Jeffery M. Gearhart

Lactational Transfer of Volatile Chemicals in Breast Milk

Lactational transfer of chemicals to nursing infants is a concern for occupational physicians when women who are breast-feeding return to the workplace. Some work environments, such as paint shops, have atmospheric contamination from volatile organic chemicals (VOCs). Very little is known about the extent of exposure a nursing infant may receive from the mothers occupational exposure. A physiologically based pharmacokinetic model was developed for a lactating woman to estimate the amount of chemical that a nursing infant ingests for a given nursing schedule and maternal occupational exposure. Human blood/air and milk/air partition coefficients (PCs) were determined for 19 VOCs. Milk/blood PC values were above 3 for carbon tetrachloride, methylchloroform, perchloroethylene, and 1,4-dioxane, while the remaining 16 chemicals had milk/blood PC values of less than 3. Other model parameters, such as solid tissue PC values, metabolic rate constants, blood flow rates, and tissue volumes were taken from the literature and incorporated into the lactation model. In a simulated exposure of a lactating woman to a threshold limit value concentration of an individual chemical, only perchloroethylene, bromochloroethane, and 1,4-dioxane exceeded the U.S. Environmental Protection Agency non-cancer drinking water ingestion rates for children. Very little data exists on the pharmacokinetics of lactational transfer of volatile organics. More data are needed before the significance of the nursing exposure pathway can be adequately ascertained. Physiologically based pharmacokinetic models can play an important role in assessing lactational transfer of chemicals.

Sulfuric Acid-Induced Airway Hyperresponsiveness

Rabbits were exposed to submicrometer sulfuric acid (H2SO4) mist at 250 micrograms/m3 for 1 hr/day, 5 days/week for 4, 8, or 12 months in order to examine the effects on bronchial responsiveness, which was assessed at the end of each exposure series by administration (iv) of doubling doses of acetylcholine and measurement of pulmonary resistance (RL). Dynamic compliance (Cdyn) and respiratory rate (f) were also measured following agonist challenge. Animals exposed for 4 months showed increased sensitivity to acetylcholine (dose required to produce a 150% increase in RL), and there was an increase in reactivity (slope of dose vs change in RL) by 8 months, with a leveling off of the response after this time. No changes in Cdyn or f were noted at any time. Thus, repeated exposures to H2SO4 resulted in the production of hyperresponsive airways in previously healthy animals. This has implications for the role of nonspecific irritants in the pathogenesis of airway disease.

Respiratory and metabolic response of rats and mice to formalin vapor

The irritant effect of repeated inhalation exposure to vapors of aqueous formalin (formaldehyde concentration, 15 ppm) in male Charles River CD rats and male C57BL6/F1 mice was determined. The data suggest that rats are relatively insensitive to this irritant while mice are substantially more sensitive, the latter showing a comparable reduction in tidal volume, but a greater decrease in respiratory rate and, as a consequence, minute volume. CO2 production, a reflection of total metabolism, as well as body temperature, were decreased to a greater extent in mice than in rats. The decreased minute ventilation and associated decrease in temperature, responses occurring to a greater extent in the mouse, may decrease both the net formaldehyde dose as well as the toxic actions of formaldehyde that are dependent on systemic metabolic activity.

Evidence for Competitive Inhibition of Iodide Uptake by Perchlorate and Translocation of Perchlorate into the Thyroid

Various published data sets that investigate the potential effect of exogenous perchlorate ( ClO 4 − ) on the uptake of iodide in the thyroid and subsequent changes in thyroid hormone levels are available. In order to best use the data towards the prediction of human health effects resulting from ClO 4 − exposure, the available literature data must be integrated into a self-consistent, coherent, and parsimonious quantitative model based on the most likely mode of action of perchlorate effect on thyroid function. We submit that the simplest mode of action for ClO 4 − in the thyroid that remains consistent with all available data involves competitive inhibition of iodide transport into the thyroid follicle, transport of perchlorate into the thyroid follicle against a concentration gradient, further transport into the thyroid lumen (where it may again interfere with iodide transport), and, finally, passive diffusion back into the blood. We believe this description of perchlorate’s kinetic behavior should serve as the foundation for predictive physiologically based pharmacokinetic (PBPK) models and as a working hypothesis for further experimental exploration.

Response of the tracheobronchial mucociliary clearance system to repeated irritant exposure: effect of sulfuric acid mist on function and structure.

This study was designed to determine quantitative and temporal alterations in tracheobronchial mucociliary clearance function and structure due to repeated inhalation exposures to a common irritant, sulfuric acid mist. Rabbits were exposed to 250 micrograms/m3 sulfuric acid (0.3 micron) for 1 h/day, 5 days/week, for up to 1 year, with some animals allowed a 3-month recovery period following the end of the acid exposures. Control animals received temperature- and humidity-conditioned water vapor. At intervals of 2 to 4 weeks, animals inhaled a radioactively tagged tracer aerosol (ferric oxide microspheres, 4.5 micron), and its clearance via mucociliary transport from the thorax was monitored by external serial counting. Clearance became slower during the first month of acid exposure, and this slowing became progressive with time through the end of the 12-month exposure period. After cessation of acid exposure, clearance became extremely slow and did not return to normal by the end of the follow-up period. To assess specific histological changes in the tracheobronchial tree, groups of rabbits were killed after 4, 8, or 12 months of exposure and after the follow-up period. Tissue samples from each lung were embedded in plastic, sectioned at 3 micron, and stained with hematoxylin and eosin or alcian blue/periodic acid-Schiff (AB/PAS). Acid exposure changed the airway diameter distribution compared to the control; except for the follow-up group, all acid-exposed animals had a shift to smaller airways. Acid inhalation also caused an increase in epithelial secretory cell density and a shift from PAS to AB staining of glycoprotein within secretory cells, both of which were unresolved by 3 months after the exposures ceased. No evidence of inflammation was found in any of the animals. Thus, repeated exposures to H2SO4 resulted in a slowing of mucociliary clearance that was associated with alterations in airway morphometry and morphology. Such changes may be involved in the early pathogenesis of chronic airway disease.

INVESTIGATION OF THE POTENTIAL IMPACT OF BENCHMARK DOSE AND PHARMACOKINETIC MODELING IN NONCANCER RISK ASSESSMENT

There has been relatively little attention given to incorporating knowledge of mode of action or of dosimetry of active toxic chemical to target tissue sites in the calculation of noncancer exposure guidelines. One exception is the focus in the revised reference concentration (RfC) process on delivered dose adjustments for inhaled materials. The studies reported here attempt to continue in the spirit of the new RfC guidelines by incorporating both mechanistic and delivered dose information using a physiologically based pharmacokinetic (PBPK) model, along with quantitative dose-response information using the benchmark dose (BMD) method, into the noncancer risk assessment paradigm. Two examples of the use of PBPK and BMD techniques in noncancer risk assessment are described: methylene chloride, and trichloroethylene. Minimal risk levels (MRLs) based on PBPK analysis of these chemicals were generally similar to those based on the traditional process, but individual MRLs ranged from roughly 10-fold higher to more than 10-fold lower than existing MRLs that were not based on PBPK modeling. Only two MRLs were based on critical studies that presented adequate data for BMD modeling, and in these two cases the BMD models were unable to provide an acceptable fit to the overall dose-response of the data, even using pharmacokinetic dose metrics. A review of 10 additional chemicals indicated that data reporting in the toxicological literature is often inadequate to support BMD modeling. Three general observations regarding the use of PBPK and BMD modeling in noncancer risk assessment were noted. First, a full PBPK model may not be necessary to support a more accurate risk assessment; often only a simple pharmacokinetic description, or an understanding of basic pharmacokinetic principles, is needed. Second, pharmacokinetic and mode of action considerations are a crucial factor in conducting noncancer risk assessments that involve animal-to-human extrapolation. Third, to support the application of BMD modeling in noncancer risk assessment, reporting of toxicity results in the toxicological literature should include both means and standard deviations for each dose group in the case of quantitative endpoints, such as relative organ weights or testing scores, and should report the number of animals affected in the case of qualitative endpoints.

Basis for a particle size-selective TLV for sulfuric acid aerosols

Abstract The occupational exposure limit for sulfuric acid (H2SO4) aerosol in the U.S. and elsewhere is 1 mg/m3, with no restrictions as to droplet size. A review of the literature shows that there are two different responses to inhaled H2SO4 which need to be considered in the selection of a Threshold Limit Value (TLV) or other occupational exposure limit. One is a reflex bronchoconstriction caused by the deposition of droplets in the larger lung airways. This bronchoconstriction is of greater magnitude and may cause concern in persons with asthma. The other is the development and progression of chronic bronchitis caused by repeated daily exposures to droplets depositing in the central and more distal conductive airways of the lung. Since the target region for both effects is the tracheobronchial tree, a particle size-selective TLV (PSS-TLV) should be expressed in terms of thoracic particulate mass (TPM). Based upon the literature review, the mass concentration limit for H2SO4 TPM should be much lower tha...

Early alveolar clearance in rabbits intermittently exposed to sulfuric acid mist

During the course of 1-h/d, 5-d/wk exposure to submicrometer sulfuric acid mist at 250 micrograms/m3, rabbits were exposed to a radioactively tagged polystyrene latex tracer aerosol to assess clearance from the alveolar region during the period 2-14 d after tracer exposure. The latex was administered on d 1, 57, and 240 following the start of the H2SO4 exposures. Early alveolar clearance was found to be accelerated during the first test, and this acceleration was maintained throughout the 8-mo monitoring period.

Intermittent exposures to mixed atmospheres of nitrogen dioxide and sulfuric acid: Effect on particle clearance from the respiratory region of rabbit lungs

Nitrogen dioxide (NO2) and sulfuric acid (H2SO4) are important constituents of the gas-particle complex in ambient air. The purpose of this study was to examine the effects of combined exposures upon the clearance of insoluble tracer particles from the respiratory region of the lungs. Rabbits were the animal model, and were exposed for 2 h/day for 14 days to either 0.3 ppm NO2, 1 ppm NO2, or 500 microgram/m3 H2SO4 alone, or to mixtures of the low and high NO2 concentrations with acid. Inhaled singly, both concentrations of NO2 accelerated clearance while H2SO4 retarded it, compared to control. Exposure to the combination of 0.3 ppm NO2 plus H2SO4 resulted in a response which was not different from that due to the acid alone. However, exposure to 1 ppm NO2 plus H2SO4 resulted in a clearance pattern which differed from that of both NO2 and H2SO4, but was more similar to that of the latter.

A Variable Feed Rate Mechanism for Fluidized Bed Asbestos Generators

A simple and inexpensive dust feed mechanism has been designed for use with a two-phase fluidized bed generator (FBG). The mechanism is especially useful for generating asbestos aerosols, but may be used with other dusts as well. Using this system, a steady state concentration (39.1 fibers/cc greater than 5 microns in length +/- 6.2%) of asbestos aerosol was maintained in an inhalation chamber for five hours. In addition, FBG output concentration was easily adjusted and quickly equilibrated (within 10 minutes). The system provides a good technique for generating asbestos aerosols for day-long animal exposures.