Nephropathies and exposure to perchloroethylene in dry-cleaners

doi:10.1016/0140-6736(92)90463-D

The Lancet

Volume 340, Issue 8813, 25 July 1992, Pages 189-193

https://doi.org/10.1016/0140-6736(92)90463-D Get rights and content

Abstract

Even in specific risk groups, the relation between exposure to organic solvents and chronic renal diseases remains controversial. Thus, in a collaborative European study, we assessed the renal effects of occupational exposure to perchloroethylene (PCE) in dry-cleaners compared with matched controls who were simultaneously examined. Single high and low molecular weight proteins, kidney-derived antigens and enzymes, and prostanoids were measured in urine. β₂-microglobulin, creatinine, laminin fragments, and anti-glomerular basement membrane antibodies were also measured in serum. A canonical function based on 23 such variables correctly classified 93% of individuals as either PCE-exposed or controls; with 13 markers, group membership was identified in 87% of subjects. Increased high molecular weight protein in urine was frequently (17/50 vs 1/50, p<0·0001) associated with tubular alterations. Changes were consistent with diffuse abnormalities along the nephron in workers exposed to low levels of PCE (median 15 parts per million). Generalised membrane disturbances might account for the increased release of laminin fragments, fibronectin, and glycosaminoglycans, for high molecular weight proteinuria, and for the increased shedding of epithelial membrane components from tubular cells with different location along the nephron (brush-border antigens and Tamm-Horsfall glycoprotein). These findings of early renal changes indicate that solvent-exposed subjects, especially dry-cleaners, need to be monitored for the possible development of chronic renal diseases.

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Citation Excerpt :
Therefore, a clear understanding of the potential adverse health effects of PCE, especially systemic toxic effects is warranted. PCE, besides causing organ toxicity and cancer, has also been implicated in autoimmune diseases (ADs), including scleroderma and systemic lupus erythematosus (SLE)-like symptoms in humans (Aschengrau et al., 2015; Chaigne et al., 2015; Guyton et al., 2014; Kilburn and Warshaw, 1992; Lash and Parker, 2001; Marie et al., 2014; Mutti et al., 1992; Pralong et al., 2009; Salahudeen, 1998). Since Sparrow's first report of a Raynaud's disease along with high titers of anti-nuclear antibodies (ANA) in a subject exposed to PCE exposure (Sparrow, 1977), a number of reports as well as epidemiologic studies have provided further evidence for the involvement of PCE in the development of ADs both from environmental and occupational exposures (Chaigne et al., 2015; Kilburn and Warshaw, 1992; Marie et al., 2014; Mora, 2009; Mutti et al., 1992; Pralong et al., 2009).
Tetrachloroethene (perchloroethylene, PCE), an ubiquitous environmental contaminant, has been implicated in inducing autoimmunity/autoimmune diseases (ADs), including systemic lupus erythematosus (SLE) and scleroderma in humans. However, experimental evidence suggesting the potential of PCE in mediating autoimmunity is lacking. This study was, therefore, undertaken to explore PCE's potential in inducing/exacerbating an autoimmune response. Six-week old female MRL +/+ mice, in groups of 6 each, were treated with PCE (0.5 mg/ml) via drinking water for 12, 18 and 24 weeks and markers of autoimmunity and oxidative stress were evaluated. PCE exposure led to significant increases in serum anti-nuclear antibodies (ANA), anti-dsDNA and anti-scleroderma-70 (anti-Scl-70) antibodies at 18 weeks and, to a greater extent at 24 weeks, suggesting that PCE exposure exacerbated autoimmunity in our animal model. The increases in autoantibodies were associated with time-dependent increases in malondialdehyde (MDA)-protein adducts and their antibodies, as well as significantly decreased levels of antioxidants GSH and SOD. The splenocytes isolated from mice treated with PCE for 18 and 24 weeks showed greater Th17 cell proliferation and increased release of IL-17 in culture supernatants following stimulation with MDA-mouse serum albumin adducts, suggesting that MDA-modified proteins may act as an immunologic trigger by activating Th17 cells and contribute to PCE-mediated autoimmunity. Our studies thus provide an experimental evidence that PCE induces/exacerbates an autoimmune response and lipid-derived aldehydes (such as MDA) contribute to this response.
Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans
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This article reports on the development of a “harmonized” PBPK model for the toxicokinetics of perchloroethylene (tetrachloroethylene or perc) in mice, rats, and humans that includes both oxidation and glutathione (GSH) conjugation of perc, the internal kinetics of the oxidative metabolite trichloroacetic acid (TCA), and the urinary excretion kinetics of the GSH conjugation metabolites N-Acetylated trichlorovinyl cysteine and dichloroacetic acid. The model utilizes a wider range of in vitro and in vivo data than any previous analysis alone, with in vitro data used for initial, or “baseline,” parameter estimates, and in vivo datasets separated into those used for “calibration” and those used for “evaluation.” Parameter calibration utilizes a limited Bayesian analysis involving flat priors and making inferences only using posterior modes obtained via Markov chain Monte Carlo (MCMC). As expected, the major route of elimination of absorbed perc is predicted to be exhalation as parent compound, with metabolism accounting for less than 20% of intake except in the case of mice exposed orally, in which metabolism is predicted to be slightly over 50% at lower exposures. In all three species, the concentration of perc in blood, the extent of perc oxidation, and the amount of TCA production is well-estimated, with residual uncertainties of ~ 2-fold. However, the resulting range of estimates for the amount of GSH conjugation is quite wide in humans (~ 3000-fold) and mice (~ 60-fold). While even high-end estimates of GSH conjugation in mice are lower than estimates of oxidation, in humans the estimated rates range from much lower to much higher than rates for perc oxidation. It is unclear to what extent this range reflects uncertainty, variability, or a combination. Importantly, by separating total perc metabolism into separate oxidative and conjugative pathways, an approach also recommended in a recent National Research Council review, this analysis reconciles the disparity between those previously published PBPK models that concluded low perc metabolism in humans and those that predicted high perc metabolism in humans. In essence, both conclusions are consistent with the data if augmented with some additional qualifications: in humans, oxidative metabolism is low, while GSH conjugation metabolism may be high or low, with uncertainty and/or interindividual variability spanning three orders of magnitude. More direct data on the internal kinetics of perc GSH conjugation, such as trichlorovinyl glutathione or tricholorvinyl cysteine in blood and/or tissues, would be needed to better characterize the uncertainty and variability in GSH conjugation in humans.
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In the last years an increasing number of subjects experienced respiratory failure and underwent tracheostomy. The aim of the present study was to analyze tracheal aspirates from the inflammatory point of view. Samples were collected from 38 consecutive tracheostomized patients: 13 COPD, 6 with neurologic disorders and 19 with other different causes of respiratory failure. We analyzed cells and soluble mediators related to inflammation and/or infection. We also compared results obtained in the tracheal aspirate of COPD patients with the same determination in the sputum of another group of non-tracheostomized COPD patients (n = 41).
Regardless of the underlying diagnosis, most of the samples were Pseudomonas aeruginosa positive and cells and soluble mediator did not differ. Treatment with steroids was associated with lower amount of total cells, neutrophils and lymphocytes, whereas treatment with antibiotics was not. Tracheal aspirate neutrophils correlated with PaCO₂ values; neutrophils and eosinophils correlated with their percentages in blood. As compared with sputa obtained from another group of culture-positive non-tracheostomized COPDs, tracheal aspirates showed similar cell count, proportions of inflammatory cells, and infection/inflammatory mediators.
In conclusion tracheal aspirates presented high amounts of viable cells and soluble mediators independently to the cause of respiratory failure leading to tracheotomy and they represent suitable specimens to study infection/inflammation interactions.
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The aim was to study the subchronic toxicity of perchloroethylene (Perc) by measuring injury and repair in liver and kidney in relation to disposition of Perc and its major metabolites. Male SW mice (25–29 g) were given three dose levels of Perc (150, 500, and 1000 mg/kg day) via aqueous gavage for 30 days. Tissue injury was measured during the dosing regimen (0, 1, 7, 14, and 30 days) and over a time course of 24–96 h after the last dose (30 days). Perc produced significant liver injury (ALT) after single day exposure to all three doses. Liver injury was mild to moderate and regressed following repeated exposure for 30 days. Subchronic Perc exposure induced neither kidney injury nor dysfunction during the entire time course as evidenced by normal renal histology and BUN. TCA was the major metabolite detected in blood, liver, and kidney. Traces of DCA were also detected in blood at initial time points after single day exposure. With single day exposure, metabolism of Perc to TCA was saturated with all three doses. AUC/dose ratio for TCA was significantly decreased with a concomitant increase in AUC/dose of Perc levels in liver and kidney after 30 days as compared to 1 day exposures, indicating inhibition of metabolism upon repeated exposure to Perc. Hepatic CYP2E1 expression and activity were unchanged indicating that CYP2E1 is not the critical enzyme inhibited. Hepatic CYP4A expression, measured as a marker of peroxisome proliferation was increased transiently only on day 7 with the high dose, but was unchanged at later time points. Liver tissue repair peaked at 7 days, with all three doses and was sustained after medium and high dose exposure for 14 days. These data indicate that subchronic Perc exposure via aqueous gavage does not induce nephrotoxicity and sustained hepatotoxicity suggesting adaptive hepatic repair mechanisms. Enzymes other than CYP2E1, involved in the metabolism of Perc may play a critical role in the metabolism of Perc upon subchronic exposure in SW mice. Liver injury decreased during repeated exposure due to inhibition of metabolism and possibly due to adaptive tissue repair mechanisms.
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ORIGINAL ARTICLESNephropathies and exposure to perchloroethylene in dry-cleaners

Abstract

Lancet

J Chromatogr Biomed Appi

Kidney Int

Clin Biochem

Clin Chim Acta

Acute nephritis due to turpentine absorbed by the skin

BMJ

Occupational solvent exposure and glomerulonephritis: a case-report and review of the literature

JAMA

Glomerulonephritis, renal carcinoma, and solvent exposure: bias from choice of referents

Br J Ind Med

Organic solvents and chronic glomerulonephritis: a cross-sectional study with negative findings for aliphatic and alicyclic C5-C7 hydrocarbons

J Appl Toxicol

Studies on kidney functions in subjects exposed to organic solvents: III. Excretion of cells in the urine

Acta Med Scand

Studies on kidney functions in subjects exposed to organic solvents: I. Excretion of albumin and β2-microglobulin in the urine

Acta Med Scand

A cross-sectional survey of kidney function in refinery workers

Am J Ind Med

Early indicators of renal damage in workers exposed to organic solvents

Int Arch Occup Environ Health

Health surveillance of workers exposed to tetrachloroethylene in dry-cleaning shops

Int Arch Occup Environ Health

ORIGINAL ARTICLES
Nephropathies and exposure to perchloroethylene in dry-cleaners

Studies on kidney functions in subjects exposed to organic solvents: I. Excretion of albumin and β₂-microglobulin in the urine