Summary of reviewer comments

Most reviewers noted that overall, the document clearly described the purpose and aims to develop an approach to integrate publicly available information to efficiently provide screening and prioritization for large lists of environmental chemicals in clear and logical manner, and would be adaptable to other large-scale chemical prioritization efforts beyond TSCA. Multiple reviewers also noted an appreciation for the inclusion of the discussion on what this approach is and is not intended to do, as this helped to bound scope of the document. Further, reviewers noted the importance of the novel information availability metric in this approach to help inform the amount of research available and potentially highlight data gaps. Along with these comments, reviewers also noted some areas for further clarification or improvement, including discussion of the selection of the POC238 compounds used and potential impacts on interpretation of the results, as well as recommendations on additional figures or tables to more clearly present the data and results.

EPA response

EPA would like to thank all of the reviewers for their thoughtful and comprehensive review of the document. We appreciate the comments on the clarity of the description of the purpose and aims of this approach and have expanded this description in the executive summary of the document. We have addressed in the revised document the recommendations to include additional figures for clarity, clarify the chemical space covered by the POC238 as compared to the full TSCA active inventory, discuss the inclusion of read-across in multiple scientific domains, and clarify the adaptability of this approach depending on decision context.

Overarching topics were raised by the reviewers, and these are summarized below.

1. POC Chemical subset selection.
   Multiple reviewers commented on the make-up of the POC chemical subset used in the case study and noted that the subset was enriched with compounds with increased information availability as compared to the TSCA Active Inventory, and therefore may not reflect the full TSCA Active inventory.
   EPA response:
   The PICS approach was developed using a small subset of compounds from the TSCA active inventory to represent specific chemical groups (e.g., substances from the TSCA workplan) or with known biological effects to use as a reference for specific scientific domains. Once developed, this approach was carried out on the broader TSCA Active Inventory, and we have included more information in the revised document demonstrating how the POC238 compounds are representative of the TSCA active inventory. We have further included additional figures to show how compounds with less information would perform in the PICS approach.
2. Incorporation of QSAR and read-across approaches.
   Multiple reviewers commented on the idea of increasing the use of mechanisms to compare related chemicals, through the application of analogue and category approaches and their associated read-across.
   EPA response: EPA appreciates the comments on including the use of both read-across and QSAR throughout the PICS approach. We have incorporated read-across and QSARs in the PICS approach when possible based on the maturity of the research. Additionally, we considered adding a QSAR estimation of in vivo PODs as a fourth level in the hazard estimation process (in vivo>IVIVE>QSAR>TTC), but at the time of development, we did not have a published QSAR model.
3. Scientific domain selection.
   Reviewers commented on some of the scientific domains selected for the case study. Specifically, reviewers were mixed on the decision to separate cancer and genotoxicity domains. One reviewer specifically noted that having separate domains for these two was appropriate for weighting this endpoint, while another reviewer questioned the increased weight on these two endpoints but not including additional endpoints for reproductive or developmental toxicity.
   EPA response:
   The decision to have separate carcinogenicity and genotoxicity domains was to be inclusive of both genotoxic and nongenotoxic carcinogens in this approach, as well as to capture any potential genotoxic environmental chemicals that may not have been assessed for cancer. In terms of additional domains for other endpoints, like reproductive or developmental toxicity, these were not included in the PICS approach case study as separate domains but incorporated into the human health domain and in calculating in information availability domain value. Depending on decision context, these could be developed into a separate domain if desired.
4. Mixtures and specific chemical classes.
   Multiple reviewers commented on issues of applying this approach to mixtures, as well as comments highlighting specific classes of chemicals that may need to be handled differently by this approach.
   EPA response:
   We appreciate the comments and recommendations and agree that prioritization of mixtures would be a good addition to this approach. However, the analysis of this approach for mixtures is a longer-term effort beyond the scope of this effort. Further, the comments related to the need to address specific classes of chemicals (e.g., metals) in a different manner are appreciated. A proposal to consider grouping some chemicals by class as a complementary approach to the PICS approach was presented, and while of possible interest it is beyond the scope of this case study. We have included a discussion in the revised document for overall longer-term efforts, which includes the future need to address mixtures and specific chemical classes. We would note that we have included IG (information gathering) flags for specific chemical categories (e.g., volatiles) and could include additional flags for some chemical classes as needed.
5. Additional data sources.
   Multiple reviewers recommended additional data types and sources for use in the PICS approach.
   EPA response:
   We thank the reviewers for sharing potential new data types and sources that we can use for expanding the dataset used in this approach. Given the time and resources needed to evaluate these additional sources, they will not be added to this pilot case study but will be proposed to be added to future use of this approach as appropriate.
6. Addition of other susceptible populations.
   Multiple reviewers recommended expanding the susceptible population domain beyond children’s exposure.
   EPA response:
   For the purpose of this pilot case study, we focused the susceptible exposure domain only on children’s exposure as this was a more mature research effort. However, if data sources are available, they could be incorporated to include additional populations (e.g., workers, elderly) as appropriate for future applications.
7. Quality control.
   One reviewer commented that since we did not review the quality of the data, EPA should reconsider using the term ‘quality control’ to describe the actions we undertook.
   EPA response:
   EPA has applied the term ‘quality control’ in this document in reference to quality of the transfer of data from the data sources to the automated system. For the purposes of this work, reviewing accuracy of data from secondary sources and available primary sources is considered quality control. EPA noted that the study quality issues were not considered for reasons of time, cost, and scope (i.e., a prioritization tool rather than a regulatory decision). The level of data quality control described by the reviewer is more in line with the expert-driven process that would follow this screening approach.

2.

SCIENTIFIC DOMAINS

Based on your knowledge of toxicology, chemistry, risk assessment, and/or exposure science, please comment on the evaluation, workflow, and metrics developed for the individual scientific domains in the TSCA POC.

2A.

Were the decisions in each of the domain-specific evaluations logical and based on sound science?

2B.

Do you see any significant issues with any of the tiered workflows and metrics developed for these scientific domains? If so, please identify and explain those issues.

For each of the scientific domains, there is a discussion of limitations and longer-term options. Based on your knowledge of toxicology, chemistry, and/or exposure science:

2C.

Are the appropriate limitations and long-term options included for each domain?

2D.

Are there additional long-term options that could be included?

Summary of reviewer comments:

Overall, the reviewers stated that the format for each of the scientific domains was clear and appreciated the sections on limitations and longer-term research ideas for each domain. No significant issues were described for the workflows and metrics, although limitations were acknowledged and the consideration of a percentile-based metric was raised.

EPA response:

EPA appreciates the thorough review of the scientific domains, and the acknowledgement from multiple reviewers as to their expertise and how that guided their comments. EPA has revised the document to address needed clarifications, with the specifics for each domain highlighted below. EPA would like to note two main points in our development and revisions to this document: First, this document was specifically designed to support TSCA decision-making process, so many aspects of the approach (e.g., specific domains, data types) are specific to that context. This approach was specifically designed to be flexible to adapt to other decision contexts, so EPA appreciates the recommendations from reviewers that can strengthen this approach for future regulatory application. Second, this document reflects a proof-of-concept case study as a starting point for this approach, and many of the longer-term research proposed in the document and by the reviewers may be excellent additions to a future research effort. Finally, the use of a percentile-based metric was discussed in the development of the approach, but the use of absolute values was selected as they have accepted meaning in the context of risk assessments. The use of percentiles (particularly quartiles) would group compounds with potentially artificial cutoff points, unrelated to the risk assessment questions being addressed. This approach would arbitrarily force (with quartiles for instance) 25% of compounds to have the highest value and 25% to have the lowest value for each domain, when an objective survey of the data would not yield anything like this distribution. We will take this into consideration for future research.

Specific comments/responses by domain

Summary of reviewer comments

In general, the reviewers stated the information availability metric was clearly described, but clarity could be increased with the addition of a flowchart on the calculation for this metric, a limitations and long-term needs section and minor revisions on topics such as the IG flags.

EPA response

We thank the reviewers for their recommendations to increase clarity on the information availability metric. These comments have been addressed in the revised document in the text and through the development of a flowchart.

4.

RESULTS and CONCLUSIONS

4A.

Are the results of the TSCA POC clearly described and presented? If no, please identify areas where clarity is needed.

4B.

Do the results presented adequately support the conclusions? If so, please identify and explain those issues.

Summary of reviewer comments

Overall, the reviewers stated that the results were clearly described and presented, but also included some suggestions to increase that clarity through graphical visualization of the results along with making the supporting data file (Appendix E) more user-friendly. One reviewer raised concerns about merging the results from the individual domains and recommended adding histograms to show the distribution across chemicals for each metric. Comments from reviewers related to the POC238 subset, mixtures and data sources are addressed under the overarching topics above.

EPA response

EPA thanks the reviewers for the comments on how well this document presents the results and conclusions. We further appreciate the recommendations from the reviewers on how to strengthen the readability of the results and conclusions. In response to these recommendations, we have revised the document to include histograms to show the chemical distributions of the active TSCA inventory compounds for each of the metrics in Appendix F.

5.

EDITORIAL OR ADDITIONAL COMMENTS

5A.

Please provide any editorial or additional comments you would like to make here. These should be any comments that are not in direct response to the technical charge questions above.

Summary of reviewer comments

Overall, the reviewers agreed that the document was clear and easy to read, while including some specific editorial comments to be addressed.

EPA response

EPA thanks the reviewers for their attention to detail and have addressed editorial comments in the revised document. This includes updates to the text and figures to improve clarity as well as addressing technical editorial comments.