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NCEA Proposed Draft Charge to External Reviewers for the 

IRIS Toxicological Review of Ammonia 

February 2012 

Introduction 

The U.S. Environmental Protection Agency (EPA) is seeking an external peer review of the 

scientific basis supporting the draft Toxicological Review of Ammonia that will appear on the 

Agency’s online database, the Integrated Risk Information System (IRIS). IRIS is prepared and 

maintained by the EPA’s National Center for Environmental Assessment (NCEA) within the 

Office of Research and Development (ORD). The existing IRIS assessment for ammonia 

includes a chronic reference concentration (RfC) posted in 1991. 

IRIS is a human health assessment program that evaluates qualitative and quantitative risk 

information on effects that may result from exposure to specific chemical substances found in the 

environment. Through the IRIS Program, EPA provides quality science-based human health 

assessments to support the Agency’s regulatory activities. Combined with specific exposure 

information, government and private entities use IRIS to help characterize public health risks of 

chemical substances in site-specific situations in support of risk management decisions. 

The external review draft Toxicological Review of Ammonia is based on a comprehensive 

review of the available scientific literature on the human and animal health effects of ammonia, 

and was developed according to general guidelines for risk assessment set forth by the National 

Research Council (1983) and guidelines and technical reports published by EPA (see Preface). 

This draft IRIS assessment provides an overview of the data regarding the toxicokinetics of 

ammonia in humans and animals and characterizes the potential hazard posed by ammonia 

exposure for noncancer and cancer health effects, including the derivation of a chronic inhalation 

reference concentration (RfC). Additionally, the draft IRIS assessment includes a qualitative 

characterization of the human cancer potential. 

Charge Questions 

Below is a set of charge questions that address scientific issues in the draft IRIS Toxicological 

Review of Ammonia. Please provide detailed explanations for responses to the charge questions. 

EPA will also consider the Science Advisory Board reviewer panel comments on other major 

scientific issues specific to the hazard identification and dose-response assessment of ammonia. 

Please consider the accuracy, objectivity, and transparency of EPA’s analyses and conclusions in 

your review. 

General Charge Questions: 

1. Is the Toxicological Review logical, clear and concise? Has EPA clearly presented and 

synthesized the scientific evidence for noncancer and cancer health effects of ammonia? 

2. Please identify any additional peer-reviewed studies from the primary literature that should be 
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considered in the assessment of noncancer and cancer health effects of ammonia. 

Chemical-Specific Charge Questions: 

(A) Oral reference dose (RfD) for ammonia

1. An RfD was not derived for ammonia. Has the scientific justification for not deriving an RfD 

been clearly described in the document? Are there available data to support the derivation of an 

RfD for ammonia? If so, please identify these data. 

(B) Inhalation reference concentration (RfC) for ammonia

1. An occupational epidemiology study of ammonia (Holness et al., 1989) was selected as the 

basis for the derivation of the RfC. Please comment on whether the selection of this study is 

scientifically supported and clearly described. If a different study is recommended as the basis 

for the RfC, please identify this study and provide scientific support for this choice. 

2. Increased respiratory irritation and decreased lung function in humans were concluded by 

EPA to be adverse effects and selected as the critical effect for the derivation of the RfC. Please 

comment on whether the selection of this critical effect and its characterization is scientifically 

supported and clearly described. If a different endpoint is recommended as the critical effect for 

deriving the RfC, please identify this effect and provide scientific support for this choice. 

3. The NOAEL/LOAEL approach was used to identify the point of departure (POD) for 

derivation of the RfC. Please comment on whether this approach is scientifically supported and 

clearly described. 

4. Please comment on the rationale for the selection of the uncertainty factors (UFs) applied to 

the POD for the derivation of the RfC. Are the UFs appropriate based on the recommendations 

described in A Review of the Reference Dose and Reference Concentration Processes (U.S. EPA, 

2002; Section 4.4.5) and clearly described? If changes to the selected UFs are proposed, please 

identify and provide scientific support for the proposed changes. 

(C) Carcinogenicity of ammonia

1. Under EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005; 

www.epa.gov/iris/backgrd.html), the draft Toxicological Review of Ammonia concludes that 

there is “inadequate information to assess the carcinogenic potential” of ammonia. Please 

comment on whether this characterization of the human cancer potential of ammonia is 

scientifically supported and clearly described. 

2. The draft Toxicological Review of Ammonia did not derive a quantitative cancer estimate for 

ammonia due to the lack of available studies. Are there available data to support the derivation 

of a quantitative cancer risk estimate? If so, please identify these data.