PRINCIPLES OF TOXICOLOGY

Methoxyflurane (1,1-difluoro-2,2-dichloromethyl ether) is a halogenated surgical anesthetic that
causes renal failure in humans and animals. Its causes a polyuria and an increase in serum osmolality,
serum sodium, and blood urea nitrogen. Methoxyflurane is metabolized to inorganic fluoride anion
and oxalate. The fluoride anion has been shown to be responsible for acting on the collecting tubules,
which results in vasopressin resistance and causes polyuria.
Bromomethane Humans exposed to high levels of bromomethane vapor commonly suffer from renal
congestion, anuria or oliguria, and proteinuria; however, renal effects after exposure are frequently
minimal or absent. Animal studies report similar signs of renal injury such as swelling, edema,
nephrosis, and tubular necrosis.
Hexachloroethane Hexachlorethane has been found to cause tubular atrophy, degeneration, hypertrophy,
and/or dilation in rats.
Other Nephrotoxic Compounds
Methyl Isobutyl Ketone In rats exposed to as low as 100 ppm of MIBK, microscopic examination
showed toxic nephrosis of the proximal tubules. The exposed rats also showed hyaline droplet
degeneration of the proximal renal tubules and occasionally tubular necrosis. The tubular damage was
considered transient and reversible.
Dioxane Dioxane exposure can be significant from both an oral and inhalation exposure route. It
has a selective action on the convoluted tubules of the kidneys, and causes renal obstruction. In several
cases of fatal industrial exposure, injuries to the kidney were identified as causing the deaths. Signs of
severe hemorrhagic nephritis and central hepatic necrosis occurred after about 2 months of what were
considered to be heavy exposures to dioxane vapor. No cases of jaundice were observed, and death
occurred within 1 week after onset of illness from acute renal failure.
Phenol In subchronic toxicity tests with guinea pigs phenol causes renal proximal tubule swelling
and edema and glomerular degeneration.
Agents Causing Obstructive Uropathies
A number of agents cause nephrotoxicity through physical deposition in the tubular sections of the
nephron. Certain chemical agents can be concentrated in the tubular fluid to levels well above their
solubility limit in water. The result is that crystals are deposited in the kidney tubules, causing physical
damage. Methotrexate and sulfonamide drugs can cause nephrotoxicity by this mechanism.
Acute renal failure of this type is also associated with the ingestion of ethylene glycol. Ethylene
glycol is metabolized to oxalic acid by the body; the acid, in turn, is deposited in the lumen of the
tubule of the nephron as well as within the cell of the tubule as insoluble calcium oxalate salt. However,
ethylene glycol additionally appears to cause a nephrotoxicity to the proximal tubule, which is
independent of oxalate deposition. The deposition of large quantities of oxalate crystals in the tubular
elements of the nephrons probably contributes to the nephrotoxicity observed. Oxalate found in the
leaves of rhubarb is of a sufficient quantity that it can cause deposition of oxalate crystals in the tubular
elements of the nephron, and can lead to nephrotoxicity. Part of the nephrotoxicity caused by
methoxyflurane is likewise believed to be caused by deposition of calcium oxalate crystals in the
tubular elements of the nephrons.
Agent Producing Pigment-Induced Nephropathies
6.3 ADVERSE EFFECTS OF CHEMICALS ON THE KIDNEY 141
A number of chemicals can cause the release of certain pigments such as methemoglobin, hemoglobin,
and myoglobin into the blood. When this occurs, an associated acute renal failure may develop. Arsine