Inhalation Toxicity of Propineb. Part II: Results of Mechanistic Studies in Rats

Abstract

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).

Derivation of occupational exposure levels (OELs) of Low-toxicity isometric biopersistent particles: how can the kinetic lung overload paradigm be used for improved inhalation toxicity study design and OEL-derivation?

“…These studies were tolerated without any evidence of pulmonary toxicity despite increased solubility and 10-fold differences in particle surface areas. This outcome supports the notion that in vitro “insolubility” in water cannot readily be translated to that present in the pulmonary system.

Figure 4 Modeling of two C × Σt-adjusted subchronic barium sulfate inhalation studies with different particle size and surface areas from Cullen et al [ 9 , 32 ]. Symbols were reproduced from figures given by these authors.

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“…The example shown in Figure 2 compares two substances commonly categorized as PSP, one is a chelate of zinc (solubility in the range of ≤1 mg/L H 2 O), the other was zinc oxide (ZnO, pigment grade; solubility in the range of ~10 mg/L H 2 O) using a 7-day 6 h/day inhalation bioassay on rats [31,32]. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were for the chelate ~1.9 μm (2.3) and for ZnO ~1.6 μm (1.6), respectively.…”

“…The highest toxicity occurred in ZnO-exposed rats at lower concentration of total dust (for more details see ref. [32]), which delineates the importance of dissolution rate and flux (for details see [31,32]).…”

“… Modeling of two C × Σt-adjusted subchronic barium sulfate inhalation studies with different particle size and surface areas from Cullen et al [ 9 , 32 ]. Symbols were reproduced from figures given by these authors.…”

Assessment of inhaled dust by workers and suspended dust for pollution control change and ergonomic intervention in metal casting industry: A cross-sectional study

“…Change of inhaled dust level on each department affected by material characteristics and process occurred, including measurement time condition [53]. Dust characteristic in Black Sand department is the raw material used continuously in recycle, additional materials in form of water to make steel cast, thus dryness level of the materials is incredibly high.…”