title: Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures.
abstract: Inhalation of hexavalent chromium [Cr(VI)] is associated with increased lung cancer risk among workers in several industries, most notably chromate production workers exposed to high concentrations of Cr(VI) (≥100 μg/m(3)), for which clear exposure-response relationships and respiratory irritation and tissue damage have been reported. Data from this industry are used to assess lung cancer risk associated with environmental and current occupational exposures, occurring at concentrations that are significantly lower. There is considerable uncertainty in the low dose extrapolation of historical occupational epidemiology data to assess risk at current exposures because no published or well recognized mode of action (MOA) for Cr(VI)-induced lung tumors exists. We conducted a MOA analysis for Cr(VI)-induced lung cancer evaluating toxicokinetic and toxicological data in humans and rodents and mechanistic data to assess plausibility, dose-response, and temporal concordance for potential MOAs. Toxicokinetic data support that extracellular reduction of Cr(VI), which limits intracellular absorption of Cr(VI) and Cr(VI)-induced toxicity, can be overwhelmed at high exposure levels. In vivo genotoxicity and mutagenicity data are mostly negative and do not support a mutagenic MOA. Further, both chronic bioassays and the epidemiologic literature support that lung cancer occurs at exposures that cause tissue damage. Based on this MOA analysis, the overall weight of evidence supports a MOA involving deposition and accumulation of particulate chromium in the bifurcations of the lung resulting in exceedance of clearance mechanisms and cellular absorption of Cr(VI). Once inside the cell, reduction of Cr(VI) results in oxidative stress and the formation of Cr ligands. Subsequent protein and DNA damage lead to tissue irritation, inflammation, and cytotoxicity. These effects, concomitant with increased cell proliferation, result in changes to DNA sequences and/or methylation status that can lead to tumorigenesis. This MOA supports the use of non-linear approaches when extrapolating lung cancer risk occurring at high concentration occupational exposures to environmentally-relevant exposures.
authors.affiliation: ToxStrategies, Inc., Mission Viejo, CA 92692, United States. Electronic address: dproctor@toxstrategies.com.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Proctor
authors.affiliation: ToxStrategies, Inc., Mission Viejo, CA 92692, United States. Electronic address: msuh@toxstrategies.com.
authors.forename: Mina
authors.initials: M
authors.lastname: Suh
authors.affiliation: University of California, Office of the President, Oakland, CA 94612, United States. Electronic address: Sharan.Campleman@ucop.edu.
authors.forename: Sharan L
authors.initials: SL
authors.lastname: Campleman
authors.affiliation: ToxStrategies, Inc., Katy, TX 77494, United States. Electronic address: cthompson@toxstrategies.com.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Thompson
mesh_terms: D000818:Animals; D002274:Carcinogens, Environmental / Q000009:adverse effects*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002857:Chromium / Q000009:adverse effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016273:Occupational Exposure / Q000009:adverse effects*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
chemical_list: D002274:Carcinogens, Environmental; D002857:Chromium; C074702:chromium hexavalent ion
keywords: Cancer risk assessment; Hexavalent chromium [Cr(VI)]; Lung cancer; Mode of action