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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"12 Formaldehyde." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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12 Formaldehyde J. Torin McCoy Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas RATIONALE FOR REASSESSMENT Spacecraft maximum allowable concentrations (SMACs) for formalde- hyde were established by the National Research Council (NRC) Committee on Toxicology and documented in Volume 1 of the SMAC documents published by the NRC (Wong 1994). Since that time, formaldehyde has become an air pollut- ant of increasing interest for the Space Shuttle as well as the International Space Station (ISS). With the deployment of air-monitoring devices (e.g., passive for- maldehyde monitoring badges) in both the orbiter and ISS beginning in the mid- 1990s, NASA now has reliable data on concentrations of formaldehyde in the space environment. Also, several ground-based, closed environment studies conducted by NASA have demonstrated airborne accumulation of formalde- hyde. This information was not available to NASA or the NRC in developing the formaldehyde SMACs in 1994. Experience with formaldehyde has shown that its concentration in the spacecraft atmosphere can often approach or exceed the 180-d formaldehyde SMAC of 0.04 parts per million (ppm). In evaluating these measurements in a crew health context, it is important for NASA to be confident that the SMAC is set at an appropriate level that will minimize the potential for significant crew health effects, but not falsely indicate cause for concern. A preliminary review of the scientific literature suggested that there may be useful information on formaldehyde that is more recent than the studies used in deriving the formaldehyde SMACs in 1994. In addition, several comprehen- sive reviews of formaldehyde have been conducted since 1994, including as- sessments by the World Health Organization (WHO 2002), the Agency for Toxic Substances and Disease Registry (ATSDR 1999), Health Canada (Health Canada 2001), and the Chemical Industry Institute of Toxicology (CIIT 1999). (See Table 12-1 for occupational exposure limits and related guidelines set by 206

Formaldehyde 207 other organizations). Review of the formaldehyde SMACs also identified an opportunity for refinement with respect to the approach taken in developing ac- ceptable concentrations (ACs) for the critical end points. TABLE 12-1 Occupational Exposure Limits and Other Established Limits for Formaldehyde Organization, Standard Limit, ppm Basis References ACGIH ceiling 0.3 Protective of sensory irritation ACGIH 1991 OSHA PEL TWA 0.75 Protective of sensory irritation, 29 CFR § other adverse respiratory effects 1910.1048 [2008] STEL 2 Protective of sensory irritation, other adverse respiratory effects NIOSH REL (TWA) 0.016 Based on lowest reliable NIOSH 2005 analytical detection limit, based on NIOSH consideration as a carcinogen STEL 0.1 Protective against sensory irritation NIOSH IDLH 20 Respiratory tract damage, severe NIOSH 1996 irritation ATSDR Acute MRL 0.4 Protective of sensory irritation. ATSDR 1999 Based on observations from Pazdrak et al. (1993) Intermediate 0.03 Degenerative effects on nasal (15-365 d) MRL epithelium. Based on work of Rusch et al. (1983). NRC EEGL, 1 h 2 ppm Weight-of-evidence evaluation of NRC 2007 CEGL, 24 h 1 ppm sensory irritation CEGL, 90 d 0.3 ppm NAC AEGL-1 0.9 ppm Weight-of-evidence evaluation of NAC 2004 (all time sensory irritation frames) Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL- 1, acute exposure guideline level (nondisabling); ATSDR, Agency for Toxic Substances and Disease Registry; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; IDLH, immediately dangerous to life and health; MRL, minimal risk level; NAC, National Advisory Council; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administra- tion; PEL, permissible exposure limit; REL, recommended exposure limit; STEL, short-term exposure limit; TWA, time-weighted average.

208 SMACs for Selected Airborne Contaminants After weighing these factors, NASA decided there was merit in updating and reconsidering critical toxicologic information on formaldehyde in the space- craft atmosphere. This is the first time a SMAC has been reassessed, and there- fore it is worth clarifying that this process is better viewed as a refinement than as a wholesale SMAC evaluation. This reassessment is intended to complement the existing SMAC for formaldehyde, and efforts will be made to avoid dupli- cating information already presented and approved by the NRC. In terms of or- ganization, this document will do the following: • Provide formaldehyde air-monitoring data relevant to the spacecraft environment. • Summarize the approach taken in developing the existing formaldehyde SMACs. • Evaluate whether toxicologic data exist that support development of ACs for end points not evaluated in the original SMAC document. • Reevaluate studies relevant to critical end points considered in SMAC development, including considering more recent data that may be available. • Provide justification for refined ACs and SMACs as appropriate; and • Set limits for the 1,000-d exposure time frame (not addressed in the original 1994 document), consistent with NASA needs in anticipation of longer- term lunar or martian missions. Review of Physical and Chemical Properties Formaldehyde is a colorless gas with a strong, pungent odor (Sax 1984). Synonyms: Formic aldehyde, methyl aldehyde, methanal Formula: HCHO CAS number: 50-00-0 Molecular weight: 30.0 Boiling point: –19.5°C Melting point: –92°C Lower explosive limit: 7% Upper explosive limit: 73% Vapor pressure: 10 mm Hg at –88°C Vapor density: 1.08 Conversion factors at 25°C, 1 atm: 1 ppm = 1.23 mg/m3, 1 mg/m3 = 0.82 ppm

Formaldehyde 209 Formaldehyde Air Measurements in the Spacecraft Environment Formaldehyde is a very common indoor air pollutant, as it can be off- gassed from textiles, foam insulation, resins, epoxys, and a myriad of other sub- stances commonly encountered in the indoor environment (both ground based and on orbit). Health Canada (2000) pooled indoor air measurements across five different ground-based indoor air studies and found that the average formalde- hyde concentration in indoor air was roughly 0.03 ppm. However, concentra- tions can vary significantly depending on the types of materials used in con- struction; Hare et al. (1996) reported that average indoor air concentrations of formaldehyde monitored in newly constructed homes range between 0.04 and 0.4 ppm. Formaldehyde can also be formed through secondary reactions of other indoor air pollutants (e.g., methane, pinene), especially in the presence of higher temperatures or chemical oxidizers. Studies by NASA have frequently observed formaldehyde releases from delrin, melamine foam, and other commonly used industrial materials. Formaldehyde air monitoring data are available for both Space Shuttle and ISS, as well as for ground-based habitations designed to mimic enclosed- environment conditions that might be experienced on the moon or on Mars. These experiences have yielded information that is highly relevant to the SMAC process, as briefly described in the following sections. Shuttle Orbiter Monitoring In an effort to gain scientific perspective on the challenges posed by ex- tended duration spaceflight, NASA conducted the Extended Duration Orbiter Medical Project from 1989 to 1995. As part of this project, formaldehyde meas- urements were collected on three STS Missions. Both area and personal moni- tors (passive dosimetry monitors, 8-h durations) were used to collect representa- tive air samples during shuttle flight. Table 12-2 presents results from this monitoring. Formaldehyde concentrations were below the current 24-h SMAC (0.1 ppm) but were consistently measured at concentrations that approached or exceeded the current 180-d SMAC (0.04 ppm). For STS-59, every 8-h meas- urement for both area and personal monitors was at or above the 0.04-ppm SMAC, with a maximum 8-h measurement of 0.064 ppm (NASA 1999). No crew symptoms were reported in association with these measured formaldehyde concentrations (J. James, National Aeronautics and Space Administration, Hous- ton, TX, personal communication, 2004). ISS Monitoring Consistent with shuttle monitoring, passive dosimetry badges are used to monitor formaldehyde concentrations on ISS. Area monitoring occurs in both the U.S. lab and the service module; samples are collected over 24 h. Given the

210 SMACs for Selected Airborne Contaminants TABLE 12-2 Shuttle Orbiter Data on Formaldehyde Concentrations (ppm) in Spacecraft Air STS Mission Type of Sample Range of Concentrations, ppm 56 Area 0.030-0.052 Personal 0.038-0.045 59 Area 0.040-0.058 Personal 0.045-0.064 67 Area 0.026-0.031 Personal 0.034-0.059 relative consistency of the formaldehyde readings over time, it is appropriate to compare the results with the 180-d SMAC of 0.04 ppm. Figure 12-1 presents results from this monitoring for bimonthly time periods between 2001 and 2004 (note that discontinuity in the graph line results from occasional data gaps). These data indicate that, for the U.S. laboratory, formaldehyde has frequently been measured above the 0.04-ppm SMAC. No adverse effects on crew health have been reported in association with these measured formaldehyde concentra- tions. As described in Figure 12-1, relatively higher amounts of formaldehyde have generally been found in the U.S. lab, although that disparity is significantly less in the more recent measurements. NASA is investigating reasons for this disparity, and preliminary results point to a slightly higher formaldehyde genera- tion rate in the U.S. lab and a greater amount of condensate removal in the ser- vice module, among other factors (J. Perry, National Aeronautics and Space Administration, Houston, TX, personal communication, 2004). Lunar-Mars Life Support Test Project NASA conducted the Lunar-Mars Life Support Test Project from 1995 to 1997 (James et al. 2002). The primary goal was to create and test an integrated closed-loop habitation that included systems for water recycling, waste process- ing, and air revitalization. This unique system enabled NASA to better under- stand human factors inherent to isolation and confinement and to develop, test, and improve capabilities to maintain the closed-loop environment. Crew volunteers lived in the habitation for the duration of several ex- tended tests (30, 60, and 90 d) conducted as part of this project. Air was moni- tored for volatile organic compounds and other pollutants and trace gases. In a 60-d test (Phase IIa), formaldehyde was monitored in the air through passive dosimetry badges and was verified by U.S. Environmental Protection Agency (EPA) impinger sampling. Formaldehyde was identified as a compound of par- ticular concern, as air concentrations increased to 0.2 ppm by Day 15 of the test. At this concentration, one of four crew members experienced eye and upper respiratory tract irritation. Source assessment determined that off-gassing of

0.06 0.05 0.04 Service 0.03 Module Lab 0.02 parts per million 0.01 0 1 01 1 1 02 2 02 02 2 2 03 3 3 3 04 4 n -0 g- -0 -0 b- r-0 n- g- -0 -0 b- r-0 -0 -0 b- r-0 Ju ct ec Ap Ju ct ec Ap ct ec Ap Au O D Fe Au O D Fe O D Fe FIGURE 12-1 Formaldehyde concentration measured in the ISS atmosphere. Source: Data from Johnson Space Center Toxicology Laboratory. 211

212 SMACs for Selected Airborne Contaminants formaldehyde from materials that had not been adequately tested for their off- gassing properties was at least partially responsible for the measured formalde- hyde concentrations. After poster murals and other possible sources were re- moved from the habitation, formaldehyde concentrations decreased to 0.12 ppm on Day 18. Reported symptoms did not persist for the crew member at this con- centration (although this reaction may be due to adaptation rather than to the reduced concentration) and the individual was able to continue for the 60-d test duration. No other irritants were identified at notable concentrations. Post-test evaluation (including a high-temperature “bake-out” study) indicated that mela- mine acoustic tiles may have been additional sources of formaldehyde during the habitation testing. A 90-d test followed (Phase III), with adjustments made to the trace con- taminant control devices and replacement of the melamine foam tiles. Air was monitored for formaldehyde in a manner consistent with the previous 60-d test- ing. The removal of potential formaldehyde sources appeared to be successful, as formaldehyde remained below the 0.04-ppm SMAC until approximately Day 60 of the test. Formaldehyde concentrations increased from that point to a maximum of 0.07 ppm, although this increase was thought to be due to an anomaly in a catalyst bed rather than to an additional off-gassing source. Al- though the 0.04-ppm long-term SMAC was exceeded for approximately 30 days, crew reported no symptoms in association with these measured formalde- hyde concentrations. SUMMARY OF EXISTING FORMALDEHYDE SMACS The existing SMACs for formaldehyde were established in 1994 after re- view and concurrence by the NRC (Wong 1994). Following an assessment of toxicologic information available in the literature, two toxicologic end points were identified as being critical (mucosal irritation and nasal carcinogenesis) and ACs were developed for these end points. The ACs for mucosal (sensory) irritation were significantly lower than those for nasal cancers and formed the basis for the formaldehyde SMACs for all exposure times. Refer to Table 12-3 for a summary of the ACs for these end points and the final SMACs established in 1994. UPDATE AND RECONSIDERATION OF CRITICAL TOXICOLOGIC DATA The following sections present the results of a review of the scientific lit- erature with regard to the inhalation toxicology of formaldehyde. This review is not meant to duplicate or replace the efforts involved in establishing the existing formaldehyde SMACs; the 1994 write-up presented in Volume 1 should also be referenced to obtain a more complete characterization of toxicokinetics, metabo- lism, and available toxicologic information on formaldehyde.

Formaldehyde 213 TABLE 12-3 Current Acceptable Concentrations and SMACs for Formaldehyde Acceptable Concentration, ppm Toxic End Point 1h 24 h 7d 30 d 180 d Mucosal Irritation 0.4 0.1 0.04 0.04 0.04 Nasal cancers 3,400 164 23 6 0.9 SMAC 0.4 0.1 0.04 0.04 0.04 In updating the SMAC evaluation, this review does not focus solely on the two critical end points (mucosal irritation and risk of nasal cancer) used to de- velop ACs for the existing SMAC document. Other potential toxicologic effects were described and considered in developing the existing SMACs, and it is im- portant to determine whether more recent data suggest that it is appropriate to establish ACs for other end points. The results of this review are presented in the following sections, with ad- ditional information on critical toxicologic studies reported in Table 12-4. Al- though Table 12-4 includes critical studies pertinent to this reassessment, it is not meant to characterize the wealth of toxicologic information on formaldehyde available in the literature. For more comprehensive references, see Bender (2002), ATSDR (1999), and WHO (2002). Pertinent occupational exposure limits for formaldehyde and calculated ACs based on this reassessment of formaldehyde are provided later in this document. Assessment of Possible Additional Toxicologic End Points of Concern The scientific literature was reviewed to assess whether there were any re- cent data that needed to be considered with regard to toxicologic end points not fully evaluated in setting the 1994 formaldehyde SMACs. The type of situation envisioned was one in which an end point may now need to be considered, al- though little supporting information was available in 1994 to suggest the need for an AC. Three toxicologic end points were identified as having some recent infor- mation in the literature that at least warranted closer evaluation; neurotoxicity, reproductive and developmental effects, and immunologic effects. With regard to neurologic effects, the overall body of evidence suggests that low-level expo- sures (<1 ppm) to formaldehyde are unlikely to result in any neurologic impair- ment. Similarly, the weight of evidence from an evaluation of reproductive and developmental toxicity suggests that these effects will not occur in association with exposures relevant to the spacecraft environment. With respect to immu- nologic effects, it does not appear necessary to develop specific ACs to protect people with asthma from formaldehyde exposures at the low levels relevant to

TABLE 12-4 Summary of Critical Toxicologic Studies on Formaldehyde Inhalation 214 Exposure Dose/Route Durationa Species Effects Reference Neurotoxicity 10 ppm 6 h/d, 5 d/wk Wistar rats,10 of each Three groups exposed to 1, 10, and 20 ppm of formaldehyde. Woutersen et (NOAEL) for 13 wk sex Uncoordinated movement and wall-climbing were reported during al. 1987 the first 30 min of exposure for the 20-ppm exposure group only. No histopathologic evidence of lesions or damage to the brain. 10 ppm 6 h/d, 5 Wistar rats, male, 40 Exposure groups included 0, 2, 4, 10, 20, and 40 ppm of Maronpot et (NOAEL) d/wk for 13 formaldehyde. No gross neurologic effects were observed in the 0-, al. 1986 wk 2-, 4-, or 10-ppm groups. Rats in the 20-ppm group were observed to be listless and to have a hunched posture. The same effects were observed at 40 ppm, along with ataxia. 2.6 ppm 10 min/d for Wistar rats, 2 Exposed animals (either 2.6 or 4.6 ppm) took longer to complete a Pitten et al. 2000 (LOAEL) 90 d groups with 13 rats maze and made more mistakes than controls. No dose-response was each exhibited for the two groups. 1.6 ppm 5h Human, 16 Exposure to 0.2, 0.4, 0.8, and 1.6 ppm resulted in no cognitive Andersen and (NOAEL) performance impairments during testing. Molhave 1983 1.0 ppm 5h Human, 16 Exposure to 0, 0.12, 0.33, and 1 ppm. In 5 of 6 tests, no dose-related Bach et al. 1990 (LOAEL) effects were observed. Performance on the digit symbol test was impaired at 1 ppm relative to the lower exposures. There was some uncertainty about the degree to which other variables were properly controlled in establishing the exposure groups. Reproductive/developmental effects 40 ppm 6 h/d SD rats, female, 25 No reproductive or developmental effects observed at 0, 5, 10, 20, or Saillenfait et (NOAEL for gestation 40 ppm. Maternal toxicity in the 40-ppm group was observed. al. 1989 reproductive day 6-20 effects)

10 ppm 6 h/d SD rats, female, 25 No reproductive or developmental effects observed with Martin 1990 (NOAEL) gestation formaldehyde exposures of 0,2, 5, or 10 ppm. day 6-15 Immunologic effects 3 ppm 20 minutes Human, 13 No asthmatic response or changes in pulmonary function parameters Frigas et al. 1984 in groups of individuals with reported formaldehyde-related asthma who were exposed to up to 3 ppm. 1.6 ppm 6 h/d for 10 BALB/c mice, 2 Preexposure to 1.6 ppm for 10 d resulted in higher serum titers of Tarkowski and d, and 6 h/d groups with10 mice IgE in response to ovalbumin administration. This effect was not Gorski 1995 once a wk each observed in the 7-wk experiment. for 7 wk 1.0 ppm 3h Human, 23 No differences in evaluated immunologic parameters among two Pross et al. 1987 groups of asthmatics (one control and one with reported sensitivity to urea-formaldehyde foam) exposed to 1 ppm of formaldehyde. 0.25 ppm 8 h/d, 5 DH guinea pigs, 12 After preexposure to formaldehyde, 10 of 12 animals in the 0.25- Riedel et al. 1996 (LOAEL) consecutive ppm group were found to exhibit a heightened immune response to 0.13 ppm days an allergen (ovalbumin), vs. 3 of 12 with the control group. The (NOAEL) response in the 0.13-ppm group was not different from the control. 80 ppb (LOAEL) 16 h/d, 5 C3H/He mice, After preexposure to formaldehyde at 0, 80, 400, and 2,000 ppb, Fujimaki et d/wk, 12 wk 5/group NGF production was reduced in the lowest two exposure groups al. 2004 compared with controls, but not in the 2,000-ppb group. No dose- response was noted. Nasal epithelial damage and nasal cancer 3 ppm 22 h/d, 7 Cynomolgus Exposure to 3 ppm resulted in statistically significant amounts of Rusch et al. 1983 (LOAEL) d/wk for 26 monkeys male, 12; squamous metaplasia/hyperplasia in the nasal epithelium in 1 ppm wk F344 rats, 20 male monkeys and rats. At this concentration monkeys also exhibited (NOAEL) and 20 female; GS hoarseness and other signs of irritation. 1 ppm was established as a hamsters, 10 male NOAEL. and 10 female (Continued) 215

TABLE 12-4 Continued 216 Exposure Dose/Route Durationa Species Effects Reference 0.3 ppm 6 h/d, 5 F344 rats, male, 32 Statistically significant epithelial cell hyperplasia was observed in Kamata et (NOAEL) d/wk for 28 the 2- and 15-ppm exposure groups. al. 1997 2 ppm mo (LOAEL) 2 ppm 6 h/d, 5 F344 rats, male, 36 Exposure to 6, 10, and 15 ppm resulted in statistically significant Monticello et (NOAEL) d/wk, 6 wk increases in epithelial hyperplasia and squamous metaplasia. al. 1991 6 ppm Increased cell proliferation was also observed with these groups. (LOAEL) 2 ppm 6 h/d, 5 F344 rats, male, n = Exposure to 6, 10, and 15 ppm resulted in statistically significant Monticello et (NOAEL) d/wk, 24-mo 327 (n = 90 in 6- increases in epithelial hyperplasia and squamous metaplasia. al. 1996 6 ppm ppm group, n = 90 Increased cell proliferation was also observed with the highest two (LOAEL) in 10-ppm group, n exposure groups. Nasal tumors were reported in the 6-, 10-, and 15- = 147 in 15-ppm ppm groups. Squamous cell carcinoma were found in 1 of 90 rats at group) 6 ppm, 20 of 90 rats at 10 ppm, and 69 of 147 rats at the 15-ppm exposure level. 2-14.3 ppm 6 h/d, 5 F344 rats, male and Nasal polyploidy adenomas were observed in 1 of 232, 8 of 236, 6 Kerns et al. 1983 d/wk, 24-mo female, 232-236 of 235, and 5 of 232 rats, and squamous cell carcinomas were found at 0 of 232, 0 of 236, 2 of 235, and 106 of 232 for the 0-, 2-, 5.6-, and 14.3-ppm groups, respectively. Sensory irritation 0.3 ppm 5 min Human, 5 A concentration response relationship was observed for mild eye Schuck et (LOAEL) irritation between 0.3 and 1 ppm. However, the degree of irritation al. 1966 at 0.5 ppm was essentially identical to that at 0.05 ppm. 0.4 ppm 2h Human, 9 with skin Increased incidence of transient eye irritation, rhinitis. Change in Pazdrak et sensitive to nasal lavage fluid (increased eosinophil counts and protein levels. A al. 1993 formaldehyde, 11 major limitation of this study is the lack of detailed monitoring of controls the formaldehyde levels generated in the exposure chamber. As calibration was not conducted on the day of testing, there is a

potential for formaldehyde levels to have exceeded the 0.4-ppm target by an unknown amount (Bender 2002). 0.4 ppm 2h Human, 10 with Increased sneezing, rhinorrhea, itching, and changes in nasal lavage Krakowiak et asthma, 10 controls fluid (increased eosinophil counts and protein levels). No al. 1998 differences in nasal response between asthmatics and controls. A major limitation of this study is the lack of detailed monitoring of the formaldehyde levels generated in the exposure chamber. As calibration was not conducted on the day of testing, there is a potential for formaldehyde levels to have exceeded the 0.4-ppm target by an unknown amount (Bender 2002). 0.5 ppm 3h Human, 2 groups, None of the nine subjects at 0.5 ppm experienced eye irritation. Half Kulle et al. 1987 (NOAEL) 19 and 9 of the subjects noted odors at this concentration. More notable 1 ppm irritant effects were noted at concentrations of 1, 2, and 3 ppm. (LOAEL) 0.6 ppm 90 min Human, 15 with No differences in sensory irritant or pulmonary effects among Harving et (NOAEL) asthma groups exposed to 0.01, 0.1, and 0.6 ppm. al. 1990 0.8 ppm 5h Human, 16 Exposure to 0.2, 0.4, 0.8, and 1.6 ppm. For the lower two exposure Andersen and (LOAEL) groups none of the subjects reported irritation or discomfort for the Molhave 1983 first 2 h of the exposure. However, irritation (characterized as “slight discomfort”) did not appear to be dose related or significantly different than exposure to clean air. A direct relationship between concentration and irritant response (mainly eye irritation) was observed at 0.8 ppm and above. 1 ppm 5h Human, 16 At formaldehyde exposure concentrations up to 1 ppm (0, 0.12, Bach et al. 1990 (NOAEL) 0.33, and 1 ppm) there was not an observable concentration- response relationship in regard to irritation. However, there was some uncertainty about the degree to which other variables were properly controlled in establishing the exposure groups. (Continued) 217

TABLE 12-4 Continued 218 Exposure Dose/Route Durationa Species Effects Reference 1 ppm 6 min Human, 5-27 Exposure concentrations of 0, 0.35, 0.56, 0.7, 0.9, and 1.0 ppm were Bender et (LOAEL) volunteers tested. Only at the highest exposure was the irritant response al. 1983 statistically significant compared with clean air. The authors noted that the smaller sample numbers at 0.7 and 0.9 ppm (5 and 7 volunteers, respectively, as opposed to 27 volunteers with the 1-ppm group) may have limited the power of the test at these concentrations. Also, only at 1 ppm did the reported irritant severity move above “slight.” 2 ppm 40 min Human, 15 with The volunteers in this study were people with asthma who were Witek et al. 1987 asthma evaluated while at rest and while engaged in moderate exercise during exposure. Odors, sore throat, and eye irritation were reported at this concentration. One volunteer noted severe irritation at 2 ppm, and four others noted moderate irritation; none of them responded during the control period. 2.1 ppm 90 s Human, 33 healthy At 2.1 ppm, 33% of the subjects experienced a doubling in their eye Weber-Tschopp (LOAEL) males blink rate compared with controls. The blink rate was not elevated et al. 1977 1.2 ppm compared with controls for the 1.2-ppm exposure group. (NOAEL) 3 ppm 1h Human, 22 healthy, There was no difference between the two groups in the degree of Green et al. 1987 16 with asthma irritation experienced. Both groups reported odors, and eye, nose, and throat irritation. Response ranged from none to severe; 27% of the healthy subjects and 19% of those with asthma scored eye irritation as moderate or above. In both groups, 31% to 32% reported nose or throat irritation as moderate or above. 3 ppm 3h Human, 9 There was a statistically significant increase in eye, nose or throat Sauder et irritation, and odor at 3 ppm compared with clean air. Five of the al. 1986 subjects scored the nose or throat irritation as moderate, whereas only one scored eye irritation as moderate.

1-5 ppm 5 min Human, 13-20/test, In the static testing, 8% of the responses at 1 ppm were positive (per Stephens et multiple tests the authors, moderate or severe irritation was considered as a al. 1961 positive response). This was similar to the 7% response rate to clean air. Between 2 and 4 ppm, this rate increased to 33%, whereas at 5 ppm, 67% of the responses were positive. a Inhalation, unless otherwise noted. Abbreviations: LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level. 219

220 SMACs for Selected Airborne Contaminants the spacecraft environment. There is some limited evidence that formaldehyde may increase individual response to other allergens (Tarkowski and Gorski 1995, Riedel et al. 1996, Fujimaki et al. 2004), but more evaluation is needed (e.g., appreciation for mechanism of action, closer evaluation of dose-response relationships) before using these data to establish ACs. Most of these immunologic studies were available before several compre- hensive scientific reviews (ATSDR 1999, WHO 2002, NAC 2004, NRC 2007), although they were not used in developing air guidelines for formaldehyde by these organizations, presumably based on recognition of these uncertainties. The neurotoxicity, reproductive and developmental, and immunologic end points are addressed in more detail in the following sections. Neurotoxicity The 1994 SMAC evaluation does not specifically discuss the potential neurotoxicity of formaldehyde, and evidence generally indicates that eye and upper respiratory tract irritation would be expected to be a more sensitive end point. Woutersen et al. (1987) exposed Wistar rats to 1, 10, and 20 ppm of for- maldehyde by inhalation (6 h/d, 5 d/wk for 13 wk). Rats in the 20-ppm group exhibited abnormal behavior, including uncoordinated movement and wall- climbing within the first 30 min of each exposure. No such effects were ob- served with the lower-exposure groups. Histopathologic examination of the brain did not indicate lesions or other damage at necropsy. In a similar study, Maronpot et al. (1986) exposed B6C3F1 mice to for- maldehyde at 0, 2, 4, 10, 20, and 40 ppm. Mice in the two highest exposure groups exhibited dyspnea, hunched posture, and general listlessness, whereas no effects were observed in the other groups. Histopathologic evaluation did not identify lesions or other damage to brain tissue. Kerns et al. (1983) did not observe any behavioral abnormalities, and histopathologic findings were negative in a 24-mo study with Fisher rats and B6C3F1 mice exposed by inhalation to formaldehyde at 0, 2, 5.6, or 14.3 ppm. Pitten et al. (2000) concluded that formaldehyde was “probably neuro- toxic” by inhalation based on the results of their study of the performance of Wistar rats in a maze trial, in which they exposed the rats for 10 min/d to for- maldehyde at concentrations of 0, 2.6, and 4.6 ppm for 90 consecutive days. Exposed rats in both groups needed more time to complete the maze and made more mistakes than controls. No dose-response was observed among the two exposure groups, and the authors cautioned that further testing with established behavioral trial methods still needs to be performed. Following a 5-h inhalation exposure to formaldehyde at concentrations of approximately 1 ppm, human volunteers reported fatigue and headache, and exhibited poorer performance on mathematical tests; no effects were observed after exposures to formaldehyde at 0.1 ppm (Bach et al. 1990). However, it is difficult to draw firm conclusions from the study results, as there were conflict-

Formaldehyde 221 ing results among the battery of tests, and the experimental design did not fully account for important variables (e.g., age, smoking status) in matching exposed and control subjects. Andersen and Molhave (1983) evaluated human performance in several tests (speed and accuracy in completing specific tasks, mathematical skills) dur- ing 5 h of exposure to formaldehyde at concentrations of approximately 1.6 ppm and did not observe any performance decrements. There is only limited epidemiologic evidence to suggest that neurologic impairment (e.g., loss of memory, sleep disturbance, lack of concentration, im- paired balance) may be a risk for workers chronically exposed to formaldehyde (Kilburn et al. 1987, Kilburn 1994). Although these effects were positively asso- ciated with increased daily exposure to formaldehyde in one cohort of histology technicians (with exposures ranging from 0.2 to 1.9 ppm), coexposure to other air pollutants and other limiting factors confound determination as to whether formaldehyde actually caused any of the observed effects (ATSDR 1999, WHO 2002). A longer-term study (Kilburn and Warshaw 1992) of a larger cohort failed to find these effects in association with formaldehyde exposure. Reproductive and Developmental Effects Reproductive and developmental effects were not considered to be critical effects in setting the 1994 SMACs for formaldehyde. However, a few studies have evaluated reproductive or developmental end points, and several critical reviews have been published since 1994. In general, only very limited evidence exists (either from studies of laboratory animals or from human epidemiologic studies) to suggest that reproductive or developmental effects could occur in association with inhalation exposures to formaldehyde. Given the reactivity and rapid metabolism of formaldehyde, toxicity at sites distant from the portal of entry is extremely unlikely, especially in association with low-level exposures (Collins et al. 2001). Various organizations have assessed available data on for- maldehyde and have come to the same conclusion (WHO 2002, ATSDR 1999, IARC 1995). Collins et al. (2001) conducted a thorough review and meta-analysis of studies that investigated the reproductive and developmental toxicity of formal- dehyde. With respect to evidence from studies of laboratory animals, they found that most of the animal studies did not report positive reproductive or develop- mental effects associated with formaldehyde exposure. One inhalation study that did observe reproductive effects with formalde- hyde was a Russian study (Guseva 1972) in which groups of male rats were ex- posed to formaldehyde by inhalation for 4 h/d 5 d/wk for 6 mo. The formalde- hyde concentrations were 0, 0.1, and 0.2 ppm. After the rats mated with unexposed females, reproductive effects were assessed. The males in the highest exposure group exhibited a significant decrease in testicular DNA, although

222 SMACs for Selected Airborne Contaminants there were no observed effects on the fetus (e.g., abnormalities in fetal weight, litter size, incidence of birth defects). Several Russian studies have also suggested a relationship between for- maldehyde exposure and various developmental effects in rats (Gofmekler 1968, Gofmekler et al. 1968, Pushkina et al. 1968). In these studies, male and female rats were exposed to formaldehyde 24 h/d by inhalation for 10-15 d, at concen- trations of 0, 0.01, and 0.83 ppm. These effects included increases in fetal body weight, reduced number of fetuses per litter, reduced amounts of nucleic acids in fetuses, and fetal histopathologic changes. Specific study details have been found to be lacking or inconsistent, and these results have not been duplicated in other studies (Staples 1983, Collins et al. 2001). They are also inconsistent with the findings from Saillenfait et al. (1989), who evaluated SD rats exposed to formaldehyde at up to 40 ppm on gestations days 6-20 and observed no changes in a number of reproductive variables (e.g., number of resorptions, implanta- tion), and with the work of Martin (1990), who evaluated a wide variety of re- productive and developmental end points and observed no effects in SD rats exposed to formaldehyde at concentrations as high as 10 ppm (6 h/d on gestation days 6-15). Collins et al. (2001) also described the results of a number of human epi- demiologic studies. In general, reproductive and developmental effects evalu- ated included spontaneous abortion rates, congenital malformations, reduced birth weights, and infertility. Among these effects, spontaneous abortion was most often investigated in the epidemiologic studies. Of nine studies identified, four suggested higher rates of spontaneous abortion in formaldehyde-exposed workers (Axelsson et al. 1984; John et al. 1994; Taskinen et al. 1994, 1999). In several cases, there was no attempt to control for confounding factors such as age and smoking status. Even in those studies that attempted to control for these major confound- ing factors, coexposures to other reproductive toxicants may be important fac- tors. For example, John et al. (1994) based their assessment on self-reported spontaneous abortion rates (relative risk factor of 2.1, with a 95% confidence interval [CI] of 1.0-4.3) from female cosmetologists who were also exposed to solvents and other potential chemical confounders. In their meta-analysis, Collins et al. (2001) reported a meta-relative risk of only 1.4 when considering reported data across all studies. They also pointed out that reporting bias was a factor in the reported relative risks, as studies that used self-reported exposure data had a relative risk of 2.0 (95% CI of 1.4-2.8), whereas studies in which the work task was specifically evaluated reported a mean relative risk of only 0.7 (95% CI of 0.5-1.0). There was little epidemiologic evidence for an increased risk of congenital malformations or low birth weight in exposed women (ATSDR 1999, Collins et al. 2001). Similarly, a population-based case-control study of low-birth-weight new- borns in Lithuania evaluated a possible association with formaldehyde expo- sures and found no statistically significant association between incidences of

Formaldehyde 223 low-birth-weight newborns and estimates of airborne concentrations of formal- dehyde (Grazuleviciene et al. 1998). Taskinen et al. (1999) evaluated a potential relationship between formal- dehyde exposure and infertility. They investigated 235 women exposed to for- maldehyde in the woodworking industry (estimated formaldehyde exposure concentrations of 0.01-1.0 ppm) and found that 21% of women in the high- formaldehyde exposure group (>0.33 ppm) experienced longer times to preg- nancy, compared with 9% in a control group. However, this study had a number of sources of uncertainty, including the fact that exposure ranges were not measured but were estimated based on expected workplace exposures, paternal exposures were not evaluated, and the study relied exclusively on self-reported data (Collins et al. 2001). Immunologic Effects Although asthma would likely be identified in astronaut health screening, the 1994 SMAC document discusses it briefly in the context of sensitive nonasthmatic individuals. Direct exposure to formaldehyde is clearly irritating to the skin, and allergic contact dermatitis related to formaldehyde exposures is not uncommon (NRC 1981, WHO 2002). Exposures to formaldehyde in air can re- sult in immunologically induced sensitization of the respiratory tract (Grammar et al. 1990, Lemiere et al. 1995, Hilton et al. 1996, Kim et al. 2001), although it is uncertain whether formaldehyde should be considered to be an asthmatic agent (Riedel et al. 1996, Frigas et al. 1984). Most immunologic studies of for- maldehyde do not support the contention that there is an IgE- or IgG-mediated response to formaldehyde exposure (ACGIH1991, Krakowiak et al. 1998, ATSDR 1999), and various publications have shown that exposures to formal- dehyde in the 1- to 3-ppm range are unlikely to trigger an asthmatic reaction in someone who has preexisting asthma (Sheppard et al. 1984, Pross et al. 1987, Uba et al. 1989). However, in some cases, exposures to formaldehyde can cause the devel- opment of asthma (Kim et al. 2001). It has been proposed that formaldehyde may be more likely to act as a direct respiratory irritant when asthmatic reac- tions are triggered by other causes (NRC 1981, Grammar et al. 1990). Also, some research suggests that the development of asthma may be more likely to be associated with particulate forms (e.g., resin dust) than with gaseous formalde- hyde (Lemiere et al. 1995) and that these particulate forms may contain complex mixture of other chemicals that could also be causing the response. In their 1997 review, a panel of the Industrial Health Foundation concluded that, at lower ex- posures up to 3 ppm, people with asthma were no more sensitive to formalde- hyde than other individuals (Paustenbach et al. 1997), a conclusion consistent with the observation that most inhaled formaldehyde at these exposures is re- tained in the upper respiratory tract because of the reactivity and high water solubility of the molecule (Egle 1972).

224 SMACs for Selected Airborne Contaminants Several studies have emerged since the 1994 SMAC that suggest formal- dehyde may interact with the immune system to enhance the response to other inhaled allergens. Tarkowski and Gorski (1995) preexposed mice to 0 and 1.6 ppm of formaldehyde by inhalation (6 h/d) for 10 d. They exposed a separate group for 6 h/d once a week over 7 wk. When challenged with ovalbumin, nei- ther the control group nor the group exposed intermittently over 7 wk demon- strated an effect on serum IgE ovalbumin. However, significantly higher serum titers were seen in the group of mice preexposed to formaldehyde for 10 con- secutive days. This type of immune effect was also evaluated in guinea pigs (Riedel et al. 1996). In this study, two groups of animals were exposed to 0.13 and 0.25 ppm of formaldehyde by inhalation (8 h/d over 5 consecutive days). Three control groups were also evaluated. The animals were then exposed to 0.5% ovalbumin in air, and their immune response (evidence of airway obstruction, circulating IgG) was evaluated again in a challenge 3 wk after the preexposure. In the group preexposed to 0.25 ppm of formaldehyde, 10 of 12 animals displayed sensitiza- tion to the ovalbumin compared with only 3 of 12 in the control group, and anti- ovalbumin IgG titers were significantly higher than in controls. The 0.13-ppm exposure group did not differ from the control group in either of these tests. The authors cautioned that the exact mechanism by which formaldehyde interacts with the immune system to exhibit these effects is unclear and noted that guinea pigs may be more sensitive than humans to the effects of formaldehyde (consis- tent with greater formaldehyde sensitivity demonstrated for pulmonary resis- tance). In a longer-term study, Fujimaki et al. (2004) exposed female mice for 12 wk (16 h/d, 5 d/wk) to formaldehyde at 0, 80, 400, and 2,000 parts per billion (ppb) and investigated the effects of this exposure on allergic inflammatory re- sponses. They observed that in ovalbumin-immunized mice, production of nerve growth factor (NGF) (measured in both plasma and broncho-alveolar lavage (BAL) fluid) decreased for mice preexposed to formaldehyde at 80 and 400 ppb, but not for those exposed at 2,000 ppb. The authors hypothesized that formalde- hyde may inhibit the immunologically mediated augmentation of NGF and IgG3 production or that reduction in NGF may affect its anti-inflammatory properties. However, there was no dose-response in NGF reductions for the three formalde- hyde exposure groups, and the authors noted that further studies are needed to better understand these findings. EVALUATION OF ADDITIONAL DATA AND REFINEMENT OF ACs Sensory Irritation Summary of Previous Approach There are a wealth of data on the sensory irritant effects of exposure to formaldehyde, including animal studies, controlled human exposure studies,

Formaldehyde 225 occupational findings, and community health surveys (e.g., mobile home stud- ies). In developing ACs for mucosal irritancy, the 1994 SMAC document used a mobile home study (Hanrahan et al. 1984) as a primary reference. This study investigated formaldehyde exposures in 65 mobile homes in Wisconsin with airborne formaldehyde concentrations between 0.1 and 0.8 ppm. Approximately half of the individuals exposed to indoor air at formaldehyde concentrations above 0.4 ppm reported mild eye irritation, and this concentration formed the basis for the 1-h AC (Table 12-5). For the 24-h AC, a smaller likelihood of irritation was desired, and the AC was set at 0.1 ppm, the concentration that produced eye irritation in only 4% of the subjects in the Wisconsin mobile home study. For the longer-term ACs (7, 30, and 180 d), there was a desire to set the guideline at a level that would be nonirritating for almost all the population. However, because of difficulty in establishing an irritation threshold and lacking a better approach, the mean out- door air concentration reported by Hanrahan et al. (1984) for the Wisconsin mo- bile home study was used as the basis for the limit (0.04 ppm). This is likely to be a relatively high estimate for typical ambient air and is more in line with cen- tral tendency estimates of indoor air concentrations of formaldehyde in conven- tional homes that are not newly constructed. For example, Health Canada (2000) recently pooled indoor air measurements across five different indoor air studies and found that the average formaldehyde concentration in indoor air was roughly 0.03 ppm, with a 95th percentile of 0.07 ppm. The 1994 SMAC document did not develop ACs based on loss of pulmo- nary function, presumably based on the conclusion that mucosal irritation would be a more sensitive end point. This conclusion is supported by evidence from the scientific literature, which generally indicates that pulmonary function is not impaired even at formaldehyde concentrations as high as 3 ppm with sensitive humans (asthmatic) (Sheppard et al. 1984) or in humans with chronic occupa- tional exposures (Horvath et al. 1988, Paustenbach et al. 1997). These observa- tions are consistent with the relatively high water solubility of formaldehyde, which makes it amenable to removal in the upper respiratory tract. Refinement of Approach and Review of Pertinent Data The mobile home studies have certain strengths. For example, the expo- sures are continuous and often focus on exposure concentrations that are espe- cially relevant to SMAC development. However, it has been recognized that the potential for confounding coexposures to other irritant gases and the general lack of sufficient control groups can significantly limit the usefulness of these studies (Paustenbach et al. 1997, Bender 2002). In addition, adaptation can po- tentially mask the acute health effects these residents experienced. Unlike many other chemicals, there are a number of controlled human exposure studies for formaldehyde, and they are widely viewed as providing the most reliable infor-

226 SMACs for Selected Airborne Contaminants TABLE 12-5 ACs for Sensory Irritation in the 1994 SMAC Document 1-h AC 24-h AC 7-d AC 30-d AC 180-d AC 0.4 ppma 0.1 ppmb 0.04 ppmc 0.04 ppmc 0.04 ppmc a AC is based on the work of Hanrahan et al. (1984) based on incidences of reported eye irritation in a mobile home study. b AC is based on the work of Hanrahan et al. (1984) based on incidences of reported eye irritation in a mobile home study. A lower response rate was deemed acceptable for 24 h compared with the 1-h AC. c AC is based on the mean ambient formaldehyde concentration for the Hanrahan et al. (1984) mobile home study. mation on the irritancy of formaldehyde (Paustenbach et al. 1997, Bender 2002, NAC 2004, NRC 2007). Accordingly, for the purposes of SMAC development, a focus was placed on using controlled human exposure study results where pos- sible, with other sources of data (e.g., animal studies, mobile home surveys) used as supporting evidence where applicable. A number of controlled human exposure studies for formaldehyde irrita- tion are available, and they vary in several important ways. For example, whereas many studies focus on healthy individuals, others have also sought to evaluate people with asthma and other potentially sensitive individuals in an attempt to better characterize the wide range of individual susceptibility to for- maldehyde irritation (Bender 2002). Other variables include the metric for re- porting irritation, the exposure durations used in the testing, and the formalde- hyde exposure concentrations. With regard to exposure concentration, those studies that evaluate formal- dehyde concentrations in the 1- to 3-ppm range can generally be separated from those primarily designed to evaluate low levels of formaldehyde (≤1 ppm). With respect to the former category, these studies were generally designed to assess pulmonary effects after acute exposures to formaldehyde, particularly in people with asthma and exercising individuals, although sensory irritation was also evaluated and reported. For example, Green et al. (1987) exposed 22 healthy subjects and 16 subjects with asthma to 3 ppm of formaldehyde for 1 h, along with clean air controls. Both groups were exposed during moderate to intense sessions of exercise. With respect to sensory irritation, both groups reported similar incidences of odors, eye irritation, and nose or throat irritation (irritation was not observed with clean air). The amount of irritation varied from none to severe, demonstrating the wide range of sensitivity to formaldehyde. Even at 3 ppm, however, most individuals did not experience any notable irritant effects. Witek et al. (1987) conducted a similar study, in which 15 volunteers with asthma were exposed to clean air and formaldehyde at 2 ppm for 40 min. The groups were evaluated while at rest and while engaged in moderate exercise during the exposures. Although exercise did not appear to affect the reported irritation, the volunteers reported higher incidences of moderate irritation with

Formaldehyde 227 formaldehyde at 2 ppm (4 of 15 volunteers reported moderate eye irritation, with another individual reporting severe, but not incapacitating, irritation) than when exposed to clean air. The irritant effects did not persist after the exposures were discontinued. One individual noted moderate irritation in the absence of formal- dehyde but reported no effects when exposed to 2 ppm. Sauder et al. (1986) evaluated slightly longer exposures (3 h) to 3 ppm of formaldehyde with nine healthy volunteers. Exposures to clean air were evalu- ated on the first day of the testing as a control. Eye and nose or throat irritation were statistically significant for the 3-ppm exposures. At 3 ppm, five of the nine volunteers reported moderate nose and throat irritation, but only one reported moderate eye irritation. The authors speculated that this may have been due to adaptation. In another 3-h study, Kulle et al. (1987) exposed 10 healthy volunteers to 0, 0.5, 1, and 2 ppm of formaldehyde at rest, with an additional 9 volunteers exposed to 0, 1, 2, and 3 ppm of formaldehyde while exercising. No exercise effect was noted with regard to the irritancy of formaldehyde. At 3 ppm, all the individuals reported eye irritation, with 44% of them characterizing it as moder- ate. With the 2-ppm exposures, 32% of the volunteers reported mild eye irrita- tion and 21% reporting moderate eye irritation when the group data were pooled. At 1 ppm, 16% of the volunteers reported mild eye irritation, with one individual still reporting moderate irritation at this concentration. No eye irrita- tion was reported for the 0.5-ppm exposure group. With respect to nose or throat irritation, 37% reported mild irritation at 2 ppm, but only 22% reported similar irritation at 3 ppm. Frequencies of nose or throat irritation for the 1- and 0.5- ppm groups were not greater than in the control group. Weber-Tschopp et al. (1977) assessed the eye irritation attributable to formaldehyde by evaluating blink rates in healthy human subjects exposed to formaldehyde at 0, 1.2, and 2.1 ppm for 90-s durations. There was no difference in eye blink rates between the lower exposure group and the controls, although the short-term duration of the testing may limit its usefulness in defining an eye irritation threshold. At 2.1 ppm, the blink rate doubled in a third of the subjects evaluated in the testing, as compared with controls. Stephens et al. (1961) exposed groups of 13-20 students to formaldehyde at concentrations ranging from 1 to 5 ppm over 5 min to evaluate eye irritation. Several replicate exposures were evaluated at each concentration so that total responses of self-reported irritation observations varied between 27 and 75 de- pending on the concentration. Observations of moderate to severe irritation were recorded as positive responses. At 1 ppm, only 8% of the exposures resulted in a positive response (at least moderate irritation), which was similar to the rate observed with clean air (7%). Between 2 and 4 ppm, 33% of the responses were positive; at 5 ppm, 67% were positive. This study is somewhat limited by the subjective evaluation of the degree of irritation, the lack of characterization of slight irritation, and the short exposure.

228 SMACs for Selected Airborne Contaminants Taken together these results suggest that the likelihood of a subject ex- periencing notable sensory irritation increases as concentrations rise above 1 ppm and that moderate irritation may occur in some individuals (although not a majority) exposed to formaldehyde in the range of 2 to 3 ppm. Although mild, transient irritation may be acceptable for certain SMAC time frames, moderate irritation is inappropriate for use as a basis for SMAC development. For this reason, studies involving exposures ≤ 1 ppm were generally viewed as being the most applicable for SMAC purposes, and these studies are described in more detail in the following section. AC Development The following factors should be emphasized in setting exposure guidelines based on the sensory irritation produced by formaldehyde: • There are a tremendous number of published studies related to the irri- tancy of formaldehyde, and it is not surprising that some of the data do not agree. This lack of agreement may be due to different descriptions and interpre- tations of the intensity of sensory irritation, among other factors. • There is a wide range of individual variability with regard to human sensitivity to formaldehyde irritation (NRC 1981, Paustenbach et al. 1997, WHO 2002), and a subset of individuals (e.g., 10% to 20% of the population) may exhibit effects at exposures that would be unnecessarily stringent for most of the population (Loomis 1979). It may not be possible to protect against mild irritant effects in all sensitive individuals, but any irritant effect that would im- pair crew performance should be precluded. • Relatively few studies provide reliable irritant information on expo- sures to low concentrations of formaldehyde (0.1 to 0.3 ppm). In assessing ex- posures at these low concentrations, it is important to recognize that control groups exposed to clean air can often experience relatively high irritant response rates (5% to 20%) (Kulle et al. 1987, Paustenbach et al. 1997). • In evaluating the relevancy of any controlled human exposure study to SMAC development for formaldehyde, the degree of irritation that is appropri- ate for each exposure time frame should be kept in mind. Both 1- and 24-h SMACs are useful in making informed decisions in contingency situations and may allow for transient and mild irritation and discomfort. This irritation should not be notable enough to impair crew performance. Although any sensory irrita- tion with formaldehyde is likely to be observed well before 24 h (Andersen and Molhave 1983), 24-h ACs are generally lower than 1-h ACs to minimize the discomfort a crew member would experience for this longer exposure. The 7-, 30-, and 180-d ACs are often identical and should represent a concentration that practically all crew members could be consistently exposed to without an expec- tation of irritant effects.

Formaldehyde 229 1-h AC Harving et al. (1990) investigated the sensory irritant effects of formalde- hyde on 15 volunteers with asthma. They were exposed to formaldehyde at 0.01, 0.1, and 0.6 ppm. The authors did not report any differences in sensory irritation response among these exposure groups, indicating that the threshold for an irri- tant response attributable to formaldehyde for their study group was above 0.6 ppm. Schuck et al. (1966) studied eye irritation in humans exposed for 5 min to formaldehyde at 0.01 to 1 ppm. Between 0.3 and 1 ppm, they observed a rela- tionship between concentration and eye irritation. However, for lower exposure concentrations, the association between formaldehyde exposure and irritant ef- fects was more uncertain. For example, the eye irritation intensity at 0.05 ppm reported by the test subjects was identical to the intensity reported at 0.5 ppm. Given that formaldehyde was generated by the photooxidation of hydrocarbons, the likelihood that other irritants were present (e.g., ethylene, peroxyacetyl ni- trate) should be noted (Paustenbach et al. 1997). These compounds were not characterized during the study, but their presence may explain the inconsisten- cies between this study and others in the literature that did not observe irritant effects associated with similar formaldehyde exposures. Several 2-h controlled human exposure studies from the same laboratory observed mild, transient irritation with exposure to formaldehyde at 0.4 ppm (Pazdrak et al. 1993, Krakowiak et al. 1998) in both sensitive (individuals with asthma and individuals sensitive to formaldehyde) and healthy individuals. In- creased sneezing, rhinorrhea, and itching were demonstrated, as well as changes in nasal lavage fluid (increased eosinophil counts and protein), although these effects were generally mild and subsided during the 2-h exposure. A major limi- tation of these two studies was the lack of detailed monitoring of the formalde- hyde concentrations generated in the exposure chamber. According to the au- thors, the chamber is calibrated only seven times annually (to an average of 0.4 ppm, with an upper range of 0.6 ppm). As calibration was not conducted on the day of the testing, there is the potential for formaldehyde levels to have ex- ceeded the 0.4-ppm target by an unknown amount (Bender 2002), which may explain why all individuals (healthy and potentially sensitive) reported mild irritation at this exposure level, contrary to observations in other studies in the scientific literature. Andersen and Molhave (1983) conducted a controlled human exposure study involving 16 healthy human volunteers. Exposure to 0.2, 0.4, 0.8, and 1.6 ppm of formaldehyde in air occurred over 5 h. Potential eye and upper respira- tory irritant effects were evaluated, along with assessments of pulmonary func- tion and cognitive performance. No adverse pulmonary or cognitive perform- ance effects were observed at any concentration. With the 0.2- and 0.4-ppm exposure groups, none of the 16 volunteers reported irritation or discomfort for the first 2 h. Although subjects in these lower exposure groups reported slight eye irritation by the end of the 5-h exposure period, there is uncertainty about

230 SMACs for Selected Airborne Contaminants whether the subjects in these groups were able to confidently distinguish irrita- tion attributable to formaldehyde. This uncertainty is supported by the observa- tion that the individuals reported more discomfort with the 0.2-ppm than with the 0.4-ppm exposures and that a greater percentage of the subjects reported irritation at 0.2 ppm (19%) than at 0.4 ppm (13%). As there was not a similar 5- h control exposure period, it is not possible to confidently attribute any irritation to formaldehyde at these concentrations. In contrast, slight discomfort was ex- perienced within the first 2 h at the 0.8-ppm exposure level and above, and a relationship between dose and irritant effect can be observed for the 0.8- and 1.6-ppm exposure groups. For the 0.8-ppm exposure group, 44% (7 of 16) of the subjects reported slight discomfort, but none of the individual characterizations of the irritation at this concentration noted strong discomfort. Kulle et al. (1987) evaluated the potential for formaldehyde exposure to result in eye and upper respiratory tract irritation as well as odors. Healthy hu- man volunteers were exposed to formaldehyde at different concentrations for 3 h, with 19 individuals exposed at 0, 1, 2, and 3 ppm, and 10 individuals exposed at 0.5 ppm. Exposures were separated by a week to avoid carryover effects. Above 0.5 ppm, the frequency and intensity of reported irritant symptoms gen- erally increased consistently with the higher formaldehyde exposures. None of the individuals exposed to 0.5 ppm experienced eye irritation, although roughly half of the volunteers discerned odors at this concentration. At 1 ppm, 3 of the 19 volunteers experienced mild eye irritation. One individual reported moderate eye irritation at this concentration. Bender et al. (1983) studied human volunteers previously determined to be responsive to formaldehyde-induced eye irritation. Exposures included 0.35, 0.56, 0.7, 0.9, and 1.0 ppm, along with a control group. Only at the 1-ppm expo- sure were the authors able to statistically distinguish the response time for eye irritation (the metric used in this test) from background exposures. With a semi- quantitative “severity index,” they determined that exposures at 1 ppm on aver- age resulted in slight to moderate irritation and any irritation response for expo- sures below 1 ppm was characterized as slight. The authors noted that the 0.7- and 0.9-ppm exposure groups had fewer subjects (5 to 7, compared with 27 for the 1-ppm exposure group) and that it is possible that results for these groups would also have been significant if not for this limitation. A strength of this study was its focus on potentially sensitive human subpopulations. One potential shortcoming was that the subjects were exposed to formaldehyde for only 6 min, which may not have been adequate to allow full characterization of the degree of sensory irritant response, particularly for the lower exposure groups. Bach et al. (1990) exposed different groups of 16 human subjects to for- maldehyde over 5.5 h. They observed no concentration-response relationship for sensory irritation in evaluating exposures to formaldehyde at 0, 0.12, 0.33, and 1 ppm. However, the exposure groups consisted of different populations of work- ers exposed to formaldehyde and control subjects, and it is not clear that other potentially important variables (e.g., smoking status, age) were properly con- trolled in the experimental design.

Formaldehyde 231 The 1-h AC is specifically based on the work of Andersen and Molhave (1983), although studies by Kulle et al. (1987) (also discussed by Kulle 1993) and Bender et al. (1983) provide additional support. The lowest-observed- adverse-effect level (LOAEL) of 0.8 ppm was not adjusted, as the degree of irritation was consistent with the intent of a 1-h SMAC. 1-h AC (irriation) = 0.8 ppm (LOAEL) 24-h AC No controlled human exposure studies were identified in which 24-h ex- posures were specifically evaluated for formaldehyde. However, many of the sensory irritation studies described previously are also relevant to the 24-h AC, because specific adjustments (e.g., Haber’s rule) to account for differences in time are not considered to be necessary for most irritants, as effects are generally understood to be primarily concentration dependent (Paustenbach et al. 1997, Shusterman et al. 2006). The work of Andersen and Molhave (1983) demonstrated that the maxi- mum irritant effect for formaldehyde is likely to be observed within the first few hours of testing and that further exposures often result in a diminishing irritant response because of subject adaptation (Paustenbach et al. 1997, Bender 2002). As discussed previously, a lower 24-h limit is generally warranted to minimize discomfort that a crew member would be expected to tolerate over this longer exposure. The Kulle et al. (1987) no-observed-adverse-effect level (NOAEL) of 0.5 ppm was used as the 24-h AC for formaldehyde. Although none of the individu- als reported eye irritation at this concentration during the 3-h exposures, it is reasonable to use this concentration as a 24-h exposure limit, as it likely repre- sents an estimate of the lower limit for eye irritation for most individuals (Kulle et al. 1987, Kulle 1993, Paustenbach et al. 1997, Bender 2002). After thoroughly reviewing the available studies, Bender (2002) concluded that it would be rare for individuals to experience sensory irritation below 0.5 ppm, and that 5-20% of individuals might report mild sensory irritation when concentrations are be- tween 0.5 and 1 ppm. The weight of evidence suggests that the vast majority of crew members could tolerate exposure up to 0.5 ppm of formaldehyde for 24 h without experiencing any notable sensory irritation and without performance decrements or other adverse effects. 24-h AC (irritation) = 0.5 ppm (NOAEL) 7-, 30-, 180-, and 1,000-d ACs Setting longer-term ACs for formaldehyde irritation is difficult, and a number of studies have concluded that there does not appear to be a clear

232 SMACs for Selected Airborne Contaminants threshold for effects (NRC 1981, Bender 2002) and that a small percentage of the population may exhibit mild irritation, even at extremely low exposures (e.g., 0.1 ppm). It is clear that at these low concentrations, the vast majority of human subjects have difficulty consistently being able to differentiate eye irrita- tion induced by the presence of formaldehyde from clean air (Schuck et al. 1966, Anderson and Molhave 1983). Although it is impractical to try to identify longer-term ACs that will definitely eliminate the possibility of an irritant re- sponse in all sensitive individuals, it is necessary that the 7-, 30-, 180-, and 1,000-d ACs protect the vast majority of crew members from even slight irrita- tion. For the 7-, 30-, 180-, and 1,000-d ACs, a formaldehyde concentration of 0.1 ppm is being identified as a reasonable guideline for long-term exposure that is unlikely to result in any irritant effects, even with sensitive individuals. In- stead of relying on one particular study, multiple lines of evidence support this AC as appropriate. This evidence, as described in more detail below, includes the findings from a number of controlled human studies, evaluations from sev- eral comprehensive scientific reviews, community health surveys, and practical NASA experience with formaldehyde in an enclosed environment designed to mimic conditions relevant to spacecraft exposures. • NASA experiences with the Lunar-Mars Life Support Test Project. Al- though exposures to 0.2 ppm produced short-term irritation with one crew mem- ber by Day 15 of the 60-d test, irritation did not persist as concentrations dropped to 0.1 ppm, a concentration that was generally maintained for the re- mainder of the test. There are possible confounding factors with these observa- tions, such as the fact that exposures were not limited to formaldehyde (other unidentified irritants may have been present at low levels) and the subsidence of irritation may have resulted from adaptation rather than from concentration re- duction. However, monitoring for this project included other potential irritants, and none was identified at a concentration that might account for the irritant effects (although potential synergistic effects of several irritants present indi- vidually at low concentrations cannot be ruled out). Overall, this study provides practical supporting evidence for a formaldehyde AC of about 0.1 ppm. In the 90-d test (following a catalyst anomaly) formaldehyde concentrations persisted for more than 30 d at 0.05 to 0.07 ppm with no reported irritation in the test sub- jects. • Benchmark dose analysis (Arts et al. 2006) of eye irritation data from Kulle (1987, 1993) and from Andersen and Molhave (1983). For both of these data sets, Arts et al. (2006) predicted that formaldehyde at 0.1 ppm would result in approximately a 1% excess risk (95% lower confidence limit on the bench- mark concentration that would result in 1% excess risk [BMCL01] of mild eye irritation or slight discomfort. • Consistent conclusions from the U.S. Consumer Product Safety Com- mission (CPSC1997), WHO (2002), NRC (1981), Paustenbach et al. (1997), and

Formaldehyde 233 others that 0.1 ppm is a conservative lower limit for formaldehyde with regard to sensory irritation, even when addressing continuous exposure conditions. • Results from sensory irritation studies in mice (Kane and Alarie 1977) that observed a 50% decrease in the respiratory rate (RD-50) after 10-min expo- sures to 3 ppm of formaldehyde in air. Alarie (1981a,b) demonstrated that mul- tiplying the rodent RD-50 by a factor of 0.03 (the log midpoint of a range from 0.1 to 0.01) provides a reasonable estimate of a long-term exposure concentra- tion that is protective of sensory irritation in humans. This calculation results in a formaldehyde limit of 0.1 ppm. Although this is a general predictive approach, it has merit in the sense that it avoids some of the subjectivity inherent in evalu- ating individual irritant response at low formaldehyde concentrations. • Supporting evidence from community health studies (e.g., mobile home exposure evaluations) regarding the potential irritancy of formaldehyde. Al- though the limitations of these studies in establishing guidelines have been rec- ognized (e.g., exposure to other irritants, general lack of control groups), they provide some useful information in support of SMAC development. For exam- ple, a strength that is particularly beneficial in setting long-term ACs for formal- dehyde is that the exposures in these studies are generally continuous. Hanrahan et al. (1984) observed that only 4% of individuals continuously exposed to 0.1 ppm of formaldehyde reported eye irritation. This is an extremely low response rate and is well within the irritation frequency rates reported for clean air in con- trolled exposure studies (Witek et al. 1987, Bender 2002). Thus, this study pro- vides further evidence that continuous exposure to 0.1 ppm of formaldehyde is very unlikely to result in sensory irritation, even in the presence of other poten- tial irritants. 7-, 30-, 180-, and 1,000-d AC (irritation) = 0.1 ppm Nasal Epithelial Damage and Tumors Summary of Previous Approach The existing 1994 SMAC document reviews the human and animal evi- dence with respect to the carcinogenic potential of formaldehyde and includes ACs based on risk of developing nasal tumors. These ACs (Table 12-6) were derived from the work of Kerns et al. (1983). The EPA also used this study in a 1987 risk assessment (EPA 1987) for formaldehyde that established the current inhalation unit risk factor for formaldehyde in the Integrated Risk Information System. In this study, the authors exposed 120 F344 rats, male and female, to 0, 2, 5.6, or 14.3 ppm of formaldehyde, 6 h/d, 5 d/wk for 24 mo. Male and female rats in the highest dose group (14.3 ppm) showed increased mortality compared with controls beginning in Month 12. Squamous cell carcinomas were observed in the nasal cavities of 51 of 117 male rats and in 52 of 115 female rats at

TABLE 12-6 Results of Benchmark Dose Risk Analysis Conducted by Schlosser et al. (2003) and Comparison with EPA 234 (1987) Risk Estimate Used as Basis for Existing SMAC Calculated Acceptable concentrations, (ppm) Human 95% Inhalation Unit Risk a Approach Rat 95% BMCL01, ppm BMCL01, ppm Factor, ppm–1 7d 30 d 180 d 1,000 d Flux-DPX extrapolation Tumors 5.58 0.71 1.4 × 10–2 26 6 1 0.2 (Weibull) Cell proliferation 3.57 0.44 2.3 × 10–2 16 4 0.6 0.1 (power law) Direct airflow extrapolation Tumors 5.58 0.71 1.4 × 10–2 26 6 1 0.2 (Weibull) Cell proliferation 3.57 0.46 2.2 × 10–2 17 4 0.7 0.1 (power law) EPA (1987) estimate Based on linearized Based on linearized 1.6 × 10–2 23 6 0.9 0.2 multistage modeling multistage modeling a Model being fit is given in parentheses below the BMCL. Abbreviation: BMCL01, Lower statistical confidence limit on the benchmark concentration associated with a 1% response.

Formaldehyde 235 14.3 ppm by the end of the experiment. At 5.6 ppm, 1 of 119 male rats and 1 of 116 female rats had squamous cell carcinomas in the nasal cavity, whereas no tumors were found in those exposed at 0 or 2 ppm. Applying linearized multi- stage modeling to the Kerns et al. (1983) results gives an excess lifetime inhala- tion cancer risk of 1.6 × 10–2/ppm for formaldehyde (EPA 1987). Cytotoxic damage to the nasal epithelium is also discussed, although specific ACs are not set for this end point apart from the nasal cancer ACs. The existing 1994 SMAC document also noted that there is some epide- miologic evidence that formaldehyde could cause lymphohematopoietic cancers and lung cancers, although ACs were not set based on these end points. Review of Pertinent New Data for Nasal Epithelia Damage and Tumors Formaldehyde is a very reactive, water-soluble compound that can damage tissues, especially mucous membranes at the portal of entry (e.g., upper respira- tory tract with inhalation exposures). Although formaldehyde can be effectively metabolized following low levels of exposure, inhalation of formaldehyde at sufficient concentrations has been shown to cause cytotoxic damage and neo- plastic lesions in the nasal epithelium in studies with laboratory animals and in evaluations of human exposures. This epithelial damage has been shown to ex- hibit regional specificity within the nasal cavity, and species dependencies have been recognized in terms of the pattern of formaldehyde distribution and dam- age, with rats and monkeys generally more sensitive to damage than mice (Mor- gan 1997, Kimbell et al. 2001). A summary of recent evaluations of formalde- hyde-related cancers is provided in the sections below. Human Epidemiologic Data Because of the commercial importance of formaldehyde, there is a wealth of human epidemiologic studies (more than 40 case-control cohort studies, and several meta-analyses) that have assessed chronic exposures to formaldehyde and the potential for these exposures to result in the development of cancer (for a comprehensive review of available studies, see ATSDR 1999, WHO 2002). Certain limitations should be considered in evaluating occupational epidemi- ologic evidence. First, many of these studies involve coexposure to other air contaminants. Also, the frequency and intensity of peak formaldehyde exposures are often poorly characterized. Given the reactivity and water solubility of formaldehyde and available evidence from laboratory animal inhalation exposures, many epidemiologic studies have focused on the incidence of upper respiratory tract cancer. Al- though many of them were summarized in the 1994 SMAC document, several more recent studies warrant discussion. There is occupational evidence that long-term human exposures can result in erosions and lesions in the upper respi- ratory tract. This cytotoxicity and the cell regeneration that accompanies it have

236 SMACs for Selected Airborne Contaminants been implicated as important factors in the formaldehyde carcinogenic process (Conolly et al. 2003, Schlosser et al. 2003). Several epidemiologic studies have found slight histologic changes in the nasal epithelium of workers chronically exposed to formaldehyde at concentrations in the range of 0.1 to 0.6 ppm (Edling et al. 1988, Holmstrom et al. 1989, Ballarin et al. 1992, ATSDR 1999,). In an epidemiologic study of chemical plant workers, furniture workers, and a control population of office workers, Holmstrom et al. (1989) observed statisti- cally significant histopathologic changes (cuboidal and squamous cell metapla- sia, loss of cilia, goblet cell hyperplasia) in the nasal epithelium of the chemical workers (exposed to a median airborne formaldehyde concentration of 0.24 ppm, with an average duration of exposure of more than 10 years). The de- scribed effects were not observed in the office workers, where the authors re- ported a median formaldehyde concentration of 0.07 ppm. Formaldehyde con- centrations were seasonal with this office worker group, with formaldehyde levels as high as 0.13 ppm measured for parts of the year. Short-term exposures to formaldehyde at concentrations approaching 1 ppm were reported to occur frequently with the chemical workers. They were also exposed to formaldehyde resins, which may not be directly comparable to exposures to gaseous formalde- hyde. With respect to sinonasal and nasopharyngeal cancers, whereas some stud- ies and at least two meta-analyses reported an exposure-response relationship (Blair et al. 1990, Partanen 1993), several recent studies and reviews failed to find such a relationship (Collins et al. 1997, Coggon et al. 2003), and the evi- dence is somewhat equivocal (ATSDR 1999, WHO 2002). However, IARC (2004) recently upgraded its classification of formaldehyde from Group 2A to Group 1 (sufficient evidence from experimental animals and humans to con- clude it is carcinogenic to humans), based to a significant degree on their opin- ion that there is sufficient epidemiologic evidence that formaldehyde causes nasopharyngeal cancers in humans. Collins et al. (1997) conducted a meta-analysis of sinonasal and naso- pharyngeal cancers reported in 47 occupational epidemiologic studies involving formaldehyde inhalation. They found that, although a few studies reported in- creased incidences of these cancers, the findings from most studies were nega- tive. The authors concluded that these observations do not support the conten- tion that there is a significant association between formaldehyde inhalation and sinonasal or nasopharyngeal cancers. Hauptmann et al. (2004) conducted a fol- low-up study of more than 25,000 U.S. industrial workers and found an associa- tion between nasopharyngeal cancers and high peak and cumulative formalde- hyde exposures (but not average exposure or exposure duration). Marsh et al. (2002) evaluated 7,000 chemical plant workers and found no association be- tween formaldehyde exposure and pharyngeal and nasopharyngeal cancers. Pinkerton et al. (2004) also did not observe an association between formalde- hyde and these cancers. Similarly, Coggon et al. (2003) conducted a follow-up evaluation of a cohort of more than 14,000 chemical workers who were exposed to formaldehyde by inhalation. The authors did not find an association between

Formaldehyde 237 formaldehyde exposures and nasopharyngeal cancers and concluded “Overall, the epidemiologic evidence now available indicates that if formaldehyde does cause nasopharyngeal cancers, then the increased risk is small.” With regard to lung cancer, Coggon et al. (2003) reported increased inci- dences for their cohort (standardized mortality ratio of 1.28 for the high- exposure group), but there was no association with duration of exposure and the authors cautioned that these results needed to be further investigated (e.g., closer evaluation of confounding factors). Collins et al. (1997) found no increased in- cidence of lung cancer for industrial workers in the available cohorts or in the case-control studies and concluded that the available epidemiologic evidence did not support an association between formaldehyde exposure and lung cancer. Hauptmann et al. (2004) reported similar negative findings with respect to for- maldehyde and lung cancer. With respect to lymphohematopoietic cancers, Hauptmann et al. (2003) evaluated a cohort of more than 25,000 workers in formaldehyde-related indus- tries across 10 different U.S. industrial plants. They reported relative risks for leukemia of 1.1 (95% CI = 0.4-3.2) and 2.4 (95% CI = 1-6) when average for- maldehyde exposures were 0.5 to 0.9 and >1 ppm, respectively (they reported larger relative risks when grouping by peak formaldehyde exposure concentra- tions). However, leukemia relative risks were not positively associated with cu- mulative formaldehyde exposure or duration of exposure, all myeloid tumor types were lumped despite their different etiologies, and leukemia risks for the exposed workers were lower than for the U.S. population. The authors stated that these results should be viewed with caution, as the overall body of evidence for an association between formaldehyde and leukemia is mixed. As an example, Coggon et al. (2003) did not find increased mortality from leukemia in their cohort, even in evaluating the subset of workers with the high- est formaldehyde exposure. Pinkerton et al. (2004) observed an association be- tween myeloid leukemia risks and exposure duration for U.S. garment workers exposed to formaldehyde, although the observed cancer risks were not signifi- cantly different than in the U.S. population. WHO (2002) echoed the need for caution in interpreting non-respiratory tract cancers with formaldehyde in stating “Available evidence for these tumors at sites other than the respiratory tract does not, therefore, fulfill traditional criteria of causality (e.g., consistency, biological plausibility) for associations observed in epidemiological studies.” Animal Bioassays Rusch et al. (1983) studied the degenerative effects of formaldehyde expo- sure on the nasal epithelium in various species (cynomolgus monkeys, rats, mice, and hamsters). They exposed test and control animals to formaldehyde concentrations of 0.2, 1, and 3 ppm by inhalation (near-continuous 22-h expo- sures daily for 26 wk) in an exposure chamber. At 3 ppm, they observed mild

238 SMACs for Selected Airborne Contaminants lesions in the nasal epithelium (squamous metaplasia) in the monkeys and rats and reported a NOAEL of 1 ppm for all species tested. Kamata et al. (1997) also observed increased incidence of squamous cell metaplasia in the nasal epithelium of F344 rats when exposed to formaldehyde at 2 ppm for 28 mo. However, several lifetime inhalation exposure studies in rodents, with formaldehyde exposures in the range of 2 ppm, did not report ad- verse degenerative effects on the nasal epithelium (Woutersen et al. 1989; Mon- ticello et al. 1991, 1996). Monticello et al. (1991) exposed F344 rats to formal- dehyde at 0.7, 2, 6, 10, and 15 ppm for 6 h/d for up to 6 wk. They reported no tissue damage at 0.7 and 2 ppm but observed squamous metaplasia and epithe- lial hyperplasia in the three highest exposure groups. Increased rates of cell pro- liferation also corresponded to the cytotoxicity observed at these formaldehyde concentrations (Table 12-7). In a chronic study, Monticello et al. (1996) exposed F344 rats to formal- dehyde concentrations of 0, 0.7, 2, 6, 10, and 15 ppm for 6 h/d 5 d/wk for 24 mo. They measured rates of cell proliferation in the nasal epithelium at several interim periods during the study and found that exposures to formaldehyde at concentrations of 6 ppm or less did not result in statistically significant increases in cell proliferation, whereas increases were observed in the two highest expo- sure groups. They observed polyploid adenomas in the nasal cavity of rats from these two exposure groups but not in any of the other exposure groups or con- trols. Squamous cell carcinomas were reported in 1 of 90 rats at the 6-ppm ex- posure, 20 of 90 at 10 ppm, and 69 of 147 at 15 ppm, with no observed inci- dences in the other exposure groups or controls. These results are generally consistent with the IARC (1995) conclusion that “Acute or subacute exposure of rats to a concentration of 2 ppm appears to cause no detectable damage to the nasal epithelium and does not significantly increase rates of cell turnover. Cell turnover rates in rat nose during subchronic or chronic exposures to formalde- hyde do not increase at 2 ppm, increase marginally at concentrations of 3-6 ppm and increase substantially at concentrations of 10-15 ppm. Concentration is more important than length of exposure in determining the cytotoxicity of for- maldehyde.” Refinement of ACs Nasal Cancer In consideration of the findings of Monticello et al. (1996) and Kerns et al. (1983), the CIIT Centers for Health Research undertook an extensive risk as- sessment in 1999 in an effort to better characterize human cancer risks associ- ated with inhalation of formaldehyde; the work was published in a series of pa- pers by various authors, including Kimbell et al. (2001), Conolly et al. (2003), and Schlosser et al. (2003). Two main risk assessment approaches were taken.

Formaldehyde 239 TABLE 12-7 Time-Weighted, Site-Averaged Unit-Length Labeling Index Data from Schlosser et al. (2003), Derived from Original Work of Monticello et al. (1996) Formaldehyde ULLI, Number/Length ± Exposure, ppm Standard Deviation Number of Animals 0 10.9 ± 3.2 48 0.7 8.2 ± 2.3 46 2 7.7 ± 2.7 47 6 15.0 ± 15.6 48 10 43.8 ± 17.6 48 15 70.7 ± 19.4 47 Abbreviation: ULLI, unit-length labeling index. Source: Schlosser et al. 2003. Reprinted with permission; copyright 2003, Risk Analysis. The first approach involved using the animal bioassay data in a benchmark dose analysis, where different methodologies were used to extrapolate formaldehyde exposures from rats to humans (see Schlosser et al. 2003). A second approach was based on computational modeling, where species-specific dosimetry of for- maldehyde within the rodent and human respiratory tracts was predicted with three-dimensional anatomically accurate computational fluid dynamics (CFD) modeling (Kimbell et al. 2001, Conolly et al. 2003). With regard to the benchmark dose analysis, a point of departure (95% BMCL01) was established to allow assessment of human health risks based on linear extrapolation from this concentration to zero. Two different data sets, generally representing two different cancer end points, were generated to sup- port this analysis. The first data set (tumor end point) was based on combining incidence data on squamous cell carcinoma from both Kerns et al. (1983) and Monticello et al. (1996), along with 94 additional animals that were not previ- ously examined in the latter study. A second data set (cell proliferation end point) was generated based on the cell proliferation data (as quantified by the unit-length labeling index) reported by Monticello et al. (1996). With labeling index data, it is possible to characterize the growth kinetics of a group of tar- geted cells. This data set was included in recognition of the significant role that cell proliferation is thought to play in formaldehyde carcinogenesis (Schlosser et al. 2003). In utilizing these data, the assumption is made that the increase in unit-length labeling index above background equates to a corresponding in- crease in cancer risk. Two different extrapolation methods were then used to estimate human health risks from the rat data. The first approach (direct airflow) used rat and human CFD models to directly estimate the flux to the entire surface of the nasal airway lining. This approach involved no fitted parameters and did not require allometric scaling between rats and humans. A second extrapolation approach was used, based on the assumption that there is a consistent relationship between

240 SMACs for Selected Airborne Contaminants DNA-protein crosslink (DPX) formation and tumor development in rats and humans; it is known as the flux-DPX approach. This approach used CFD model- ing, but also incorporated a pharmacokinetic modeling of DPX formation in rats and humans. The extrapolation approach assumed that equal amounts of DPX (used as a measure of tissue dose) in rats and humans correspond to equivalent nasal tissue concentrations of formaldehyde. Schlosser et al. (2003) examined different statistical models for bench- mark dose analysis for the tumor end point (Weibull, multistage, log-probit) and cell proliferation end point (power-law, polynomial) and selected the Weibull and power-law models as appropriate for the two end points, respectively. Benchmark concentrations (lower 95% BMCL01 values) are presented in Table 12-6. The cell proliferation 95% BMCL01 values were slightly lower than for the tumor end point. Given that the 95% BMCL01 values across both end points and extrapolation methods vary by less than a factor of 2, there is considerable agreement between the approaches (Schlosser et al. 2003). ACs were calculated based on the benchmark dose analysis results (95% BMCL01) from Schlosser et al. (2003). The following equation, based on Crump and Howe’s 1984 multistage model (with only the first stage dose related) was used to calculate the exposure concentrations (D) that would yield a tumor risk of 1 × 10–4 for exposure durations of 7, 30, 180, and 1,000 d (1- and 24-h ACs are no longer calculated for carcinogenic effects based on current NRC policy): D = d · (25,600)k · (10–4/risk) (25,600 – 365 · age)k – [(25,600 – 365 · age) – t]k where d = BMCL01, 25,600 = number of days in a 70-y human lifetime, k = number of stages in the model (1 in this case), 10–4 = acceptable risk level, age = minimum age of an astronaut, in years (30 y in this case), t = exposure duration, in days (7, 30, 180, and 1,000 d), and risk = risk of tumor for lifetime exposure to d (10–2 in this case). As indicated in Table 12-6, calculated ACs based on the benchmark dose analysis fall on either side but are very similar to the AC based on the original 1987 EPA risk estimate for formaldehyde. For the purposes of setting an AC for nasal carcinogenesis, the Schlosser et al. (2003) modeled results for the cell- proliferation end point were used in conjunction with the direct airflow extrapo- lation method. The use of the cell proliferation end point recognizes its impor- tance in the formaldehyde carcinogenic process and results in slightly more con- servative ACs compared with the tumor data. The use of the direct airflow extrapolation approach required fewer assumptions and did not rely on allomet- ric scaling compared with the flux-DPX method and was subject to less mecha-

Formaldehyde 241 nistic uncertainty in terms of the exact role of DPX formation in formaldehyde- induced tumor development (Schlosser et al. 2003). This approach resulted in ACs of 17, 4, and 0.7 ppm, for the 7-, 30-, 180-, and 1,000-d time frames, re- spectively. These ACs are very similar to the previous ACs based on the EPA 1987 risk estimate. As described in Table 12-6, the selection of end point (tumor or cell proliferation) or extrapolation method has little real effect on the final ACs for nasal cancers, as there is considerable agreement among approaches. These ACs based on carcinogenic effects are considerably higher than the calculated ACs based on the irritancy of formaldehyde (Table 12-8). This is consistent with the observations of Connolly et al. (2004) and Arts et al. (2006), who noted that protection against the noncarcinogenic effects of formaldehyde should be sufficient to guard against potential carcinogenic effects. The ap- proach taken with formaldehyde in setting cancer-based ACs is also believed to be conservative, as Schlosser et al. (2003) noted that there is some uncertainty about the appropriateness of linear extrapolation from the point of departure with formaldehyde, as the dose-response for both cell proliferation (resulting from the cytotoxicity of formaldehyde) and tumor induction has been shown to be highly nonlinear. Conolly et al. (2003) used three-dimensional CDF and clonal growth modeling to evaluate two modes of action for formaldehyde carcinogenesis: mutagenicity mediated through DPX formation and cytotoxicity-induced cell proliferation. Their work suggests that the cell proliferation mode of action is dominant with formaldehyde and that below a certain threshold (e.g., less than about 2 ppm) there is no increase in cancer risk relative to controls. Using the full computational modeling, CIIT estimated an inhalation unit risk factor of approximately 6 × 10–6/ppm (Schlosser et al. 2003), which is at least 3 orders of magnitude less than the risk estimates based on linear extrapolation (see Table 12-6). This risk estimate is more in line with the low incidences of sinonasal and nasopharyngeal cancers observed in most epidemiologic studies of occupational exposures to formaldehyde (Schlosser et al. 2003). Nasal Epithelial Damage It is appropriate to set ACs for the degenerative effects of formaldehyde exposure on the nasal epithelium separate from those for nasal cancer risks. Monticello et al. (1996) exposed F344 rats to formaldehyde concentrations of 0, 0.7, 2, 6, 10, and 15 ppm, 6 h/d 5 d/wk for 24 mo. They measured rates of cell proliferation in the nasal epithelium at several interim periods during the study and found that exposures to formaldehyde at concentrations of 6 ppm or less did not result in statistically significant increases in cell proliferation, whereas in- creases were observed in the two highest exposure groups. As discussed previously, the cytotoxicity of inhaled formaldehyde and re- sulting cell proliferation has been recognized as an important part of the car-

TABLE 12-8 Acceptable Concentrations 242 Uncertainty Factor Acceptable Concentration, ppm Inter- Space- indivi- End Point, Exposure Data (Reference) NOAEL Time Species flight dual 1h 24 h 7d 30 d 180 d 1,000 d Sensory irritation 0.8 ppm (LOAEL), mild eye irritation, 5-h Human 1 1 1 1 1 0.8 — — — — — exposure (Andersen and Molhave 1983) 0.5 ppm (NOAEL) for sensory irritation, Human 1 1 1 1 1 — 0.5 — — — — 3-h exposure (Kulle et al. 1987) 0.1 ppm (NOAEL) (James et al. 2002, Human 1 1 1 1 1 — — 0.1 0.1 0.1 0.1 Arts et al. 2006) Nasal tumors Based on linear extrapolation/application of F344 — 1b 1a 1 1 — — 17 4 0.7 0.1 rat 95% BMCL01 (3.57 ppm), using cell Rats proliferation data (Monticello et al. 1996), and direct airflow extrapolation (Schlosser et al. 2003) Nasal epithelial damage Benchmark dose analysis of cell F344 — 1b 1a 1 1 — — 0.5 0.5 0.5 0.5 proliferation data, rat 95% BMCL01 (3.57 rats ppm) (Monticello et al., 1996) and direct airflow extrapolation to human 95% BMCL01 (0.46 ppm) (Schlosser et al. 2003) SMAC 0.8 0.5 0.1 0.1 0.1 0.1 Abbreviation: —, Not applicable. a This study incorporated specific modeling to extrapolate between rats and humans, so additional adjustment for species differences was not necessary. b Schlosser et al. (2003) adjusted the 24-mo, 6-h/d, 5-d/wk animal study to reflect continuous exposure conditions.

Formaldehyde 243 cinogenic process for formaldehyde (Conolly et al. 2003). Although Schlosser et al. (2003) used the cell proliferation data (as represented by the unit-length la- beling index) from Monticello et al. (1996) in a cancer risk assessment frame- work by assuming that a given increase in cell proliferation corresponds to an equivalent increase in cancer risk, noncancer effects can also be assessed with this data set. There are no reliable data upon which to base an AC for the degenerative effects of formaldehyde for the 1- or 24-h exposures. For these time frames, there is no evidence that damage to the nasal epithelium will occur following exposures to environmentally relevant concentrations of formaldehyde. In addi- tion, it is worth nothing that short-term concentrations will be maintained at concentrations that will minimize the potential sensory irritant effects of formal- dehyde. Thus, for these exposure times, formaldehyde ACs protective of sensory irritation should also adequately protect against any damage to the nasal epithe- lium. Using the unit-length labeling index results provided in Table 12-7, Schlosser et al. (2003) calculated a rat 95% BMCL01 of 3.57 ppm. When related to human exposures through direct airflow extrapolations (as described in the section above), a human 95% BMCL01 of 0.46 ppm is derived. Given that Schlosser et al. (2003) incorporated detailed species extrapolation modeling, it is not necessary to incorporate an additional uncertainty factor for species extrapo- lation. In addition, further exposure time corrections are not necessary for the study, as the authors adjusted the 95% BMCL01 concentration for the 24-mo study to reflect continuous exposure conditions. This approach is likely to be conservative, as some have suggested that increased cell proliferation is better related to concentration than to cumulative formaldehyde exposure (McGregor et al. 2006) (cytotoxicity and resulting cell proliferation are likely to exhibit a clear threshold). The nasal cancer and noncancer proliferation approaches result in slightly different long-term ACs (0.5 ppm for noncancer and 0.1 ppm for can- cer ACs) because of inherent differences in risk modeling, even though the two end points are thought to be biologically related. 7-, 30-, and 1,000-d ACs = human 95% BMCL01 = 0.46 ppm, rounded to 0.5 ppm REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Formalde- hyde. Pp. 664-688 in Documentation of the Threshold Limit and Biological Expo- sure Limits, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Alarie, Y. 1981a. Dose-response analysis in animal studies: Prediction of human re- sponses. Environ. Health Perspect. 42:9-13.

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NASA is aware of the potential toxicologic hazards to crew that might be associated with prolonged spacecraft missions. Despite major engineering advances in controlling the atmosphere within spacecraft, some contamination of the air appears inevitable. NASA has measured numerous airborne contaminants during space missions. As the missions increase in duration and complexity, ensuring the health and well-being of astronauts traveling and working in this unique environment becomes increasingly difficult. As part of its efforts to promote safe conditions aboard spacecraft, NASA requested the National Research Council to develop guidelines for establishing spacecraft maximum allowable concentrations (SMACs) for contaminants and to review SMACs for various spacecraft contaminants to determine whether NASA's recommended exposure limits are consistent with the guidelines recommended by the committee.

This book is the fifth volume in the series Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, and presents SMACs for acrolein, C3 to C8 aliphatic saturated aldehydes, C2 to C9 alkanes, ammonia, benzene, carbon dioxide, carbon monoxide, 1,2-dichloroethane, dimethylhydrazine, ethanol, formaldehyde, limonene, methanol, methylene dichloride, n-butanol, propylene glycol, toluene, trimethylsilanol, and xylenes.

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