SAAM-6636-001: Industrial Toxicology – Winter 2019

Class 11: Toxicology of Specific Systems

1. Occupational toxicology of the liver

1.1. Physiology of the liver
The functions of the liver are varied, working closely with nearly every fundamental system
and process in the human body. It is estimated that the liver may have close to 500 functions.
1.1.1. Biotransformation of chemicals
1.1.2. Regulation of blood sugar (glycogen), lipids, and
amino acids
1.1.3. Formation of bile
1.1.4. Metabolism of cholesterol
1.1.5. Formation of plasma proteins
1.1.6. Making heparin. This is an anticoagulant substance
which prevents the blood from clotting as it travels
through the body.
1.1.7. Storage of blood. The liver can swell to hold huge amounts of blood
1.1.8. Removal of hemoglobin molecules (when they become fragile)
1.1.9. Storage of vitamins. Vitamin A is also made in the liver from carotene.
1.1.10.Production of heat.
1.2. Classification of chemical-induced injury
1.2.1. Histological change
 Necrosis, which is one type of cell death
 Steatosis, or intracellular fat
accumulation
 Cholestasis, which means cessation or
slowing of bile flow
 Apoptosis (programmed cell death), a
form of tissue injury, such as chronic
active hepatitis.
 Fibrosis and cirrhosis are the end result of
ongoing liver injury, generally following
long-term exposure
 Neoplasia (abnormal growth) including
hepatic carcinoma

1.2.2. Predictability
 Predictable: for example, alcohol related.
 Unpredictable or idiosyncratic: immunological based or due to a metabolic
abnormality.
 1.2.3. Organelle damage
A less commonly used method of classifying hepatotoxicants is according to the
organelle (one small part of a cell that has a very specific function or job) primarily
affected.
1.3. Detection and evaluation of liver injury
 Liver damage can be detected with a range of procedures, from external palpation to
enlargement and tenderness, blood enzyme tests, through to needle biopsy.
 Acute hepatotoxicity can be detected with commonly used noninvasive tests.
 Detection of subacute and chronic hepatic damage is more difficult.
 Methods for testing for liver damage in response to chemical exposure:
 Physical examination
 Clinical chemistry
 Enzymes
 Bilirubin
 Bile salts
 Proteins
 Histopathology
 Light microscopy
 Electron microscopy
  Organ function tests
 Dye excretion
 Drug biotransformation
 In testing for liver damage, the activity of a range of enzymes may be measured (see text).
 Elevated levels of one or more of these enzymes may indicate liver damage.
 Other markers include bile acids and bilirubin.
 However, the histological appearance of the liver remains the most definitive indicator of
liver injury.
 Biopsy in humans for confirmation of diagnosis is usually employed when there is
uncertainty.
1.4. Examples of hepatotoxicity from workplace exposures
 Many chemicals have the potential to cause liver injury in workers due to
biotransformation activities.
 In the past, chemicals such as carbon tetrachloride have been associated with both acute
and chronic liver injury in exposed workers.
 With increased knowledge and improved workplace conditions such examples are now
less frequent.
 Nevertheless, they do continue to occur as evidenced by case reports of workers
 experiencing liver damage after using various chemicals such as dimethyl formamide and
methylene dianiline.

2. Occupational toxicology of the kidneys (Text 2 Chapter 7)

 While filtration of the blood is probably the
most important function of the kidney, it is
also involved in other functions.
 The kidney plays a principal role in the
regulation of extracellular fluid volume,
acid-base balance and electrolyte
composition, as well as excretion of
metabolic waste products, and others (see
text).
 The kidney has a high blood flow to mass
ratio and is thus typically exposed to higher
concentrations of blood-borne chemicals than most other organs.
 It also has a unique function of concentrating urine and its constituents, which can include
exogenous compounds such as chemicals and drugs.
 These properties make the kidney uniquely susceptible to injury.
 Occupational renal injury can occur through trauma, biochemical, hemodynamic or
immunological mechanisms.

2.1. Kidney disease and occupation

 The primary cause of occupational kidney damage is from chemical exposures.
 It is estimated that nearly four million workers in the USA are exposed to chemicals at
concentrations that may damage the kidney (nephrotoxicity).
 Although the best documented toxic causes of renal failure are drugs, occupational
exposure to chemicals, such as heavy metals and solvents, also plays a role in the
development of chronic renal failure.
 Chemicals can induce renal injury due to a primary effect on the kidney, or secondarily
through systemic effects such as cardiac failure or intravascular hemolysis (the rupture or
destruction of red blood cells).
 The two common manifestations of chemically induced renal disease are acute and chronic
renal failure.
2.2. Detection and evaluation of kidney damage
 There are a number of clinical signs in patients with renal
injury, as follows:
  Anuria (no urine output), oliguria (decreased urine output) or less commonly polyuria
(increased urine output)
 Edema from severe hypoalbuminemia (low albumin in blood) due to glomerular
dysfunction (e.g. blood in urine)
 Hypertension
 Anemia
 Kidney damage is identified by evaluating indicators of kidney function in blood and
urine.

 Since the kidney is able to compensate extremely well for loss of renal functional mass,
changes in renal function may not be identified until there is significant (more than 70%)
nephron (smallest kidney unit) damage or loss.
 Decreased GRF (glomerular filtration rate) can cause azotemia (high N) characterized by
elevation of the blood urea nitrogen (BUN) and creatinine.
 Changes in electrolytes and acid-base balance may also be present in the blood of patients
with renal disease.
 Urine volume can be determined and urine can be examined (urinalysis) for the presence
of cells, proteins, casts, and crystals which are not normally present.
 Indicators of renal damage include:
 Albuminuria or proteinuria (albumin, protein in urine)
 Aminoaciduria (amino acids in urine)
 Globulinuria (globulins in urine), either myoglobin or hemoglobin
 Glycosuria (glucose in urine)
 Hematuria (blood in urine)
 Inflammatory cells in urine
 Tubular cells in urine
 Presence of these components in the urine may indicate injury to the glomerulus resulting
in increased permeability and/or lack of reabsorption in the tubules.
 Proteinuria is often an early and sensitive indicator of renal injury.
 High molecular weight proteins in the urine indicate glomerular dysfunction,
 Low molecular weight proteins indicate tubular dysfunction.
  Because of the marked improvement of workplace hygiene in recent years, most patients
with chemically induced renal injury due to workplace exposure present mild
abnormalities, such as proteinuria.
 A history of occupational exposure, identification of exposure to known or suspected
nephrotoxicants and the confirmation of exposure through detection of the toxicant, its
adduct, or other specific effect in blood, urine or tissues, are most important for diagnosis.
 It is important to exclude other possible causes of kidney injury, including
nonoccupational exposure to chemicals and drugs, infection or metabolic abnormalities.
 Methods for detecting and evaluating chemical-induced renal injury include:
 Clinical examination
 Urinalysis and microscopy
 Estimation of glomerular filtration rate
2.3. Examples of damage to the kidney from workplace exposure
 Many chemicals have been reported to cause renal toxicity following workplace (or
environmental or therapeutic) exposure.
 These include glycols, halogenated solvents, metals, biological toxins, organic solvents
and hydrocarbons, and pesticides.
2.4. Rehabilitation of the individual with kidney damage
 The problems of rehabilitation of the individual differ according to whether the individual
suffers from acute or chronic disease.
 If a ‘critical mass’ of the kidney is not affected, then repair through cell proliferation and
compensatory mechanisms are initiated and renal function can return to normal.
 However, if injury is severe or exposure continues then a return to normal is not possible.
 The first consideration in worker rehabilitation is to ensure that a worker is not returned to
the same work environment that precipitated the injury.
 This requires an assessment of the workplace for nephrotoxicants, and elimination or
control of any contaminant found.
 Further, it involves identification of other risk factors, not necessarily of an occupational
nature, that may interact with occupational nephrotoxic factors.