Agency for Toxic Substances and Disease
Registry
Case Studies in Environmental Medicine (CSEM)
Ethylene Glycol and Propylene
Glycol Toxicity
Course: WB 4342
CE Original Date: March 20, 2020
CE Expiration Date: March 20, 2022
Key
• Ethylene glycol ingestion first affects the centra
l
nervous system (CNS). After a characteristic laten
t
pe
riod, toxic metabolites might produce signs o
f
i
nebriation followed by serious illness and even death
.
Concepts
• No studies were located regarding a link between
ethylene glycol exposure and cancer or reproductive o
r
d
evelopmental hazards in humans
.
• Propylene glycol is much less toxic than ethylene glycol.
About This
and Other
Case Studies
in
Environment
al Medicine
This educational case study is one in a series of self-
instructional modules designed to increase the primary
care provider’s knowledge of hazardous substances in the
environment. The modules also promote adoption of
medical practices that aid in the evaluation and care of
potentially exposed patients. You can access the complete
series of Case Studies in Environmental Medicine on the
Agency for Toxic Substances and Disease Registry
(ATSDR) website at URL:
https://www.atsdr.cdc.gov/emes/health_professionals/ind
ex.html.
A downloadable PDF v
ersion of this educational series and
other environmental medicine materials provides content
in an electronic, printable format, especially for those who
might lack adequate Internet service.
Page 1 of 124
Acknowledgments
How to Apply for
and Receive
Continuing
Education Credit
Including the
Assessment and
Posttest
We gratefully acknowledge the work of the
medical writers, editors, and reviewers in
producing this educational resource. Listed
below are the contributors to this version of the
Case Study in Environmental Medicine.
Please Note: Each content expert for this case
study has indicated that he or she has no
conflict of interest to disclose that would bias
the case study content.
ATSDR Authors: Dianyi Yu, MD
ATSDR Planners: Charlton Coles, PhD; Sharon L.
Hall, PhD; Delene Roberts MSMHC; Julia Smith, MPH,
CHES; Germania Pinheiro MD, MSc, PhD; Dianyi Yu,
MD
Peer Reviewers: Obaid Faroon, DVM, PhD, and Ki
Moon Bang, PhD, MPH
ATSDR Commenters: Alaina Steck, MD
In order to receive continuing education (CE) for
WB4342 - ATSDR CSEM: Ethylene Glycol/Propylene
Glycol Toxicity please visit TCEO and follow these
9
Simple Steps before March 20, 2020.
Complete the activity
Complete the Evaluation at www.cdc.gov/GetCE
Pass the posttest at ___80___% at
www.cdc.gov/GetCE
To receive free continuing education, please visit the
CSEM Ethylene Glycol/Propylene Glycol Toxicity
registration page
Page 2 of 124
Accrediting
Organization
Credits Offered
The Centers for Disease Control and Prevention is
jointly accredited by the Accreditation Council for
Continuing Medical Education (ACCME), the
Accreditation Council for Pharmacy Education (ACPE),
and the American Nurses Credentialing Center (ANCC),
to provide continuing education for the healthcare
team.
CME
The Centers for Disease Control and Prevention
designates this enduring activity for a maximum of
1.75 AMA PRA Category 1 Credits™. Physicians should
claim only the credit commensurate with the extent of
their participation in the activity.
CNE
The Centers for Disease Control and Prevention
designates this activity for 1.6 nursing contact hours.
CEU
The Centers for Disease Control and Prevention is
authorized by IACET to offer 0.2 CEU's for this
program.
CECH
Sponsored by the Centers for Disease Control and
Prevention, a designated provider of continuing
education contact hours (CECH) in health education by
the National Commission for Health Education
Credentialing, Inc. This program is designated for
Certified Health Education Specialists (CHES®) and/or
Master Certified Health Education Specialists (MCHES®)
to receive up to 1.5 total Category I continuing
education contact hours. Maximum advanced level
continuing education contact hours available are 0.
Continuing Competency credits available are 0. CDC
provider number 98614.
Page 3 of 124
CPH
The Centers for Disease Control and Prevention is a
pre-approved provider of Certified in Public Health
(CPH) recertification credits and is authorized to offer
2.0 CPH recertification credits for this program.
Disclaimer and
Disclaimer
Disclosure What we know about treating patients potentially
exposed to hazardous substances in the environment is
constantly evolving and is often uncertain. In
developing its educational products, the Agency for
Toxic Substances and Disease Registry (ATSDR) has
worked hard to ensure the accuracy and the currency of
the presented information. However, ATSDR makes no
claim that the environmental medicine and health
education resources discussed in these products
comprehensively address all possible situations related
to various substances. These products are intended for
educational use to build the knowledge of physicians
and other health professionals in assessing the
conditions and managing the treatment of patients
potentially exposed to hazardous substances. The
products are not a substitute for a healthcare provider's
professional judgment. Please interpret the
environmental medicine and the health education
resources in light of specific information regarding the
patient and in conjunction with other medical
authorities.
Use of trade names in ATSDR products is for
identification purposes only and does not imply
endorsement by the ATSDR or the U.S. Department of
Health and Human Services.
Disclosure
In compliance with continuing education requirements,
all presenters must disclose any financial or other
associations with the manufacturers of commercial
products, suppliers of commercial services, or
commercial supporters as well as any use of unlabeled
product(s) or product(s) under investigational use.
Page 4 of 124
CDC, our planners, content experts, and their
spouses/partners wish to disclose they have no financial
interests or other relationships with the manufacturers
of commercial products, suppliers of commercial
services, or commercial supporters. Planners have
reviewed content to ensure there is no bias.
Content will not include any discussion of the unlabeled
use of a product or a product under investigational use.
CDC did not accept commercial support for this
continuing education activity.
U.S. Department of Health and Human Services
Agency for Toxic Substances and Disease Registry
Division of Toxicology and Human Health Sciences
Environmental Medicine Branch
Page 5 of 124
Table of Contents
How to Use This Course.........................................................................7
How Should Patients Exposed to Ethylene Glycol Be Treated and Managed?
What Instructions Should You Give to Patients Regarding Ethylene
What Is Ethylene Glycol?
.....................................................................1
3
Where Is Ethylene Glycol Found?
..........................................................23
W
hat Are Routes of Exposure to Ethylene Glycol?
...................................2
6
Who is at Risk of Exposure to Ethylene Glycol?.......................................
3
0
What Are U.S. Regulations and Guidelines for Ethylene Glycol Exposure?
... 36
W
hat Is the Biological Fate of Ethylene Glycol?
.......................................39
W
hat Are the Toxicological Effects of Ethylene Glycol Poisoning?
.............. 43
C
linical Assessment—History and Physical Examination ...........................56
Clinical Assessment—Laboratory Tests
..................................................6
9
7
9
79
W
hat Is Propylene Glycol?
...................................................................87
G
lycol/Propylene Glycol Exposure?
........................................................98
S
ources of Additional Information
....................................................... 1
00
Posttest
........................................................................................... 1
07
Literature Cited
............................................................................... 1
12
Page 6 of 124
How to Use This Course
Introduction
Case Studies in Environmental Medicine’s goal is to
increase the primary care provider’s knowledge of
hazardous substances in the environment and to help in
evaluation and treating of potentially exposed patients.
This case study focuses on ethylene glycol and
propylene glycol toxicity.
Availability
Two versions of the Ethylene Glycol/Propylene Glycol
Toxicity CSEM are available.
• The HTML version (To be added after clearance
during Web production) provides content through
the Internet.
• The downloadable PDF version (To be added after
clearance during web production) provides content
in an electronic, printable format, especially for
those who might lack adequate Internet service.
• The HTML version offers interactive exercises and
prescriptive feedback to the user.
Instructions
Follow these steps to make the most effective use of
this course:
• Take the Initial Check to assess your current
knowledge about ethylene glycol and propylene
glycol toxicity.
• Read the title, learning objectives, text, and key
points in each section.
• Complete the progress check exercises at the end
of each section and check your answers.
• Complete and submit your assessment and
posttest response online if you want continuing
education credit. You can print continuing
education certificates immediately after course
completion.
Page 7 of 124
Instructional
Format
This course is designed to help you learn efficiently.
Topics are clearly labeled; you can skip sections or
quickly scan sections with which you are already
familiar. This labeling also allows you to use this training
material as a handy reference. To help you identify and
absorb important content quickly, we’ve structured each
section as follows:
Section
Element
Purpose
Title
Serves as a “focus question” you should be able to
answer after completing the section
Learning
Objectives
Describes specific content addressed in each section and
focuses your attention on important points
Text
Provides the information you need to answer the focus
question(s) and achieve the learning objectives
Key Points
Highlights important issues and helps you review
Progress Check
Exercises
Enables you to test yourself to determine whether you
have mastered the learning objectives
Progress Check
Answers
Provides feedback to ensure you understand the content
and can locate information in the text
Learning
Objectives
After completing the Ethylene Glycol and Propylene
Glycol CSEM, you will be able to accomplish the
following:
Content Area
Learning Objectives
What Is Ethylene
Glycol?
• Describe the properties of ethylene glycol
Where Is Ethylene
Glycol Found?
• Identify sources of ethylene glycol exposure
Page 8 of 124
What Are Routes of
Exposure to
Ethylene Glycol?
•
Identify the most common route of exposure to
ethylene glycol that results in toxicity in the
general U.S. population
Who Is at Risk of
Exposure to
Ethylene Glycol?
•
Identify who is at risk of exposure to ethylene
glycol
What Are U.S.
Regulations and
Guidelines for
Ethylene Glycol
Exposure?
•
Describe current U.S. regulations and
guidelines for ethylene glycol exposure
What Is the
Biologic Fate of
Ethylene Glycol?
•
Explain the major pathway of ethylene glycol
metabolism in the body
What Are the
Toxicological
Effects of Ethylene
Glycol Poisoning?
•
Describe the toxicological effects of ethylene
glycol poisoning.
Clinical Assessment
– History and
Physical Exam
• Describe what is included in the initial history
and physical examination of patients potentially
exposed to ethylene glycol
• D
escribe how the clinical presentation changes
over time
Clinical Assessment
- Laboratory Tests
• Identify the abnormal laboratory findings
associated with ethylene glycol poisoning
•
List three measurements that can assist with
diagnosis of ethylene glycol poisoning
How Should
Patients Exposed to
Ethylene Glycol Be
Treated and
Managed?
•
Describe treatment strategies for managing
ethylene glycol poisoning cases
What Is Propylene
Glycol?
•
Describe the uses of propylene glycol
• Explain the potential risk of propylene glycol
Page 9 of 124
toxicity
What Instructions
Should You Give to
Patients Regarding
Ethylene
Glycol/Propylene
Glycol Exposure?
•
Describe self-care and clinical follow-up
instructions for patients exposed to ethylene
glycol or propylene glycol
Page 10 of 124
Initial Check
Instructions
Case Study,
First Patient
This Initial Check will help you assess your current
knowledge about ethylene glycol toxicity. To take the
Initial Check, read the case below and then answer the
questions that follow.
Disorientation, Ataxia, and Abdominal Symptoms
in Visitors to a Municipal Airport
A 67-year-old man arrives at the emergency department
(ED) of a small community hospital where you are the
family physician on call. The patient is experiencing
• ataxia,
• dizziness, and
• vomiting.
He is hyperventilating. On physical examination, the
patient appears well nourished, but agitated and
disoriented. He has no odor of ethanol on his breath.
Vital Signs
The patient’s vital signs are as follows:
•
Bl
ood pressure (BP): 120/80 mm Hg
•
Temperature: 98.5°F
•
Pulse: 80 beats/minute
• Respirations: 40 breaths/minute
Neurologic examination is otherwise normal, with no
focal findings, particularly no nystagmus. Abdominal
examination is normal.
Additional Information
The patient’s friend brought him to the ED. The friend
said that late the previous night the patient complained
of dizziness and had begun to vomit. The patient was
hyperventilating in the morning and continued to vomit.
Both men are retired pilots who teach at the local
airport’s ground school. The friend wonders whether the
food at the airport cafeteria was responsible because
two other people collapsed at the airport that morning
Page 11 of 124
Results of Laboratory Tests
• Potassium: 3.8 mmol/L (normal 3.1–5.3 mmol/L).
• Chloride: 105 mEq/L (normal 98–109 mEq/L).
• BUN: 20 mg/dL (normal 8–18 mg/dL).
Note that results might vary from laboratory to
laboratory and depend on the elevation above sea
level (see Table 1).
and were taken by ambulance to another hospital. Both
the friend and the patient ate hot dogs and coleslaw
from the cafeteria, but the friend states that he feels
fine.
• Blood
ethanol and routine urine drug screen are
negative.
• Arterial blood gases (ABG) results: pH 7.10; PaCO₂
= 20 mm Hg; PaO₂ = 95 mm Hg; and bicarbonate
= 8 mEq/L.
• Sodium: 145 mmol/L (normal 135–145 mmol/L).
• Creatinine: 1.0 mg/dl (normal 0.6–1.2 mg/dL).
• Glucose: 80 mg/dl (normal 65–110 mg/dL).
• Calculated anion gap: 32 (normal 12–16).
Table 1. Arterial blood gases – Ranges Considered Within Normal
Limits at Sea Level and Breathing Room Air.
Partial pressure of oxygen
(PaO₂)
70–100 millimeters of mercury (mm
Hg)
Partial pressure of carbon
dioxide (PaCO₂)
35–45 mm Hg
pH 7.35–7.44
Bicarbonate (HCO₃) 21–28 milliequivalents per liter (mEq/L)
Oxygen content (O₂CT) 15%–23% (15–23 milliliters [mL] per
100 mL of blood)
Page 12 of 124
Oxygen saturation (O₂Sat) 95%–100%
Case Study,
Second Patient
Fewer than 30 minutes later, a 4-year-old boy arrives at
the ED. On examination, you find a sleepy but
responsive child who shows no evidence of trauma or
focal neurologic signs. Abdominal examinations are
normal.
Vital Signs
The patient’s vital signs are as follows:
B
P: 94/76 mm Hg
Rectal temperature: 98.5°F
Respirations: 12 breaths/minute
Pulse: 78 beats/minute
Additional Information
The parents tell you they were attending a local fliers’
club luncheon at the airport. When they noticed the
child staggering and incoherent, they rushed him to the
ED. On the way, he vomited in the car.
Results of Laboratory Tests
You order the same laboratory tests for the child that
you ordered for the 67-year-old patient. The tests reveal
that the child is
• hy
poglycemic,
• ha
s slight acidosis, and
• has an anion gap of 13.
A
dditional Information
You contact the local health department. They tell you
they are investigating the earlier incidents at the airport.
They have not identified the contaminant, but they
suspect the airport’s water supply is contaminated.
Page 13 of 124
Initial Check
Questions
1. What would you include in the problem list for
each patient? What is the differential diagnosis
for an anion gap metabolic acidosis?
2. What additional tests, if any, will you order for
these patients?
3. How will you initially treat these patients?
4. What questions would health department
investigators ask airport visitors and employees
to establish the exposure source?
5. The health department identifies the water
contaminant as ethylene glycol. While repairing
the water supply system, construction crews at
the airport inadvertently connected the heating
system water supply to the drinking water
system. The concentration of ethylene glycol
measured at the cafeteria’s water source was 9%
(90,000 parts per million [ppm]). The U.S.
Environmental Protection Agency (EPA) has an
ethylene glycol drinking water quality guideline of
7 ppm (FSTRAC 1990). The lethal dose of 95%
ethylene glycol is about 100 mL for an adult or
1.4 mL/kg.
Who in the case study might be at risk of adverse
health effects? Explain.
6. An airport employee comes to your office a week
after the water contamination incident. One of his
jobs is to de-ice aircraft. A major spill occurred on
the previous day, drenching him with de-icing
fluid. He knows that de-icing agents contain large
amounts of ethylene glycol. Immediately after the
spill, he showered and changed clothes. He is
worried about possible adverse health effects,
such as cancer. What will you tell him?
7. A pregnant airport worker consults you because
she drank tea brewed with the contaminated
water at the airport. Although she drank only a
small amount of tea and had no ill effects, she is
worried that even that small amount of
contaminant will adversely affect her fetus. How
will you counsel her?
Page 14 of 124
8. You later learn that during dinner at the cafeteria,
the 67-year-old man drank several cups of coffee,
w
hile his friend, who did not become ill, drank onl
y
ca
nned soda. The serum ethylene glycol level fo
r
th
e 67-year-old patient is 55 mg/dL; the anio
n
g
ap is 35. How will you treat the 67-year-ol
d
patient?
9.
T
he child’s ethanol level is 85 mg/dL. You repea
t
t
he ethanol test, and again the result is high. Th
e
p
arents are incredulous. They state the luncheo
n
did include wine and cocktails, but they did not
s
upervise the child closely. Potential ethylen
e
g
lycol exposure sources for the child were no
t
i
mmediately identifiable. How will you treat th
e
c
hild
?
Initial Check
Answers
1. The man’s medical problems include the following:
• Ataxia
• V
omitin
g
• A
gitatio
n
• D
isorientatio
n
• H
yperventilatio
n
• Elevated anion-gap metabolic acidosis
Th
e child’s medical problems include the following:
• Somnolenc
e
• Ataxia
• M
ental status change
s
• V
omitin
g
• H
ypoglycemi
a
• L
ow body temperatur
e
• Slight anion-gap metabolic acidosis
D
ifferential diagnoses include toxic alcohol ingestion and
diabetic or starvation ketoacidosis.
(Table 3 shows common toxic agents associated with an
elevated anion gap.)
Page 15 of 124
2. Additional testing of these patients should include the
following:
• Urinalysis
• Com
plete blood coun
t
• S
erum osmolality measured by the freezing-
point–depression techniqu
e
• E
thylene glycol and methanol level
s
• Ammonia, acetaminophen, and aspirin levels
• L
iver functio
n
F
ind more information for this answer in the
“Clinical Assessment – Laboratory Tests” section.
3
. B
ecause the critical ingestion occurred several hour
s
a
go, emesis or gastric lavage will be of little value,
and activated charcoal will be ineffective. However,
it is important to act promptly to correct the
metabolic acidosis and to prevent further
conversion of the remaining ethylene glycol into its
toxic metabolites.
Intravenous administration of the antidote,
fomepizole, will inhibit further ethylene glycol
metabolism. In the absence of both renal
insufficiency and significant metabolic acidosis,
fomepizole may be used without hemodialysis.
Start hemodialysis if severe metabolic acidosis or
renal failure develops.
Find more information for this answer in the “How
should patients exposed to ethylene glycol be
treated and managed?” section.
4
. T
he most common sources of epidemic poisoning
s
i
nclude
• contaminated food
,
• beverages, and
• w
ater supplie
s.
Incident investigators would ask about types of
food and drink available at the airport. They would
take a detailed history of food and beverage intake
Page 16 of 124
from the patients and all others at the airport. They
would attempt to find a common factor that would
include those who were ill and exclude those who
did not become ill. Investigators can usually
identify the exposure source or restrict the
exposure source possibilities by gathering and
statistically analyzing data from a large group of
people.
Find more information for this answer in the
“Where is ethylene glycol found?” section.
5
. T
he lethal dose of antifreeze (95% ethylene glycol) i
s
a
bout 100 mL or 1.4 mL/kg, although amounts in
the reported cases vary widely. A cup (240 mL) of
the contaminated water would contain about 22 mL
of ethylene glycol. This dose could cause significant
toxicity. Even mild symptoms of ethylene glycol
poisoning would be a concern for air traffic
controllers and other airport personnel responsible
for judgments affecting many lives. Healthcare
providers should examine every employee and
visitor who consumed beverages or food prepared
with water at the airport.
Find more information for this answer in the
“Where is ethylene glycol found?” section.
6
. A
bsorption of ethylene glycol is minimal throug
h
intact skin and is not likely to lead to toxic effects.
Because the patient showered and changed clothes
immediately, it is unlikely he will experience toxic
effects from the spill. In the case of chronic
exposure during the de-icing process, few particles
from a spraying device are likely to be inhaled, so
inhalation of ethylene glycol would be minimal.
Contact during the de-icing process would not
contribute substantially to toxicity, especially if the
exposed person wore protective clothing and
respiratory protection. No studies were located
regarding carcinogenicity in humans after exposure
to ethylene glycol.
Page 17 of 124
Find more information for this answer in the
Sections of “Where is ethylene glycol found?”, “What Are
Routes of Exposure to Ethylene Glycol?”, and “What Are
the Toxicological Effects of Ethylene Glycol Poisoning?”.
7. You can inform the pregnant patient that
e
xperimental animal studies indicate that ethylene
glycol at high, prolonged levels can cause
developmental effects. However, no human studies
specifically assess the effects of ethylene glycol on
fetal development.
Find more information for this answer in the “What
are the toxicological effects of ethylene glycol
poisoning?” section.
8
. T
he initial treatment is described in answer
3.
T
raditionally, an ethylene glycol level of 50 mg/d
L
w
as an indication for hemodialysis. However, som
e
p
atients with normal renal function and no evidenc
e
of metabolic acidosis have been treated effectively
w
ith fomepizole, despite having ethylene glycol level
s
o
f 50 mg/dL. In the absence of both rena
l
i
nsufficiency and significant metabolic acidosis
,
f
omepizole may be used without hemodialysis
.
Hemodialysis should be started if metabolic acidosis
d
evelops
.
F
ind more information for this answer in the “Ho
w
s
hould patients exposed to ethylene glycol be treat
ed
and managed?” section.
9.
The child could be intoxicated with ethanol alone or
w
ith ethanol and ethylene glycol. If intoxication i
s
f
rom ethanol only, carefully monitor blood glucos
e
a
nd ethanol until the intoxication resolves.
If
l
aboratory results indicate that ingestion of ethylen
e
glycol occurred, the patient can be treated with
f
omepizole. The limited data available suggest tha
t
f
omepizole, at the same dosage used for adults, i
s
ef
fective and well tolerated in pediatric patients. F
or
m
any pediatric patients treated with fomepizole fo
r
ethylene glycol poisoning, hemodialysis might not be
Page 18 of 124
needed, despite high ethylene glycol concentrations
and the presence of metabolic acidosis.
Find more information for this answer in the “How
should patients exposed to ethylene glycol be
treated and managed?” section.
What Is Ethylene Glycol?
Learning
Objectives
After completing this section, you will be able to
describe the properties of ethylene glycol.
Page 19 of 124
Definition
Ethylene glycol is a liquid that is
• clear,
• co
lorless
,
• od
orless, an
d
• s
weet tasting
.
Ethylene glycol has low vapor pressures at room
temperature and, therefore, low potential for significant
inhalation exposure.
Its chemical structure is HOCH
2
CH
2
OH.
Synonyms
Common synonyms for ethylene glycol include
• ethylene alcohol,
• gl
ycol alcohol
,
• gl
ycol
,
• 1,2-
dihydroxyethane, an
d
• 1,2-
ethanediol
.
Properties
Ethylene glycol
• dissolves in water and alcohol,
• ca
n hold large amounts of heat before boiling
,
• lo
wers the freezing point of water, an
d
• ab
sorbs twice its weight in water
.
Page 20 of 124
Uses
Ethylene glycol is widely used as antifreeze
(concentration range: 80%–99%) or de-icing solutions
(concentration range: 3%–40%) for cars, boats, and
aircraft. It is also used in the chemical synthesis of
plastics, films, and solvents. It can be found in many
consumer products, including solvents, paints, and
coolants (concentration range: 20%–95%) (Caravati et
al. 2005).
Toxicity
Ethylene glycol poisoning is a relatively common
occurrence worldwide. Thousands of cases of poisoning
and some fatal cases occur annually in the United States
alone (AAPCC 2016).
Systemic ethylene glycol toxicity can occur following
ingestion. The toxic metabolic by-products of ethylene
glycol metabolism cause a buildup of acids in the blood
(metabolic acidosis). These toxic substances first affect
the central nervous system, then the cardiopulmonary
system, and finally can cause renal failure. Untreated
ethylene glycol poisoning can be fatal (NIOSH 2014).
The lethal oral dose in humans is approximately 1.4
mL/kg of pure ethylene glycol (Brent 2001).
Key Points
• Ethylene glycol is widely used in antifreeze and in
de-icing solutions for cars, boats, and aircraft.
• Untreated ethylene glycol poisoning can be fatal.
Progress
1. Which of the following statements is NOT true?
Check
A. Ethylene glycol is a colorless, odorless, and
sweet-tasting liquid.
B. Ethylene glycol can lower the freezing point of
water.
C. Ethylene glycol can hold large amounts of heat
before boiling.
D. Ethylene glycol poisoning is rare.
Page 21 of 124
Answers
1. The false statement is D. Ethylene glycol poisoning
is, in fact, a relatively common occurrence
worldwide. More than 5,000 cases of poisoning
occur in the United States each year. Untreated
ethylene glycol poisoning can be fatal; such deaths
have occurred annually in the United States.
Additionally, ethylene glycol is a colorless, odorless,
and sweet-tasting liquid that can lower the freezing
point of water and hold large amounts of heat
before boiling.
Feedback for A. (Web only): The false statement is D. In
fact, ethylene glycol poisoning is a relatively common
occurrence worldwide. Additionally, ethylene glycol is
a colorless, odorless, and sweet-tasting liquid. It can
lower the freezing point of water and hold large
amounts of heat before boiling.
Feedback for B. (Web only): The false statement is D. In
fact, ethylene glycol poisoning is a relatively common
occurrence worldwide. Ethylene glycol also can lower
the freezing point of water. It is a colorless, odorless,
and sweet-tasting liquid that holds large amounts of
heat before boiling.
Feedback for C. (Web only): The false statement is D. In
fact, ethylene glycol poisoning is a relatively common
occurrence worldwide. Ethylene glycol also can hold a
large amount of heat before boiling. It can lower the
freezing point of water and is a colorless, odorless,
and sweet-tasting liquid.
Feedback for D. (Web only): Correct. The false
statement is D. In fact, ethylene glycol poisoning is a
relatively common occurrence worldwide. More than
5,000 cases of poisoning occur in the United States each
year. Untreated ethylene glycol poisoning can be fatal;
such deaths have occurred annually in the United
States. Additionally, ethylene glycol is a colorless,
odorless, and sweet-tasting liquid. It can lower the
freezing point of water and hold large amounts of heat
before boiling.
Page 22 of 124
To review relevant content, see “Definition”,
“Properties”, and “Toxicity” in this section.
Where Is Ethylene Glycol Found?
Learning
Objective
After completing this section, you will be able to identify
sources of ethylene glycol exposure.
Introduction
The most common source of ethylene glycol exposure is
antifreeze. Antifreeze, which is readily available at
hardware and automotive stores, can contain up to 95%
ethylene glycol.
The primary sources of ethylene glycol in the environment
are disposal of used antifreeze and use of de-icing
solutions at airports (ATSDR 2010; EPA 2000).
Environmental
The primary sources of ethylene glycol in the environment
Sources
are from disposal of used antifreeze and use of de-icing
solutions at airports.
Air
Ethylene glycol does not persist in large amounts in
ambient air. This is because breakdown is rapid (half-life
in air is 8–84 hours).
Page 23 of 124
Water
Ethylene glycol is miscible with water. Its half-life ranges
from 2 to 12 days in surface water and 4 to 24 days in
groundwater. Bioconcentration and bioaccumulation are
insignificant because ethylene glycol is not fat-soluble and
biodegrades rapidly [Howard 1991].
Soil
Ethylene glycol will leach through soil to groundwater. It
biodegrades rapidly in soil (ATSDR 2010).
Occupational
Sources
Workers in industries producing or using products
containing ethylene glycol might be exposed to ethylene
glycol.
Sources from
A number of household products contain ethylene glycol
consumer
as an ingredient [(NLM 2016)]. Those containing high
products
concentrations of ethylene glycol include antifreeze
products.
Key Points
• The primary sources of ethylene glycol in the
environment are disposal of used antifreeze and use
of de-icing solutions at airports.
• Most antifreeze products contain high concentrations
of ethylene glycol.
Progress
Check
2. The most common source of ethylene glycol exposure
that leads to poisoning in the general U.S. population is
which of the following?
A. Polyester fibers
B. Antifreeze
C. Cosmetics
D. Resin products
An
swer
2. The best choice is B. Ethylene glycol is a significant
ingredient of automotive fluids such as antifreeze,
coolants, and hydraulic fluids. Antifreeze, which typically
consists of 95% ethylene glycol, accounts
Page 24 of 124
for about 40% of the ethylene glycol produced. It is
sold in many hardware and automotive stores and
therefore easily accessible to the public.
Feedback for A. (Web only): The best choice B. The
industrial uses of ethylene glycol include production of
polyester fibers, films, resin products, cosmetics, and fat
extractants. Antifreeze, however, which typically consists
of 95% ethylene glycol and accounts for about 40% of
ethylene glycol produced, is the most common source of
ethylene glycol exposure in the general population.
Feedback for B. (Web only): Correct. The best choice is B.
Ethylene glycol is a significant ingredient of automotive
fluids such as antifreeze, coolants, and hydraulic fluids.
Antifreeze, which typically consists of 95% ethylene
glycol, accounts for about 40% of the ethylene glycol
produced. It is sold in many hardware and automotive
stores and therefore easily accessible to the public.
Feedback for C. (Web only): The best choice is B. The
industrial uses of ethylene glycol include production of
polyester fibers, films, resin products, cosmetics, and fat
extractants. Antifreeze, however, which typically consists
of 95% ethylene glycol and accounts for about 40% of
ethylene glycol produced, is the most common source of
ethylene glycol exposure in the general population.
Feedback for D. (Web only): The best choice is B. The
industrial uses of ethylene glycol include production of
polyester fibers, films, resin products, cosmetics, and fat
extractants. Antifreeze, however, which typically consists
of 95% ethylene glycol and accounts for about 40% of
ethylene glycol produced, is the most common source of
ethylene glycol exposure in the general population.
To review relevant content, see the “Introduction” in
this section.
Page 25 of 124
What Are Routes of Exposure to Ethylene Glycol?
Learning
Objective
After completing this section, you will be able to identify
the most common route of exposure to ethylene glycol
that results in toxicity in the general U.S. population.
Introduction
Accidental or intentional ingestion of antifreeze is the
most common route of exposure leading to ethylene
glycol toxicity, resulting in thousands of poisonings
reported each year in the United States (AAPCC 2016;
ATSDR 2010).
Ethylene glycol is not expected to be found in the
environment away from areas where it is released.
Outside of those areas, the general public has little risk
for exposure through air, drinking water, or skin contact
with water or soil.
Dermal
Skin contact is the most likely route of occupational
exposure. However, dermal absorption is limited and
exposure by this route is generally not likely to lead to
toxic effects.
Dermal exposure to ethylene glycol may occur while
handling
• automotive antifreezes,
• coola
nts, an
d
• br
ake fluids
.
S
uch exposures are not likely to cause adverse health
effects.
Inhalation
Ethylene glycol’s low vapor pressure precludes
substantial inhalation exposure at ambient temperatures
in the environment (Howard PH 1991). Upper
respiratory tract irritation is possible when the liquid is
heated, agitated, or sprayed.
Page 26 of 124
Ingestion
Accidental or intentional ingestion of antifreeze is the
most common route of exposure leading to ethylene
glycol toxicity, resulting in thousands of poisonings
reported each year in the United States (AAPCC 2016;
ATSDR 2010)].
In the general U.S. population, ethylene glycol exposure
occurs most commonly through antifreeze ingestion.
Annual reports of the American Association of Poison
Control Centers (AAPCC) have reported
• 6,600 ethylene glycol exposures and 16 deaths i
n
2
0
13,
• 6,809 ethylene glycol exposures and 26 deaths in
2
014, an
d
• 6,
895 ethylene glycol exposures and 22 deaths i
n
2
015
.
Key Points
•
Accidental or intentional ingestion of antifreeze is
the most common route of exposure leading to
e
thylene glycol toxicity, resulting in thousands o
f
p
oisonings reported each year in the United States
.
• I
nhalation of ambient air, ingestion of drinkin
g
wa
ter, or skin contact with water or soil are no
t
ex
pected to be significant routes of exposure f
or
the general U.S. population.
Progress
C
heck
3. Which of the following is the most common route of
exposure leading to ethylene glycol toxicity in the
general U.S. population?
A. Inhalation.
B. Ingestion.
C. Dermal contact.
D. All of the above are equally common routes of
exposure leading to ethylene glycol toxicity in
the general U.S. population.
Page 27 of 124
Answer
3. The best choice is B. In the general U.S. population,
ethylene glycol toxicity occurs most commonly through
accidental or intentional antifreeze ingestion. Although
the most likely route of occupational exposure is skin
contact, such dermal exposure rarely leads to toxic
effects.
Feedback for A. (Web only): The best choice is B. The
most common route of exposure leading to ethylene
glycol toxicity in the general U.S. population is by
ingestion. Because of its low vapor pressure at room
temperature, the potential for ethylene glycol toxicity is
limited for inhalation exposures. However, people can
inhale ethylene glycol vapor and mist, particularly when
the chemical is heated, agitated, or sprayed.
Feedback for B. (Web only): Correct. In the general U.S.
population, ethylene glycol toxicity occurs most
commonly through accidental or intentional antifreeze
ingestion. Although the most likely route of occupational
exposure is skin contact, such dermal exposure rarely
leads to toxic effects.
Feedback for C. (Web only): The best choice is B. The
most common route of exposure leading to ethylene
glycol toxicity in the general U.S. population is by
ingestion. Although skin contact is the most likely
occupational exposure route, such dermal exposure
rarely leads to toxic effects. Under normal conditions,
skin contact while handling automotive antifreezes,
coolants, and brake fluids is not likely to cause adverse
health effects.
Feedback for D. (Web only): The best choice is B. In the
general U.S. population, ethylene glycol toxicity occurs
most commonly through accidental or intentional
antifreeze ingestion. Although skin contact is the most
likely route of occupational exposure, such dermal
exposure rarely leads to toxic effects. Inhalation
exposure can occur, but is not the most common route
leading to ethylene glycol toxicity in the general U.S.
population.
Page 28 of 124
To review relevant content, see “Ingestion” in this
section.
Page 29 of 124
Who is at Risk of Exposure to Ethylene Glycol?
Learning
Objectives
After completing this section, you will be able to identify
who is at risk of exposure to ethylene glycol.
Introduction
For the general population, the primary risk of exposure
to ethylene glycol is through contact with automobile
antifreezes and coolants.
People potentially at greater risk for ethylene glycol
exposure include those who live near
● airports where large amounts of ethylene glyco
l
a
re used for aircraft de-icing
or
● h
azardous waste sites contaminated with ethylen
e
g
lycol
.
W
orkers in industries producing or using products that
contain ethylene glycol are at greatest risk for exposure.
General U.S.
In the general U.S. population, exposure leading to
Population
ethylene glycol toxicity occurs most commonly through
accidental or intentional ingestion of antifreeze. The
2015 annual report of the American Association of
Poison Control Centers documented 6,895 ethylene
glycol exposures and 22 deaths.
The general U.S. population also can be exposed to
ethylene glycol by skin contact while handling
automotive antifreezes, coolants, and brake fluids.
However, such exposure is generally not likely to cause
adverse health effects.
Page 30 of 124
Special
Populations –
Environmental
Persons living near airports where large amounts of
ethylene glycol are used for aircraft de-icing or persons
who live near hazardous waste sites contaminated with
Exposures
ethylene glycol are potentially at greater risk for
ethylene glycol exposure, particularly if they consume
contaminated groundwater. Large amounts of ethylene
glycol are sprayed onto airplane wings as an aerosol or
mist to prevent ice buildup. Used in this manner,
ethylene glycol might contaminate groundwater near
airports through runoff. The spray also might expose
workers to air levels ranging from .05- 22 milligrams per
cubic meter (mg/m
3
) [(ATSDR 2010).
Ethylene glycol rapidly degrades in air, water, and soil.
Available monitoring data indicate that it is only found
near areas of release. Ethylene glycol is not expected to
be found in the environment away from areas where it
is released. Because of that, the general U.S. population
is not expected to be exposed to significant
environmental background levels of this substance
(ATSDR 2010).
Workers -
Products containing high concentrations of ethylene
Occupational
Exposure
glycol include antifreeze, coolants, de-icing fluids, brake
fluids, solvents, and latex paints. Workers in industries
producing or using those products potentially are at high
risk for exposure.
Although skin contact is the main route of occupational
exposure, vapors or mists can be inhaled when the
chemical is heated, agitated, or sprayed.
Page 31 of 124
• In the general U.S. population, ethylene glycol
toxicity occurs most commonly through accidental
o
r intentional ingestion of antifreeze
.
Key Points
● People potentially at increased risk for ethylen
e
g
lycol exposure include those who live nea
r
o
h
azardous waste sites contaminated wi
th
et
hylene glycol
,
o
industrial facilities where ethylene glycol is
pr
oduced or used, o
r
o
a
reas where ethylene glycol-based de-icin
g
f
ormulations are used
.
• Workers in industries producing or using products
t
hat contain ethylene glycol are at potentiall
y
i
ncreased risk of exposure
.
Progress
C
heck
4. Which of the following statements about risk of
exposure is NOT true?
A. Et
hylene glycol might contaminate groundwate
r
near airports through runoff and might expose
w
orkers
.
B.
Pe
ople living near airports where large amounts o
f
ethylene glycol are used for aircraft de-icing
p
otentially are at greater risk for ethylene glyco
l
e
xposure
.
C. I
n the general population, ethylene glycol toxicit
y
o
ccurs most commonly through skin contact wi
th
a
ntifreeze
.
D. B
ecause ethylene glycol is mostly limited to area
s
where it is released, the general U.S. population is
n
ot expected to be exposed to significan
t
e
nvironmental background levels of thi
s
su
bstance
.
Page 32 of 124
Answer
4. The false statement is C. In the general
p
opulation, ethylene glycol toxicity occurs mo
st
c
ommonly through accidental or intentional ingestio
n
o
f antifreeze. The general U.S. population can b
e
ex
posed to ethylene glycol by skin contact whil
e
handling automotive antifreezes, coolants, and brake
f
luids. However, such exposure is less likely to caus
e
a
dverse health effects. Ethylene glycol coul
d
c
ontaminate groundwater near airports throug
h
r
unoff and might expose workers. People living nea
r
airports where large amounts of ethylene glycol are
u
sed for aircraft de-icing potentially are at greate
r
r
isk for ethylene glycol exposure. Because ethylen
e
g
lycol is not expected to be found in the environmen
t
a
way from areas where it is released, the genera
l
U.S. population is not expected to be exposed to
s
ignificant environmental background levels of thi
s
su
bstance
.
Feedback for A. (Web only): The false statement is C.
In the general population, ethylene glycol toxicity
occurs most commonly through accidental or
intentional ingestion of antifreeze. The general U.S.
population can be exposed to ethylene glycol by skin
contact while handling automotive antifreezes,
coolants, and brake fluids. However, such exposure is
less likely to cause adverse health effects. The other
statements are true.
● Ethylene glycol might contaminate groundwate
r
n
ear airports through runoff and might expos
e
workers.
● Pe
ople living near airports where large amount
s
o
f ethylene glycol are used for aircraft de-icin
g
potentially are at greater risk for ethylene
g
lycol exposure
.
● B
ecause ethylene glycol is not expected to b
e
f
ound in the environment away from area
s
w
here it is released, the general U.S
.
po
pulation is not expected to be exposed t
o
significant environmental background levels of
t
his substance
.
Page 33 of 124
Feedback for B. (Web only): The false statement is C.
In the general population, ethylene glycol toxicity
occurs most commonly through accidental or
intentional ingestion of antifreeze. The general U.S.
population can be exposed to ethylene glycol by skin
contact while handling automotive antifreezes,
coolants, and brake fluids. However, such exposure is
less likely to cause adverse health effects. The other
statements are true.
● People living near airports where large amount
s
o
f ethylene glycol are used for aircraft de-icin
g
p
otentially are at greater risk for ethylen
e
g
lycol exposure
.
● Et
hylene glycol might contaminate groundwate
r
near airports through runoff and might expose
w
orkers
.
● B
ecause ethylene glycol is not expected to b
e
f
ound in the environment away from area
s
w
here it is released, the general U.S
.
p
opulation is not expected to be exposed t
o
significant environmental background levels of
t
his substance
.
F
eedback for C. (Web only): Correct. The false
statement is C. In the general population, ethylene
glycol toxicity occurs most commonly through
accidental or intentional ingestion of antifreeze. The
general U.S. population can be exposed to ethylene
glycol by skin contact while handling automotive
antifreezes, coolants, and brake fluids. However,
such exposure is less likely to cause adverse health
effects. The other statements are true.
● Ethylene glycol might contaminate groundwate
r
n
ear airports through runoff and might expos
e
w
orkers
.
● Pe
ople living near airports where large amount
s
of ethylene glycol are used for aircraft de-icing
p
otentially are at greater risk for ethylen
e
g
lycol exposure
.
● B
ecause ethylene glycol is not expected to b
e
found in the environment away from areas
w
here it is released, the general U.S
.
population is not expected to be exposed to
Page 34 of 124
significant environmental background levels of
this substance.
Feedback for D. (Web only): The false statement is
C
. I
n the general U.S. population, ethylene glyco
l
t
oxicity occurs most commonly through accidental o
r
i
ntentional ingestion of antifreeze. The general U.S
.
p
opulation can be exposed to ethylene glycol by ski
n
contact while handling automotive antifreezes,
co
olants, and brake fluids. However, such exposure i
s
l
ess likely to cause adverse health effects. The othe
r
s
tatements are true
.
● B
ecause ethylene glycol is not expected to b
e
f
ound in the environment away from area
s
where it is released, the general U.S.
p
opulation is not expected to be exposed t
o
s
ignificant environmental background levels o
f
t
his substance
.
● Et
hylene glycol might contaminate groundwate
r
n
ear airports through runoff and might expos
e
workers.
● Pe
ople living near airports where large amount
s
o
f ethylene glycol are used for aircraft de-icin
g
potentially are at greater risk for ethylene
g
lycol exposure
.
F
or relevant content, review the whole section “Who
is at Risk of Exposure to Ethylene Glycol?”
Page 35 of 124
What Are U.S. Regulations and Guidelines for
Ethylene Glycol Exposure?
Learning
Objectives
After completing this section, you will be able to
describe current U.S. regulations and guidelines for
ethylene glycol exposure.
Introduction
The U.S. government has developed ethylene glycol
regulations and guidelines intended to protect the public
and workers from potential adverse health effects
should exposure occur.
Workplace
The Occupational Safety and Health Administration
Standards
(OSHA) has not established a permissible exposure limit
(PEL).
The National Institute for Occupational Safety and
Health (NIOSH) has provided a recommended ethylene
glycol exposure limit (REL) of 50 ppm (ceiling limit)
(NIOSH 2005).
The American Conference of Governmental Industrial
Hygienists (ACGIH) has established threshold limit
values (TLVs) for workplace exposure [(ACGIH 2017)].
Environmental
Air
Standards
The Environmental Protection Agency (EPA) has
designated ethylene glycol as a hazardous air pollutant
under the Clean Air Act (EPA 2007).
Water
EPA recommends that children not be exposed to more
than 20 mg/L (20 ppm) ethylene glycol in drinking
water for 1 day, or 6 mg/L (6 ppm) per day over 10
days.
EPA also recommends that adults not be exposed to
more than a daily total of 7 mg/L (7 ppm) for a lifetime
[FSTRAC 1990].
Page 36 of 124
Food
The Food and Drug Administration (FDA) has approved
ethylene glycol as an indirect food additive, for use only
as a component of packaging adhesives.
The U.S. Department of Health and Human Services
(HHS), the International Agency for Research on Cancer
(IARC), and EPA have not classified ethylene glycol as a
human carcinogen.
Key Points
• NIOSH and ACGIH have established limits for
exposure to ethylene glycol in the workplace.
• EPA has established limits for exposure to ethylene
g
lycol in drinking water for children and adults
.
• E
thylene glycol is not classified as a huma
n
ca
rcinogen
.
Progress
5. Which of the following statements is FALSE regarding
Check
U.S. government guidelines for ethylene glyco
l
exposure?
A.
E
PA has established exposure limits of ethylen
e
g
lycol in drinking water for children and adults
.
B.
A
CGIH has established threshold limit values f
or
workplace exposure.
C.
F
DA has approved ethylene glycol as an indirect foo
d
a
dditive
.
D.
E
thylene glycol is classified as a human carcinogen
.
Page 37 of 124
Answers
5. The false statement is D. Ethylene glycol is not
classified as a human carcinogen. The other
s
tatements are true
.
● EPA has established limits to ethylene glycol
ex
posure in drinking water for children an
d
a
dults
.
● AC
GIH has established threshold limit value
s
f
or workplace exposure
.
● FDA has approved ethylene glycol as an
i
ndirect food additive
.
F
eedback for A. (Web only): The false statement is D.
Ethylene glycol is not classified as a human carcinogen.
The other statements are true.
● EPA has established limits to ethylene glyco
l
ex
posure in drinking water for children and adults
.
● A
CGIH has established threshold limit values fo
r
w
orkplace exposure
.
● F
DA has approved ethylene glycol as an indirec
t
f
ood additive
.
F
eedback for B. (Web only): The false statement is D.
Ethylene glycol is not classified as a human carcinogen.
The other statements are true.
● ACGIH has established threshold limit values fo
r
w
orkplace exposure
.
● EPA has established limits to ethylene glycol
ex
posure in drinking water for children an
d
a
dults
.
● F
DA has approved ethylene glycol as an indirec
t
f
ood additive
.
F
eedback for C. (Web only): The false statement is D.
Ethylene glycol is not classified as a human carcinogen.
The other statements are true.
● FDA has approved ethylene glycol as an indirect
f
ood additive
.
● EPA has established limits to ethylene glycol
ex
posure in drinking water for children an
d
adults.
Page 38 of 124
● ACGIH has established threshold limit values for
workplace exposure.
F
eedback for D. (Web only): Correct. Ethylene glycol is
not classified as a human carcinogen. The other
statements are true,
● EPA has established limits to ethylene glyco
l
ex
posure in drinking water for children an
d
a
dults
.
● A
CGIH has established threshold limit values fo
r
workplace exposure.
● F
DA has approved ethylene glycol as an indirec
t
f
ood additive
.
T
o review relevant content, see “Environmental
Standards” in this section.
What Is the Biological Fate of Ethylene Glycol?
Learning
Objectives
After completing this section, you will be able to explain
the major pathway of ethylene glycol metabolism in the
body.
Introduction
Ethylene glycol is rapidly absorbed from the
gastrointestinal tract and slowly absorbed through the
skin or lungs. It is distributed throughout total body
water. Most of an absorbed dose of ethylene glycol is
metabolized by the liver and a small portion is excreted
unchanged in the urine.
Page 39 of 124
Absorption
and
Distribution
Metabolic
Pathway
Ethylene glycol is rapidly absorbed from the
gastrointestinal tract and slowly absorbed through the
skin or lungs. Studies involving animals fed single doses
of ethylene glycol by gavage show that absorption is
rapid and nearly complete. Peak plasma concentrations
occurred in 1–4 hours, increasing linearly with dose
among various species (i.e., rats, mice, monkeys).
(International Programme on Chemical Safety 2002).
Because it is highly water-soluble, ethylene glycol is
distributed throughout total body water. The normal
serum half-life of ethylene glycol is estimated at about
2.5 hours in children and 3–8 hours in untreated adults
(Eder et al. 1998).
The parent compound ethylene glycol has relatively low
toxicity other than its inebriating effects. The liver
metabolizes ethylene glycol by successive oxidations to
a variety of compounds that include
• glycoaldehyde,
• gl
ycolic acid
,
• gl
yoxylic acid, an
d
• ox
alic acid
.
These compounds are more toxic than ethylene glycol
itself (Figure 1).
The rate-limiting step in this metabolic process is the
conversion of ethylene glycol to glycoaldehyde, a
process catalyzed by alcohol dehydrogenase (ADH).
Several factors might influence susceptibility to ethylene
glycol-induced toxicity, including the following:
• Individual differences in ADH activity
• Nu
tritional deficiencies, notably lack of thiamine o
r
p
yridoxine (two vitamins that mediate the metaboli
c
d
etoxification of ethylene glycol
)
Concomitant ethanol exposure can decrease or prevent
toxicity by preferentially competing for ADH, thereby
inhibiting transformation of ethylene glycol to
glycoaldehyde.
Page 40 of 124
Figure 1. Metabolism of ethylene glycol. Adapted from (Hall AH
1992).
Page 41 of 124
Elimination
If the patient is free of ethanol exposure, the liver
metabolizes approximately 80% of an absorbed dose of
ethylene glycol [Brent 2001].
A small fraction of ethylene glycol (less than 20% after
low-dose ingestion) passes unchanged in the urine.
The breakdown of ethylene glycol metabolites can
generate CO
2
, which is eliminated through the lungs
(ATSDR 2010).
Key Points
• Ethylene glycol is rapidly absorbed from the
gastrointestinal tract and slowly absorbed through
t
he skin or lungs
.
• Ethylene glycol is metabolized in the liver to a
v
ariety of more toxic compounds
.
• I
n untreated adults, approximately 20% of a dos
e
o
f ethylene glycol is excreted unchanged by th
e
ki
dneys
.
• The half-life of ethylene glycol in untreated adult
p
atients is 3–8 hours
.
Progress Check
After being absorbed in the body, what happens to
most of the ethylene glycol?
A. I
t is metabolized in the kidney
.
B.
I
t is eliminated unchanged by the kidneys
.
C.
I
t is metabolized in the liver
.
D.
I
t is eliminated unchanged by the lungs
.
Answer
6. The correct answer is C. About 80% of an
a
bsorbed dose of ethylene glycol is metabolized i
n
t
he liver
.
F
eedback for A. (Web only): The correct answer is
C. A
bout 80% of an absorbed dose of ethylen
e
g
lycol is metabolized in the liver. Only a smal
l
portion (less than 20%) of absorbed ethylene glycol
i
s eliminated unchanged by the kidney
.
F
eedback for B. (Web only): The correct answer is
C. About 80% of an absorbed dose of ethylene
Page 42 of 124
glycol is metabolized in the liver. Only a small
portion (less than 20%) of absorbed ethylene glycol
is eliminated unchanged by the kidney.
Feedback for C. (Web only): Correct. About 80% of
an absorbed dose of ethylene glycol is metabolized
in the liver.
Feedback for D. (Web only): The correct answer is C.
About 80% of an absorbed dose of ethylene glycol is
metabolized in the liver. The breakdown of
metabolites of ethylene glycol can generate CO
2
,
which is one of the elimination pathways of ethylene
glycol through the lungs.
To review relevant content, see “Metabolic
Pathway” and “Elimination” in this section.
What Are the Toxicological Effects of Ethylene
Glycol Poisoning?
Learning
Objectives
After completing this section, you will be able to
describe the toxicological effects of ethylene glycol
poisoning.
Introduction
Ethylene glycol’s toxicity mainly results from the
accumulation of its toxic metabolites.
Ethylene glycol is a central nervous system (CNS)
depressant that produces acute effects similar to those
of ethanol. These CNS effects predominate during the
first hours after exposure.
If undetected or untreated, ethylene glycol ingestion can
cause serious or fatal toxicity. This section describes the
systemic effects associated with significant ethylene
glycol exposure.
Page 43 of 124
Mechanism of
The main toxicity of ethylene glycol results from hepatic
Toxicity
metabolism of ethylene glycol to
• glycoaldehyde
,
• g
lycolate
,
• g
lyoxylate, an
d
• oxalate.
T
hese metabolites inhibit
• oxidative phosphorylation and cellular respiration
,
• glucose and serotonin metabolism,
• pr
otein synthesis
,
• D
NA replication, an
d
• ri
bosomal RNA formation
.
The effects include CNS depression and cardiopulmonary
and renal failure (Bove 1966; Jacobsen and McMartin
1986).
The accumulation of organic acid metabolites, especially
glycolic acid, results in an elevated anion gap metabolic
acidosis.
Stages of
Intoxication
• A three-stage theory of ethylene glycol poisoning
was introduced in the 1950s (Berman et al. 1957;
Ka
hn and Brotchner 1950). These stages ar
e
t
heoretical descriptions of ethylene glyco
l
p
oisoning, but the onset and progression of th
e
c
linical course is frequently not consistent o
r
predictable. One stage might predominate,
w
hereas another stage might be absen
t
(
Jammalamadaka and Raissi 2010)
.
• T
he three stages include the following
:
o
Stage 1 (the neurological stage) occurs
w
ithin 30 minutes to 12 hours afte
r
i
ngestion
.
o
S
tage 2 (the cardiopulmonary stage) occur
s
b
etween 12 and 24 hours after ingestion
.
o
Stage 3 (the renal stage) occurs between 24
a
nd 72 hours after ingestion
.
Page 44 of 124
See more details in the section titled “Clinical
Assessment—History and Physical.”
Neurologic
The initial phase of ethylene glycol poisoning in humans
Effects is characterized by inebriation caused by unmetabolized
ethylene glycol. The following effects are common in
acute poisoning cases (Buell et al. 1998; Hess et al.
2004; Parry and Wallach 1974):
• Ataxi
a
• Sl
urred speec
h
• Drowsiness
• Ir
ritatio
n
• Re
stlessne
ss
• Di
sorientatio
n
Possible consequences of neurologic effects in severe
poisonings (Froberg et al. 2006; Hantson et al. 2002;
Walder and Tyler 1994) include the following:
• Myoclonic jerk
s
• Convulsions
• Coma
• D
ea
th
C
erebral edema and deposition of calcium oxalate
crystals in the walls of small blood vessels in the brain
contribute to this CNS toxicity (Bey et al. 2002; Froberg
et al. 2006; Jobard et al. 1996; Tobe et al. 2002). Some
studies have documented brain dysfunction with
corresponding cranial computed tomography (CT)
findings after ethylene glycol ingestion, such as low-
density areas in the basal ganglia, thalami, midbrain,
and upper pons. The neurologic findings reflect
dysfunction of all the areas of hypodensity on the cranial
CT scan. In one study, magnetic resonance imaging of
the brain obtained 24 days after ingestion revealed
Page 45 of 124
Respiratory
Effects
bilateral putamen necrosis (Chung and Tuso 1989;
Morgan et al. 2000; Zeiss et al. 1989).
According to some investigators, effects on cranial
nerves appear late (generally 5–20 days after ingestion)
and constitute a fourth, late cerebral phase in ethylene
glycol intoxication (Chung and Tuso 1989; Gardner et
al. 2004; Lewis et al. 1997). The following cranial nerve
effects have been reported after acute exposure:
• Facial pals
y
• He
aring los
s
• Dy
sphagi
a
• Ophthalmoplegia
• Vi
sual disturbance
s
S
uch adverse effects are uncommon, but delayed
treatment might contribute to their development
(Broadley et al. 1997; Lewis et al. 1997; Momont and
Dahlberg 1989; Tobe et al. 2002).
Inhaled ethylene glycol can irritate the respiratory tract
(Wills et al. 1974).
• Throat and upper respiratory irritation were the
m
ost common complaints after prolonge
d
e
xperimental exposures in humans (4 weeks a
t
co
ncentrations of 1–25 parts per million [ppm])
.
• E
xposure to 60 ppm aerosolized ethylene glyco
l
caused noticeable respiratory irritation.
• E
xposure to 80 ppm aerosolized ethylene glyco
l
w
as “intolerable” because respiratory discomfor
t
de
veloped rapidly
.
Pulmonary effects typically occur 12–72 hours after
ethylene glycol ingestion. Pulmonary edema, adult
respiratory distress syndrome (ARDS), and death have
occurred in persons exposed to ethylene glycol (Gordon
and Hunter 1982; Haupt et al. 1988; Piagnerelli et al.
1999).
Page 46 of 124
The following respiratory effects often occur 12 hours or
more after exposure in victims of severe ethylene glycol
poisoning:
• Tachypne
a
• Hy
perventilatio
n
• Kussmaul respirations
S
uch effects most often reflect physiological
compensation for severe metabolic acidosis rather than
primary lung disease (Friedman et al. 1962; Godolphin
et al. 1980; Parry and Wallach 1974). Autopsies [(Vale
1979) of ethylene glycol victims revealed the following:
• Pulmonary edema with diffuse hemorrhagi
c
ex
udat
es
• Bronchopneumonia (probably caused by aspiration)
• De
posits of calcium oxalate crystals in lun
g
p
arenchym
a
Cardiovascular
Effects
The following severe cardiovascular effects have been
reported in persons 12-24 hours (stage 2) after
ingesting ethylene glycol (Friedman et al. 1962; Gordon
and Hunter 1982; Parry and Wallach 1974; Vale 1979):
• Hypertension or hypotensio
n
• Dysrhythmias (from electrolyte abnormalities)
• Co
ngestive heart failure with cardiogeni
c
p
ulmonary edem
a
• Ci
rculatory collaps
e
• C
ardiac arres
t
• Death
Page 47 of 124
Metabolic
Effects
Ethylene glycol exposure is characterized by an elevated
osmolal gap and metabolic acidosis with an elevated
anion gap.
• Onset occurs within 24 hours after ingestion
.
• A
cidosis is caused primarily by the accumulation o
f
glycolic and glyoxylic acids. Oxalic acid and lactic
a
cid also contribute
.
E
thylene glycol is a small, osmotically active molecule
that
• increases plasma osmolality, an
d
• ca
n cause a large osmolal gap
.
Te
tany, including muscle twitches, cramps, and
contractions, can sometimes result from hypocalcemia,
which results from calcium precipitation by the oxalate
formed during ethylene glycol metabolism (Parry and
Wallach 1974).
Renal Effects
Adverse renal effects after ethylene glycol ingestion
typically occur during the third stage of ethylene glycol
toxicity, 24–72 hours after acute exposure (Davis et al.
1997; Hess et al. 2004).
• Kidney damage manifests as acute oliguric rena
l
failure.
• Th
e most common physical finding i
s
cos
tovertebral angle tenderness (Friedman et al
.
1
962)
.
• T
he most characteristic abnormality is the presenc
e
of large numbers of “tent-shaped” (octahedral) or
n
eedle-shaped oxalate crystals in the urin
e
(
Froberg et al. 2006; Hantson et al. 2002; Huh
n
a
nd Rosenberg 1995; Leth and Gregersen 2005
;
M
cMartin K 2009; Olivero 1993; Takayesu et al
.
2006).
• A
bsence of oxalate crystals does not rule out a
n
e
thylene glycol poisoning diagnosis (Baum et al
.
2
000; Boyer et al. 2001; Curtin et al. 1992
;
H
antson et al. 2002; Haupt et al. 1988)
.
Page 48 of 124
Other typical urinalysis abnormalities include the
following:
• Low specific gravit
y
• Pr
oteinuri
a
• Mi
crohematuri
a
• Pyuria
Re
nal dysfunction might be mild and short-lived or
severe and persistent. Although uncommon, permanent
renal insufficiency does occur (Berman et al. 1957; Buell
et al. 1998; Friedman et al. 1962; Hantson et al. 1998;
Parry and Wallach 1974; Takayesu et al. 2006).
The toxicity of ethylene glycol is linked with all four
metabolites.
• Glycolic acid contributes to the metabolic acidosis
.
• O
xalic acid is poorly soluble in the presence o
f
ca
lcium
.
o
Calcium oxalate crystals in the urine are
s
upportive of the diagnosis
.
o
T
he precipitation of oxalate crystals in th
e
t
ubular lumen leads to luminal blockage an
d
co
mpression-induced loss of glomerula
r
filtration (renal failure).
o
I
n transformed kidney cells, the oxalate io
n
i
nduces cytotoxic damage (McMartin KE an
d
C
enac 2000)
.
• Glycoaldehyde and glyoxylate might be responsible
f
or ethylene glycol nephrotoxicity (Poldelski et al
.
2
001)
.
Carcinogenici-
ty
Studies in humans and animals have not shown any
associations between ethylene glycol exposure and the
incidence of any cancer (ATSDR 2014).
Developmental
and
Reproductive
Effects
No known human studies have evaluated a link between
ethylene glycol exposure and reproductive or
developmental hazards in humans (ATSDR 2014).
Page 49 of 124
• Ethylene glycol exposure was teratogenic to mice
and rats, resulting in craniofacial and neural tube
cl
osure defects and skeletal dysplasia [Lamb et al
.
1
985; Marr et al. 1992; Price et al. 1985; Tyl e
t
a
l. 1995
].
• L
arge oral doses of ethylene glycol (>500 mg kg-
1
i
n mice and >1,000 mg kg-1 in rats) might cau
se
d
evelopmental toxicity in those animals, includin
g
o
a
xial skeletal malformations
,
o
r
educed body weights
,
o
e
xternal malformations, an
d
o
i
ncreased post-implantation loss [IPCS 2002
;
NTP-CERHR 2004].
Other Effects
Nausea, vomiting (with or without blood), and
abdominal pain often occur soon after ethylene glycol
ingestion (Davis et al. 1997; Johnson et al. 1999;
Moossavi et al. 2003; Singh et al. 2001; Verrilli et al.
1987). Ethylene glycol is only a minor skin and mucous
membrane irritant, although a few patients have had
allergic contact dermatitis (Clayton GD & Clayton FE
1994). Reported effects on the blood have included
(Hantson et al. 1998; Rasic et al. 1999; Verrilli et al.
1987)
• leukocytosis
,
• me
themoglobinemia (rare), an
d
• bon
e marrow arrest
.
Reported musculoskeletal effects have included
• muscle tenderness an
d
• el
evation of creatine kinase (Friedman et al. 1962
;
P
arry and Wallach 1974; Verrilli et al. 1987)
.
Key Points
• After ethylene glycol ingestion, signs of inebriation
are among the first manifestations.
• U
nmetabolized ethylene glycol causes CN
S
d
epression. Delays in initiating treatment ca
n
r
esult in more severe adverse effects
.
• T
he most common cause of tachypnea i
s
uncompensated metabolic acidosis.
Page 50 of 124
Progress
Check
• Ethylene glycol poisoning through ingestion can
cause noncardiogenic pulmonary edema and ARDS.
• Ethylene glycol poisoning can cause dysrhythmias
a
nd heart failure
.
• E
thylene glycol toxicity is characterized by a
n
o
smolal gap and metabolic acidosis with a
n
e
levated anion gap
.
• Nephrotoxicity after ethylene glycol ingestion
t
ypically occurs 24-72 hours after acute exposure
.
• No st
udies were located that link ethylene glyco
l
ex
posure to cancer or reproductive o
r
d
evelopmental hazards in humans
.
7. Which of the following cellular biochemical reactions
can ethylene glycol’s acid and aldehyde metabolites
inhibit?
A. Ox
idative phosphorylation and cellula
r
r
espiration
.
B.
Pr
otein synthesis
.
C.
D
NA replication
.
D.
All of the above.
8. After ethylene glycol ingestion, signs of inebriation,
caused by which of the following, are among the first
clinical manifestations?
A. Et
hanol
.
B.
Unmetabolized ethylene glycol.
C.
Met
abolites of ethylene glycol
.
D.
Non
e of the above
.
9. Respiratory effects such as tachypnea and
hyperventilation often occur 12 hours or more after
exposure in victims of severe ethylene glycol poisoning.
Tachypnea seen with ethylene glycol toxicity most often
reflects which of the following?
A. Ph
ysiological compensation for severe metaboli
c
a
cidosis
.
B.
Pr
imary lung disease
.
C.
Ad
ult respiratory distress syndrome (ARDS)
.
D.
All of the above.
Page 51 of 124
Answers
10. The metabolic acidosis of ethylene glycol
poisoning is characterized as which of the
following?
A. Normochloremic.
B. Low bicarbonate level and pH.
C. Acidemia and elevated anion gap.
D. All of the above.
11. Which of the following statements
bestcharacterizes nephrotoxicity resulting from
significant ethylene glycol poisoning?
A. Kidney damage manifests as acute oliguric renal
failure.
B. Urine contains many oxalate crystals.
C. Absence of oxalate crystals in the urine does not
rule out a diagnosis of ethylene glycol poisoning.
D. All of the above.
7. The best choice is D. All of the above. The main
toxicity of ethylene glycol results from its conversion in
the liver to acid and aldehyde metabolites. The latter
inhibits many cellular biochemical reactions, including
oxidative phosphorylation and cellular respiration,
glucose and serotonin metabolism, protein synthesis,
DNA replication, and ribosomal RNA formation.
Feedback for A. (Web only): The best choice is D. All of
the above. The main toxicity of ethylene glycol results
from its conversion in the liver to acid and aldehyde
metabolites. The latter inhibits many cellular
biochemical reactions, including oxidative
phosphorylation and cellular respiration, glucose and
serotonin metabolism, protein synthesis, DNA
replication, and ribosomal RNA formation.
Feedback for B. (Web only): The best choice is D. All of
the above. The main toxicity of ethylene glycol results
from its conversion in the liver to acid and aldehyde
metabolites. The latter inhibits many cellular
biochemical reactions, including oxidative
phosphorylation and cellular respiration, glucose and
Page 52 of 124
serotonin metabolism, protein synthesis, DNA
replication, and ribosomal RNA formation.
Feedback for C. (Web only): The best choice is D. All of
the above. The main toxicity of ethylene glycol results
from its conversion in the liver to acid and aldehyde
metabolites. The latter inhibits many cellular
biochemical reactions, including oxidative
phosphorylation and cellular respiration, glucose and
serotonin metabolism, protein synthesis, DNA
replication, and ribosomal RNA formation.
Feedback for D. (Web only): Correct. All of the above.
The main toxicity of ethylene glycol results from its
conversion in the liver to acid and aldehyde metabolites.
The latter inhibits many cellular biochemical reactions,
including oxidative phosphorylation and cellular
respiration, glucose and serotonin metabolism, protein
synthesis, DNA replication, and ribosomal RNA
formation.
To review relevant content, see “Mechanism of
Toxicity” in this section.
8. Th
e best choice is B. The initial phase of ethylen
e
g
lycol poisoning is characterized by inebriatio
n
c
aused by unmetabolized ethylene glycol
.
Feedback for A. (Web only): The best choice is B. The
initial phase of ethylene glycol poisoning is characterized
by inebriation caused by unmetabolized ethylene glycol.
Ethanol is not part of ethylene glycol metabolism.
Feedback for B. (Web only): Correct. The initial phase of
ethylene glycol poisoning is characterized by inebriation
caused by unmetabolized ethylene glycol.
Feedback for C. (Web only): The best choice is B. The
initial phase of ethylene glycol poisoning is characterized
by inebriation caused by unmetabolized ethylene glycol.
The metabolites of ethylene glycol are associated with
the main toxic effects, including kidney damage.
Page 53 of 124
Feedback for D. (Web only): The best choice is B. The
initial phase of ethylene glycol poisoning is characterized
by inebriation caused by unmetabolized ethylene glycol.
To review relevant content, see “Neurologic
Effects” in this section.
9. T
he best choice is A. Tachypnea, hyperventilation
,
a
nd Kussmaul respirations often occur 12 hours or mor
e
after exposure in victims of severe ethylene glycol
p
oisoning. Tachypnea seen with ethylene glycol toxicit
y
m
ost often reflects physiological compensation fo
r
s
evere metabolic acidosis rather than primary lun
g
d
isease or ARDS
.
F
eedback for A. (Web only): Correct. Tachypnea,
hyperventilation, and Kussmaul respirations often occur
12 hours or more after exposure in victims of severe
ethylene glycol poisoning. Tachypnea seen with ethylene
glycol toxicity most often reflects physiological
compensation for severe metabolic acidosis rather than
primary lung disease or ARDS. The most common cause
of tachypnea is uncompensated metabolic acidosis.
Feedback for B. (Web only): The best choice is A.
Tachypnea, hyperventilation, and Kussmaul respirations
often occur 12 hours or more after exposure in victims
of severe ethylene glycol poisoning. Tachypnea seen
with ethylene glycol toxicity most often reflects
physiological compensation for severe metabolic acidosis
rather than primary lung disease or ARDS.
Feedback for C. (Web only): The best choice is A.
Pulmonary edema and adult respiratory distress
syndrome (ARDS) have been reported in ethylene glycol
victims. Tachypnea, however, is most likely one of the
effects that reflects physiological compensation for
severe metabolic acidosis
Feedback for D. (Web only): The best choice is A.
Tachypnea often occurs 12 hours or more after
exposure in victims of severe ethylene glycol poisoning.
It most often reflects physiological compensation for
Page 54 of 124
severe metabolic acidosis rather than primary lung
disease or adult respiratory distress syndrome (ARDS).
To review relevant content, see “Respiratory
Effects” in this section.
10
. Th
e best choice is D. All of the above. The metaboli
c
a
cidosis of ethylene glycol poisoning is characterized a
s
normochloremic, with low bicarbonate level and pH, and
a
cidemia with an elevated anion gap
.
F
eedback for A. (Web only): The best choice is D. All of
the above. Although the metabolic acidosis of ethylene
glycol poisoning is characterized as normochloremic, it is
also characterized as having a low bicarbonate level and
pH, and acidemia with an elevated anion gap.
Feedback for B. (Web only): The best choice is D. All of
the above. Although the metabolic acidosis of ethylene
glycol poisoning is characterized as having a low
bicarbonate level and pH, it is also characterized as
normochloremic with acidemia and an elevated anion
gap.
Feedback for C. (Web only): The best choice is D. All of
the above. Although the metabolic acidosis of ethylene
glycol poisoning is characterized as having acidemia
with an elevated anion gap, it is also characterized as
normochloremic with a low bicarbonate level and pH.
Feedback for D. (Web only): Correct.
All of the above. The metabolic acidosis of ethylene
glycol poisoning is characterized as normochloremic,
with low bicarbonate level and pH, and acidemia with an
elevated anion gap.
To review relevant content, see “Metabolic Effects”
in this section.
11
.
The best choice is D. All of the above. Kidney
d
amage after ethylene glycol ingestion typically occur
s
2
4-72 hours after acute exposure and manifests a
s
a
cute oliguric renal failure. Often many tent-shaped o
r
needle-shaped oxalate crystals are seen in the urine.
Page 55 of 124
However, absence of oxalate crystals does not rule out
the diagnosis of ethylene glycol poisoning.
Feedback for A. (Web only): The best choice is D. All of
the above. Kidney damage after ethylene glycol
ingestion typically occurs 24-72 hours after acute
exposure and manifests as acute oliguric renal failure.
Often many tent-shaped or needle-shaped oxalate
crystals also are seen in the urine. However, absence of
oxalate crystals does not rule out the diagnosis of
ethylene glycol poisoning.
Feedback for B. (Web only): The best choice is D. All of
the above. Although many of tent-shaped or needle-
shaped oxalate crystals often are seen in the urine,
absence of oxalate crystals does not rule out the
diagnosis of ethylene glycol poisoning. In addition,
kidney damage manifests as acute oliguric renal failure.
Feedback for C. (Web only): The best choice is D. All of
the above. Absence of oxalate crystals in the urine does
not rule out the diagnosis of ethylene glycol poisoning.
However, many tent-shaped or needle-shaped oxalate
crystals often are seen in the urine. In addition, kidney
damage manifests as acute oliguric renal failure.
Feedback for D. (Web only): Correct. All of the above.
Kidney damage after ethylene glycol ingestion typically
occurs 24-72 hours after acute exposure and manifests
as acute oliguric renal failure. Often many tent-shaped
or needle-shaped oxalate crystals are seen in the urine.
However, absence of oxalate crystals does not rule out
the diagnosis of ethylene glycol poisoning.
To review relevant content, see “Renal Effects” in
this section.
Clinical Assessment—History and Physical
Examination
Learning
After completing this section, you will be able to
Objective
Page 56 of 124
• describe what is included in the initial history and
physical examination of patients potentially
ex
posed to ethylene glycol, an
d
• describe how the clinical presentation changes over
t
ime
.
Introduction
Ethylene glycol ingestion is a medical emergency
requiring prompt recognition and aggressive treatment.
• The clinical presentation changes over time a
s
i
ntoxication progresses
.
• S
igns and symptoms depend on the amount
of
ethylene glycol ingested and concurrent use of
a
lcohol
.
T
herefore, making a correct diagnosis requires a reliable
history of the
• time
,
• r
oute, an
d
• i
ntensity of exposure
.
In some cases, the patient’s altered mental state can
make a detailed history difficult to obtain. Begin
appropriate treatment while waiting for laboratory
confirmation if ethylene glycol poisoning is strongly
suspected (Howland 2015; Johnson et al. 1999; Shah
2013; Stokes and Aueron 1980).
Patient History
● An exposure history* should be part of the patient
history. If you suspect a temporal association
b
etween symptoms and exposure to certai
n
p
roducts, try to identify the specific chemica
l
i
ngredients involved
.
(
*ATSDR has developed other CSEMs, includin
g
“
Taking an Exposure History” and “Taking
a
Pediatric Exposure History.” To view these CSEMs,
g
o to http://www.atsdr.cdc.gov/csem/
.)
• I
n all suspected ethylene glycol poisonings,
a
ca
reful history of possible substance abuse shoul
d
b
e taken and a meticulous search in the hom
e
should be made for ethylene glycol-containing
Page 57 of 124
Physical
Examination
compounds.
• A history of alcohol use might suggest ingestion of
e
thylene glycol as an alcohol substitute. Teen
s
mi
ght experiment with this compound
.
• R
egional poison control centers often can assist i
n
identifying the contents of bottles and packages if
p
roduct labels do not list the chemical ingredients
.
• A
sking about similar symptoms in family members
,
p
ets, friends, and coworkers might be helpful i
n
identifying a common source of exposure.
• Cl
arify when the ingestion occurred and whethe
r
e
thanol also was ingested. Most serious poisoning
s
o
ccur from ingestion. Inhalation and derma
l
exposures rarely cause toxicity. In the absence of
tr
eatment, ingestion of approximately 1 g/kg o
f
e
thylene glycol is considered lethal. Product label
s
r
arely provide the concentrations of toxic alcohols
.
As
an approximate guide, a 50% v/v solutio
n
contains 0.6 g/mL of ethylene glycol (Sivilotti
2
018)
.
A brief initial screening examination, including vital
signs, mental status, and pupils, should be performed to
identify immediate measures required to stabilize the
patient (Sivilotti 2018).
The mental status, vital signs,
and pupillary examination are the most useful elements.
They provide information to classify the patient as being
in a state of physiologic excitation or depression (Rhyee
2018; Velez L.I. 2017).
The onset of ethylene glycol toxicity is delayed when
ethanol also is ingested. The possibility of concomitant
ethanol and toxic alcohol ingestion must be considered
(Sivilotti 2018).
A mental status examination includes evaluation of
alertness, orientation, cognition, and short–term
memory. Peripheral nerve function is evaluated by
assessing proprioception, deep tendon reflexes, motor
Page 58 of 124
Symptoms and
Signs
strength, postural stability (Romberg test), and
cutaneous sensitivity to vibration, light touch, and pin
prick (Fiedler 2007).
The time course for each stage and the severity of
illness depend on the amount of ethylene glycol the
patient ingested and whether the patient also ingested
ethanol. Individual patients might develop any
combination of organ or systemic effects (Table 2).
Stage 1 (CNS depression phase)
CNS depression begins soon after exposure, lasting for
up to 12 hours after ingestion. This depression appears
similar to ethanol intoxication, but without the
characteristic odor of alcohol. The inebriation, euphoria,
slurred speech, and lethargy result from unmetabolized
ethylene glycol.
After glycoaldehyde forms (at 4–12 hours) and
metabolic acidosis begins, CNS depression — especially
in cases with high-dose exposures — can lead to the
following effects:
• Nausea and vomitin
g
• Seizures
• Coma
• Cer
ebral edema (in some cases
)
A
n osmolal gap without metabolic acidosis might be
seen before significant metabolism of ethylene glycol
occurs. As ethylene glycol is metabolized, the osmolal
gap, if present, will decrease and an anion gap
metabolic acidosis will evolve. Patients seen by a
healthcare provider longer after exposure might have
renal failure with normal osmolal and anion gaps and no
acidosis or measurable ethylene glycol levels (Ford M
1991).
Signs of metabolic acidosis caused by the metabolites
might become apparent late in stage 1.
Page 59 of 124
Stage 2 (Cardiopulmonary toxicity phase)
The following cardiorespiratory symptoms might appear
12–24 hours after ingestion:
• Tachycardi
a
• Ta
chypne
a
• Hypertension or hypotension
T
he following conditions might develop in this stage:
• Pulmonary ede
ma
• Pneumonitis
• Co
ngestive cardiac failur
e
• Sh
o
ck
F
ormation of oxalic acid might lead to deposition of
calcium oxalate crystals in the
• meninges
,
• blood v
essel walls
,
• lu
ng, an
d
• myocardium.
T
hese crystal deposits can cause tissue injury and can
lead to hypocalcemia secondary to calcium oxalate
precipitation. Most deaths from ethylene glycol
poisoning occur during stage 2.
Stage 3 (Renal toxicity phase)
Kidney damage usually develops 24–72 hours after
exposure. Acidosis and acute renal failure might result
from deposition of calcium oxalate crystals in the
kidneys (McMartin K 2009).
The following conditions characterize the third phase:
• Flank pai
n
• Co
stovertebral angle tendernes
s
• Ol
iguric renal failur
e
Page 60 of 124
Prolonged, rarely permanent, kidney failure is
distinguished by
• proteinuria,
• he
maturia
,
• cr
ystalluria, an
d
• in
creased serum BUN and creatinine
.
Calcium oxalate crystals might appear in the urine soon
after exposure, but absence of these crystals does not
rule out ethylene glycol poisoning.
Patients might experience delayed (days to weeks after
ingestion) neurological deficits. Cranial nerve deficits
have occurred after ethylene glycol poisoning — an
outcome likely associated with better survival rates.
Severe ethylene glycol poisoning was often fatal before
widespread use of hemodialysis (Rahman et al. 2012).
Page 61 of 124
Table 2. Clinical course in acute ethylene glycol intoxication
Stage
Onset
after
ingestion
Primary
systems
affected
Signs and symptoms
1
30
minutes to
12 hours
Central nervous
system
● Inebriation
● Euphoria
● A
taxi
a
● S
lurred spee
ch
● D
rowsines
s
● I
rritatio
n
● Restlessness
● Di
sorientatio
n
Gastrointestinal
● Nausea
● Vomiting
Metabolic
● Elevated osmolal gap
2
12–24
hours
Cardiovascular
● Mild hypertension
● Tachycardia
● Sh
o
ck
Pulmonary
● Tachypnea
● Adult respiratory distress
sy
ndrom
e
● Pu
lmonary ede
ma
● Pn
eumoniti
s
Metabolic
● Metabolic acidosis with
elevated anion gap and
d
ecreased osmolal ga
p
● Possible tetany from
h
ypocalcemi
a
● Hy
perventilatio
n
3
24–72
hours
Renal
● Flank pain
● Costovertebral angle
t
endernes
s
● Ol
iguric renal failur
e
● Hy
perkalemi
a
● Hy
pocalcemi
a
Page 62 of 124
Metabolic
● Possible normal anion
and osmolal gaps
• Taking a detailed patient history that includes an
exposure history is important in diagnosing
e
thylene glycol poisoning
.
Key Points
•
Prompt recognition and early therapeutic
i
ntervention are essential to prevent sequelae
of
ethylene glycol poisoning.
Page 63 of 124
• Patients poisoned by ethylene glycol might initially
appear inebriated, but might lack other signs and
sy
mptoms of severe toxic exposure
.
• A
fter a characteristic latent period, metabolites o
f
e
thylene glycol can cause potentially life-
threatening illness
.
• Delayed clinical toxicity results from conversion of
e
thylene glycol to metabolites of greater toxicity
.
Page 64 of 124
Progress
Check
12. Why is a detailed medical and exposure history
important in diagnosing ethylene glycol poisoning?
A. A correct diagnosis requires a reliable history of
the time, route, and magnitude of exposure.
B. A history of ethanol abuse might suggest
ingestion of ethylene glycol as an ethanol
substitute.
C. A careful history about similar symptoms in
family members, pets, friends, and coworkers
might be helpful in identifying a common source
of exposure.
D. All of the above.
13. Prompt recognition and early therapeutic
intervention is essential in clinical management of
ethylene glycol poisoning. Why?
A. After a characteristic latent period, metabolites
of ethylene glycol can cause potentially life-
threatening illness.
B. Prompt recognition and aggressive treatment
might prevent latent effects and potential
sequelae of ethylene glycol poisoning.
C. Time is of the essence in the case of serious
ethylene glycol poisoning. Without appropriate
treatment, renal failure could occur in just a few
days.
D. All of the above.
14. Tachypnea usually develops in which of the following
stages?
A. Sta
ge 1 (0.5–12 hours).
B. Stage 2 (12–24 hours).
C. Stage 3 (24–72 hours).
D. None of the above.
Page 65 of 124
Answers
12. The best choice is D. All of the above. As
i
ntoxication evolves, the clinical presentation of ethylen
e
g
lycol poisoning changes over time. Signs an
d
s
ymptoms depend on the amount ingested an
d
c
oncurrent use of alcohol. Therefore, making a correc
t
diagnosis requires a reliable history of the time, route,
a
nd magnitude of exposure. A history of ethanol abus
e
mi
ght suggest ingestion of ethylene glycol as an ethano
l
s
ubstitute. Asking about similar symptoms in famil
y
m
embers, friends, pets, and coworkers might hel
p
identify a common exposure source.
F
eedback for A. (Web only): The best choice is D. All of
the above. As intoxication evolves, the clinical
presentation of ethylene glycol poisoning changes over
time. Signs and symptoms depend on the amount
ingested and concurrent use of alcohol. Making a correct
diagnosis requires a reliable history of the time, route,
and magnitude of exposure. A history of ethanol abuse
might suggest ingestion of ethylene glycol as an ethanol
substitute, and a careful history about similar symptoms
in family members, friends, pets, and coworkers might
be helpful in identifying a common source of exposure.
Feedback for B. (Web only): The best choice is D. All of
the above. As intoxication evolves, the clinical
presentation of ethylene glycol poisoning changes over
time. Signs and symptoms depend on the amount
ingested and concurrent use of alcohol. A history of
ethanol abuse might suggest ingestion of ethylene glycol
as an ethanol substitute. Making a correct diagnosis
requires a reliable history of the time, route, and
magnitude of exposure. A careful history about similar
symptoms in family members, friends, pets, and
coworkers might be helpful in identifying a common
source of exposure.
Feedback for C. (Web only): The best choice is D. All of
the above. As intoxication evolves, the clinical
presentation of ethylene glycol poisoning changes over
time. Signs and symptoms depend on the amount
ingested and concurrent use of alcohol. Taking a careful
history about similar symptoms in family members,
friends, pets, and coworkers might help identify a
Page 66 of 124
common exposure source. Making a correct diagnosis
also requires a reliable history of the time, route, and
magnitude of exposure. A history of ethanol abuse
might suggest ingestion of ethylene glycol as an ethanol
substitute.
Feedback for D (Web only): Correct. All of the above. As
intoxication evolves, the clinical presentation of ethylene
glycol poisoning changes over time. Signs and
symptoms depend on the amount ingested and
concurrent use of alcohol. Making a correct diagnosis
requires a reliable history of the time, route, and
magnitude of exposure. A history of ethanol abuse
might suggest ingestion of ethylene glycol as an ethanol
substitute. Asking about similar symptoms in family
members, friends, pets, and coworkers might help
identify a common exposure source.
To review relevant content, see “Exposure History”
in this section.
13. The best choice is D. All of the above. Ethylene
g
lycol ingestion is a medical emergency. It requir
es
p
rompt recognition and early therapeuti
c
i
ntervention. After a characteristic latent period
,
m
etabolites of ethylene glycol can cause potentiall
y
life-threatening illness. Prompt recognition and
a
ggressive treatment might prevent latent effec
ts
a
nd potential sequelae of ethylene glycol poisoning
.
Ti
me is of the essence in the case of serious ethylen
e
g
lycol poisoning. Without appropriate treatmen
t,
renal failure could occur within a few days.
Feedback for A. (Web only): The best choice is D. All of
the above. Ethylene glycol ingestion is a medical
emergency. It requires prompt recognition and early
therapeutic intervention. After a characteristic latent
period, metabolites of ethylene glycol can cause
potentially life-threatening illness. Prompt recognition
and aggressive treatment might prevent latent effects
and potential sequelae of ethylene glycol poisoning.
Time is of the essence in the case of serious ethylene
Page 67 of 124
glycol poisoning. Without appropriate treatment, renal
failure could occur in just a few days.
Feedback for B. (Web only): The best choice is D. All of
the above. Ethylene glycol ingestion is a medical
emergency. It requires prompt recognition and early
therapeutic intervention. Prompt recognition and
aggressive treatment might prevent latent effects and
potential sequelae of ethylene glycol poisoning. Time is
of the essence in the case of serious ethylene glycol
poisoning. Without appropriate treatment, renal failure
could occur in just a few days.
Feedback for C. (Web only): The best choice is D. All of
the above. Ethylene glycol ingestion is a medical
emergency. It requires prompt recognition and early
therapeutic intervention. Time is of the essence in the
case of serious ethylene glycol poisoning. Without
appropriate treatment, renal failure could occur in just a
few days. After a characteristic latent period,
metabolites of ethylene glycol can cause potentially life-
threatening illness. Prompt recognition and aggressive
treatment might prevent latent effects and potential
sequelae of ethylene glycol poisoning.
Feedback for D. (Web only): Correct. All of the above.
Ethylene glycol ingestion is a medical emergency. It
requires prompt recognition and early therapeutic
intervention. After a characteristic latent period,
metabolites of ethylene glycol can cause potentially life-
threatening illness. Prompt recognition and aggressive
treatment might prevent latent effects and potential
sequelae of ethylene glycol poisoning. Time is of the
essence in the case of serious ethylene glycol poisoning.
Without appropriate treatment, renal failure could occur
in just a few days.
To review relevant content, see “Clinical
Presentation” in this section.
14
.
The best choice is B. Stage 2 involves
c
ardiorespiratory symptoms appearing 12–24 hour
s
a
fter ingestion of ethylene glycol, with tachycardia
,
tachypnea, and hypertension as the most frequent
Page 68 of 124
signs. The body hyperventilates in an attempt to
compensate for severe metabolic acidosis.
Feedback for A. (Web only): The best choice is B. Stage
2 involves cardiorespiratory symptoms appearing 12-24
hours after ethylene glycol ingestion, with tachycardia,
tachypnea, and hypertension as the most frequent
signs. The body hyperventilates in an attempt to
compensate for severe metabolic acidosis. The most
prominent finding in Stage 1 is CNS depression.
Feedback for B. (Web only): Correct. Stage 2 involves
cardiorespiratory symptoms appearing 12-24 hours after
ethylene glycol ingestion, with tachycardia, tachypnea,
and hypertension as the most frequent signs. The body
hyperventilates in an attempt to compensate for severe
metabolic acidosis.
Feedback for C. (Web only): The best choice is B. Stage
2 involves cardiorespiratory symptoms appearing 12-24
hours after ethylene glycol ingestion, with tachycardia,
tachypnea, and hypertension as the most frequent
signs. The body hyperventilates in an attempt to
compensate for severe metabolic acidosis. Stage 3 is
characterized by renal toxicity, with symptoms such as
flank pain, costovertebral tenderness, and oliguric renal
failure.
Feedback for D. (Web only): The best choice is B. Stage
2 involves cardiorespiratory symptoms appearing 12-24
hours after ethylene glycol ingestion, with tachycardia,
tachypnea, and hypertension as the most frequent
signs. The body hyperventilates in an attempt to
compensate for severe metabolic acidosis.
To review relevant content, see “Table 2” in this
section.
Clinical Assessment—Laboratory Tests
Learning
After completing this section, you will be able to
Objectives
• identify the abnormal laboratory findings
associated with ethylene glycol poisoning, and
Page 69 of 124
• list three measurements that can assist with
diagnosis of ethylene glycol poisoning.
Introduction
Ethylene glycol is a relatively common cause of
overdose treated in U.S. emergency departments.
Among the thousands of cases of ethylene glycol
poisoning reported in the United States each year,
several deaths occur.
Timely and accurate measurement of ethylene glycol is
vital to establish the correct diagnosis.
Serum
Diagnosis of ethylene glycol poisoning usually depends
Analysis
on the detection of the toxicant or toxic metabolites in
serum or plasma. The most commonly used analytic
methods for detection and quantification of ethylene
glycol use gas chromatography (GC) coupled to flame
ionization detection (FID) or mass spectrometric
detectors [Juenke et al. 2011]. However, many hospitals
do not have this testing capacity. In fact, in many
hospitals these are only available as “send out” tests, so
results arrive too late for meaningful clinical decision
making (Goldfrank LR et al 2019).
An elevated serum level of ethylene glycol confirms
ethylene glycol poisoning. Significant toxicity is often
associated with levels greater than 25 milligrams per
deciliter (mg/dL) (Goldfrank LR FN 1998; Hall AH 1992).
However, potentially toxic serum concentrations of
ethylene glycol (≥20–30 mg/dL) do not always produce
early symptoms in children or adults. Therefore, the lack
of symptoms does not exclude a potentially toxic
ingestion (Caravati et al. 2005).
Page 70 of 124
False Positives
Routine Tests
Communication with the laboratory is critical in
poisoning cases for several reasons:
• 2,3-butanediol, often found in the plasma of
a
lcoholics, mistakenly can be identified as ethylen
e
g
lycol when the analysis is performed by ga
s
c
hromatography (Jones AW et al. 1991)
.
• P
ropylene glycol can interfere with some ethylen
e
glycol assays (Apple et al. 1993; Hilliard et al.
2
004; Robinson et al. 1983)
.
• La
boratory results can show an inherited metaboli
c
d
isorder as ethylene glycol intoxication [(Pien et al
.
2
002)
.
• Some blood gas analyzers might mistake elevated
se
rum glycolic acid as elevated lactic acid, leadin
g
t
o a false positive lactic acid result (Marwick et al
.
2
012; Meng et al. 2010)
.
All patients with known or suspected ethylene glycol
ingestion require the following tests:
• Arterial or venous blood gas
• Blood
glucos
e
• Se
rum electrolytes (including calcium an
d
ma
gnesiu
m)
• B
lood urea nitrogen (BUN) and creatinin
e
• Liver function tests
• S
erum acetaminophen and salicylat
e
c
oncentration
s
• U
rinalysis with microscopic evaluation for crystal
s
• Bl
ood ethan
ol
• Measured serum osmolality (sample must be
o
btained from the same blood draw used to obtai
n
s
erum electrolytes
)
• S
amples for a serum volatile acid screen (whic
h
w
ill test for methanol and isopropanol) and seru
m
ethylene glycol should also be collected and sent.
N
ote that many hospitals must send these sample
s
t
o a reference laboratory, and results are no
t
u
sually available in time to guide initial clinica
l
m
anagement. Check with your hospital’s laborator
y
for specific instructions on how to order these
n
ecessary tests
.
Page 71 of 124
Ethanol,
Methanol,
Ketoacidosis
Anion and
Osmolal Gaps
A blood or serum ethanol level will establish whether
ethanol is contributing to the initial CNS symptoms. If
present, ethanol will substantially affect metabolism and
influence therapy. Patients who have suspected ethylene
glycol exposure also should be assessed with serum
methanol tests. If alcoholic ketoacidosis is suspected,
serum lactate and β-hydroxybutyrate levels might help
identify alcoholic patients.
The presence of metabolic acidosis with anion and
osmolal gaps is an important clue to the diagnosis
(Friedman et al. 1962; Parry and Wallach 1974; Szerlip
1999). Numerous toxic substances are associated with
an elevated anion gap (Table 3) (Goldfrank LR FN
1998). An elevated osmolal gap suggests the presence
of a low-molecular weight substance.
A measured osmolality by the freezing point depression
method is needed to detect an osmolal gap. Results of
this test are used to calculate the osmolal gap (Figure
2).
Metabolic acidosis might be inhibited or delayed when
large quantities of ethanol and ethylene glycol are
ingested concurrently. In such cases, an elevated anion-
gap metabolic acidosis will take longer to develop than if
ethylene glycol alone were ingested. This is because
aldehyde dehydrogenase (ADH) has a higher affinity for
ethanol than for ethylene glycol. The presence of
ethanol delays the metabolism of ethylene glycol to its
acidic metabolites.
An osmolal gap is often cited as indirect evidence of an
exogenous alcohol or glycol, but other substances or
conditions also can cause an increased osmolal gap.
Conversely, failure to find an elevated osmolal gap
might lead to a wrong assumption that no exogenous
substances are present. Even a small osmolal gap might
represent a significant ethylene glycol level.
The point is, use caution when interpreting the osmolal
gap. Recent reviews have argued that using the osmolal
gap as a screening tool for ethylene glycol has
Page 72 of 124
significant limitations and remains hypothetical (Glaser
1996; Koga et al. 2004; Purssell et al. 2004).
Page 73 of 124
Calcium oxalate or hippurate crystals in the urine,
Urinary
together with an elevated anion gap or osmolal gap,
strongly suggest ethylene glycol poisoning (Albertson
1999). Urinary crystals result from
Crystals
• the precipitation of calcium by the oxalic aci
d
m
etabolite of ethylene glycol, an
d
• t
he reaction of the glycine metabolite with benzoi
c
acid, which forms hippuric acid.
U
rinary crystals can take many forms:
• Dumbbell
s
• Envelopes
• Need
les (most commonly) (Jacobsen et al. 1988)
.
A
bsence of urinary crystals, however, does not rule out
poisoning. Many studies have shown that renal damage
can occur after ethylene glycol ingestion, without
deposition of calcium oxalate crystals in the kidney (Hall
AH 1992; Vale 1979).
Urine from an exposed person might fluoresce under a
Urine
Wood’s lamp because some antifreeze products contain
fluorescein. Still, false positives and negatives often
occur. An expert panel has concluded that using an out-
of-hospital ultraviolet light to diagnose ethylene glycol
ingestion by urine fluorescence is unreliable and
contraindicated (Caravati et al. 2005).
Fluorescence
Page 74 of 124
Table 3. A few examples of toxic agents associated with an
elevated anion gap.
Substance
CNS
Depress-
ion
Metabo-
lic
Acidosis
Keto-
sis
Increased
Osmolal-
ity
Characteristic
Findings
Methanol + ++ – +
●
Blindness and
pink
e
demato
us
o
ptic di
sk
(
delaye
d
f
indings
)
● Metabolic
a
cidosi
s
Ethanol + + + +
● Alcoholi
c
k
etoacidos
is
E
thylene
glycol
+ ++ – + ● Renal failur
e
● Cal
ci
um
o
xalate an
d
hippurate
c
rystal
s
● CNS
de
pressio
n
● Tac
hycardi
a
● Tachypnea
I
sopropan-
ol
+ – ++ + ● Hemorrhagi
c
tr
acheobron
c
hitis
● Ga
striti
s
S
alicylates + + + – ● Vomitin
g
● Ti
nnitu
s
● Hy
perthermi
a
Adapted from (Goldfrank LR FN 1998).
Figure 2. Formulas for calculating anion and osmolal gaps.
(Goldfrank LR 2015)
Page 75 of 124
An ethylene glycol level (in mg/dL) might be estimated from the osmolal gap (OG) if it
is the only osmotically active poison present and levels are taken early in the course.
This is most accurate if the ethylene glycol level is between 50 to 100 mg/dL:
Estimated ethylene glycol level = OG × 6.2.
The serum anion gap (AG) is determined from serum electrolytes measured in mEq/L
and is be defined by the formula:
AG = (Na
+
+ K
+
) – (Cl
–
+ HCO
3
–
)
(Normal anion gap: 12–16)
The serum osmolal gap (OG) is most commonly approximated by the formula:
OG = osmolality (measured)* – 2Na
+
+ [BUN divided by 2.8] + [glucose divided by 18]
+ [BAT (ethanol) divided by 4.6 (if present)] (Normal osmolal gap: –14 to +10)
*
I
n this formula, osmolality (measured) is obtained by the freezing point–depressio
n
method and expressed in milliosmoles per liter (mOsm/L): Na
+
in mEq/L, BUN and
g
lucose in mg/dL, blood alcohol test (BAT) in mg/dL
.
Key Points
• Ethylene glycol poisoning is strongly suggested by
o an elevated anion-gap metabolic acidosis,
o
an e
levated osmolal gap, an
d
o
urinary calcium oxalate or hippuric acid crystals.
• M
easurement of serum ethylene glycol levels ca
n
c
onfirm poisoning
.
Progress
C
heck
15. Which of the following is the most reliable
diagnostic index for suspected ethylene glycol
ingestion?
A. An elevated anion gap and an increased osmolal
gap.
B. Normochloremic metabolic acidosis.
C. Calcium oxalate or hippurate crystalluria.
D. Elevated serum ethylene glycol level.
Page 76 of 124
15. The best choice is D. The presence of metabolic
acidosis (answer B) with anion and osmolal gaps
(a
nswer A) are important clues to the diagnosis
.
H
owever, numerous toxic substances are associate
d
w
ith an elevated anion gap (Table 3). Numerous studie
s
h
ave documented that renal damage occurs afte
r
ethylene glycol ingestion, even without deposition in the
ki
dney of calcium oxalate crystals (answer C). Althoug
h
a
nswers A, B, and C together strongly suggest ethylen
e
g
lycol poisoning, elevated serum ethylene glycol lev
el
r
emains the most reliable diagnostic index. At the tim
e
of testing for ethylene glycol poisoning, all, some, or
n
one of the findings in answers A, B, or C might b
e
p
resent
.
Feedback for A. (Web only): The best choice is D. The
presence of anion and osmolal gaps are important clues
to the diagnosis. However, numerous toxic substances
are associated with an elevated anion gap (Table 3).
Although an elevated anion gap and an increased
osmolal gap strongly suggest ethylene glycol poisoning,
an elevated serum ethylene glycol level is the most
reliable diagnostic index.
Feedback for B. (Web only): The best choice is D. The
presence of normochloremic metabolic acidosis is an
important clue to the diagnosis. However, numerous
toxic substances are associated with metabolic acidosis
(Table 3). Thus, an elevated serum ethylene glycol level
is the most reliable diagnostic index.
Feedback for C. (Web only): The best choice is D.
Numerous studies have documented that renal damage
occurs after ethylene glycol ingestion, even without
deposition of calcium oxalate crystals in the kidney.
Although calcium oxalate or hippurate crystalluria
strongly suggests ethylene glycol poisoning, an elevated
serum ethylene glycol level is the most reliable
diagnostic index.
Feedback for D. (Web only): Correct. The presence of
metabolic acidosis (answer B) with anion and osmolal
gaps (answer A) are important clues to the diagnosis.
However, numerous toxic substances are associated
Page 77 of 124
with an elevated anion gap (Table 3). Numerous studies
have documented that renal damage occurs after
ethylene glycol ingestion, even without deposition in the
kidney of calcium oxalate crystals (answer C). Although
answers A, B, and C together strongly suggest ethylene
glycol poisoning, an elevated serum ethylene glycol level
remains the most reliable diagnostic index. At the time
of testing for ethylene glycol poisoning, all, some, or
none of the findings in answers A, B, or C might be
present.
To review relevant content, see “Serum Analysis”
in this section.
Page 78 of 124
How Should Patients Exposed to Ethylene Glycol Be
Treated and Managed?
Learning
Objectives
After completing this section, you will be able to describe
treatment strategies for managing ethylene glycol
poisoning cases.
Introduction
Treatment should not be delayed pending results of
ethylene glycol serum levels if the patient’s condition or
history suggests such poisoning. Treatment advice can be
obtained from a regional poison control center or medical
specialists such as the following with expertise and
experience treating patients exposed to ethylene glycol:
• Board-certified occupational and environmenta
l
medicine physicians
• B
oard-certified pediatric environmental healt
h
sp
ecialist
s
• B
oard-certified medical toxicologist
s
Supportive
Care
For initial patient stabilization, the clinician should first
assess and secure the patient's airway, breathing, and
circulation.
Gastrointestina
Gastrointestinal decontamination measures, such as
l
activated charcoal, gastric lavage, and gastric
Decontaminati
aspiration, provide little benefit in ethylene glycol
on
poisoning because ethylene glycol is rapidly absorbed
(Sivilotti 2018).
Specific
Treatment
Specific treatment for ethylene glycol poisoning may
include the following:
• Sodium bicarbonate to temporarily correct th
e
m
etabolic acidosis, as indicate
d
• Fo
mepizole or ethanol to competitively inhibi
t
metabolism of ethylene glycol to its more toxic
m
etabolites (Baud et al. 1988; Brent et al
. 1999;
J
ones AL and Volans 1999; Sivilotti 2018
)
• If
indicated, hemodialysis to remove ethylene glyco
l
and glycolic acid (Bey et al. 2002; Cheng et al.
Page 79 of 124
1987; Gabow et al. 1986; Jacobsen and McMartin
1997; Malmlund et al. 1991; Moreau et al. 1998;
Sivilotti 2018; Stokes and Aueron 1980).
The above treatment strategies are effective in most
cases, but if treatment is delayed, renal failure and death
can occur (Leth and Gregersen 2005; Pellegrino et al.
2006).
Fomepizole
Therapy
Fomepizole, an alcohol dehydrogenase enzyme (ADH)
antagonist, is the preferred therapy for ethylene glycol
poisoning. The American Academy of Clinical Toxicology
developed the following criteria for using fomepizole
rather than ethanol (Barceloux et al. 1999):
• Ingestion of multiple substances, resulting i
n
d
epressed level of consciousnes
s
• Altered consciousness
• La
ck of adequate intensive care staffing or laborator
y
s
upport to monitor ethanol administratio
n
• Re
lative contraindications to ethano
l
• Cr
itically ill patient with an anion-gap metaboli
c
acidosis of unknown origin and potential exposure to
et
hylene glyco
l
• Pa
tients with active hepatic disea
se
Advantages of
Fomepizole
Therapy
Fomepizole therapy might obviate the need for
hemodialysis in the absence of renal insufficiency and
significant metabolic acidosis (Battistella 2002; Borron et
al. 1999; Brent 2001; Bronstein et al. 2009; Druteika et
al. 2002; Harry et al. 1998; Harry et al. 1994; Watson
2000).
In comparison with ethanol (Lepik et al. 2009),
fomepizole
• is easier to use clinically and requires les
s
m
onitoring
,
• ha
s a slower rate of elimination
,
• has a longer duration of action,
• ha
s a reasonable dosing schedule
,
• has less potential for adverse effects,
Page 80 of 124
• is easier to administer,
• results in shorter hospital stays,
• ha
s more predictable and prolonged results, an
d
• do
es not cause central nervous system (CNS
)
d
epression or hypoglycemia
.
If fomepizole is unavailable or the patient has a known
Ethanol
allergy, alcohol dehydrogenase can be blocked with 10
mL/kg of a 10% ethanol solution, followed by 1 mL/kg of
10% ethanol solution infused per hour. Titrate to a serum
ethanol concentration of 100 mg/dL (Sivilotti 2018).
Therapy
The disadvantages of ethanol are that it
• requires continuous administration and frequen
t
m
onitoring of serum ethanol and glucose levels
,
• can cause CNS depression and hypoglycemia, and
• po
ses problems in patient care, such as drunkenness
.
A
lthough ethanol costs much less, the savings might be
offset by additional costs for
• monitoring the patient
,
• laboratory tests, and
• he
modialysis for some patients
.
Page 81 of 124
Hemodialysis
Hemodialysis can rapidly remove toxic acid metabolites
and parent alcohols. Several studies (Barceloux et al.
1999; Brent et al. 1999; Jammalamadaka and Raissi
2010; Sivilotti 2018) suggest considering hemodialysis
when
• serum ethylene glycol levels exceed 50 mg/dL (8.
1
mmo
l/L
),
• severe acidemia (pH <7.25) or fluid/electrolyte
d
isturbances persist despite ethanol or fomepizol
e
t
herapy
,
• vi
tal signs continue to deteriorate despite intensiv
e
s
upportive treatment, o
r
• renal failure develops.
Co
ntinue hemodialysis until
• acidosis is controlled, an
d
• serum ethylene glycol level falls below 20 mg/dL.
W
hen renal function is preserved, patients often can be
treated without hemodialysis. This outcome underscores
the effectiveness of supportive care and the use of
fomepizole in the treatment of ethylene glycol poisoning,
even at levels that have traditionally required
hemodialysis (Buchanan et al. 2010; Levine et al. 2012;
Velez L. I. et al. 2007).
Vitamin
Thiamine and pyridoxine are two water-soluble B-complex
Treatment
vitamins that act as metabolic cofactors in the
metabolism of ethylene glycol. The benefits of giving
supplemental thiamine (100 mg IV) or pyridoxine (50 mg
IV) to patients poisoned with ethylene glycol are
u
nknown. However, both are routinely administered
,
p
articularly if the patient's nutritional status is suspec
t
(
Sivilotti 2018)
.
P
ediatric Cases
For those pediatric patients who do show signs of
ethylene glycol poisoning, the diagnostic and treatment
considerations described above for adults largely apply.
The limited published experience with fomepizole
Page 82 of 124
supports its safe and effective use in children at the same
dosing protocol given above
(Brent 2010; Caravati et al. 2004; Schwerk et al. 2007;
Sivilotti 2018).
Key Points
• Supportive care is the cornerstone of treatment of
the poisoned patient.
• Because ethylene glycol is rapidly absorbed,
gastrointestinal decontamination has little role in
treatment.
• Fomepizole therapy might obviate the need for
hemodialysis in the absence of renal insufficiency and
significant metabolic acidosis.
• A regional poison control center or medical specialists
with expertise and experience treating patients
exposed to ethylene glycol can provide treatment
advice.
Progress Check
16. Which of the following best describes the
treatment strategy for managing patients with
ethylene glycol poisoning?
A. Sodium bicarbonate to correct the metabolic
acidosis as indicated.
B. Ethanol or fomepizole to competitively inhibit
metabolism of ethylene glycol to its more toxic
metabolites.
C. Hemodialysis, if indicated, to remove ethylene
glycol and glycolic acid.
D. All of the above.
17. Which of the following IS NOT considered a
current indication for hemodialysis after ethylene
glycol ingestion?
A. Severe acidemia (pH <7.25) or fluid/electrolyte
disturbances that persist despite fomepizole
therapy.
B. Vital signs continue to deteriorate despite
intensive supportive treatment.
C. Renal failure develops.
D. A serum ethylene glycol level of 10–15 mg/dL.
Page 83 of 124
Answers
16. The best choice is D. All of the above. A treatment
strategy to best manage patients with ethylene glycol
p
oisoning includes, when indicated
,
● u
se of sodium bicarbonate to correct metaboli
c
a
cidosis
,
● use of ethanol or fomepizole (antizol) to
c
ompetitively inhibit the metabolism of ethylen
e
g
lycol to its more toxic metabolites, an
d
● h
emodialysis to remove ethylene glycol an
d
g
lycolic acid
.
T
his treatment strategy is effective in most cases, but
if treatment is delayed, renal failure and death can
occur.
Feedback for A. (Web only): The best choice is D. All of
the above. A treatment strategy to best manage
patients with ethylene glycol poisoning includes, when
indicated, use of bicarbonate to correct metabolic
acidosis. It also might include use of ethanol or
fomepizole to competitively inhibit metabolism of
ethylene glycol to its more toxic metabolites.
Hemodialysis might be needed to remove ethylene
glycol and glycolic acid.
Feedback for B. (Web only): The best choice is D. All of
the above. A treatment strategy to best manage patients
with ethylene glycol poisoning includes, when indicated,
use of ethanol or fomepizole to competitively inhibit
metabolism of ethylene glycol to its more toxic
metabolites. It also might include use of bicarbonate to
correct metabolic acidosis and hemodialysis to remove
ethylene glycol and glycolic acid.
Feedback for C. (Web only): The best choice is D. All of
the above. A treatment strategy to best manage
patients with ethylene glycol poisoning includes, when
indicated, hemodialysis to remove ethylene glycol and
glycolic acid. It also might include use of bicarbonate
to correct metabolic acidosis, and use of ethanol or
fomepizole to competitively inhibit metabolism of
ethylene glycol to its more toxic metabolites.
Page 84 of 124
Feedback for D. (Web only): Correct. All of the above. A
treatment strategy to best manage patients with ethylene
glycol poisoning includes, when indicated,
● use of sodium bicarbonate to correct metabolic
a
cidosis
,
● u
se of ethanol or fomepizole (antizol)
to
c
ompetitively inhibit the metabolism of ethylen
e
g
lycol to its more toxic metabolites, an
d
● hemodialysis to remove ethylene glycol and glycolic
a
cid
.
T
his treatment strategy is effective in most cases, but if
treatment is delayed, renal failure and death can occur.
To review relevant content, see “Specific Treatment”
in this section.
17
. Th
e best choice is D. Indications for hemodialysi
s
treatment after ethylene glycol ingestion include
● sev
ere acidemia (pH <7.25) or fluid/electrolyt
e
d
isturbances that persist despite fomepizol
e
therapy,
● vi
tal signs that continue to deteriorate despit
e
i
ntensive supportive treatment, an
d
● d
evelopment of renal failure
.
Although a serum ethylene glycol level of ≥50 mg/dL was
considered an indication for hemodialysis, there are
reports of patients with levels of ≥50 mg/dL being
successfully treated with fomepizole, with or without
bicarbonate, and without hemodialysis.
Feedback for A. (Web only): The best choice is D. An
indication for hemodialysis treatment after ethylene glycol
ingestion is severe acidemia (pH <7.25) or
fluid/electrolyte disturbances that persist despite
fomepizole therapy. Indications also include vital signs
that continue to deteriorate despite intensive supportive
treatment, and development of renal failure. Although a
serum ethylene glycol level of ≥50 mg/dL was considered
an indication for hemodialysis, there are reports of
patients with levels of ≥50 mg/dL being successfully
Page 85 of 124
treated with fomepizole, with or without bicarbonate, and
without hemodialysis.
Feedback for B. (Web only): The best choice is D. An
indication for hemodialysis treatment after ethylene
glycol ingestion is vital signs that continue to
deteriorate despite intensive supportive treatment.
Indications also include severe acidemia (pH <7.25) or
fluid/electrolyte disturbances that persist despite
fomepizole therapy, and development of renal failure.
Although a serum ethylene glycol level of ≥50 mg/dL
was considered an indication for hemodialysis, there
are reports of patients with levels of ≥50 mg/dL being
successfully treated with fomepizole, with or without
bicarbonate, and without hemodialysis.
Feedback for C. (Web only): The best choice is D. An
indication for hemodialysis treatment after ethylene glycol
ingestion is development of renal failure. Indications also
include severe acidemia (pH <7.25) or fluid/electrolyte
disturbances that persist despite fomepizole therapy, and
vital signs that continue to deteriorate despite intensive
supportive treatment. Although a serum ethylene glycol
level of ≥50 mg/dL was considered an indication for
hemodialysis, there are reports of patients with levels of
≥50 mg/dL being successfully treated with fomepizole,
with or without bicarbonate, and without hemodialysis.
Feedback for D. (Web only): Correct. Indications for
hemodialysis treatment after ethylene glycol ingestion
include
● severe acidemia (pH <7.25) or fluid/electrolyt
e
d
isturbances that persist despite fomepizol
e
therapy,
● vi
tal signs that continue to deteriorate despit
e
i
ntensive supportive treatment, an
d
● development of renal failure.
A
lthough a serum ethylene glycol level of ≥50 mg/dL
was considered an indication for hemodialysis, there
are reports of patients with levels of ≥50 mg/dL
(ethylene glycol ≥7.5 mmol/L) being successfully
treated with fomepizole, with or without bicarbonate,
and without hemodialysis.
Page 86 of 124
To review relevant content, see “Hemodialysis” in
this section.
What Is Propylene Glycol?
Learning
After completing this section, you will be able to
Objective
• describe the uses of propylene glycol, an
d
• e
xplain the potential risk for propylene glyco
l
t
oxicity
.
Page 87 of 124
Definition
Propylene glycol is a
• clear,
• c
olorless
,
• v
iscous liquid with a faintly sweet taste
.
Its
chemical structure is CH
3
CH[OH]CH
3
OH.
P
ropylene glycol and ethylene glycol have similar
physical properties and uses.
Their chemical structures
differ by only one methyl group (ethylene glycol
=
HOCH
2
CH
2
OH; propylene glycol = CH
3
CH[OH]CH
2
OH).
E
thylene glycol is a potent cause of acute toxicity in
humans
. In contrast, propylene glycol is a “generally
recognized as safe” additive for foods and medications.
Most
reported cases of propylene glycol toxicity have
resulted from propylene glycol used as a diluent
for
intravenous administration of
benzodiazepines (Kraut
and Kurtz 2008)
.
Synonyms
Synonyms for propylene glycol (ATSDR 1997) include
• 1,2-propanediol,
• 1,2-
dihydroxypropane
,
• me
thyl glycol, an
d
• t
rimethyl glycol
.
Page 88 of 124
Uses
Propylene glycol is generally recognized as safe by the
Food and Drug Administration (FDA) (FDA 2017) for
uses in
• food and tobacco products
,
• ph
armaceuticals, an
d
• cosmetics.
I
t has a wide range of other practical applications
(ATSDR 2008), including use in
• deicers,
• co
olant
s,
• a
ntifreez
e,
• h
eat transfer and hydraulic fluids
,
• p
lasticizers, an
d
• other applications (smoke screen, smoke
s
imulator, etc.
).
Sources of
In the general population, propylene glycol exposure
Exposure occurs primarily through ingestion of food and
medications and through skin contact with cosmetics or
topical medications. Propylene glycol is used as a
solvent in cosmetics and pharmaceuticals, in various
• oral
,
• in
jectable, an
d
• topical formulations.
P
ropylene glycol is a diluent found in many intravenous
and oral drugs, including
• phenytoin,
• di
azepam, an
d
• lo
razepam
.
No adverse health effects are likely to occur from
normal use of these products. However, heavy use of
injectable medications with propylene glycol has caused
excess levels of propylene glycol in the body (Horinek et
al. 2009; Louis et al. 1967; Neale et al. 2005; Seay et
al. 1997; Wilson et al. 2000; Yorgin et al. 1997; Zar et
al. 2007; Zosel et al. 2010). Prolonged and extensive
Page 89 of 124
topical application on compromised skin, such as burns,
has also caused excess propylene glycol levels (Peleg et
al. 1998).
Who Is at Risk
Patients in intensive care, for example, might
experience toxicity from either of the following:
• Excessively large or rapidly infused intravenous
i
njections of propylene glycol-containin
g
m
edications (Horinek et al. 2009; Louis et al
.
1
967; Neale et al. 2005; Seay et al. 1997; Wilso
n
e
t al. 2000; Yorgin et al. 1997; Zar et al. 2007
;
Zosel et al. 2010)
• Pr
olonged dermal contact during treatment o
f
b
urns (Peleg et al. 1998
)
P
atients at risk for propylene glycol toxicity (Lim et al.
2014) include the following:
• Patients with underlying kidney diseas
e
• P
atients with less effective or impaired alcoho
l
d
ehydrogenase enzyme systems (e.g., childr
en
y
ounger than 4 years, pregnant women, patient
s
with hepatic disease, and patients treated with
d
isulfiram or metronidazole
)
• Pa
tients with epileps
y
• Bu
rn patients who receive extensive derma
l
applications of propylene glycol
Page 90 of 124
Biological Fate
Absorption of propylene glycol from the gastrointestinal
tract is rapid. The maximal plasma concentrations in
humans occur within 1 hour after ingestion.
Metabolites
Propylene glycol is metabolized in the liver by alcohol
dehydrogenase to
• lactic acid, and the
n
• py
ruvic acid
.
B
oth of these metabolites are normal constituents of the
citric acid cycle and are further metabolized to
• carbon dioxide an
d
• wa
ter
.
About 45% of an absorbed propylene glycol dose is
excreted unchanged by the kidneys or as the
glucuronide conjugate.
Half-life
In adults with normal liver and kidney function, the
terminal half-life of propylene glycol ranges from 1.4
hours to 3.3 hours (Speth et al. 1987). In contrast, the
mean half-life is significantly longer in infants — 19.3
hours (range: 10.8–30.5 hours) — because of
decreased renal elimination (Lim et al. 2014).
Toxicological
Effects at a
Glance
Although propylene glycol is a commonly used solvent
for intravenous medications, it might become toxic
when administered in large doses over a short period
(Bledsoe and Kramer 2008; Zar et al. 2007). Iatrogenic
propylene glycol overdose can cause the following:
• Hyperosmolality and an anion gap metaboli
c
a
cidosis, often accompanied by acute kidney injury
,
and potential multisystem organ failure (Arroliga et
a
l. 2004; Greller and Gupta 2017; Tietze and Fuch
s
2
018; Wilson et al. 2000; Wilson et al. 2005
;
Yahwak et al. 2008; Zar et al. 2007)
Page 91 of 124
• Refractory hypotension (Wilson et al. 2000)
• Arrhythmias (Louis et al. 1967)
• He
molysis (Demey et al. 1988
)
• Re
nal dysfunction (e.g., increased serum creatinin
e
c
oncentrations, proximal renal tubular cell injury
,
e
tc.) (Yaucher et al. 2003; Yorgin et al. 1997
)
• Seizure, coma (Greller and Gupta 2017)
P
ediatric patients also might develop CNS depression
and seizures (Lim et al. 2014; O'Donnell et al. 2000).
Clinical
Evaluation
Propylene glycol toxicity should be suspected in any
patient receiving medication that contains propylene
glycol as a diluent or solvent and who has
• hyperosmolality
,
• l
actic acidosi
s,
• acute kidney injury, or
• a c
linical scenario similar to sepsis or systemi
c
i
nflammatory response syndrome (SIRS) (Zar et al
.
2
007)
.
The clinical diagnosis of propylene glycol intoxication
may be difficult because many hospitals do not measure
propylene glycol levels. However, the osmolar gap,
anion gap, and lactate are commonly elevated in
propylene glycol intoxication (Lim et al. 2014).
An osmolar gap at 48 hours after continuous infusion
strongly predicts propylene glycol accumulation. An
elevated anion gap and lactic acidosis are poor
indicators (Arroliga et al. 2004; Barnes et al. 2006;
Wilson et al. 2005; Yahwak et al. 2008; Zar et al.
2007).
An osmolar gap >10 mmoles/L suggests that the serum
propylene glycol concentration is high enough to cause
toxicity (Barnes et al. 2006; Tietze and Fuchs 2018;
Yahwak et al. 2008).
Page 92 of 124
Treatment
Because this disorder is iatrogenic, prevention by
limiting the dosage of propylene glycol given to patients
in the intensive care unit might be the best treatment
[(Kraut and Kurtz 2008). Healthcare providers should
consider a 50% reduction in the maximum daily dose
for patients with underlying risk factors (see discussion
on “Who’s at Risk”). The maximum daily dose of drug
for a pediatric patient can be extrapolated from the
adult data (based on a 70-kg patient) (Lim et al. 2014).
Metabolic acidosis caused by large amounts of propylene
glycol in injected medications can be treated by
discontinuing the offending medication and providing
sodium bicarbonate and fomepizole (Zosel et al. 2010).
In severe cases, hemodialysis is effective in correcting
hyperosmolality by removing propylene glycol from the
blood (Demey et al. 1988; Kraut and Kurtz 2008; Lim et
al. 2014; Parker et al. 2002; Wilson et al. 2000).
Standards and
No workplace or environmental standards govern
Regulations propylene glycol.
Propylene glycol is “generally recognized as safe” by the
U.S. Food and Drug Administration (FDA) (FDA 2017).
FDA considers an average daily dietary intake of 23
mg/kg of body weight to be safe for persons 2–65 years
of age (ATSDR 2008).
Key Points
• Various foods, cosmetics, and pharmaceutical
products contain propylene glycol.
• P
ropylene glycol is metabolized to compounds tha
t
a
re normal constituents of the citric acid cycle
.
• P
ropylene glycol toxicity generally is not a factor i
n
environmental or occupational exposures.
• I
atrogenic propylene glycol overdose is the mo
st
c
ommon cause of propylene glycol poisoning
.
Page 93 of 124
Progress
Check
• The major toxicological effects of propylene glycol
poisoning include the following:
o Hyperosmolality
o
E
levated lacta
te
o
Re
fractory hypotens
ion
o
Ar
rhythmia
s
o
He
molysi
s
o
Renal dysfunction
• B
ecause this disorder is iatrogenic, prevention b
y
l
imiting the dosage of propylene glycol given t
o
p
atients in the intensive care unit might be th
e
best treatment.
18. Propylene glycol is used in which of the following
products?
A. Emulsifying agents.
B. Industrial drying agents.
C. Surfactants or solvents.
D. All of the above.
19. In contrast with ethylene glycol, propylene glycol less
commonly causes toxic effects. Why is that?
A. A
bsorption of propylene glycol from th
e
g
astrointestinal tract is slow
.
B.
Propylene glycol is metabolized to more toxic
co
mpound
s.
C.
E
thylene glycol is metabolized in the liver to les
s
t
oxic metabolites
.
D.
P
ropylene glycol is metabolized to compound
s
that are normal constituents of the citric acid
cy
cle
.
20. Metabolic acidosis caused by large amounts of
propylene glycol in injected medications can be treated
with all of the following EXCEPT which?
A. So
dium bicarbonate
.
B
. Fomepizole
.
C. Ethanol.
Page 94 of 124
Answers
D. Hemodialysis.
18. The best choice is D. All of the above. Propylene
glycol is used in certain medicines, cosmetics, and food
p
roducts as an emulsifying agent, an industrial dryin
g
a
gent, a surfactant or, a solvent
.
Feedback for A. (Web only): The best choice is D. All of
the above. In certain medicines, cosmetics, and food
products, propylene glycol is used as an emulsifying
agent. It also serves as an industrial drying agent, a
surfactant, and a solvent.
Feedback for B. (Web only): The best choice is D. All of
the above. In certain medicines, cosmetics, and food
products, propylene glycol is used as an industrial
drying agent. It also serves as an emulsifying agent, a
surfactant, and a solvent.
Feedback for C. (Web only): The best choice is D. All of
the above. In certain medicines, cosmetics, and food
products, propylene glycol is used as a surfactant or
solvent. It also serves as an emulsifying agent and an
industrial drying agent.
Feedback for D. (Web only): Correct. Propylene glycol is
used in certain medicines, cosmetics, and food products
as an emulsifying agent, an industrial drying agent, a
surfactant or a solvent.
To review relevant content, see “Uses” in this
section.
19. T
he best choice is D. Unlike the more toxi
c
m
etabolites from ethylene glycol metabolism, propylen
e
g
lycol is metabolized in the liver by alcoho
l
d
ehydrogenase to lactic acid, then to pyruvic acid. Bot
h
of these metabolites are normal constituents of the citric
a
cid cycle and are further metabolized to carbon dioxid
e
a
nd water
.
Feedback for A. (Web only): The best choice is D.
Absorption of propylene glycol from the gastrointestinal
Page 95 of 124
tract is rapid. Propylene glycol is metabolized in the liver
by alcohol dehydrogenase to lactic acid and then pyruvic
acid. Both of these metabolites are normal constituents
of the citric acid cycle and are further metabolized to
carbon dioxide and water.
Feedback for B. (Web only): The best choice is D.
Propylene glycol is metabolized in the liver by alcohol
dehydrogenase to lactic acid and then pyruvic acid. Both
of these metabolites are normal constituents of the citric
acid cycle and are further metabolized to carbon dioxide
and water.
Feedback for C. (Web only): The best choice is D.
Ethylene glycol is metabolized in the liver to more toxic
metabolites. Propylene glycol is metabolized in the liver
by alcohol dehydrogenase to lactic acid and then pyruvic
acid. Both of these metabolites are normal constituents
of the citric acid cycle and are further metabolized to
carbon dioxide and water.
Feedback for D. (Web only): Correct. Unlike the more
toxic metabolites from ethylene glycol metabolism,
propylene glycol is metabolized in the liver by alcohol
dehydrogenase to lactic acid, then to pyruvic acid. Both
of these metabolites are normal constituents of the citric
acid cycle and are further metabolized to carbon dioxide
and water.
To review relevant content, see “Biological Fate” in
this section.
20
. Th
e correct choice is C. Metabolic acidosis caused b
y
l
arge amounts of propylene glycol in injecte
d
m
edications can be treated with sodium bicarbonate an
d
f
omepizole. In severe cases, hemodialysis is effective i
n
correcting hyperosmolality by removing propylene glycol
f
rom the blood. Propylene glycol is metabolized in th
e
l
iver by alcohol dehydrogenase (ADH) to the norma
l
c
onstituents of the citric acid cycle. Ethanol is no
t
n
eeded to exhaust ADH because ADH metabolize
s
propylene glycol to nontoxic constituents.
Page 96 of 124
Feedback for A. (Web only): The correct choice is C.
Metabolic acidosis caused by large amounts of propylene
glycol in injected medications can be treated with
sodium bicarbonate and fomepizole. In severe cases,
hemodialysis is effective in correcting hyperosmolality
by removing propylene glycol from the blood. Ethanol is
not needed to exhaust ADH because ADH metabolizes
propylene glycol to nontoxic constituents.
Feedback for B. (Web only): The best choice is C.
Metabolic acidosis caused by large amounts of propylene
glycol in injected medications can be treated with
sodium bicarbonate and fomepizole. In severe cases,
hemodialysis is effective in correcting hyperosmolality
by removing propylene glycol from the blood. Ethanol is
not needed to exhaust ADH because ADH metabolizes
propylene glycol to nontoxic constituents.
Feedback for C. (Web only): Correct. Propylene glycol is
metabolized in the liver by alcohol dehydrogenase
(ADH) to the normal constituents of the citric acid cycle.
In severe cases, hemodialysis is effective in correcting
hyperosmolality by removing propylene glycol from the
blood. Ethanol is not needed to exhaust ADH because
ADH metabolizes propylene glycol to nontoxic
constituents.
Feedback for D. (Web only): The correct choice is C.
Metabolic acidosis caused by large amounts of propylene
glycol in injected medications can be treated with
sodium bicarbonate and fomepizole. In severe cases,
hemodialysis is effective in correcting hyperosmolality
by removing propylene glycol from the blood. Ethanol is
not needed to exhaust ADH because ADH metabolizes
propylene glycol to nontoxic constituents.
To review relevant content, see “Biological Fate” in
this section.
Page 97 of 124
What Instructions Should You Give to Patients
Regarding Ethylene Glycol/Propylene Glycol
Exposure?
Learning
Objectives
After completing this section, you will be able to
describe self-care and clinical follow-up instructions for
patients exposed to ethylene glycol or propylene glycol.
Introduction
• All patients with ethylene glycol poisoning should
be evaluated and treated immediately.
• A
ll patients exposed to ethylene glycol or propylen
e
g
lycol need basic guidance o
n
o
se
lf-care, so they can minimize further risks an
d
avoid complications to the extent possible, and
o
cl
inical follow-up, so they understand when an
d
w
hy to return for further medical attention
.
• AT
SDR has developed a patient education sheet o
n
ethylene glycol and propylene glycol that you might
f
ind useful. It is available a
t
h
ttp://www.atsdr.cdc.gov/csem/egpg/pated_shee
t.
h
tml
.
Self-Care
Advise patients to avoid exposures and conditions that
might further increase their risk for disease or worsen
their existing health condition(s). You might offer the
following advice to your patient:
• If you have any antifreeze in your home, keep it i
n
o
riginal, labeled containers and securely stored an
d
ou
t of children’s reach
.
• I
f you suspect that someone has ingeste
d
antifreeze, be sure he or she sees a healthcare
p
rovider immediately
.
Clinical Follow
Up
Patients should be advised to consult their healthcare
provider if they develop
• any sign or symptom of CNS involvement,
or
Page 98 of 124
• signs or symptoms of other health changes
(especially those possibly related to heart and
k
idney problems)
.
A
TSDR’s patient education and care instruction sheet
on ethylene glycol and propylene glycol is a job aid
that provides relevant follow-up instructions for
patients possibly exposed to ethylene glycol or
propylene glycol including follow-up instructions.
Key Points
• Advise patients to avoid exposures and conditions
that might further increase their risk for disease or
w
orsen their existing health condition(s
).
• Patients should seek immediate evaluation if they
d
evelop neurological problems or other healt
h
ch
anges after exposure
.
• A
patient education and care instruction sheet fo
r
e
thylene glycol and propylene glycol is available at
:
h
ttp://www.atsdr.cdc.gov/csem/egpg/pated_shee
t.
h
t
ml
Progress
Check
Patients who have been exposed to ethylene glycol
should take what action?
A. Se
ek clinical evaluation and treatment as soo
n
a
s possible
.
B.
Learn how to avoid further exposure.
C.
Kn
ow when to call their healthcare provider
.
D.
Al
l of the above
.
A
nswers
21. The best choice is D: All of the above. Medical tests
and treatment are available for ethylene glycol
p
oisoning, and treatment should begin as soon a
s
p
ossible. The treating physician should find ou
t
wh
ether the patient has any materials at home o
r
wo
rk that contain ethylene glycol and advi
se
patients to avoid exposures and conditions that
m
ight increase their risk for disease or worsen thei
r
e
xisting health condition(s). In addition, patien
ts
s
hould contact their physician if they develo
p
n
eurological problems or other health changes
.
Page 99 of 124
Feedback for A. (Web only): The best choice is D. All of
the above. All patients with ethylene glycol poisoning
should be evaluated and treated as soon as possible.
Even patients with no or mild symptoms should undergo
appropriate blood and urine tests if they have a history
of significant ingestion.
Feedback for B. (Web only): The best choice is D. All of
the above. Advise patients to avoid exposures and
conditions that might increase their risk for disease or
worsen their existing health condition(s).
Feedback for C. (Web only): The best choice is D. All of
the above. Patients should contact their healthcare
provider if they develop neurological problems or other
health changes.
Feedback for D. (Web only): Correct. Medical tests and
treatment are available for ethylene glycol poisoning,
and treatment should begin as soon as possible. The
treating physician should find out whether the patient
has any materials at home or work that contain ethylene
glycol and advise patients to avoid exposures and
conditions that might increase their risk for disease or
worsen their existing health condition(s). In addition,
patients should contact their healthcare providers if they
develop neurological problems or other health changes.
To review relevant content, see “Self Care” and
“Clinical Follow-Up” in this section.
Sources of Additional Information
Ethylene
The following Web resources may provide more
Glycol and information on the adverse effects of ethylene glycol
Propylene and propylene glycol, treatment of ethylene glycol and
Glycol Specific propylene glycol associated diseases, and management
Information of persons exposed to ethylene glycol and propylene
glycol.
Page 100 of 124
o Agency for Toxic Substances and Disease
R
egistry (ATSDR) http://www.atsdr.cdc.go
v
o
F
or chemical, emergency situation
s
CDC Emergency Response: 770-488-7100
a
nd request the ATSDR Duty Office
r
o
F
or chemical, non-emergency situation
s
CDC-INFO http://www.cdc.gov/cdc-info/
8
00-CDC-INFO (800-232-4636) TTY 888-
232-6348 - 24 Hours/Da
y
E-mail: cdcinfo@cdc.gov
N
ote:
ATSDR cannot respond to questions about
individual medical cases, provide second
opinions, or make specific recommendations
regarding therapy. Those issues should be
addressed directly with your healthcare
provider.
o T
oxicological profile for ethylene glyco
l
h
ttp://www.atsdr.cdc.gov/toxprofiles/tp.asp?id
=
8
6&tid=21
o T
OXFAQs for ethylene glycol (English
)
h
ttp://www.atsdr.cdc.gov/toxfaqs/TF.asp?id
=85
&tid=21
o
T
OXFAQs for ethylene glycol (Spanish
)
h
ttp://www.atsdr.cdc.gov/toxfaqs/TF.asp?id
=85
&ti
d
=21
o
AT
SDR medical management guidelines fo
r
ethylene glycol
h
ttp://www.atsdr.cdc.gov/MMG/MMG.asp?id=
82
&tid=21
o
AT
SDR minimal response level
s
h
ttp://www.atsdr.cdc.gov/mrls/index.htm
l
o
AT
SDR ToxFAQs for propylene glycol (English
)
h
ttp://www.atsdr.cdc.gov/toxfaqs/tf.asp?id=1
12
1&tid=240
Page 101 of 124
o ATSDR ToxFAQs for propylene glycol (Spanish)
http://www.atsdr.cdc.gov/es/toxfaqs/es_tfacts1
89.h
tm
l
• N
IOSH pocket guide to chemical hazards
–
e
thylene glyco
l
http://www.cdc.gov/niosh/npg/npgd0272.html
• E
PA Technology Transfer Network – ethylene glyco
l
http://www.epa.gov/ttn/atw/hlthef/ethy-gly.html
• O
SHA Safety and Health Topics – ethylene glyco
l
https://www.osha.gov/SLTC/ethyleneoxide/index.h
tml
General
Environmental
Health
Information
The following Web resources provide general
information on environmental health.
• Agency for Toxic Substances and Disease Registr
y
h
ttp://www.atsdr.cdc.go
v
o
T
aking an exposure history CSE
M
h
ttp://www.atsdr.cdc.gov/csem/csem.asp?cse
m
=
17&po=
0
o
To view the complete library of CSEMs
h
ttp://www.atsdr.cdc.gov/csem/csem.htm
l
o
Exposure history form
h
ttp://www.atsdr.cdc.gov/csem/csem.asp?cse
m
=
17&po=1
9
A
TSDR Division of Regional Operations
Through the working relationships they have established
with EPA, other federal and state agencies, individual
citizens, and community groups, ATSDR regional
representatives are able to maintain current and historic
knowledge of the sites and issues in their regions.
Information about ATSDR's regional offices, the states
and territories that they cover, and contact information,
is available at
http://www.atsdr.cdc.gov/DRO/dro_contact.html
• ATSDR State Cooperative Agreement Progra
m
http://www.atsdr.cdc.gov/states/index.html.
Page 102 of 124
• The Cooperative Agreement Program provides
essential support in communities nationwide to
f
ulfill ATSDR’s mission
.
• The program funds 30 states and one tribal
g
overnment to develop and strengthen thei
r
a
bilities to evaluate and respond to environmenta
l
p
ublic health issue
s.
Centers for Disease Control and Prevention (CDC)
http://www.cdc.gov
CDC works to protect public health and the safety of
people by providing information to support health
decisions. CDC also promotes health through
partnerships with state health departments and other
organizations.
CDC focuses national attention on developing and
applying disease prevention and control (especially
infectious diseases), environmental health, occupational
safety and health, health promotion, prevention, and
education activities designed to improve the health of
the people of the United States.
National Center for Environmental Health (NCEH)
http://www.cdc.gov/nceh
NCEH works to prevent illness, disability, and death
from interactions between people and the environment.
It is especially committed to safeguarding the health of
populations that are particularly vulnerable to certain
environmental hazards — children, the elderly, and
people with disabilities.
NCEH seeks to achieve its mission through science,
service, and leadership.
National Institute of Health (NIH)
http://www.nih.gov
Page 103 of 124
A part of the U.S. Department of Health and Human
Services, NIH is the primary federal agency for
conducting and supporting medical research.
National Institute for Occupational Safety and Health
(NIOSH) http://www.cdc.gov/niosh/
NIOSH is in the U.S. Department of Health and Human
Services. NIOSH was established to help assure safe
and healthful working conditions for workers by
providing research, information, education, and training
in the field of occupational safety and health.
American College of Occupational and
Environmental Medicine (ACOEM)
http://www.acoem.org/
ACOEM is the nation's largest medical society dedicated
to promoting the health of workers through preventive
medicine, clinical care, research, and education.
ACOEM members include specialists in a variety of
medical practices united to develop positions and
policies on vital issues relevant to the practice of
preventive medicine within and outside of the
workplace.
American College of Medical Toxicologists (ACMT)
http://www.acmt.net
ACMT is a professional, nonprofit association of
physicians with recognized expertise in medical
toxicology.
ACMT is dedicated to advancing the science and practice
of medical toxicology through a variety of activities.
American College of Preventive Medicine (ACPM)
http://www.acpm.org
Page 104 of 124
ACPM is the national professional society for physicians
committed to disease prevention and health promotion.
ACPM's 2,000 members are engaged in preventive
medicine practice, teaching, and research.
Association of Occupational and Environmental
Clinics(AOEC) http://aoec.org
AOEC is a network of more than 60 clinics and more
than 250 individuals committed to improving the
practice of occupational and environmental medicine
through information sharing and collaborative research.
Pediatric Environmental Health Specialty Units
(PEHSUs) http://www.pehsu.net
Based at an academic center, each PEHSU is
collaboration between the pediatric clinic and the AOEC
occupational and environmental clinic at each site.
The PEHSUs were developed to provide education and
consultation for health professionals, public health
professionals, and others, about the topic of children's
environmental health.
PEHSU staff members are available for consultation
about potential pediatric environmental health concerns
affecting the child and the family. Healthcare
professionals can contact their regional PEHSU site for
clinical advice.
Poison Control Center http://www.aapcc.org
The American Association of Poison Control Centers
supports the nation’s 55 poison centers in their efforts
to prevent and treat poison exposures. Poison centers
offer free, confidential medical advice 24 hours a day,
seven days a week, through the Poison Help line at 1-
800-222-1222. This service is a primary resource fo
r
p
oisoning information and helps reduce costl
y
e
mergency department visits through in-ho
me
tr
eatmen
t.
Page 105 of 124
AAPCC's mission is to actively advance the health care
role and public health mission of our members through
information, advocacy, education, and research.
Page 106 of 124
Posttest
Instructions
Posttest
For each question, select the one best answer.
1. What are characteristics of ethylene glycol?
A. It is a clear, colorless, odorless, sweet-tasting
liquid.
B. It causes acute toxicity in humans if ingested.
C. It is poorly absorbed by skin and has low
potential for significant inhalation exposure.
D. All of the above.
2. Which of the following products might contain
ethylene glycol?
A. La
tex Paints.
B. Antifreeze.
C. Solvents.
D. All of the above.
3. Which of the following statements about ethylene
glycol are true?
A. In
halation is a common route of exposure
because of the high vapor pressure.
B. Accidental or intentional ingestion accounts for
most poisonings.
C. It is absorbed readily through intact skin.
D. All of the above.
4. Propylene glycol is generally recognized as safe by
the Food and Drug Administration (FDA) for use in
which of the following?
A. Food
and tobacco products.
B. Pharmaceuticals.
C. Cosmetics.
D. All of the above.
5. After ingestion, what happens to ethylene glycol?
A. It
is slowly absorbed by the gastrointestinal
tract.
B. It is stored and persists in fatty tissue.
Page 107 of 124
C. It reaches peak tissue levels after 24 hours.
D. It is metabolized in the liver to a variety of
co
mpounds of increased toxicity
.
6. The first signs of ethylene glycol poisoning
generally include which of the following?
A. A c
haracteristic odor of ethanol on the breath
.
B.
Si
gns and symptoms similar to those of ethano
l
i
ntoxication
.
C.
Ca
rdiopulmonary signs such as tachypnea an
d
pulmonary edema.
D.
Ol
iguric renal failure
.
7. Acute ethylene glycol exposure can adversely
affect all of the following except which?
A. Lu
ngs
.
B.
Heart.
C.
Pa
ncreas
.
D.
Ki
dneys
.
8. Which of the following statements regarding
nephrotoxicity from ethylene glycol poisoning is
false?
A. K
idney damage manifests as acute oliguric rena
l
failure.
B.
C
ostovertebral angle tenderness is the mo
st
c
ommon physical finding
.
C.
A
bsence of oxalate crystals will rule out th
e
d
iagnosis of ethylene glycol poisoning
.
D.
Urinalysis shows proteinuria.
9. While determining the patient’s exposure history,
what additional information should you ask about?
A. A h
istory of ethanol abuse
.
B.
A h
istory of possible substance abuse
.
C.
Si
milar symptoms in family members, friends
,
p
ets, and coworkers
.
D.
All of the above.
Page 108 of 124
10. Useful laboratory tests for diagnosing ethylene
glycol poisoning include which of the following?
A. Arterial blood gases (ABG).
B. Blood glucose.
C. Blood ethanol.
D. All of the above.
11. Treatment strategies for ethylene glycol
poisoning may include which of the following?
A. So
dium bicarbonate to correct the metabolic
acidosis, as indicated.
B. Fomepizole to competitively inhibit metabolism of
ethylene glycol to its more toxic metabolites.
C. Hemodialysis, if indicated, to remove ethylene
glycol and glycolic acid.
D. All of the above.
12. What are the disadvantages of ethanol therapy?
A. It requires continuous administration and
frequent monitoring of serum ethanol and
glucose levels.
B. It can cause CNS depression and hypoglycemia.
C. It poses problems in patient care, such as
drunkenness.
D. All of the above.
13. Treatment for acute propylene glycol poisoning
might include which of the following?
A. Sodium bicarbonate therapy.
B. Administration of calcium gluconate.
C. Ethanol administration.
D. Hyperbaric oxygen.
14. Which of the following statements comparing
ethylene glycol and propylene glycol are true?
A.
Propylene glycol is most commonly found in
foods and medicines, and ethylene glycol is
found in antifreeze and other commercial
products.
Page 109 of 124
B. Both glycols are used for aircraft de-icing.
C. Neither compound is likely to persist for long in
the environment.
D. All of the above.
EG/PG Post-test Answers:
1. D
2. D
3. B
4. D
5. D
6. B
7. C
8. C
9. D
10. D
11. D
12. D
13. A
14. D
Relevant
Content
You can review content relevant to the posttest
questions in the following areas
Question
Location of relevant content
1
What is ethylene glycol?
• Describe the properties of ethylene glycol
.
2
W
here is ethylene glycol found?
• Identify sources of ethylene glycol exposure
.
3
W
hat are routes of exposure to ethylene glycol?
Page 110 of 124
• Identify the most common route of exposure to
ethylene glycol that results in toxicity in the
g
eneral U.S. population
.
4
What are U.S. regulations and guidelines for ethylene
glycol exposure?
• Describe current U.S. regulations and guideline
s
f
or ethylene glycol exposure
.
5
What is the biological fate of ethylene glycol?
• Explain the major pathway of ethylene glyco
l
metabolism in the body.
6
C
linical assessment – history and physical examination
• Describe how the clinical presentation change
s
over time.
7
What are the toxicological effects of ethylene glycol
poisoning?
• Describe the toxicological effects of ethylene glyco
l
p
oisoning
.
8
W
hat are the toxicological effects of ethylene glycol
poisoning?
• Describe the toxicological effects of ethylene glyco
l
p
oisoning
.
9
C
linical assessment — history and physical examination
• Describe what is included in the initial history and
p
hysical examination of patients potentiall
y
ex
posed to ethylene glycol
.
10
Clinical assessment — laboratory tests
• Identify the abnormal laboratory finding
s
associated with ethylene glycol poisoning.
11
How should patients exposed to ethylene glycol be
treated and managed?
• Describe treatment strategies for managin
g
e
thylene glycol poisoning case
s.
1
2
How should patients exposed to ethylene glycol be
treated and managed?
Page 111 of 124
• Describe treatment strategies for managing
ethylene glycol poisoning cases.
13
What is propylene glycol?
• Describe the uses of propylene glycol
.
1
4
What is propylene glycol?
• Describe the uses of propylene glycol.
Literature Cited
References
[ACGIH] American Conference of Governmental Industrial
Hygienists. 2017. TLVs & BEIs: Threshold limit values for
chemical substances and physical agents and biological
exposure indices for 2017. American Conference of
Governmental Industrial Hygienists, Cincinnatti, OH.
Albertson TE. 1999. Plenty to fear from toxic alcohols. Crit Care Med
27(12):2834-6.
Apple FS, Googins MK, Resen D. 1993. Propylene glycol interference
in gas-chromatographic assay of ethylene glycol. Clin Chem
39(1):167.
Arroliga AC, Shehab N, McCarthy K, et al. 2004. Relationship of
continuous infusion lorazepam to serum propylene glycol
concentration in critically ill adults. Crit Care Med 32(8):1709-
14.
[ATSDR] Agency for Toxic Substances and Disease Registry. 1997.
Toxicological profile for ethylene glycol and propylene glycol.
Atlanta: Agency for Toxic Substances and Disease Registry,
US Department of Health and Human Services.
[ATSDR] Agency for Toxic Substances and Disease Registry. 2008.
Addendum for propylene glycol. Supplement to the 1997
toxicological profile for propylene glycol. Atlanta: Agency for
Toxic Substances and Disease Registry, US Department of
Health and Human Services.
[ATSDR] Agency for Toxic Substances and Disease Registry. 2010.
Toxicological profile for ethylene glycol. Atlanta: Agency for
Page 112 of 124
Toxic Substances and Disease Registry, US Department of
Health and Human Services.
[ATSDR] Agency for Toxic Substances and Disease Registry. 2014.
Medical management guidelines for ethylene glycol. Atlanta:
Agency for Toxic Substances and Disease Registry. Available
from: https://www.atsdr.cdc.gov/mmg/mmg.asp?id=82&tid=21.
Barceloux DG, Krenzelok EP, Olson K, et al. 1999. American
Academy of Clinical Toxicology practice guidelines on the
treatment of ethylene glycol poisoning. Ad Hoc Committee. J
Toxicol Clin Toxicol 37(5):537-60.
Barnes BJ, Gerst C, Smith JR, et al. 2006. Osmol gap as a surrogate
marker for serum propylene glycol concentrations in patients
receiving lorazepam for sedation. Pharmacotherapy 26(1):23-
33.
Battistella M. 2002. Fomepizole as an antidote for ethylene glycol
poisoning. Ann Pharmacother 36(6):1085-9.
Baud FJ, Galliot M, Astier A, et al. 1988. Treatment of ethylene glycol
poisoning with intravenous 4-methylpyrazole. N Eng J Med
319(2):97-100.
Baum CR, Langman CB, Oker EE, et al. 2000. Fomepizole treatment
of ethylene glycol poisoning in an infant. Pediatrics
106(6):1489-91.
Berman LB, Schreiner GE, Feys J. 1957. The nephrotoxic lesion of
ethylene glycol. Ann Intern Med 46(3):611-9.
Bey TA, Walter FG, Gibly RL, et al. 2002. Survival after ethylene
glycol poisoning in a patient with an arterial pH of 6.58. Vet
Hum Toxicol 44(3):167-8.
Bledsoe KA, Kramer AH. 2008. Propylene glycol toxicity
complicating use of barbiturate coma. Neurocrit Care 9(1):122-
4.
Borron SW, Megarbane B, Baud FJ. 1999. Fomepizole in treatment of
uncomplicated ethylene glycol poisoning. Lancet
354(9181):831.
Bove KE. 1966. Ethylene glycol toxicity. Am J Clin Pathol 45(1):46-
50.
Page 113 of 124
Boyer EW, Mejia M, Woolf A, et al. 2001. Severe ethylene glycol
ingestion treated without hemodialysis. Pediatrics 107(1):172-3.
Brent J. 2001. Current management of ethylene glycol poisoning.
Drugs 61(7):979-88.
Brent J. 2010. Fomepizole for the treatment of pediatric ethylene and
diethylene glycol, butoxyethanol, and methanol poisonings.
Clin Toxicol 48(5):401-6.
Brent J, McMartin K, Phillips S, et al. 1999. Fomepizole for the
treatment of ethylene glycol poisoning. Methylpyrazole for
Toxic Alcohols Study Group. N Engl J Med 340(11):832-8.
Broadley SA, Ferguson IT, Walton B, et al. 1997. Severe sensorimotor
polyradiculoneuropathy after ingestion of ethylene glycol. J
Neurol Neurosurg Psychiatry 63(2):261.
Bronstein AC, Spyker DA, Cantilena LR, Jr., et al. 2009. 2008 Annual
report of the American Association of Poison Control Centers'
National Poison Data System (NPDS): 26th Annual Report.
Clin Toxicol 47(10):911-1084.
Buchanan JA, Alhelail M, Cetaruk EW, et al. 2010. Massive ethylene
glycol ingestion treated with fomepizole alone-a viable
therapeutic option. J Med Toxicol 6(2):131-4.
Buell JF, Sterling R, Mandava S, et al. 1998. Ethylene glycol
intoxication presenting as a metabolic acidosis associated with a
motor vehicle crash: case report. J Trauma 45(4):811-3.
Caravati EM, Erdman AR, Christianson G, et al. 2005. Ethylene glycol
exposure: an evidence-based consensus guideline for out-of-
hospital management. Clin Toxicol 43(5):327-45.
Caravati EM, Heileson HL, Jones M. 2004. Treatment of severe
pediatric ethylene glycol intoxication without hemodialysis. J
Toxicol Clin Toxicol 42(3):255-9.
Cheng JT, Beysolow TD, Kaul B, et al. 1987. Clearance of ethylene
glycol by kidneys and hemodialysis. J Toxicol Clin Toxicol
25(1-2):95-108.
Chung PK, Tuso P. 1989. Cerebral computed tomography in a stage IV
ethylene glycol intoxication. Conn Med 53(9):513-4.
Page 114 of 124
Clayton GD, Clayton FE. 1994. Patty's industrial hygiene and
toxicology. Vol. 2, Part F, Toxicology. 4th ed. New York: John
Wiley & Sons.
Curtin L, Kraner J, Wine H, et al. 1992. Complete recovery after
massive ethylene glycol ingestion. Arch Intern Med
152(6):1311-3.
Davis DP, Bramwell KJ, Hamilton RS, et al. 1997. Ethylene glycol
poisoning: case report of a record-high level and a review. J
Emerg Med 15(5):653-67.
Demey HE, Daelemans RA, Verpooten GA, et al. 1988. Propylene
glycol-induced side effects during intravenous nitroglycerin
therapy. Intensive Care Med 14(3):221-6.
Druteika DP, Zed PJ, Ensom MH. 2002. Role of fomepizole in the
management of ethylene glycol toxicity. Pharmacotherapy
22(3):365-72.
Eder AF, McGrath CM, Dowdy YG, et al. 1998. Ethylene glycol
poisoning: toxicokinetic and analytical factors affecting
laboratory diagnosis. Clin Chem 44(1):168-77.
[EPA] US Environmental Protection Agency. 2000. Ethylene glycol.
Washington DC: US Environmental Protection Agency.
Available from:
https://www.epa.gov/sites/production/files/2016-
09/documents/ethylene-glycol.pdf
[EPA] US Environmental Protection Agency. 2007. Clean Air Act. 42
USC Sec. 7412. Hazardous air pollutants. Available from:
https://www.gpo.gov/fdsys/pkg/USCODE-2013-
title42/html/USCODE-2013-title42-chap85-subchapI-partA-
sec7412.htm.
[FDA] US Food and Drug Administration. 2017. 21 CFR 184.1 Direct
food substances affirmed as generally recognized as safe.
Available from:
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRS
earch.cfm?fr=184.1.
Fiedler NL. 2007. Organic solvents and fuels. In: Rom, WN, editor.
Environmental and occupational medicine. 4th ed. Philadelphia:
Lippincott Williams & Wilkins.
Page 115 of 124
Ford M GL. 1991. Alcohols and glycols. In: Rippe JM, Irwin RS,
Alpert JS, Fink MP, editors. Intensive care medicine. 2nd ed.
Boston: Little, Brown and Co. p. 1160-73.
Friedman EA, Greenberg JB, Merrill JP, et al. 1962. Consequences of
ethylene glycol poisoning. Report of four cases and review of
the literature. Am J Med 32:891-902.
Froberg K, Dorion RP, McMartin KE. 2006. The role of calcium
oxalate crystal deposition in cerebral vessels during ethylene
glycol poisoning. Clin Toxicol 44(3):315-8.
[FSTRAC] Federal-State Toxicology and Regulatory Alliance
Committee. 1990. Summary of state and federal drinking water
standards and guidelines. Washington DC: US Environmental
Protection Agency. Available from:
https://nepis.epa.gov/Exe/ZyPDF.cgi/10003I4B.PDF?Dockey=
10003I4B.PDF.
Gabow PA, Clay K, Sullivan JB, et al. 1986. Organic acids in ethylene
glycol intoxication. Ann Intern Med 105(1):16-20.
Gardner TB, Manning HL, Beelen AP, et al. 2004. Ethylene glycol
toxicity associated with ischemia, perforation, and colonic
oxalate crystal deposition. J Clin Gastroenterol 38(5):435-9.
Glaser DS. 1996. Utility of the serum osmol gap in the diagnosis of
methanol or ethylene glycol ingestion. Ann Emerg Med
27(3):343-6.
Godolphin W, Meagher EP, Sanders HD, et al. 1980. Unusual calcium
oxalate crystals in ethylene glycol poisoning. Clin Toxicol
16(4):479-86.
Goldfrank LR, Flomenbaum NE, Lewin NA, et al. 1998. Toxic
alcohols. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al.,
editors. Goldfrank's toxicologic emergencies. Stamford, CT:
Appleton and Lange, p. 1049-60.
Goldfrank LR, Nelson LS, et al 2019. Toxic Alcohols. In: Goldfrank's
Toxicologic Emergencies. 11
th
edition. McGraw-Hill
Education, New York. p. 1425.
Gordon HL, Hunter JM. 1982. Ethylene glycol poisoning. A case
report. Anaesthesia 37(3):332-8.
Page 116 of 124
Greller H, Gupta A. 2017. Benzodiazepine poisoning and withdrawal.
Available from:
https://www.uptodate.com/contents/benzodiazepine-poisoning-
and-withdrawal
Gummin DD, Mowry JB, Spyker DA, et al. 2016. 2016 annual report
of the American Association of Poison Control Centers'
National Poison Data System (NPDS): 34th Annual Report.
Clin Toxicol (Phila) 55(10):1072-1254.
Hall AH. 1992. Ethylene glycol and methanol: poisons with toxic
metabolic activation. Emerg Med Rpt 13(4):29-38.
Hantson P, Hassoun A, Mahieu P. 1998. Ethylene glycol poisoning
treated by intravenous 4-methylpyrazole. Intensive Care Med
24(7):736-9.
Hantson P, Vanbinst R, Mahieu P, et al. 2002. Determination of
ethylene glycol tissue content after fatal oral poisoning and
pathologic findings. Am J Forensic Med Pathol 23(2):159-61.
Harry P, Jobard E, Briand M, et al. 1998. Ethylene glycol poisoning in
a child treated with 4-methylpyrazole. Pediatrics 102(3):E31.
Harry P, Turcant A, Bouachour G, et al. 1994. Efficacy of 4-
methylpyrazole in ethylene glycol poisoning: clinical and
toxicokinetic aspects. Hum Exp Toxicol 13(1):61-4.
Haupt MC, Zull DN, Adams SL. 1988. Massive ethylene glycol
poisoning without evidence of crystalluria: a case for early
intervention. J Emerg Med 6(4):295-300.
Hess R, Bartels MJ, Pottenger LH. 2004. Ethylene glycol: an estimate
of tolerable levels of exposure based on a review of animal and
human data. Arch Toxicol 78(12):671-80.
Hilliard NJ, Robinson CA, Hardy R, et al. 2004. Pathologic quiz case:
repeated positive ethylene glycol levels by gas chromatography.
Central venous line contamination of blood samples by
propylene glycol from intravenous lorazepam injections. Arch
Pathol Lab Med 128(6):e79-80.
Horinek EL, Kiser TH, Fish DN, et al. 2009. Propylene glycol
accumulation in critically ill patients receiving continuous
Page 117 of 124
intravenous lorazepam infusions. Ann Pharmacother
43(12):1964-71.
Howard PH, Boethling RS, Jarvis WF, Meylan WM, Michalenko EM.
1991. Handbook of environmental degradation rates. Cheslsea,
MI: Lewis Publishers, Inc., p. 392-3.
Howland M. 2015. Antidotes in depth. In: Hoffman RS, Howland M,
Lewin NA, Nelson LS, Goldfrank LR, editors. Goldfrank's
toxicologic emergencies. 10th ed. New York: McGraw-Hill.
Huhn KM, Rosenberg FM. 1995. Critical clue to ethylene glycol
poisoning. CMAJ 152(2):193-5.
[IPCS] International Programme on Chemical Safety. 2002. Ethylene
glycol: human health aspects. Concise International Chemical
Assessment Document 45. Geneva: World Health Organization.
Available from:
http://www.inchem.org/documents/cicads/cicads/cicad45.htm
Jacobsen D, Hewlett TP, Webb R, et al. 1988. Ethylene glycol
intoxication: evaluation of kinetics and crystalluria. Am J Med
84(1):145-52.
Jacobsen D, McMartin KE. 1986. Methanol and ethylene glycol
poisonings. Mechanism of toxicity, clinical course, diagnosis
and treatment. Med Toxicol 1(5):309-34.
Jacobsen D, McMartin KE. 1997. Antidotes for methanol and ethylene
glycol poisoning. J Toxicol Clin Toxicol 35(2):127-43.
Jammalamadaka D, Raissi S. 2010. Ethylene glycol, methanol and
isopropyl alcohol intoxication. Am J Med Sci 339(3):276-81.
Jobard E, Harry P, Turcant A, Roy PM, Allain P. 1996. 4-
Methylpyrazole and hemodialysis in ethylene glycol poisoning.
J Toxicol Clin Toxicol 34(4):373-7.
Johnson B, Meggs WJ, Bentzel CJ. 1999. Emergency department
hemodialysis in a case of severe ethylene glycol poisoning. Ann
Emerg Med 33(1):108-10.
Jones AL, Volans G. 1999. Management of self poisoning. BMJ
319(7222):1414-7.
Page 118 of 124
Jones AW, Nilsson L, Gladh SA, et al. 1991. 2,3-Butanediol in plasma
from an alcoholic mistakenly identified as ethylene glycol by
gas-chromatographic analysis. Clin Chem 37(8):1453-5.
Kahn HS, Brotchner RJ. 1950. A recovery from ethylene glycol (anti-
freeze) intoxication; a case of survival and two fatalities from
ethylene glycol including autopsy findings. Ann Intern Med
32(2):284-94.
Koga Y, Purssell RA, Lynd LD. 2004. The irrationality of the present
use of the osmole gap: applicable physical chemistry principles
and recommendations to improve the validity of current
practices. Toxicol Rev 23(3):203-11.
Kraut JA, Kurtz I. 2008. Toxic alcohol ingestions: clinical features,
diagnosis, and management. Clin J Am Soc Nephrol 3(1):208-
25.
Lepik KJ, Levy AR, Sobolev BG, et al. 2009. Adverse drug events
associated with the antidotes for methanol and ethylene glycol
poisoning: a comparison of ethanol and fomepizole. Ann Emerg
Med 53(4):439-50.e10.
Leth PM, Gregersen M. 2005. Ethylene glycol poisoning. Forensic Sci
Int 155(2-3):179-84.
Levine M, Curry SC, Ruha AM, et al. 2012. Ethylene glycol
elimination kinetics and outcomes in patients managed without
hemodialysis. Ann Emerg Med 59(6):527-31.
Lewis LD, Smith BW, Mamourian AC. 1997. Delayed sequelae after
acute overdoses or poisonings: cranial neuropathy related to
ethylene glycol ingestion. Clin PharmacolTher 61(6):692-9.
Lim TY, Poole RL, Pageler NM. 2014. Propylene glycol toxicity in
children. J Pediatr Pharmacol Ther 19(4): 277–82.
Louis S, Kutt H, McDowell F. 1967. The cardiocirculatory changes
caused by intravenous Dilantin and its solvent. Am Heart J
74(4):523-9.
Malmlund HO, Berg A, Karlman G, et al. 1991. Considerations for the
treatment of ethylene glycol poisoning based on analysis of two
cases. J Toxicol Clin Toxicol 29(2):231-40.
Page 119 of 124
Marwick J, Elledge RO, Burtenshaw A. 2012. Ethylene glycol
poisoning and the lactate gap. Anaesthesia 67(3):299.
McMartin K. 2009. Are calcium oxalate crystals involved in the
mechanism of acute renal failure in ethylene glycol poisoning?
Clin Toxicol 47(9):859-69.
McMartin KE, Cenac TA. 2000. Toxicity of ethylene glycol
metabolites in normal human kidney cells. Ann N Y Acad Sci
919:315-7.
Meng QH, Adeli K, Zello GA, et al. 2010. Elevated lactate in ethylene
glycol poisoning: True or false? Clinica Chimica Acta 411(7-
8):601-4.
Momont SL, Dahlberg PJ. 1989. Ethylene glycol poisoning. Wisc Med
J 88(9):16-20.
Moossavi S, Wadhwa NK, Nord EP. 2003. Recurrent severe anion gap
metabolic acidosis secondary to episodic ethylene glycol
intoxication. Clin Nephrol 60(3):205-10.
Moreau CL, Kerns W 2nd, Tomaszewski CA, et al. 1998. Glycolate
kinetics and hemodialysis clearance in ethylene glycol
poisoning. META Study Group. J Toxicol Clin Toxicol
36(7):659-66.
Morgan BW, Ford MD, Follmer R. 2000. Ethylene glycol ingestion
resulting in brainstem and midbrain dysfunction. J Toxicol Clin
Toxicol 38(4):445-51.
Neale BW, Mesler EL, Young M, et al. 2005. Propylene glycol-
induced lactic acidosis in a patient with normal renal function: a
proposed mechanism and monitoring recommendations. Ann
Pharmacother 39(10):1732-6.
Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR.
2014. Goldfrank's toxicological emergencies. 10th ed.
Columbus, OH: McGraw-Hill Education.
[NIOSH] National Institute for Occupational Safety and Health. 2005.
NIOSH pocket guide to chemical hazards. Publication No.
2005-149. Washington DC: National Institute for Occupational
Safety and Health. Available from:
https://www.cdc.gov/niosh/npg/default.html.
Page 120 of 124
[NIOSH] National Institute for Occupational Safety and Health. 2014.
Ethylene glycol: systemic agent. Washington DC: National Institute for
Occupational Safety and Health. Available from:
https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750031.
html.
[NLM] US National Library od Medicine. 2016. Household Products
Database: Ethylene glycol. Bethesda, MD: US National Library
of Medicine. US Department of Health and Human Services.
Available from: https://hpd.nlm.nih.gov/cgi-
bin/household/search?tbl=TblChemicals&queryx=107-21-1.
O'Donnell J, Mertl SL, Kelly WN. 2000. Propylene glycol toxicity in a
pediatric patient: the dangers of diluents. J Pharm Pract
13(3):214-24.
Olivero JJ. 1993. A comatose man with marked acidosis and
crystaluria. Hosp Pract (Off Ed) 28(7):86-8.
Parker MG, Fraser GL, Watson DM, et al. 2002. Removal of propylene
glycol and correction of increased osmolar gap by hemodialysis
in a patient on high dose lorazepam infusion therapy. Intensive
Care Med 28(1):81-4.
Parry MF, Wallach R. 1974. Ethylene glycol poisoning. Am J Med
57(1):143-50.
Peleg O, Bar-Oz B, Arad I. 1998. Coma in a premature infant
associated with the transdermal absorption of propylene glycol.
Acta Paediatr 87(11):1195-6.
Pellegrino B, Parravani A, Cook L, et al. 2006. Ethylene glycol
intoxication: disparate findings of immediate versus delayed
presentation. W V Med J 102(4):32-4.
Piagnerelli M, Carlier E, Lejeune P. 1999. Adult respiratory distress
syndrome and medullary toxicity: two unusual complications of
ethylene glycol intoxication. Intensive Care Med 25(10):1200.
Pien K, van Vlem B, van Coster R, et al. 2002. An inherited metabolic
disorder presenting as ethylene glycol intoxication in a young
adult. Am J Forensic Med Pathol 23(1):96-100.
Poldelski V, Johnson A, Wright S, et al. 2001. Ethylene glycol-
mediated tubular injury: identification of critical metabolites
and injury pathways. Am J Kidney Dis 38(2):339-48.
Page 121 of 124
Purssell RA, Lynd LD, Koga Y. 2004. The use of the osmole gap as a
screening test for the presence of exogenous substances.
Toxicol Rev 23(3):189-202.
Rahman SS, Kadakia S, Balsam L, et al. 2012. Autonomic dysfunction
as a delayed sequelae of acute ethylene glycol ingestion : a case
report and review of the literature. J Med Toxicol 8(2):124-9.
Rasic S, Cengic M, Golemac S, et al. 1999. Acute renal insufficiency
after poisoning with ethylene glycol. Nephron 81(1):119-20.
Rhyee SH. 2018. General approach to drug poisoning in adults.
Available from: https://www.uptodate.com/contents/general-
approach-to-drug-poisoning-in-adults.
Robinson CA, Jr., Scott JW, Ketchum C. 1983. Propylene glycol
interference with ethylene glycol procedures. Clin Chem
29(4):727.
Schwerk N, Desel H, Schulz M, et al. 2007. Successful therapy of
paediatric ethylene glycol poisoning: a case report and annual
survey by a regional poison centre. Acta Paediatr 96(3):461-3.
Seay RE, Graves PJ, Wilkin MK. 1997. Comment: possible toxicity
from propylene glycol in lorazepam infusion. Ann
Pharmacother 31(5):647-8. Erratum in: Ann Pharmacother
1997;31(11):1413.
Shah RR, De La Calzada-Jeanlouie, Weiselberg RS, Su M. 2013.
Chapter 17. Toxicology. In: Shah BR, Lucchesi M, Amodio J,
Silverberg M, editors. Atlas of pediatric emergency medicine.
2nd ed. New York: McGraw-Hill.
Singh M, Murtaza M, D'Souza N, et al. 2001. Abdominal pain and
lactic acidosis with ethylene glycol poisoning. Am J Emerg
Med 19(6):529-30.
Sivilotti MLA. 2018. Methanol and ethylene glycol poisoning.
Available from: https://www.uptodate.com/contents/methanol-
and-ethylene-glycol-poisoning.
Speth PA, Vree TB, Neilen NF, et al. 1987. Propylene glycol
pharmacokinetics and effects after intravenous infusion in
humans. Ther Drug Monit 9(3):255-8.
Page 122 of 124
Stokes JB, 3rd, Aueron F. 1980. Prevention of organ damage in
massive ethylene glycol ingestion. JAMA 243(20):2065-6.
Szerlip HM. 1999. A 27-year-old homeless man with mental
obtundation and a metabolic acidosis. Chest 115(5):1447-8.
Takayesu JK, Bazari H, Linshaw M. 2006. Case records of the
Massachusetts General Hospital. Case 7-2006. A 47-year-old
man with altered mental status and acute renal failure. N Engl J
Med 354(10):1065-72. Erratum in: N Engl J Med
2006;355(4):429.
Tietze KJ, Fuchs B. 2018. Sedative-analgesic medications in critically
ill adults: Properties, dosage regimens, and adverse effects.
Available from: https://www.uptodate.com/contents/sedative-
analgesic-medications-in-critically-ill-adults-properties-dosage-
regimens-and-adverse-effects.
Tobe TJ, Braam GB, Meulenbelt J, et al. 2002. Ethylene glycol
poisoning mimicking Snow White. Lancet 359(9304):444-5.
Vale JA. 1979. Ethylene glycol poisoning. Vet Hum Toxicol
21(Suppl):118-20.
Velez LI. 2017. Approach to the child with occult toxic exposure.
Available from: https://www.uptodate.com/contents/approach-
to-the-child-with-occult-toxic-exposure.
Velez LI, Gracia R, Neerman MF. 2007. Ethylene glycol poisoning:
current diagnostic and management issues. J Emerg Nurs
33(4):342-5.
Verrilli MR, Deyling CL, Pippenger CE, et al. 1987. Fatal ethylene
glycol intoxication. Report of a case and review of the
literature. Cleve Clin J Med 54(4):289-95.
Walder AD, Tyler CK. 1994. Ethylene glycol antifreeze poisoning.
Three case reports and a review of treatment. Anaesthesia
49(11):964-7.
Watson WA. 2000. Ethylene glycol toxicity: closing in on rational,
evidence-based treatment. Ann Emerg Med 36(2):139-41.
Wills JH, Coulston F, Harris ES, et al. 1974. Inhalation of aerosolized
ethylene glycol by man. Clin Toxicol 7(5):463-76.
Page 123 of 124
Wilson KC, Reardon C, Farber HW. 2000. Propylene glycol toxicity in
a patient receiving intravenous diazepam. N Engl J Med
343(11):815.
Wilson KC, Reardon C, Theodore AC, et al. 2005. Propylene glycol
toxicity: a severe iatrogenic illness in ICU patients receiving IV
benzodiazepines: a case series and prospective, observational
pilot study. Chest 128(3):1674-81.
Yahwak JA, Riker RR, Fraser GL, et al. 2008. Determination of a
lorazepam dose threshold for using the osmol gap to monitor
for propylene glycol toxicity. Pharmacotherapy 28(8):984-91.
Yaucher NE, Fish JT, Smith HW, et al. 2003. Propylene glycol-
associated renal toxicity from lorazepam infusion.
Pharmacotherapy 23(9):1094-9.
Yorgin PD, Theodorou AA, Al-Uzri A, et al. 1997. Propylene glycol-
induced proximal renal tubular cell injury. Am J Kidney Dis
30(1):134-9.
Zar T, Graeber C, Perazella MA. 2007. Recognition, treatment, and
prevention of propylene glycol toxicity. Semin Dial 20(3):217-
9.
Zeiss J, Velasco ME, McCann KM, et al. 1989. Cerebral CT of lethal
ethylene glycol intoxication with pathologic correlation. AJNR:
Am J Neuroradiol 10(2):440-2.
Zosel A, Egelhoff E, Heard K. 2010. Severe lactic acidosis after an
iatrogenic propylene glycol overdose. Pharmacotherapy
30(2):219.
Page 124 of 124
