Advanced Toxicology
In the CSU Online Library, locate a research article that discusses an industrial or environmental toxicant that causes nephrotoxicity. The article that you review should be at least two pages in length and no more than five years old. The Academic OneFile database in the CSU Online Library is a great place to begin your research. Review the article and briefly summarize the purpose for the study. The discussion should include the following:
- Include a summary of the purpose of the research and the research findings.
- Discuss how the findings of at least two other articles support or contradict the findings of the main article.
- Discuss how this information might be useful in the field of safety.
Your critique should be at least three pages in length, not including title and reference pages. The article critique should include a minimum of three sources, including the article you review as well as the textbook. Use APA format for your critique, including all references and in-text citations.
MOS 5425, Advanced Toxicology 1
Course Learning Outcomes for Unit V
Upon completion of this unit, students should be able to:
6. Assess the effects of various toxicants on body systems.
6.1 Analyze research findings related to nephrotoxicity.
6.2 Relate scientific research findings to the field of safety.
Course/Unit
Learning Outcomes
Learning Activity
6 Unit Lesson
6.1
Unit Lesson
Chapter 7
Article Critique
6.2
Chapters 7 and 9
Article Critique
Reading Assignment
Chapter 7: Nephrotoxicity: Toxic Responses of the Kidney, pp. 139-155
Chapter 9: Dermatotoxicity: Toxic Effects on the Skin, pp. 169-176
Unit Lesson
This unit covers toxicology of the kidneys and skin. Although not discussed in the textbook, this lesson also
includes a noteworthy discussion of the eye. Your reading begins with examining toxicology of the kidneys. If
you have ever taken an anatomy course, you may recall that we have two kidneys that are each about the
size of your fist, located near the base of the rib cage. The main function of the kidneys is to remove waste
products from the body. This is a very important job because waste that is not removed and remains in the
body can be potentially toxic. The kidneys are also involved in other important functions such as maintenance
of the balance of certain electrolytes in the body, blood pressure regulation, vitamin D activation, and red
blood cell production (National Kidney Foundation, n.d.).
The kidneys are commonly known for their function of removing wastes from the body, but the kidneys
also perform other important functions. Another function of the kidneys is to maintain homeostasis of
various electrolytes such as potassium and sodium and to maintain proper levels of water within the body.
The kidneys also possess specialized endocrine functions such as production of vitamin D and the
protein erythropoietin (Roberts, James, & Williams, 2015). In additional, the kidneys are able to metabolize
certain drugs.
How do the kidneys remove waste from the body? This is done by the excretion of waste products in the
urine. There are many terms that you will want to understand and identify when studying the kidneys. When
discussing the production of urine and removal of waste from the body, you will need to focus your attention
to the nephrons. Imagine the nephron as a long, continuous tube with varying diameters. This tube is bigger
in some sections and smaller in other sections. In addition to the varying diameter, this tube has many bends
and turns. Keeping this in mind, pay attention to the different names and specific functions of each area along
this tube. Your textbook provides a diagram of the nephrons with each section labeled with the appropriate
name. Take some time to look for other diagrams of nephrons on the Internet; doing so may provide a clearer
overall understanding.
UNIT V STUDY GUIDE
Toxicology of the Kidneys, Skin, and Eyes
MOS 5425, Advanced Toxicology 2
UNIT x STUDY GUIDE
Title
The kidneys function to remove wastes, drugs, and toxicants from the body through the excretion of urine.
Different toxicants affect specific parts of the kidneys and ultimately can affect the proper functioning of the
kidneys as organs. Many antibiotics are secreted by the proximal tubules and can induce alterations in the
tubular functions and affect the overall function of the kidneys. In your textbook reading, note the different
toxicants and the specific areas of the kidneys that they affect.
Chemicals may cause acute as well as chronic injury to the kidneys. Various chemicals in the environment
and industry as well as therapeutic drugs can induce nephrotoxicity. Halogenated solvents (e.g.,
dichloroethylene and perchloroethylene), heavy metals (e.g., mercury and cadmium), analgesics (e.g.,
acetaminophen, antibiotics), and antineoplastics (e.g., cisplatin) are all examples of chemicals that can induce
nephrotoxicity (Roberts et al., 2015). The degree of damage that is induced depends not only on the type of
chemical but the dose and duration of exposure to the chemical.
The next section in your reading is about toxicology of the skin. The skin may be referred to as one of the
largest organs of the body. The skin has several protective functions. It protects against water loss, slows
chemical absorption, acts as a barrier for physical trauma, prevents ultraviolet (UV) light penetration and
damage, inhibits microorganism growth and penetration, and helps to maintain homeostasis through
regulation of body temperature and water loss (Roberts et al., 2015). It is the first line of defense in protecting
our bodies from the invasion of harmful substances and toxicants. The skin serves as a barrier between
external factors and the internal environment of our bodies. As a result, this barrier comes in contact with and
encounters damage from a variety of substances as it serves to protect the body. Despite the skin being fairly
thin compared to other organs of the body, it consists of three different layers: (1) the epidermis, (2) the
dermis, and (3) the hypodermis. Your textbook discusses the first two layers. The epidermis is the outermost
layer, and it is much thinner than the dermis. While reading the textbook, you should pay attention to the
different cells that make up each of these layers and the role that each type of cell plays in the skin. Not only
can toxicants damage the layers of skin, but they can also alter the hair, sebaceous glands, and sweat glands
that span the epidermis and are embedded in the dermis (Roberts et al., 2015).
The skin is a good barrier but not a perfect barrier against numerous substances. There are some substances
that the skin is not able to shield from entering the body. Many factors influence the entrance or diffusion rate
of chemicals across the skin (Roberts et al., 2015). The stratum corneum is the primary layer determining the
rate of diffusion of chemicals through the skin. Due to the composition of the stratum corneum, small
hydrophobic agents can more readily cross the skin barrier than molecules that are larger in size or molecules
that are hydrophilic (Roberts et al., 2015). Certain conditions may compromise the skin’s ability to act as an
effective barrier. One example is skin that has been exposed to water for an extended periods of time
becomes more susceptible to hydrophilic substances passing through the skin’s surface.
Toxicants can have different effects on the skin. Irritant dermatitis can occur on initial exposure; repeated
exposure is not required becaise it is in contact dermatitis. Irritant dermatitis is limited to the local area of
exposure and can include symptoms such as skin redness, blistering, eczema, and rashes (Roberts et al.,
2015). Other types of dermal toxicity include allergic contact dermatitis, which is a hypersensitive reaction by
the immune system following a repeat exposure to a chemical, and systemic contact dermatitis when a
contact allergen enters an individual’s systemic circulation. Some of the symptoms of systemic contact
dermatitis include headaches and malaise. Photosensitivity can be a result of dermal toxicity. It can be
described simply as an extreme sensitivity to sunlight. Acneiform dermatoses, commonly referred to as acne,
can be a response to dermal toxicity as a result of workplace exposures to petroleum, coal, and tar (Roberts
et al., 2015). One of the last effects of dermal toxicity that the textbook mentions is the most common cancer
in humans, skin cancer. UV exposure is the main cause of skin cancer, but chemical exposure to the skin
may also induce skin cancer.
The textbook does not include a discussion of the eye nor toxicity that may occur. However, the eyes are a
vital part of the average person’s ability to function, so it is a noteworthy topic to address. The main function of
the eye is for sight. The sense of sight serves an important role in protecting the body from harm. The eye has
a complex anatomy with many intricate parts. You are encouraged to utilize your resources on the Internet to
look at several detailed colored pictures and diagrams of the eye to get a good basic understanding of this
structure. One question that may arise is how do we see objects? Light that is reflected off of objects travels
MOS 5425, Advanced Toxicology 3
UNIT x STUDY GUIDE
Title
through many parts of the eye, including the cornea and aqueous humor all the way to the lens and retina.
Signals that travel to the optic nerve are sent to the brain for interpretation to create the forms that we see.
Damage to any part of the structure of the eye can inhibit light
from successfully traveling to the optic nerve and sending
signals to the brain to interpret sight. Various chemicals may
have different effects on various parts of the eyes. A brief
search on corneal toxicity may reveal numerous chemicals
that cause toxicity to the eye. Take note of how various
chemicals affect different structures of the eye.
There are several tests that can be performed to assess
damage caused by exposure to various toxicants. Rabbits are
the most common animal used in testing effects of chemicals
on the eye. It is not uncommon for products that are sold in
stores and are common household products used daily to be
tested for the toxicological effects on the eye. One product
that comes to mind is makeup. There is a high probability that
in applying and wearing make-up people will at some point
get make-up in their eyes. Consumers would like to believe
that these products will not have adverse effects and, thus,
are tested prior to being placed on the retail shelves to be
sold. The tests performed to determine toxicity to the eye may
include, but are not limited to, procedures for gross anatomy testing, instrumental examinations using
ophthalmoscopy, visual perimetry, and histological and biochemical examinations (Roberts et al., 2015).
References
Clker-Free-Vector-Images. (2012). Eye diagram [Image]. Retrieved from https://pixabay.com/en/eye-diagram-
eyeball-body-pupil-39998/
National Kidney Foundation. (n.d.). How your kidneys work. Retrieved from
http://www.kidney.org/kidneydisease/howkidneyswrk.cfm#where
Roberts, S. M., James, R. C., & Williams, P. L. (Eds.). (2015). Principles of toxicology: Environmental and
industrial applications (3rd ed.). Hoboken, NJ: Wiley.
Cross-section of the eye showing major
components
(Clker-Free-Vector-Images, 2012)
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Original Article
Abstract
Background: For many years, several studies drew attention to the possible nephrotoxic ef-
fects of silica and distinct renal dysfunction involving glomerular and renal tubules in workers
exposed to silica.
Objective: To determine the early signs of subclinical nephrotoxic effects among some Egyp-
tian workers exposed to silica in the pottery industry.
Methods: This study was carried out in El-Fawakhir handicraft pottery area, in Greater Cairo,
Egypt. The studied population included 29 non-smoking male workers occupationally exposed
to silica in addition to 35 non-smoking administrative male subjects who represented the
comparison group in the study. Measured urinary parameters were concentrations of total
protein (TP), microalbumin (Malb), activities of alkaline phosphatase (ALP), g-glutamyl trans-
ferase (g-GT), lactate dehydrogenase (LDH), kidney injury molecule-1 (KIM-1), and silicon
(Si).
Results: Silica-exposed workers showed significantly (p<0.05) increased levels of urinary TP, Malb, ALP, g-GT, LDH, and KIM-1 compared with the comparison group. Among the silica- exposed group, increased urinary Si levels were positively and significantly correlated (Spear- man's ρ>0.60, p<0.001 for all variables) with the elevated urinary proteins (including KIM-1) and enzymes levels. All measured urinary parameters were positively and significantly corre- lated (ρ>0.75, p<0.001 for all variables) with the duration of work among exposed subjects. No significant correlation was observed between the measured variables and the age of work- ers.
Conclusion: There is associated subclinical glomerular and tubular affection among silica-
exposed workers, which is related to the duration and intensity of exposure.
Keywords: Silicon dioxide; Occupational exposure; Kidney diseases; Renal insufficiency;
Kidney glomerulus; Kidney tubules; Proteinuria
Demonstration of Subclinical
Early Nephrotoxicity Induced
by Occupational Exposure
to Silica among Workers in
Pottery Industry
Basma Hussein Mourad1, Yasmin Adel Ashour2
1Department of Occu-
pational and Envi-
ronmental Medicine,
Faculty of Medicine,
Cairo University, Cairo,
Egypt
2Department of Clinical
Pathology, Hospitals
of Ministry of Health,
Cairo, Egypt
Correspondence to
Basma Hussein Mourad,
PhD, Faculty of Medi-
cine, Cairo University,
Cairo, Egypt.
Tel: +2-023-569-2145
E-mail: basma.hus-
sein@ymail.com
Received: Dec 12, 2019
Accepted: Feb 15, 2020
Cite this article as: Mourad BH, Ashour YA. Demonstration of subclinical early nephrotoxicity induced by oc-
cupational exposure to silica among workers in pottery industry. Int J Occup Environ Med 2020;11:85-94. doi:
10.34172/ijoem.2020.1886
Introduction
O
ccupational exposure to crystal-
line silica has long been known to
cause various lung diseases, most
notably silicosis. The main route of entry
of silica into the human body is through
the respiratory system as dust; the expo-
sure via skin or the gastrointestinal tract
is negligible. The most common industries
https://doi.org/10.34172/ijoem.2020.1886
www.theijoem.com Vol 11, Num 2; April, 202086
a r t i c l e
and occupations that have the potential for
silica exposure include mining, quarrying,
foundry work, glass manufacture, ceramic,
pottery, and cement production.1
Silica dust was suspected to affect the
human kidney over 90 years ago. The
detected pathologic renal changes are
similar to those induced by nephrotoxic
heavy metals in the form of dose-related
nephropathy that causes degenerative
changes in tubular epithelium and inter-
stitial inflammation, fibrous nephrosis,
glomerulonephritis, and systemic vascu-
litis. Additionally, it was demonstrated
that silica exposed workers can experience
distinct renal histologic alterations in glo-
merular and proximal tubules.2,3
Various urinary biomarkers have been
proved to be useful to locate defects in spe-
cific parts of the nephron and can detect
early renal changes resulted from expo-
sure to nephrotoxins. These biomarkers
include high molecular-weight protein,
and albumin for evaluating glomerular
integrity—low molecular weight protein
for assessing tubular protein reabsorption.
As a result of tubular epithelial damage and
cellular lysis, both cytosolic and lysosomal
enzymes are released. Evaluating the uri-
nary concentrations of these enzymes can
be considered a perfect non-invasive sen-
sitive method to assess tubular integrity.
These significant urinary renal enzymes
include alkaline phosphatase (ALP) and
g-glutamyltransferase (g-GT), which are
found on the epithelial cells of the proxi-
mal tubule; lactate dehydrogenase (LDH)
is located at distal tubular cells. Referring
to several recent human studies, these uri-
nary biomarkers have been used to detect
early subclinical renal dysfunction.3-5
Another novel urinary biomarker that
has recently been shown to have more sen-
sitivity and specificity in the detection of
the initial preclinical renal tubular insult,
is the urinary kidney injury molecule-1
(KIM-1). A meta-analysis including 11
studies (2979 patients) estimates the uri-
nary KIM-1 specificity for the diagnosis of
acute renal injury at 86% and sensitivity
at 74%.6 KIM-1 is a type I transmembrane
glycoprotein mainly expressed on the
surface of T cells. It has two extracellular
domains. KIM-1 expression is low in nor-
mal kidneys but is significantly increased
in proximal tubular cells following kidney
injury. Upon kidney injury, the extracel-
lular domains of KIM-1 separate from the
cell surface and enter the urine through
a metalloproteinase-dependent process.7
As the tubular injury appears to precede
glomerular damage in the pathophysiol-
ogy of renal diseases, several recent stud-
ies resorted to study the urinary levels of
KIM-1 as a reliable evidence for the degree
of subclinical tubular affection and hence
assessing the extent of preclinical nephro-
toxicity.8-10
We therefore conducted this study to
demonstrate the early signs of subclinical
nephrotoxic effects involving renal glom-
eruli and tubules among some Egyptian
workers occupationally exposed to silica in
pottery industry.
Materials and Methods
In this cross-sectional study, 29 occu-
pationally silica-exposed subjects were
recruited from non-smoking male workers
in El-Fawakhir handicraft pottery area, in
Greater Cairo, Egypt. A comparison group
of non-smoking male population were also
selected from the administrative depart-
ment of Kasr Al-Ainy hospital to include
35 matching subjects with history of usual
exposure to silica during their daily life but
without occupational exposure.
A questionnaire was used to identify the
main demographic and lifestyle character-
istics of the studied subjects such as smok-
ing habit, detailed occupational history
and medical history with the medication
intake to reveal the possible indicators of
Early Nephrotoxicity Induced by Occupational Silica Exposure
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nephrotoxicity among the studied popula-
tion during the time of urine collection.
The whole number of the workers in
this factory was 93. The exposed group
included those workers in the factory who
have been exposed to the manufacturing
process. It is worth to mention that 64
workers were excluded before starting the
study based on the pre-determined exclu-
sion criteria. Workers were excluded from
the study if any was a smoker, had experi-
enced kidney disease or any disease likely
to impair renal functions and/or parame-
ters that were to be tested (creatinine, ALP,
g-GT, and LDH). Others excluded from the
study were those who had previous or cur-
rent potential exposure to agents capable
of damaging the kidney such as lead, cad-
mium, and mercury or other nephrotoxi-
cants such as organic solvents. The work-
ers might also be excluded if they revealed
a history of having consumed drugs with
potential nephrotoxicity such as analgesics
and anti-inflammatory agents and abuse
of aminoglycoside antibiotic therapy. The
comparison group subjects were selected
with comparable sex, age, socioeconomic
standards, and special habits of medical
importance (especially in being non-smok-
ers) to the exposed group after applying
the previously mentioned exclusion crite-
ria.
Sample Collection
A random single-voided urine sample in a
closed container was collected from each
participant. The container was labelled
with the study number of the participant
which is written on the questionnaire form
to avoid any risk of mix-ups or incorrect
identification of samples. Spot urine was
used because urinary protein/creatinine
ratio,11 as well as dividing urinary enzyme
activity by the urine creatinine concentra-
tion in the random sample,12 correlates
with 24-hour urinary excretion and elimi-
nates variations due to changing rates
of urine output and provides a measure-
ment of concentration. The collected urine
sample was transported in a closed box at
room temperature within two hours after
the collection.
Sample Analysis
Each urine sample was analyzed to assess
glomerular integrity through measur-
ing urinary levels of total protein (TP)
using the semiautomated Technicon Bay-
er RA 1000® analyzer (Ireland Techni-
con Limited), and microalbumin (Malb)
using Hemocue® urine albumin system
(Hemocue AB, Angelhom, Sweden); proxi-
mal and distal tubular structural integ-
rity by determining urinary activities of
g-GT and ALP, which are proximal tubule
enzymes, and LDH located at distal tubular
cells,13 using automated Olympus AU640®
analyser (Japan Mishima Olympus Optical
Company Limited); and urinary silicon lev-
els using the Buck Model 210 VGP Atomic
Absorption Spectrophotometer® (Bulk
Scientific, Inc).3 Urine level of KIM-1 was
determined using a commercially available
quantitative sandwich immunoassay tech-
nique (SunRed Biotechnology Company,
Shanghai, China), as per manufacturers’
instructions. Urinary KIM-1 level was nor-
malized by dividing by urine creatinine.10
Internal Quality Control
The internal quality control sample mate-
TAKE-HOME MESSAGE
● Prolonged and intensive occupational exposure to silica
could result in subclinical nephrotoxicity. It can thus be as-
sociated with an increased risk of future end-stage renal
disease.
● Usage of urinary biomarkers to detect signs of preclinical
glomerular and tubular affection seems to be a simple and
non-invasive screening tool to identify silica-exposed work-
ers who carry a higher risk of future nephropathy.
B. H. Mourad, Y. A. Ashour
a r t i c l e
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a r t i c l e
rials were run together with the urine
specimen from the study subjects. Values
obtained for the internal quality control
materials for each of the measured param-
eters was accepted if it was within ±2 SD
from the target value.
Ethics
Ethical approval was sought and granted
by the Ethical Committee of the Occu-
pational and Environmental Medicine
Department, Kasr Al-Ainy Hospital, Fac-
ulty of Medicine, Cairo University, Cai-
ro, Egypt. Approval was taken from the
Chief Executive Officer (CEO) of the fac-
tory. The participants were reassured of
confidentiality in the handling of informa-
tion and procedures involved in this study.
Informed written consent for sharing in
the study was voluntarily obtained from
each individual after a proper explanation
of the objectives of the current study.
Statistical Analysis
Results of all measured parameters were
each divided by the levels of urinary con-
centration of creatinine (in g/L)11 so as
to correct for variations in urinary con-
centration due to hydration.14 Data gen-
erated from the study were entered into
MS Excel® software and then exported to
SPSS® for Windows® ver 25 for statistical
analysis.
Data were tabulated as median (IQR)
because most of the measured parameters
were not normally distributed. Differences
between investigated groups (male refer-
ents, male silica-exposed subjects) were
assessed by Mann-Whitney U test. Corre-
lation between quantitative variables was
done using Spearman’s rank correlation
coefficient (ρ). Univariate linear regression
between quantitative variables was done
to test significant predictors for measured
urinary proteins and enzymes among the
exposed group. A p value <0.05 was con-
sidered statistically significant.
Results
Table 1 shows the levels of urinary pro-
teins, enzymes, KIM-1, and silicon among
the studied groups. Silica-exposed male
workers had significantly increased lev-
els of urinary TP, Malb, ALP, g-GT, LDH,
KIM-1 and Si (p<0.001 for all except Malb,
p=0.03), compared to that of the compari-
son subjects.
A significant positive correlation was
observed between the work duration and
the urinary Si level vs all other measured
urinary parameters among the exposed
group (Figs 1, 2; Spearman’s ρ>0.60,
p<0.001 for all variables). There was no
significant correlation between the age and
the measured urinary parameters among
silica-exposed workers.
Work duration in addition to the uri-
nary Si level could be considered signifi-
Table 1: Median (IQR) of studied demographic characteristics,
and the levels of urinary proteins, enzymes, KIM-1 and silicon
among silica-exposed and the comparison groups
Parameter
Silica-exposed
(n=29)
Comparison
(n=35) p value
Age (yrs) 45 (25) 39 (29) 0.096
Work duration (yrs) 25 (19) 17 (21) 0.117
TP/Cr (mg/g Cr) 560.4 (1264.6) 15.4 (137.9) 0.001
Malb/Cr (mg/g Cr) 54.3 (88.7) 1.0 (25.5) 0.03
ALP/Cr (IU/g Cr) 20.0 (25.9) 2.4 (4.6) 0.001
g-GT/Cr (IU/g Cr) 235.1 (341.3) 20.5 (74.1) 0.001
LDH/Cr (IU/g Cr) 201.4 (236.6) 29.0 (28.4) 0.001
KIM-1/Cr (pg/mg Cr) 210.4 (126.6) 120.1 (100.0) 0.001
Si/Cr (mg/g Cr) 26.4 (15.0) 2.1 (3.3) 0.001
TP: Total protein, Malb: microalbumin, ALP: Alkaline phosphatase, g-GT: g-glu-
tamyl transferase, LDH: Lactate dehydrogenase, KIM-1: kidney injury molecule-1,
Si: Silicon, Cr: Creatinine
Early Nephrotoxicity Induced by Occupational Silica Exposure
www.theijoem.com Vol 11, Num 2; April, 2020 89
Figure 1: Scatter plots representing linear regression between all measured urinary proteins,
enzymes, KIM-1 of silica-exposed workers vs their work duration
B. H. Mourad, Y. A. Ashour
a r t i c l e
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a r t i c l e
Figure 2: Scatter plots representing linear regression between all measured urinary proteins,
enzymes, KIM-1 of silica-exposed workers vs their urinary silicon level
Early Nephrotoxicity Induced by Occupational Silica Exposure
www.theijoem.com Vol 11, Num 2; April, 2020 91
cant (p<0.001) predictors for the elevated urinary parameters among silica-exposed workers. There was no significant asso- ciation between workers' age and elevated urinary parameters among the workers (Table 2).
Discussion
The results of the significantly increased
urinary TP, Malb, and Si among the silica-
exposed workers compared to the compar-
ison subjects suggested that occupational
silica exposure could result in glomerular
injury and would consequently induce
glomerular-type proteinuria. Normally,
the glomerular capillary epithelial cells are
coated with sialoprotein layer that repels
and prevents the passage of serum proteins
in urine. Maintenance of sialoprotein coat
integrity is mainly the function of epithe-
lial cells, so damage to this system could
result in proteinuria.15 These findings were
in line with those of other investigators
who report that crystalline silica exposure
results in an elevation of urinary proteins
Table 2: Univariate linear regression analysis to detect significant predictors of
measured urinary proteins, enzymes and KIM-1 from the age, work duration and
urinary silicon levels among silica-exposed workers
Independent variable Dependent variables Coefficient (95% CI)
Age (yrs) TP/Cr (mg/g Cr) 16.75 (-13.52 to 45.97)
Malb/Cr (mg/g Cr) 1.07 (-1.05 to 3.08)
ALP/Cr (IU/g Cr) 0.21 (-0.41 to 0.82)
g-GT/Cr (IU/g Cr) 3.15 (-4.87 to 11.43)
LDH/Cr (IU/g Cr) 2.06 (-3.41 to 8.71)
KIM-1/Cr (pg/mg Cr) 1.07 (-3.57 to 6.58)
Work duration (yrs) TP/Cr (mg/g Cr) 43.46 (33.37 to 53.56)
Malb/Cr (mg/g Cr) 2.71 (1.987 to 3.44)
ALP/Cr (IU/g Cr) 0.69 (0.54 to 0.85)
g-GT/Cr (IU/g Cr) 10.09 (7.85 to 12.32)
LDH/Cr (IU/g Cr) 7.43 (5.43 to 9.43)
KIM-1/Cr (pg/mg Cr) 5.37 (4.07 to 6.68)
Urinary Si/Cr (mg/g Cr) TP/Cr (mg/g Cr) 44.00 (22.80 to 65.21)
Malb/Cr (mg/g Cr) 3.14 (1.86 to 4.42)
ALP/Cr (IU/g Cr) 0.83 (0.55 to 1.11)
g-GT/Cr (IU/g Cr) 10.63 (5.95 to 15.31)
LDH/Cr (IU/g Cr) 8.74 (5.28 to 12.20)
KIM-1/Cr (pg/mg Cr) 6.42 (4.11 to 8.73)
TP: Total protein, Malb: microalbumin, ALP: Alkaline phosphatase, g-GT: g-glutamyl transferase,
LDH: Lactate dehydrogenase, KIM-1: kidney injury molecule-1, Si: Silicon, Cr: Creatinine
B. H. Mourad, Y. A. Ashour
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a r t i c l e
among silica-exposed industrial work-
ers.2,3,16,17
The significant elevation of urinary
ALP, g-GT, and LDH among silica-exposed
group compared to their controls suggest-
ed renal tubular affection and agreed with
the results of previous studies that report
significantly increased biomarkers for
renal proximal tubular dysfunction such as
urinary retinol-binding protein (RBP) and
urinary N-acetyl-β-D-glucosaminidase
(NAG) among silica-exposed industrial
workers.2,18,19 More recent studies used the
same urinary enzymes (ALP, g-GT, and
LDH) to detect early signs of subclinical
nephropathic tubular effect among silica-
exposed workers3 and among patients with
diabetes.4,5
Additionally, the novel urinary
biomarker for preclinical nephrotoxic-
ity (KIM-1) showed significantly elevated
levels among silica-exposed subjects com-
pared with their comparison group. Uri-
nary KIM-1 is not normally present but
is expressed on the proximal tubule api-
cal membrane with renal injury. KIM-1
has proved to be an outstanding indica-
tor of kidney injury, outperforming blood
urea nitrogen and serum creatinine as
predictors of histopathological changes
in the proximal tubule in response to
many pathophysiological states or toxi-
cants. Studies in man indicate that tissue
expression and urinary excretion of the
ectodomain of KIM-1 are sensitive and
specific markers for renal injury as well as
predictors of outcome.20 Consequently, the
observed significantly elevated levels of
KIM-1 in addition to the presence of sig-
nificantly increased levels of urinary sili-
con detected among the studied exposed
group denoted the implications of occupa-
tional exposure in inducing this nephro-
toxicity. The mechanisms by which silica
may damage the kidney could be either
through direct (ie, renal silica particles)
or indirect toxicity.21 The indirect toxicity
likely occurs when the lungs, after being
exposed to silica particles, start to produce
macrophages to attack the particles. This
process, in addition to lymph node stim-
ulation, would activate the immune sys-
tem and can lead to glomerulonephritis.22
More recently, some reports and studies
are associating autoimmune renal diseas-
es and silica exposure where autoantibod-
ies against nuclear and other self-antigens
deposit in and damage kidneys.23,24
The results revealed that there was
a highly significant positive correlation
between the duration of occupational
exposure to silica and the elevated levels of
the measured urinary biomarkers among
silica-exposed workers. Additionally, the
linear regression analysis showed that the
duration of silica exposure could be consid-
ered a highly significant predicting factor
for the glomerular and tubular subclinical
affection. Various recent studies report an
increased risk for kidney diseases with the
longer duration of silica exposure based
upon a dose-response trend.25-27
The observed significant positive cor-
relation between the urinary Si level and
all other measured urinary biomarkers
among silica-exposed workers supported
the suggestion that occupational silica
exposure might result in disruption of
both the glomerular and tubular structural
integrity. Also, the results of linear regres-
sion analysis revealed that the urinary Si
level could be considered a significant pre-
dictor for the elevated urinary parameters
among the exposed group. Several studies
point out that the silica-exposed industri-
al workers can be exposed to highly toxic
fresh crystalline silica generated during the
processing of pottery products, ceramics,
bricks, and tiles, while the general popula-
tion could be exposed to amorphous aged
silica particles with low toxicity.1,3,28 A very
recent interdisciplinary research relates
the variable toxicity of silica particles to
their surface chemistry. New physico-
Early Nephrotoxicity Induced by Occupational Silica Exposure
www.theijoem.com Vol 11, Num 2; April, 2020 93
chemical methods can finely characterize
and quantify silanols at the surface of silica
particles. A silanol is a functional group in
silicon chemistry with the connectivity Si–
O–H. Surface silanols are critical determi-
nants of the interaction between silica par-
ticles and biomolecules, membranes, and
cell systems in animal models.29
The observed lack of a correlation
between the workers’ age and their uri-
nary levels of biomarkers of renal affec-
tion might imply that renal insult due to
silica exposure is duration and intensity
related, not age-related. Furthermore, it is
worth to mention that among the studied
silica-exposed group, there were younger
workers (aged 20’s) with relatively lon-
ger work duration (>10 years) and higher
levels of urinary biomarkers compared to
older workers with relatively shorter work
duration and experienced lower levels of
urinary biomarkers. This finding was also
encountered by another investigator who
observed no correlation between age and
the studied parameters of kidney function
among silica-exposed subjects.30
At the end of the study, individuals
found with evidence of nephrotoxicity
were referred to Kasr El-Ainy hospital for
further nephrologic evaluation and follow
up. The industry was also advised to apply
rotational schedules for staff working in
areas with significant occupational silica
dust exposure to minimize the risk of renal
affection.
Regarding the limitations of the study,
since the used biomarkers were limited to
urinary ones, we cannot deduce “definite
nephrotoxicity” due to the lack of blood
biomarkers and biopsies. However, uri-
nary biomarkers usually provide a simple
and non-invasive method of assessment
with reliable results to some extent. The
use of urinary ALP, g-GT and LDH rep-
resented accompanied changes in urine
rather than being biomarkers of kidney
injury. These biomarkers, although are
not definite signs of kidney injury, were
used as surrogates for kidney injury in
this study. Certainly, blood biomarkers
and renal biopsies should have been con-
sidered for more accurate assessments of
nephrotoxicity.
In conclusion, this study could draw
attention to the potential subclinical neph-
rotoxic effects resulted from occupational
exposure to silica in pottery industry. The
significant elevated levels of urinary bio-
markers of glomerular and tubular affec-
tion among exposed workers could support
the hypothesis that silica might influence
the occupationally exposed population
and predispose them to expected end-
stage renal diseases, depending on their
exposure duration and intensity.
Conflicts of Interest: None declared.
Financial Support: None.
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