Previous repeated inhalation exposure studies revealed two independent organotropic effects of inhaled
propineb dust: One was restricted to the lung, the other to
muscle weakness of hindlimbs. These effects were believed to be causally related to the principle decomposition products of this type of dithiocarbamate in the
biological milieu and related to
zinc and
carbon disulfide. Two mechanistic 1-wk inhalation studies were performed, each focusing on one of these findings. The 7 x 6-h/day repeated-exposure inhalation study analyzed whether the nature of the response occurring at the alveolar level is "adaptive" or "early adverse" and whether soluble
zinc is the causative agent. Groups of 18 female rats were exposed nose-only to mean concentrations of 0, 1.1, 5.5, and 25.8 mg
propineb/m(3) and 6.9 mg ZnO/m(3). On postexposure days 1, 3, and 15 the time course of responses was analyzed by bronchoalveolar lavage (BAL), including quantification of Zn and
metallothionein (MT) in BAL cells. Clinical evidence of
muscular weakness was investigated separately in 20 female Wistar rats exposed to 70 mg
propineb/m(3) on 5 consecutive days (6 h/day), followed by a 2-wk postexposure period. Clinical signs,
body weights, and feed and water consumption were recorded as frequently as technically feasible. Fifty percent of rats received an oral
cysteine supplementation to verify/refute the hypothesis that the incapacitation observed in previous studies is the cause of
emaciation and associated impairment of CS(2) detoxification. The findings of the first study are consistent with this hypothesis, namely, that soluble Zn triggers a series of pulmonary events that is consistent with the homeostasis of this essential
metal. It is concluded, accordingly, that the adjusted maximal workplace level for ZnO is also valid for
propineb to preclude Zn-mediated responses to occur in the lung. With respect to muscular effects, this mechanistic study demonstrates further that the increased detoxification capacity afforded by oral supplementation of
cysteine mitigates markedly the toxic potency of
propineb. Procedural variables specific to the inhalation bioassay appear to be decisive for the elicitation of muscular effects. The major variable is considered to be the large drop in
body weights associated with each exposure session and the concomitantly decreased uptake of essential nutritional factors (e.g.,
cysteine) involved in the detoxification of this compound. Accordingly, the muscular deficits elicited by high concentrations of
propineb are viewed to be secondary effects in an animal species likely to be more susceptible to this type of change than humans (Pauluhn & Rosenbruch, 2003).