Quantifying cellular concentrations of arsenic species for risk assessment in human populations

The National Institute of Environmental Health Sciences awarded The University of Chicago $435,145 on July 11, 2026, under the Environmental Health Program (CFDA 93.113) to develop capability and infrastructure for measuring arsenic species, including trivalent and pentavalent forms, in human cells collected from Bangladeshi individuals with varying arsenic exposure levels. The research addresses limitations in prior studies that focused primarily on measuring arsenic species in urine and blood, which has constrained understanding of arsenic metabolism efficiency—the human variability in converting ingested inorganic arsenic to methylated forms—and its role as a determinant of arsenic-related health risks including cancer and cardiovascular disease. The project will isolate and quantify arsenic species in accessible cell types to advance knowledge of arsenic distribution across human tissues and to distinguish between toxic trivalent species that are unstable in urine and cannot be accurately measured using standard methods, as well as to clarify genetic effects on arsenic species specific to whole blood. The award is structured as a Project Grant with a period of performance through July 10, 2028, and performance takes place in Chicago, Illinois.

Abstract

Approximately 200 million people worldwide, consume water contaminated with inorganic arsenic (as), a toxicant that increases the risk of cancer, cardiovascular disease, and other conditions. In the U.S., >2 million are exposed to as through drinking water, while exposure to as-contaminated food (e.g., rice) is widespread. Ingested inorganic as is methylated in the liver, producing mono-methylated as (MMA) and then DI-methylated as (DMA) species. Methylation facilitates the elimination of as in urine, but also generates toxic intermediates, most notably trivalent mmaiii. Humans vary in their ability to methylate as, and this variability, known as as metabolism efficiency (AME), is an important determinant of as-related health risks. AME is commonly assessed in humans studies as the relative abundance of methylated as species (e.g., DMA%) in urine samples, and this AME phenotype is impacted by demographic, lifestyle, and genetic factors. Prior studies have primarily focused on measuring as species in urine and blood, which has limited our ability to understand AME in several ways. These include (1) limiting knowledge of the distribution of as species in human tissues, (2) ignoring the distinction between pentavalent (v) species and the more toxic trivalent (III) species, as trivalent species (i.e., mmaiii and dmaiii) are unstable in urine and cannot be accurately quantified, and (3) convoluting as species in plasma and blood cells by using whole blood for as speciation, which limits our understanding of genetic effects on as species that are specific to as in whole blood (i.e., FMO4 and GSTO1). In light of these limitations, we propose to develop the capability and infrastructure to measure as species, including trivalent and pentavalent forms, in human cells collected from bangladeshi individuals with a wide range of as exposure levels. We will isolate accessible cell types from blood (mononuclear cells), urine (exfoliated urothelial cells), and the oral cavity (buccal cells). We will measure as species using hydride generation (HG)-cryotrapping (CT)-inductively coupled plasma (ICP)-mass spectrometry (MS). Our fist aim is to develop and assess the reliability of a workflow for oxidative-state-specific as speciation analysis in human cells collected from as-exposed individuals (blood cells, urothelial cells, and buccal cells). Our second aim is to characterize variability in as species in cells across BIO-specimen types, correlations across biospecimen types, and association of as species with participant characteristics. Our team has extensive experience in as epidemiology, as speciation technologies, as toxicology, and genetic studies of AME, positioning US well to achieve these aims. The development of infrastructure and methods to measure as species in human cells, in a way that distinguishes between valence states with markedly different toxicity profiles, has the potential to transform our understanding of as metabolism, distribution, and elimination in humans. This capability will allow US to further dissect the biological mechanisms underlying susceptibility to as exposure. Applying these new capabilities to larger studies in the U.S. Will enhance our ability to (1) study and understand as related health risks in the U.S., and (2) develop strategies for risk prediction, prevention, and interventions to reduce as-related risks.