Behavioral toxicity acute effects

The data in animals are insufficient to derive an acute inhalation MRL because serious effects were observed at the lowest dose tested (Hoechst 1983a). No acute oral MRL was derived for the same reason. The available toxicokinetic data are not adequate to predict the behavior of endosulfan across routes of exposure. However, the limited toxicity information available does indicate that similar effects are observed (i.e., death, neurotoxicity) in both animals and humans across all routes of exposure, but the concentrations that cause these effects may not be predictable for all routes. Most of the acute effects of endosulfan have been well characterized following exposure via the inhalation, oral, and dermal routes in experimental animals, and additional information on the acute effects of endosulfan does not appear necessary. However, further well conducted developmental studies may clarify whether this chemical causes adverse developmental effects. 

The precise mechanism of dimethylhydrazine toxicity is uncertain. In addition to the contact irritant effects, the acute effects of dimethylhydrazine exposure may involve the central nervous system as exemplified by tremors and convulsions (Shaffer and Wands 1973) and behavioral changes at sublethal doses (Streman et al. 1969). Back and Thomas (1963) noted that the deaths probably involve respiratory arrest and cardiovascular collapse. The central nervous system as a target is consistent with the delayed latency in response reported for dimethylhydrazine (Back and Thomas 1963). There is some evidence that 1,1-dimethylhydrazine may act as an inhibitor of glutamic acid decarboxylase, thereby adversely affecting the aminobutyric acid shunt, and could explain the latency of central-nervous-system effects (Back and Thomas 1963). Furthermore, vitamin B6 analogues that act as coenzymes in the aminobutyric acid shunt have been shown to be effective antagonists to 1,1-dimethylhydrazine toxicity (reviewed in Back and Thomas 1963). 

Acute exposure to high doses of lindane is known to cause CNS stimulation (usually developing within 1 hour), mental/motor impairment, excitation, clonic (intermittent) and tonic (continuous) convulsions, increased respiratory rate and/or failure, pulmonary edema, and dermatitis. Toxic symptoms in humans are more behavioral in nature (e.g., loss of balance, teeth grinding, and hyperirritability. Most acute effects in humans have been the result of accidental or intentional ingestion, although inhalation toxicity occurred (especially among children) when lindane was used in vaporizers. 

Hundreds of patients have received huge doses of atropine and scopolamine (up to 250 mg), sometimes given three times a week for up to 4 mo, and this form of therapy continues in Eastern Europe today. A chronic behavioral syndrome of toxicity appears unlikely, and single or even multiple exposures to the anticholinergic drugs used In the volunteers, frequently at low doses, are deemed Insufficient to stimulate a persistent toxic syndrome. Of course. Individual susceptibility to acute effects, which may trigger a long-term effect, cannot be excluded. 

One final common inclusion in many studies of occupational behavioral toxicology and in some test batteries is assessments of symptoms experienced by those exposed to chemicals. While this might be perceived as an ostensibly simple procedure, it entails numerous potential confounds. These evaluations are typically administered via questionnaires. Items for the questionnaire must be carefully constructed with respect to not only the choices of items but also the wording of the text and the manner in which the response is recorded. Clearly, the motivation of the subject in answering the questions must be considered. One problem can arise when the list of symptoms includes only those that are associated with the toxicant of concern. It is necessary to include symptoms that are not associated with the particular toxicant under evaluation so that some assessment of the tendency of the subject to respond positively to all symptoms can be evaluated. Several such evaluations of subjective and mood states are available. The most widely used is the Profile of Mood States (POMS), which consists of 65 adjectives of various moods that the subject answers according to a 5-point rating scale. The POMS has been used extensively in the evaluation of the acute effects of CNS drugs and toxicants. 

Safety/Toxicity Acute toxicity carcinogenicity childhood behavior effects chromosomal aberra-tion cytotoxicity genotoxicity mutagenicity " neurotoxicity reproductive toxicity Certification/Approval Approved by Food Drugs Administration (FDA)... 

No acute oral MRL was derived for methyl parathion because data regarding the most sensitive effect that was observed after acute oral exposure are conflicting. Increased pup mortality and altered behavior occurred in offspring of rats exposed to 1 mg/kg/day methyl parathion during, but no effects on pup survival or on sensitive electrophysiological indices of neurotoxicity were seen at virtually the same dose, 0.88 mg/kg/day, in a similar developmental toxicity study. 

In summary, neurotoxic effects of endosulfan are usually apparent only after acute ingestion of relatively high doses. Cumulative neurotoxicity does not appear to be significant. If the animal survives the acute toxic effects, then no long-term neurotoxic effects are evident from behavioral, gross, and microscopic observations. However, some impairment may occur that can be detected only by specialized neurobehavioral testing. 

The precise mechanism of monomethylhydrazine toxicity is uncertain. In addition to the contact irritant effects, the acute toxicity of dimethylhydrazine exposure probably involves the central nervous system as exemplified by tremors and convulsions (Shaffer and Wands 1973) and behavioral changes at sublethal doses (Streman et al. 1969). Additionally, renal and hepatic toxicity and hemolytic effects imply alternate mechanisms of toxicity. 

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