From: Kathryn Sargeant/AA/USEPA/US 

To: drostker@omb.eop.gov 

Cc: Paul Argyropoulos/DC/USEPA/US@EPA, Paul Machiele/AA/USEPA/US@EPA, Catherine 

Yanca/AA/USEPA/US@EPA, Margaret Zawacki/AA/USEPA/US@EPA, Ken 

Davidson/DC/USEPA/US@EPA, Marion Hoyer/AA/USEPA/US@EPA, Rich Cook/AA/USEPA/US@EPA, 

Amanda Evans/DC/USEPA/US@EPA, Robert Fegley/DC/USEPA/US@EPA 

Date: 01/13/2010 04:30 PM 

Subject: Info in response to OMB comments on acrolein health effects in RFS2 

David, this morning we discussed OMB's comments on the acrolein health effects discussion in 

the RFS2 RIA (section 3.5.5.6). This note includes some additional information as you 

requested, for you to distribute to your colleagues. 

As I mentioned at the time, the paragraph you were commenting is the same as what we have 

used in rules dating back to (at least) the locomotive/marine final rule in June 2008 (73 FR 

37713). 

You expressed concern about the fact that the study cited in footnote 353 was in German, and 

you requested an English version so you could independently determine whether it was 

appropriate for us to be citing this study. Here is a copy, which contains an English summary. 
From: Kathryn Sargeant/AA/USEPA/US 

To: drostker@omb.eop.gov 

Cc: Paul Argyropoulos/DC/USEPA/US@EPA, Paul Machiele/AA/USEPA/US@EPA, Catherine 

Yanca/AA/USEPA/US@EPA, Marion Hoyer/AA/USEPA/US@EPA, Joseph Somers/AA/USEPA/US@EPA, 

Rich Cook/AA/USEPA/US@EPA, Margaret Zawacki/AA/USEPA/US@EPA, Amanda 

Evans/DC/USEPA/US@EPA, Kathleen Deener/DC/USEPA/US@EPA 

Date: 01/21/2010 12:09 PM 

Subject: Changes to RFS2 formaldehyde and acrolein write-ups in response to OMB comments 

Here are the formaldehyde and acrolein paragraphs excerpted into a document, with changes 

tracked. 

Note that since they are excerpts, the footnotes are numbered differently than they will be in the 

full document. 
From: Kathryn Sargeant/AA/USEPA/US 

To: "Rostker, David" <David_Rostker@omb.eop.gov> 

Cc: Paul Argyropoulos/DC/USEPA/US@EPA 

Date: 01/21/2010 11:50 AM 

Subject: Re: Formaldehyde and acrolein write-ups 

Here is the acrolein study Nancy requested on our call. 

The next version of the rule that you receive will have edits to the formaldehyde and acrolein 

sections. 
From: "Rostker, David" <David_Rostker@omb.eop.gov> 

To: Paul Argyropoulos/DC/USEPA/US@EPA, Kathryn Sargeant/AA/USEPA/US@EPA 

Date: 01/15/2010 10:00 AM 

Subject: Formaldehyde and acrolein write-ups 

I think we would like to have a further conversation on these two chemicals. Can we set 

something up for Tuesday? Say 11:30? 

 

David Rostker 

OMB/OIRA 

drostker@omb.eop.gov 
3.5.5.4 Formaldehyde 

Since 1987, EPA has classified formaldehyde as a probable human carcinogen 

based on evidence in humans and in rats, mice, hamsters, and monkeys.1

 EPA is 

currently reviewing recently published epidemiological data. For instance, research 

conducted by the National Cancer Institute (NCI) found an increased risk of 

nasopharyngeal cancer and lymphohematopoietic malignancies such as leukemia among 

workers exposed to formaldehyde.2,3 In an analysis of the lymphohematopoietic cancer 

mortality from an extended follow-up of these workers, NCI confirmed an association 

between lymphohematopoietic cancer risk and peak exposures.4

 A recent National 

Institute of Occupational Safety and Health (NIOSH) study of garment workers also 

found increased risk of death due to leukemia among workers exposed to formaldehyde.5

 

Extended follow-up of a cohort of British chemical workers did not find evidence of an 

increase in nasopharyngeal or lymphohematopoietic cancers, but a continuing statistically 

significant excess in lung cancers was reported.6

 In the past 15 years there has been substantial research on the inhalation 

dosimetry for formaldehyde in rodents and primates by the CIIT Centers for Health 

Research (formerly the Chemical Industry Institute of Toxicology), with a focus on use of 

rodent data for refinement of the quantitative cancer dose-response assessment.7,8,9 

CIIT’s risk assessment of formaldehyde incorporated mechanistic and dosimetric 

information on formaldehyde. However, it should be noted that recent research published 

by EPA indicates that when two-stage modeling assumptions are varied, resulting doseresponse estimates can vary by several orders of magnitude.10,11,12,13 These findings are 

not supportive of interpreting the CIIT model results as providing a conservative (health 

protective) estimate of human risk.14 EPA research also examined the contribution of the 

two-stage modeling for formaldehyde towards characterizing the relative weights of key 

events in the mode-of-action of a carcinogen. For example, the model-based inference in 

the published CIIT study that formaldehyde’s direct mutagenic action is not relevant to 

the compound’s tumorigenicity was found not to hold under variations of modeling 

assumptions.15

Based on the developments of the last decade, in 2004, the working group of the 

IARC concluded that formaldehyde is carcinogenic to humans (Group 1), on the basis of 

sufficient evidence in humans and sufficient evidence in experimental animals - a higher 

classification than previous IARC evaluations. After reviewing the currently available 

epidemiological evidence, the IARC (2006) characterized the human evidence for 

formaldehyde carcinogenicity as “sufficient,” based upon the data on nasopharyngeal 

cancers; the epidemiologic evidence on leukemia was characterized as “strong.”16 EPA is 

reviewing the recent work cited above from the NCI and NIOSH, as well as the analysis 

by the CIIT Centers for Health Research and other studies, as part of a reassessment of 

the human hazard and dose-response associated with formaldehyde. 

Formaldehyde exposure also causes a range of noncancer health effects, including 

irritation of the eyes (burning and watering of the eyes), nose and throat. Effects from 

repeated exposure in humans include respiratory tract irritation, chronic bronchitis and 
nasal epithelial lesions such as metaplasia and loss of cilia. Animal studies suggest that 

formaldehyde may also cause airway inflammation – including eosinophil infiltration into 

the airways. There are several studies that suggest that formaldehyde may increase the 

risk of asthma – particularly in the young.17,18

3.5.5.6 Acrolein

EPA determined in 2003 that the human carcinogenic potential of acrolein could 

not be determined because the available data were inadequate. No information was 

available on the carcinogenic effects of acrolein in humans and the animal data provided 

inadequate evidence of carcinogenicity.19 The IARC determined in 1995 that acrolein 

was not classifiable as to its carcinogenicity in humans.20

Acrolein is extremely acrid and irritating to humans when inhaled, with acute 

exposure resulting in upper respiratory tract irritation, mucus hypersecretion and 

congestion. The intense irritancy of this carbonyl has been demonstrated during 

controlled tests in human subjects, who suffer intolerable eye and nasal mucosal sensory 

reactions within minutes of exposure.21 These data and additional studies regarding acute 

effects of human exposure to acrolein are summarized in EPA’s 2003 IRIS Human 

Health Assessment for acrolein.22 Evidence available from studies in humans indicate 

that levels as low as 0.09 ppm (0.21 mg/m3

) for five minutes may elicit subjective 

complaints of eye irritation with increasing concentrations leading to more extensive eye, 

nose and respiratory symptoms.23 Lesions to the lungs and upper respiratory tract of rats, 

rabbits, and hamsters have been observed after subchronic exposure to acrolein.24 Acute 

exposure effects in animal studies report bronchial hyper-responsiveness.25 In a recent 

study, the acute respiratory irritant effects of exposure to 1.1 ppm acrolein were more 

pronounced in mice with allergic airway disease by comparison to non-diseased mice 

which also showed decreases in respiratory rate.26 Based on these animal data and 

demonstration of similar effects in humans (i.e., reduction in respiratory rate), individuals 

with compromised respiratory function (e.g., emphysema, asthma) are expected to be at 

increased risk of developing adverse responses to strong respiratory irritants such as 

acrolein. 

 

1 U.S. EPA. 1987. Assessment of Health Risks to Garment Workers and Certain Home 

Residents from Exposure to Formaldehyde, Office of Pesticides and Toxic Substances, 

April 1987. 

2 Hauptmann, M..; Lubin, J. H.; Stewart, P. A.; Hayes, R. B.; Blair, A. 2003. Mortality 

from lymphohematopoetic malignancies among workers in formaldehyde industries. 

Journal of the National Cancer Institute 95: 1615-1623. 

3 Hauptmann, M..; Lubin, J. H.; Stewart, P. A.; Hayes, R. B.; Blair, A. 2004. Mortality 

from solid cancers among workers in formaldehyde industries. American Journal of 

Epidemiology 159: 1117-1130. 

4

 Beane Freeman, L. E.; Blair, A.; Lubin, J. H.; Stewart, P. A.; Hayes, R. B.; Hoover, R. 

N.; Hauptmann, M. 2009. Mortality from lymphohematopoietic malignancies among 

Deleted: Levels considerably lower 

than 1 ppm (2.3 mg/m3

) elicit subjective 

complaints of eye and nasal irritation and 

a decrease in the respiratory rate.

Deleted: This was demonstrated in 

mice with allergic airway-disease by 

comparison to non-diseased mice in a 

study of the acute respiratory irritant 

effects of acrolein.EPA is currently in the 

process of conducting an assessment of 

acute exposure effects for acrolein. The 

intense irritancy of this carbonyl has been 

demonstrated during controlled tests in 

human subjects, who suffer intolerable 

eye and nasal mucosal sensory reactions 

within minutes of exposure.
 

workers in formaldehyde industries: The National Cancer Institute cohort. J. National 

Cancer Inst. 101: 751-761. 

5 Pinkerton, L. E. 2004. Mortality among a cohort of garment workers exposed to 

formaldehyde: an update. Occup. Environ. Med. 61: 193-200. 

6

 Coggon, D, EC Harris, J Poole, KT Palmer. 2003. Extended follow-up of a cohort of 

British chemical workers exposed to formaldehyde. J National Cancer Inst. 95:1608-

1615. 

7 Conolly, RB, JS Kimbell, D Janszen, PM Schlosser, D Kalisak, J Preston, and FJ Miller. 

2003. Biologically motivated computational modeling of formaldehyde carcinogenicity 

in the F344 rat. Tox Sci 75: 432-447. 

8 Conolly, RB, JS Kimbell, D Janszen, PM Schlosser, D Kalisak, J Preston, and FJ Miller. 

2004. Human respiratory tract cancer risks of inhaled formaldehyde: Dose-response 

predictions derived from biologically-motivated computational modeling of a combined 

rodent and human dataset. Tox Sci 82: 279-296. 

9 Chemical Industry Institute of Toxicology (CIIT).1999. Formaldehyde: Hazard 

characterization and dose-response assessment for carcinogenicity by the route of 

inhalation. CIIT, September 28, 1999. Research Triangle Park, NC. 

10 U.S. EPA. Analysis of the Sensitivity and Uncertainty in 2-Stage Clonal Growth 

Models for Formaldehyde with Relevance to Other Biologically-Based Dose Response 

(BBDR) Models. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/R08/103, 2008 

11 Subramaniam, R; Chen, C; Crump, K; .et .al. (2008) Uncertainties in biologicallybased modeling of formaldehyde-induced cancer risk: identification of key issues. Risk 

Anal 28(4):907-923. 

12 Subramaniam, R; Chen, C; Crump, K; .et .al. (2007). Uncertainties in the CIIT 2-stage 

model for formaldehyde-induced nasal cancer in the F344 rat: a limited sensitivity 

analysis-I. Risk Anal 27:1237 

13 Crump, K; Chen, C; Fox, J; .et .al. (2008) Sensitivity analysis of biologically motivated 

model for formaldehyde-induced respiratory cancer in humans. Ann Occup Hyg 52:481-

495. 

14 Crump, K; Chen, C; Fox, J; .et .al. (2008) Sensitivity analysis of biologically motivated 

model for formaldehyde-induced respiratory cancer in humans. Ann Occup Hyg 52:481-

495.

15 Subramaniam, R; Chen, C; Crump, K; .et .al. (2007). Uncertainties in the CIIT 2-stage 

model for formaldehyde-induced nasal cancer in the F344 rat: a limited sensitivity 

analysis-I. Risk Anal 27:1237

16 International Agency for Research on Cancer (2006) Formaldehyde, 2-Butoxyethanol 

and 1-tert-Butoxypropan-2-ol. Monographs Volume 88. World Health Organization, 

Lyon, France. 

17 Agency for Toxic Substances and Disease Registry (ATSDR). 1999. Toxicological 

profile for Formaldehyde. Atlanta, GA: U.S. Department of Health and Human Services, 

Public Health Service. http://www.atsdr.cdc.gov/toxprofiles/tp111.html 

18 WHO (2002) Concise International Chemical Assessment Document 40: 

Formaldehyde. Published under the joint sponsorship of the United Nations Environment 

Programme, the International Labour Organization, and the World Health Organization, 
 

and produced within the framework of the Inter-Organization Programme for the Sound 

Management of Chemicals. Geneva. 

19 Integrated Risk Information System File of Acrolein. Research and Development, 

National Center for Environmental Assessment, Washington, DC. This material is 

available at http://www.epa.gov/iris/subst/0364.htm 

20 International Agency for Research on Cancer (IARC). 1995. Monographs on the 

evaluation of carcinogenic risk of chemicals to humans, Volume 63, Dry cleaning, some 

chlorinated solvents and other industrial chemicals, World Health Organization, Lyon, 

France. 

21 Sim VM, Pattle RE. Effect of possible smog irritants on human subjects JAMA165: 

1980-2010, 1957. 

22 U.S. EPA (U.S. Environmental Protection Agency). (2003) Toxicological review of 

acrolein in support of summary information on Integrated Risk Information System 

(IRIS) National Center for Environmental Assessment, Washington, DC. EPA/635/R03/003. Available online at: http://www.epa.gov/ncea/iris. 23 Weber-Tschopp, A; Fischer, T; Gierer, R; et al. (1977) Experimentelle reizwirkungen 

von Acrolein auf den Menschen. Int Arch Occup Environ Hlth 40(2):117-130. In German 

24 Integrated Risk Information System File of Acrolein. Office of Research and 

Development, National Center for Environmental Assessment, Washington, DC. This 

material is available at http://www.epa.gov/iris/subst/0364.htm 

25 U.S. EPA (U.S. Environmental Protection Agency). (2003) Toxicological review of 

acrolein in support of summary information on Integrated Risk Information System (IRIS) 

National Center for Environmental Assessment, Washington, DC. EPA/635/R-03/003. 

Available online at: http://www.epa.gov/ncea/iris. 26 Morris JB, Symanowicz PT, Olsen JE, et al. 2003. Immediate sensory nerve-mediated 

respiratory responses to irritants in healthy and allergic airway-diseased mice. J Appl 

Physiol 94(4):1563-1571. 

Deleted: Integrated Risk Information 

System File of Acrolein. Office of 

Research and Development, National 

Center for Environmental Assessment, 

Washington, DC. This material is 

available at 

http://www.epa.gov/iris/subst/0364.htm