On February 27, 2023, the U.S. Environmental Protection Agency (EPA) announced the availability of and solicited public comment on two draft documents that are being submitted to the Science Advisory Committee on Chemicals (SACC) for peer review: “Draft Proposed Principles of Cumulative Risk Assessment under the Toxic Substances Control Act” (draft proposed principles) and “Draft Proposed Approach for Cumulative Risk Assessment of High-Priority Phthalates and a Manufacturer-Requested Phthalate under the Toxic Substances Control Act” (draft proposed approach). 88 Fed. Reg. 12354. SACC will consider and review these documents at a four-day virtual public meeting on May 8 to 11, 2023. Comments are due April 28, 2023, for distribution to SACC before the meeting.
In its February 24, 2023, press release, EPA states, until now, it has generally approached Toxic Substances Control Act (TSCA) risk assessments by looking at the risk posed by a single chemical. In many cases, people are exposed to multiple chemicals with similar effects at the same time, however, and in some of these cases, EPA “believes that the best approach to evaluate risk to human health may be to look at the combined risk to health from these chemicals.”
Principles of Cumulative Risk Assessment (CRA)
In the draft proposed principles, EPA outlines the proposed principles of CRA as potentially conducted in support of TSCA risk evaluations. EPA notes that it is not explicitly required to conduct CRAs under TSCA, but states that “TSCA does require EPA to consider reasonably available information and to use the best available science to ensure that decisions are based on the weight of the scientific evidence.” According to the draft proposed principles, EPA “recognizes that for some chemical substances, the best available science may indicate that the development of a CRA is appropriate to ensure that risk is adequately characterized.”
The proposed principles of CRA under TSCA include:
- Populations for Consideration: EPA proposes to focus its CRA efforts on human health, not on ecological taxa. In the future, EPA may develop an approach for conducting CRA under TSCA for ecological taxa. Under TSCA, the key human populations considered include the general population and potentially exposed or susceptible subpopulation(s) (PESS) such as workers and occupational non-users (ONU), consumers and consumer bystanders, fenceline communities, and tribal populations. According to the draft proposed principles, as the Office of Pollution Prevention and Toxics (OPPT) continues to develop its approaches for CRA, it will take into consideration PESS in hazard, exposure, and risk methods and results.
- Stressors for Consideration: At this time for purposes of TSCA risk evaluations, EPA proposes to focus its quantitative CRA efforts on the evaluation of chemical substances. EPA states that if it identifies potential non-chemical stressors that may be reasonably anticipated to impact cumulative risk estimates from chemical substance exposure, then it may include a qualitative discussion of the non-chemical stressors and their potential impact on a case-by-case basis until such time that peer-reviewed, Agency-wide guidance for quantitative evaluation of non-chemical stressors is available.
- Sources, Pathways, and Routes of Exposure Considered: EPA will consider relevant pathways and routes of exposure to a person from various sources. The draft proposed principles state that potentially relevant routes of exposure include inhalation, oral, and dermal routes. Possible pathways of exposure to a chemical substance may include, but are not limited to, ingestion of contaminated groundwater, inhalation of volatile compounds emitted in an indoor environment, or dermal exposure to products during use. The draft proposed principles state that the determination of which exposure routes and pathways to include in a CRA requires consideration of the toxicological endpoint(s) selected on the basis of toxicologic similarity and the likelihood of single or multiple routes or pathways to result in co-exposure within a relevant timeframe. For example, if a toxicologic effect is only observed following exposure via certain routes, then it may be appropriate to evaluate only those routes of exposure as part of the CRA. Similarly, unless various pathways of exposure result in co-exposures within a relevant timeframe, they may not be considered as part of a CRA.
- Chemical Grouping Considerations: Consistent with available guidance, toxicological similarity and evidence of co-exposure will be the principal considerations when determining chemical groupings for CRA under TSCA. EPA states that it will develop the establishment of a cumulative chemical group for purposes of CRA using a narrative that clearly characterizes the strengths and uncertainties of the evidence of toxicological similarity, as well as the potential co-exposure for each chemical substance in the cumulative chemical group considered.
- Toxicologic Similarity: The draft proposed principles state that evidence for toxicological similarity exists along a continuum and includes, but may not be limited to (from most to least informative/restrictive with regard to data and knowledge requirements): identical toxicodynamics; similar toxicodynamics; shared syndrome; shared apical; effect on the same target organ; structural similarity; and similarly shaped dose-response curves in comparable toxicity studies. According to the draft proposed principles, “[g]enerally, EPA is unlikely to conduct CRAs under TSCA when the reasonably available information is limited to an effect on the same target organ as this approach may introduce too much uncertainty to risk estimates.”
- Co-Exposure Considerations: The draft proposed principles state that taken together, frequency and duration impact the potential for co-exposure to multiple chemical substances. According to the draft proposed principles, some data sources that can provide evidence of co-exposures within relevant timeframes to individuals and populations considered under TSCA include: biomonitoring data; product formulation data; survey of consumer behavior demonstrating co-use; workplace monitoring; facility releases; and environmental monitoring.
- Additivity Considerations for Evaluating Cumulative Chemical Groups: The draft proposed principles state that consistent with Agency mixtures guidance documents, EPA plans to rely upon a default assumption of dose addition when conducting CRAs for cumulative chemical groups under TSCA, unless empirical evidence supports application of another approach (e.g., response addition or integrated addition). The draft proposed principles note that deciding, based on their toxicological similarity, which chemical substances to include in a cumulative chemical group that subsequently would be evaluated using dose additive models is an important element of a CRA. According to the draft proposed principles, when available, various lines of evidence can be used to evaluate the toxicological similarity and membership of a chemical substance in a cumulative chemical group.
- Addressing Data Gaps: The draft proposed principles note that TSCA Section 4(b) requires test rules and orders to include protocols and methodologies for the development of information for the identified chemical substance(s) or mixture(s); Section 4(b)(2)(A) provides that the health and environmental effects for which such protocols and methodologies may be prescribed include “cumulative or synergistic effects.” The draft proposed principles state that EPA may use this authority to require the development of data to inform the toxicological similarity of a group of chemical substances undergoing risk evaluation in a CRA. Additionally, EPA may use its test order authority to obtain further information on product formulation, emissions testing, and manufacturing process information to support evidence for co-exposure.
- CRA Refinement Considerations: The draft proposed principles state that not all CRAs need to be of the same depth or scope. According to the draft proposed principles, the availability of data for evidence of toxicological similarity and co-exposure will dictate the level of refinement of cumulative hazard and exposure assessments, and assessments may still be possible with limited data.
CRA of Phthalates
In the draft proposed approach, EPA proposes a methodology for evaluating cumulative risk for the phthalate chemicals currently under review. EPA proposes that di-ethylhexyl phthalate (DEHP), butyl benzyl phthalate (BBP), dibutyl phthalate (DBP), di-isobutyl phthalate (DIBP), dicyclohexyl phthalate (DCHP), and di-isononyl phthalate (DINP) (but not di-isodecyl phthalate (DIDP)) are toxicologically similar (and pose an additive hazard) and that the U.S. population is co-exposed to these phthalates. Therefore, EPA proposes to group these phthalates for CRA under TSCA.
EPA states in its press release that the proposed approach “is not itself a cumulative risk assessment nor does it make a finding of risk, but rather is a methodology that EPA proposes to use and seeks public input about and peer review on.” Additionally, since EPA has not yet developed risk estimates for the individual chemicals, EPA “cannot predetermine the results of that work in this cumulative risk assessment approach.” EPA is conducting the CRA for phthalates and individual risk evaluations in parallel, and EPA notes that those risk evaluations will undergo their own public comment and peer review, as appropriate. By releasing the draft proposed approach for public comment and peer review now, EPA “is assuring that the methods used to conduct the cumulative risk assessment will be based on the best available science.” According to EPA, the results of the phthalate CRA may help inform its individual phthalate risk evaluations and ultimately the unreasonable risk determinations.
EPA will hold a public virtual meeting of the SACC on May 8-11, 2023, to peer review the CRA principles and framework. EPA states that the review will ensure that the approach incorporates independent scientific advice and recommendations, and that EPA follows a transparent process. Information on registering to attend the public virtual meeting will be available in April 2023 on the SACC website. EPA provides the following chronological listing of dates for specific activities:
- April 24, 2023: Deadline for submitting a request for special accommodations for participating in the virtual public meeting to allow EPA time to process the request before the meeting;
- April 28, 2023: Deadline for providing comments for distribution to SACC before the meeting; and
- May 1, 2023: Deadline for registering to be listed on the meeting agenda to make oral comments during the virtual meeting. Those not making oral comments may continue to register through May 11, 2023, to receive the links to observe the meeting.
Bergeson & Campbell, P.C. (B&C®) is pleased to see that EPA chose to incorporate existing EPA methodologies and those used by other agencies when preparing its draft CRA principles and approach for CRA on phthalate. This decision will aid with ensuring that the resulting CRA on phthalates is developed using methods that represent the best available science. The individual phthalate risk evaluations will inform the CRA and vice versa. We note this because of the unresolved scientific issues that exist regarding many of the “first 10” risk evaluations (e.g., carbon tetrachloride, N-methylpyrrolidone, and Colour Index Pigment Violet 29 (PV29)) and the likelihood that specific decisions that EPA makes in the individual phthalate risk evaluations and the CRA on phthalates will lead to disagreements on whether EPA complied with the scientific standards under TSCA. Below, we summarize EPA’s proposed approach for its CRA on phthalates and highlight points of interest as EPA moves forward.
EPA proposes to group the following phthalates for its CRA: DEHP, BBP, DBP, DIBP, DCHP, and DINP because they are “toxicologically similar and induce effects on the developing male reproductive system consistent with phthalate syndrome” and may have common uses that provide “evidence of co-exposure to the chemicals over a relevant timeframe.” We anticipate objections to this grouping, with some commenters requesting the inclusion of additional phthalates to ensure that EPA’s CRA on phthalates does not underestimate potential risks, and other commenters requesting removal from the grouping. For example, EPA noted that monocyclohexyl phthalate, a DCHP metabolite, “was included in NHANES from 1999 to 2010, [but] it has since been excluded from the NHANES survey due to low detection levels and a low frequency of detection in human urine.”
EPA intends on quantifying risks in the CRA on phthalates using the most sensitive effect for phthalate syndrome rather than addressing the syndrome as a whole, using an assumption of dose addition rather than response addition, and limiting the PESS to those individuals susceptible to phthalate syndrome (e.g., pregnant women, women of reproductive age, male infants, male toddlers, and male children). We appreciate that using the most sensitive effect for phthalate syndrome and dose addition represents pragmatic decisions for the CRA on phthalates, which are consistent with the National Research Council’s (NRC) 2008 recommended options. We anticipate, however, that some commenters may request the inclusion of other PESS (e.g., male workers), given their potential for co-exposures to phthalates and the relevance of hazard concerns other than phthalate syndrome to this subpopulation.
EPA proposed using a primarily scenario-based approach for estimating non-attributable and non-TSCA exposures, which could be combined with exposures from TSCA conditions of use (COUs), as developed in each of the phthalate risk evaluations, to develop cumulative exposure estimates. EPA noted, however, that “[t]he availability of current and reliable monitoring data, which the approach relies on, is one limitation of this approach.” Based on EPA’s estimated number of non- per- and polyfluoroalkyl substances (PFAS) test orders it intends on initiating per year, approximately 30, we expect that EPA will use its test order authority under TSCA Section 4(a)(2) to require the development of data that will aid with informing worker exposure estimates, facility release estimates, including the possibility of fenceline monitoring, and emission testing on consumer products for each of the phthalates undergoing risk evaluation.
EPA considered two well-known component-based approaches for dose addition, including the hazard index (HI) approach used by EPA’s Office of Land and Emergency Management and the relative potency factor (RPF) approach used by EPA’s Office of Pesticide Programs. EPA proposed using the RPF approach, recognizing that NRC recommended against using an RPF approach in 2008, yet noting that the science has evolved since the NRC made its recommendation. We anticipate that this will be a point of contention for the CRA on phthalates given that the RPF approach scales the dose of one chemical to an equitoxic dose of another chemical called the “index chemical,” which will likely be DEHP for the CRA on phthalates.
We encourage readers to follow EPA’s progress with developing the individual phthalate risk evaluations and the CRA on phthalates, even if these substances are not part of your supply chain. EPA’s decision making for the CRA on phthalates will be precedent-setting and may result in the adoption of default assumptions that favor risk outcomes rather than objective assessments of cumulative risk. Though EPA will not issue risk determinations as part of its CRAs, EPA will use the CRAs to inform its unreasonable risk determinations of the individual substances evaluated as part of the CRA. This means that any chemical substance included as part of a future CRA could have individual COUs with no identified unreasonable risks, but the results of the CRA could prompt EPA to make a determination of unreasonable risk for an individual substance (i.e., the whole chemical substance) based on overlapping exposure with other, similar substances. This may lead EPA to a difficult decision, if exposure to two (or more) substances in a CRA are an unreasonable risk, how will EPA propose managing that risk? Will it attribute risk equally or proportionally and how will EPA approach risk management when the risk is spread across multiple substances?
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