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 formaldehyde 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 pollutant 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 formaldehyde 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 formaldehyde. 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 comprehensive reviews of formaldehyde have been conducted since 1994, including assessments 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



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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

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207 Formaldehyde 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.

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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 1 ppm = 1.23 mg/m3, 1 mg/m3 = Conversion factors at 25°C, 1 atm: 0.82 ppm

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209 Formaldehyde 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

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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

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

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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.

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213 Formaldehyde 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

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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)

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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

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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

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239 Formaldehyde 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

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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-

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241 Formaldehyde 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-

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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 Rats rat 95% BMCL01 (3.57 ppm), using cell 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 rats proliferation data, rat 95% BMCL01 (3.57 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.

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243 Formaldehyde 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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