an average airborne concentration of 0.4 ppm; however, half of the control workers also complained of eye irritation. Thus, complaints of sensory

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants irritation at the lowest-reported study concentrations are not necessarily indicative of a response above background attributable to formaldehyde exposure. Overall, the occupational studies support the results of the chamber studies—they show that formaldehyde is a concentration-dependent irritant of the eyes and mucous membranes that has little or no adverse effects on pulmonary function in workers exposed at concentrations below 3 ppm. Even after long exposure durations (for example, mean exposure times of 10-12 years), there is no consistent evidence of permanent impairment resulting from those low exposure concentrations. In addition to irritation, histopathologic changes in the nasal epithelium of workers was examined in some studies. Some studies have noted changes in nasal histology (typically mild dysplasia) in workers exposed at average concentrations of 0.5-2.4 ppm; peak exposures in those studies, when noted, were considerably higher (5-18.5 ppm) (IARC 1995). WHO (2002) noted that the available data are consistent with the hypothesis that formaldehyde induces histopathologic lesions in the nose; however, the weight of evidence for causality is weak because of limitations in the number of studies, study sizes, and study designs that did not allow for evaluation of exposure-response relationships. Several studies have been conducted in residential populations exposed to formaldehyde in their homes (Paustenbach et al. 1997; ACGIH 2001; Bender 2002). Unlike occupational exposures, residential exposures potentially involve continuous exposures more similar to those experienced by submariners (that is, 24 h per day rather than 8 h per day). Unfortunately, studies of residential exposures typically lack sufficient control for the presence of other irritants and the many confounding factors that could affect subject responses. Many of the studies also rely on self-reported health status. One of the largest studies involved nearly 2,000 residents of 397 mobile homes and 494 conventional homes (Ritchie and Lehnen 1987). Participants were not selected randomly; they responded to a free testing service for formaldehyde, which was offered to individuals by the state of Minnesota when an examining physician made a written request. Thus, those recruited in the study had complained of symptoms thought to be related to airborne formaldehyde exposures. Over 60% of the residents reported eye, nose, and throat irritation or headache at airborne concentrations above 0.3 ppm; 12-32% reported eye irritation at 0.1-0.3 ppm; and only 1-2% reported eye irritation at 0.1 ppm, which was the background rate. The background rate of nose and throat irritation was 20%. Nevertheless, Bender (2002) notes that the symptoms reported at formaldehyde

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants TABLE 5-2 Irritant Effects of Formaldehyde in Controlled Human Studies Concentration (ppm) Time Subjects (no.) and Effects Reference 0, 0.41 2 h Healthy, occupationally exposed (5) and contact dermatitis (13) subjects No effect on pulmonary parameters (VC, FEV1); immune response in subjects with contact dermatitis (increased chemi-luminescense of neutrophils) Gorski et al. 1992 0, 0.41 2 h Healthy (11) and patients with skin hypersensitivity to formaldehyde (9) (all nonsmokers) No differences in response between groups; transient increase in symptoms of sneezing, rhinorrhea, or itchy eyes; nasal washings showed increases in eosinophils, albumin, and total protein, but not neutrophil, basophil, or mononuclear cells Pazdrak et al. 1993 0, 0.41 2 h Healthy, nonoccupationally exposed subjects (10) and occupationallyexposed asthmatic subjects (10) No differences in response between groups; transient increase in nasal symptoms of sneezing, rhinorrhea, edema, or itchy eyes; increases inleucocytes and eosinophils in nasal washings; no allergic response; no clinical symptoms of bronchial irritation or effects on pulmonaryfunction parameters (FEV1, PEF) Krakowiak et al. 1998 0, 0.10, 0.69 90 min Asthmatic nonsmoking subjects (15) No significant change in pulmonary function parameters (FEV1 and airway resistance) or in bronchial reactivity; no association of subjective ratings of asthmatic symptoms, if any, with increasing air concentration Harving et al. 1986, 1990

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants Concentration (ppm) Time Subjects (no.) and Effects Reference 0, 0.17, 0.39, 0.9 5.5 h Formaldehyde exposed workers (32); controls (29) Subjective symptoms (headache, tiredness) did not correlate with exposure; no clear effect of concentration on memory—some concentration-related effect on a few tests (addition speed, response time) but limitations in experimental design and control issues Bach et al. 1990 0, 0.35, 0.56, 0.7, 0.9, 1.0 6 min Healthy subjects (groups of 5-28), excluded those reporting eye irritation in clean air or nonresponders at 1.3 or 2.2 ppm Eye irritation evaluated—average scores of none to slight at 0.35 to 0.9 ppm; slight to moderate at 1.0 ppm; slight adaptation with time Bender et al. 1983 1 90 min Healthy (9) and formaldehyde-sensitive (9) subjects (previously complained about nonrespiratory effects of urea-formaldehyde foam insulation) No effects on pulmonary function parameters (FVC, FEV1, max and mid expiratory flow rate); complaints of eye irritation, nasal congestion, tearing, and throat irritation Day et al. 1984 0, 1.0 3 h Control asthmatic subjects (4); subjects with asthma attributed to urea-formaldehyde foam (23) No differences between groups in immunologic parameters, either before or after exposure; minor immunologic changes in both groups post-exposure Pross et al. 1987

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 0, 0.2, 0.4, 0.8, 1.6 5 h Healthy subjects (16) No differences in nasal airway resistance or pulmonary function parameters; decrease in nasal mucus flow at all concentrations; no discomfort at 0.2 or 0.4 ppm for 2 h, some slight discomfort reported in the 3-5 h period (conjunctival irritation, dryness of nose and throat), but discomfort rated higher at 0.2 ppm than at 0.4 ppm, and only five or fewer subjects reported any discomfort; average discomfort scored as slight during exposure at 1.6 ppm and first noted in the latter part of the first h but decreased some what after 3 h; no effect on performance on mathematical tests or number-transfer tasks Andersen and Molhave 1983 0, 2.0 (at rest) 0, 2.0 (exercise) 40 min Healthy (15) and asthmatic (15) nonsmoking subjects No significant decrement in pulmonary function parameters (flow-volume parameters and airway resistance) or bronchial reactivity both atrest and with exercise; subjective symptoms ranged up to severe (but not incapacitating) for odor for some individuals, but median scores for nose, throat, and eye irritation were ≤moderate; no increase in symptomology with exercise Witek et al. 1986;1987; Schachter et al. 1985; 1986 0, 0.1, 1.0, 3.0 20 min Asthmatic patients who suspected formaldehyde as the cause (13) No significant difference in pulmonary function parameters (FEV1, VC); no asthmatic response to formaldehyde challenge Frigas et al. 1984

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants and should not interfere with critical duties, such as opening a hatch, but also protects against moderate eye irritation that could occur in a few individuals and interfere with duties. No uncertainty factors were considered necessary for the 1-h EEGL because of the robust data set from the controlled studies in human subjects, including potentially more sensitive individuals, such as nonsmokers, asthmatic individuals, and formaldehyde-sensitive individuals. 24-Hour EEGL Because the irritation effects associated with airborne formaldehyde depend on concentration rather than the product of concentration and exposure duration (C × t), the 24-h EEGL should be similar to the 1-h EEGL. However, because a few crew members might experience moderate irritation at 2 ppm, the subcommittee concluded that 2 ppm would not be as tolerable for a 24-h period. Therefore, the recommended 24-h EEGL is 1 ppm. At that concentration, most crew members should experience no irritation to mild irritation, and very few, if any, would experience moderate irritation. It is also likely that adaptation over the 24-h exposure period would further abate any discomfort experienced. The 24-h SMAC of 0.1 ppm, which is the same as the Navy’s proposed value, was based on the lower end of the concentration range anticipated to cause eye irritation in 4% of subjects as reported in the Wisconsin mobile home study, in which TABLE 5-4 Emergency and Continuous Exposure Guidance Levels for Formaldehyde Exposure Level U.S. Navy Values (ppm) NRC Recommended Values (ppm) Current Proposed EEGL           1 h 3 0.4 2   24 h 1 0.1 1 CEGL           90 days 0.5 0.04 0.3 Abbreviations: CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; h, hour; NRC, National Research Council; ppm, parts per million.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants confounders, such as exposures to other irritants and smoking, were not controlled (NRC 1994). As noted above, the larger database of controlled studies in humans supports a much higher exposure level. 90-Day CEGL Irritation also is the end point of greatest concern for subchronic and chronic exposures to formaldehyde, and concentrations that cause no irritation to moderate irritation (up to 3 ppm) are not associated with other irreversible adverse health effects. For longer exposure periods, however, it is more important to avoid discomfort from irritation. Although a threshold for irritation is difficult to set, even with the wealth of information on formaldehyde, that level is typically set on the basis of a concentration that would not cause irritation in any of the exposed individuals. Individual susceptibility to formaldehyde appears to be difficult to predict, and typically sensitive groups, such as asthmatic individuals, do not appear to be any more sensitive to irritation effects than healthy subjects at exposure concentrations below 3 ppm. On the basis of the information available, a concentration of 0.3 ppm is unlikely to result in discomfort in the submariner population. Reported symptoms of eye and mucous membrane irritation at that concentration were not increased above control conditions in controlled chamber studies (see Table 5-2). In workers, 0.3 ppm is the lower level at which most occupational studies begin to report increasing irritation in some individuals, most of whom simultaneously are exposed to formaldehyde and other irritant chemicals and substances. In the survey of 2,000 residents, which suffered from potential under-reporting of exposure concentrations, 0.3 ppm is the concentration above which a majority of subjects reported irritation or headache and above which rates of irritation could not be explained by smoking (Richie and Lehnen 1987). CARCINOGENICITY ASSESSMENT The EPA cancer unit risk factor for assessing the upper-bound cancer risk associated with inhaled formaldehyde was developed in 1991 (EPA 2003). EPA’s slope factor assumes no low-dose threshold for cancer risk and is extrapolated from rates of nasal carcinomas in rats at formaldehyde concentrations above 5 ppm. Use of the EPA unit risk factor of 1.3 × 10-5 per microgram per cubic meter (1.6 × 10-2 per ppm) results in a theoretical

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants upper-bound excess risk over background of 5 × 10-3 (50 in 10,000) for continuous lifetime (estimated to be 70 years) exposure at the 0.3-ppm 90-day CEGL. Because the maximum length of cumulative exposure is estimated to be 5 years of a submariner’s career, the theoretical upper-bound excess risk for a submariner at 0.3 ppm would be 3 × 10-4. In reality, the risk is far lower. On the basis of the evidence that the contributory mechanisms of action at high doses in rodents (that is, cytolethality and regeneration) would not occur at lower doses, the EPA unit risk factor for formaldehyde overestimates the risk at doses not associated with cytotoxicity. A two-stage clonal growth model developed by CIIT (1999) that was reviewed by an external scientific review panel convened by Health and Welfare Canada and EPA (Health Canada/EPA 1998) incorporates the scientific evidence in a nonlinear model for formaldehyde risk assessment. As of 2004, EPA has yet to revise the existing unit risk factor for formaldehyde. The two-stage clonal growth model is based on the available data on rodent carcinogenicity, formaldehyde dosimetry in regions of the nose, pharmacokinetic differences between rodents and primates, and mutagenicity. The model incorporates two separate modes of action for carcinogenicity. At high doses, the dose-response relationship is primarily determined by cytotoxicity and regenerative cellular proliferation. The data suggest a curve shaped like a hockey stick or the letter “J,” indicating a lower dose threshold for risk (CIIT 1999; Conolly et al. 2003). On the basis of the genotoxicity of formaldehyde, the model also assumes a low-dose linear mechanism related to direct mutagenicity, which is supported by data on DNA-protein cross-link formation (CIIT 1999; Conolly et al. 2003). Thus, on the basis of mutagenicity, lower doses conservatively are assumed to have a linear dose-response curve. Without significant cytotoxicity and regenerative cellular proliferation, the slope of the dose-response relationship at low doses is much smaller than at high doses. Consequently, the threshold for zero difference from the control response has been predicted at 5.4 ppm with a 95% lower confidence limit of 2.7 ppm (Gaylor et al. 2004). The model also predicts separate dose-response outcomes for nonsmokers, mixed smoking, and smokers, with smoking resulting in a steeper slope. Research and analysis related to the CIIT (1999) model has been published in separate papers (Kimbell et al. 2001a,b; Overton et al. 2001; Conolly et al. 2003; Georgieva et al. 2003; Schlosser et al. 2003; Conolly et al. 2004; Gaylor et al. 2004). WHO (2002) and Health Canada (2001) relied on the model in their risk assessments for inhaled formaldehyde.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants On the basis of the dose-response relationship presented for lower doses by CIIT (1999), the estimated risk for continuous lifetime exposure to formaldehyde at 0.3 ppm is substantially lower than that predicted by the current EPA unit risk factor (that is, lifetime risks on the order of 1 × 10-7 for nonsmokers and 3 × 10-6 for smokers). The risks associated with 5-year cumulative exposures over submariners’ careers would be even lower. In summary, the carcinogenicity assessment based on EPA’s unit risk factor for formaldehyde indicates that exposure at the 0.3-ppm 90-day CEGL over a submariner’s career would be associated with an upper-bound risk that is 3 times the risk goal of 1 in 10,000. The available evidence, however, strongly suggests that the risk from formaldehyde at high doses demonstrated in animals studies cannot be extrapolated to lower doses using the EPA’s approach (Conolly et al. 2003; Gaylor et al. 2004). The more recent CIIT assessment results in a theoretical cancer risk well below the U.S. Department of Defense “acceptable” risk level of 1 in 10,000, even for lifetime exposure at the 0.3-ppm 90-day CEGL. The subcommittee concluded that the CIIT assessment more accurately reflects the scientific weight of evidence for formaldehyde carcinogenicity than does EPA’s approach. DATA ADEQUACY AND RESEARCH NEEDS Formaldehyde has a relatively robust data set for developing health-protective exposure levels that includes controlled human studies, occupational and nonoccupational studies, and animal studies. Uncertainties for setting exposure levels include the short-term nature of controlled human studies (less than 24 h) and the apparent variation and subjectiveness in individual reporting and rating of irritation associated with formaldehyde. The variation is not related to the typical sensitivities of such subgroups as asthmatic individuals. Because the available evidence indicates that adaptation occurs with time, the lack of longer-term studies is not considered to be a serious data limitation for setting EEGLs. Continued research and publication on the low-dose carcinogenicity of formaldehyde will help support the confidence of the CEGL for protecting submariners from the effects of longer-term exposures to formaldehyde.

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