Human activities, adverse effects concentrations

Neurotoxicity. No information is available on neurotoxic effects of hexachloroethane in humans following any route of exposure. Acute inhalation exposure in rats caused staggering gait after exposure to high concentrations (5,900 ppm) (Weeks et al. 1979). The usefulness of this data is limited since this concentration was lethal. Tremors have been reported at 260 ppm but not 48 ppm following inhalation exposure of rats in a developmental study and in a study of 6-weeks duration (Weeks et al. 1979). The lack of tremors at 48 ppm in the developmental study serves as the basis for the acute inhalation MRL, and the lack of tremors at 48 ppm in the 6-week study serves as the basis for the intermediate inhalation MRL. One study that evaluated spontaneous motor activity and avoidance behavior in rats during 6 weeks of exposure to 260 ppm hexachloroethane vapors did not reveal adverse effects of hexachloroethane on these neurobehavioral functions (Weeks et al. 1979). 

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans following inhalation exposure to mirex. Electrocardiography of 23 workers with active symptoms of chlordecone intoxication resulting from intermediate- or chronic-duration inhalation exposures to high blood concentrations (in excess of 2 pg/L) of chlordecone revealed no adverse effects on the heart (Taylor 1982, 1985). 

This herb has been part of folk medicine since pre-Christian times (247). It has been primarily used as a sedative and for the treatment of epilepsy. Consistent with this use, this herb reportedly can increase synaptic concentrations of GABA (248). GABA has also been isolated from Valeria and extracts of Valeria have been reported to bind to GABA receptors in rat brain. Although Valeria has been reported to be active in rodent models of depression, there have been no efficacy trials in humans. The potential adverse effects of Valeria include the sensation of strangeness ( 247) and several cases of liver damage (e.g., central lobular necrosis) (249). Mutagenicity in bacteria has been reported and attributed to unstable, water-insoluble valepotriates ( 238). As a result of these reports, many, but not all, commercial preparations of Valeria use water-soluble extracts standardized for their content of valeric acid. 

In humans, bupropion undergoes extensive biotransformation to three metabolites that have pharmacological activity ( 469). During treatment, these metabolites accumulate in concentrations several times higher than the parent compound (352). High plasma levels of these metabolites, particularly hydroxybupropion, may be associated with an increased incidence of serious adverse effects, as well as poorer antidepressant response ( 314). These observations form the basis of the possible utility of using TDM to guide dose adjustment with bupropion. 

The Army s interim RfD of 6 x 10 mg/kg per day for VX was based on an oral toxicity study in sheep, in which depression in blood-ChE activity was observed. After evaluating that study, the subcommittee concludes that uncertainties about the relevance of this animal model to humans and weaknesses in the study design undermine the use of the study for deriving the RfD. Instead, the subcommittee recommends using a 1964 study of human volunteers in whom depression in RBC ChE was observed after oral exposure to low concentrations of VX. Although that study also has weaknesses and involves a biomarker of exposure rather than an adverse effect, the subcommittee believes it is preferable to use human data rather than data from a questionable animal model, because the uncertainty associated with extrapolating from animals to humans is avoided. On the basis of the human study, the subcommittee concludes that the data on VX support an RfD of 5 x 10 mg/kg per day, which is slightly lower than the Army s interim RfD of 6 x 10 mg/kg per day. 

Antithrombin III is a plasma alpha2-glycoprotem that accounts for most of the antithrombin activity in plasma and also inhibits other proteolytic enzymes. Hereditary or acquired antithrombin III deficiency results in thromboembolism. The effectiveness of treatment with antithrombin III, prepared as a concentrate from human plasma, is stiU a matter of dispute (1,2). Apart from vasodilatation, leading to a reduction in blood pressure, remarkably few adverse effects have been noted (2,3). The fall in blood pressure seems to be related to the rate of the infusion. 

---