Evaluation of a Physiologically Based Pharmacokinetic (PBPK) Model for Inorganic Arsenic Exposure Using Data from Two Diverse Human Populations

Abstract

Background:Multiple epidemiological studies exist for some of the well-studied health endpoints associated with inorganic arsenic (iAs) exposure; however, results are usually expressed in terms of different exposure/dose metrics. Physiologically based pharmacokinetic (PBPK) models may be used to obtain a common exposure metric for application in dose–response meta-analysis.Objective:A previously published PBPK model for inorganic arsenic (iAs) was evaluated using data sets for arsenic-exposed populations from Bangladesh and the United States.Methods:The first data set was provided by the Health Effects of Arsenic Longitudinal Study cohort in Bangladesh. The second data set was provided by a study conducted in Churchill County, Nevada, USA. The PBPK model consisted of submodels describing the absorption, distribution, metabolism and excretion (ADME) of iAs and its metabolites monomethylarsenic (MMA) and dimethylarsenic (DMA) acids. The model was used to estimate total arsenic levels in urine in response to oral ingestion of iAs. To compare predictions of the PBPK model against observations, urinary arsenic concentration and creatinine-adjusted urinary arsenic concentration were simulated. As part of the evaluation, both water and dietary intakes of arsenic were estimated and used to generate the associated urine concentrations of the chemical in exposed populations.Results:When arsenic intake from water alone was considered, the results of the PBPK model underpredicted urinary arsenic concentrations for individuals with low levels of arsenic in drinking water and slightly overpredicted urinary arsenic concentrations in individuals with higher levels of arsenic in drinking water. When population-specific estimates of dietary intakes of iAs were included in exposures, the predictive value of the PBPK model was markedly improved, particularly at lower levels of arsenic intake.Conclusions:Evaluations of this PBPK model illustrate its adequacy and usefulness for oral exposure reconstructions in human health risk assessment, particularly in individuals who are exposed to relatively low levels of arsenic in water or food. https://doi.org/10.1289/EHP3096

Benefits of basic research from the Superfund Research Program

“…Findings from the Health Effects of Arsenic Longitudinal Study (HEALS) cohort are cited in the ongoing arsenic risk assessment being conducted by the EPA (124). In addition, HEALS cohort data also contributed to a physiologically based pharmacokinetic (PBPK) model for inorganic arsenic developed by the EPA with major implications for arsenic risk assessment in populations exposed to low or moderate arsenic levels (125).…”

Exploratory study of the association in the United Kingdom between hypertension and inorganic arsenic (iAs) intake from rice and rice products

“…For MN, a score of 0 or 1 was assigned to participants with less than (\) or greater than or equal to (C) the mean daily intake level of each nutrient, respectively, with a composite measure then created by summing the individual score to indicate the intake level of these micro-nutrients (cf. El-Masri et al 2018).…”

Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use of a threshold approach

“…Methylation is primarily performed in mammalian systems by the enzyme arsenic (þ3 oxidation state) methyltransferase (As3mt) (Chen, Arnold et al 2011;Thomas 2015). The methylated forms and non-methylated inorganic arsenic are excreted predominantly in the urine (El-Masri and Kenyon 2008;Kenyon et al 2008;El-Masri et al 2018).…”

“…Transport of arsenicals is also dependent on oxidative state and whether they are in inorganic or organic form (Drobna, Walton, Harmon et al 2010;Cohen et al 2013;El-Masri et al 2018). Arsenate can be transported by a number of transporters in various tissues, primarily by those involved in phosphate transport.…”