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.gov3.5.5.4 Formaldehyde

Since 1987, EPA has classified formalde hyde as a probable human carcinogen based on evidence in humans and in rats, mice, hamsters, and monkeys. 1 EPA is currently reviewing recently published epidem iological 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 ch emical 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 qua ntitative 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 publishedby 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 andnasal 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 da ta 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 suffe r 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/m 3 ) 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 observe d 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 respons es to strong respiratory irritants such as

acrolein.

1 U.S. EPA. 1987. Assessment of Health Ri sks to Garment Workers and Certain Home Residents from Exposure to Formaldehyde, O ffice 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/m 3 ) 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. Mo rtality among a coho rt 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-motivat ed 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 assessmen t 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 Diseas e 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 spons orship 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 ch emicals, 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 Environmenta l 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 Environm ental 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 Asse ssment, 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