David G. Hoel

Is occupational organic solvent exposure a risk factor for scleroderma

OBJECTIVE The primary objective was to determine whether occupational exposure to organic solvents is related to an increased risk of systemic sclerosis (SSc; scleroderma). METHODS Occupational histories were obtained from 178 SSc patients and 200 controls. Exposure scores were computed for each individual using job exposure matrices, which were validated by an industrial expert. RESULTS Among men, those with SSc were more likely than controls to have a high cumulative intensity score (odds ratio [OR] 2.9, 95% confidence interval [95% CI] 1.1-7.6) and a high maximum intensity score (OR 2.9, 95% CI 1.2-7.1) for any solvent exposure. They were also more likely than controls to have a high maximum intensity score for trichloroethylene exposure (OR 3.3, 95% CI 1.0-10.3). Among men and women, significant solvent-disease associations were observed among SSc patients who tested positive for the anti-Scl-70 autoantibody; these trends were not observed among the men and women who tested negative for anti-Scl-70. CONCLUSION These results provide evidence that occupational solvent exposure may be associated with an increased risk of SSc.

Evidence of Health Impacts of Sulfate-and Nitrate-Containing Particles in Ambient Air

Ambient particulate matter (PM) is a complex mixture of inorganic and organic compounds. The U.S. Environmental Protection Agency (EPA) regulates PM as a criteria pollutant and promulgates National Ambient Air Quality Standards for it. The PM indicator is based on mass concentration, unspecified as to chemical composition, for specific size fractions. The numerical standards are based on epidemiologic evidence of associations between the various size-related particle mass concentrations as indicators and excess mortality and cardiorespiratory health effects as endpoints. The U.S. National Research Council has stated that more research is needed to differentiate the apparent health effects associated with different particle chemical constituents. Sulfate and nitrate constitute a significant portion of the particle mass in the atmosphere, but are accompanied by similar amounts of carbonaceous material, along with low concentrations of various species, including bioactive organic compounds and redox cycling metals. Extensive animal and human toxicology data show no significant effects for particles consisting only of sulfate and nitrate compounds at levels in excess of ambient air concentrations. A few epidemiologic studies, including both short-term time-series studies and long-term cohort studies, have included the sulfate content of PM as a specific variable in health effect analyses. There are much less data for nitrate. The results from the epidemiologic studies with PM sulfate are inconsistent. A detailed analysis of the time-series epidemiological studies shows that PM sulfate has a weaker “risk factor” than PM2.5 for health effects. Since sulfate is correlated with PM2.5, this result is inconsistent with sulfate having a strong health influence. However, there are many limitations with these types of studies that warrant caution for any comparison between a chemical component and mass concentration. In total, the epidemiologic and toxicologic evidence provide little or no support for a causal association of PM sulfate and health risk at ambient concentrations. For nitrate-containing PM, virtually no epidemiological data exist. Limited toxicological evidence does not support a causal association between particulate nitrate compounds and excess health risks. There are some possible indirect processes through which sulfate and nitrate in PM may affect health-related endpoints, including interactions with certain metal species and a linkage with production of secondary organic matter. There is insufficient evidence to include or exclude these processes as being potentially important to PM-associated health risk.

Review and evaluation of updated research on the health effects associated with low-dose ionising radiation

While radiation health risks at low doses have traditionally been estimated from high-dose studies, we have reviewed recent literature and concluded that the mechanisms of action for many biological endpoints may be different at low doses from those observed at high doses; that acute doses <100 mSv may be too small to allow epidemiological detection of excess cancers given the background of naturally occurring cancers; that low-dose radiation research should use holistic approaches such as systems-based methods to develop models that define the shape of the dose-response relationship; and that these results should be combined with the latest epidemiology to produce a comprehensive understanding of radiation effects that addresses both damage, likely with a linear effect, and response, possibly with non-linear consequences. Continued research is needed to understand how radiobiology and epidemiology advances should be used to effectively model radiation worker risks.

Mortality among US commercial pilots and navigators

The airline industry may be an occupational setting with specific health risks. Two environmental agents to which flight crews are known to be exposed are cosmic radiation and magnetic fields generated by the aircrafts electrical system. Other factors to be considered are circadian disruption and conditions specific to air travel, such as noise, vibration, mild hypoxia, reduced atmospheric pressure, low humidity, and air quality. This study investigated mortality among US commercial pilots and navigators, using proportional mortality ratios for cancer and noncancer end points. Proportional cancer mortality ratios and mortality odds ratios were also calculated for comparison to the proportional mortality ratios for cancer causes of death. Results indicated that US pilots and navigators have experienced significantly increased mortality due to cancer of the kidney and renal pelvis, motor neuron disease, and external causes. In addition, increased mortality due to prostate cancer, brain cancer, colon cancer, and cancer of the lip, buccal cavity, and pharynx was suggested. Mortality was significantly decreased for 11 causes. To determine if these health outcomes are related to occupational exposures, it will be necessary to quantify each exposure separately, to study the potential synergy of effects, and to couple this information with disease data on an individual basis.

Using Median Regression to Obtain Adjusted Estimates of Central Tendency for Skewed Laboratory and Epidemiologic Data

BACKGROUND Laboratory studies often involve analyses of highly skewed data for which means are not an adequate measure of central tendency because they are sensitive to outliers. Attempts to transform skewed data to symmetry are not always successful, and medians are better measures of central tendency for such skewed distributions. When medians are compared across groups, confounding can be an issue, so there is a need for adjusted medians. METHODS We illustrate the use of quantile regression to obtain adjusted medians. The method is illustrated by use of skewed nutrient data obtained from black and white men attending a prostate cancer screening. For 3 nutrients, saturated fats, caffeine, and vitamin K, we obtained medians adjusted by age, body mass index, and calories for men in each race group. RESULTS Quantile regression, linear regression, and log-normal regression produced substantially different adjusted estimates of central tendency for saturated fats, caffeine, and vitamin K. CONCLUSIONS Our method was useful for analysis of skewed and other nonnormally distributed continuous outcome data and for calculation of adjusted medians.

Threshold models in radiation carcinogenesis

Cancer incidence and mortality data from the atomic bomb survivors cohort has been analyzed to allow for the possibility of a threshold dose response. The same dose-response models as used in the original papers were fit to the data. The estimated cancer incidence from the fitted models over-predicted the observed cancer incidence in the lowest exposure group. This is consistent with a threshold or non-linear dose-response at low-doses. Thresholds were added to the dose-response models and the range of possible thresholds is shown for both solid tumor cancers as well as the different leukemia types. This analysis suggests that the A-bomb cancer incidence data agree more with a threshold or non-linear dose-response model than a purely linear model although the linear model is statistically equivalent. This observation is not found with the mortality data. For both the incidence data and the mortality data the addition of a threshold term significantly improves the fit to the linear or linear-quadratic dose response for both total leukemias and also for the leukemia subtypes of ALL, AML, and CML.

Impact of nutrients on insulin-like growth factor-I, insulin-like growth factor binding protein-3 and their ratio in African American and white males.

OBJECTIVE Higher levels of insulin-like growth factor-I (IGF-I) and lower levels of IGF binding protein-3 (IGFBP-3) have been associated with an increased risk of prostate cancer. Nutrition is known to partially regulate IGF levels and it is possible that nutritional factors mediate the impact of IGF levels on prostate cancer risk. DESIGN A cross-sectional analysis of the impact of nutritional factors measured by a dietary questionnaire on plasma levels of IGF-I, IGFBP-3 and their molar ratio. Multiple linear regression analysis was used to test for effects of nutrients on IGF levels. SETTING Prostate cancer screening at the Hollings Cancer Center in Charleston, South Carolina. SUBJECTS Ninety-five African American and 138 white males aged 33-83 years attending the screening. RESULTS In whites, intakes of total, saturated and monounsaturated fats were positively associated with an increase in the molar ratio, while there was no association in African Americans. In African Americans, we found that increasing intake of calcium and dairy servings was positively associated with IGF-I levels. Increased vegetable intake was positively associated with IGFBP-3 in African Americans, while there was no effect in whites. A higher percentage of alcohol in the total diet was significantly associated with a decrease in the molar ratio and an increase in IGFBP-3 in both groups. CONCLUSIONS Our results confirm previous findings of nutritional determinants of IGF levels. Additionally, we found the impact of several nutrients on IGF levels to be different in whites and African Americans, which warrants further investigation.

Trichloroethylene risk assessment: A review and commentary

Trichloroethylene (TCE) is a widespread environmental contaminant that is carcinogenic when given in high, chronic doses to certain strains of mice and rats. The capacity of TCE to cause cancer in humans is less clear. The current maximum contaminant level (MCL) of 5 ppb (μg/L) is based on an US Environment Protection Agency (USEPA) policy decision rather than the underlying science. In view of major advances in understanding the etiology and mechanisms of chemically induced cancer, USEPA began in the late 1990s to revise its guidelines for cancer risk assessment. TCE was chosen as the pilot chemical. The final guidelines emphasized a “weight-of-evidence” approach with consideration of dose-response relationships, modes of action, and metabolic/toxicokinetic processes. Where adequate data are available to support reversible binding of the carcinogenic moiety to biological receptors as the initiating event (i.e., a threshold exists), a nonlinear approach is to be used. Otherwise, the default assumption of a linear (i.e., nonthreshold) dose-response is utilized. When validated physiologically based pharmacokinetic (PBPK) models are available, they are to be used to predict internal dosimetry as the basis for species and dose extrapolations. The present article reviews pertinent literature and discusses areas where research may resolve some outstanding issues and facilitate the reassessment process. Key research needs are proposed, including role of dichloroacetic acid (DCA) in TCE-induced liver tumorigenesis in humans; extension of current PBPK models to predict target organ deposition of trichloroacetic acid (TCA) and DCA in humans ingesting TCE in drinking water; use of human hepatocytes to ascertain metabolic rate constants for use in PBPK models that incorporate variability in metabolism of TCE by potentially sensitive subpopulations; measurement of the efficiency of first-pass elimination of trace levels of TCE in drinking water; and assessment of exogenous factors’ (e.g., alcohol, drugs) ability to alter metabolic activation and risks at such low-level exposure.

Cosmic radiation and magnetic field exposure to airline flight crews

BACKGROUND Flight crews are exposed to elevated levels of cosmic radiation and to magnetic fields generated by the aircrafts electrical system. The purpose of this study was to quantify these two occupational exposures. METHODS Magnetic fields were measured during 37 flights (23 in the cockpit and 14 in the cabin) using an Emdex Lite personal dosimeter. All cockpit measurements were taken on the B737/200. Cabin measurements were taken in several aircraft types, including the B737, B757, DC9, and L1011. Cosmic radiation was computer estimated for 206 flights using the Federal Aviation Administrations program CARI-3C. RESULTS Magnetic field levels in the cockpit had a mean value of approximately 17 milliGauss (mG), while cabin measurements were lower (mean values of approximately 3 or less in economy, 6 in first class, 8 in front serving areas). Cosmic radiation equivalent dose rates to bone marrow and skeletal tissue ranged from 0.3 to 5.7 microsieverts per hour. CONCLUSIONS Elevated magnetic field levels in front serving areas and the cockpit suggest the need for further study to evaluate long-term exposure to flight crew members who work in these areas. Cosmic radiation levels are well below occupational limits for adults, but may require some pregnant flight crew members to adjust their flying time or routes.

The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation

Abstract Purpose: This review evaluates the role of dose rate on cell and molecular responses. It focuses on the influence of dose rate on key events in critical pathways in the development of cancer. This approach is similar to that used by the U.S. EPA and others to evaluate risk from chemicals. It provides a mechanistic method to account for the influence of the dose rate from low-LET radiation, especially in the low-dose region on cancer risk assessment. Molecular, cellular, and tissues changes are observed in many key events and change as a function of dose rate. The magnitude and direction of change can be used to help establish an appropriate dose rate effectiveness factor (DREF). Conclusions: Extensive data on key events suggest that exposure to low dose-rates are less effective in producing changes than high dose rates. Most of these data at the molecular and cellular level support a large (2–30) DREF. In addition, some evidence suggests that doses delivered at a low dose rate decrease damage to levels below that observed in the controls. However, there are some data human and mechanistic data that support a dose-rate effectiveness factor of 1. In summary, a review of the available molecular, cellular and tissue data indicates that not only is dose rate an important variable in understanding radiation risk but it also supports the selection of a DREF greater than one as currently recommended by ICRP (2007) and BEIR VII (NRC/NAS 2006).