Page 346 - Industrial Ventilation Design Guidebook

3 02 CHAPTER 5 PHYSIOLOGICAL AND TOXICOLOGiCAL CONSIDERATIONS

balance. In addition, the kidney is responsible for the synthesis of a number of
hormones that regulate several systemic metabolic events. These hormones in-
clude 1,25-dihydroxyvitamin D 3, erythropoietin, renin, and several vasoactive
prostanoids and kinins. In addition to these physiologically important" func-
tions, the kidneys are also metabolically active organs that contribute to the
biotransforrnation of xenobiotics.
The sensitivity of the kidneys to various toxic insults is due to large blood
flow, ability to concentrate compounds to be excreted in the urine, and to met-
abolically activate xenobiotics. About 25% of cardiac output continuously
flows through the kidneys even though the relative weight of the kidneys is
only 0.5% of the human body mass. Due to the key role of the kidney in the
excretion of metabolic wastes, it inevitably becomes exposed to high concen-
trations of metabolic endproducts. The primary urine filtrated in the glomeruli
is concentrated 100-fold before its excretion. The amount of primary urine
formed during a 24-hour period is about 100 L, and is being concentrated
down to one liter. Therefore, the concentrations of several toxic compounds in
the urine may become very high compared to their corresponding concentra-
tions in the bloodstream. Furthermore, excretory and reabsorptive functions
14g
may expose kidney cells to high concentrations of harmful compounds.
Alterations in the ability of the kidneys to excrete or reabsorb compounds
from the proximal and distal tubules are immediately reflected in the amount
of extracellular fluid in the mammalian organism. For example, reduced ex-
cretion in the glomeruli leads to increased volume of extracellular fluid, and
this may contribute to cardiac insufficiency, in which the working capacity of
the heart is exceeded. The kidneys are active metabolic organs; this ability has
toxicological significance when it leads to the formation of toxic reactive me-
l47 148
tabolites that damage kidney cells. -
Mechanisms of Kidney Toxicity Alterations in the levels of free intracellu-
lar calcium in kidney cells are important in kidney toxicity caused by several chemi-
cal compounds since cell calcium participates in cell activation and the formation of
89
reactive oxygen species that contribute to hypoxic cell injury. Kidney injury may
also be due to an indirect mechanism: long-term hypotension may be a reason for
kidney injuries, e.g., due to reduced oxygen supply. Irnmunological mechanisms
may also play a role in kidney injuries, and for example, metallothionein, a protein
synthesized by the liver to complex heavy metals, may accumulate in the kidneys as
a protein-metal complex and cause kidney injury. The primary goal of the protein is
to protect the mammalian organism against metal toxicity, but excessive accumula-
tion of the metal-metallothionein complex in the kidneys leads to cellular damage
and impaired kidney function, e.g., reduced formation of urine. Also accumulation
of calcium oxalate, which occurs after exposure to ethylene glycol, the parent com-
36
pound of the oxalate, may induce kidney injury.
Compounds that Cause Kidney Damage Several drugs and some anes-
thetic compounds such as methoxyflurane cause kidney damage when present
at high doses. Kidney-toxic compounds found in occupational environments
include mycotoxins, halogenated hydrocarbons, several metals, and solvents
(see Table 5.16).