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National Toxicology Program. Report on Carcinogens Monograph on Antimony Trioxide: RoC Monograph 13 [Internet]. Research Triangle Park (NC): National Toxicology Program; 2018 Oct.
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Report on Carcinogens Monograph on Antimony Trioxide: RoC Monograph 13 [Internet].
Show detailsMethods for Developing the RoC Monograph
Process Leading to the Selection of Antimony(III) Trioxide for Review
As per the process for preparation of the RoC, the Office of the Report on Carcinogens (ORoC) released a draft concept document, “Antimony Trioxide,” which outlined the rationale and proposed the approach for the review, for public comment. The ORoC also presented the draft to the NTP Board of Scientific Counselors (BSC) at its meeting on December 14–15, 2016, which provided opportunity for written and oral public comments. After the meeting, the concept was finalized, and antimony was approved by the NTP Director as a candidate substance for review. The concept document is available on the RoC website (https://ntp.niehs.nih.gov/go/809361).
Public comments on scientific issues were requested at several time points prior to the development of the RoC monograph, and they include the request for information on the nomination and the request for comment on the draft concept document, which outlined the rationale and approach for conducting the scientific review. In addition, NTP posted its protocol for preparing the draft RoC monograph on antimony trioxide for public input on the RoC webpage (https://ntp.niehs.nih.gov/go/809361) prior to the release of the draft monograph.
Monograph Development
This monograph evaluates the available, relevant scientific information and assesses its quality, applies the RoC listing criteria to the scientific information, and recommends a RoC listing status. The monograph also includes a draft substance profile containing NTP’s listing recommendation for antimony(III) trioxide, a summary of the scientific evidence considered key to reaching that recommendation, and data on antimony(III) trioxide’s properties, use, production, and exposure, along with federal regulations and guidelines to reduce exposure.
The process of applying the RoC listing criteria to the body of evidence includes assessing the level of evidence from cancer studies of antimony(III) trioxide in humans and experimental animals. In addition, the available mechanistic and other relevant data (such as disposition and toxicokinetics) are assessed, and the final listing recommendation is based on an integration of all the relevant information (as summarized in the table above). This information is captured in the following sections of the monograph:
- Chemical Identification and Properties (Section 1)
- Human Exposure (Section 2)
- Disposition and Toxicokinetics (Section 3)
- Human Cancer Studies (Section 4)
- Studies of Cancer in Experimental Animals (Section 5)
- Mechanistic Data (Section 6)
- Other Relevant Data (Section 7)
- Evidence Integration and Listing Recommendation (Section 8)
The overall cancer hazard evaluation in Section 8 is informed by the information and assessments of the data reported in the earlier sections. The information must come from publicly available sources. The appendices in the RoC Monograph contain important supplementary information, including the literature search strategy, disposition data tables, study-quality tables for cancer studies in experimental animals, and findings from studies of mechanistic and other relevant studies.
Key Scientific Questions for Each Type of Evidence Stream
The monograph provides information relevant to the following questions for each type of evidence stream or section topic.
Questions Related to the Evaluation of Properties and Human Exposure Information
- What are the physicochemical properties of antimony(III) trioxide and other relevant antimony compounds?
- What are the sources of exposure? How are people exposed to antimony(III) trioxide?
- Are a significant number of people residing in the United States exposed to antimony(III) trioxide?
- To what chemical forms of antimony are humans exposed?
Questions Related to the Evaluation of Disposition and Toxicokinetics
- How are antimony compounds absorbed, distributed, metabolized, and excreted (i.e., ADME information)?
- What evidence do we have regarding antimony metabolism in mammals and potential effects from antimony metabolites?
- To what extent does transformation between Sb(III) and Sb(V) occur in vivo? Is Sb(III) the ultimate carcinogenic species?
- How can toxicokinetics models (if any) inform biological plausibility, interspecies extrapolation, or other questions about potential mechanisms of carcinogenicity?
Questions Related to the Evaluation of Human Cancer Studies
- What are the methodological strengths and limitations of these studies?
- What are the potential confounding factors for cancer risk at the tumor sites of interest?
- Is there a credible association between exposure to antimony and cancer?
- If so, can the relationship between cancer end points and exposure to antimony be explained by chance, bias, or confounding?
Questions Related to the Evaluation of Cancer Studies in Experimental Animals
- What is the level of evidence (sufficient, limited, or inadequate) for the carcinogenicity of antimony(III) trioxide in animal studies?
- What are the methodological strengths and limitations of the studies?
- At what tissue sites was cancer observed?
- If lung tumors are seen in rats after inhalation exposure to antimony(III) trioxide, what role does lung overload play in causing observed rat lung tumors?
Questions Related to the Evaluation of Mechanistic Data and Other Relevant Data
- What are the genotoxic effects of antimony(III) trioxide exposure?
- What are the major biological effects contributing to the potential carcinogenicity of antimony(III) trioxide?
- For biological effects contributing to potential carcinogenicity that have not been tested in studies with exposure to antimony(III) trioxide, could data from other antimony compounds be used to infer likely results for antimony(III) trioxide?
Methods for Preparing the Monograph
The methods for preparing the RoC monograph on antimony(III) trioxide are described in the RoC Protocol for preparing the draft monograph on antimony(III) trioxide, which incorporated a systematic review approach for identification and selection of the literature (see Appendix A), using inclusion/exclusion criteria, extraction of data and evaluation of study quality according to specific guidelines, and assessment of the level of evidence for carcinogenicity according to established criteria. Links are provided to the appendices within the document, and specific tables or sections can be selected from the table of contents (see below).
General procedures. See the Handbook for Preparing RoC Monographs (hereinafter referred to as RoC Handbook) for a detailed description of methods.
Selection of the literature. Preparation of the monograph began with development of a literature search strategy to obtain information relevant to the topics listed above for Sections 1 through 6 using search terms outlined in the Protocol. Approximately 5,500 citations were identified from these searches and uploaded to web-based systematic review software for separate evaluation by two reviewers applying the inclusion/exclusion criteria. Based on these criteria, 232 references were selected for final inclusion in the monograph. Literature searches were updated on a monthly basis prior to posting the peer review draft online (November 29, 2017) and the last update of these searches was received on November 13, 2017. References recommended by the peer reviewers were also considered for the final revisions.
Data extraction and quality assurance procedures. Information for the relevant cancer and mechanistic studies was systematically extracted in tabular format and/or summarized in the text from studies selected for inclusion in the monograph. All sections of the monograph underwent scientific review and quality assurance (i.e., assuring that all the relevant data and factual information extracted from the publications had been reported accurately) by a separate reviewer. Any discrepancies were resolved by the writer and the reviewer through discussion and reference to the original data source.
Evaluation of human cancer studies. The available epidemiological studies are not specific for exposure to antimony(III) trioxide. Based on the studies’ descriptions, it is likely that the workers were exposed to other forms of antimony in addition to the trioxide. Two reviewers evaluated the quality of each study using a series of questions (and guidelines for answering the questions) related to risk of bias and to study sensitivity (as described in the Protocol). Any disagreements between the two reviewers were resolved through discussion or by consultation with a third reviewer and reference to the original data source. The approach to synthesizing the evidence across studies and reaching a conclusion on the level of evidence for carcinogenicity is also outlined in the Protocol. Level-of-evidence conclusions (inadequate, limited, or sufficient) were made by applying the RoC criteria (see below) to the body of evidence.
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RoC Listing Criteria.
Evaluation of cancer studies in experimental animals. Two reviewers evaluated the quality of each study using methods described in the Protocol. Any disagreements between the two reviewers were resolved through discussion or by consultation with a third reviewer and reference to the original data source. The level-of-evidence conclusions (sufficient, not sufficient) were made by applying the RoC criteria (see below) to the body of evidence. These conclusions were made after the evaluation of the mechanistic data and are reported in the overall cancer hazard evaluation.
Evaluation of mechanistic and other relevant data. As mentioned in the protocol, the mechanistic data were organized by characteristics of carcinogens (such as genotoxicity, oxidative stress, epigenetic alterations, and promotion of cell proliferation) to help inform understanding of the relevant biological effects potentially contributing to carcinogenesis. Mechanistic data, toxicokinetics data, and other relevant data (such as non-cancer health outcomes and carcinogenicity studies of other antimony compounds) are discussed for other inorganic trivalent antimony compounds to help inform the cancer evaluation of antimony(III) trioxide and whether there is sufficient information to identify the antimony species ultimately responsible for carcingenicity.
Overall evaluation and listing recommendation. The evidence from the cancer studies in humans and experimental animals was integrated with the assessment of the mechanistic and other relevant data. The RoC listing criteria were then applied to the body of knowledge to reach a listing recommendation regarding antimony(III) trioxide.
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