Dichloroacetylene: effects on the rat trigeminal nerve somatosensory evoked potential.

Humans overexposed to trichloroethylene (TCE), under specific conditions, were reported to develop trigeminal nerve dysfunction. A degradation byproduct dichloroacetylene (DCA), however, has been suggested as the probable neurotoxicant rather than TCE. Studies in mice, rats, and rabbits support the hypothesis of DCA-induced trigeminal neurotoxicity. This study, therefore, was conducted to characterize DCA-induced trigeminal nerve dysfunction in rats using the electrodiagnostic procedure trigeminal nerve-stimulated somatosensory evoked potential (TSEP). A group of six rats was exposed once to DCA (approximately 300 ppm) or room air for 2.25 h and a separate group of six rats was not exposed and served as controls. Trigeminal nerve somatosensory evoked potentials (TSEPs) were collected before exposure and 2, 4, and 7 days postexposure. Because DCA was manufactured from TCE with acetylene added as a stabilizer, another group of rats was exposed to TCE and acetylene without generation of DCA. TSEPs from DCA-exposed rats were smaller and slower compared to their baseline recordings and to the concurrent negative controls. TSEPs from the controls and the TCE/acetylene-exposed rats were unchanged. Neuropathology did not reveal treatment-related lesions. It was concluded that the rat is mildly to markedly susceptible to DCA-induced trigeminal nerve dysfunction as assessed by TSEP, but that the kidney was the likely target organ based on gross observations and the DCA literature.

Inhalation toxicity of sulfuryl fluoride in rats and rabbits.

The inhalation toxicity of the structural fumigant sulfuryl fluoride (SO2F2) was evaluated in rats and rabbits. Exposures for a preliminary 2-week study were 6 hr/day, 5 days/week, to 0, 100, 300, or 600 ppm SO2F2. Nine of ten rats at 600 ppm died or were moribund between the second and sixth exposures. Extensive kidney lesions were present in all rats exposed to 600 ppm, whereas only minimal renal changes were noted in rats at 300 ppm. Upper and lower respiratory tissues were inflamed in the single rat that survived the 2-week exposure to 600 ppm. Rabbits exposed to 600 ppm SO2F2 were hyperactive and one animal had a convulsion. Exposure to 300 or 600 ppm for 2 weeks resulted in vacuolation and/or malacia in the cerebrum of all rabbits and most of these rabbits also had moderate inflammation of nasal tissues; a few rabbits at 600 ppm had inflammation of the trachea or bronchi. A subsequent 13-week study evaluated rats and rabbits exposed to 0, 30, 100, or 300 ppm SO2F2 (337 ppm TWA for rabbits). Rabbits initially were exposed to a high concentration of 600 ppm; however, convulsions were noted in two animals after nine exposures and the concentration subsequently was reduced to 300 ppm. Vacuolation and/or malacia were observed in the cerebrum of all rabbits at the highest concentration; one rabbit exposed to 100 ppm also had cerebral vacuolation. Rabbits at the highest concentration, as well as one rabbit exposed to 100 ppm, had inflammation of the nasal tissues. Rats exposed to 300 ppm SO2F2 for 13 weeks had mottled incisor teeth, minimal renal effects, pulmonary histiocytosis, inflammation of nasal tissues, and cerebral vacuolation. Also, rats exposed to 100 ppm SO2F2 for 13 weeks had mottled teeth. Fluoride toxicity was suggested by mottled teeth in rats as well as elevation of serum fluoride levels in rats and rabbits exposed to SO2F2 for 13 weeks. Although repeated exposure of rats and rabbits to 100-600 ppm SO2F2 resulted in toxicity of the kidneys (rats only), brain, and respiratory system, no effects were detected in animals exposed to 30 ppm for 13 weeks.

Methylene chloride: two-generation inhalation reproductive study in rats.

Reproductive parameters in Fischer 344 rats were evaluated following inhalation of methylene chloride (MeCl2) for two successive generations. Thirty male and female rats were exposed to 0, 100, 500, or 1500 ppm MeCl2 for 6 hr/day, 5 days/week for 14 weeks and then mated to produce f1 litters. After weaning, 30 randomly selected f1 pups/sex/group were exposed to MeCl2 for 17 weeks and subsequently mated to produce f2 litters. Reproductive parameters examined included fertility, litter size and neonatal growth, and survival. All adults and selected weanlings were examined for grossly visible lesions. Tissues from selected weanlings were examined histopathologically. No adverse effects on reproductive parameters, neonatal survival, or neonatal growth were noted in animals exposed to methylene chloride in either the f0 or f1 generations. Similarly, there were no treatment-related gross pathologic observations in f0 or f1 adults or f1 and f2 weanlings. Histopathologic examination of tissues from f1 and f2 weanlings did not reveal any lesions attributed to methylene chloride. Thus, exposure of rats to concentrations as high as 1500 ppm methylene chloride, which has been shown in a 2-year study to produce treatment-related effects, did not affect any reproductive parameters.

Incapacitation and treatment of rats exposed to a lethal dose of sulfuryl fluoride.

Rats exposed to 4000 ppm sulfuryl fluoride (VIKANE gas fumigant, SO2F2) were incapacitated within 45 min and died within several hours after exposure. Exposure to higher concentrations resulted in a shorter time to incapacitation and death occurred within minutes. Treatment with calcium gluconate before exposure to 4000 ppm SO2F2 for 45 min resulted in 80% survival. However, calcium gluconate did not alleviate SO2F2-induced convulsions. Administration of phenobarbital before or after exposure to 4000 ppm SO2F2 for 45 min effectively reduced the frequency and severity of convulsions and resulted in survival of all animals. Exposure of rats to 10,000 ppm SO2F2 for 15 min followed by treatment with phenobarbital reduced the frequency of convulsions and delayed death, but did not prevent death. Diazepam was less effective than phenobarbital while diphenylhydantoin had no beneficial effect and, in fact, made the convulsions more severe and longer in duration. The results of this study indicate that phenobarbital was effective in ameliorating the acute toxic effects of an overexposure to SO2F2 in rats.

Dermal sensitization potential and inhalation toxicological evaluation of 4-phenylcyclohexene.

4-Phenylcyclohexene (4-PCH) is a by-product formed in trace amounts during the production of styrene-butadiene latexes, which are used in carpet manufacturing. The dermal sensitization potential of 4-PCH was evaluated by using a modification of the Buehler method. The condition of the test site was evaluated 24 and 48 hr after the challenge application with no response observed in any of the guinea pigs. For the acute inhalation study, groups of five Fischer 344 rats/sex were exposed to 16 or 60 ppm 4-PCH for a single 6-hr exposure. Subsequently, groups of 10 Fischer 344 rats/sex were exposed to time-weighted average concentrations of 0, 1, 10, or 50 ppm (0, 6.6, 65, or 320 mg/m3) 4-PCH for 6 hr/day, 5 days/week for nine exposures. The highest vapor concentration, 50 ppm, was the maximum attainable during the course of the 2-week study. It was only achieved by acclimating the chamber with saturated vapor prior to each animal exposure. The following parameters were evaluated for the 2-week study: clinical signs, body weights, selected organ weights, hematology, clinical chemistry, urinalysis, and histopathology. All rats survived to the termination of the study and had no clinical or pathologic evidence of eye, skin, nasal, or respiratory tract irritation. There were no exposure-related effects identified in any of the parameters monitored. Thus, 4-PCH produced no toxicity at the highest concentration that could be generated and did not produce delayed contact hypersensitivity in guinea pigs.

Comparison of the teratogenic potential of inhaled ethylene glycol monomethyl ether in rats, mice, and rabbits.

Studies to assess the effects of inhaled ethylene glycol monomethyl ether (EGME) on embryonal and fetal development were conducted on groups of Fischer 344 rats, CF-1 mice, and New Zealand White rabbits. Rabbits and rats were exposed to vapor concentrations of 0, 3, 10, or 50 ppm for 6 hr/day on Days 6 through 18, or Days 6 through 15 of gestation, respectively; mice were exposed to 0, 10, or 50 ppm on Days 6 through 15 of gestation. Exposure of pregnant rabbits to 50 ppm produced significant increases in the incidence of malformations, minor variations, and resorptions, as well as a decrease in fetal body weight. Rats and mice exposed to 50 ppm showed no evidence of a teratogenic effect, although indications of slight fetotoxicity were observed in both species. Transient decreases in maternal body weight gain among rats, mice, and rabbits exposed to 50 ppm were the only consistent signs of maternal effects. No significant treatment-related effects on fetal development were observed in any of the species tested at 10 ppm of EGME or below.

Embryotoxicity of inhaled sulfuric acid aerosol in mice and rabbits.

The effect of inhaled sulfuric acid (H2SO4) on embryonal and fetal development was assessed in CF-1 mice and in New Zealand white rabbits. Both species were exposed for 7 hr/day to 0, 5, or 20 mg H2SO4/m3 during the period of major organogenesis (mice, days 6 through 15 of gestation; rabbits, days 6 through 18 of gestation). Little evidence of toxicity was seen in the fetuses of mice or rabbits exposed to H2SO4. Slight maternal toxicity was seen at 20 mg H2SO4/m3 in both species. Teratogenicity was not observed in either mice or rabbits exposed to H2SO4.

Methylene chloride: a 2-year inhalation toxicity and oncogenicity study in rats.

Male and female Sprague-Dawley rats were exposed to 0, 50, 200, or 500 ppm methylene chloride for 6 hr/day, 5 days/week for 2 years. Blood carboxyhemoglobin levels were elevated in a dose-dependent (less than linear) manner in rats exposed to 50-500 ppm methylene chloride. Histopathologic lesions related to methylene chloride exposure were confined to the liver and mammary tissue of rats. An increased incidence of hepatocellular vacuolization was observed in male and female rats exposed to 500 ppm methylene chloride. Female rats exposed to 500 ppm methylene chloride also had an increased incidence of multinucleated hepatocytes and number of spontaneous benign mammary tumors/tumor-bearing rat (adenomas, fibromas, and fibroadenomas with no progression toward malignancy); the incidence of benign mammary tumors in female rats exposed to 50 or 200 ppm methylene chloride was comparable to historical control values. No increase in the number of any malignant tumor type was observed in rats exposed to concentrations as high as 500 ppm methylene chloride. Additional groups of female rats were exposed to 500 ppm methylene chloride for the first 12 months or the last 12 months of the 24-month study. The response observed in female rats exposed to 500 ppm for the first 12 months was the same as that observed in female rats exposed to 500 ppm for 2 years. Conversely, the response observed in female rats exposed to 500 ppm during the last 12 months of the study was similar to that observed in control animals. Based upon the results of this study, the no-adverse-effect level for chronic inhalation exposure of Sprague-Dawley rats was judged to be 200 ppm methylene chloride.

In vitro kinetics of styrene and styrene oxide metabolism in rat, mouse, and human.

Styrene oxide (SO), a labile metabolite of styrene, is generally accepted as being responsible for any genotoxicity associated with styrene. To better define the hazard associated with styrene, the activity of the enzymes involved in the formation (monooxygenase) and destruction of SO (epoxide hydrolase and glutathione-S-transferase) were measured in the liver and lungs from naive and styrene-exposed male Sprague-Dawley rats and B6C3F1 mice (three daily 6-h inhalation exposures at up to 600 ppm styrene) and Fischer 344 rats (four daily 6-h inhalation exposures at up to 1000 ppm styrene), and in samples of human liver tissue. Additionally, the time course of styrene and SO in the blood was measured following oral administration of 500 mg styrene/kg body weight to naive Fischer rats and rats previously exposed to 1000 ppm styrene. The affinity of hepatic monooxygenase for styrene, as measured by the Michaelis constant (Km), was similar in the rat, mouse, and human. Based on the Vmax for monooxygenase activity and the relative liver and body size, the mouse had the greatest capacity and humans the lowest capacity to form SO from styrene. In contrast, human epoxide hydrolase and a greater affinity (i.e., lower Km) for SO than epoxide hydrolase from rats or mice while the apparent Vmax for epoxide hydrolase was similar in the rat, mouse, and human liver. However, the activity of epoxide hydrolase relative to monooxygenase activity was much greater in the human than in the rodent liver. Hepatic glutathione-S-transferase activity, as indicated by the Vmax, was 6- to 33-fold higher than epoxide hydrolase activity. However, the significance of the high glutathione-S-transferase activity is unknown because hydrolysis, rather than conjugation, is the primary pathway for SO detoxification in vivo. Human hepatic glutathione-S-transferase activity was extremely variable between individual human livers and much lower than in rat or mouse liver. Prior exposure to styrene had no effect on monooxygenase activity or on blood styrene levels in rats given a large oral dose of styrene. In contrast, prior exposure to styrene increased hepatic epoxide hydrolase activity 1.6-fold and resulted in lower (0.1 > P > 0.05) blood SO levels in rats given a large oral dose of styrene. Qualitatively, these data indicate that the mouse has the greatest capacity and the human the lowest capacity to form SO. In addition, human liver should be more effective than rodent liver in hydrolyzing low levels of SO.(ABSTRACT TRUNCATED AT 400 WORDS)

Methylene chloride: a two-year inhalation toxicity and oncogenicity study in rats and hamsters.

A long-term study was conducted to determine the possible chronic toxicity and oncogenicity of methylene chloride. Rats and hamsters were exposed by inhalation to 0, 500, 1500, or 3500 ppm of methylene chloride for 6 hr per day, 5 days a week, for 2 years. No exposure-related cytogenetic effects were present in male or female rats exposed to 500, 1500, or 3500 ppm. Females rats exposed to 3500 ppm had an increased mortality rate while female hamsters exposed to 1500 or 3500 ppm had decreased mortality rates. Carboxyhemoglobin values were elevated in rats and hamsters exposed to 500, 1500, or 3500 ppm with the percentage increase in hamsters greater than in rats. Minimal histopathologic effects were present in the livers of rats exposed to 500, 1500, or 3500 ppm. Decreased amyloidosis was observed in the liver and other organs in hamsters exposed to 500, 1500 or 3500 ppm. While the number of female rats with a benign tumor was not increased, the total number of benign mammary tumors was increased in female rats in an exposure-related manner. This effect was also evident in male rats in the 1500- and 3500-ppm exposure groups. Finally, male rats exposed to 1500 or 3500 ppm had an increased number of sarcomas in the ventral neck region located in or around the salivary glands. Therefore, in this 2-year study, some effects were observed in male and female rats exposed to 500, 1500, or 3500 ppm of methylene chloride. In contrast, hamsters exposed to the same exposure concentrations had less extensive spontaneous geriatric changes, decreased mortality (females), and lacked evidence of definite target organ toxicity.