Methods for Developing the RoC Monograph

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.

Box

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.