The effect of repeated methyl iso-butyl ketone vapor exposure on schedule-controlled operant behavior in rats

Methyl iso-butyl ketone (MiBK), a commercial solvent, was selected by the U S Environmental Protection Agency (US EPA) for testing under the Multi-Subs tance Rule for the Testing of Neurotoxicity (US EPA, 1993) using schedule-c ontrolled operant behavior (SCOB) to determine if subchronic exposure to Mi BK vapor had the potential to alter behavior as an indicator of neurotoxici ty. Food-restricted and ad libitum-fed Sprague-Dawley male rats were expose d to 0, 250, 750, or 1500 ppm MiBK for 6 h/day, 5 d/wk for 13 weeks. SCOB t esting of food-restricted animals, using a multiple fixed ratio (FR)/fixed interval (FI) schedule (FR20:FI120), was conducted prior to each exposure t o maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. SCOB testing was also evaluated fo r two weeks following the cessation of exposures. Ad libitum-fed animals we re included to assess systemic effects using routine indicators such as cha nges in body weight, food consumption, and organ weight. No significant dif ferences were seen in fixed-ratio run rate, FR pause duration, fixed-interv al response rate, and index of curvature values at any concentration. Anima ls exposed to 750 and 1500 ppm MiBK exhibited clinical signs associated wit h transient reduced activity levels, but only during exposure. No signs of reduced activity were observed immediately after exposure for either group. No other treatment-related abnormalities were observed during exposure. Fo od-restricted animals did not demonstrate any increased or decreased sensit ivity to the CNS depressive effects of MiBK, relative to the ad libitum-fed animals. No treatment-related body weight differences were observed within either the food-restricted groups or the ad libitum-fed groups, although b ody weights of the former were clearly depressed compared with those of the latter. Relative and absolute liver, and relative kidney weights were sign ificantly greater for the 750 and 1500 ppm ad libitum-fed animals. No diffe rences in kidney weight were observed for food-restricted animals, but abso lute and/or relative liver weights were significantly higher for all the tr eated food-restricted groups. The results of this study indicate that repet itive exposures to high concentrations of MiBK vapors do not result in adve rse effects on operant behavior in the rat. (C)1999 Intox Press, Inc.