Time is an important, but underappreciated component in chemical safety decisions. An estimated 15% of the chemicals in domestic commerce have traditional repeated dose toxicity testing data and even fewer have human health assessments that can be used to inform regulatory actions. The time and resources required to perform traditional toxicity testing and develop a human health assessment are substantial and, for many chemicals, human exposure continues to occur while toxicity data are collected, interpreted, and integrated into a human health reference value. Although new methods and approaches are increasingly available to more rapidly and cost effectively evaluate toxicity and develop human health assessments, there is hesitation to utilize newer approaches as compared with traditional paradigms. Objective approaches are needed to evaluate the potential trade-offs between timeliness of the toxicity testing and human health assessment, uncertainty of the information, and the associated costs and benefits of the testing and assessment approaches.

The United States Environmental Protection Agency (EPA) Office of Research and Development (ORD) recently developed a value of information (VOI) framework for comparing human health and economic benefits of toxicity-testing methodologies (Hagiwara et al. 2022). VOI analysis is a decision analytic method for objectively quantifying the expected value of collecting additional information to reduce uncertainty when considering the benefits of improved outcomes against the associated costs. The ORD VOI framework incorporates a series of input parameters relevant to chemical risk assessment that would be considered by risk managers, including chemical exposure, associated adverse health effects, costs of potential exposure mitigation actions, the size of affected populations, and the amount of uncertainty reduced in human health assessments by performing additional toxicity tests. The VOI framework builds on previous work in this field by explicitly incorporating the value of additional toxicity testing data in reducing the uncertainty of human health risks while accounting for the cost of delay in decision making that results from the time required for testing and assessment.

This report outlines a case study using the VOI framework to evaluate the human health and economic trade-offs between uncertainty, timeliness, and costs associated with a recently released five-day in vivo transcriptomic-based toxicity study and EPA Transcriptomic Assessment Product (ETAP) compared to a two-year rodent bioassay and traditional human health assessment (THHA) process. Both the ETAP and the THHA result in the derivation of a reference value that represents the daily dose of a chemical substance for which exposure to humans would be unlikely to result in an adverse health effect following oral exposure. The ETAP and THHA processes differ in the cost of the study, duration of the study and assessment process, and the degree of uncertainty around the point-of-departure (POD)¹, with ETAP having the inherently shorter-duration and lower cost assay, but with the trade-off of presumed greater uncertainty. The ETAP is intended to be applied to substances with no existing or publicly accessible repeated dose toxicity studies or human evidence suitable for use as a POD and reference value derivation. The comparison was performed for various combinations of exposure conditions, health endpoints, control costs, population characteristics, and decision types using a range of values informed by real-world data. For the exposure and decision type, the range of values for each component were combined into a set of baseline scenarios to capture the multiple exposure characteristics and decision contexts for a chemical for which ETAP may be applicable. In addition, a separate set of sensitivity analyses (i.e., sensitivity analysis scenarios) were performed to evaluate additional chemical characteristics and other potential sources of uncertainty. A total of 360 baseline and sensitivity analysis scenarios were summarized across multiple VOI metrics to bound the relative difference in value between the ETAP and THHA across the diverse range of characteristics and contexts for chemicals that are suitable for ETAP.

The results of the case study showed that ETAP was favored over THHA in most of the scenarios examined and across multiple VOI metrics. The benefit-risk decision-maker (BRDM) chooses to regulate a chemical if the reduction in health cost (or increased health benefit) outweighs the associated cost of control. For the BRDM, 83% of the scenarios favored ETAP, while the remaining 17% favored neither ETAP nor THHA. The target-risk decision maker (TRDM) takes regulatory action to mitigate exposure whenever the risk exceeds a prespecified target risk level. For the TRDM, 7% of the scenarios required neither ETAP nor THHA, while between 87 and 99% of the remaining scenarios favored ETAP, depending on the VOI metric evaluated. Across the scenarios examined, the median difference in the expected net benefit of sampling (ENBS), which considers the reduction in total costs from the additional testing and assessment activities adjusted for delay and the cost of testing (COT), was approximately $44 billion for the benefit-risk decision context and $81 billion for the target-risk decision context². Negative values for ENBS were frequently observed for THHA in the benefit-risk decision context, suggesting that the delay and costs associated with decision-making for the traditional toxicity testing and human health assessment process are greater than the eventual benefit. In contrast, the ETAP less frequently had a negative ENBS for the benefit-risk decision context, suggesting that the benefit gained by collecting toxicity information via ETAP outweighed both the delay and the COT for most scenarios evaluated.

Overall, the results of the case study indicate that under the exposure scenarios and assumptions considered, the ETAP was more frequently preferred over the traditional toxicity testing and human health approach for more rapidly and cost effectively evaluating chemicals with no existing or publicly accessible repeated dose toxicity studies or human evidence suitable for use as a POD and reference value derivation. The amount of time needed to conduct the toxicity testing and develop the human health assessment was particularly important when the risks were high, as the delay in implementing regulatory action resulted in significant health costs.

Footnotes

1

In human health risk assessment practice, a point-of-departure (POD) represents the dose-response point that marks the beginning of a low-dose extrapolation. This point can be the lower bound on dose for an estimated incidence or a change in response level from a dose-response model (e.g., Benchmark Dose; BMD), or a No Observed Adverse Effect Level (NOAEL) or Lowest Observed Adverse Effect Level (LOAEL) for an observed incidence or change in level of response. For BMD values, this is typically the BMD lower confidence bound (BMDL).

2

Total benefits over the twenty-year time horizon for which the costs were calculated. To put these numbers in perspective, as an example, preventing a chronic health condition (costing $10,000 per year) among 330,000 people (approximately 1/10th of 1% of the US population) would provide a benefit of $66B over a 20-year time horizon.