David A. Dankovic

An Approach to Risk Assessment for TiO2

Titanium dioxide (TiO2) is a poorly soluble, low-toxicity (PSLT) particle. Fine TiO2 (<2.5 μm) has been shown to produce lung tumors in rats exposed to 250 mg/m3, and ultrafine TiO2 (< 0.1 μm diameter) has been shown to produce lung tumors in rats at 10 mg/m3. We have evaluated the rat dose-response data and conducted a quantitative risk assessment for TiO2. Preliminary conclusions are: (1) Fine and ultrafine TiO2 and other PSLT particles show a consistent dose-response relationship when dose is expressed as particle surface area; (2) the mechanism of TiO2 tumor induction in rats appears to be a secondary genotoxic mechanism associated with persistent inflammation; and (3) the inflammatory response shows evidence of a nonzero threshold. Risk estimates for TiO2 depend on both the dosimetric approach and the statistical model that is used. Using 7 different dose-response models in the U.S. Environmental Protection Agency (EPA) benchmark dose software, the maximum likelihood estimate (MLE) rat lung dose associated with a 1 per 1000 excess risk ranges from 0.0076 to 0.28 m2/g-lung of particle surface area, with 95% lower confidence limits (LCL) of 0.0059 and 0.042, respectively. Using the ICRP particle deposition and clearance model, estimated human occupational exposures yielding equivalent lung burdens range from approximately 1 to 40 mg/m3 (MLE) for fine TiO2, with 95% LCL approximately 0.7–6 mg/m3. Estimates using an interstitial sequestration lung model are about one-half as large. Bayesian model averaging techniques are now being explored as a method for combining the various estimates into a single estimate, with a confidence interval expressing model uncertainty.

Predicted Lung Cancer Risk Among Miners Exposed to Diesel Exhaust Particles

Several quantitative risk assessment models have been published for occupational and environmental exposures to diesel exhaust particles (DEP). These risk assessment models are reviewed and applied to predict lung cancer for miners exposed to DEP. The toxicologically based unit risk estimates varied widely (from 2 to 220 x 10(-6) per micrograms/m3). The epidemiologically based unit risk estimates were less variable and suggest higher risks (from 100 to 920 x 10(-6) per micrograms/m3). The wide range of risk estimates derived from these analyses reflects the strong assumptions and large uncertainties underlying these models. All of the models suggest relatively high risks (i.e., > 1/1,000) for miners with long-term exposures greater than 1,000 micrograms/m3. This is not surprising, given the fact that miners may be exposed to DEP concentrations similar to those that induced lung cancer in rats and mice, and substantially higher that the exposure concentrations in the positive epidemiologic studies.

Oxidative stress and DNA damage in Fischer rats following acute exposure to trichloroethylene or perchloroethylene.

Oxidative DNA damage is emerging as an biomarker of effect in studies assessing the health risks of occupational chemicals. Trichloroethylene (TCE) and perchloroethylene (PERC) are used in the dry cleaning industry and their metabolism can produce reactive oxygen compounds. The present study examined the potential for TCE and PERC to induce oxidative DNA damage in rats that was detectable as increased urinary excretion of 8-hydroxydeoxyguanosine (8OHdG). Thiobarbaturic acid reactive substances (TBARS) and 8-epiprostaglandin F2alpha (8epiPGF) were also measured as biomarkers of increased oxidative stress. Male Fischer rats were administered a single i.p. injection of 0, 100, 500, or 1000 mg/kg of PERC or TCE. Control rats received only vehicle (1:4 v/v of Alkamuls/water). A positive control group received 100 mg/kg 2-nitropropane (2NP). Rats were sacrificed 24 h after dosing. In rats receiving 2NP or TCE but not PERC, TBARS and the 8OHdG/dG ratios were significantly elevated in liver. Lymphocyte 8OHdG/dG was not affected significantly by 2NP, TCE or PERC. In rats receiving 2NP, urinary excretion of 8OHdG and 8epiPGF2 were significantly increased. In rats receiving TCE or PERC, significant increases in 8epiPGF2 or 8OHdG were not evident. Results indicate that a single high dose of TCE, but not PERC, can induce an increase in oxidative DNA damage in rat liver. However, the usefulness of 8OHdG as a biomarker of TCE-induced oxidative DNA damage is questionable.

Paternal Occupational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Birth Outcomes of Offspring: Birth Weight, Preterm Delivery, and Birth Defects

Agent Orange is a phenoxy herbicide that was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We studied pregnancy outcomes among wives of male chemical workers who were highly exposed to chemicals contaminated with TCDD and among wives of nonexposed neighborhood referents. For exposed pregnancies, we estimated serum TCDD concentration at the time of conception using a pharmacokinetic model. The mean TCDD concentration for workers’ births was 254 pg/g lipid (range, 3–16,340 pg/g). The mean referent concentration of 6 pg/g was assigned to pregnancies fathered by workers before exposure. A total of 1,117 live singleton births of 217 referent wives and 176 worker wives were included. Only full-term births were included in the birth weight analysis (≥37 weeks of gestation). Mean birth weight among full-term babies was similar among referents’ babies (n = 604), preexposure workers’ babies (n = 221), and exposed workers’ babies (n = 292) (3,420, 3,347, and 3,442 g, respectively). Neither continuous nor categorical TCDD concentration had an effect on birth weight for term infants after adjustment for infant sex, mother’s education, parity, prenatal cigarette smoking, and gestation length. An analysis to estimate potential direct exposure of the wives during periods of workers’ exposure yielded a nonstatistically significant increase in infant birth weight of 130 g in the highest exposure group (TCDD concentration > 254 pg/g) compared with referents (p = 0.09). Mothers’ reports of preterm delivery showed a somewhat protective association with paternal TCDD (log) concentration (odds ratio = 0.8; 95% confidence interval, 0.6–1.1). We also include descriptive information on reported birth defects. Because the estimated TCDD concentrations in this population were much higher than in other studies, the results indicate that TCDD is unlikely to increase the risk of low birth weight or preterm delivery through a paternal mechanism.

Rat- and human-based risk estimates of lung cancer from occupational exposure to poorly-soluble particles: A quantitative evaluation

In risk assessment there is a need for quantitative evaluation of the capability of animal models to predict disease risks in humans. In this paper, we compare the rat- and human-based excess risk estimates for lung cancer from working lifetime exposures to inhaled poorly-soluble particles. The particles evaluated include those for which long-term dose-response data are available in both species, i.e., coal dust, carbon black, titanium dioxide, silica, and diesel exhaust particulate. The excess risk estimates derived from the rat data were generally lower than those derived from the human studies, and none of the rat- and human-based risk estimates were significantly different (all p-values>0.05). Residual uncertainty in whether the rat-based risk estimates would over- or under-predict the true excess risks of lung cancer from inhaled poorly-soluble particles in humans is due in part to the low power of the available human studies, limited particle size exposure data for humans, and ambiguity about the best animal models and extrapolation methods.

Incorporating uncertainty and variability in the assessment of occupational hazards

Uncertainty reflects ignorance associated with population traits (e.g. average exposure levels to a contaminant), with models used to predict risk (e.g. which statistical model is correct), and with a host of other considerations. Variability reflects an intrinsic property of a system (e.g. body mass indices possess a distribution across a population). The incorporation of uncertainty and variability in the assessment of occupational hazards is an important objective. General issues of uncertainty and variability in occupational risk estimation are discussed. This is followed by three illustrations where: firstly, the impact of variability in an exposure assessment and sampling variability in a regression model on risk estimates is considered; secondly, the impact of uncertainty in the size of a workforce on rate modelling is considered; and thirdly, the impact of using different models to predict risk is considered.

EVALUATION OF PARTICLE CLEARANCE AND RETENTION KINETICS IN THE LUNGS OF U.S. COAL MINERS

Rodent studies are frequently used to assess risk in humans, yet it is not known whether the overloading of lung clearance, as observed in rodents, occurs in humans, or whether overloading is related to particle-related lung diseases in humans. The objective of this study is to develop a biologically based mathematical model to describe the retention and clearance of respirable coal mine dust in the lungs of humans. A human dosimetric lung model was developed that includes alveolar, interstitial, and hilar lymph-node compartments. The model describes the particle mass transfer kinetics among these compartments and clearance via the tracheobronchi. The model was calibrated using data in U.S. coal miners, including individual working lifetime exposure histories and lung and lymph-node particle burdens. The model fit to the human data was evaluated using a least-squared error criterion. The end-of-life lung dust burdens of all coal miners in this study were substantially greater than expected from a simple, linear first-order model with effective clearance, yet their lung and lymph-node dust burdens were lower than expected from the rodent-based overload model, particularly at higher exposures. The best fitting model included a predominant first-order interstitial compartment, in which the particles are essentially sequestered (with very slow clearance to the lymph nodes), and a first-order alveolar clearance compartment with either no dose-dependent decline (overloading) or much less than expected from the rodent studies. These findings are consistent with the findings from magnetopneumography studies of clearance in retired miners and from studies of particle retention patterns in rodents and primates. This human dosimetric lung model is useful for evaluating the kinetic differences of particle retention in humans and rodents, and for evaluating the lung closes in humans given different exposure scenarios.