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Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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] ×

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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-

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Concentration (ppm)

Time

Subjects (no.) and Effects

Reference

0, 0.5, 1.0, 2.0, 3.0 at rest; 2.0 with exercise

3 h

Healthy nonsmoking subjects (19; only 9 exposed at 3 ppm and 10 exposed at 0.5 ppm)

No significant decrements in pulmonary function parameters (FVC, FEV1, FEF25-75%, SGaw) or increases in bronchial reactivity (methacholine challenge) at any concentration; nasal flow resistance increased at 3 ppm; significant dose-response relationship for odor sensation and eye irritation, but eye irritation scored mild or mild (in five of nine) to moderate (in four of nine) at 3 ppm; eye irritation beginning at 1 ppm

Kulle et al. 1987; Kulle 1993

0, 3.0 with heavy exercise (healthy subjects); moderate exercise (asthmatic subjects)

1 h

Healthy (22) and asthmatic (16) nonsmoking subjects

No difference in symptoms between groups; eye, nose, and throat irritation scored mild to mild-moderate (group means); small decreases in some pulmonary function parameters (FEV1, FVC, FEV3, but not FEF25-75%) in healthy individuals engaging in heavy exercise; no change in specific conductance or nonspecific airway reactivity of either group

Green et al. 1987

0, 3.0 with heavy exercise (15 min each 0.5 h)

2 h

Healthy nonsmoking subjects (24)

Increase in subjective symptoms of eye, nose, and throat irritation, rated mild to moderate on average; small, but statistically significant increasein two (FEF25-75%, specific airway resistance) of several pulmonary function measurements at some time intervals (no effect on FEV1, FVC, FEV3); no increase in cough

Green et al. 1989

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

0, 3.0 with intermittent exercise

3 h

Healthy nonsmoking subjects (9)

Nonbiologically significant, transient change in some pulmonary function parameters (FEV1, FEF25-75%); increase in nose, throat, and eye irritation, rated mild to moderate by individuals; only one subject rated eye irritation as moderate

Sauder et al. 1986

0, 3.0

3 h

Asthmatic nonsmoking subjects (9)

No significant group change in pulmonary function parameters (FEV1, FVC, FEF25-75%, SGaw, or FRC) or airway reactivity; significant increase in nose, throat (at 30 min), and eye irritation (at 60 min), rated as none to mild-moderate except for one subject who reported severe eye irritation

Sauder et al. 1987

0, 1, 3

10 min

Asthmatic nonsmoking subjects (7)

Similar responses in airway resistance following exposure at 0, 1, or 3 ppm with and without exercise (exercise increased all responses)

Sheppard et al. 1984

0.03 to 3.2; 0, 1.0, 2.0, 2.9, 4.0; or 1.2, 2.1, 2.8, 4.0

37 min (n = 33); 1.5 min (n =48)

Healthy subjects (two exposure groups of 33 and 48)

Poorer air quality and greater nose irritation reported during the short exposures than during the 37-min exposure, whereas the opposite was true for eye irritation; with increasing concentrations, both eye and nose irritation increased from none to “a little”; eye blinking not affected at 1.2 ppm but was statistically significantly increased at 2.1 ppm

Weber-Tschopp et al. 1977

0, 1, 2, 4, 5

5 min except for 2 ppm (12 min)

Healthy students (groups of 7 to 75)

Assessed eye irritation only: 1 ppm) considered threshold for detection; 5ppm produced severe eye irritation

Stephens et al. 1961

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

Concentration (ppm)

Time

Subjects (no.) and Effects

Reference

8, 12

≤15 seconds

Healthy, atopic subjects (1-6)

Eye irritation for 5 of 6 subjects at 12 ppm but only for 1 of 5 at 8 ppm; irritation of the throat at both concentrations; changes in airway resistance

Douglas 1974

13.8

30 min

Healthy male subjects (12)

Nasal and eye irritation (not severe) with mild lacrimation; adaptation to the eye irritation

Sim and Pattle 1957

20

Several min

Healthy subjects (2)

Lacrimation within 15-30 seconds; eye, nose, and throat irritation considered objectionable

Barnes and Speicher 1942

Source: Adapted from NAC (2003).

Abbreviations: FEF25-75%, forced expiratory flow rate between 25% and 75% of forced vital capacity; FEV1, forced expiratory volume at 1 second; FEV3, forced expiratory volume at 3 seconds; FRC, functional residual capacity; FVC, forced vital capacity; ppm, parts per million; h, hour; min, minute; PEF, peak expiratory flow; SGaw, specific airway conductance; VC, vital capacity.

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

concentrations below 0.3 ppm could in part be attributed to smoking or passive smoke exposures because below that concentration, rates of reported symptoms were highest in smokers, were intermediate in passive smokers, and were lowest in nonsmokers. Only above 0.3 ppm did the frequency of reported symptoms become similar among smokers, passive smokers, and nonsmokers. In addition, only formaldehyde was measured, and because the methodology underestimated the actual exposure concentrations, the reported concentrations could be 10-20% too low (Paustenbach et al. 1997). Past exposures also could have been higher than those reported given the length of time between the filing of health complaints and the actual survey of formaldehyde in the residential structures (Bender 2002).

Effects in Animals

As summarized in other reviews (Paustenbach et al. 1997; ATSDR 1999; ACGIH 2001; Health Canada 2001; WHO 2002; Liteplo and Meek 2003; NAC 2003), a number of studies have been conducted in animals. Many of those studies are not directly useful for evaluating exposure limits in humans because of the very high exposure concentrations used. The studies in animals, however, included more continuous exposures under controlled conditions over longer time periods, such as 26 weeks, and provided supporting evidence for the nature of toxic effects, the target tissues, and the concentration-response relationship observed in human studies.

Some important physiologic differences among animals that affect the extrapolation of results to humans must be noted. Unlike nonhuman primates and humans, rats are obligate nose-breathers. Because of their nasal anatomy and physiology, rats have greater localized tissue damage in the anterior nasal passages but less penetration to lower airways when exposed at the same air concentrations as primates (Monticello et al. 1991; Kimbell et al. 2001a). Thus, formaldehyde reaches a greater range of respiratory tissues in monkeys, as measured by DNA-protein cross-link formation (Casanova et al. 1991). The middle turbinates of rhesus monkeys were found to be the major target site; very little formaldehyde reached extra-nasal tissues (the larynx, trachea, and proximal portions of major intrapulmonary airways) at 2 and 6 ppm. No detectable DNA-protein cross-links were reported in extranasal tissues of monkeys exposed to 0.7 ppm.

Data from lower air exposure concentrations in animal studies are generally consistent with experimental studies in humans in the following ways:

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×
  • Adverse effects at the lowest airborne-formaldehyde exposure concentrations involve sensory irritation.

  • The degree of sensory and irritant effects at lower exposure levels depends on concentration rather than duration.

  • Formaldehyde is well scrubbed by nasal and upper respiratory passages at exposure concentrations below 3 ppm and relatively little reaches the lungs at those low concentrations.

  • Few to very slight signs of irritation occur below 1 ppm, and those signs are relatively mild; acute effects are reversible at below 3 ppm.

Reflex reductions in respiration rate via trigeminal nerve stimulation in the nasal passages have been used to quantify sensory irritation in rodents (Paustenbach et al. 1997; ATSDR 1999; ACGIH 2001). That measure is a more sensitive indicator in mice than in rats, because rats are less able to reduce their respiration rates. Ten-minute exposures at 3 ppm produced 50% decreases in the respiration rates (RD50) of mice (Kane and Alaire 1977). Repeated 3-h exposures on 4 consecutive days produced progressively greater decreases in the respiration rates of mice at 1 ppm (decreases of about 15% on day 1 to about 35% on day 4) and at 3 ppm (decreases of about 45% on day 1 to about 70% on day 4) (Kane and Alaire 1977). During the exposures, the degree of response reached a plateau in the first 10 min and then decreased over the remainder of the 3-h period, although that decrease in response was delayed on day 4 during exposures at 3 ppm.

Guinea pigs appear to be susceptible to changes in lower airway resistance and hyperreactivity of the lungs resulting from acute formaldehyde exposure. However, there are apparent inconsistencies among the studies with regard to the concentrations and exposure periods that induced those changes (that is, whether concentrations as low as 0.3 ppm or as high as 9.4 ppm are required) (ATSDR 1999).

Studies in rodents and a few monkeys (ATSDR 1999; WHO 2002) indicate that at concentrations beginning at about 3 ppm for short-term exposures (for example, 6-22 h per day for 3 days) and above 2 ppm for longer-term exposures (for example, 13 weeks), cellular lesions, such as cytolethality and hyperplasia, might develop in the nasal passages and, with increasing concentrations, in other areas of the respiratory system. Epithelial lesions of the upper respiratory tract observed in rats and monkeys were histologically similar, although regional differences in occurrence were evident. Site-specific damage in the nasal epithelium of rats also was correlated in a concentration-dependent manner with the degree of inhibi-

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

tion of mucociliary function at 2, 6, and 15 ppm (6 h per day for 1-3 weeks). Overall, studies in animals have demonstrated that the adverse effects of formaldehyde exposures, including nasal tumors (discussed below in the section on carcinogenicity), are associated with the overt cytotoxicity and tissue hyperplasia caused by the chemical’s potent irritant properties (Connolly et al. 2003).

Reproductive Toxicity in Males

No compelling evidence of male reproductive toxicity due to formaldehyde exposure was noted in the literature (ATSDR 1999). One human study (Ward et al. 1984) examined sperm samples from 11 workers exposed at time-weighted average air concentrations of 0.6-1.3 ppm. The mean sperm count of the exposed workers was lower, but not significantly lower, than controls. No differences were found in the frequency of abnormal sperm.

Several studies in rodents exposed to formaldehyde concentrations at up to 10-40 ppm reported no effects on male reproductive organs (ATSDR 1999).

Immunotoxicity

Although exposures to airborne formaldehyde have been associated with occupational asthma, consistent evidence of a formaldehyde-induced allergic respiratory syndrome is lacking (ATSDR 1999). Formaldehyde resin dust appears to be more likely to induce asthma than gaseous formaldehyde (Lemiere et al. 1995).

A few studies show limited evidence of increased IgE antibody activity in a small fraction of formaldehyde-exposed adult subjects, but allergen-specific IgE against formaldehyde have not been identified. Even in a case that reported probably the most compatible history (occupational exposure to formaldehyde and symptoms of bronchial spasms) and immunologic findings (positive skin test results to formaldehyde-human serum albumin [F-HAS] and positive IgE and IgG titers to F-HAS), the subject had a negative methacholine challenge at 25 mg per milliliter (mL) and negative formaldehyde inhalation challenges at 0.3, 1, 3, and 5 ppm for 20 min (Grammar et al. 1993). In general, investigations in formaldehyde-

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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exposed populations have not found an immunologic basis for respiratory or conjunctival reactions to formaldehyde (Patterson et al. 1987; Grammar et al. 1990, 1993; IARC 1995; ATSDR 1999; Kim 2001). Evidence from animal studies does not indicate that repeated inhalation exposures to formaldehyde have a direct effect on the immune system, although suggestive evidence indicates that formaldehyde might indirectly facilitate sensitization of the nasal tissues to high-molecular-weight allergens (ATSDR 1999).

Formaldehyde solutions are irritating to the skin and can induce allergic contact dermatitis. It has been estimated that 8.4% of the U.S. population have positive patch-test reactions; however, that percentage probably is considerably inflated (IARC 1995). Maibach (1983) notes that more than 40% of patch-test results are not reproducible, especially for chemicals such as formaldehyde that cause an allergic or irritant response at similar concentrations.

Genotoxicity

Various mutagenicity studies—for example, tests of frequency of chromosomal aberrations and sister chromatid exchange in peripheral lymphocytes or micronuclei in oral and respiratory nasal mucosa cells and peripheral lymphocytes—have been conducted in worker populations and have yielded both positive and negative results (IARC 1995). There is uncertainty in interpreting these studies because of small sample sizes, inconsistencies in findings, and the lack of dose-response for the increased frequency of micronuclei in the nasal mucosa cells of exposed groups compared with controls (IARC 1995). Occupational exposures included other chemicals and substances in addition to formaldehyde. Urinary fractions from hospital autopsy service workers that were assayed for mutagenicity in Salmonella typhimurium showed no evidence of increased mutagenicity compared with control samples (Connor et al. 1985).

Formaldehyde has been demonstrated to be genotoxic in a wide variety of experimental systems both in vitro in animal and human cells and in vivo in animals (IARC 1995). As summarized by IARC (1995), formaldehyde reacts readily with DNA, and formaldehyde exposures have been associated with DNA-protein cross-links in the nasal respiratory mucosa of rats and monkeys. The frequency of cross-links increases in a linear fashion with increasing formaldehyde concentration, then inflects upward around 2-3 ppm and above. In human and rodent cells in vitro, formaldehyde

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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induces DNA-protein cross-links, DNA single-strand breaks, chromosomal aberrations, sister chromatid exchange, and gene mutation. Cell transformation also has been demonstrated in rodent cells in vitro.

As noted by Casanova et al. (1991), DNA-protein cross-link formation is more related to the delivered dose (the concentration of formaldehyde at the tissues) to various regions of the upper respiratory tract than to the administered dose (the ambient concentration of formaldehyde initially inhaled). Cross-links can occur in rat nasal tissues at exposure concentrations that are not associated with demonstrable cytolethality or carcinogenicity. Species differences in DNA-protein cross-link formation are thus related to anatomic and physiologic differences that affect the delivered dose. Although DNA-protein cross-link formation might not be directly related to gene mutations at subcytotoxic doses, it has been used as a predictor of the probability of procarcinogenic mutation per cell division and has been incorporated in models for low-dose carcinogenicity in animals and in humans (CIIT 1999; Conolly et al. 2003).

Carcinogenicity

A large number of studies (>40 epidemiologic studies) have examined the carcinogenic potential of formaldehyde in animals and humans. The findings from those studies have been evaluated by a number of agencies and committees engaged in setting regulatory standards and guidelines (IARC 1995; Paustenbach et al. 1997; ATSDR 1999; ACGIH 2001; WHO 2002; EPA 2003; NAC 2003). The reviews concur that inhaled formaldehyde induces tumors, such as nasal squamous cell carcinoma, in rats and mice exposed at airborne concentrations that are associated with significant irritation and result in hyperplasia and tissue damage after repeated exposures (>6 ppm, typically 10-15 ppm). In humans, the overall evidence for carcinogenicity is less consistent, and any statistically significant associations are generally weak. Some epidemiologic studies (ATSDR 1999) have found an excess number of nasopharyngeal cancers, and two meta-analyses (Blair et al. 1990; Partanen 1993) reported a significantly higher risk of such cancers among workers with substantial exposure compared with those with low to moderate exposure or no exposure. However, those associations were relatively weak (relative risks [RR] = 2.1 [95% confidence interval (CI) = 1.1-3.5] and 2.7 [95% CI = 1.4-5.6] in Blair et al. [1990] and Partanen [1993], respectively). IARC (1995) considered the two meta-

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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analyses to be suggestive of a causal relationship between formaldehyde and nasopharyngeal cancer but noted that its “conclusion is tempered by the small numbers of observed and expected cases in the cohort studies.”

A more recent meta-analysis by Collins et al. (1997) did not find a significant association once the cohort studies were adjusted for under-reporting of nasopharyngeal cancer (RR = 1.0 [95% CI = 0.5-1.8]) and the case-control studies were analyzed separately (RR = 1.3 [95% CI = 0.9-2.1]). Collins et al. (1997) also noted that the exposure information in the case-control studies was less certain than the exposure information in the cohort studies.

Several recent studies have continued to investigate the association between formaldehyde exposure and cancer. In an updated study of 7,000 workers from a U.S. chemical plant, Marsh et al. (2002) reported that although statistically significant excesses in nasopharyngeal and pharyngeal cancer were observed in exposed versus unexposed workers, most of the cancer cases were among workers who had less than 1 year of employment in the earlier years of the plant’s history. Nasopharyngeal cancer cases among workers with greater than 1 year of employment had low-average formaldehyde exposure. Thus, Marsh et al. (2002) concluded that the cancer excesses observed were not associated with formaldehyde exposure.

A follow-up study of 14,014 British workers (Coggon et al. 2003) did not find an increase in sinonasal cancer or nasopharyngeal cancer. The study authors concluded that the evidence for formaldehyde carcinogenicity in humans is unconvincing and that although the occurrences of sinonasal or nasopharyngeal cancer cannot be ignored, the small increase in lung cancer mortality (standardized mortality ratio = 1.28 [95% CI = 1.13-1.44]) observed in subjects occupationally exposed to formaldehyde is of greater concern, particularly among the highest-exposure groups (>2 ppm). However, no increases in lung cancer mortality were associated with longer durations of high exposure or the time elapsed since the first high exposure. Another recent follow-up study of a cohort of 25,619 industrial workers from 10 U.S. plants found no associations with lung cancer. However, a significant increasing risk trend for nasopharyngeal cancer was observed with highest peak or cumulative exposure measured in ppm-years, although not for average exposure or duration of exposure measured in years (Hauptmann et al. 2004). The significant trend was based on small numbers. For peak exposures, nasopharyngeal cancers were observed in seven workers in the highest-exposed group (>4 ppm; RR = 1.83), no workers in each of the other two exposure groups (>0 to <2 ppm and >2 to <4 ppm), and two

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

workers in the control group (RR = 1.00). The trend for cumulative exposure was based on setting the relative risk for the low-exposure group to 1.00. Thus, the number of cancer deaths and relative risks for the cumulative exposure groups were two workers (RR = 2.40) for unexposed controls, three workers (RR = 1.00) for >0 to <1.5 ppm-years, one worker (RR = 1.19) for >1.5 to <5.5 ppm-years, and three workers (RR = 4.14) for >5.5 ppm-years. A cohort study of 11,039 U.S. garment workers in three plants reported no nasal or nasopharyngeal cancers or increases in respiratory cancers with duration of formaldehyde exposure or with historical exposure when concentrations were presumably higher (Pinkerton et al. 2004).

Although the toxicologic and mechanistic evidence is weaker for cancers at locations other than the upper airways, some evidence has indicated an association of formaldehyde exposure with leukemia in workers. Some studies, particularly those involving medical workers and other professionals exposed to formaldehyde, have reported increased risk of leukemia; however, studies in industrial workers who are often exposed at higher concentrations provide less evidence of such increased risk (IARC 1995; ATSDR 1999). Among the recent studies, the study of British workers by Coggon et al. (2003) did not find an increased risk of leukemia in all workers or in those with high exposure (>2 ppm) or with more years at high exposure. Peak exposures were not specifically evaluated. Hauptmann et al. (2003) reported an increased risk for myeloid leukemia with high peak exposures to formaldehyde (peak concentrations >4 ppm compared with 0.1-1.9 ppm; SMR = 3.46, 95% CI = 1.27-9.43) in the same cohort of U.S. industrial workers evaluated by Hauptmann et al. (2004) for solid tumors and respiratory cancers. Risk of myeloid leukemia was not associated with cumulative exposure measured in ppm-years and was described as “weakly,” but not significantly, associated with duration of exposure measured in years. Overall risk of leukemia in those workers was lower than that in the U.S. population. Pinkerton et al. (2004) likewise found no significant increase in leukemia or myeloid leukemia in garment workers as compared with the U.S. population but reported significant increases in myeloid leukemia in those employed in the early years when exposures were presumably higher, those with 10 or more years of exposure, and those with 20 or more years since first exposure.

In general, however, the biologic plausibility for formaldehyde exposures to cause leukemia or other nonrespiratory cancers in humans has been considered weaker than that for high-dose formaldehyde exposures to cause nasopharyngeal cancers on the basis of pharmacokinetic and toxicologic

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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evidence (IARC 1995, 2004; ATSDR 1999; WHO 2002; EPA 2003). IARC (2004) recently changed its previous classification of formaldehyde as “probably carcinogenic to humans (Group 2A),” on the basis of limited evidence in humans and sufficient evidence in animals, to “carcinogenic to humans (Group 1),” on the basis of sufficient evidence in animals and humans. Although the monograph with the full documentation was not available for review, the summary provided by IARC (2004) indicates that the basis for this decision was primarily the trend for increased risk of nasopharyngeal cancers in workers with peak and cumulative exposures reported by Hauptmann et al. (2004)—considered “the largest and most informative cohort study of industrial workers exposed to formaldehyde” and supported by other epidemiological studies (IARC 2004). The U.S. Environmental Protection Agency’s (EPA’s) review of formaldehyde in their Integrated Risk Information System database, last revised in 1991, rated formaldehyde as a “probable human carcinogen” (Group B1) on the basis of limited evidence in humans and sufficient evidence in animals (EPA 2003).

Several reviews generally agree that the carcinogenicity of formaldehyde observed in animals appears to occur by a mechanism that would result in a practical threshold for significant cancer risk (Paustenbach et al. 1997; CIIT 1999; ACGIH 2001; WHO 2002; Connolly et al. 2003; NAC 2003; Gaylor et al. 2004). Specifically, a high incidence of tumor formation appears to be related to chronic tissue irritation at higher doses. Chronic tissue irritation at those high doses leads to cytotoxicity and regenerative hyperplasia. As a result, exposure limits that are protective against significant irritation and irreversible changes in the nasal mucosa would also be protective against carcinogenic effects. The recent findings from some epidemiologic studies of increased risks for higher-exposure groups and high-peak exposures are consistent with this general theory.

TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS

Consistent with its action as an upper respiratory irritant, formaldehyde is a highly water-soluble vapor that is readily absorbed by the upper respiratory tract and is rapidly metabolized to formic acid or formate (IARC 1995; ATSDR 1999). Because absorption appears to be limited to the respiratory tissues at the point of contact and formaldehyde is rapidly metabolized, little if any formaldehyde is found in the blood streams of

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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humans or animals (Heck et al. 1985; Casanova et al. 1988). Absorption via the skin is considered to be very limited.

All tissues of the body metabolize formaldehyde to formate via form-aldehyde dehydrogenase, a major metabolic enzyme that routinely metabolizes formaldehyde produced endogenously in the body. Formate is oxidized to carbon dioxide and exhaled, and small amounts of formate are excreted in the urine. Sometimes the carbon from metabolized formate is used in cellular structures in the body. Studies on the kinetics of formaldehyde in primates have reported a biologic half-life of about 1.5 min (McMartin et al. 1979). The classic formate toxicity associated with methanol ingestion is not considered an issue for the smaller amounts of formate produced in the body after inhalation exposures to formaldehyde (ATSDR 1999). Therefore, toxicity as a result of accumulation and storage is not an issue for formaldehyde.

INHALATION EXPOSURE LEVELS FROM THE NRC AND OTHER ORGANIZATIONS

A number of organizations have established or proposed inhalation exposure levels or guidelines for formaldehyde. Selected values are summarized in Table 5-3.

Occupational and public criteria for air are based largely on preventing the irritation effects of formaldehyde. Most levels are time-weighted average (TWA) concentrations over a designated period, although the American Conference of Governmental Industrial Hygienists (ACGIH) and the National Institute for Occupational Safety and Health (NIOSH) have specified ceiling values. Those ceiling values have been called into question by a panel of experts convened by the Industrial Health Foundation at the request of the Formaldehyde Institute (Paustenbach et al. 1997). On the basis of the chamber studies, which are more reliable for setting effect levels compared with worker studies, the panel concluded that 0.3 ppm was sufficiently protective as a TWA concentration and recommended a ceiling value of 1.0 ppm.

The NASA spacecraft maximum allowable concentrations (SMAC) values, which may be more analogous to submarine exposure levels than other limits, are based on a Wisconsin mobile home study (1-h and 24-h SMACs) and background concentrations (30-day and 180-day SMACs)

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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TABLE 5-3 Selected Inhalation Exposure Levels for Formaldehyde from NRC and Other Agenciesa

Organization

Type of Level

Exposure Level (ppm)

Reference

Occupational

 

 

 

ACGIH

TLV-Ceiling

0.3 (A2, suspected human carcinogen)

ACGIH 2001

NIOSH

REL-Ceiling

0.1 (15 min)

NIOSH 2004

 

REL-TWA

0.016

 

OSHA

PEL-STEL

2 (15 min)

29 CFR

 

PEL-TWA

0.75

1910.1048 (c)

Spacecraft

 

 

 

NASA

SMAC

 

NRC 1994

 

1 h

0.4

 

 

24 h

0.1

 

 

30 days

0.04

 

 

180 days

0.04

 

General Public

 

 

 

ATSDR

Acute MRL

0.04

ATSDR 1999

 

Intermediate MRL

0.03

 

 

Chronic MRL

0.008

 

NAC/NRC

Proposed AEGL-1 (1 h)

1

EPA 2004

 

Proposed AEGL-2 (1 h)

8

 

 

Proposed AEGL-1 (8 h)

1

 

 

Proposed AEGL-2 (8 h)

8

 

aThe comparability of EEGLs and CEGLs with occupational and public health standards or guidance levels is discussed in Chapter 1, section “Comparison to Other Regulatory Standards or Guidance Levels.”

Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; ATSDR, Agency for Toxic Substances and Disease Registry; h, hour; min, minute; MRL, minimal risk level; NAC, National Advisory Committee; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; ppm, parts per million; REL, recommended exposure limit; SMAC, spacecraft maximum allowable concentration; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average.

(NRC 1994). In contrast, the National Advisory Committee for Acute Exposure Guideline Levels (AEGLs) (NAC 2003) developed higher short-term levels based on the numerous human experimental studies, which were

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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considered a more reliable basis for the short-term AEGLs than the single, uncontrolled study and background levels used by NASA.

SUBCOMMITTEE RECOMMENDATIONS

The subcommittee’s recommendations for EEGL and CEGL values for formaldehyde are summarized in Table 5-4. The current and proposed U.S. Navy values are provided for comparison.

1-Hour EEGL

Exposure limits for formaldehyde should be set to prevent moderate irritation effects in the eyes and mucous membranes of submariners. Unfortunately, it is difficult to quantify a threshold for irritation because at the lowest levels the symptoms are subjective, individuals vary in sensitivity, and variable rates of background irritation occur in the population. Bender (2002) stated that even with the wealth of human and animal studies, a no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) for irritation could not be determined for setting a reference concentration.

The subcommittee found that the most reliable data set for determining the 1-h and 24-h EEGLs was from the controlled experimental studies in humans rather than the relatively uncontrolled and uncertain Wisconsin mobile home study used to develop the 1-h SMAC of 0.4 ppm (NRC 1994). The 1-h SMAC is identical to the 1-h EEGL proposed by the Navy. On the basis of the controlled experimental studies in humans, the appropriate range for a short-term exposure concentration that would produce only mild to moderate irritation in almost all submariners is 1-3 ppm. The controlled chamber studies indicate that 1 ppm is the concentration at which reports of irritation begin to increase significantly over background and that by 3 ppm most subjects report mild to moderate irritation. Tests have been conducted at up to 3 ppm in a large number of human subjects. The few studies conducted in human subjects at concentrations above that range indicated more severe effects, and the animal data indicate that irreversible respiratory tissue damage can occur at concentrations above that range, although generally with repeated exposures.

A midrange concentration of 2 ppm was selected as the 1-h EEGL. A concentration of 2 ppm allows for some sensory irritation that is reversible

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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.

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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.

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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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.

Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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REFERENCES

ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Acrolein in Documentation of the Threshold Limit Values and Biological Exposure Indices, 7th Ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

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Suggested Citation:"5 Formaldehyde." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1 Get This Book
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U.S. Navy personnel who work on submarines are in an enclosed and isolated environment for days or weeks at a time when at sea. Unlike a typical work environment, they are potentially exposed to air contaminants 24 hours a day. To protect workers from potential adverse health effects due to those conditions, the U.S. Navy has established exposure guidance levels for a number of contaminants. The Navy asked a subcommittee of the National Research Council (NRC) to review, and develop when necessary, exposure guidance levels for 10 contaminants.

Overall, the subcommittee found the values proposed by the Navy to be suitable for protecting human health. For a few chemicals, the committee proposed levels that were lower than those proposed by the Navy. In conducting its evaluation, the subcommittee found that there is little exposure data available on the submarine environment and echoed a previous recommendation from an earlier NRC report to conduct monitoring that would provide a complete analysis of submarine air and data on exposure of personnel to contaminants.

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