Comparison of contact site cancer potency across dose routes: case study with epichlorohydrin.

Risk assessment for airborne carcinogens is often limited by a lack of inhalation bioassay data. While extrapolation from oral-based cancer potency factors may be possible for some agents, this is not considered feasible for contact site carcinogens. The change in contact sites (oral: g.i. tract; inhalation: respiratory tract) when switching dose routes leads to possible differences in tissue sensitivity as well as chemical delivery. This research evaluates the feasibility to extrapolate across dose routes for a contact site carcinogen through a case study with epichlorohydrin (EPI). EPI cancer potency at contact sites is compared across three bioassays involving different dose routes (gavage, drinking water, inhalation) through the use of dosimetry models to adjust for EPI delivery to contact sites. Results indicate a large disparity (two orders of magnitude) in potency across the three routes of administration when expressed as the externally applied dose. However, when expressed as peak delivered dose, inhalation and oral potency estimates are similar and overall, the three potency estimates are within a factor of seven. The results suggest that contact site response to EPI is more dependent upon the rate than the route of delivery, with peak concentration the best way to extrapolate across dose routes. These results cannot be projected to other carcinogens without further study.

Risk assessment of oxidant gases and particulate air pollutants: uncertainties and research needs.

The assessment of risks to human health associated with exposure to oxidant air pollutants has not received adequate attention despite the recognized public health threat posed by the ubiquitous presence of these compounds in the environment. In this article, research needs and uncertainties at each of the steps in the risk assessment of oxidant air pollutants are identified: hazard identification, dose-response assessment, exposure assessment, and risk characterization. Many of these limitations and uncertainties arise at the interface between the laboratory and the regulatory arenas. Therefore, as a case study, relevant methodologic problems associated with the application of experimental findings to the risk assessment of respirable dusts are also discussed. These issues include the extrapolation of animal data to the human case and extrapolation from high-dose to environmentally relevant, low-level exposures.

Quantitative assessment of cancer risk from exposure to diesel engine emissions.

Quantitative estimates of lung cancer risk from exposure to diesel engine emissions were developed using data from three chronic bioassays with Fischer 344 rats. Human target organ dose was estimated with the aid of a comprehensive dosimetry model. This model accounted for rat-human differences in deposition efficiency, normal particle clearance rates, transport of particles to lung-associated lymph nodes, respiration rates, and lung surface area, as well as high-dose inhibition of particle clearance. Recent evidence indicates that the inert carbon core of the diesel particulate matter is likely to be the primary source of carcinogenicity. The epithelial tissue lining the alveoli and lower airways is the primary target site for induction of lung tumors. Dose was therefore based upon the concentration of carbon particulate matter per unit lung surface area. Unit risk estimates were developed using either a time-to-tumor or a linearized multistage model. The unit risk estimates, defined as the 95% upper confidence limit of the cancer risk from continuous lifetime exposure to 1 microgram/m3 of diesel exhaust particulate matter, varied from 1.0 to 4.6 x 10(5) with a geometric mean of 1.7 x 10(5).

Effect of exposure route on potency of carcinogens.

To compare the effectiveness of different exposure routes for the induction of cancer in experimental animals, the estimated dose associated with a 25% additional risk of cancer (RRD(25)) was calculated using a group of carcinogenic agents for which both inhalation and oral ingestion cancer bioassays were available. Comparisons were made of 14 agents in rats and 9 in mice. Seven of the nine compared in mice were also compared in rats. Among rats, 8 of 14 agents were more effective via the oral route, while 7 of 9 were more effective via the oral route in mice. The variation in RRD(25) values with route, however, was less than 10-fold for all the agents tested in mice and for 11 of 14 tested in rats. An overall difference in potency with route could not be detected statistically. In rats, differences in potency greater than 10-fold were found for asbestos, vinyl chloride, and hydrazine. In the case of asbestos, the agent was in the form of relatively insoluble particulate matter. The greater potency via inhalation is likely due to longer residence time of the particles in the deep lung than in the gut, allowing for a greater degree of particle dissolution with an accompanying increase in bioavailability. Vinyl chloride was generally tested by inhalation at doses high enough to saturate activation pathways, resulting in underestimates of low-dose potency. Many of the smaller potency differences with route, as well as those for hydrazine, were considered likely to be the result of variability in the design and/or quality of studies. It was concluded that, if the design and conduct of the experiments were adequate, if agents in the form of relatively insoluble particulate matter are eliminated, and if corrections are made to account for incomplete activation, then large errors during route extrapolation are unlikely to occur.

Feasibility of dose adjustment based on differences in long-term clearance rates of inhaled particulate matter in humans and laboratory animals.

Long-term pulmonary clearance rates were evaluated for several laboratory animal species, dogs, and humans to determine if differences among species exist, and if so, the adequacy of the data for dose adjustment. Within each species, large variations in clearance rates were seen, probably as a result of differences in solubility of the aerosol particles, differences in measurement techniques, possible lung damage, transport to lung-associated lymph nodes, and binding of dissolved chemicals to cellular macromolecules in the lung. While few direct comparisons among species using the same aerosol were available, mechanical clearance of particles from the alveolar regions of dogs and humans was generally slower than in most laboratory species, with t1/2 values several-fold longer. Particle clearance rate variations of this magnitude were shown to induce potentially large differences in bioavailability. This can result in large errors in assessing human risk from animal studies unless a dose adjustment is made. It is suggested that despite limitations on available data, a two- to threefold adjustment of dose when extrapolating from small laboratory animals to humans, for quantitative risk assessment, should be considered, unless solubility half-times are very short.

Methods for route-to-route extrapolation of dose.

Results of acute toxicity studies for a variety of chemicals have indicated that, in most cases, although the inhalation route was more effective than the IG route, wide variations in toxicity occurred between these two routes. The major factors that may result in variations in toxicity between routes include: differences in absorption efficiency; differences in systemic effects; occurrence of critical toxicological effects at the portal of entry; first-pass effects resulting in inactivation or activation of the chemical agent before it reaches the target organ; and variations in temporal patterns of target organ concentrations. Extrapolation to determine safe exposure levels during chronic exposure becomes less reliable, not only as information relating to these factors decreases, but also as the quality or length of exposure decreases in the available toxicologic studies. VDC is an example of one of a few chemicals for which both chronic inhalation and oral toxicity data are available, along with detailed pharmacokinetic information. On the basis of the pharmacokinetic data, differences in toxicity between the two routes did not appear to be very likely for this chemical. This conjecture was supported by the results of chronic toxicity studies. Finally, assuming sufficient data and pharmacokinetic parameters are available, this paper presents a useful and practical approach to route extrapolation.

Pulmonary function responses in cats following long-term exposure to diesel exhaust.

Long-term inhalation studies were carried out to evaluate the toxic pulmonary effects of diesel engine emissions. Cats were exposed for over 2 years to whole, diluted diesel exhaust at levels expected to produce frank toxic effects. During the first 61 weeks of exposure, the cats received exhaust having a particulate level of 6 mg m-3. This was followed by a doubling of the exposure level from weeks 62 to 124 resulting in particulate levels of 12 mg m-3. No definitive pattern of pulmonary function response was observed following 61 weeks; however, a classic pattern of restrictive lung disease was found at 124 weeks. The significantly reduced lung volumes and diffusing capacity were indicative of a pulmonary interstitial response which was later verified by histopathology.

Peribronchiolar fibrosis in lungs of cats chronically exposed to diesel exhaust.

This study reports the quantitative changes in the pulmonary proximal acinar region following chronic exposure to diesel exhaust and following an additional 6 months in clean air. Cats (13 months of age) from a minimum disease colony were exposed to clean air (eight cats for 27 months and nine cats for 33 months), diesel exhaust for 8 hours/day, 7 days/week (nine cats for 27 months), or diesel exhaust for 27 months followed by 6 months in clean air (10 cats). Morphologic and morphometric evaluation using light microscopy and scanning and transmission electron microscopy revealed two major exposure-related lesions in proximal acinar regions of lungs of cats: peribronchiolar fibrosis associated with significant increases in lymphocytes, fibroblasts, and interstitial macrophages containing diesel particulate-like inclusions and bronchiolar epithelial metaplasia associated with the presence of ciliated and basal cells and alveolar macrophages containing diesel particulate-like inclusions. Peribronchiolar fibrosis was greater at the end of the 6 months in clean air following exposure, whereas the bronchiolar epithelial metaplasia was most severe at the end of exposure. Following an additional 6 months in clean air the epithelium more closely resembled the control epithelial cell population. The labeling index of terminal bronchiolar epithelium was significantly increased at the end of exposure but was not significantly different from controls or exposed cats following an additional 6 months in clean air. The ultrastructural appearance of epithelial cells remained relatively unchanged following diesel exhaust exposure with the exception of diesel particulate-like inclusions. Total lung collagen, expressed as hydroxyproline per left caudal lobe, was apparently increased (although the difference was not significant) in lungs of cats allowed to recover 6 months in clean air. Newly synthesized collagen (evaluated as the amount of cross-link-derived aldehydes in collagen) was significantly increased to more than twice the control values. The ratio of collagen aldehydes to hydroxyproline was also significantly increased. These observations imply that chronic exposure to diesel exhaust has a persistent fibrogenic effect on the proximal acinar region of the lung.

Pulmonary function and pathology in cats exposed 28 days to diesel exhaust.

Young adult male cats were exposed 28 days, 20 hrs per day, to a 1:14 dilution of diesel exhaust emissions. Following termination of exposure, the following pulmonary function measurements were carried out: lung volumes, maximum expiratory flow rates (MEF), MEF at 50%, 25% and 10% of vital capacity (VC): forced expiratory volume (FEV) after 0.2, 0.3 and 0.4 sec, dynamic compliance, resistance and helium washout at 25, 50, 75, and 100 breaths per min. The only significant functional change was a decrease in MEF at 10% of VC (P x .02). The lungs of the exposed cats appeared charcoal grey with frequent focal black spots visible on the pleural surface. Pathologic changes in the exposed cats included a predominantly peribronchiolar localization of black-pigmented macrophages within the alveoli producing a focal pneumonitis or alveolitis. In general, evidence of serious lung damage was not observed following the 28-day exposure period.

Arterial blood gases, pulmonary function and pathology in rats exposed to 0.75 or 1.0 ppm ozone.

Arterial blood gases, residual lung volume (RV), deflation pressure volume (PV) curves, pulmonary pathology and body weight changes were studied in rats exposed up to 14 days to either 0.75 or 1.0 ppm ozone. Arterial PO2 and body weights decreased progressively with length of exposure while PaCO2 and RV increased. The slope of the PV curve decreased in all groups exposed to ozone. Pathological changes in the lung increased in severity with concentration and length of exposure. The present findings have shown that arterial blood gas measurements represent a sensitive index of altered lung function in rats, a species very sensitive to ozone exposure.

Arterial blood gases in conscious rats exposed to hypoxia, hypercapnia, or both.

Adult male rats were anesthetized and catheters were implanted in the caudal artery. Soon after recovery from short-lasting anesthesia, a total of 20 groups of six each were individually exposed to five different oxygen levels varying from 21.0 to 9.0% combined with four CO2 levels ranging from 0 to 12.9% at a mean barometric pressure of 744 Torr. Arterial blood samples were collected and analyzed for pH, Po2, and Pco2 before and near the end of 20-min exposures. During an air-breathing control period, pH averaged 7.466 plus or minus 0.020 SD, Paco2 41.2 plus or minus 1.9 Torr and Pao2 91.8 plus or minus 3.5 Torr. During hypoxia, Pao2 levels were similar to that of acutely hypoxic humans. Rats apparently differ from man in that blood buffering is greater, resulting in a higher pH during air breathing and a smaller [H-+] increase with increasing Paco2. Differences between arterial and inspired CO2 were about 10 Torr at 60 and 90 Torr Plco2 and were not influenced by Plo2.

Tissue oxygenation and splenic erythropoiesis during chronic hypoxia and hypercapnia.

Tissue (gas pocket) oxygen levels and erythropoietic activity were monitored in groups of rats chronically exposed to hypoxia (70 Torr PIO2), hypercapnia (60 Torr PICO2), or a combination of the two conditions. Arterial gas tensions and pH were also measured. Overall condition of the animals was assessed by comparison of growth rates with pair-fed controls. Hypoxic-hypercapnic pocket PO2 values (24-40 Torr) were similar to normoxic-normocapnic values (28-37 Torr), but greater than in hypoxia-normocapnia, and less than in normoxia-hypercapnia. Erythropoietic activity during hypoxia-hypercapnia ceased and the rats had a growth rate significantly below that of other groups. While chronic CO2 does increase tissue (pocket) oxygenation to near normal levels, probably due to increased ventilation and subsequently PaO2, the hypoxic-hypercapnic rats evidenced greater detrimental effects than did rats in hypoxic or hypercapnic environments.