This study was designed to examine the role of flavin-containing monooxygenase (FMO) on the auditory and vestibular neurotoxicity of 3,3'-iminodipropionitrile (IDPN) using the FMO substrate and competitive inhibitor methimazole (MMI). Specifically, the purpose was to block the FMO-mediated conversion of IDPN to the putative neurotoxic metabolite N-hydroxy3,3'-iminodipropionitrile (HOIDPN). In three separate experiments, adult male Long-Evans hooded rats were administered (ip) saline (vehicle), MMI, IDPN, or HOIDPN individually, or a combination of IDPN and MMI or HOIDPN and MMI. Animals were observed daily for signs of the ECC syndrome (excitation with choreiform and circling movements) for 10 days. One to 2 weeks after exposure, a battery of behavioral tests was used to examine vestibular and auditory function. MMI completely blocked the neurotoxicity associated with a 600 mg/kg dose of IDPN and partially blocked the effects of a 1000 mg/kg dose of IDPN. In contrast, MMI failed to block, and instead increased, the neurotoxicity associated with HOIDPN. These data suggest that FMOmediated metabolism of IDPN is necessary for the generation of a metabolite responsible for the vestibular and auditory neurotox- icitieS. C 1997 Society of ToThe synthetic organonitrile 3,3'-iminodipropionitrile (IDPN) is known to produce the ECC syndrome excitation with cho-' This article has been reviewed by the National Health Effects and Environmental Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. This work was supported in part by the North Carolina Agricultural Research Service (M.B.G.), NIEHS Grant ES-00044 (M.B.G.), and NIH Grant NS22688 (L.M.S.).2 To whom correspondence should be addressed at Neurotoxicology Division [MD-74B] USEPA, R.T.P., NC 27711. E-mail: crofton.kevin® EPAMAIL.EPA.GOV. reiform and circling movements (Delay, 1952; Thullier and Burger, 1954;Selye, 1957) through degeneration of the vestibular system (Slagel and Hartman, 1965;Llorens et al., 1993;Llorens and Dememes, 1994). IDPN has also been associated with auditory and olfactory damage, and proximal axonopathy (Chou and Hartman, 1964;Griffin et al., 1978;Crofton and Knight, 1991;Genter et al, 1992Genter et al, , 1994aCrofton et al., 1994). Currently, the role of metabolism in IDPNinduced neurotoxicity is unclear.Theories on the activation of LDPN have involved three possible metabolic pathways: (1) cytochrome P450 metabolism, (2) monoamine oxidase (MAO) metabolism, and (3) flavin-containing monooxygenase (FMO) metabolism (e.g., Jacobson et al., 1987). It has also been suggested that IDPN is the toxic compound and needs no hepatic bioactivation (Llorens and Crofton, 1991). Tanii et al. (1984) first demonstrated that the neurotoxicity of some related neurotoxic nitriles (e.g., 2-pentenenitrile) was increased by inactivation of hepatic P450s with carbon tetrachloride (CC1 4 ) pretreatment. After observing enhanced v...

Residential indoor concentration of asbestos, lead, synthetic vitreous fiber (SVF), crystalline silica, calcite, gypsum, dioxin, and polycyclic aromatic hydrocarbons (PAHs) were measured in 25 residences and 9 building-interior common areas in upper Manhattan, NY. This was done to characterize the background levels of contaminants, identified in dust related to the collapse of the World Trade Center towers, at locations that were minimally impacted by the dust fallout. The study was initiated due to the paucity of background concentrations on building-related materials and combustion byproducts in urban residential dwellings. Asbestos, lead, SVF, crystalline silica, and dioxin were detected at very low concentration at some locations, and many samples tested below their respective analysis detection limits. Almost all of the environmental samples for PAHs, calcite, gypsum, and certain other building materials tested below their respective analysis detection limits. A comparative analysis to the limited literature data showed general agreement with the values found in this study. This study provides insight into the levels of these contaminants in lower Manhattan residential buildings prior to the attack, and these data will serve to enhance the available database for characterizing indoor environments for these contaminants.

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