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PubMed1996

Nasal pathology and ultrastructure in patients with chronic airway inflammation (RADS and RUDS) following an irritant exposure.

BACKGROUND: Reactive airways dysfunction syndrome is a chronic asthma-like condition developing after an acute irritant exposure, and chronic inflammation has been seen on endobronchial biopsy. Reactive upper-airways dysfunction syndrome is chronic rhinitis developing in temporal association with a toxic inhalation exposure, but the pathophysiology is unknown. OBJECTIVES: To study biopsies of the nasal mucosa in patients with reactive upper-airways dysfunction syndrome and in some cases reactive airways dysfunction syndrome developing in temporal association with a chlorine dioxide exposure, to see if a histologic basis for the persistent rhinitis and sensitivity to chemical irritants could be determined. METHODS: Specimens were stained with hematoxylin-eosin and immunoperoxidase stains for substance P, vasointestinal peptide, and S-100 (nerve fibers), and fixed in glutaraldehyde for electron microscopy. Biopsies of three nonexposed subjects were performed for comparison. A pathologist blinded to clinical data interpreted the specimens. RESULTS: Inflammation ratings of exposed individuals were higher than for the nonexposed individuals. The number of nerve fibers stained was greater for patients vs controls. Substance P and vasointestinal peptide staining was nonspecific. Electron microscopy showed desquamation of the epithelium and permeability of epithelial cell junctions. CONCLUSION: This study suggests a mechanism by which ongoing low level exposures perpetuate airway inflammation after an inducing toxic inhalation. A possible overlap between reactive airways dysfunction syndrome, reactive upper-airway dysfunction syndrome and the multiple chemical sensitivity syndrome is suggested.

Adult↗
PubMed1994

The role of the intestinal tract in the elimination of carbon tetrachloride.

The target organ toxicity, mechanisms of toxicity, and metabolism of carbon tetrachloride (CCl4) have been studied extensively. However, there is a paucity of information concerning its elimination. Previous inhalation studies showed that a significant amount of 14C appeared in the feces of rats and monkeys exposed to 14CCl4. The nature of the compound(s) excreted in the feces has not been well characterized. Fecal excretion is a major route of elimination for many lipophilic compounds that are resistant to metabolism. A mechanism of excretion for these compounds is the direct exsorption from the blood to the lumen of the intestinal tract. The primary purpose of this study was to determine if fecal elimination contributes significantly to the elimination of CCl4. The secondary purpose was to determine the mechanism (biliary and/or nonbiliary, i.e., direct exsorption) of fecal elimination of CCl4 and/or its metabolite(s) in Sprague-Dawley rats. The results indicate that both biliary and nonbiliary mechanisms contribute to the fecal elimination of CCl4 following a single iv dose (1 mmol/kg), but this route accounts for less than 1% of the administered dose. The results also indicate that CCl4 is not eliminated unchanged in the feces following either acute treatment (iv or ip) or repeated inhalation exposures. Fecal elimination of CCl4 does not significantly contribute to the overall elimination of CCl4.

Administration, Inhalation↗
PubMed1994

Estimation of long-term exposure to pesticides.

Quantifying the exposure of agricultural workers to pesticides is difficult in the face of the heterogeneity of the pesticides used, the variability in methods of application, and the lack of adequate exposure data. This report describes an attempt to estimate long-term dermal and inhalation exposure of bulb farmers by the development of an exposure index. This proposed exposure index consists of generic levels of exposure specific to the method of application, which were derived from databases as well as from field studies. The index is further determined by farm-related parameters such as acreage and number of pesticide applications ascertained from questionnaire responses. A widely used dithiocarbamate mixture served as a marker compound for exposure to other pesticides. Ranking of 127 bulb farmers according to calculated lifetime dermal exposure correlated only moderately to ranking based on duration of exposure, e.g., years of exposure and farm acreage. This finding indicates that the proposed exposure index could provide a useful estimate of long-term exposure to a mixture of pesticides in epidemiological investigations.

Agricultural Workers' Diseases↗
PubMed1997

Time-resolved cutaneous absorption and permeation rates of methanol in human volunteers.

This paper reports on an experimental study of dermal exposure to neat methanol in human volunteers for the purposes of estimating percutaneous absorption rates, permeation kinetics, baseline (pre-exposure) levels of methanol in blood, and inter- and intrasubject variability. A total of 12 volunteers (seven men and five women) were exposed to methanol via one hand for durations of 0 to 16 min in a total of 65 sessions, making this the largest controlled study of percutaneous absorption for this common solvent. In each session, 14 blood samples were collected sequentially and analyzed for methanol. These data were used to derive absorption rates and delivery kinetics using a two compartment model that accounts for elimination and pre-exposure levels. The pre-exposure methanol concentration in blood was 1.7 +/- 0.9 mg 1(-1), and subjects had statistically different mean concentrations. The maximum methanol concentration in blood was reached 1.9 +/- 1.0 h after exposure. Delivery rates from skin into blood lagged exposure by 0.5 h, and methanol continued to enter the systemic circulation for 4 h following exposure. While in vitro studies have reported comparable lag times, the prolonged permeation or epidermal reservoir effect for such miscible solvents has not been previously measured. The mean derived absorption rate, 8.1 +/- 3.7 mg cm-2 h-1, is compatible with that found in the other in vivo study of methanol absorption. Both in vivo absorption rate estimates considerably exceed in vitro estimates. The maximum concentration of methanol in blood following an exposure to one hand lasting approximately 20 min is comparable to that reached following inhalational exposures at a methanol concentration of 200 ppm, the threshold limit value-time weighted average (TLV-TWA). While variability in blood concentrations and absorption rates approached a factor of two, differences between individuals were not statistically significant. The derived absorption and permeation rates provide information regarding kinetics and absorbed dose that can help to interpret biological monitoring data and confirm mathematical models of chemical permeation.

Adult↗
PubMed1990

Pathways of human exposure to arsenic in a community surrounding a copper smelter.

Several studies have found elevated levels of urinary arsenic among residents living near a copper smelter in Tacoma, Washington. To assess pathways of exposure to arsenic from the smelter, biological and environmental samples were collected longitudinally from 121 households up to 8 miles from the smelter. The concentration of inorganic and methylated arsenic compounds in spot urine samples was used as the primary measure of exposure to environmental arsenic. Urinary concentration of arsenic dropped off to a constant background level within one-half mile of the smelter in contrast to environmental concentrations, which decreased more steadily with increasing distance. Among all age-sex-specific groups in all areas, only children ages 0-6 living within one-half mile of the smelter had elevated levels of arsenic in urine. A separate analysis of data for these children suggests that hand-to-mouth activity was the primary source of exposure. Inhalation of ambient air and resuspension of contaminated soil were not important sources of exposure for children or adults.

Adolescent↗
PubMed1985

Lung response to particulates with emphasis on asbestos and other fibrous dusts.

Many theories have been proposed to explain asbestosis and asbestos-related pulmonary disease. However, none of the theories give a completely plausible explanation for the pathogenesis. Recently, attention has been drawn to a theory that the fibrogenicity or carcinogenicity of fibrous dust particles is related to fiber diameter and length rather than to chemical properties. This theory may help partially elucidate the disease process but is still far from solving the enigma of pulmonary fibrosis or carcinogenesis. The theory cannot explain the absence of these pathological effects among fiberglass workers or experimental animals exposed by inhalation (even though mesotheliomas are induced by intrapleural implantation and fiber dimension-related fibrogenicity is demonstrated by intratracheal injection). Little information regarding the pulmonary response to manmade fibrous particles is available in animals following inhalation exposure. Attempts should be made to confirm the absence of adverse effects using animal inhalation experiments even though to this point there is no conclusive evidence that either lung cancer or pulmonary diseases can be produced among employees in manmade fiber industries. A new research trend seems concentrated on testing the durability of asbestos or manmade fibers. This is based on the concept that biological effects of fibrous particles are the result of relative durability and that particles which can be fragmented or shortened may be less pathogenic. In the last two decades, considerable understanding about pulmonary fibrosis and carcinogenesis of asbestos has been achieved by clinical and animal experiments. In vitro tests including cytotoxicity, hemolysis, immunology, and enzyme biochemistry have provided important information on the interrelationships among these various biological effects of asbestos.

Animals↗
PubMed2002

[Characteristics of combined effect of thermal and welding aerosol exposure].

While studying a concurrent exposure to thermal loads and welding aerosols (WA) it has been ascertained that in inhalational exposure of the body to WA under conditions of simultaneous exposure of animals to a high temperature of the air environment the total pathogenic effect tends to be higher and higher. It is suggested that in a concomitant exposure to the above factors WA might lower bodily resistance to the thermal load. The above factors produce summation type harmful effects which have clearly a dose-dependent character. Studies on the occupational environment of workers engaged in welding involving heating suggested to us that it is those WA containing harmful substances of I and II hazard class that is the leading adverse factor of the working environment, and also thermal loads as high as 8000-9000 wt/m2. A concurrent exposure to the above factors lays a stress on the thermoregulatory function of the organism, and is resultant in the development of autoimmune processes and in premature aging of workers.

Aerosols↗
PubMed2002

Occupational health guidelines for remediation workers at Bacillus anthracis-contaminated sites--United States, 2001-2002.

Despite the apparently low disease rate from exposure, protection for remediation workers at B. anthracis-contaminated sites is warranted because inhalational anthrax is rapidly progressive and highly fatal, PPE does not guarantee 100% protection, and the risk for developing disease cannot be characterized adequately. The guidelines described here go beyond HAZWOPER requirements and include recommendations for treating inhalation exposure to B. anthracis spores as a medical emergency, medical follow-up as long as the risk for anthrax persists or a worker is receiving antibiotic prophylaxis, accommodation of a mobile workforce, and assurance that workers understand the need for immediate medical attention should symptoms of anthrax occur. Completion of the 6-dose series of anthrax vaccine followed by annual booster doses will decrease the reliance on antibiotics for the prevention of anthrax. Measures to protect workers must include both medical measures (i.e., vaccination, antibiotic prophylaxis, or a combination of both) and measures to prevent exposure (e.g., PPE and environmental controls).

Anthrax↗
PubMedDate not supplied

Neurobehavioral effects of subchronic exposure of weanling rats to toluene or hexane.

Using several behavioral and neurophysiologic tests, we examined the effects of subchronic inhalation exposure of rats to toluene and compared them with the effects of the known neurotoxicant hexane. The rats were exposed to toluene (900 and 1400 ppm) or hexane (2000 ppm) 14 hr/day, 7 days/week for 14 weeks. Both solvents inhibited weight gain. Hexane caused a neurotoxic syndrome characterized by reductions of grip strength (especially hindlimb), motor activity, and startle responses, and increased latencies of several evoked potential components. Initial acquisition of a conditioned avoidance response (CAR) was also impaired, but subsequent performance was intact. Toluene did not cause the peripheral motor symptoms associated with exposure to hexane. However, a component of the brainstem auditory-evoked response was depressed and CAR acquisition was impaired along with the acquisition of a tone-intensity discrimination task when tested within hours after the daily exposure ended.

Action Potentials↗
PubMed1997

Dosimetry, toxicity and carcinogenicity of inspired acetaldehyde in the rat.

Acetaldehyde is a ubiquitous air pollutant. It is an important industrial chemical and is also produced during the combustion of wood or tobacco. In smoky indoor atmospheres concentrations of the aldehyde may reach 100 ppb. Acetaldehyde is metabolized to acetate (releasing hydrogen ion) by aldehyde dehydrogenase a process which, in most tissues, represents a detoxification pathway. In vitro, acetaldehyde forms DNA-DNA and DNA-protein crosslinks. It is a clastogen, and inducer of sister chromatid exchanges, and is, perhaps, a weak mutagen. Inhalation exposure to 1000 ppm may induce DNA-protein crosslink formation in nasal tissues in the rat in vivo. Inhalation toxicity studies have shown acetaldehyde vapor causes chronic tissue injury and tumor formation in nasal tissues at exposure concentrations of 750 ppm or higher, with nasal olfactory mucosa being more sensitive than respiratory mucosa. Dosimetric estimates suggest that marked tissue injury and carcinogenicity occurs only at inspired concentrations which are sufficiently high to overwhelm nasal aldehyde dehydrogenase detoxification capacity. The induction of squamous cell carcinomas in the respiratory mucosa by acetaldehyde displays many analogies to the induction of squamous cell carcinomas by formaldehyde. For both vapors, non-linear concentration response relationships are observed for DNA-protein crosslink formation, tissue injury, and carcinogenicity, suggesting these responses are associated. For both vapors it is possible to document an exposure concentration that produces nasal respiratory epithelial injury without increasing tumor incidence, suggesting that for respiratory mucosa-derived tumors, exposure to non-cytotoxic concentrations may pose limited carcinogenic risk. In addition to squamous cell carcinomas of the respiratory epithelium, acetaldehyde exposure also results in nasal olfactory injury and tumors (adenocarcinomas) in the rat. The studies performed to date have not demonstrated a no observable effect level for these responses, therefore, the precise role of cytotoxicity and regenerative cell proliferation in the carcinogenic process in olfactory tissues can not be evaluated. Acetaldehyde metabolism via aldehyde dehydrogenase results in the formation of two hydrogen ions. The olfactory mucosa is quite sensitive to acid and dosimetric estimates suggest that the intracellular acid production rates that may occur in olfactory mucosa during acetaldehyde exposure may be sufficiently high to cause tissue damage. Such acid-induced tissue damage may enhance the genotoxic and tumorigenic potential of acetaldehyde in olfactory mucosa, and may, therefore, represent an important process in the production of tumors in this tissue.

Acetaldehyde↗
PubMed1997

Alveolar breath sampling and analysis to assess trihalomethane exposures during competitive swimming training.

Alveolar breath sampling was used to assess trihalomethane (THM) exposures encountered by collegiate swimmers during a typical 2-hr training period in an indoor natatorium. The breath samples were collected at regular intervals before, during, and for 3 hr after a moderately intense training workout. Integrated and grab whole-air samples were collected during the training period to help determine inhalation exposures, and pool water samples were collected to help assess dermal exposures. Resulting breath samples collected during the workout demonstrated a rapid uptake of two THMs (chloroform and bromodichloromethane), with chloroform concentrations exceeding the natatorium air levels within 8 min after the exposure began. Chloroform levels continued to rise steeply until they were more than two times the indoor levels, providing evidence that the dermal route of exposure was relatively rapid and ultimately more important than the inhalation route in this training scenario. Chloroform elimination after the exposure period was fitted to a three compartment model that allowed estimation of compartmental half-lives, resulting minimum bloodborne dose, and an approximation of the duration of elevated body burdens. We estimated the dermal exposure route to account for 80% of the blood chloroform concentration and the transdermal diffusion efficiency from the water to the blood to in excess of 2%. Bromodichloromethane elimination was fitted to a two compartment model which provided evidence of a small, but measurable, body burden of this THM resulting from vigorous swim training. These results suggest that trihalomethane exposures for competitive swimmers under prolonged, high-effort training are common and possibly higher than was previously thought and that the dermal exposure route is dominant. The exposures and potential risks associated with this common recreational activity should be more thoroughly investigated.

Adult↗
PubMed1978

Effects of short-term exposures to sulfuric acid and ammonium sulfate aerosols upon bronchial airway function in the donkey.

The effects of one-hour inhalation exposures to 0.3-0.6 micrometer H2SO4 and (NH4)2SO4 aerosols in the donkey were studied in terms of alterations in pulmonary flow resistance and dynamic compliance, and changes in the regional deposition and tracheobronchial mucocilliary clearance of an inert test aerosol. Short-term slowing of clearance followed certain single exposures to H2SO4 at 194-1364 microgram/m3 in three of four animals, while two of the four demonstrated a more persistent slowing of their clearance. These exposure levels produced no measurable change in resistance, compliance or regional deposition. Exposures to (NH4)SO4 up to approximately 2000 microgram/m3 had no mearurable effect upon resistance, compliance, regional deposition or mucociliary clearance.

Aerosols↗
PubMed1985

Acrylonitrile inhalation in rats: II. Excretion of thioethers and thiocyanate in urine.

In male Wistar rats, the inhalation exposure to acrylonitrile (AN), 271 mg X m-3, 8 hours a day, 5 days a week, did not affect protein sulfhydryl concentration in liver and blood and decreased glutathione concentration in the liver, but not in the brain at the end of the fifth exposure. The urinary excretion of the main AN metabolites, thioethers (AN-mercapturic acids) and thiocyanate was proportional to the inhaled AN concentration (57, 125, 271 mg X m-3, respectively) in a single exposure for 12 hours, and their mutual ratio was greatly different from that after injection of AN. The results revealed that the urinary excretion of thioethers is a very sensitive and dose-related indicator of exposure to AN and extrapolation of the results indicates that the exposure to AN concentration below 10 mg X m-3 could thus be demonstrated.

Acetylcysteine↗
PubMed1998

Chronic toxicity, oncogenicity, and mutagenicity studies with chlorotetrafluoroethane (HCFC-124).

The chronic toxicity, oncogenicity, and mutagenicity of chlorotetrafluoroethane (HCFC-124) were evaluated. In the chronic toxicity/oncogenicity study, male and female rats were exposed to 0, 2000, 10,000, or 50,000 ppm HCFC-124 for 6 hr/day, 5 days/week, for 2 years. Body weights were obtained weekly during the first three months of the study and every other week for the remainder of the study. Food consumption was determined weekly. Clinical signs of toxicity were monitored throughout the study. An ophthalmological examination was performed on all animals prior to study start, and all surviving rats were examined at approximately 3, 12, and 24 months after study start. Clinical pathology was evaluated at 3, 6, 12, 18, and 24 months. An interim termination was conducted at 12 months. All surviving rats were necropsied at 24 months. A complete set of tissues was collected for microscopic examination, and selected tissues were weighed. There were no compound-related, adverse effects on body weight, food consumption, survival, clinical signs of toxicity, ophthalmoscopically observable ocular lesions, serum hormone concentrations, or clinical pathology parameters at any exposure concentration in either male or female rats. Compared to controls, urine fluoride was increased in males and females at all exposure concentrations, and plasma fluoride was increased in females at all exposure concentrations. Excretion of fluoride represents conversion of the parent molecule, and as such is not considered to be an adverse effect. There were no toxicologically significant, compound-related organ weight changes or gross or microscopic findings in male or female rats at any of the exposure concentrations tested. HCFC-124 was not toxic or carcinogenic in rats of either sex after inhalation exposure at concentrations of up to 50,000 ppm in this two-year chronic toxicity/oncogenicity study. After exposure to HCFC-124 for six hours per day, five days per week, for 24 months, the no-observed-adverse-effect level for male and female rats was 50,000 ppm. HCFC-124 was not mutagenic in Salmonella typhimurium strains TA1535, TA97, TA98, and TA100 with and without activation when evaluated at concentrations up to 60% HCFC-124 for 48 hours. No evidence of clastogenic activity was observed in cultured human lymphocytes at atmospheric concentrations up to 100% HCFC-124 for 3 hours, with and without metabolic activation. In vivo, no micronuclei were induced in mouse bone marrow cells following exposure of mice to concentrations of 99,000 ppm HCFC-124 6 hours/day for 2 days.

Administration, Inhalation↗
PubMed1988

Toluene diisocyanate-induced airway hyperresponsiveness to intravenous acetylcholine: a study on single and repeated exposure in guinea-pigs.

We examined the changes in airway responsiveness to increasing doses of intravenous acetylcholine (ACh), in groups of 10 anaesthetized and tracheotomized spontaneously breathing guinea-pigs, 20 h after inhalation exposure to toluene diisocyanate (TDI). TDI exposure consisted of a single 4-h exposure to 1.2 ppm, intermittent exposures to 1.078 and 0.126 ppm for 4 h daily for 2 consecutive days, and continuous exposures to 0.118 ppm for 48 h or to 0.045 and 0.023 ppm for 1 week. Airway resistance (Raw) of the corresponding control groups, which inhaled clean filtered air, was used as baseline, and was similar for air and TDI groups. All the patterns of exposure, except exposure to 0.126 ppm TDI for 4 h daily for 2 consecutive days, significantly reduced by 28-60% the dose of ACh calculated to cause a 200% increase in Raw (ED200). The results indicate that TDI-induced airway hyperresponsiveness to ACh in guinea-pigs can occur at a level of exposure as low as 0.023 ppm for 1 week, and is consistent with the hypothesis of a cumulative effect.

Acetylcholine↗
PubMed1997

Oils and cancer.

Epidemiologic evidence on the relationship between mineral oil exposure and cancer is reviewed. The review is restricted to occupations involving substantial dermal and inhalational exposure and for which an epidemiologic literature exists: metal machining, print press operating, and cotton and jute spinning. Mineral oils are complex mixtures of aliphatic hydrocarbons, naphthenics, and aromatics, the relative distribution of which depends on the source of the oil and the method of refinement. End-use products contain a variety of additives, and contamination by other agents generally occurs during use. Suspect agents include polycyclic aromatic hydrocarbons (PAH) (particularly benz[a]pyrene), nitrosamines, chlorinated paraffins, long-chain aliphatics, sulfur, N-phenyl-2-naphthylamine, and formaldehyde. The heterogeneity of this exposure makes epidemiologic study difficult and meta-analysis inappropriate. Nonetheless, several associations emerge from the literature with varying degrees of support. There is clear evidence that early formulations of mineral oils used in cotton and jute spinning and in metal machining were carcinogenic to the skin. Associations of mineral oil exposure with laryngeal and rectal cancer have received some support in the literature, particularly with respect to straight oils. Evidence is suggestive that grinding operations (which can entail either mineral oil-based or ethanolamine-based fluids) are associated with excess risk of cancer of the esophagus, stomach, and pancreas. A number of bladder cancer case-control studies have noted an association with work as a machinist. There is limited evidence of an association with cancer of the colon, prostate, and sinonasal region. Several studies of printers have yielded positive findings for lung cancer, whereas studies in metal machinists have been generally negative. The PAH and nitrosamine content of current formulations is lower than in the past and the implications of these changes in composition to the carcinogenicity of the formulations are not yet known.

2-Naphthylamine↗
PubMed1996

A mathematical model of bronchial absorption of vapors in the human lung and its significance in pharmacokinetic modeling.

This work formulates a model description of moderately soluble gas and vapor uptake in the bronchial region of the lung during initial inhalation exposure. The mass transport problem is solved using an iterative-analytical approach in which inhaled chemical is partitioned to alveolar blood-gas exchange, bronchial wall absorption, and exhalation. Results of 109 simulations allowed regression analysis to provide simple algebraic equations to describe the fraction of total inhaled mass taken up by the two alternative absorption pathways. These fractions are dependent on the chemical's solubility and liquid diffusivity. The derived relationships are then used in a modified physiologically based pharmacokinetic (PBPK) model which accounts for bronchial uptake. The results are compared to identical results from a traditional (unmodified) PBPK model to draw conclusions concerning the effect of bronchial uptake on systemic chemical distribution in addition to elevated bronchial tissue concentrations.

Absorption↗
PubMedDate not supplied

Acute intravenous and inhalation pharmacokinetics of 2,4-pentanedione in the Fischer 344 rat.

2,4-Pentanedione (2,4-PD; CAS No. 123-54-6), an industrial chemical, was investigated for its comparative pharmacokinetics in male Fischer 344 rats by a single intravenous (i.v.) injection of (4.3, 43, 148.5, and 430 mg/kg), or a 6-hr nose-only inhalation exposure (400 ppm) to 14C-2,4-PD. For the i.v. route, the plasma concentration of 14C-2,4-PD-derived radioactivity declined in a biexponential fashion. The overall form of the 14C plasma concentration-time curves and derived pharmacokinetic parameters indicated that dose-linear kinetics occurred in the i.v. dose range 4.3-148.5 mg/kg, but not with 430 mg/kg. Metabolism of 2,4-PD was quite rapid as the concentration of unmetabolized 2,4-PD declined steadily to undetectable after 8 hr. 14C-2,4-PD derived radioactivity was eliminated mainly as 14CO2 and in urine. For the 4.3, 43 and 148.5 mg/kg doses 14CO2 elimination was relatively constant (36.8, 38.8 and 42.3% in 48 hr samples respectively) and greater than urinary excretion (17.9, 14.3 and 29.6%; 48 hr specimens). At 430 mg/kg i.v. there was a reversal of the excretion pattern, with urine 14C excretion (54.7%) becoming greater than that for 14CO2 (27.3%). Excretion in expired volatiles and feces was small. Radiochromatograms of urine showed free 2,4-PD in the 12 hr sample, together with 7 other metabolites. Free 2,4-PD and 6 of the metabolites decreased or were not detectable in a 24 or 48 hr urine sample, but one peak (retention 7.9 min) increased progressively to become the major fraction (97%). Nose-only exposure to 400 ppm 14C-2, 4-PD produced a mean decrease in breathing rate of 20.1%, which was constant and sustained throughout exposure, due to a lengthening of the expiratory phase of the respiratory cycle. 14C-2,4-PD was rapidly absorbed during the first 3 hr of exposure, then began to plateau, but did not reach a steady state. Postexposure elimination of 14C from plasma followed a biexponential form with a t1/2 for the terminal disposition phase of 30.72 hr. Plasma unmetabolized 2,4-PD was present throughout the whole of the exposure phase, but was significantly less than total 14C. Postexposure, plasma unmetabolized 2,4-PD declined rapidly to undetectable concentrations by 12 hr. Radiolabel excretion was approximately equivalent in urine (37.6%) and expired 14CO2 (36.3%). Urine radiochromatograms showed a minor 2,4-PD contaminant (0.6-5.9% over 48 hr), along with 7 other peaks probably representing metabolites. As with the 148.5 mg/kg i.v. dose, the major metabolite peak was at 7.8 min retention, increasing from 41.1% (12 hr) to 62.8% (48 hr). Immediately postexposure, radioactivity was present in all tissues examined, but on a concentration basis (microgram equiv/g) there was no preferential accumulation of 14C in any tissue or organ. On a total organ basis, highest contents were in liver and kidney, presumably related to the metabolism and excretion of 2,4-PD. By 48 hr postexposure, concentrations had decreased in all tissues except fat, presumably due to the lipophilicity of 14C residues. The profile of the plasma-time radioactivity curves, and the presence of residual radioactivity in tissues at 48 hr postexposure, suggests that a cumulative process could occur with frequent repeated exposures.

Administration, Inhalation↗