DRAFT DELIBERATIVE 1 DO NOT CITE OR QUOTE

Draft Charge to External Peer Reviewers for the IRIS Toxicological Review of 1,4-Dioxane

May 2011

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

scientific basis supporting the human health assessment (inhalation route of exposure) of 

1,4-dioxane 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).

There is a current assessment on the IRIS database for the health effects associated with 

1,4-dioxane exposure which was first available in 2010 that derived oral toxicity values only.

During the development of the 2010 Toxicological Review of 1,4-Dioxane, new studies (Kasai, et 

al., 2009; Kasai, et al., 2008) regarding the toxicity of 1,4-dioxane through the inhalation route of 

exposure became available. These studies have been added to the previously posted assessment 

(U.S. EPA, 2010). An evaluation of the data and a draft reference concentration (RfC) and 

inhalation unit risk (IUR) have been derived and are presented in this document for review. 

Sections where the new inhalation studies have impacted the assessment are the focus of the 

current review and can be identified by the red underlined text in the document. This review is 

to evaluate only the data and qualitative and quantitative decisions relevant to the inhalation 

route of exposure. Although this review is focused only on sections that were revised based on 

the new inhalation studies, the entire document is being provided for completeness. Below are a 

set of charge questions that address scientific issues in the assessment of 1,4-dioxane

(inhalation). Please provide detailed explanations for responses to the charge questions.

(A) 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 hazards via the inhalation 

route of exposure?

2. Please identify any additional studies that would make a significant impact on the 

conclusions of the Toxicological Review. 

Chemical-Specific Charge Questions:

(B) Inhalation reference concentration (RfC) for 1,4-dioxane

1. A chronic RfC for 1,4-dioxane has been derived from a 2-year inhalation bioassay

(Kasai, et al., 2009) in male rats. Please comment on whether the selection of this study 

as the principal study is scientifically supported and clearly described. Please identify 

and provide the rationale for any other studies that should be selected as the principal 

study.

2. Atrophy of the olfactory epithelium was selected as the critical effect. Please comment 

on whether the rationale for the selection of this critical effect is scientifically supported 

and clearly described. Please identify and provide the rationale for any other endpoints 

that should be considered in the selection of the critical effect.
DRAFT DELIBERATIVE 2 DO NOT CITE OR QUOTE

3. A LOAEL based upon the observation of atrophy of the olfactory epithelium was used as 

the point of departure (POD) for the RfC. Please provide comments with regard to 

whether the LOAEL approach is the best approach for determining the POD. Please 

identify and provide rationales for any alternative approaches for the determination of the 

POD and discuss whether such approaches are preferred to EPA’s approach.

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

POD for the derivation of the RfC. Are the UFs scientifically supported and clearly 

described? If changes to the selected uncertainty factors are proposed, please identify and 

provide a rationale(s). 

(C) Inhalation carcinogenicity of 1,4-dioxane

Please Note: An external peer review for 1,4-dioxane (oral assessment) was completed in 2009. 

The conclusions of this panel can be found in Appendix A and provide informative information, 

especially regarding the cancer descriptor and cancer mode of action evaluation, that may be 

useful for the review of the 1,4-dioxane (inhalation assessment). 

1. Under the EPA’s 2005 Guidelines for Carcinogen Risk Assessment

(www.epa.gov/iris/backgr-d.htm), the Agency concluded that 1,4-dioxane is likely to 

be carcinogenic to humans. Please comment on whether the cancer weight of 

evidence characterization is scientifically justified and clearly described. 

2. Several hypothesized MOAs were evaluated within the Toxicological Review and 

EPA reached the conclusion that a MOA(s) could not be supported for any tumor 

types observed in animal models. Please comment on whether the weight of the 

scientific evidence supports this conclusion and whether the analysis is clearly 

described. 

3. A two-year inhalation cancer bioassay (Kasai, et al., 2009) was selected for the

derivation of an inhalation unit risk (IUR). Please comment on whether the selection 

of this study for quantification is scientifically justified and clearly described. Please 

identify and provide the rationale for any other studies that should be selected. 

4. Data on the incidence of hepatocellular adenomas and carcinomas, nasal cavity 

squamous cell carcinoma, renal cell carcinoma, peritoneal mesothelioma, mammary 

gland fibroadenoma, Zymbal gland adenoma, and subcutis fibroma were used to 

estimate the inhalation unit risk. Please comment on whether this selection is

scientifically justified and clearly described. Please identify and provide the rationale 

for any other endpoints that should be selected to serve as the basis for the 

quantitative cancer assessment. 

5. The inhalation unit risk was calculated based on multiple carcinogenic effects of 1,4-

dioxane observed in rats via the inhalation route. A Bayesian analysis was performed 

to estimate a BMDL10 associated with the occurrence of multiple tumors, and then a 

linear low-dose extrapolation was applied. Please comment on this modeling 
DRAFT DELIBERATIVE 3 DO NOT CITE OR QUOTE

approach. In addition, an alternative modeling approach has been included in 

Appendix G. Has the modeling been appropriately conducted and clearly described?