Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

Abstract

The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg−1 day−1, is based on a no‐observable‐adverse‐effect‐level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as “low.” A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non‐neoplastic lesions from the 2 year cancer bioassay were modeled in a three‐step process. First, a rodent physiological‐based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg−1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)‐induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non‐cancer endpoints; all RfD values ranged 0.003–0.02 mg kg−1 day−1. The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg−1 day−1, the confidence is greatly improved due to the use of a 2‐year bioassay, mechanistic data, PBPK models and benchmark dose modeling.

Letter to “Chepelev et al. Establishing a quantitative framework for regulatory interpretation of genetic toxicity dose–response data: Margin of exposure case study of 48 compounds with both in vivo mutagenicity and carcinogenicity dose–response data”

“…Most chromium in groundwater sources is Cr(VI) (Seidel & Corwin, 2013) and US Environmental Protection Agency's (EPA) own environmental monitoring data indicate median and 95th percentile Cr(VI) levels of 0.001 and 0.003 ppm, 2 respectively, resulting in daily exposures on the order of 3E-5 to 9E-5 mg/kg/day. Adjusting the dichromate benchmark dose lower confidence limit (BMDL) for intestinal tumors in mice listed in Table 1 of Chepelev et al to Cr(VI) results in MOE values above 10,000, as does our previous analyses on the oral tumors in rats (Thompson et al, 2018). Notably, Health Canada (2016) lists estimated daily exposures to Cr(VI) as 0.065 μg/kg/day, which also results in MOEs >10,000.…”

Development of the InTelligence And Machine LEarning (TAME) Toolkit for Introductory Data Science, Chemical-Biological Analyses, Predictive Modeling, and Database Mining for Environmental Health Research

“…These examples highlight the importance of evaluating model fit to ultimately determine which model should be used to derive final BMD estimates ( Figure 3 ). Trainees are lastly pointed to example dose-response publications that have addressed environmental health questions ( Rager et al, 2017 ; Auerbach and Paules, 2018 ; Thompson et al, 2018 ; Johnson et al, 2020 ), as well as additional modeling tools and guidance documents surrounding dose-response assessments. The importance of this module is that BMD modeling represents a foundational topic in environmental health, where methods can be used to better understand which exposure concentrations/doses are required to elicit toxicity by evaluating trends in datasets.…”

An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet

“…at least 6-12 months). For Cr(VI), the human equivalent dose (HED) in mg/kg for duodenal hyperplasia was estimated from mice to be 0.02 mg/kg-day (Thompson et al 2018), which is equivalent to 0.54 ppm of Cr(VI) in drinking water daily for a lifetime, based on the 95th %-ile drinking water intake of 37 ml/kg-day (U.S. EPA 2019). This is 180-fold higher than the 95th %-ile Cr(VI) concentration in U.S. drinking water of 3 ppb.…”

“…A rather large number of studies targeted at informing risk assessment of Cr(VI) were conducted from $2010 to 2019, including pharmacokinetics (Kirman et al 2012(Kirman et al , 2013(Kirman et al , 2016(Kirman et al , 2017Proctor et al 2012;De Flora et al 2016), in vivo genotoxicity assays (De Flora et al 2008;O'Brien et al 2013;Thompson, Young, et al 2015;2017;Aoki et al 2019), transcriptomic analyses Thompson, Gregory, et al 2012;Rager et al 2017), and histopathological analyses Cullen et al 2016). Based on this large body of new information, both the scientists directly involved in the research as well as others reviewing the work have concluded that Cr(VI) causes SI cancer through a non-mutagenic MOA and that non-linear risk assessment approaches are most appropriate (Thompson et al 2014;Haney 2015;Health Canada 2016;TCEQ 2016;Thompson et al 2018;FSCJ 2019;WHO 2019).…”