A chronic inhalation toxicity/oncogenicity study of methylethylketoxime in rats and mice.

To evaluate the oncogenic potential of methylethylketoxime (MEKO), CD-1 mice (50/sex/group) and F-344 rats (50/sex/group) were coexposed 6 h/day, 5 days/wk for 18 mo (mice) or 26 mo (rats) via whole-body inhalation exposures to target vapor concentrations of 0, 15, 75, and 375 ppm (actual concentrations of 0, 15 +/- 1, 75 +/- 2, or 374 +/- 10 ppm). Satellite groups of rats and mice (10/sex/group/interval) were exposed for 12 mo (mice) and 3, 12, or 18 mo (rats) to evaluate chronic toxicity. Methyl ethyl ketone (MEK), a possible hydrolysis product of MEKO, was present at less than 1%. Treatment-related effects included increased body weight (male rats only), methemoglobin formation, hematology and clinical chemistry changes, increased liver weight, and increased spleen and testes weights (rats only). A high incidence of cataracts and corneal dystrophy occurred in both control and MEKO-exposed rats, with an earlier appearance and slightly higher incidence for these ocular lesions in MEKO-exposed animals compared to controls. Degenerative and reparative changes of the olfactory epithelium in the nasal turbinates, primarily limited to the dorsal meatus, occurred in both rats (75 and 374 ppm) and mice (15, 75, and 374 ppm). In addition, in the mice, liver changes included increased incidences of pigment in reticuloendothelial cells, centilobular hypertrophy, granulomatous inflammation, and a slightly increased incidence of necrosis (75 and 374 ppm). An increase in hepatocellular carcinomas occurred in male mice at 374 ppm. Additional MEKO-related findings in the rat included congestion of the spleen with pigment in reticuloendothelial cells and extramedullary hematopoiesis and a decreased incidence of lymphoreticular mononuclear cell leukemia. Effects observed in the liver of the rats included decreases in the incidence of both peribiliary fibrosis and hyperplasia/proliferation of the biliary duct, an increase of spongiosis hepatis in males, and an increase in the incidence of intracytoplasmic vacuoles and hepatocellular basophilic foci. The effects on the liver were generally most profound in the high-exposure groups and, with the exception of the spongiosis hepatis, occurred in both sexes. An increase in hepatocellular adenomas occurred in the male rats at 75 and 374 ppm, and hepatocellular carcinomas in the male rats at 374 ppm. In both species, the liver tumors appeared relatively late in the life of the animals, with no significant increase in tumors at 12 mo of exposure in mice and at 18 mo of exposure in rats. Lifespan shortening was not observed, as MEKO-exposed animals survived generally as well as, or slightly better than, the controls.

Thirteen-week subchronic rat inhalation toxicity study with a recovery phase of trivalent chromium compounds, chromic oxide, and basic chromium sulfate.

The toxicity of trivalent chromium compounds; chromic oxide and basic chromium sulfate, was investigated in rats in a 13-week nose-only inhalation study that included a 13-week recovery period. Nose-only exposures to insoluble chromic oxide dust at 4.4, 15, or 44 mg/m3 or soluble basic chromium sulfate dust at 17, 54, or 168 mg/m3 (trivalent chromium equivalent concentrations of 3, 10, and 30 mg/m3) were carried out for 6 h/day, 5 days/week. No compound-related mortality occurred. General toxic effects, only observed with high-exposure levels of basic chromium sulfate, included sporadic signs of labored breathing and depressed body weights. No apparent compound-related effects were noted for sperm motility or morphology, for any concentration of either test material. Bronchoalveolar lavage fluid evaluations showed test material in mononuclear cells with chromic oxide and increased neutrophils, protein, lactic dehydrogenase and cellular debris with basic chromium sulfate. The principle effects for both materials were primarily to the respiratory tract. Chromic oxide caused pathological changes in the bronchial and mediastinal lymphatic tissue and lungs, consisting of the presence of pigment-laden macrophages, lymphoid and septal hyperplasia, and interstitial inflammation similar to that observed with other inert dusts. Basic chromium sulfate produced more severe and widespread effects in the nasal cavity, larynx, lungs, and mediastinal lymph node. Effects were characterized by accumulation of foreign material, infiltration of alveolar macrophages, septal cell hyperplasia, and granulomatous and chronic inflammation. Pigment was still present in chromic oxide and, to a lesser extent, in basic chromium sulfate-treated animals after the 13-week recovery period, with partial recovery of the pathological lesions. A NOAEL was not established for either test material, but 4.4 mg/m3 was thought to be near the NOAEL level for subchronic exposure to chromic oxide. The results of this study indicate significant differences in toxicity to the respiratory tract between trivalent chromium compounds chromic oxide and basic chromium sulfate. These are likely related to differences in acidity and water solubility, rather than chromium concentration per se. This conclusion is substantiated by the lack of effect on other internal organs.

Subchronic inhalation toxicity study of caprolactam (with a 4-week recovery) in the rat via whole-body exposures.

This study was designed to assess the potential subchronic inhalation toxicity of caprolactam when administered as a 3-micron aerosol from an aqueous solution to Sprague-Dawley CD rats (10/sex/group) via whole-body exposure. The study was enhanced with the inclusion of motor activity measurements and a functional observational battery to assess the neurotoxic potential of caprolactam. The rats were exposed at least 65 times over a 13-week period for 6 h per day, 5 days per week, to target concentrations (3 microns, mass median aerodynamic diameter) of 0, 25, 75, and 250 milligrams per cubic meter (mg/m3). An additional 10 animals/sex/group were similarly exposed and then held for a 4-week recovery period. Exposure levels were determined gravimetrically six times daily; one daily sample was analyzed by high-pressure liquid chromatography. No deaths were observed in the study during the exposure or recovery periods. Treatment-related responses such as labored breathing and nasal discharge were seen during many of the exposures. Similar responses as well as moist rales were seen during the nonexposure periods during the 13 weeks of exposure. However, these responses abated during the 4-week recovery period. There were no clearly treatment-related responses observed with ophthalmoscopic examinations, body weight measurements, food consumption measurements, neurobehavioral evaluations, clinical pathology evaluations, organ weight measurements, or macroscopic pathology examinations. Microscopic findings that were considered related to exposure to the test material were seen in the nasoturbinal tissues (hypertrophy/hyperplasia of goblet cells in the respiratory mucosa and intracytoplasmic eosinophilic material in epithelial cells of the olfactory mucosa) of the two higher-exposure group animals and in the laryngeal tissues (squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium covering the ventral seromucous gland) of all three exposure group animals. These changes were considered to be adaptive responses to an irritant (caprolactam). The keratinization of the metaplastic epithelium in the larynx was considered to be an adverse effect. By the end of the 4-week recovery period, there was complete regression of the keratinization in the larynx, but recovery of the adaptive nasoturbinal effects had not completely resolved. In conclusion, the whole-body exposure of Sprague-Dawley rats to caprolactam as a respirable aerosol for 6 h/day, 5 days/week, for 13 weeks at gravimetrically determined levels of 24, 70, and 243 mg/m3 resulted in respiratory tract effects (laryngeal) at the highest exposure level with complete recovery within 4 weeks postexposure. The results indicate that the no-observed-adverse-effect level for caprolactam is 70 mg/m3, based on upper respiratory effects, with 243 mg/m3 representing a no-observed-effect level for systemic toxicity, neurotoxicity, and lower respiratory tract effects.

Reproductive toxicity evaluation of methylethyl ketoxime by gavage in CD rats.

Methylethyl ketoxime (CAS No. 96-29-7; MEKO; 2-butanone oxime), an antioxidant agent used in paints, resins, and adhesives, was tested for reproductive toxicity in a two-generation study with CD (Sprague-Dawley) rats. Thirty-eight-week-old rats/sex/group (F0) were administered MEKO in water, by gavage, at 0, 10, 100, or 200 mg/kg/day (at a dosing volume of 2 ml/kg), 5 days/week for 10 weeks with vaginal cytology evaluation (VCE) of F0 females during the last 3 weeks of the prebreed period. Animals were mated within groups for 3 weeks with dosing during mating, gestation, and lactation for 7 days/week. F0 parents and F1 weanlings, 10/sex/dose, were necropsied (after a 2-week postwean VCE in F0 females) with hematologic evaluation (including methemoglobin) and histology of adult livers, spleens, and reproductive organs. F1 weanlings, 30/sex/dose, were dosed for 11 weeks and mated as described above. Because of poor reproductive performance, not treatment related, F1 animals with no F2a litters were rebred to produce F2b litters. F1 parents and F2a weanlings, 10/sex/dose, were necropsied and evaluated as described above. Inguinal mammary glands were examined histologically from all nonselected F1 and F2 (a and b) female weanlings. Adult toxicity was observed in both generations and both sexes at all doses. Treatment-related parental deaths occurred at 200 mg/kg/day. At 100 and 200 mg/kg/day, parents exhibited dose-related reduced body weights and weight gains, reduced feed consumption, clinical signs of toxicity, and anemia with concomitant extramedullary hematopoiesis and hemosiderosis in livers and spleens (and increased spleen weights). At 10 mg/kg/day, only adult liver and spleen histologic effects were present. There was no evidence of reproductive organ or mammary glad pathology or of reproductive or postnatal toxicity at any dose tested. There was no adult "no observable adverse effect level" (NOAEL) established; the NOAEL for reproductive and postnatal toxicity was at least 200 mg/kg/day for rats in this study.

Toxicity of calcium sodium metaphosphate fiber. II. Chronic inhalation and oncogenicity study.

Male and female Fischer 344 rats (80/sex/group) were exposed to CSM fiber 6 hr/day, 5 days/week at target-exposure levels of 0, 1, 5, or 25 mg/m3 for 24 months, corresponding to 0, 27, 80, and 513 fibers/cc, respectively. Number and size of the airborne fibers were determined during the course of the study. At 3 and 12 months, 10 rats/sex/group were euthanized and at 18 and 24 months 5 rats/sex/group were euthanized. In addition, 5 rats/sex/group were removed from exposure at 18 months and maintained for a 6-month recovery period. All animals surviving at the completion of the exposure period were maintained in a clean environment for up to 5 additional months. Clinical laboratory examinations were performed on 10 animals/sex/group at 3, 12, and 24 months. The number of fibers in the lung were also determined at 3, 12, 18, and 24 months. Body weight and survival did not appear to be affected by treatment. There were no biologically significant effects on clinical parameters. There was a dose-related increase in lung weight during the exposure period which was generally reversible during the recovery periods. There also was a dose-related increase in the number of fibers/milligram of lung, but no increase in lung fiber burden after the first 3 months. The number of fibers in the lungs of animals exposed to CSM fiber for 18 months and allowed 6-month recovery period showed a decrease especially at the high dose. No increase in tumors (benign or malignant) was observed in this study. Microscopic changes considered reflective of an irritant response were observed in the nasal turbinates notably at the 5 and 25 mg/m3 levels. Histological changes were also observed in the lungs at the 5 and 25 mg/m3 levels. The incidence and/or severity of histopathological changes in the 1 mg/m3 group was considered to be essentially comparable to controls.

The health hazards posed by chromium-contaminated soils in residential and industrial areas: conclusions of an expert panel.

Between 1905 and 1971, over 2 million tons of residue from chromite ore processing was generated in Hudson County, New Jersey, of which substantial amounts were used as fill and tank diking. A panel of medical, toxicology, and risk assessment experts was convened in early 1990 to evaluate the potential health hazards posed by the resulting chromium contaminated soil. The Panel concluded that soils containing concentrations of 75 ppm hexavalent chromium [Cr(VI)] and 1000 ppm total chromium compounds (about 95% was trivalent chromium [Cr(III)]) did not pose a significant health hazard to nearby residents and workers. They also determined that exposure to chromium from Hudson County sites posed a negligible cancer hazard to residents. Using risk assessment methods, the Panel estimated that the plausible incremental cancer risk to individuals at residential sites would be substantially less than 1 in 1,000,000. The average measured levels of airborne Cr(VI) at typical industrial sites were more than 1000-fold lower than the current OSHA Permissible Exposure Limit (PEL). The maximum plausible increased cancer risk for an average worker at a dusty industrial site was estimated to be less than 1 in 100,000. The Panel also concluded that chromium-containing crystals, which have occasionally been found in Hudson County buildings, do not pose a significant hazard. However, they suggested that were the concentration to exceed 5000 ppm Cr(VI) in the crystals, site-specific health risk assessments would be conducted and remediation considered. The Panel evaluated the dermal hazard posed by chromium-contaminated soil and acknowledged that there is a small group of persons (approximately 0.1% of the United States population) who currently have a dermal sensitization to Cr(VI) primarily through occupational exposure. Based on published studies of human volunteers, the Panel concluded that a small percentage (less than 5%) of persons already sensitized may respond to Cr(VI) in solution at concentrations above 35 ppm. They decided that a much higher concentration in soil, perhaps 350 ppm Cr(VI), would be necessary to elicit dermatitis because only a fraction of the chromium in soil is soluble. The Panel concluded that it was highly unlikely (if not impossible) for a person to become dermally sensitized to Cr(VI) or Cr(III) at the soil concentrations found in most areas in Hudson County.(ABSTRACT TRUNCATED AT 400 WORDS)

Toxicity of hydroxylamine sulfate following dermal exposure: variability with exposure method and species.

The acute toxicity of hydroxylamine sulfate (HS) and phenylhydrazine hydrochloride (PHZ) were compared in the rabbit and rat following a single 24-hr dermal exposure. The test materials were applied topically and occluded under a plastic or gauze cover or were injected sc. Distilled water served as a control. HS and PHZ produced similar hematotoxic effects consisting of methemoglobin formation, anemia, and reticulocytosis. HS and PHZ proved to be more toxic to the rabbit than to the rat although both chemicals produced similar hematological effects at equivalent dose levels within the same species. HS proved strikingly more toxic when administered under plastic than under gauze despite the fact that both methods included occlusion. PHZ toxicity was less variable with exposure method. HS and PHZ were lethal to the rabbit but no deaths occurred in the rat. The results of this study indicate that HS and PHZ show similar hematotoxicity and, therefore, the clinical data available on PHZ may be useful in predicting the hematological effects of HS on humans.

Acute inhalation study in the rat of comparative uptake, distribution and excretion for different cadmium containing materials.

Single 2-hr inhalation exposures were conducted at levels of approximately 100 mg/m3 (based on cadmium content) with the use of two cadmium pigments (cadmium red and cadmium yellow), a dust of cadmium carbonate, and a cadmium fume. An air exposed control group also was included. The rate of elimination of cadmium in the urine and feces, and the cadmium levels in selected tissues were measured at several intervals following the exposure. In addition, observations of the animals for clinical signs of toxicity and mortality and measurements of organ weights and body weight were performed. There was no mortality in the control, cadmium red or cadmium yellow exposed groups. In the cadmium carbonate exposed group, 3 out of 52 rats died, and in the cadmium fume exposed group, 25 out of 52 rats died. Cadmium blood levels indicated that cadmium from the cadmium carbonate and fume was absorbed to a greater degree than cadmium from the red and yellow pigments. The major route of elimination of cadmium following exposure to the two pigments was via the feces, with 80% being cleared within 24 hr. Elimination was slower following exposure to the carbonate. The levels of cadmium in the liver and kidneys were much higher following exposure to the carbonate than following exposure to the red and yellow pigments. It appeared that these cadmium compounds were not equivalent with respect to toxicity, absorption, distribution or excretion. Exposure to the two insoluble compounds, cadmium red and cadmium yellow, did not produce mortality and resulted in rapid elimination in the feces with lower tissue levels of cadmium than observed following exposure to the cadmium carbonate.

Current concepts in occupational health: metals-chromium.

Chromium and its compounds have long been generally recognized as having potentially severe occupational health hazards. A brief review of the historical perspectives is provided. Failure to properly differentiate between the various valence states, which exhibit different toxicological properties and the physical state (solubility, particle size, etc.) as well as poor quantitation and characterization of exposure has led to confusion and potential error in estimating the risk inherent in working with chromium and its compounds. An overview is provided of the most recent and available data which address these issues in light of current concepts of scientific evaluation.

Inhalation toxicity studies with boron trifluoride.

An acute study of boron trifluoride (BF3) in rats indicated the 4-hr LC50 to be 1.21 mg/liter. In a 2-week study, all animals exposed to 180 mg/m3 died prior to the sixth exposure, rats exposed at concentrations of 66 and 24 mg/m3 showed clinical signs of respiratory irritation, body weight gain depressions, increased lung weights, and depressed liver weights. Histopathology showed necrosis and pyknosis of the proximal tubular epithelium of the kidneys. This effect was limited to the high-concentration exposure group. Based on the results of these studies, Fischer 344 rats were exposed 6 hr/day, 5 days/week for 13 weeks to a respirable, liquid aerosol of BF3 at concentrations of 0, 2.0, 6.0, and 17 mg/m3. One rat in the high exposure group died. The most significant finding in this group was necrosis of the proximal tubular epithelium of the kidneys. Other observations noted during the study included dried material around the nose and mouth, rales and excessive lacrimation, reversible depression of serum total protein and globulin concentrations, and increases in urinary, serum, and bone fluoride amounts. In the lower exposure groups, findings of respiratory irritation were minimal. All observations occurred in a dose-related pattern. Based on this study, exposure to BF3 at 17 mg/m3 resulted in renal toxicity, while exposure at 6 mg/m3, although showing elevations of fluoride amounts, did not result in a toxic response.

A method for repeated evaluation of benzene uptake in rats and mice during a six hour inhalation period.

Benzene uptake measurements and respiratory minute volume (RMV) were assessed in rats and mice during a 6-hour inhalation exposure to 300 ppm (v/v) of benzene vapor. The values for benzene uptake and RMV were used to compare predictions of inhaled dose in both species. The theoretical prediction assumed an unchanging RMV. The next prediction allowed adjustments for changes in RMV during exposure. The final prediction addressed benzene uptake directly. The uptake characteristics of benzene in both species were different from the theoretical prediction, from the prediction adjusted for changing RMV and from each other. The greatest difference was seen in rats where the observed benzene dose was only 28% of the theoretical value. The experiment was not designed to elucidate the causes for the difference between the predictions, nor was the data sufficient to suggest whether the rat or the mouse was a suitable model of benzene uptake in humans.

A 26-week inhalation toxicity study with formaldehyde in the monkey, rat, and hamster.

This inhalation study involved simultaneous exposure of five groups of 6 male Cynomolgus monkeys, 20 male and 20 female Fischer 344 rats, and 10 male and 10 female Syrian golden hamsters for 22 hr per day, 7 days per week for 26 weeks to formaldehyde gas. The cumulative mean exposure concentrations were 0, 0, 0.19, 0.98, and 2.95 ppm for the two control groups, low-, mid-, and high-level exposure groups, respectively. There was no treatment-related mortality during the study. In monkeys, the most significant findings were hoarseness and congestion and squamous cell metaplasia in the nasal turbinates of the 2.95-ppm exposure group. There were no signs of toxicity in the lower-level exposure groups. In the rat, the only observations of possible responses to exposure were found in the 2.95-ppm exposure group. These findings consisted of squamous metaplasia in the nasal turbinates, decreased body weights starting during the second week of the study, and decreased liver weights. In contrast to monkeys and rats, hamsters did not show any significant responses to exposure even at 2.95 ppm. It was concluded that nearly continuous exposure of monkeys and rats for six months at a level of 2.95 ppm of formaldehyde clearly elicited an effect while exposures below this level did not appear to demonstrate an effect. It further appeared that the monkey and rat were more sensitive to formaldehyde exposure than the hamster.

Acute inhalation toxicology of nitrogen trichloride.

The LC50 of nitrogen trichloride (NCl3) was determined in rats following a one hour inhalation exposure. Five groups of 10 animals per group were exposed to a concentration range of NCl3 from 58 ppm to 157 ppm. The one hour LC50 is 112 ppm with the 95% confidence interval between 107 ppm and 117 ppm. All mortality occurred during or within one day following the exposure. Gross necropsy of the animals which died as a result of exposure to NCl3 showed noticeable fluid in the trachea and lungs. This was not the case for those animals which survived the exposure (gross necropsies performed 14 days post-exposure). Pulmonary edema appears to contribute significantly to mortality produced by NCl3.

Personnel monitoring for tetraalkyl lead in the workplace.

Personnel monitoring for alkyl lead and inorganic lead in air was carried out for six weeks on five workers in an alkyl lead manufacturing plant. Lead in air values were compared to biological values for lead blood, lead in urine, and delta aminoleuvlinic acid in urine. While variations in each of these measurements occurred, there was no correlation between any of these three measurements and lead in air. Measurements of atmospheric exposure to alkyl lead by personnel monitoring does not provide an accurate assessment of the degree of hazard to workers. When such measurements are performed frequently, they can provide information useful in controlling respiratory exposure. Biological monitoring of lead in urine as practiced by the alkyl lead industry remains the best protection against overexposure to organic lead.