7
Formaldehyde

J. Torin McCoy NASA-Johnson Space Center Habitability and Environmental Factors Office Houston, Texas

OCCURRENCE AND USE

Formaldehyde (HCHO) is an organic substance that is widely used and can occur as a result of both natural and anthropogenic processes (see Table 7-1). At room temperature, formaldehyde exists as a colorless gas with a distinct and pungent odor. Formaldehyde has been widely used since the early 1900s in commercial and industrial applications. Much of its use centers around the manufacturing of plastics and resins (such as urea-formaldehyde resins) or applications in the production of chemical intermediates. Other diverse uses include application as a preservative for biologic samples, an ingredient in shampoos and household cleaning agents, use as an agricultural fumigant, and use in various products as an antimicrobial agent. In addition to these numerous commercial

TABLE 7-1 Physical and Chemical Properties

Formula

HCHO

 

Synonym

methanal, formic aldehyde, methyl aldehyde

CAS registry no.

50-00-0

Molecular weight

30.0

Boiling point

−19.5°C

Melting point

−92°C

Water solubility

55 g/100 mL

Vapor pressure

10 mm Hg at 88°C

Vapor density

1.08

Specific gravity

0.81 at 20°C

Log Kow

0.35

Source: Data from ATDSR 1999.



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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 7 Formaldehyde J. Torin McCoy NASA-Johnson Space Center Habitability and Environmental Factors Office Houston, Texas OCCURRENCE AND USE Formaldehyde (HCHO) is an organic substance that is widely used and can occur as a result of both natural and anthropogenic processes (see Table 7-1). At room temperature, formaldehyde exists as a colorless gas with a distinct and pungent odor. Formaldehyde has been widely used since the early 1900s in commercial and industrial applications. Much of its use centers around the manufacturing of plastics and resins (such as urea-formaldehyde resins) or applications in the production of chemical intermediates. Other diverse uses include application as a preservative for biologic samples, an ingredient in shampoos and household cleaning agents, use as an agricultural fumigant, and use in various products as an antimicrobial agent. In addition to these numerous commercial TABLE 7-1 Physical and Chemical Properties Formula HCHO   Synonym methanal, formic aldehyde, methyl aldehyde CAS registry no. 50-00-0 Molecular weight 30.0 Boiling point −19.5°C Melting point −92°C Water solubility 55 g/100 mL Vapor pressure 10 mm Hg at 88°C Vapor density 1.08 Specific gravity 0.81 at 20°C Log Kow 0.35 Source: Data from ATDSR 1999.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 applications, formaldehyde is a common combustion byproduct and can be measured at low concentrations in almost all ambient air samples. Although it is often thought of as strictly an environmental pollutant, formaldehyde is a normal metabolic product formed endogenously from the breakdown of serine (Restani and Galli 1991) and serves as an intermediary cellular metabolite in the biosynthesis of purines, thymidine, and several amino acids (ATSDR 1999). Formaldehyde is also a normal byproduct from the metabolism of many N-methyl substituted drugs and other xenobiotics (Dahl and Hadley 1983). Endogenous concentrations of formaldehyde in blood are estimated at 2.6 micrograms per gram (µg/g) for humans (Heck et al. 1985). Dietary exposure is also relevant because formaldehyde is found naturally (and even as a food additive) in some animal products, fruits, vegetables, cheeses, seafood, and other commodities (Restani and Galli 1991). Formaldehyde is a common contaminant that may be discharged to the spacecraft environment from both direct and indirect sources. Its occurrence in water is also closely tied to releases to air, thus providing a good example of the interdependency of these media onboard the space shuttle and International Space Station (ISS). Formaldehyde is occasionally detected, although at relatively low concentrations (1-3 µg per liter [L]), in drinking water provided to the ISS from ground-based sources (Schultz 2004). However, much higher concentrations of formaldehyde (up to 9,000 µg/L) have been measured in the humidity condensate onboard the ISS (Schultz 2004). The relatively high concentrations of formaldehyde in this condensate are largely attributable to the number of sources that may release formaldehyde, as well as to its chemical and physical properties. Formaldehyde is one of the most common indoor air pollutants. Formaldehyde can be off-gassed from textiles, foam insulation, resins, epoxies, and a myriad of other substances commonly encountered in the indoor environment (both ground based and in orbit). Furthermore, formaldehyde can be formed through secondary reactions of other indoor air pollutants (for example, methane, pinene), especially in the presence of higher temperatures and/or chemical oxidizers. Studies by the National Aeronautics and Space Administration (NASA) have frequently observed formaldehyde releases from Delrin and other commonly used industrial materials (James 2004). Once present in the air, the high water solubility of formaldehyde relative to its vapor pressure (a relationship expressed by its Henry’s law constant) results in a significant removal of formaldehyde from the air by condensing moisture. Given this interdependency, exposure to formaldehyde through drinking water ingestion is a relevant exposure pathway on-orbit, despite ground-based experiences that suggest

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 that this pathway might be insignificant in comparison to inhalation exposures. TOXICOKINETICS For the purposes of this document, the toxicokinetics of ingested formaldehyde will be highlighted. As with any chemical, a thorough understanding of its absorption, metabolism, distribution, and elimination is crucial to gaining a perspective on its toxicity and to the setting of appropriate spacecraft water exposure guidelines (SWEGs). Absorption Formaldehyde is readily absorbed into gastrointestinal (GI) mucosal cells following oral exposures (IARC 1995). However, it is difficult to distinguish the fraction of formaldehyde that is ultimately absorbed across the GI tract (ATSDR 1999). As evidenced by rapid increases in formic acid concentrations in the blood (within minutes per observations of Eells et al. 1981), absorbed formaldehyde is either metabolized to formate in the GI tract (which is then quickly absorbed), or formaldehyde is quickly absorbed and metabolized to formate in the blood (Galli et al. 1983; Burkhart et al. 1990). No studies were found that were able to distinguish the oral absorption kinetics of formaldehyde apart from the kinetics of its metabolism to formic acid. Metabolism Although metabolism rates are thought to vary somewhat across species, the basic sequence of metabolism is the same in all mammalian systems (Pandey et al. 2000). Figure 7-1 describes the basic metabolic process by which formaldehyde is converted to formate/formic acid and ultimately to carbon dioxide and water. The conversion of formaldehyde to formic acid is mainly catalyzed by the formaldehyde dehydrogenase (FDH)/alcohol dehydrogenase 3 complex (with glutathione [GSH] and nicotinamide adenine dinucleotide [NAD+] acting as cofactors), because of its specific affinity for formaldehyde, although other enzyme systems also have the capability to oxidize aldehydes (Teng et al. 2001). FDH (which is also defined as alcohol dehydrogenase [ADH3] according to

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 FIGURE 7-1 Metabolism and biologic fate of formaldehyde. Source: Modified figure printed with permission; copyright 1995, World Health Organization. current nomenclature) is present in almost all tissues but is especially prevalent in the liver and erythrocytes and is very efficient in acting upon endogenous or exogenous formaldehyde. Researchers have observed polymorphisms in the ADH3 gene that encodes FDH/ADH3 among several population groups, and this variability suggests that the capacity to metabolize formaldehyde will likely exhibit some interindividual variation (Hedberg et al. 2001). Upon metabolism from formaldehyde, formic acid can then be metabolized to carbon dioxide and water, although much more slowly than the FDH/ADH3-dependent metabolism of formaldehyde (55 minute [min] plasma half-life as compared to 1 min with

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 formaldehyde) (Stratemann et al. 1968). This metabolic step relies upon tetrahydrofolate-dependent enzymatic action (Pandey et al. 2000). Alternately, formic acid can be excreted as a salt in the urine or can enter the one-carbon metabolic pool (Restani and Galli 1991) where it can be incorporated as a methyl group into nucleic acids and proteins (Thrasher and Kilburn 2001). Distribution and Elimination In rodents, Buss et al. (1964) observed that about 40% of radiolabeled formaldehyde that was administered orally (7 milligrams per kilogram [mg/kg] of body weight dose) was eliminated as carbon dioxide within 12 hours (h), while another estimated 10% was eliminated in urine and 1% in feces. Incorporation into macromolecules was postulated by the authors to account for much of the remaining radiolabeled carbon. Formaldehyde is not generally expected to be absorbed into the blood-stream and carried as an unmetabolized molecule to other organ systems. Thus, distribution and excretion are not thought to be significant considerations with formaldehyde exposure and toxicity. Instead, its rapid metabolism and reactivity suggest that it will either be metabolized or it will exert its toxic effects locally at the point of exposure. It is postulated that the toxicity of formaldehyde is evidenced when exposure is of sufficient magnitude that this detoxification mechanism for formaldehyde is saturated and the reactive formaldehyde molecule is allowed to exert its effects on local tissues and macromolecules (for example, proteins and DNA) (Heck and Casanova 1990). TOXICITY SUMMARY Given its commercial importance and potential for human exposure, formaldehyde has been the subject of a relatively large amount of toxicologic research. Much of this work has been focused on investigations of inhalation exposures to formaldehyde, and the literature on its oral toxicity is not quite as robust. However, there are a number of studies (both human and animal) focusing on a variety of toxicologic end points and exposure durations that provide a basis for setting SWEGs for formaldehyde. The following discussion is not meant to represent a comprehensive review of all available data on the toxicity of formaldehyde. Instead, the focus is on those studies that appear to be the most applica-

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 ble to SWEG development (that is, exposure to formaldehyde through drinking water). The discussion of the oral toxicity of formaldehyde is organized into four different categories based on the duration of the exposures: acute (1-5 days [d]), short-term (6-30 d), subchronic (30-180 d), and chronic (180 d to lifetime). Data for these individual exposure durations generally correspond to timeframes relevant to the development of 1-, 10-, 100-, and 1,000-d SWEGs, respectively. Complete descriptions of studies cited in the discussion below are provided in Table 7-2. It is important to note that some of the data discussed below came from studies involving gavage exposures to formaldehyde. These results should be viewed with some caution because gavage exposures may have a greater potential to overwhelm formaldehyde metabolic capabilities, resulting in greater distribution and toxicity of formaldehyde than might be experienced with episodic drinking water exposures. Acute Toxicity (1-5 d) Several human cases of accidental, homicidal, or suicidal ingestion of formaldehyde have been reported in the literature (Eells et al. 1981; Kochhar et al. 1986; Burkhart et al. 1990). Eells et al. (1981) reported on the death of a 41-year [y]-old woman following the intentional ingestion of formaldehyde (620 mg/kg). The woman was cyanotic and severely hypotensive when admitted to the emergency room and died within 28 h of admission. Observed toxicologic effects prior to death included renal failure, abdominal pains, and symptoms of metabolic acidosis. Similar effects were reported by Burkhart et al. (1990) after the ingestion of formaldehyde at 520 mg/kg in a suicide attempt. The victim complained of difficulty breathing and severe abdominal pains before experiencing a significant drop in blood pressure and slipping into a coma. Upon autopsy, the stomach of the victim was reported to be hard, white, and leathery. In a nonfatal case, Kochhar et al. (1986) described a 26-y-old woman who accidentally ingested formaldehyde at 230 mg/kg. The patient experienced ulceration and sloughing of the soft palate and posterior pharyngeal wall and epiglottis, as well as ulceration of the stomach and upper GI tract. Mild tachycardia was also observed following the ingestion of formaldehyde. In summary, acute oral human exposures to formaldehyde have resulted in adverse respiratory, cardiac, GI, metabolic, renal, and neurologic effects.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TABLE 7-2 Toxicity Summary Dose/Route Exposure Duration Species Effects Reference Acute Exposures 520 mg/kg/dm, oral One event Human, male (n = 1) Death; decreased blood pressure; GI irritation; cardiac arrest; acidosis Burkhart et al. 1990 620 mg/kg/d, oral One event Human, female (n = 1) Death; decreased blood pressure; GI irritation; acidosis; loss of consciousness Eells et al. 1981 230 mg/kg/d, oral One event Human, female (n = 1) Ulceration of esophagus mucosa; GI irritation; tachycardia Kochhar et al. 1986 Short-Term Exposures 185 mg/kg/d (LOAEL), gavage Gestation days 6-15 CD-1 mice, female Increased mortality (22 of 34 mice); no observed teratogenic effects Marks et al. 1980 40 ppm (NOAEL), formaldehyde vapor Gestation days 6- 20, 6 h/d Sprague-Dawley rats, female (n = 25) No reproductive or developmental effects observed at concentrations of 0, 5, 10, 20, and 40 ppm; maternal toxicity in the 40-ppm group was observed Saillenfait et al. 1989 10 ppm (NOAEL), formaldehyde vapor Gestation days 6- 15, 6 h/d Sprague-Dawley rats, female (n = 25) No reproductive or developmental effects observed with exposures of 0, 2, 5, or 10 ppm Martin 1990 10,000 mg/L (as HMT) (NOAEL), drinking water 2 wk (exposures to dams continued through gestation and lactation) Wistar rats, male and female No malformations noted in 124 pups born to females exposed to 0 or 1% hexamethylenetetramine (HMT) Della Port et al. 1970 80 mg/kg/d (LOAEL), gavage 4 wk Wistar rats, male Reduced weight gain Vargova et al. 1993

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 20 mg/kg/d (LOAEL), gavage 4 wk Wistar rats, male Dose-dependent reduced antibody response Vargova et al. 1993 125 mg/kg/d (LOAEL), 25 mg/kg/d (NOAEL), drinking water 4 wk Wistar rats, male and female Significant hyperkeratosis of the stomach; focal gastritis; bodyweight reductions; decreases in blood protein and albumin concentrations; increased kidney weight Til et al. 1988 30 mg/L (0.003 %) (LOAEL), auxiliary spray test 2 wk Humans No ACD other than very mild dermatitis observed (2/13 subjects) in formaldehyde- sensitized individuals at this concentration Jordan et al. 1979 300 mg/kg/d (LOAEL), drinking water 24 mo, but effects observed after several wk Wistar rats, male and female Mortality as early as 9 d, reduced weight gain and food/water intake Tobe et al. 1989 82 mg/kg/d (LOAEL), drinking water 24 mo, but effects observed after 1 wk Wistar rats, male Decreased bodyweight and liquid consumption Til et al. 1989 Subchronic Exposures 150 mg/kg/d (rats) (LOAEL), drinking water. 100 mg/kg/d (dogs) (LOAEL), 50 mg/kg/d (NOAEL), oral in feed 90 d Sprague-Dawley rats, male and female; beagles, male and female Reduced weight gain; reduction in water/feed consumption Johannsen et al. 1986 9.4 mg/kg/d (NOAEL), oral in feed 52 d, gestation days 4-56 Beagles, female No effect on pregnancy rate, weight gain, length of gestation, or malformation Hurni and Ohder 1973

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Dose/Route Exposure Duration Species Effects Reference Chronic Exposures 258 mg/kg/d (LOAEL), drinking water 32 wk Wistar rats, male Reduced weight gain; gastric ulceration; papillomas; regenerative mucosa Takahashi et al. 1986 82 mg/kg/d (LOAEL), 15 mg/kg/d (NOAEL), drinking water 24 mo Wistar rats, male Reduced body weight; thickened limiting ridge; gastric ulceration; mucosal thickening Til et al. 1989 300 mg/kg/d (severe effects), 50 mg/kg/d (LOAEL), 10 mg/kg/d, (NOAEL), drinking water 24 mo Wistar rats, male and female Significant mortality; non-neoplastic gastric lesions; hyperplasia of fundic mucosa; reduced weight gain; lower food and water intake Tobe et al. 1989 (1) 188 mg/kg/d (2) 125 mg/kg/d (3) 63 mg/kg/d (4) 13 mg/kg/d (5) 6 mg/kg/d (6) 1 mg/kg/d 104 wk Sprague-Dawley rats, male and female (n = 50 each) Leukemia incidence (male and female) by dose group (1) 22,14% (2) 12,14% (3) 16,8% (4) 10,8% (5) 10,8% (6) 2,4% Soffritti et al. 1989 Drinking water     4,3% (control) 10,6% (methanol)  

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 (1) 188 mg/kg/d (2) 125 mg/kg/d (3) 63 mg/kg/d (4) 13 mg/kg/d (5) 6 mg/kg/d (6) 1 mg/kg/d 104 wk Sprague-Dawley rats, male and female GI tract malignant neoplasias (male and female) (1) 6,0% (2) 2,0% (3) 0,0% (4) 0,0% (5) 0,4% (6) 4,0% Soffritti et al. 1989 Drinking water     0% (control) 0% (methanol)   313 mg/kg/d 104 wk Sprague-Dawley breeders (n = 36) Malignant GI neoplasias (male and female): 2.8% in breeders Soffritti et al. 1989 Drinking water   and their offspring (n = 73) 15.1% in offspring 0% in controls Leukemias (male and female) 11% in breeders 5.5% in offspring 2.5% in control 5.5% methanol  

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Dose/Route Exposure Duration Species Effects Reference (1) 188 mg/kg/d (2) 125 mg/kg/d (3) 63 mg/kg/d (4) 13 mg/kg/d (5) 6 mg/kg/d (6) 1 mg/kg/d 104 wk Sprague-Dawley rats, male and female (n = 50 each) Leukemias (M,F) (1) 22,18% (2) 18,24% (3) 6,20% (4) 16,12% (5) 8,12% (6) 4,6% Soffritti et al. 2002 Drinking water     14,6% (control) 11,10% (methanol)   (1) 188 mg/kg/d (incidences primarily limited to highest dose group), drinking water 104 wk Sprague-Dawley rats, male and female (n = 50 each) Glandular stomach: 12% adenomatous polyp (male only), 0% in control Intestine: 10% malignant tumors (male only), 0% in control Soffritti et al. 2002 (1) 188 mg/kg/d (2) 125 mg/kg/d (3) 63 mg/kg/d (4) 13 mg/kg/d (5) 6 mg/kg/d (6) 1 mg/kg/d 104 wk Sprague-Dawley rats, male (n = 50) Testes: interstitial-cell adenoma (1) 18% (2) 24% (3) 20% (4) 12% (5) 12% (6) 6% Soffritti et al. 2002 Drinking water     10% (control) 6% (methanol)  

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 the potential for formaldehyde to remain unmetabolized and circulate through the bloodstream in a manner that would not occur following administration of equivalent daily doses in drinking water. Irritation Studies from both humans and laboratory animals have shown that irritation and other adverse GI effects can occur with sufficient oral exposure to formaldehyde. Although no designed studies were found that dealt specifically with very short-term exposures (1-2 d) to formaldehyde, observations from longer-duration studies suggest that this is a credible adverse effect to be considered in AC development. The AC for this irritation is based on the NOAEL (25 mg/kg/d) for the Til et al. (1988) 4-wk administration of formaldehyde to rats in drinking water. At the next highest dose level (125 mg/kg/d), significant thickening of the limiting ridge and hyperkeratosis in the forestomach, along with gastritis in the glandular stomach were observed. A UF of 10 was applied to account for necessary species extrapolation, and a standard drinking water rate (2.8 L/d) and body weight (70 kg) for astronauts was assumed in calculating the AC. It is not possible to ascertain exactly how long an exposure was necessary to result in the observed gastric effects. However, this and other studies (Til et al. 1989; Tobe et al. 1989), have reported reduced food and drinking water intake (proceeding observed GI effects) in formaldehyde-exposed rats as early as the first week of exposure. Although a single day of exposure may not be sufficient to produce the marked GI changes observed in these animal studies, the establishment of an AC for this end point is supported by the potential for milder gastric irritation. With inhalation exposures, some variability in human response to the irritant effects of formaldehyde has been shown. Individual sensitivity may be partially related to observed genetic polymorphisms which influence the activity of FDH/ADH3, the key enzyme involved in the rapid metabolism and detoxification of formaldehyde (Hedberg 2001). Given that a range of irritant responses is likely with drinking water exposures to formaldehyde, and considering that this type of sensitivity is not evaluated in astronaut health screening, an additional UF of 3 was applied in calculating the AC to account for variability in individual response.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 In regard to the 100- and 1,000-d ACs, Til et al. (1989) conducted a 2-y drinking water study where formaldehyde was administered to male and female rats at various doses. At the highest doses (82 mg/kg/d in males, 109 mg/kg/d in females), significant and marked GI effects were observed relative to controls. Effects were observed during the 53-, 79-, and 105-wk autopsy evaluations. These effects consisted of ulceration and hyperkeratosis in the forestomach (especially along the limiting ridge) and focal gastritis and significant mucosal inflammation in the glandular stomach. A NOAEL of 15 mg/kg/d was noted for these effects. These results were consistent with the findings of Til et al. (1988), who conducted a similar study over a 4-wk exposure period. A UF of 10 was applied to account for species extrapolation, along with an additional factor of 3 to address variations in individual response to formaldehyde. A standard drinking water rate (2.8 L/d) and body weight (70 kg) for astronauts was assumed in calculating the AC. The rationale for applying the results of a chronic study to the 100-d SWEG is that there is sufficient evidence that the gastric effects observed in the chronic study could occur over a shorter timeframe. Til et al. (1988) observed the same gastric changes in their 4-wk study, at very similar doses (125 mg/kg/d as compared to 82 and 109 mg/kg/d in the chronic study). Also, Til et al. (1989) observed significantly reduced weight gain, water intake, and food intake throughout much of their study (especially with the male rats), which is suggestive that there were treatment-related effects relevant to the 100-d exposure timeframe. Allergic Contact Dermatitis Jordan et al. (1979) evaluated low-level exposure to formaldehyde with respect to the potential for elicitation of ACD. Among other tests, the authors performed repeated axillary spray tests on 13 human volunteers with ACD. Solutions of 30 ppm (0.003%) formaldehyde were sprayed onto the axilla twice a day for 2 wk. This type of experimental design is likely to be more applicable than closed patch testing to on-orbit exposures to formaldehyde in water. With the exception of two in-

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 dividuals, no response was observed in this testing. The two individuals who might be characterized as responders only displayed very mild perifolicular dermatitis after 2 wk of testing. The authors concluded that formaldehyde concentrations below 30 ppm can be tolerated without notable response (even by individuals with ACD) for extended exposure durations (Jordan et al. 1979). In developing ACs for ACD, the 30 mg/L threshold was taken as the starting concentration that will be protective of responsive individuals. Adjustment to estimate a NOAEL was not accomplished. With ACD, it can be difficult, if not impossible, to establish an AC that will protect all individuals (Loomis 1979). For example, one highly responsive individual was reported to elicit an ACD response to formaldehyde at concentrations in water as low as 0.2 ppm (Horsfall 1934). However, contact with water containing less than 30 mg/L of formaldehyde is unlikely to result in any notable ACD response, even for individuals who already have ACD (WHO 2002). Since the Jordan et al. results are based on a human study of individuals with ACD, no adjustment was necessary for species extrapolation or to ensure protection of a susceptible population. Also, accounting for the small number of volunteers is not considered necessary given the populations studied and the mildness of the potential response to this low concentration of formaldehyde. There is no evidence in the literature to suggest that low-level exposures to formaldehyde in water will cause ACD in crew members who do not already have ACD. Also, given the ubiquitous ground-based use of formaldehyde (for example, use in consumer products, laboratories), it is likely that crew members would have experienced more-significant exposures to formaldehyde prior to flight. With respect to the 100-d and 1,000-d ACs for ACD, it is probable that any ACD response would have been experienced within the timeframe (2-wk study) observed by Jordan et al., and no adjustment was made in setting the 100- or 1,000-d ACs. A significantly higher AC for this end point would be acceptable for the vast majority (96-99%) of the population (Marks et al. 1995) that does not already have contact dermatitis from exposure. All timeframe ACs = 30 mg/L. Carcinogenicity Interpretation of the Soffritti et al.’s (1989, 2002) cancer findings for formaldehyde in terms of their applicability to SWEG derivation is complex. First, two chronic duration animal studies (Til et al. 1989; Tobe

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 et al. 1989) did not report increased tumor incidence in the GI tract or other evaluated organ systems. As discussed previously, Soffritti et al. (1989, 2002) reported both GI tumors and cancers at other sites distant from the portal of entry. With respect to observed GI tumors, it is biologically plausible that sufficient formaldehyde exposure could result in cancers at the portal of entry (through incorporation of formaldehyde into critical macromolecules and tissue damage and cell proliferation at the point of contact). However, given the rapid metabolism of formaldehyde, it is likely that a threshold would exist below which formaldehyde ingestion would not pose a credible cancer risk (CIIT 1999). Additionally, both Soffritti et al. studies showed a relatively low incidence of treatment-related GI tumors, and these tumors were generally limited to the high-exposure groups (188 and 313 mg/kg/d). Consistent with the understood mechanism of action of formaldehyde in the development of tumors in association with inhalation exposures, oral portal-of-entry tumors would likely be dependent on cytotoxicity, hyperplasia, and regenerative cell proliferation (CIIT 1999; WHO 2002). Even when considering the possibility of a mutagenic mechanism of action (expressed through DNA-protein crosslink formation), cancer risks associated with low levels of formaldehyde exposure would be much lower than those based on extrapolations from doses sufficient to evidence cytotoxicity and cell proliferation (Schlosser et al. 2003). Overall, these studies suggest that formaldehyde exposures that do not result in GI irritation or damage are also unlikely to represent a concern for GI cancers. ACs were not established for GI cancers based on this assessment. This approach is consistent with the WHO (2002) conclusion that the “lack of evidence for the potential carcinogenicity of ingested formaldehyde precludes an analysis of exposure–response for this effect.” With respect to the Soffritti et al. observations of tumors at sites distant from the portal of entry (that is, leukemias, mammary gland adenocarcinomas, testicular adenomas), there is uncertainty as to their applicability to SWEG development. The Soffritti et al. findings contradict other drinking water studies (Til et al. 1989; Tobe et al. 1989) in which these types of tumors were not observed, and are inconsistent with the lack of increased concentrations of formaldehyde in the blood (Heck et al. 1985) and the general absence of tumors at sites other than the portal of entry with inhalation exposures to formaldehyde. The findings from the Soffritti et al. (1989) study were reviewed by WHO (2002) and IRIS (2004) but were not utilized in development of oral-cancer risk estimates by these organizations. Similarly, ACs for these cancer end points were not developed in this document.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 REFERENCES ACGIH (American Conference of Governmental Industrials Hygienists). 1994. Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed., Vol. I. Cincinatti, OH: ACGIH. Albert, R.E., A.R. Sellakumar, S. Laskin, M. Kuschner, N. Nelson, and C.A. Snyder. 1982. Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat. J. Natl. Cancer Inst. 68:597-603. ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Profile for Formaldehyde. Prepared by Syracuse Research Corporation, July 1999. Agency for Toxic Substances and Disease Registry, Atlanta, GA. Ballarin, C., F. Sarto, L. Giacomelli, G.B. Bartolucci, and E. Clonfero. 1992. Micronucleated cells in nasal mucosa of formaldehyde-exposed workers. Mutat. Res. 280:1-7. Blair, A., R. Saracci, P.A. Stewart, R.B. Hayes, and C. Shy. 1990. Epidemiologic evidence on the relationship between formaldehyde and cancer. Scand. J. Work Environ. Health 16:381-393. Bolt, H.M. 1987. Experimental toxicology of formaldehyde. J. Cancer Res. Clin. Oncol. 113:305-309. Burkhart, K.K., K.W. Kulig, and K.E. McMartin. 1990. Formate levels following formalin ingestion. Vet. Hum. Toxicol. 32(2):135-137. Buss, J., K. Kuschinsky, H. Kewitz, and W. Koransky. 1964. Enteric resorption of formaldehyde. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 247:380-381 (as cited in IARC 1995). Casanova, M., D.F. Deyo, and H.D. Heck. 1989. Covalent binding of inhaled formaldehyde to DNA in the nasal mucosa of Fischer 344 rats: Analysis of formaldehyde and DNA by high-performance liquid chromatography and provisional pharmacokinetic interpretation. Fundam. Appl. Toxicol. 12:319-417. Casanova, M., K.T. Morgan, W.H. Steinhagen, J.I. Everitt, J.A. Popp, H.D. Heck. 1991. Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of Rhesus monkeys: Pharmacokinetics, rat-to-monkey interspecies scaling and extrapolation to man. Fundam. Appl. Toxicol. 17:409-428. CDHS (California Department of Health Services). 2003. Drinking Water Notification Levels: An Overview [online]. Available: www.dhs.ca.gov/ps/ddwem/chemicals/al/notificationoverview.pdf [accessed March 23, 2005]. Chebotarev, A.N., N.V. Titenko, T.G. Selezneva, V.N. Fomenko, and L.M. Katosova. 1986. Comparison of the chromosome aberrations, sister chromatid exchanges and unscheduled DNA synthesis in the evaluation of the mutagenicity of environmental factors [in Russian]. Tsitol. Genet. 20:21-26. CIIT (Chemical Industry Institute of Toxicology). 1999. Formaldehyde: hazard characterization and dose-response assessment for carcinogenicity by the

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Marsh, G.M, A.O. Youk, L.D. Buchanich, L.D. Cassidy, L.J. Lucas, N.A. Esman, and I.M. Gathuru. 2002. Pharyngeal cancer mortality among chemical plant workers exposed to formaldehyde. Toxicol. Ind. Health 18(6):257-268. Martin, W.J. 1990. A teratology study of inhaled formaldehyde in the rat. Reprod. Toxicol. 4:237–239. Merk, O., and G. Speit. 1998. Significance of formaldehyde-induced DNA protein crosslinks for mutagenesis. Environ. Mol. Mutagen. 32(3):260-8. Miller, C.A., and M. Costa. 1989. Analysis of proteins cross-linked to DNA after treatment of cells with formaldehyde, chromate, and cisdiamminechloroplatinum. Mol. Toxicol. 2:11-26. Monticello, T.M., J.A. Swenberg, E.A. Gross, J.R. Leininger, J.S. Kimbell, S. Seilkop, T.B. Starr, J.E. Gibson, and K.T. Morgan. 1996. Correlation of regional and nonlinear formaldehyde-induced nasal cancer with proliferating populations of cells. Cancer Res. 56:1012-1022. Morgan, K.T. 1997. A brief review of formaldehyde carcinogenicity in relation to rat nasal passages and human health risk assessment. Toxicol. Pathol. 25(3):291-307. NTP (National Toxicology Program). 2005. 11th report on carcinogenesis. National Toxicology Program, U.S. Department of Health and Human Services, Research Triangle Park, NC. Pandey, C.K., A. Agarwal, and A. Baronia. 2000. Toxicity of ingested formalin and its management. Hum. Exp. Toxicol. 19(6):360-6. Partanen, T. 1993. Formaldehyde exposure and respiratory cancer- a metaanalysis of the epidemiologic evidence. Scan. J. Work Environ. Health 19:8-15. Pinkerton, L.E, M.J. Hein, and L.T. Stayner. 2004. Mortality among a cohort of garment workers exposed to formaldehyde: An update. Occup. Environ. Med. 61:193-200. Pushkina, N.N., V.A. Gofmekler, and G.N. Kievtsova. 1968. Changes in content of ascorbic acid and nucleic acids produced by benzene and formaldehyde. Bull. Exp. Biol. Med. 66:868-870. Restani, P., and C.L. Galli. 1991. Oral toxicity of formaldehyde and its derivatives. Crit. Rev. Toxicol. 21(5):315-78. Saillenfait, A.M., P. Bonnet, and J. de Ceaurriz. 1989. The effects of maternally inhaled formaldehyde on embryonal and foetal development in rats. Food Chem. Toxicol. 8:545–548. Schlosser, P.M., P.D. Lilly, R.B. Conolly, D.B. Janszen, and J.S. Kimbell. 2003. Benchmark dose risk assessment for formaldehyde using airflow modeling and a single-compartment, DNA-protein cross-link dosimetry model to estimate human equivalent doses. Risk Anal. 23(3):473-487. Schmid, E., W. Googelmann, and M. Bauchinger. 1986. Formaldehyde-induced cytotoxic, genotoxic, and mutagenic response in human lymphocytes and Salmonella typhimurium. Mutagenesis 1:427-431.

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