Acute (24 hr) toxicity of a combination of four nephrotoxicants in rats compared with the toxicity of the individual compounds.
To identify possible hazards of combined exposure to chemicals with the same target organ, a 24-hr single dose experiment was carried out in which the renal toxicity of mercuric chloride, potassium dichromate, d-limonene and hexachloro-1:3-butadiene administered simultaneously was compared with the nephrotoxicity of the individual compounds, using a total of 11 groups each consisting of five 12-wk-old male Wistar rats. The dose levels used were based on the results of a range-finding study with the individual compounds in the same strain of rats kept under similar experimental conditions, and comprised the 'Minimum-Nephrotoxic-Effect Level' (MNEL) and the 'No-Nephrotoxic-Effect Level' (NNEL) of each of the four compounds alone and in combination. A group of vehicle-treated rats served as controls. At the MNEL of the combination, antagonism of effects was encountered, seen for example as less severely increased activity of gamma-glutamyl transferase in the urine. Synergism of effects was also observed, for example increased severity of renal tubular necrosis, and more markedly increased activity of urinary lysozyme, lactate dehydrogenase, alkaline phosphatase and N-acetyl-beta-glucosaminidase. More importantly, however, at the NNEL of the combination no signs of impaired renal function or renal damage were observed, suggesting absence of both dose additivity and potentiating interaction at the tested subeffective levels of the individual nephrotoxicants.
Jonker
D
D
TNO Toxicology and Nutrition Institute, Zeist, The Netherlands.
Jones
M A
MA
van Bladeren
P J
PJ
Woutersen
R A
RA
Til
H P
HP
Feron
V J
VJ
D000118:Acetylglucosaminidase / Q000652:urine; D000469:Alkaline Phosphatase / Q000652:urine; D000818:Animals; D002070:Butadienes / Q000008:administration & dosage / Q000633:toxicity*; D053138:Cyclohexenes; D004347:Drug Interactions; D007668:Kidney / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology / Q000652:urine; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced; D007770:L-Lactate Dehydrogenase / Q000652:urine; D000077222:Limonene; D008297:Male; D008627:Mercuric Chloride / Q000008:administration & dosage / Q000633:toxicity*; D009113:Muramidase / Q000652:urine; D011192:Potassium Dichromate / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013729:Terpenes / Q000008:administration & dosage / Q000633:toxicity*; D005723:gamma-Glutamyltransferase / Q000652:urine
D002070:Butadienes; D053138:Cyclohexenes; D013729:Terpenes; D008627:Mercuric Chloride; D000077222:Limonene; C001335:hexachlorobutadiene; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase; D009113:Muramidase; D000118:Acetylglucosaminidase; D011192:Potassium Dichromate