Comparative Pulmonary Toxicity of Inhaled Metalworking Fluids in Rats and Mice

Ryan KR, Cesta MF, Herbert R, Brix A, Cora M, Witt K, Kissling G, Morgan DL.
Toxicol Ind Health. 2017 DOI: https://doi.org/10.1177/0748233716653912 PMID: 27343050

Publication

Abstract

Metalworking fluids (MWFs) are complex formulations designed for effective lubricating, cooling, and cleaning tools and parts during machining operations. Adverse health effects such as respiratory symptoms, dermatitis, and cancer have been reported in workers exposed to MWFs. Several constituents of MWFs have been implicated in toxicity and have been removed from the formulations over the years. However, animal studies with newer MWFs demonstrate that they continue to pose a health risk. This investigation examines the hypothesis that unrecognized health hazards exist in currently marketed MWF formulations that are presumed to be safe based on hazard assessments of individual ingredients. In vivo 13-week inhalation studies were designed to characterize and compare the potential toxicity of four MWFs: Trim VX, Cimstar 3800, Trim SC210, and Syntilo 1023. Male and female Wistar Han rats or Fischer 344N/Tac rats and B6C3F1/N mice were exposed to MWFs via whole-body inhalation at concentrations of 0, 25, 50, 100, 200, or 400 mg/m3 for 13 weeks, after which, survival, body and organ weights, hematology and clinical chemistry, histopathology, and genotoxicity were assessed following exposure. Although high concentrations were used, survival was not affected and toxicity was primarily within the respiratory tract of male and female rats and mice. Minor variances in toxicity were attributed to differences among species as well as in the chemical components of each MWF. Pulmonary fibrosis was present only in rats and mice exposed to Trim VX. These data confirm that newer MWFs have the potential to cause respiratory toxicity in workers who are repeatedly exposed via inhalation.

Figures

Figure 1. H&E staining of tissue sections from the lung, larynx, and nose of rats or mice.

(a) Lung fibrosis in a male Wistar Han rat exposed to 400 mg/m3 Trim VX for 13 weeks. (b) Hyperplasia (arrows) of the normally single-layered bronchiolar epithelium in a terminal bronchiole in a male B6C3F1/N mouse exposed to 400 mg/m3 Trim VX for 13 weeks. (c) Squamous metaplasia (arrowheads) and dysplasia (arrow) of the normally cuboidal to columnar respiratory epithelium at the base of the epiglottis in the larynx of a male F344/NTac rat exposed to 50 mg/m3 Cimstar 3800 for 13 weeks. There is minimal chronic active inflammation in the submucosa underlying the epithelium (asterisk). (d) Hyperplasia of the squamous epithelium overlying the arytenoid cartilages (arrows) in the larynx of a male F344/NTac rat exposed to 400 mg/m3 Trim SC210 for 13 weeks. There is also chronic active inflammation in the submucosal tissue adjacent to the arytenoid cartilages (asterisks). (e) Hyaline droplet accumulation (arrows) in the olfactory epithelium of the nose in a rat exposed to 400 mg/m3 Trim VX for 13 weeks. There is also suppurative inflammation (neutrophils) in the submucosal tissue subjacent to the epithelium (asterisks). (f) Goblet cell hyperplasia (arrows) in the respiratory epithelium lining the nasal septum of the nose in a male rat exposed to 400 mg/m3 Trim SC 210 for 13 weeks. H&E: hematoxylin and eosin.

Figure 1 (1 MB)

Figure 2. Frozen tissue sections of the lung stained with the Oil-Red-O histochemical stain.

Frozen tissue sections of the lung stained with the Oil-Red-O histochemical stain for oil/lipids. (a) Male rat exposed to 400 mg/m3 Trim VX by inhalation. There are infiltrates of lipid-laden macrophages (infiltration cellular, histiocyte) within the alveolar spaces (arrowheads) associated with focal fibrosis (asterisk). (b) Male rat exposed to 400 mg/m3 Cimstar 3800 by inhalation. Compared to Figure 2(a), there are significantly fewer and smaller lipid-ladened macrophages (arrowheads) in the alveolar space. (c) Male rat exposed to 400 mg/m3 Trim SC210 by inhalation. There are focal areas of free lipid and low numbers lipid-laden macrophages (arrows) within lung parenchyma. (d) Male rat exposed to 400 mg/m3 Syntilo 1023 by inhalation. Note that there are no lipid-ladened macrophages within the alveolar space.

Figure 2 (958 KB)

Tables

Table 1. Chemical characterization of metalworking fluids.

Table 1 (428 KB)

Table 2. Decreased mean final body weights of rats and mice exposed to metalworking fluids.

Table 2 (298 KB)

Table 3. Increased lung weights of rats and mice exposed to metalworking fluids.

Table 3 (624 KB)

Table 4. Histopathological lesions in the lungs of male rats and mice exposed to metalworking fluids.

Table 4 (547 KB)

Table 5. Histopathological lesions in the larynx of male rats and mice exposed to metalworking fluids.

Table 5 (643 KB)

Table 6. Histopathological lesions in the nasal cavity of male rats and mice exposed to metalworking fluids.

Table 6 (706 KB)