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The received dose, tissue distribution, metabolism, routes and rates of excretion of [(14)C]-4, 4(')-methylenediphenyl diisocyanate (MDI) were investigated in the male rat following a 6-h inhalation exposure to [(14)C]-MDI at a target concentration of 2 mg m(-3). The mean dose received was equivalent to 0.078 mg MDI per animal, of this between 25 and 32% of radiolabelled material was available systemically. Radioactivity was distributed to all tissues examined with the highest proportions present in the respiratory and gastrointestinal tracts, suggesting that both oral ingestion and pulmonary absorption contributed to the systemic dose of [(14)C]-MDI derived material, with the oral ingestion and the majority of the internal dose resulting from ingestion of radiolabelled material by grooming the pelt after exposure. Radioactivity was excreted mainly via faeces (about 80% of the received dose). Excretion in bile and urine each accounted for less than 15% of the dose. MDI was extensively metabolized after uptake, with two routes of transformation evident; the proposed spontaneous formation of mixed molecular weight polyureas and the enzyme catalysed metabolism of systemically available MDI or MDI derivatives to give N-acetylated and N-acetylated hydroxylated products. No free MDA was detected in any of the biomatrices (urine, faeces, bile) investigated.

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Polymeric diphenylmethane di-isocyanate (PMDI) is a precursor or an intermediate in the manufacture of pure MDI and is used in many industrial applications. Potential health effects of diisocyanates are generally considered to include irritation and respiratory sensitization, dictating the need for low occupational hygiene standards and robust hygiene monitoring methods. A wide range of methods has been developed or adopted for this purpose but questions concerning their ability to accurately sample MDI aerosols in the occupational environment have often been raised. In order to provide such information, studies have been conducted to compare several MDI sampling systems: the Institute of Occupational Medicine (IOM) 25-mm open-faced inhalable dust sampler; the 13-mm Millipore Swinnex Cassette sampler; the 37-mm open-face Millipore cassette; the midget-impinger, the glass tube containing glass wool, and two direct reading paper tape monitors. The program was comprised of two phases, the first being a preliminary comparison of the collection efficiencies of the IOM, 13 mm and midget-impinger at a range of orientations to air flow, aerosol particle sizes, and sampling flow rates, using inert polyethylene glycol aerosols. The second phase compared all samplers operating according to each manufacturer's recommendations and sampling PMDI aerosols at a range of particle sizes and concentrations. All studies were conducted in a wind tunnel. All filter methods performed well in atmospheres containing small particles except impingers that required a filter backup. In general, the variability of all the samplers was high for larger particle size ranges. Direct reading monitors showed low efficiencies.

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An investigation of the time course of development and recovery of the nasal lesion induced in rats by inhalation of methyl methacrylate (MMA) was conducted. Groups of 45 female F344 rats (five animals per time point) were exposed whole body for 6 hours per day to 0 (control), 110 or 400 ppm MMA for 1, 2, 5, 10 or 28 consecutive days. Additional animals were retained for a period of 4, 13, 24 or 36 weeks following exposure to assess reversibility of any nasal tissue effects. After inhalation of MMA there was damage to the olfactory epithelium at 110 and 400 ppm. This was apparent following the first day of exposure, but recovery/regeneration was evident during the subsequent days of the exposure phase of the study. The most severely affected section of the nasal passages was that which included the ethmoturbinates. Focal adhesions between the septum and turbinates and between the turbinates themselves were seen in some animals exposed to 400 ppm MMA at time points after 5 days of exposure. There were no lesions in the squamous, transitional or respiratory epithelia and none in control rats. Lesions that developed in rats exposed to 110 ppm MMA subsequently repaired during the exposure period. At 400 ppm, the majority of the olfactory epithelium had returned to normal within 13 weeks of the end of the exposure phase, but minimal respiratory metaplasia remained evident and there were some focal adhesions between the septum and turbinates and between the turbinates themselves.

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This study investigated the combined effect in rat lungs of simultaneous exposure to chrysotile asbestos and N-nitrosoheptamethyleneimine (NHMI), with the objective of determining the potential for chrysotile to promote or otherwise enhance the pathological responses to this potent rodent lung carcinogen. Groups of 15 or 20 male and female animals were treated with 0, 3, or 10 mg kg(-1) NHMI subcutaneously, once a week for 10 wk, plus either clean air (control) or 50 mg m(-3) chrysotile by nose-only inhalation for 4 wk. A broad range of pulmonary metaplastic, hyperplastic, and neoplastic lesions was observed. Effects were more marked in male than in female animals. NHMI treatment increased the incidence of hyperplastic lesions, with apparent augmentation by chrysotile exposure (not statistically significant). Similarly, a "promoting" effect of chrysotile in the induction of lung tumors was observed, with all but 2 of the 11 primary tumors detected being in animals treated with both NHMI and asbestos. However, this apparent interaction was again not confirmable statistically, probably because of the low number of observed tumors (stemming from premature termination of the experiment). The study results are in line with those of similar previous studies, which found a higher incidence of hyperplastic and neoplastic changes in animals treated with both nitrosamine and asbestos than in those given nitrosamine alone. It is proposed that the method described (with minor modification) could be used to investigate either (1) the ability of other inhaled particles to augment NHMI carcinogenicity, or (2) the propensity of other chemical carcinogens to interact with asbestos in the production of pulmonary neoplasms.

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We present a preliminary report of a bioassay designed to compare and contrast selected pulmonary responses of female B6C3F1 mice, Fischer 344 rats, and Syrian golden hamsters to inhaled pigmentary titanium dioxide (TiO2). Animals were administered 10, 50, or 250 mg/m(3) TiO2 for 6 h/day and 5 days/wk, for 13 wk. Recovery groups were held for an additional 4-, 13-, or 26-wk period. Following exposure and at each recovery time, TiO2 burdens in the lung and lung-associated lymph nodes were determined. A separate group of animals was used at each time point to assess the inflammatory response of the lung by assaying total protein in bronchoalveolar lavage fluid (BALF) and cytologic examination of cells recovered in BALF. Burdens (mg/mg dry weight) of TiO2 in the lung following exposure to 10, 50, or 250 mg/m(3) TiO2 were 5.2, 53.5, and 170.2 for the mouse; 7.1, 45.1, and 120.4 for the rat; and 2.6, 14.9, and 120.3 for the hamster. With time after exposure, lung burdens of TiO2 particles were decreased and lymph-node burdens increased. Changes in the hamsters' burdens were more rapid than those in mice and rats. Increases in BALF cell numbers (macrophages and neutrophils) and in total protein were observed in all 3 species following exposure to 50 and 250 mg/m(3) TiO2, with the magnitude of response being the grea test in the rat. These responses remained elevated relative to control levels at 26 wk postexposure. Histopathologic examination of lungs showed a concentration-dependent retention pattern of particles that varied by species. Hypertrophy and hyperplasia of alveolar epithelium along with alveolar metaplastic and fibrotic changes were observed in rats exposed to 250 mg/m(3) TiO2. Alveolar epithelial proliferative changes were associated with inflammation in mice and hamsters, but the metaplastic and fibrotic changes noted in rats were not present in similarly exposed mice or hamsters. These data suggest that rats exposed subchronically to extremely high concentrations of pigmentary TiO2 differ from mice and hamsters in their cellular responses in the lung as well as in the way they clear and sequester particles. These differences may partly explain the differential outcome of pulmonary responses in various rodent species following chronic inhalation exposure to poorly soluble particles.

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Diets containing antimony trioxide were fed to male and female Wistar rats of the Alpk:APSD strain over 90 days. Dose levels were 0 (control), 1000, 5000 and 20,000 ppm (equivalent to mean daily doses of 84, 421 and 1686 mg kg(-1) in males and 97, 494 and 1879 mg kg(-1) in females). There was no effect of compound on growth or growth rate, food consumption or clinical signs. Minor changes in haematology and urine biochemistry were considered incidental to treatment. Small reductions in plasma alkaline phosphatase activity and increases in aspartate aminotransferase activity at the high dose, together with a small (ca. 10%) increase in liver weight, could be indicative of a minor effect on the liver, but in the absence of any histological effects these changes are also considered incidental to treatment. This study confirms the inert nature of antimony trioxide.

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Published evidence demonstrates successful induction and elicitation of respiratory hypersensitivity in guinea pigs by the known human respiratory allergens trimellitic anhydride (TMA) and diphenylmethane-4,4'-diisocyanate (MDI). From these data it is apparent that TMA-related respiratory hyperresponsiveness can be elicited readily in guinea pigs upon inhalation challenge with the free chemical. Despite the interlaboratory variability in methodological procedures used for the sensitization as well as elicitation of response and the wide range of concentrations of TMA employed for challenge exposures (6-57 mg/m(3) air), TMA had been unequivocally identified as a benchmark respiratory sensitizer by measurements of the respiratory rate during challenge. The protocols were duplicated to examine the respiratory sensitizer MDI. In intradermally sensitized guinea pigs, changes in immediate-onset-like respiratory response were observed when MDI challenge concentrations exceeded approximately 30 mg MDI/m(3) air. Collective experimental evidence suggests that the respiratory responses observed upon challenge with TMA were markedly more pronounced and easier to identify than those recorded following challenge with MDI or MDI conjugate. In contrast to TMA, irritant concentrations of MDI had to be used to elicit any respiratory response and the differentiation of irritant and allergic responsiveness became increasingly difficult. Despite the absence of unequivocal changes in breathing patterns upon MDI challenge, MDI-sensitized animals displayed elevated anti-MDI immunoglobulin G1 (IgG1) antibodies, and a significant influx of eosinophilic granulocytes in the bronchial wall and lung-associated lymph nodes. Therefore, it is believed that the robustness of this animal model to identify low-molecular-weight agents as respiratory sensitizer is increased when several endpoints are considered. These are (1) positive respiratory response upon challenge with the hapten, and if negative, also challenge with the conjugate of the hapten; (2) an influx of eosinophilic granulocytes; and (3) increased specific IgG1 response. Furthermore, it appears that particles in the range of approximately 2-6 microm evoke more consistent respiratory response upon challenge exposure than particles in the 1-2 microm range.

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Rats exposed to trichloroethylene, either by gavage or by inhalation, excreted large amounts of formic acid in urine which was accompanied by a change in urinary pH, increased excretion of ammonia, and slight increases in the excretion of calcium. Following a single 6-h exposure to 500 ppm trichloroethylene, the excretion of formic acid was comparable to that seen after a 500 mg/kg dose of formic acid itself, yet the half-life was markedly different. Formate excretion in trichloroethylene treated rats reached a maximum on day 2 and had a half-life of 4-5 days, whereas urinary excretion was complete within 24 h following a single dose of formic acid itself. Formic acid was shown not to be a metabolite of trichloroethylene. When rats were exposed to 250 or 500 ppm trichloroethylene, 6 h/day, for 28 days, the only significant effects were increased formic acid and ammonia excretion, and a change in urinary pH. There was no evidence of morphological liver or kidney damage. Long-term exposure to formic acid is known to cause kidney damage suggesting that excretion of this acid may contribute to the kidney damage seen in the long-term studies with trichloroethylene.

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Difluoromethane (HFC32) is under development as a replacement for chlorofluorocarbons (CFCs) in some refrigeration applications. It has been evaluated by standard studies of toxicity, developmental toxicity, and genotoxicity. In addition, the metabolism and disposition of HFC32 was investigated and a physiologically based pharmacokinetic (PB-PK) model constructed. Inhalation of HFC32 (up to 50,000 ppm) caused no organ-specific effects, but resulted in slight maternal toxicity to the pregnant rat and rabbit and some fetotoxicity to the rat. HFC32 did not sensitize the heart to adrenaline. The pharmacokinetics of [14C]difluoromethane (10,000 to 50,000 ppm/6 hr) revealed that about 2.1% of the inhaled HFC32 was absorbed and that steady state blood levels were achieved within 2 hr and were proportional to dose. Carbon dioxide was the major metabolite of HFC32 at all exposure levels. Carbon monoxide was not detected. The in vivo data were used to validate a PB-PK model to describe the uptake and metabolism of HFC32. Absorption and distribution are adequately described using rat blood:air and tissue:air partition coefficients. Metabolism, which was linear across the dose range, was described by a first order rate constant (Kf = 8.98 hr-1). Of the absorbed HFC32, about 63% was metabolized at all doses; however, when metabolism was expressed as a percentage of the inhaled dose it was much lower, being about 1.4% of the HFC32 entering the airways. Overall, the results indicate that HFC32 is of very low toxicity and should be an acceptable alternative to CFCs.

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Subchronic and chronic studies were carried out in the rat and a developmental toxicity study in the rabbit with exposures to 1,1,1,2-tetrafluoroethane (HFC 134a) by inhalation. In the rat repeated exposure to 50,000 ppm HFC 134a for 13, 52, and 104 weeks elicited no effect on clinical condition, growth, and survival, or on a variety of hematological, clinical chemistry, and urinary parameters. Treatment-related pathological changes were seen only at study termination at 2 years and were confined to increased incidence of Leydig cell hyperplasia and adenoma in male rats exposed to 50,000 ppm. The tumors, which were also seen in control animals, were benign and not life-threatening. A battery of in vitro and in vivo tests gave no evidence of genotoxic activity. With exposure to pregnant rabbits, the only treatment-related effects were of minimal maternal toxicity at high exposure concentrations; there were no effects on fetal development. It is concluded that HFC 134a is of very low toxicity and should be an acceptable alternative to CFCs.

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This study evaluated a single intradermal injection model in the guinea pig with subsequent inhalation challenge and serological analysis as a method to predict the potential of chemicals to induce respiratory allergy. Four known respiratory allergens (trimellitic anhydride, diphenyl methane diisocyanate, phthalic anhydride and toluene diisocyanate (TDI)) were screened by two industrial research laboratories using this protocol. Dinitrochlorobenzene, a potent contact allergen, was included as a negative control material. In both laboratories, the respiratory allergens, but not the contact allergen, induced high titre antigen-specific antibodies in treated animals. The inhalation challenge results were similar in both laboratories but were less conclusive in that exposure to free TDI failed to induce pulmonary responses, probably because it fails to penetrate to the deep lung in sufficient concentration. Although the assay shows promise as a means of identifying chemical respiratory sensitisers, its use as a routine screen for the prediction of the ability of materials to induce respiratory allergy in man is probably questionable.

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1. Chronic exposure to insoluble particulates can lead to the development of pulmonary tumours. These have been classified as broncho-alveolar or squamous/epidermoid according to their histopathological characteristics and have been reported in inhalation studies in rats of materials ranging from diesel exhaust and silica to titanium dioxide. 2. The sequence of changes within the rat lung leading to tumours has been characterised. It is apparent that one prerequisite is that the lung load of the particulate matter must exceed the normal clearance capacity, either by overloading the normal alveolar macrophage mediated mechanism or by induction of toxicity with materials such as silica. This results in inflammatory responses, including, or resulting in, epithelial hypertrophy and/or hyperplasia and squamous metaplasia. The persistence of these tissue responses over chronic time periods can lead to tumorigenesis. 3. Research into the mechanisms involved in the initiation and progression of both the inflammatory response and subsequent tumorigenic response to lung particulate loading is in progress. Impairment of macrophage function and mobility by inert particles constitutes one route by which this can arise, as does toxicity to this cell type by biologically reactive particles. At the molecular level, the role of inflammatory mediators, especially the cytokines, has received much attention. 4. Particulate induced lung tumours are perceived to be a phenomenon specific to the rat and their relevance to man is questionable.

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The induction of respiratory sensitization in guinea pigs to diphenylmethane-4,4'-diisocyanate (MDI), a known human respiratory allergen, has been investigated and different routes of exposure compared. Guinea pigs were exposed to MDI by i.d. injection, by topical application or by inhalation. Pulmonary hypersensitivity was measured subsequently as a function of changes in respiratory rate following challenge with atmospheres containing MDI. In addition, contact hypersensitivity was measured by topical challenge and antibody responses evaluated by enzyme-linked immunosorbent assay (ELISA) and passive cutaneous anaphylaxis (PCA). Attempts to sensitize guinea pigs by inhalation exposure to MDI were unsuccessful. Antibody responses and contact sensitization were both infrequent and low grade, and no animals exhibited pulmonary responses following challenge with atmospheric MDI. In contrast, sensitization by either i.d. injection or topical application of MDI induced antibody responses in the majority of animals. Moreover, a proportion of animals in each case exhibited pulmonary responses following subsequent inhalation challenge. These data indicate that the route of exposure influences markedly the effectiveness of sensitization to respiratory allergens such as MDI and that skin contact may be an important cause of occupational respiratory allergy.

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Male B6C3F1 mice were exposed to 4000 ppm methylene chloride (MC) for 6 hr/day, 5 days/week for up to 13 weeks. Groups of mice were killed at intervals from Day 2 to Week 13. Whole lungs were examined morphologically, immunocytochemically, and biochemically. Biochemical and morphological examination was also performed on isolated Clara cells. The major initial morphological effect seen in lungs was acute Clara cell damage after one exposure to MC. However, this damage appeared to resolve after five consecutive daily exposures to MC. After a 2-day interval the Clara cell lesion reappeared on subsequent reexposure to MC. However, the severity of the lesion decreased over the duration of the study. The appearance and disappearance of the lesion in the Clara cell correlated well with the activity of cytochrome P450 monooxygenase in the Clara cell as assessed immunocytochemically (cytochromes P450IIB 1 and 2) in the whole lung and biochemically in the freshly isolated Clara cell (determined by ethoxycoumarin O-dealkylation and aldrin epoxidation). When there was a marked decrease in cytochrome P450 monooxygenase activity the lesion was not present. This suggested that with time the lung (Clara cell) has developed tolerance to MC possibly due to the inactivation of a cytochrome P450 isozyme. The glutathione S-transferase metabolism of MC by the lung cytosol remained virtually unaltered throughout the study. Events accompanying the discussed changes include (1) a significant increase in nonprotein sulfhydryl in the lungs of all exposed animals, (2) altered plating characteristics of the isolated Clara cells from exposed lungs after 24 hr in culture, and (3) an increase in the number of bronchiolar cells in the S-phase after the first exposure to MC. The study also demonstrates the advantages of target cell isolation and study over whole lung biochemical investigation alone.

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The accumulation of [methyl-14C]3-trifluoromethylpyridine (14C-3-FMP) by rat olfactory and hepatic tissue in vivo and in vitro has been investigated. 14C-3-FMP accumulates rapidly and selectively in both tissues in vivo, with an appreciable proportion of this activity being associated with the protein macromolecular fractions. Similar results were seen when isolated tissues were incubated in vitro in the presence of 14C-3-FMP. Studies with a range of metabolic inhibitors demonstrated that accumulation into olfactory tissue in vitro was virtually abolished by metyrapone and SKF-525A, indicating a key role of cytochrome P-450 mediated metabolism in this process. This was substantiated further by the in vivo inhibition of accumulation by metyrapone. Studies on the in vitro metabolism of 14C-3-FMP by isolated rat olfactory tissue demonstrated the major metabolite to be 3-trifluoromethylpyridine-N-oxide (3-FMP N-oxide) which is known to cause olfactory and hepatic toxicity in the rat. Metyrapone, while inhibiting accumulation of radioactivity derived from both 14C-3-FMP and 14C-3-FMP N-oxide in this tissue in vitro, only inhibited the synthesis of this metabolite by approximately 60%, indicating that several metabolic stages are involved in the metabolism and accumulation of 14C-3-FMP.

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Rats were exposed for a single 6-h period to varying concentrations of aerosols of the polyamine, spermidine trihydrochloride. They were subsequently killed at 6 h, 1, 2, 5, 9 and 14 days after the start of exposure. The lungs were examined for histopathological alterations at both light and electron microscopic level and assays of lung spermidine burdens performed. In rats killed at the 6-h termination period, lung spermidine levels had increased approximately 1.5-fold although concentrations in animals killed on days 1 and 2 showed only marginal increases. Concentrations peaked again on day 5 and henceforth decreased until control spermidine levels were again achieved on day 14. Exposure of rat lungs to spermidine resulted in a specific dose-dependent necrosis of Clara cells of the bronchiolar epithelium and alveolar Type II cells. At the lowest dose used (6 mg/m3) specific necrosis of the Clara cells was seen at the earliest time interval studied, i.e. 6 h, but these cells were rapidly lost and subsequently replaced without evidence of significant cell proliferation by the 2-day sacrifice period. At all higher dose levels additional necrosis of the alveolar Type II cells occurred which was not reversible but which progressed through alveolitis to a fully developed subchronic pneumonitis by 14 days.

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The effects of a single exposure to 3-trifluoromethyl pyridine (3FMP), were investigated in two studies. In the first study, rats were exposed nose only to 0, 50 or 800 ppm 3FMP for periods of 15 min to 4 h. Half were sacrificed on day 3 and the remainder on day 10. In the second study, rats were exposed whole body to 0, 0.1, 1.0, 10 or 50 ppm 3FMP for 6 h, with sacrifices immediately after exposure (6 h), 24 h and on days 3 (48 h after exposure started) 5, 8, 11, 35, 70 and 157. Effects were seen in the olfactory epithelium at concentrations of 1 ppm and above and in the liver at concentrations of 50 ppm and above. In the olfactory epithelium the earliest changes were seen immediately after exposure and by 24 h this progressed to extensive necrosis with sloughing of the epithelium. By day 3, the epithelium was replaced by undifferentiated basophilic cells, considered to reflect early regeneration. Regeneration progressed to complete recovery between days 70 and 157, no changes were seen in the nasal respiratory epithelium, an olfactory function test on rats exposed for 6 h to 50 or 10 ppm 3FMP showed a reduced sense of olfaction at days 3 and 5 with complete recovery on subsequent days, indicating functional recovery in advance of histological normality. Single cell necrosis was seen in the liver at day 3 after 30 min exposure and immediately after 6 h exposure to 50 ppm 3FMP. At 24 h after a 6 h exposure to 50 ppm this had progressed to necrosis, haemorrhage and moderate cytoplasmic hepatocyte vacuolation in centrilobular areas. The lesion had completely recovered by day 5.

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Guinea-pigs injected intradermally with the known respiratory sensitiser trimellitic anhydride (TMA) developed high-titre antigen-specific homocytotropic (IgG1 and IgE) antibodies. Many of the sensitised animals responded to a challenge by inhalation with either free TMA or a TMA-protein conjugate with a change in respiratory rate, reflecting the onset of bronchoconstriction. Guinea-pigs were also injected intradermally with 2,4-dinitrochlorobenzene (DNCB), which is a potent skin sensitiser in man but which has not been reported to cause respiratory allergy. These animals developed only low-titre homocytotropic antibodies and were unresponsive to an inhalation challenge with either free or conjugated hapten. The animals were, however, contact-sensitised to the chemical.

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Rats exposed by inhalation to 3-trifluoromethylpyridine (3-FMP) for 10, 30 or 90 days showed an unusual response in the nasal passages. Focal histological change including reduction in the number of cell layers, disorganisation, vacuolation and minimal necrosis was confined to the olfactory epithelium. Axon bundles and the olfactory bulb were unaffected but there was loss of PAS staining affinity in Bowman's glands. The onset of the lesion showed a very steep dose-relationship approximating a quantal response; no effects were seen after 90 days exposure to 0.1 ppm but the changes were fully developed after 30 days exposure to 0.5 ppm. There was no marked progression with either increased exposure concentrations (up to 329 ppm) or with increased duration of exposure (10-90 days). The respiratory epithelium was generally unaffected apart from a mild irritant response seen only after 90 days. Exposures also resulted in a response in the liver. Centrilobular and midzonal vacuolation was observed at 10 and 30 days following exposures at or above 5 ppm 3-FMP and the severity increased with concentration. The lesion regressed with time even when exposure continued and only minimal changes were evident after 90 days, probably indicating an adaptive response. This work demonstrates the high organ specificity of 3-FMP, particularly for the olfactory epithelium.

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Guinea pigs could be immunologically sensitised (as shown by the development of antigen-specific homocytotropic antibodies) to toluene diisocyanate by exposing them for 3 h a day for 5 consecutive days to atmospheres containing free chemical. Pulmonary reactions could be elicited in many of the sensitised animals by challenging them with atmospheres containing protein conjugates of the chemical and then measuring changes in respiratory rate. Successful elicitation of pulmonary reactions appeared to depend upon a number of factors, including the quality of the protein conjugate used for the challenge, but possibly also the development of IgE as well as IgG1 antibodies. Antigen-specific homocytotropic antibodies were detected in guinea pigs similarly exposed by inhalation to two non-isocyanate respiratory allergens, trimellitic anhydride and a reactive dye. Although the animals were immunologically sensitised to the chemicals, challenge with atmospheres containing appropriate chemical-protein conjugates failed to stimulate changes in respiratory rate.

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