A Search for Thresholds and Other Nonlinearities in the Relationship Between Hexavalent Chromium and Lung Cancer

Abstract

The exposure-response relationship for airborne hexavalent chromium exposure and lung cancer mortality is well described by a linear relative rate model. However, categorical analyses have been interpreted to suggest the presence of a threshold. This study investigates nonlinear features of the exposure response in a cohort of 2,357 chemical workers with 122 lung cancer deaths. In Poisson regression, a simple model representing a two-step carcinogenesis process was evaluated. In a one-stage context, fractional polynomials were investigated. Cumulative exposure dose metrics were examined corresponding to cumulative exposure thresholds, exposure intensity (concentration) thresholds, dose-rate effects, and declining burden of accumulated effect on future risk. A simple two-stage model of carcinogenesis provided no improvement in fit. The best-fitting one-stage models used simple cumulative exposure with no threshold for exposure intensity and had sufficient power to rule out thresholds as large as 30 microg/m3 CrO3 (16 microg/m3 as Cr+6) (one-sided 95% confidence limit, likelihood ratio test). Slightly better-fitting models were observed with cumulative exposure thresholds of 0.03 and 0.5 mg-yr/m3 (as CrO3) with and without an exposure-race interaction term, respectively. With the best model, cumulative exposure thresholds as large as 0.4 mg-yr/m3 CrO3 were excluded (two-sided upper 95% confidence limit, likelihood ratio test). A small departure from dose-rate linearity was observed, corresponding to (intensity)0.8 but was not statistically significant. Models in which risk-inducing damage burdens declined over time, based on half-lives ranging from 0.1 to 40 years, fit less well than assuming a constant burden. A half-life of 8 years or less was excluded (one-sided 95% confidence limit). Examination of nonlinear features of the hexavalent chromium-lung cancer exposure response in a population used in a recent risk assessment supports using the traditional (lagged) cumulative exposure paradigm: no intensity (concentration) threshold, linearity in intensity, and constant increment in risk following exposure.

Metal concentrations around thermal power plants, rural and urban areas using honeybees (Apis mellifera L.) as bioindicators

“…The lungs are affected with hyperemia, erosion and an inflammatory change in the respiratory system mucosa, or even nose septum perforation (Lee et al 2002). It can also cause small cell cancer of the lung tissue (Park and Stayner 2006). Fe is an essential nutrient needed to produce chlorophyll in plants (Hänsch and Mendel 2009), while in animals it can be found in hemoglobin, myoglobin, cytochromes, iron-containing enzymes and in iron storage proteins, ferritin and hemosiderin.…”

Development of a cancer-based chronic inhalation reference value for hexavalent chromium based on a nonlinear-threshold carcinogenic assessment

“…Analyses of statistically significant trends across exposure categories. Park and Stayner (2006) discuss the potential thresholds found by Crump et al (2003) for the Painsville cohort and by Exponent (2002a) for the Baltimore cohort, which will be the focus here. Strengths of the Baltimore cohort include a relatively large group of workers (2357) and tens of thousands of CrVI air measurements from which to estimate exposure, although as with other epidemiology studies there are also limitations.…”

“…Several human studies provide data adequate for dose-response assessment or evaluate such data, including Luippold et al (2003), Birk et al (2006), Applied Epidemiology (2002), Crump et al (2003), Park et al (2004), and Park and Stayner (2006). The data from these studies, some of which evaluate the same workers (in whole or in part), were analyzed to identify potential PODs for use in a nonlinear-threshold carcinogenic assessment.…”

“…The TCEQ evaluates and considers adopting low-dose extrapolation approaches (e.g., linear, nonlinear, threshold) informed by relevant chemical-specific data on a chemicalby-chemical basis. While other studies have statistically evaluated the epidemiological data for thresholds or other nonlinearities (e.g., Crump et al, 2003;Park and Stayner, 2006), this study conducts such analyses more fully taking into account MOA-relevant information such as lung CrVI reductive capacity estimates. It should be noted that the intent of the current study is not to perform an exhaustive weight of evidence evaluation of all data potentially relevant to the MOA (or MOAs), but rather to present available summary MOA information and statistical evidence interpreted as consistent with (albeit not proof of) a potential practical threshold for CrVI-induced inhalation carcinogenicity and the results of the consequential nonlinear-threshold carcinogenic assessment.…”

Exploring the statistical uncertainty in acceptable exposure limit values for hexavalent chromium exposure

“…Two cohort studies are playing a central role in the analyses as they account for smoking status among the workers. The first, the so-called Baltimore cohort study, was first analysed by Gibb et al 4 with follow ups by Park et al, 1,5 and recently by Haney et al 6 The second cohort study, the so-called Painesville study was presented by Crump et al 7 and Luippold et al 8 We here refer to both studies and analyse the published summarised data with respect to quantifying the uncertainty of derived exposure limit values.…”