Neurotoxicity animal studies

Cholinesterase inhibition can sometimes persist for weeks thus, repeated exposures to small amounts of this material may result in accumulation of acetylcholinesterase inhibition with possible sudden-onset acute toxicity. Chlorpyrifos may be capable of causing organophosphate-induced delayed neurotoxicity in humans a massive overdose resulted in signs characteristic of delayed neurotoxicity. Animal studies generally indicate, however, that doses several times higher than the LD50 would be required to initiate delayed neurotoxicity. 

Evidence of neurotoxicity was also observed in animal studies. Nose-only exposure of rats to endosulfan at concentrations of 3.6 mg/m in females and 12.3 mg/m in males resulted in trembling and ataxia (Hoechst 1983a). At higher concentrations in both sexes, tremors, tonic-clonic convulsions, and reduced corneal, pupillary, placing, shock, paw-pinch, and cutaneous reflexes were observed. Nose-only exposure of male and female rats to concentrations of endosulfan of up to 2 mg/m for 6 hours/day,... 

Additional animal studies of trichloroethylene following intermediate-duration oral exposure are necessary to further define dose-response relationships. Because developmental neurotoxicity appears to be a sensitive end point, a focus on this end point would be useful. Animals studies following intermediate-duration dermal exposure are necessary. These studies would indicate whether targets following dermal exposure differ compared to inhalation and oral exposure. 

Ferguson and Bowman 1990 Gilbert and Rice 1987 Hopper et al. 1986 Krasovskii et al. 1979 Levin et al. 1988 Massaro and Massaro 1987 Overmann 1977 Rice 1985a). It appears that animals are affected at roughly the same blood lead levels as humans. Measured neurotoxic effects in animals include significantly delayed motor function and reflexes, decreased performance on learning tasks, and impaired spatial discrimination. Additional animal studies are needed to investigate the neurotoxic effects of subchronic inhalation exposures to establish external dose-effect relationships. 

Neurotoxicity. Clinical signs indicative of disturbances of the nervous system in exposed humans have been well documented in short-term studies at high doses and appear to be reversible. These effects are characteristic of cyanide toxicity. Animal studies confirm findings in humans. In longer-term studies, effects on the nervous system have also been reported, but it is not certain if these effects are permanent or reversible following termination of acrylonitrile exposure. 

Data adequacy The key study was well designed, conducted, and documented used 20 human subjects and utilized a range of concentrations and exposure durations. Occupational exposures support the 8-h AEGL value. The mechanism of headache induction (vasodilation) is well understood and occurs following therapeutic administration of nitrate esters to humans. Animal studies utilized several mammalian species and addressed metabolism, neurotoxicity, developmental and reproductive toxicity, and potential carcinogenicity. ... 

Experimental studies with human subjects and several mammalian species (monkey, dog, rat, mouse, and rabbit) were located. Animal studies addressed neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitization and were conducted over acute, subchronic, and chronic exposure durations. 

The database for HFC-134a is extensive it contains studies with both human subjects and animal models. Potentially sensitive populations, including patients with COPD and adult and pediatric asthmatic patients, were tested with direct inhalation of HFC-134a from metered-dose inhalers. The response of these groups was no different than that of healthy adults. The animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The metabolism of HFC-134a is well understood, and the relationship of exposure con... 

The data base for HCFC-141b is extensive and contains studies with human subjects as well as several mammalian species. The study with human subjects was well conducted and addressed clinical symptoms, respiratory effects, cardiotoxicity, hematology and clinical chemistry effects, and pharmacokinetics. The study with humans established a no-effect level (AEGL-1) that may be conservative, because a lowest-observed-effect level was not attained. The AEGL-1 of 1,000 ppm is supported by the animal data, which show an absence of effects at concentrations that are higher by a factor of 10. Animal studies addressed both acute and chronic exposure durations as well as neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitiza... 

Data adequacy The key study was well designed, conducted, and documented. Exercise takes into consideration some of the stress that humans might experience under emergency conditions. Animal studies addressed both acute and chronic exposure durations as well as neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitization. In animal studies, concentrations up to 11,000 ppm for up to 6 h did not produce adverse effects. Adjustment of the 11,000-ppm concentration by interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same concentration (1,100 ppm) as that derived from the human data. 

In other studies where histopathological examination of the respiratory tract was performed after inhalation of -hexanc, no lesions were noted in male Sprague-Dawley rats exposed to up to 500 ppm M-hexane for 22 hours a day, 7 days a week for 6 months (IRDC 1981) or in Fischer 344 rats of both sexes exposed to up to 10,000 ppm for 6 hours a day, 5 days a week for 13 weeks (Cavender et al. 1984). It should be noted that respiratory effects observed in these animal studies occurred at concentrations that are substantially higher than needed to cause neurotoxicity in rats (see Section 2.2.1.4). Thus, respiratory effects do not appear to be a sensitive indicator of -hexanc toxicity. 

It is not entirely clear whether the acetone co-exposure in the Sanagi et al. (1980) study contributed to the observed effects. Indirect evidence from an occupational study (Cardona et al. 1996) showed that workplace acetone concentrations had a statistical correlation with the ratio of urinary -hexane metabolites to /i-hcxanc air concentration, although it did not correlate with measured urinary metabolites. No animal studies are available describing the effects of inhalation co-exposure to acetone and -hexane, although there are several studies which report interactions between acetone and the neurotoxic metabolite of -hexane 2,5-hexanedione (See Section 2.4, Mechanisms of Action). Oral administration of acetone has been reported to potentiate the neurotoxicity caused by oral exposure to the neurotoxic u-hexane metabolite 2,5-hexanedione in rats (Ladefoged et al. 1989, 1994). Oral exposure to acetone alone in rats at 650 mg/kg/day resulted in a statistically significant decrease in motor nerve conduction velocity after 6 weeks co-exposure to acetone and 2,5-hexanedione resulted in greater effects... 

Neurological Effects. The major public health concern regarding -hexane exposure is the potential for the development of neurotoxicity. Occupational studies have documented that human exposure to -hexane can result in a peripheral neuropathy that in severe cases can lead to paralysis (Altenkirch et al. 1977 Yamamura 1969 Wang et al. 1986). The dose-duration relationship has not been well characterized in humans, but concentrations of 500 ppm and above, and exposure for 2 months or more have been associated with human neurotoxicity. Brief exposure to extremely high concentrations of w-hexane may cause signs of narcosis in humans prostration and coma have been observed in animals exposed to a mixture of hexanes at concentrations of 70,000-80,000 ppm (Hine and Zuidema 1970). At these levels, however, explosion and fire would be the main concern. 

ATSDR has derived an intermediate oral MRL of 0.002 mg/kg/day based on a laboratory animal study showing neurotoxic effects in dogs (Treon et al. 1955). 

ATSDR has derived a chronic oral MRL of 0.0003 mg/kg/day based on a laboratory animal study showing neurotoxic effects in dogs (Kettering Lab 1969). The EPA reference dose for endrin is 3xl0 4 mg/kg/day, and the critical dose is 0.025 mg/kg/day (IRIS 1995). Critical effects were occasional convulsions and mild histological lesions in the liver (Kettering Lab 1969). No EPA reference concentration exists for the compound. 

Information regarding health effects of fuel oils in humans and animals is available for the inhalation, oral, and dermal routes of exposure. Most of the information in humans is from cases of accidental ingestion of kerosene that resulted in respiratory, neurotoxic, and to a lesser extent, gastrointestinal effects. In addition, a few case studies have identified these effects as well as cardiovascular, hematological, and renal effects in humans after inhalation and/or dermal exposures to fuel oils. Fuel oils appear to be eye and skin irritants in both animals and humans following direct contact. Animal data exist for most systemic effects however, the data are inconclusive for many of the endpoints. Further, a number of the animal studies... 

Neurotoxicity in humans from dermal exposures has been reported in 1 case study in which anorexia was noted (Crisp et al. 1979) inhalation exposure may have also occurred. One animal study found no histopathological changes in the organs of the nervous system in mice following chronic and/or intermediate dermal exposures to marine diesel fuel and JP-5 (NTP/NIH 1986). However, increased response to tactile stimuli and hyperactivity occurred in mice from acute dermal exposures to kerosene (Upreti et al. 1989). 

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