Transient renal impairment in rats after oral exposure to diethylene glycol

Abstract

Volume, specific gravity, creatinine, lactate dehydrogenase (LDH), leucine aminopeptidase (LAP), beta-galactosidase (GAL), leucocytes, erythrocytes, nitrite, protein (albumin), glucose, ketone, urobilinogen, bilirubin and pH were estimated in urine of rats after single (by gavage) or repeated (via drinking water) oral administration of diethylene glycol (DEG). Following single or repetitive doses (daily over 90 days) of 0.2 g DEG kg-1 body weight, no change in renal function was observed (no effect level). In urine of rats treated once with 0.7 g DEG kg-1 body weight, LDH activity was significantly enhanced one day after treatment. A single dose of 2.0 g DEG kg-1 body weight resulted in an additional rise in urinary GAL activity two days after treatment, a significant rise of urinary volume and a decrease in creatinine concentration and pH on the first day. One day following a single dose of 8.0 g DEG kg-1 body weight, in addition to the changes mentioned before, LAP activity was significantly elevated and the specific gravity decreased. However, in all experiments the wet weight of the kidneys remained normal as compared to controls. The results thus show dose-dependent changes in several renal parameters, indicating a slight-to-moderate and reversible renal impairment.

Pre-existing liver cirrhosis reduced the toxic effect of diethylene glycol in a rat model due to the impaired hepatic alcohol dehydrogenase

“…These effects have also been confirmed in a myriad of species, including the mouse, rat, cat, pig and rabbit following oral or intraperitoneal exposure (Ballantyne and Snellings, 2005;Freundt and Weis, 1989;Herbert et al, 1978;Kraul et al, 1991;Mathews et al, 1991;Wiener and Richardson, 1989). Additionally, liver injury characterized by jaundice and moderate increases in liver enzymes has been reported in humans (Singh et al, 2001).…”

“…Normal, healthy rats exposed to a large single dose of DEG typically develop metabolic acidosis and acute renal failure (Kraul et al, 1991;Freundt and Weis, 1989). In this study, the model rats were less sensitive to the toxic effects of DEG compared with control rats in terms of the observed rats of metabolic acidosis and acute renal failure.…”

“…Sprague-Dawley rats are commonly used in DEG toxicity studies (Freundt and Weis, 1989;Kraul et al, 1991;Mathews et al, 1991;Wiener and Richardson, 1989). Metabolic acidosis, acute renal failure and liver damage, which are similar to human poisoning cases, are typically observed following DEG exposure.…”

“…Following acute exposure to DEG, metabolic acidosis and kidney injury develop rapidly (Hanif et al, 1995;O'Brien et al, 1998;Okuonghae et al, 1992;Singh et al, 2001;Vale and Buckley, 1985), and hepatic injury has also been noted (Vale and Buckley, 1985). These effects have also been confirmed in a myriad of species, including the mouse, rat, cat, pig and rabbit following oral or intraperitoneal exposure (Ballantyne and Snellings, 2005;Freundt and Weis, 1989;Herbert et al, 1978;Kraul et al, 1991;Mathews et al, 1991;Wiener and Richardson, 1989). Additionally, liver injury characterized by jaundice and moderate increases in liver enzymes has been reported in humans (Singh et al, 2001).…”

Diethylene glycol-induced toxicities show marked threshold dose response in rats

“…Although these studies demonstrated that metabolite accumulation was necessary for DEG toxicity (Besenhofer et al, 2010, 2011), EG (oxalate) accumulation was minimal and is now considered to be irrelevant for DEG toxicity. Although studies assessing the toxicity, pharmacokinetics, and biotransformation of DEG have been done using a variety of species including dogs, cats, mice, and rats (Winek et al, 1978; Lenk et al, 1989; Freundt and Weis, 1989; Wiener and Richardson, 1989; Mathews et al, 1991; Durand et al, 1976; Hebert at al., 1978; Harris, 1949), whether there is a sensitivity difference between Wistar and F-344 rats in renal toxicity or in DGA accumulation is yet unknown. Hence, this study was primarily designed to provide insight into an appropriate rat model by using a DEG dose response paradigm (0, 2, 5, or 10 g/kg) that covers the range of no to severe toxicity in Wistar rats (Besenhofer et al, 2010).…”