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AbstractDiesel exhaust in the latter half of the 20th century has been found to be a lung carcinogen. Conventional diesel emissions continue in the transportation, mining, construction, and farming industries. From the Diesel Exhaust in Miners Study, a public‐use dataset was used to calculate the excess lifetime risk of lung cancer associated with diesel exposure (1947–1997). Excess rates of lung cancer mortality associated with respirable elemental carbon (REC) and possible other mining exposures (e.g., oil mists, explosives emissions) were investigated using Poisson regression methods. Lung cancer mortality declined with increasing employment duration while increasing with cumulative REC and non‐diesel exposures, suggesting a strong worker survivor effect. Attenuation of the REC effect was observed with increasing cumulative exposure. After adjustment for employment duration, the excess rate ratio for lung cancer mortality was 0.67 (95% CI = 0.35–0.99) for a 10‐year lagged exposure to 200 μg/m3 REC, a typical below‐ground exposure in the study mines. At exposures of 200, 10, and 1 μg/m3 REC, the estimated excess lifetime risks, respectively, were 119, 43, and 8.7 per thousand. Analysis of an inception cohort hired after dieselization commenced produced smaller and less certain estimates of lifetime risk. From exposures to conventional diesel engine exhaust common in occupational groups in the past, the excess lifetime risk of lung cancer was more than 5%. Ambient REC exposures in the general population were estimated to confer lifetime risks of 0.14 to 14 per thousand, depending on assumptions made.

AbstractUncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. A particular interest is the internal concentration of an agent in biological systems as a function of external exposure concentrations. Physiologically based pharmacokinetic (PBPK) models permit estimation of internal exposure concentrations in target tissues but most assume that model parameters are either fixed or instantaneously dose‐dependent. Taking into account response times for biological regulatory mechanisms introduces new dynamic behaviors that have implications for low‐dose exposure response in chronic exposure. A simple one‐compartment simulation model is described in which internal concentrations summed over time exhibit significant nonlinearity and nonmonotonicity in relation to external concentrations due to delayed up‐ or downregulation of a metabolic pathway. These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects.

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 μg/m3 CrO3 (16 μg/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.

AbstractQuantitative risk assessment often begins with an estimate of the exposure or dose associated with a particular risk level from which exposure levels posing low risk to populations can be extrapolated. For continuous exposures, this value, the benchmark dose, is often defined by a specified increase (or decrease) from the median or mean response at no exposure. This method of calculating the benchmark dose does not take into account the response distribution and, consequently, cannot be interpreted based upon probability statements of the target population. We investigate quantile regression as an alternative to the use of the median or mean regression. By defining the dose–response quantile relationship and an impairment threshold, we specify a benchmark dose as the dose associated with a specified probability that the population will have a response equal to or more extreme than the specified impairment threshold. In addition, in an effort to minimize model uncertainty, we use Bayesian monotonic semiparametric regression to define the exposure–response quantile relationship, which gives the model flexibility to estimate the quantal dose–response function. We describe this methodology and apply it to both epidemiology and toxicology data.

The purpose of this investigation was to estimate excess lifetime risk of lung cancer death resulting from occupational exposure to hexavalent‐chromium‐containing dusts and mists. The mortality experience in a previously studied cohort of 2,357 chromate chemical production workers with 122 lung cancer deaths was analyzed with Poisson regression methods. Extensive records of air samples evaluated for water‐soluble total hexavalent chromium were available for the entire employment history of this cohort. Six different models of exposure‐response for hexavalent chromium were evaluated by comparing deviances and inspection of cubic splines. Smoking (pack‐years) imputed from cigarette use at hire was included in the model. Lifetime risks of lung cancer death from exposure to hexavalent chromium (assuming up to 45 years of exposure) were estimated using an actuarial calculation that accounts for competing causes of death. A linear relative rate model gave a good and readily interpretable fit to the data. The estimated rate ratio for 1 mg/m3‐yr of cumulative exposure to hexavalent chromium (as CrO3), with a lag of five years, was RR= 2.44 (95% CI = 1.54–3.83). The excess lifetime risk of lung cancer death from exposure to hexavalent chromium at the current OSHA permissible exposure limit (PEL) (0.10 mg/m3) was estimated to be 255 per 1,000 (95% CI: 109–416). This estimate is comparable to previous estimates by U.S. EPA, California EPA, and OSHA using different occupational data. Our analysis predicts that current occupational standards for hexavalent chromium permit a lifetime excess risk of dying of lung cancer that exceeds 1 in 10, which is consistent with previous risk assessments.