Standardizing Benchmark Dose Calculations to Improve Science-Based Decisions in Human Health Assessments

Abstract

Background: Benchmark dose (BMD) modeling computes the dose associated with a prespecified response level. While offering advantages over traditional points of departure (PODs), such as no-observed-adverse-effect-levels (NOAELs), BMD methods have lacked consistency and transparency in application, interpretation, and reporting in human health assessments of chemicals.Objectives: We aimed to apply a standardized process for conducting BMD modeling to reduce inconsistencies in model fitting and selection.Methods: We evaluated 880 dose–response data sets for 352 environmental chemicals with existing human health assessments. We calculated benchmark doses and their lower limits [10% extra risk, or change in the mean equal to 1 SD (BMD/L10/1SD)] for each chemical in a standardized way with prespecified criteria for model fit acceptance. We identified study design features associated with acceptable model fits.Results: We derived values for 255 (72%) of the chemicals. Batch-calculated BMD/L10/1SD values were significantly and highly correlated (R2 of 0.95 and 0.83, respectively, n = 42) with PODs previously used in human health assessments, with values similar to reported NOAELs. Specifically, the median ratio of BMDs10/1SD:NOAELs was 1.96, and the median ratio of BMDLs10/1SD:NOAELs was 0.89. We also observed a significant trend of increasing model viability with increasing number of dose groups.Conclusions: BMD/L10/1SD values can be calculated in a standardized way for use in health assessments on a large number of chemicals and critical effects. This facilitates the exploration of health effects across multiple studies of a given chemical or, when chemicals need to be compared, providing greater transparency and efficiency than current approaches.Citation: Wignall JA, Shapiro AJ, Wright FA, Woodruff TJ, Chiu WA, Guyton KZ, Rusyn I. 2014. Standardizing benchmark dose calculations to improve science-based decisions in human health assessments. Environ Health Perspect 122:499–505; http://dx.doi.org/10.1289/ehp.1307539

Risk assessment׳s insensitive toxicity testing may cause it to fail

“…This encourages testing of low doses (though distinguishing harmful from harmless changes may be controversial). A validation of BMDs using 352 long studied chemicals not only verified that more testing at low doses improved the accuracy of a dose/response data set, but that these lower doses frequently caused toxicity below the alleged NOAELs (Wignall et al, 2014). Allowing academia's low dose toxicity tests to be considered in risk assessment would encourage wider adoption of BMD in risk assessment.…”

Comparison of Points of Departure for Health Risk Assessment Based on High-Throughput Screening Data

“…Because the use of in vitro data significantly increases the amount of concentration–response data that needs to be processed, the use of standardized modeling protocols, including standardized PODs, may be of importance, at least from a practical point of view. Wignall et al (2014) recently discussed the use of a standardized protocol for BMD analysis that was argued to provide greater transparency and efficiency than current approaches. Their approach was illustrated for traditional animal toxicity data, but the relevance of this type of approach was also suggested to be of particular value in the case of high-throughput in vitro testing (Wignall et al 2014).…”

A quantitative framework to group nanoscale and microscale particles by hazard potency to derive occupational exposure limits: Proof of concept evaluation

“…As a result, BMDs from SK modeling were chosen to represent the potency of the nanoscale or microscale particles. Other published software that allow for the fitting of several BMD model forms to numerous dose-response relationships in succession (Wignall et al, 2014; Shao and Shapiro, 2016) may be useful considerations for future investigations.…”