EPA does not agree to delete the last two (of three total) paragraphs discussing the health effects 

associated with exposure to ethanol, and does not agree this language is “speculative,” as OMB 

claims. This language is consistent with EPA’s previous statements about relevant available 

information on ethanol health effects (e.g., the 2010 RFS2 rule). As we have indicated in 

previous discussions, we have included this information because the ingestion literature is 

critical to understand the health endpoints of potential interest, and which populations may be 

most susceptible. Because health effects of ethanol are determined primarily by its concentration 

in the target tissue, and tissue concentrations associated with adverse health effects are 

achievable by both the oral and inhalation routes, the literature on the effects of oral ethanol are 

essential to inform decisions about the health consequences of inhaled ethanol. As we indicate in

the RIA, EPA is developing and evaluating pharmacokinetic models as tools to compare 

quantitatively the tissue concentrations achieved by oral and inhaled ethanol, and thus assess the 

health impacts of inhaled ethanol based on the extensive oral literature.1 These models also 

enable extrapolating doses and effects across species (animal to human) to better characterize 

the health hazards and dose-response relationships for low levels of ethanol exposure in the 

environment. 

For the reasons articulated above, the EPA believes its summary of the available science on 

ethanol health effects is objective, balanced and transparent. The Agency also believes there is 

no scientific reason for changing our description of the current state of science. We have used

this language consistently, whether we are talking about potential ethanol emission increases, as 

in the RFS2 rule, or decreases, as is the case with Tier 3. The language makes it clear that 

literature on inhalation exposure is limited, and that the Agency is evaluating the relevance of 

observed health effects to low level exposures in the environment. 

 

1 Martin, S., et al. 2012. Development of multi-route physiologically-based pharmacokinetic models for 

ethanol in the adult, pregnant, and neonatal rat. Inhalation Toxicology 24(11) 698-722.
Tier 3 RIA Health Effects Text on Ethanol

EPA is planning to develop an assessment of the health effects of exposure to ethanol, a 

compound which is not currently listed on EPA’s IRIS database. Extensive health effects data 

are available for ingestion of ethanol, while data on inhalation exposure effects are sparse. In 

developing the assessment, EPA is evaluating pharmacokinetic models as a means of 

extrapolating across species (animal to human) and across exposure routes (oral to inhalation) to 

better characterize the health hazards and dose-response relationships for low levels of ethanol 

exposure in the environment.

The IARC has classified “alcoholic beverages” as carcinogenic to humans based on 

sufficient evidence that malignant tumors of the oral cavity, pharynx, larynx, esophagus, and 

liver are causally related to the consumption of alcoholic beverages.i The U.S. DHHS in the 12th

Report on Carcinogens also identified “alcoholic beverages” as a known human carcinogen (they

have not evaluated the cancer risks specifically from exposure to ethanol), with evidence for 

cancer of the mouth, pharynx, larynx, esophagus, liver and breast.ii There are no studies 

reporting carcinogenic effects from inhalation of ethanol. EPA is currently evaluating the 

available human and animal cancer data to identify which cancer type(s) are the most relevant to 

a human health assessment of low-level oral and inhalation exposure to ethanol.

Noncancer health effects data are available from animal studies as well as epidemiology

studies. The epidemiologic data were obtained from studies of alcoholic beverage consumption. 

Reported effects included neurological impairment, developmental effects, cardiovascular 

effects, immune system depression, and effects on the liver, pancreas and reproductive system.iii 

There is evidence that children prenatally exposed via maternal ingestion of alcoholic beverages 

during pregnancy are at increased risk of hyperactivity and attention deficits, impaired motor 

coordination, a lack of regulation of social behavior or poor psychosocial functioning, and 

deficits in cognition, mathematical ability, verbal fluency, and spatial memory.

iv,v,vi,vii,viii,ix,x,xi

Genetic factors influencing ethanol metabolism may render certain subpopulations more 

susceptible to the health effects of ethanol exposure by altering internal levels of ethanol and/or 

its metabolites (e.g., acetaldehyde).

 

i International Agency for Research on Cancer (IARC). (1988). Monographs on the evaluation of carcinogenic risk of chemicals to humans, Volume 44, Alcohol Drinking, World 

Health Organization, Lyon, France.

ii NTP. (2011). Report on Carcinogens, Twelfth Edition. Research Triangle Park, NC: U.S. Department of Health 

and Human Services, Public Health Service, National Toxicology Program. 499 pp.

iii U.S. Department of Health and Human Services. (2000). 10th Special Report to the U.S. Congress on Alcohol and 

Health. June. 2000.

iv Goodlett CR, KH Horn, F Zhou. (2005). Alcohol teratogeniesis: mechanisms of damage and strategies for 

intervention. Exp. Biol. Med. 230:394-406.
 

vRiley EP, CL McGee. (2005). Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain 

and behavior. Exp. Biol. Med. 230:357-365.

vi Zhang X, JH Sliwowska, J Weinberg. (2005). Prenatal alcohol exposure and fetal programming: effects on 

neuroendocrine and immune function. Exp. Biol. Med. 230:376-388.

vii Riley, E. P., McGee, C. L. and Sowell, E. R. (2004). Teratogenic effects of alcohol: A decade of brain imaging. 

American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 127C: 35–41. 

doi: 10.1002/ajmg.c.30014

viii Gunzerath, L., Faden, V., Zakhari, S. and Warren, K. (2004), National Institute on Alcohol Abuse and 

Alcoholism Report on Moderate Drinking. Alcoholism: Clinical and Experimental Research, 28: 829–847. 

doi: 10.1097/01.ALC.0000128382.79375.B6

ix World Health Organization (WHO). (2004). Global status report on alcohol 2004. Geneva, Switzerland: 

Department of Mental Health and Substance Abuse. Available: 

http://www.who.int/substance_abuse/publications/global_status_report_2004_overview.pdf

x Chen W-JA, SE Maier, SE Parnell, FR West. (2003). Alcohol and the developing brain: neuroanatomical studies. 

Alcohol Res. Health 27:174-180.

xi Driscoll CD, AP Streissguth, EP Riley. (1990). Prenatal alcohol exposure comparability of effects in humans and 

animal models. Neurotoxicol. Teratol. 12:231-238.