1
AGENCY FOR TOXIC SUBSTANCES AND DISEASE REGISTRY
CASE STUDIES IN ENVIRONMENTAL MEDICINE
(CSEM)
CARBON TETRACHLORIDE TOXICITY
Course: WB2888
CE Original Date: December 31, 2017
CE Expiration Date: December 31, 2019
Key Concepts
•
Chronic exposure to carbon tetrachloride (CCl
4
) —
and sometimes acute exposure to very high
concentrations — produces liver and kidney damage.
• CCl
4
is highly toxic. It is reasonably anticipated to be
a human carcinogen, based on sufficient evidence of
carcinogenicity from studies in experimental animals.
About This and
Other Case
Studies in
Environmental
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 medical
practices that can aid in evaluating and caring for
potentially exposed patients. The complete series of
Case Studies in Environmental Medicine is available on
the ATSDR website at:
https://www.atsdr.cdc.gov/csem/csem.html. In
addition, the downloadable PDF version of this
educational series and other environmental medicine
materials provides content in an electronic, printable
format, especially for those who may lack adequate
Internet service.
2
Acknowledge-
ments
We gratefully acknowledge the work of the medical
writers, editors, and reviewers in producing this
educational resource. Contributors to this version of the
“ATSDR Case Studies in Environmental Medicine: Carbon
Tetrachloride Toxicity” are listed below.
Note: Each content expert for this case study has
indicated that he or she has no conflict of interest that
would bias the case study content.
CDC/ATSDR Author(s): Dianyi Yu, MD
CDC/ATSDR Planners: Germania Pinheiro, MD, PhD;
Dianyi Yu, MD; John Doyle, MPA; Diana Cronin
CDC/ATSDR Commenters: Obaid Faroon, DVM, PhD;
Kim Gehle, MD, MPH; Dan Middleton, MD; Alaina Steck,
MD
How to Apply
for and
Receive
Continuing
Education, and
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Assessment
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Visit https://www.atsdr.cdc.gov/csem/conteduc.html for
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https://www2a.cdc.gov/TCEOnline/registration/det
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Disclaimer and
Disclosure
Disclaimer
The state of knowledge regarding the treatment of
patients potentially exposed to hazardous substances in
the environment is constantly evolving and is often
uncertain. In developing its educational products,
ATSDR has made a diligent effort to ensure the accuracy
and the currency of the presented information. ATSDR,
however, makes no claim that the environmental
medicine and health education resources discussed in
these products comprehensively address all possible
situations related to various substances. The 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 health care 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 Agency for Toxic Substances and
Disease Registry 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.
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.
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Planning committee 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
Table of Contents
How to Use This Course ......................................................................... 6
Initial Check ........................................................................................ 9
What Is Carbon Tetrachloride? ............................................................. 18
Where Is Carbon Tetrachloride Found? .................................................. 20
What Are Routes of Exposure to Carbon Tetrachloride? ........................... 23
Who Is at Risk for Exposure to Carbon Tetrachloride? ............................. 26
What Are Guidelines and Regulations for Carbon Tetrachloride Exposure? .. 28
What Is the Biologic Fate of Carbon Tetrachloride in the Body? ................ 33
What Are the Toxicological Effects of Carbon Tetrachloride Exposure? ....... 36
Clinical Assessment – History and Physical Exam .................................... 45
Clinical Assessment — Laboratory Tests ................................................ 50
6
How Should Patients Exposed to Carbon Tetrachloride Be Treated and
Managed? .......................................................................................... 53
What Instructions Should Be Given to Patients Exposed to Carbon
Tetrachloride? .................................................................................... 57
Sources of Additional Information ......................................................... 59
Posttest ............................................................................................. 63
Literature Cited .................................................................................. 68
How to Use This Course
Introduction
The goal of Case Studies in Environmental Medicine
(CSEM) is to increase the primary care provider’s
knowledge of hazardous substances in the environment
and to help in the evaluation and treatment of
potentially exposed patients. This CSEM focuses on
carbon tetrachloride toxicity.
Availability
Two versions of the carbon tetrachloride toxicity CSEM
are available.
• The HTML version
https://www.atsdr.cdc.gov/csem/csem.asp?csem=
35&po=0 provides content through the Internet.
• The downloadable PDF version
http://www.atsdr.cdc.gov/csem/carbon_tetrachlori
de/docs/Carb_Tet-508.pdf 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
To make the most effective use of this course:
• Take the Initial Check to assess your current
knowledge about carbon tetrachloride toxicity.
• Read the title, learning objectives, text, and key
points in each section.
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•
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 free continuing
education credit. You can print your continuing
education certificate immediately after course
completion.
Instructional
Format
This course is designed to help you learn efficiently.
Topics are clearly labeled so that you can skip sections
or quickly scan sections with which you are already
familiar. The labels also allow you to use this training
material as a handy reference. To help you identify and
absorb important content quickly, each section is
structured as follows:
Section
Element
Purpose
Title
Serves as a “focus question” that 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
Enables you to test yourself to determine whether you
have mastered the learning objectives
Answers
Provides feedback to ensure you understand the content
and can locate information in the text
Learning
Objectives
On completion of the Carbon Tetrachloride Toxicity
CSEM you will be able to
Content Area
Learning Objectives
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What Is Carbon
Tetrachloride?
• Describe carbon tetrachloride (CCl
4
).
Where Is Carbon
Tetrachloride
Found?
• Identify sources of carbon tetrachloride (CCl
4
)
exposure.
What Are Routes of
Exposure to Carbon
Tetrachloride?
• Identify the routes of exposure to carbon
tetrachloride (CCl
4
).
Who Is at Risk for
Exposure to Carbon
Tetrachloride?
• Identify who is at risk for exposure to carbon
tetrachloride (CCl
4
).
What Are
Guidelines and
Regulations for
Carbon
Tetrachloride
Exposure?
• Describe current U.S. guidelines and
regulations for carbon tetrachloride (CCl
4
)
exposure
What Is the
Biologic Fate of
Carbon
Tetrachloride in the
Body?
• Describe the characteristics of carbon
tetrachloride (CCl
4
) metabolism.
What Are the
Toxicological
Effects of Carbon
Tetrachloride
Exposure?
• Describe the toxicological effects associated
with carbon tetrachloride (CCl
4
) exposure.
Clinical Assessment
– History and
Physical Exam
• Describe what is included in the initial history
and physical exam of patients potentially
exposed to carbon tetrachloride (CCl
4
).
Clinical Assessment
- Laboratory Tests
• Describe tests that may assist with diagnosis of
carbon tetrachloride (CCl
4
) toxicity.
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How Should
Patients Exposed to
Carbon
Tetrachloride Be
Treated and
Managed?
• Describe treatment strategies for patients with
carbon tetrachloride (CCl
4
) poisoning.
What Instructions
Should Be Given to
Patients Exposed to
Carbon
Tetrachloride?
•
Describe instructions that can be provided to
patients exposed to carbon tetrachloride (CCl
4
).
Initial Check
Instructions
This initial check will help you assess your current
knowledge about carbon tetrachloride toxicity. To take
the initial check, read the case below and then answer
the questions that follow.
Case
A hazardous waste worker has delayed-onset
abdominal pain, nausea, vomiting, and diarrhea.
As the physician on duty at a hospital emergency
department (ED) in an urban community, you are
notified that an ambulance is bringing three hazardous
waste workers—two males (ages 40 and 25 years) and a
female (age 30 years)—directly from their worksite to
your emergency room. All three workers are
complaining of
• Headache,
• Dizziness, and
• Nausea.
You learn that the workers were handling several dozen
barrels of a sweet-smelling hazardous waste liquid in a
hot, unventilated room. Their work required taking
samples from barrels obtained from a defunct
chlorofluorocarbon manufacturing plant. All three
workers were initially wearing full-face respirators and
protective clothing. However, the younger of the two
males removed his respirator early in the day. He said
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he had a hangover with nausea and felt it was easier to
work without being hampered by the respirator. The
other two workers continued in full protective gear.
After 3–4 hours, all three workers began to experience
headache, dizziness, and nausea and notified their
supervisor.
On clinical evaluation at the ED, initial routine laboratory
results were within normal limits for all three workers.
Two of the workers (the older male and female) had
resolution of their symptoms within 2 hours, had no
abnormal physical findings, and were discharged. The
third worker (younger male) did not show significant
symptom improvement at 2 hours and developed mild
ataxia and concentration deficits on mental status exam.
He was kept in the ED under close observation. You
learn from this patient that he has been in good health
with no history of similar problems. The previous
evening, in celebration of his birthday, he drank 9–12
beers, which accounts for his hangover this morning. He
also mentions that this morning, while cleaning several
wounds sustained in a fight the previous evening, he
spilled isopropyl alcohol on his hands and clothing, but
did not bother to change his clothing.
Six hours later, while still in the ED, the younger male
becomes acutely ill. He has
• Abdominal pain,
• Nausea,
• Vomiting, and
• Diarrhea.
His rectal temperature is now 101°F, pulse 140/minute,
and he has become disoriented and drowsy. Two days
after hospital admission, he still has an elevated
temperature and abnormal laboratory test results, as
follows:
• Serum creatinine — 2.0 mg/dL (normal 0.7–1.5
mg/dL);
•
AST (SGOT) — 80 U/L (normal 7–45 U/L);
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•
Total bilirubin — 2.4 mg/dL (normal 0.1–1.4
mg/dL);
• Prothrombin time (PT) — 15 seconds (normal 10–
13 seconds).
Urinalysis reveals 2+ proteinuria, and urine output has
decreased, despite intravenous hydration.
Initial Check
Questions
1.
How will you identify the material to which the
workers have been exposed?
2. You discuss the acute exposures with the workers’
company supervisor. He suspects that the waste
barrels contain carbon tetrachloride (CCl
4
) — a
chemical with a sweet odor used as a starting
material in the synthesis of chlorofluorocarbons.
The 40-year-old (older) male worker in the case
study has a full beard. He has a history of
alcoholism, but he has been abstinent for several
years. He also has a history of hepatitis B, the
result of a blood transfusion more than 10 years
ago. If the material in the barrels is CCl
4
, is this
worker at increased risk for CCl
4
's adverse health
effects?
3. The female co-worker later discovers she was
almost 6 weeks pregnant at the time of this
exposure episode. Her obstetrician calls you to
discuss the implications of the exposure to the
fetus. What is your recommendation? Explain.
4. Early that evening, the manager calls to inform you
that the company has identified the hazardous
waste as CCl
4
. Now that you know the exposure is
confirmed as CCl
4
, do you consider the younger
male worker to be at increased risk for acute health
effects? Why?
5. What is the possible clinical course for the younger
male?
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6.
What laboratory work-up is advised for patients
exposed to CCl
4
?
7. What initial action should be taken in the
emergency department for patients exposed to
CCl
4
?
8. What treatment or antidote would you consider for
the younger male worker?
9. What follow-up would you recommend for the
younger male worker and his potentially exposed
co-workers?
10. What specialized clinical resources are available for
consultation or referral of patients exposed to
hazardous substances, including CCl
4
? What actions
will the waste management company take to
comply with the Occupational Safety and Health
Administration (OSHA) Act and OSHA Hazard
Communication Standard that protect workers from
adverse health effects from exposure to hazardous
substances in the workplace?
Initial Check
Answers
1.
History of the source plant as a chlorofluorocarbon
manufacturer is suggestive of CCl
4
.
You can request a
CCl
4
safety data sheet (SDS) from the company while
awaiting their barrel sample test results. You can also
consider clinical consultation with a medical specialist
with expertise and experience evaluating and treating
patients exposed to hazardous substances, including
CCl
4.
Publicly available information on these types of
clinical consultation and referral resources are provided
under “Clinical Resources” in the “Sources of Additional
Information” section of this course.
More information for this answer can be found in
the “What Is Carbon Tetrachloride?” and “Sources
of Additional Information” sections.
2. The older male’s history of alcoholism and
hepatitis B could put him at increased risk for CCl
4
's
adverse health effects. Underlying liver damage would
13
increase the risk for acute effects and subsequent
hepatocellular carcinoma. Although he was working in
an appropriate protective suit and full-face respirator, he
still could have been exposed. For example, his beard
might have prevented proper fit of the respirator face
piece. His symptoms could also be the result of working
in a hot, enclosed space, or they could be
psychophysiological.
More information for this answer can be found in
the “Who Is at Risk for Exposure to Carbon
Tetrachloride?” section.
3. It is unclear if the female patient has been
exposed to CCl
4
. Her symptoms might be related to
“morning sickness” associated with her pregnancy.
Nevertheless, it is important that she discuss this
possible exposure with her obstetrician.
CCl
4
is lipophilic and can readily pass through the
placenta to the fetus after maternal exposure. However,
studies have not found sufficient evidence to associate
CCl
4
exposure and adverse birth outcomes in humans. In
animal studies, CCl
4
can induce embryotoxic and embryo
lethal effects, but only at doses that are toxic to the
mother.
More information for this answer can be found in
the “What Are the Toxicological Effects of Carbon
Tetrachloride Exposure?” section.
4. Because the younger male removed his respirator
and presumably breathed the solvent for a prolonged
time, he is at higher risk for acute health effects from
CCl
4
exposure. His previous ethanol intake and possibly
his recent exposure to isopropyl alcohol increase his risk
for CCl
4
-induced adverse health effects. Alcohols can
induce production of mixed function oxidase enzymes,
thereby potentiating the formation of CCl
4
toxic
intermediates and metabolites.
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More information for this answer can be found in
the “Who Is at Risk for Exposure to Carbon
Tetrachloride?” section.
5. Acute hepatic necrosis and renal impairment can
occur up to 2 weeks after a CCl
4
exposure. Other
secondary health effects can include coagulation
disorders, cardiac dysrhythmias, and pulmonary edema.
Without improvement in the kidney and liver disorders,
these effects are not likely to resolve. Because of the
patient’s multiple exposures to hepatotoxic agents (i.e.,
recent heavy consumption of ethanol and potential
occupational exposure), acute care should begin as soon
as possible as a preventive measure.
Note: Whether or not the isopropyl alcohol spilled on
the patient’s clothing will affect the patient’s medical
condition is unclear. Reports of isopropyl alcohol’s ability
to potentiate the harmful effects of CCl
4
are based on
inhalation studies in experimental animals. Significant
inhalation of isopropyl alcohol in this case is unlikely and
intact skin does not readily absorb isopropyl alcohol.
Most cases of fatal, CCl
4
-induced hepatotoxicity involve
persons with a history of heavy ethanol abuse. Although
the patient consumed ethanol the night before the
incident, he denies frequent alcohol use, which might
make it more likely that his liver is healthy.
Nevertheless, exposure to ethanol within 12 hours
before CCl
4
exposure will potentiate CCl
4
's toxicity. If
the patient survives the first 2 weeks, the prognosis is
good for complete recovery or for only mildly
compromised liver and kidney function.
More information for this answer can be found in
the “What Are the Toxicological Effects of Carbon
Tetrachloride Exposure?” section.
6. The following laboratory workup is recommended
for patients exposed to any volatile solvent (including
CCl
4
): baseline hepatic and renal function tests (i.e.,
AST [SGOT], ALT [SGPT], bilirubin, alkaline
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phosphatase, BUN, creatinine, electrolytes, urinalysis,
PT, PTT, and CBC.
Some solvents might cause dysrhythmias and
pulmonary edema (probably secondary to renal
toxicity); therefore, you should obtain a baseline
electrocardiogram and chest radiograph. To monitor the
patient’s condition, you should repeat these tests
periodically. Acutely ill patients should have their blood
oxygen levels and cardiac rhythm monitored.
You should also make sure appropriate public or
occupational health reports are filed. Some states might
require filing a doctor’s first report of illness with the
state health department. ED physicians might overlook
filing these reports.
More information for this answer can be found in
the “Clinical Assessment — Laboratory Tests”
section.
7. Initial actions include removing all contaminated
clothing (dermal absorption of some solvents is high)
and cleansing the skin with mild soap and water. Care
should be taken to prevent exposure of ED personnel to
fumes from and skin contact with contaminated clothing.
If possible, decontaminate the patient before he or she
enters the ED.
More information for this answer can be found in
the “How Should Patients Exposed to Carbon
Tetrachloride Be Treated and Managed?” section.
8. Treatment is generally supportive. Maintain an
open airway and assist ventilation if necessary. Treat
coma and arrhythmias. Avoid use of epinephrine and
other sympathomimetic amines that might worsen any
arrhythmias resulting from myocardial sympathomimetic
sensitization caused by CCl
4
. Treat tachyarrhythmias
with propranolol or esmolol.
Case reports from Europe, where antioxidants such as
N-acetylcysteine (NAC) (Mucomyst, Acetadote) are
used, suggest that when these free-radical scavengers
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are given intravenously within 12–16 hours after a high-
level acute CCl
4
exposure, they might prevent or
decrease hepatic and renal damage [De Ferreyra et al.
1974; De Ferreyra et al. 1977; Prescott et al. 1977;
Kearney 2007]. No treatments (e.g., multi-dose
activated charcoal, hemodialysis) are currently known to
enhance CCl
4
elimination. Consider consulting with a
medical toxicologist (poison center) or other medical
specialist with expertise and experience treating and
managing patients exposed to CCl
4
, and also consulting
with a gastroenterologist/hepatologist.
More information for this answer can be found in
the “How Should Patients Exposed to Carbon
Tetrachloride Be Treated and Managed?” section.
9. Immediate follow-up for the acutely ill patient
includes monitoring liver and kidney function for up to 2
weeks. You should also periodically evaluate the
patient’s cardiac and pulmonary systems and clotting
ability; abnormalities can occur secondary to hepatic
and renal damage.
You should advise all three persons (the patient and his
two coworkers) to avoid other hepatotoxic agents, such
as ethanol, drugs, solvents, and chlorinated compounds.
Both the 40-year-old male (with possible liver injury as
a result of alcoholism and hepatitis B) who was
discharged the morning after the incident and the
acutely ill 25-year-old male patient might be at
increased risk for hepatocellular carcinoma; they should
be monitored periodically. If the 25-year-old patient’s
vaccinations are not up-to-date, advise him to get the
hepatitis B vaccine. The 30-year-old female, who used
full protective gear and whose symptoms disappeared
quickly, is probably at minimal risk.
More information for this answer can be found in
the “What Instructions Should Be Given to Patients
Exposed to Carbon Tetrachloride?” section.
10. Typically, companies consult or hire health care
providers with expertise in occupational health and
safety to work with industrial hygienists and other
17
worksite health personnel to provide care and assist
with development of worker health and medical
surveillance programs required by the Occupational
Safety and Health Administration (OSHA). This includes
protocols for periodic health examinations of all
employees and confidential maintenance and storage of
employee medical records (which should contain a
complete exposure history). Under the OSHA Hazard
Communication regulation (right-to-know provisions),
safety data sheets (SDSs) for hazardous chemicals in
the workplace must be made available to the workers,
to their physician, and to a designated worker
representative. All employees using a respirator should
be fit-tested and properly trained before entering a
hazardous environment. Proper supervision is necessary
at all times. Employees who are ill should not be allowed
to remain at work, nor should employees be permitted
to work without the requisite protective gear.
More information for this answer can be found in
the “What Instructions Should Be Given to Patients
Exposed to Carbon Tetrachloride?” section.
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What Is Carbon Tetrachloride?
Learning
Objective
After completing this section, you will be able to
describe carbon tetrachloride (CCl
4
).
Definition
Carbon tetrachloride (CCl
4
) is a manufactured chemical
that does not occur naturally in the environment. Its
chemical structure is shown below:
Figure 1. Carbon tetrachloride
chemical structure
CCl
4
is a clear, nonflammable, heavy liquid that
evaporates readily, producing a sweet characteristic
odor similar to chloroform.
CCl
4
is classified as a volatile organic compound (VOC).
Properties
Although CCl
4
does not occur naturally, it is ubiquitous
as a result of industrial uses. It is a stable compound,
with a half-life of 6–12 months in water or soil and a
half-life of 30–100 years in the atmosphere.
Synonyms
Common synonyms for carbon tetrachloride include
• Carbon tet,
• Freon 10,
• Perchloromethane,
• Tetrachloromethane.
A more detailed list of synonyms is available from:
https://chem.nlm.nih.gov/chemidplus/name/carbon%20
tetrachloride%20%5Bnf%5D.
19
Production
and Usage
Historically, CCl
4
was mainly used to produce
chlorofluorocarbons (CFCs), which are used as heat
transfer agents in refrigerating equipment and as
aerosol propellants [Holbrook 1991]. In the United
States, CCl
4
was also an ingredient in many industrial
fluids, and was an effective metal degreaser. It was
found in household cleaning supplies and spot removers
for carpets, clothing, and furniture [Doherty 2000;
Odabasi 2008]. CCl
4
was also used as an antihelminthic,
a grain fumigant, and a component in fire extinguishers.
Carbon tetrachloride’s toxicity was recognized in the
early 1900s [Abbott and Miller 1948; Hardin 1954], and
most of the uses were discontinued by the mid-1960s.
The U.S. Environmental Protection Agency cancelled
CCl
4
’s use as a fumigant in 1986. In the United States,
CCl
4
use is restricted to industrial and laboratory
applications only [Seifert 1994; ATSDR 2005; NTP
2016]. It is not permitted in products intended for home
use; however, chemicals containing CCl
4
can still be
purchased online [EPA 2017].
Both the internationally ratified Montreal Protocol (which
first went into effect in 1989) and the United States
1990 Clean Air Act Amendments were instrumental in
reducing environmental concentrations of CCl
4
and other
ozone-depleting chemicals [ATSDR 2005]. By 2009, the
United States no longer regularly imported CCl
4
; only 90
pounds (41 kilograms) were imported during 1996–
2009. Likewise, U.S. production and export of CCl
4
dropped precipitously during this time [NTP 2016]. By
2009, only 26 manufacturers worldwide produced
carbon tetrachloride, including three in the United States
[NTP 2016].
Key Points
•
Most industrial CCl
4
is used in the synthesis of CFCs
and chlorinated solvents. Production of CCl
4
has
been continuously declining in response to
regulation.
• Because of CCl
4
’s
toxicity, use in consumer
products, and as a fumigant it is no longer
permitted in the United States; only industrial uses
and laboratory applications remain.
20
Progress
Check
1.
Which of the following statements regarding CCl
4
is
correct?
A. In the United States today, CCl
4
is used widely
in the home to remove spots from clothing,
furniture, and carpets.
B. In the United States today, CCl
4
is used as a
fumigant to kill insects in grain.
C. The major use of CCl
4
has been to produce
CFCs, which are used primarily as refrigerants.
D. CCl
4
has a short half-life in the air.
To review relevant content, see “Properties” and
“Production and Usage” in this section.
Where Is Carbon Tetrachloride Found?
Learning
Objective
After completing this section, you will be able to
• Identify sources of carbon tetrachloride (CCl
4
)
exposure.
Introduction
CCl
4
does not occur naturally, but has been released
into the environment by human activities. Because of
past
and present releases, CCl
4
is still found in ambient
air, water, and soil, but at very low background levels.
The U.S. public can be exposed to CCl
4
from ambient
air. CCl
4
is one of the priority pollutants regulated by
the U.S. Environmental Protection Agency (EPA) [EPA
2014].
Workers involved in the manufacture or use of CCl
4
are
more likely to have significant CCl
4
exposure than are
members of the general public.
Environmen-
tal Sources
Air Contamination
People can be exposed to small amounts of CCl
4
through ambient air. The 2001–2002 National Health
and Nutrition Examination Survey (NHANES) reported
that for the U.S. population aged 20-59 years, the
95th percentile of blood CCl
4
concentrations was 0.02
21
nanograms per milliliter (ng/mL). In the 2003–2008
survey, the 95th percentile of blood CCl
4
concentration
had fallen to less than 0.005 ng/mL [CDC 2017].
Using an analysis of 4,913 ambient air samples
reported in the National Ambient Volatile Organic
Compounds Database — including remote, rural,
suburban, urban, and source dominated sites in the
United States — the average carbon tetrachloride
concentration was 0.168 parts per billion (ppb) (1.1
µg/m³) [Shah and Heyerdahl 1988]. More recent
studies demonstrate a decrease in levels of CCl
4
(0.072-0.09 ppb) in the ambient air, which could be a
reflection of the current drop in production.
Nevertheless, the resistance to atmospheric
degradation allows for levels to remain somewhat
constant [Mohamed et al. 2002].
Concentrations in indoor air are usually higher than in
outdoor air. A review of 2,120 indoor air samples in
the late 1980s in the United States showed that the
average CCl
4
concentration was 0.4 ppb (2.6 µg/m³)
[Shah and Heyerdahl 1988]. Contemporary data
suggest that this remains true today. A sampling of
volatile organic compounds in day-care facilities in
Washington, DC, found carbon tetrachloride air
concentrations ranging from undetectable to 0.24 ppb
(1.6 µg/m³) [Quirós-Alcalá 2016]. Household cleaning
products containing bleach can produce volatile
organic compounds, including chloroform and carbon
tetrachloride [Odabasi 2008]. Use of these common
agents might, in part, explain elevated indoor CCl
4
concentrations.
Although overall ambient air concentrations are slowly
declining, some regions might still have above-average
concentrations. These include some National Priorities
List (also known as Superfund) sites [EPA 2017] and
the few industrial locations where CCl
4
is still
manufactured or used. A searchable database of
current National Priorities List sites is available at:
https://cumulis.epa.gov/supercpad/cursites/srchsites.c
fm.
22
Water and Soil Contamination
CCl
4
can contaminate water, air, and soil if it is not
properly discarded. According to the 2015 Toxic
Release Inventory,
• More than 5.9 million pounds of CCl
4
were
recycled,
• Approximately 12,600 pounds of CCl
4
were
transferred to landfills or waste management
sites, and
• Approximately 140,000 pounds of CCl
4
were
discharged into air, water, and soil.
Persons living near hazardous waste sites where CCl
4
is actively being released into the surrounding
environment could be at higher risk for exposure to
CCl
4
in soil or water supplies.
Occupation-
al Sources
Workers involved in the manufacture or use of carbon
tetrachloride are more likely to have significantly
higher exposure to CCl
4
than are other persons. CCl
4
is
currently used to manufacture some of the following
products:
• Brake cleaners,
• Electrical equipment and machinery cleaner,s
• Industrial-strength structural and plastic
adhesives,
• Perchloroethylene (also known as PERC or
tetrachloroethylene),
• Reference chemicals for laboratory applications,
and
• Synthetic rubbers [EPA 2017].
Key Points
•
Sources of environmental contamination include
industrial facilities and hazardous waste sites.
• Household cleaning products containing bleach
can produce volatile organic compounds, including
chloroform and carbon tetrachloride. Use of these
common agents might, in part, explain elevated
indoor CCl
4
concentrations.
• Workers involved in the manufacture or use of
CCl
4
are more likely to have significant CCl
4
23
exposure than are other persons.
Progress
Check
2.
Which of the following scenarios has/have the
potential to increase the risk for overexposure to
carbon tetrachloride?
A. Living in areas near hazardous waste sites
where discharges into air, water, or soil are not
properly controlled.
B. Exposure to CCl
4
contaminated indoor air.
C. Working in manufacturing plants involved in the
manufacture or use of CCl
4
.
D. All of the above.
To review relevant content, see all content in
this section.
What Are Routes of Exposure to Carbon
Tetrachloride?
Learning
Objective
After completing this section, you will be able to
• Identify the routes of exposure to carbon
tetrachloride (CCl
4
).
Introduction
Inhalation is the primary means of exposure to CCl
4
.
Rarely, people might ingest contaminated drinking water
or absorb CCl
4
through skin contact.
24
Inhalation
Inhalation is the most common route of exposure to
CCl
4
.
Exposure can occur through breathing contaminated air
• During work with CCl
4
or
• While near others who are working with CCl
4
.
CCl
4
might also be inhaled from
• Accidental spills or product use in small,
enclosed spaces,
• Landfills in which it was disposed,
• Releases to air and water by evaporation or
emissions from industrial plants, or
• Using contaminated tap water for bathing and
other household purposes.
Adolescents and others might be exposed to carbon
tetrachloride by intentionally inhaling hydrocarbons.
Ingestion
Exposure to carbon tetrachloride by ingestion can occur
through consumption of contaminated drinking water or
food.
Exposure from contaminated food is possible, but is not
likely to be of much significance, because levels of
carbon tetrachloride in most foods are below the limit of
detection [NTP 2016]. Intentional ingestions of carbon
tetrachloride in homicide or suicide attempts are beyond
the scope of this case study.
Dermal
Although CCl
4
is absorbed through the skin [Stewart and
Dodd 1964; Morgan et al. 1991], no studies to date
suggest that dermal absorption from contaminated
water, air, or soil is a significant route of human
exposure. However, direct skin exposure to a high dose
of CCl
4
can cause systemic effects (i.e., respiratory,
cardiovascular, gastrointestinal, hepatic, renal, ocular,
and dermal) in humans [ATSDR 2005; Gummin 2015].
25
Key Points
•
Inhalation of contaminated air is the most common
route of exposure to carbon tetrachloride in the
United States.
Progress
Check
3.
Which of the followings is (are) the most common
route(s) of exposure to carbon tetrachloride in the
United States?
A. Inhalation.
B. Ingestion.
C. Skin contact.
D. Inhalation and ingestion.
To review relevant content, see all content in this
section.
26
Who Is at Risk for Exposure to Carbon
Tetrachloride?
Learning
Objective
After completing this section, you will be able to
• Identify who is at risk for exposure to carbon
tetrachloride (CCl
4
).
Introduction
Exposures that occur to workers involved in the
manufacture or use of CCl
4
are potentially higher than
exposures occurring in the general U.S. population.
People living near waste sites or areas of heavy carbon
tetrachloride use might have an increased risk for
exposure from contaminated media (air, water, or soil).
Workers
Workers employed in industries that manufacture or use
CCl
4
are at greater risk for exposure to higher levels of
CCl
4
than the general U.S. population.
Workers who might be exposed to CCl
4
include:
• Air transportation workers,
• Hazardous waste workers,
• Museum workers,
• Pharmaceutical manufacturers,
• Steel mill and blast furnace workers,
• Telephone and telegraph equipment
manufacturers, and
• Workers in tin-waste recovery operations.
Other workers who no longer use CCl
4
, such as the
following, might have been exposed in the past:
• Automobile mechanics,
• Dry cleaners,
• Grain workers (inspection, storage, milling,
processing), and
• Pesticide applicators.
27
Special
Populations
Subsets of the U.S. population, such as people who live
near hazardous waste sites or facilities that use or
manufacture CCl
4
, might be exposed to localized higher
air concentrations of CCl
4
.
General
Populations
Because background levels of CCl
4
in ambient air are
low and continue to decline, the U.S. general population
is not likely to be exposed to large amounts of carbon
tetrachloride. The 2015 annual report of the American
Association of Poison Control Centers documented 52
CCl
4
exposures that had no major outcomes [AAPCC
2015].
Key Points
•
Workers using CCl
4
or CCl
4
-containing products are
potentially at risk for exposure to higher levels of
CCl
4
than the general U.S. population.
• People who live near hazardous waste sites or
facilities that use or manufacture CCl
4
, might be
exposed to localized higher air concentrations of
CCl
4
.
Progress
Check
4.
Of the following, who is at risk for CCl
4
exposure?
Select the best answer.
A. Workers using CCl
4
or CCl
4
-containing products.
B. Residents near industrial locations where CCl
4
is
used.
C. People living near chemical waste sites where
emissions to the environment might occur.
D. All of the above.
To review relevant content, see all content in this
section.
28
What Are Guidelines and Regulations for Carbon
Tetrachloride Exposure?
Learning
Objectives
After completing this section, you will be able to
• Describe current U.S. guidelines and regulations
for carbon tetrachloride (CCl
4
) exposure.
Introduction
The U.S. government has developed regulations and
guidelines for CCl
4
. These are designed to protect
workers and the U.S. public from potential adverse
health effects from CCl
4
exposure. Table 1 summarizes
the regulations and guidelines pertaining to CCl
4
.
*Note: At the time of publication of this CSEM, the listed
guidelines and regulations were up to date. Guidelines and
regulations are subject to change. For the most up-to-date
information, see the following websites:
• Occupational Safety and Health Administration (OSHA):
https://www.osha.gov/dsg/annotated-pels/tablez-
2.html
• National Institute of Occupational Safety and Health
(NIOSH):
https://www.cdc.gov/niosh/npg/npgd0107.html
• Environmental Protection Agency (EPA):
https://nepis.epa.gov
• Food and Drug Administration (FDA):
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfc
fr/CFRSearch.cfm?fr=165.110
29
Workplace
Standards
Air
The Occupational Safety and Health Administration
(OSHA) permissible exposure limit (PEL) is an 8-hour
time-weighted average (TWA) of 10 parts per million
(ppm) in workplace air. This is the highest level of CCl
4
in air to which a worker may be exposed, averaged over
an 8-hour workday for up to a 40-hour workweek.
The National Institute for Occupational Safety and
Health (NIOSH) recommends a 60-minute time-
weighted average (TWA) short-term exposure limit
(STEL) of 2 ppm [NIOSH 2005]. The NIOSH immediately
dangerous to life and health (IDLH) value for CCl
4
is 200
ppm.
The American Conference of Governmental Industrial
Hygienists (ACGIH) recommends an 8-hour TWA of 5
ppm and a 15-minute STEL of 10 ppm [ACGIH 2017].
Environmental
Standards
Air
CCl
4
is on the list of 187 hazardous air pollutants listed
in the Clean Air Act. The U.S. Environmental Protection
Agency (EPA) classifies CCl
4
as a hazardous air pollutant
[EPA 2014].
Water
The EPA maximum contaminant level (MCL) for CCl
4
in
drinking water is 5 ppb [EPA 2008].
Federal regulations have banned the use of all pesticide
products containing CCl
4
. An exception is the use of CCl
4
on encased museum specimens.
Food
The U.S. Food and Drug Administration (FDA) classifies
carbon tetrachloride as an indirect food additive for use
only as a component of adhesives. FDA also monitors
bottled water and uses a level of 5 µg/L as acceptable
for bottled water [FDA, 2017].
30
Table 1. Regulations and Guidelines for Carbon Tetrachloride
Agency
Focus
Level
Comments
American
Conference of
Governmental
Industrial
Hygienists (ACGIH)
Workplace
air
5 ppm
(31 mg/m³)
Advisory: 8-hour TLV-
TWA*
10 ppm (63
mg/m3) = 15-
minute TWA
STEL
†
; skin
absorption
notation
National Institute
for Occupational
Safety and Health
(NIOSH)
Workplace
air
2 ppm
(12.6 mg/m³)
Advisory: REL
‡
(60-
minute STEL
†
)
Occupational
Safety and Health
Administration
(OSHA)
Workplace
air
10 ppm
Regulation: PEL
§
as 8-
hour TWA;
25 ppm = acceptable
ceiling
¶
concentration;
200 ppm =
acceptable maximum
peak above the
acceptable ceiling
concentration for an 8
hour shift (max
duration = 5 minutes
in any 4 hours).
U.S. Environmental
Protection Agency
(EPA)
Drinking
water
5 ppb
(0.005 mg/L)
Regulation: current
MCL**
31
U.S. Food and Drug
Administration
(FDA)
Food:
Bottled
drinking
water
allowable
Indirect
food
additive:
adhesives
5 µg/L
Yes
Regulation
*TLV-TWA (threshold limit value–time-weighted average) — ACGIH TLVs
are listed in the order of 8-hour time-weighted averages (TWAs during a
40-hour workweek, unless otherwise indicated), short-term exposure
limits, and ceilings levels, if available. A TLV is a level to which it is
believed a worker can be exposed day-after-day for a working lifetime
without adverse health effects. These are not regulatory limits unless
OSHA adopts them as a PEL.
†
STEL (short-term exposure limit) — Unless noted otherwise, the STEL is
a 15-minute TWA maximum exposure that should not be exceeded at
any time during a workday (a single work shift) to prevent adverse
health effects.
‡
REL (recommended exposure limit) — NIOSH RELs are for up to 10-hour
TWAs during up to a 40-hour work week, unless otherwise indicated (can
also be a STEL or ceiling limit). These are not regulatory limits.
§
PEL (permissible exposure limit) — OSHA PELs are 8-hour TWAs, unless
otherwise indicated (can also be short-term exposure limits (STEL) or
ceiling limits). The PEL represents an employee's average airborne
exposure in any 8-hour work shift of a 40-hour work week, which shall
not be exceeded. OSHA enforces these limits under section 5(a)(2) of the
Occupational Safety and Health Act. The 8-hour TWA PEL is the level of
exposure established as the highest level of exposure an employee may
be exposed to without incurring the risk for adverse health effects.
¶
Ceiling limit — A ceiling limit, unless otherwise noted, is a maximum
concentration level of exposure that should not be exceeded at any time
during a workday in an effort to prevent adverse health effects.
32
**MCL (maximum contaminant level) — The highest level of a
contaminant that is allowed in drinking water.
Key Points
•
The U.S. government has developed regulations
and guidelines for CCl
4
.
Progress
Checks
5.
Which of the following statements is FALSE
regarding U.S. regulations and guidelines for CCl
4
levels?
A. Federal regulations allow continued use of
pesticide products containing CCl
4
.
B. EPA has set a maximum contaminant level for
CCl
4
in drinking water.
C. NIOSH has recommended a 60-minute exposure
limit on CCl
4
exposure at the workplace.
D. None of the above.
To review relevant content, see all content in this
section.
33
What Is the Biologic Fate of Carbon Tetrachloride in
the Body?
Learning
Objective
After completing this section, you will be able to
• Describe the characteristics of carbon tetrachloride
(CCl
4
)
metabolism.
Introduction
CCl
4
is well absorbed from the respiratory and
gastrointestinal tracts. Dermal absorption of liquid is
possible, but dermal absorption of the vapor is limited.
Absorbed CCl
4
is distributed throughout the whole body,
with highest concentrations in liver, brain, kidney,
muscle, fat, and blood.
CCl
4
is primarily metabolized in the liver, where it is
transformed by cytochrome P450 enzymes to a toxic
metabolite.
Any unchanged parent compound is eliminated primarily
in exhaled air.
Absorption
Pulmonary: Absorption from the lung was estimated to
be about 60% in humans [Lehmann and Schmidt-Kehl
1936; Astrand 1975].
Gastrointestinal: Results from several animal studies
have shown that CCl
4
is rapidly and extensively
absorbed from the gastrointestinal tract [Paul et al.
1963; Kim et al. 1990].
Dermal: Liquid CCl
4
is readily absorbed through the skin
of humans. A study showed that immersion of both
hands in liquid CCl
4
for 30 minutes would yield an
exposure equivalent to breathing 100–500 ppm for 30
minutes [Stewart and Dodd 1964].
Distribution
CCl
4
is distributed to all organs [Bergman 1983;
Paustenbach et al. 1986], and concentrates in the
• Fat,
• Liver,
• Bone marrow,
•
Adrenals,
34
•
Blood,
• Brain,
• Spinal cord, and
•
Kidney.
Metabolism
Carbon tetrachloride is metabolized primarily in the
liver.
The first step in metabolism is a phase I dehalogenation
reaction, which converts CCl
4
to the trichloromethyl
radical (•CCl
3
). This reaction is governed primarily by
the cytochrome P450 isoform CYP2E1, though additional
isoforms such as CYP3A4 can also metabolize CCl
4
when
it is present in high concentrations [Slater 1984; Slater
et al. 1985; Recknagel et al. 1989; Weber et al. 2003].
The centrilobular localization of CYP2E1 in the liver
explains the histopathological findings of CCl
4
-induced
liver damage, which will be discussed in the following
section (“What Are the Toxicological Effects of Carbon
Tetrachloride?”).
The •CCl
3
radical can have several different fates (see
Figure 2). It might
• React with intracellular molecules to cause lipid
peroxidation and other forms of oxidative damage,
• Be converted to the trichloromethyl peroxy radical,
•OOCCl
3
[Weber et al. 2003],
• Acquire a hydrogen atom to form chloroform
(CHCl
3
),
• Combine with other •CCl
3
radicals to form
hexachloroethane (Cl
3
CCCl
3
), or
• Be further metabolized to carbon dioxide (CO
2
) by
successive oxidation reactions.
35
Figure 2. Common metabolic fates of •CCl
3
.
One animal model estimates that 60% of an inhaled
dose of CCl
4
is metabolized, and the remaining 40% is
excreted unchanged. Approximately 96% of this
metabolized CCl
4
generates free radicals, as described
above; the remaining 4% is ultimately converted to CO
2
[Paustenbach et al. 1988].
Excretion
Animal studies evaluated elimination of carbon
tetrachloride following oral or inhalation exposures. In
rats receiving equivalent doses by inhalation or bolus
gavage, terminal elimination half-lives (t1/2) were about
4 hours [EPA 2010].
In humans and animals exposed to carbon tetrachloride
by any route, most of the unmetabolized parent
compound is excreted in exhaled air. Animal studies
show that volatile metabolites (such as chloroform
[CHCl
3
]) are released in exhaled air, whereas its
nonvolatile metabolites are excreted in feces and, to a
lesser degree, in urine [EPA 2010].
Key Points
•
CCl
4
is well-absorbed by inhalation, ingestion, and
dermal absorption.
• CCl
4
is metabolized primarily in the liver to the
trichloromethyl free radical (CCl
3
).
36
•
Approximately 40% of a CCl
4
dose is eliminated
unchanged in exhaled air.
Progress
Check
6.
Which of the following statements about the biologic
fate of CCl
4
is NOT correct?
A. Absorption across the lung was estimated to be
about 60% in humans.
B. Once absorbed, CCl
4
is evenly distributed to all
organs in the body.
C. Carbon tetrachloride is metabolized primarily in
the liver.
D. Most of the unmetabolized parent compound is
excreted in exhaled air.
To review relevant content, see all content in this
section.
What Are the Toxicological Effects of Carbon
Tetrachloride Exposure?
Learning
Objective
After completing this section, you will be able to
• Describe the toxicological effects associated with
carbon tetrachloride (CCl
4
)
exposure.
Introduction
The primary effects of CCl
4
in humans are on the central
nervous system (CNS), liver, and kidneys. Symptoms of
acute inhalation or ingestion of CCl
4
include
• Headache,
•
Weakness,
•
Nausea, and
•
Vomiting.
Chronic exposure to carbon tetrachloride — and
sometimes acute exposure to very high concentrations
— produces liver and kidney damage [EPA 2000].
37
Neurologic
Effects
Acute Effects
The immediate effect of acute CCl
4
exposure by all
routes is CNS depression [Laine and Riihimaki 1986].
The intensity of the effects is proportional to exposure
dose. Symptoms can include initial euphoria and
disinhibition, followed by
• Dizziness,
• Nausea and vomiting,
• Incoordination,
• Paresthesia,
• Increased salivation, and
• Tachycardia.
The symptoms are generally transient, disappearing
quickly after the exposure ends. Higher-dose exposures,
however, can lead to
• Respiratory depression (as a result of CNS
depression),
•
Seizures,
•
Coma, and
•
Death [Rom and Markowitz 2007].
In fatal cases, autopsies reveal permanent damage to
nerve cells, with focal areas of fatty degeneration and
necrosis [Stevens et al. 1953; Cohen 1957].
Chronic Effects
The CNS effects of chronic exposure are open to
question. Many of the impairments observed in workers
chronically exposed to solvents could be attributable to
other causes [Rom and Markowitz 2007], such as
• Chronic alcohol abuse,
• Other neurologic disorders, or
• Injuries.
Chronic neurologic effects can be classified as follows:
38
•
Mild — consisting mainly of affective changes and
loss of concentration,
• Moderate — with some impairment of concentration
and memory, or
• Severe — with significant loss of intellectual
functioning [WHO 1985].
Sensorimotor neuropathy and abnormalities of vision
have been reported, but epidemiological data are
insufficient to support an association between CCl
4
exposure and these effects [O'Donoghue 2000].
Hepatic
Effects
Liver damage occurs more often from swallowing liquid
CCl
4
than from inhaling CCl
4
vapor [Hathaway et al.
1991]. Direct skin exposure to high doses of CCl
4
can
also cause hepatic effects in humans [ATSDR 2010;
Gummin 2015].
Acute hepatic injury usually manifests after CNS effects
have subsided, typically 1 to 4 days after acute
exposure. Chronic hepatic injury (cirrhosis) takes longer
to develop.
The typical signs of liver injury are nonspecific and
include
• Swollen and tender liver (acute);
• Elevated levels of hepatic enzymes (e.g., AST and
ALT);
• Elevated serum bilirubin levels, with or without
jaundice;
• Decreased serum levels of proteins, such as
albumin and fibrinogen; and
• Elevated prothrombin time (PT) or international
normalized ratio (INR).
39
Acute exposure to CCl
4
causes a hepatocellular pattern
of injury, with elevated AST and ALT and primarily
centrilobular (zone 3) damage. This occurs because
CYP2E1 enzymes are concentrated in the perivenous
(zone 3) region of the hepatic acinus, and accordingly,
the highest concentrations of CCl
3
are produced in this
region first. In cases of lethal exposures, this histologic
variation in injury is lost, and pronounced diffuse
hepatic steatosis and frank liver necrosis can occur.
In the case of chronic exposure, ongoing subclinical cell
death promotes activation of stellate cells and collagen
deposition. Over time, this results in fibrosis and
cirrhosis. As hepatic synthetic function fails, a decrease
in clotting factors might predispose the patient to
hemorrhage [Zimmerman and Ishak 2002; ATSDR
2005]. Additionally, continual oxidative stress from
•CCl
3
causes DNA damage, protein malfunction, and
disrupted calcium homeostasis. These mechanisms, in
addition to increased cell death and turnover, are
thought to lead to steatosis and carcinogenesis [Palmer
and Phillips 2007].
Persons at increased risk for CCl
4
induced
hepatotoxicity
The toxic metabolites of CCl
4
are produced from
reactions catalyzed by cytochrome P450 enzymes,
particularly CYP2E1 and CPY3A4 [Zimmerman 1986;
Recknagel et al. 1989; Weber et al. 2003; Manibusan et
al. 2007]. Although no human data clearly define the
relationship between CYP2E1 or CYP3A4 activity and
CCl
4
toxicity, animal studies have shown that CYP2E1
activity is positively correlated with the degree of CCl
4
-
induced hepatotoxicity [Wong et al. 1998; Dai et al.
2014]. Thus, patients with a history of chronic, heavy
alcohol intake (which induces CYP2E1) or patients who
are on medications known to induce CYP3A4 (e.g.,
barbiturates, protease inhibitors) might be at increased
risk for free radical damage resulting from increased
bioactivation of CCl
4
.
40
Renal Effects
Nephritis and nephrosis are common following CCl
4
exposure
.
A number of derangements might appear
within hours to days after exposure:
• Proteinuria,
• Hemoglobinuria,
• Glucosuria,
• Oliguria, and/or
• Anuria.
The mechanism of nephrotoxicity is thought to be
similar to the pathophysiology of liver toxicity:
bioactivation by cytochrome P450 enzymes to the CCl
3
radical, with resulting oxidative injury [Abraham et al.
1999; Ozturk et al. 2003]. The intracellular and cell
membrane damage is seen as proximal tubule cell
edema and vacuolization, protein leakage into the
tubule lumen, glomerular necrosis, and interstitial
hemorrhage [Elmubarak 2015; Yoshioka et al. 2016;
Yoshioka et al. 2016].
Respiratory
Effects
Pulmonary effects can occur through various means of
exposure:
● Inhalation [Kirkpatrick and Sutherland 1956; Love
and Miller 1951],
● Oral [Ruprah 1985], and/or
● Parenteral [Das et al. 2014; Ferrari et al. 2012;
Zhang et al. 2014].
Signs of respiratory damage appear to be exceedingly
rare in human case reports. However, autopsies of
humans and pathological evaluations in animal studies
consistently show numerous gross and histological
findings, including:
• Pulmonary edema,
• Interstitial and alveolar hemorrhage,
• Epithelial cell damage and death,
• Alveolar infiltrates,
• Damage to pulmonary vasculature,
• Alveolar wall thickening, and
• Fibrosis [Naz et al. 2014; Taslidere et al. 2014].
41
The mechanism of pulmonary toxicity is multifactorial
and includes:
• Direct bioactivation of CCl
4
to CCl
3
and other free
radicals by cytochrome P450 enzymes in the lung
parenchyma [Boyd 1980], specifically by CYP2E1
[Gundert-Remy et al. 2014],
• Hepatopulmonary syndrome [Zhang et al. 2014],
and
• Direct and indirect oxidative stress [Das et al.
2014; Ferrari et al. 2012].
Carcinogen
-ic Effects
A number of epidemiological studies have evaluated the
association between occupational exposure to CCl
4
and
cancer risk. Evidence remains inadequate to make
definitive conclusions about the carcinogenicity of
carbon tetrachloride in humans [IARC 1999; ATSDR
2005; NTP 2016].
In animal studies [IARC 1999; Manibusan et al. 2007;
Nagano et al. 2007], CCl
4
has induced hepatocellular
carcinomas in rodents via all exposure routes. With
sufficient evidence of carcinogenicity in experimental
animals such as this, and limited evidence of
carcinogenicity in humans, various agencies have
concerns about the risks for cancer from CCl
4
exposure.
• The International Agency for Research on Cancer
[IARC 1999] has determined that CCl
4
is possibly
carcinogenic to humans (Group 2B).
• The National Institute for Occupational Safety and
Health (NIOSH) has identified CCl
4
as a potential
occupational human carcinogen [NIOSH 2005].
• The American Conference of Governmental
Industrial Hygienists (ACGIH) considers CCl
4
to be
a suspected human carcinogen [ACGIH 2016].
• The National Toxicology Program reports that CCl
4
is reasonably anticipated to be a human carcinogen
[NTP 2016].
42
Genotoxic and
Mutagenic
Effects
CCl
4
has been extensively studied for its genotoxic and
mutagenic effects, with largely negative results. When
such changes have been seen, they have generally been
related to hepatic cytotoxicity. Mutagenic effects, if they
occur, would likely be generated through indirect
mechanisms resulting from oxidative and lipid
peroxidative damage [ATSDR 2005; Manibusan et al.
2007].
Developmental
and
Reproductive
Effects
No information is available on the reproductive effects of
CCl
4
in humans. Epidemiological studies have
investigated possible associations between oral
exposure to carbon tetrachloride and various adverse
birth outcomes [Croen et al. 1997; Bove et al. 1995,
1992a, 1992b]. Because of multiple chemical exposures
and insufficient power, these studies are considered
limited and insufficient to determine whether carbon
tetrachloride exposure and adverse birth outcomes are
associated [EPA 2010]. CCl
4
can induce embryotoxic and
embryo lethal effects, but only at doses that are toxic to
the mother, as observed in the inhalation studies in rats
and mice. No adequate reproductive toxicity studies
have been conducted in animals exposed by the oral
route. Teratogenicity has not been observed in the
offspring of rats orally exposed to CCl
4
[ATSDR 2005;
WHO 1999; EPA 2010].
Cardiac Effects
Most case reports of human CCl
4
toxicity do not have
cardiovascular injury as a predominant feature.
However, volatile hydrocarbons, particularly the
halogenated hydrocarbons, are associated with cardiac
dysrhythmias and sudden sniffing death [Adgey 1995;
Williams and Cole 1998]. The mechanism is not fully
known, but is thought to involve “sensitization” of the
myocardium to the effects of catecholamines, increasing
heart rate, QT dispersion, and the rate of after-
depolarizations. A large acute exposure to CCl
4
could
possibly produce similar clinical effects.
43
Case reports have described cardiomegaly, congestive
heart failure, and cardiac fibrosis after exposure to CCl
4
.
The cardiac effects are thought to occur largely
secondary to the fluid overload caused by hepatic and
renal damage.
More recently, multiple cytochrome P450 enzymes have
been found in cardiac tissue, including the CYP 2E family
of isoenzymes [Chaudhary et al. 2009]. Though the
exact role of each CYP isoform in myocardial cells is not
yet clear, many of these appear to be involved in lipid
and drug metabolism. Rodents exposed to CCl
4
demonstrate increased markers of inflammation,
myocyte injury (troponin, CK-MB) [Al-Rasheed et al.
2014], and oxidative stress in the heart [Manna et al.
2007; Jayakumar et al. 2008]. These biochemical
changes might reflect a systemic increase in oxidative
stress caused by CCl
4
, local bioactivation of CCl
4
with
resulting myocardial damage, or both.
Other Effects
Common gastrointestinal effects of exposure to CCl
4
include
• Nausea,
• Vomiting, and
• Abdominal pain.
Prolonged or repeated contact of skin with liquid CCl
4
can cause defatting of the skin and dermatitis, with
redness and blister formation [NIOSH 1995].
Key Points
•
The immediate effect of acute CCl
4
exposure by all
routes is CNS depression.
• The NTP classified CCl
4
as “reasonably anticipated
to be a human carcinogen based on sufficient
evidence of carcinogenicity from studies in
experimental animals” [NTP 2016].
44
Progress
Checks
7.
Which of the following is considered an immediate
effect after acute exposure by all routes to CCl
4
?
A. Acute hepatitis.
B. Acute renal failure.
C. CNS depression.
D. Pulmonary fibrosis.
To review relevant content, see “Neurologic
Effects,” “Hepatic Effects,” “Renal Effects,” and
“Respiratory Effects” in this section.
8. Which of following statements on carcinogenicity of
CCl
4
is NOT CORRECT?
A. CCl
4
is a possible human carcinogen.
B. CCl
4
is a known animal carcinogen.
C. Animal studies have shown that CCl
4
induces
hepatocellular carcinomas in rodents by oral,
inhalation, and skin exposure.
D. Human studies have conclusive data on the
carcinogenic effects of CCl
4
.
To review relevant content, see “Carcinogenic
Effects” in this section.
45
Clinical Assessment – History and Physical Exam
Learning
Objectives
After completing this section, you will be able to
• Describe what is included in the initial history and
physical exam of patients potentially exposed to
carbon tetrachloride (CCl
4
).
Introduction
Symptoms and signs potentially associated with CCl
4
exposure are nonspecific making a careful medical and
exposure history essential to diagnosis.
The initial history and physical exam of patients
potentially exposed to CCl
4
can be used to
• Determine possible sources and pathways of
exposure to CCl
4,
• Detect symptoms and signs that could be
attributable to CCl
4
exposure, and
• Reveal history of any preexisting or underlying
condition(s) that might complicate the diagnostic
and clinical approach to the patient.
This information guides development of a differential
diagnosis and selection of laboratory/imaging studies,
which are discussed in the next section.
Patient History
An exposure history should be taken as part of the
patient medical history. This should cover occupational
and non-occupational CCl
4
exposure risks.
See the “Sources of Additional Information” section later
in this CSEM for links to ATSDR’s Taking an Exposure
History CSEM, Taking a Pediatric Exposure History
CSEM, and Pediatric Principles CSEM.
Additionally, a link is provided to the Exposure History
Form, which is available for download in a "fillable" PDF
form that can be printed and saved:
Exposure History Form [PDF - 455 KB).
Environmental Exposure History
46
An environmental exposure history (non-occupational)
for CCl
4
can be used to obtain the following information:
• Type of water supply,
• Location and duration of residence,
• Proximity to industry or National Priorities List
(NPL) sites or both,
• The patient’s hobbies, and
• History of exposure to other known hepatotoxic
agents (e.g., medications and alcohol) .
Occupational Exposure History
The patient’s occupational history is crucial. The
information on the current occupation would be most
valuable, especially in cases of acute toxicity. For each
job held, the exposure history should include:
• Name and location of the company,
• Job title,
• Description of chemical processes used,
• Known toxic agents,
• History of worker illness,
• Enclosure of solvent-related processes,
• Use of hood or other ventilation, and
• Proper use of personal protective equipment (PPE).
Information on the specific constituents of the solvent-
containing materials and other potentially hazardous
substances used should be collected. This might
necessitate requests for Safety Data Sheets (SDSs)
from employers, suppliers, or manufacturers. Use and
type of personal protective equipment should be
determined. The occupational history should also include
the patient’s general assessment of the hygienic
conditions of the work setting, including the availability
of separate washing, changing, and eating facilities.
Information about potential exposure(s) from the
activities of coworkers should also be gathered from the
patient.
Medical History
47
Medical history and a review of systems should include
assessments of current and past diagnoses or symptoms
of
• Neurologic,
•
Hepatic,
•
Renal, and
•
Dermatologic disease.
It is important not to overlook the association between
solvent exposure and conditions such as
• Glomerulonephritis,
• Contact dermatitis,
• Cognitive impairment, and
• Peripheral neuropathy [Rom and Markowitz 2007].
Patient’s alcohol use should also be evaluated.
The patient's complaints should be identified in terms of
• Onset,
• Duration,
• Frequency and
• Intensity.
Symptoms that vary in time with exposure are a
function of the anesthetic property of organic solvents.
Specially, dizziness, light-headedness, impaired
concentration, and headaches that have a temporal
relationship to solvent exposure are likely the result of
acute CNS effects [Meredith et al. 1989; Rom and
Markowitz 2007]. These symptoms are likely to resolve
quickly after removal from the contaminated
environment into a fresh air environment and might
significantly improve or resolve by the time the patient
is evaluated at a health care facility.
Physical
Examination
After an acute exposure, the initial physical examination
should concentrate on the neurologic system. Within 1
to 6 days after an acute exposure, the patient might
develop severe hepatic necrosis and renal failure, which
48
can affect the cardiovascular and pulmonary systems.
When performing the physical exam, emphasis should
be placed on major organ systems likely affected by
exposure to CCl
4
(e.g., CNS, gastrointestinal, dermal,
and hepatic). Note that lack of clinical findings on initial
exam does not exclude potential carbon tetrachloride
toxicity. The patient might show subclinical, delayed, or
individual variability in the initial presentation.
Vital signs should be recorded, especially noting any
abnormalities of heart rate or rhythm. Head, eyes, ears,
nose, and throat should be examined noting any
inflammation or irritation. The skin should be inspected,
especially the hands, for signs of
• Redness,
• Drying,
• Cracking, or
• Fissuring.
Also check for signs of jaundice.
Chest examination should include assessment of the
heart and lungs.
Abdominal exam should include palpation for liver and
spleen size (i.e., hepatomegaly, hepatosplenomegaly,
etc.) and tenderness.
A mental status examination should be conducted to
evaluate
• Alertness,
• Orientation,
• Cognition, and
• Short-term memory.
Peripheral nerve function should be evaluated by
assessing
• Proprioception,
•
Deep tendon reflexes,
•
Motor strength,
49
•
Postural stability (Romberg test), and
• Cutaneous sensibility to vibration, light touch, and
pin prick (which should always be included in the
evaluation).
Key Points
•
The occupational and environmental exposure
history is essential to diagnosing CCl
4
toxicity.
• The physical examination should focus on major
organ systems likely affected by exposure to CCl
4
(e.g., CNS, gastrointestinal, dermal, and hepatic).
Progress
Checks
9.
Which of the following is true regarding goals of the
initial history and physical exam of patients
potentially exposed to CCl
4
?
A. To determine possible sources and pathways of
exposure to CCl
4.
B. To detect symptoms and signs that might be
attributable to CCl
4
exposure.
C. To obtain a history of any preexisting or
underlying condition that might complicate the
diagnostic and clinical approach to the patient.
D. All of the above.
To review relevant content, see “Patient History”
and “Physical Examination” in this section.
10. In general, patients over-exposed to CCl
4
by any
route PREDOMINANTLY exhibit which of the
following manifestations?
A. CNS depression.
B. Hepatomegaly.
C. Pulmonary edema.
D. Nephritis.
To review relevant content, see “Possible Signs and
Symptoms of CCl4 Toxicity” in this section.
50
Clinical Assessment — Laboratory Tests
Learning
Objective
After completing this section, you will be able to
• Describe tests that may assist with diagnosis of
carbon tetrachloride (CCl
4
) toxicity.
Introduction
The laboratory evaluation for patients exposed to CCl
4
should be guided by a careful, thorough history and
physical exam. Indiscriminate testing for all exposures is
not warranted.
Direct Biologic
Indicators
According to the results of the National Health and
Nutrition Examination Survey (NHANES), the 95th
percentile of blood CCl
4
concentrations was less than
0.005 ng/mL in the 2003–2008 survey years for the
U.S. population aged 20–59 years [CDC 2017]. These
concentrations reflect the known background exposure
of the U.S. population.
While it is technically possible to measure CCl
4
in blood
and exhaled air, these tests are not routinely
recommended and are very rarely done due to practical
and clinical limitations. Interpretation of CCl
4
concentrations is not straightforward. No human data
explicitly associate specific organ damage with a given
CCl
4
concentration in blood. The clinical response to a
given exposure can also vary substantially from person-
to-person. Thus, a patient’s quantitative CCl
4
result
cannot be correlated with clinical symptoms. Unless
needed to confirm recent, excessive exposure,
quantitative testing of CCl
4
in biological samples is not
indicated because the results do not guide clinical
management. If you are concerned that your patient
needs such testing, referral to specialty providers in
occupational medicine, medical toxicology, or
environmental medicine is indicated.
51
Indirect
Biologic
Indicators
Testing for end-organ damage may be considered for
patients who provide a history of potential above-
background CCl
4
exposures.
Hepatic damage may be assessed with the following
studies:
• Alanine aminotransferase (ALT [SGPT]),
• Aspartate aminotransferase (AST [SGOT]),
• Alkaline phosphatase,
• Serum albumin and total protein,
• Prothrombin time (PT) and/or international
normalized ratio (INR), and
• Partial thromboplastin time (PTT).
Imaging studies, such as ultrasound or computed
tomography (CT) scan, may also be considered.
Renal damage may be assessed with the following
studies:
• Blood urea nitrogen (BUN) and serum creatinine
(Cr),
• Chemistry panel to check electrolytes,
• Urinalysis (to assess for the presence of protein,
blood, casts, or other findings suggestive of tubular
or glomerular damage), and
• Complete blood count (CBC) to evaluate for
anemia.
Imaging studies, such as renal ultrasound or CT scan,
may also be considered.
Respiratory symptoms may be assessed as follows:
• Obtain a chest radiograph to evaluate for
pulmonary edema,
• Institute continuous cardiac and respiratory
monitoring with continuous pulse oximetry, and
• Consider arterial or venous blood gas analysis as
warranted by patient’s clinical condition.
52
An electrocardiogram (ECG) should be obtained for any
patient with acute CCl
4
exposure.
It is critical to consider the role of confounding medical
problems (e.g., diabetes mellitus, hypertension,
structural or ischemic heart disease) and other
exposures (e.g., alcohol, hepatotoxic medications) when
interpreting these results.
Key Points
•
Laboratory results need to be interpreted
carefully within the context of other pertinent
clinical information.
Progress
Check
11.
The following statements about laboratory tests are
all correct EXCEPT:
A. The laboratory evaluation for patients exposed
to CCl
4
should be guided by a careful, thorough
history and physical exam.
B. A patient’s quantitative CCl
4
result is correlated
with clinical symptoms.
C. Testing for end-organ damage may be
considered for patients who provide a history of
potential above-background CCl
4
exposures.
D. It is critical to consider the role of confounding
medical problems and other exposures when
interpreting nonspecific laboratory results.
To review relevant content, see all content in this
section.
53
How Should Patients Exposed to Carbon
Tetrachloride Be Treated and Managed?
Learning
Objective
After completing this section, you will be able to
• Describe treatment strategies for patients with
carbon tetrachloride (CCl
4
) poisoning.
Introduction
Treatment for acute or chronic CCl
4
poisoning is
primarily symptomatic and supportive.
Acute
Exposure
Because liquid CCl
4
can be absorbed through the skin,
remove clothing from persons exposed through this
route and clean the skin with copious amounts of soap
(or mild detergent) and water. If liquid CCl
4
is splashed
in the eyes, irrigate the eyes for at least 15 minutes.
For patients who have ingested CCl
4
, the practical value
of gastric lavage and administration of activated
charcoal is doubtful as absorption from a gastro-
intestinal exposure is likely to be nearly complete by the
time the patient reaches appropriate medical care.
Patients with significant exposure might be clinically
unstable and gastric lavage and/or activated charcoal
might place the patient at increased risk for
complications such as aspiration and chemical
pneumonitis.
Induced emesis is contraindicated because of the risk for
pulmonary aspiration.
Human case reports from Europe, where antioxidants
such as
• Methionine,
• Cysteine, and
• N-acetylcysteine (NAC, Mucomyst, or Acetadote)
were used, suggest that when these free-radical
scavengers are given intravenously within 12 to 16
hours after a high-dose acute CCl
4
exposure, they might
prevent or decrease hepatic and renal damage [De
54
Ferreyra et al. 1974; De Ferreyra et al. 1977; Prescott
et al. 1977; Kearney 2007].
Elevated oxygen concentrations in vitro and in vivo
reduce lipid peroxidation and hepatotoxicity. Hyperbaric
oxygen (HBO) has been found to play a therapeutic role
in human and animal CCl
4
poisoning [Larcan et al. 1973;
Truss et al. 1982; Burk et al. 1986; Burkhart et al.
1991]. HBO appears to inhibit the mixed function
oxidase system responsible for conversion of CCl
4
to
hepatotoxic free radicals. Because there are no proven
antidotes for CCl
4
poisoning, HBO may be considered for
potentially severe CCl
4
exposures. However, there might
be a delicate balance between oxidative processes that
are therapeutic and those that mediate hepatotoxicity.
Therefore, when HBO is being considered, it should be
instituted before the onset of liver function abnormalities
[Thom 2006].
Hemodialysis has been used to treat renal failure, but it
has not been proven successful in reversing CCl
4
pathology [Meredith 1989; Ruprah 1985].
Patients should be observed for onset of hepatic and
renal effects for up to 2 weeks after exposure. To a
large extent, survival depends on the patient’s
nutritional status and the underlying condition of the
hepatorenal system.
55
Chronic
Exposure
Other than removal from the source of exposure and
avoidance of other hepatotoxins, there is no specific
treatment for patients chronically exposed to CCl
4
. The
exposure dose along with individual risk factors will
contribute to the likelihood of lasting adverse health
effects from CCl
4
exposure.
Exposed patients should be instructed to avoid
• Stimulants,
• Ethanol,
• CCl
4
and
• Other hepatotoxicants.
Administration of the hepatitis B vaccine should be
considered for unvaccinated persons.
Patients with complaints of persistent mood alteration or
cognitive dysfunction, including memory loss, should be
referred to a clinical neuropsychologist for evaluation.
Those with persistent neurologic complaints, such as
• Numbness,
• Tingling,
• Weakness, or
• Pain,
should be referred for neurologic consultation or
electrophysiologic evaluation of peripheral nerve
function.
Exposure
Intervention
Evaluation of an exposed worker provides an
opportunity to reduce exposures and prevent additional
health effects for the patient and his or her coworkers.
When the results of a clinical evaluation suggest that
significant exposure is occurring, the clinician should
explore with the worker and the employer avenues of
exposure reduction and prevention.
56
Clinical
Consultation
Clinical consultation and referral information can be
found in the “Sources of Additional Information” section.
This publicly available information pertains to
credentialed clinicians with expertise and experience
treating patients exposed to hazardous substances
including carbon tetrachloride.
Key Points
•
N-acetylcysteine might reduce complications in
patients with severe CCl
4
exposure.
• Hyperbaric oxygen treatment has been used as a
therapeutic intervention for acute CCl
4
poisoning.
• Other than removal from the source of exposure
and avoidance of other hepatotoxins, there is no
specific treatment for patients chronically exposed
to CCl
4
.
• The exposure dose, along with individual risk
factors, will contribute to the likelihood of lasting
adverse health effects from CCl
4
exposure.
Progress
Check
12.
Strategies for managing patients with acute CCl
4
poisoning may include which of the following?
A. Reduction or elimination of exposure.
B. Supportive measures.
C. Use of antioxidants (such as methionine,
cysteine, and N-acetylcysteine) and hyperbaric
oxygen intervention.
D. All of the above.
To review relevant content, see all content in this
section.
57
What Instructions Should Be Given to Patients
Exposed to Carbon Tetrachloride?
Learning
Objective
After completing this section, you will be able to
• Describe instructions that can be provided to
patients exposed to carbon tetrachloride (CCl
4
).
Introduction
Patients over-exposed to CCl
4
need basic guidance on
• Self-care, so they can minimize further risks and
avoid complications to the extent possible, and
• Potential health effects including symptoms and
signs from exposure to carbon tetrachloride, so
they understand when and why to return for
further medical attention.
ATSDR has developed a patient education and care
instruction sheet on CCl
4
. It can be found at
http://www.atsdr.cdc.gov/csem/carbon_tetrachloride/do
cs/Carbon_Tetra_Patient_Ed_Sheet-508
Self-care
Patients should be advised to avoid exposures or
conditions that might further increase their risk for
disease or worsen any existing condition.
At work
Employers are required to provide labeling, SDSs
(formerly called material safety data sheets [MSDSs]),
and training as part of the OSHA Hazard Communication
Standard. Patients should be encouraged to protect
themselves in the following ways.
• Use recommended personal protective equipment
(PPE) such as gloves, goggles, masks, respirators,
and other body protection specific to the type of
work they do with CCl
4.
• Refer to employer provided SDSs (formerly called
MSDS) on products used at work.
• Follow safe workplace practices, including labeling
all containers for chemical(s) used at work.
58
•
Be attentive during employer provided training on
how to safely use chemicals at work.
At home
Patients should be encouraged to take steps such as the
following to protect against the effects of CCl
4
exposure.
• Check labels of imported consumer products for
CCl
4.
• Use safer alternatives to products with CCl
4.
• If they must handle CCl
4
, check with the health
department or poison control center for instructions
and recommendations regarding respirators,
gloves, and other necessary personal protective
equipment.
• Avoid alcohol if exposure occurs.
• Discard any products that contain carbon
tetrachloride at home, including products that may
have been used in the past. Contact the local
health department or poison center for instructions
on disposal of these toxic substances.
• Store household chemicals out of the reach of
children and in their original containers.
• Get well water tested if they live near an area
contaminated with CCl
4
.
Clinical
Follow-up
Because CCl
4
is reasonably anticipated to be a human
carcinogen, according to the National Toxicology
Program of the U.S. Department of Health and Human
Services [NTP 2016], periodic clinical assessments might
be of value in detecting abnormalities at an early stage.
Advise patients to consult their physician if they develop
any signs or symptoms of central nervous system (CNS)
or other health changes, including those possibly related
to the heart, liver, and kidney.
ATSDR’s patient education and care instruction sheet on
CCl
4
poisoning can be used as a job aid for patient
education and follow-up care.
59
Key Points
•
Patients should be advised to avoid exposures and
circumstances that might further increase their risk
for adverse health effects from exposure to CCl
4
or
worsen an existing health condition.
• Advise patients to consult their physician if they
develop any signs or symptoms of CNS or other
health changes, including those possibly related to
the heart, liver, and kidney.
Progress
Check
13.
Patients who have confirmed exposure to CCl
4
should
A. Verify the source of exposure (if possible).
B. Learn how to avoid further exposure.
C. Know when to call their doctor.
D. All of the above.
To review relevant content, see all content in this
section.
Sources of Additional Information
Introduction
Refer to the following resources for more information on
the adverse effects of carbon tetrachloride, the
treatment of carbon tetrachloride-associated diseases,
and the management of persons exposed to carbon
tetrachloride.
Carbon
Tetrachloride
Specific
Information
•
Agency for Toxic Substances and Disease Registry
https://www.atsdr.cdc.gov
o For chemical, emergency situations
CDC Emergency Response: 770-488-
7100 and request the ATSDR Duty
Officer
For chemical, nonemergency situations
CDC-INFO https://www.cdc.gov/cdc-info/
(800-232-4636) TTY 888-232-6348 - 24
Hours/Day
60
Email: cdcinfo@cdc.gov
NOTE: ATSDR cannot respond to questions
about individual medical cases, provide
second opinions, or make specific
recommendations regarding therapy.
Address those issues with your health care
provider directly or with a medical
consultant who has clinical experience
treating patients with CCl
4
exposure and
toxicity.
o Toxicological Profile for Carbon Tetrachloride
https://www.atsdr.cdc.gov/toxprofiles/tp.asp?id
=196&tid=35
o TOXFAQs for Carbon Tetrachloride (English)
https://www.atsdr.cdc.gov/toxfaqs/tf.asp?id=19
5&tid=35
• NIOSH Pocket Guide to Chemical Hazards —
Carbon Tetrachloride
https://www.cdc.gov/niosh/npg/npgd0107.html
• EPA Technology Transfer Network Air Pollutants
Website — Carbon Tetrachloride -
https://www.epa.gov/technical-air-pollution-
resources
• Safety Data Sheet (SDS) online
http://www.ilpi.com/msds/
• TOXNET https://toxnet.nlm.nih.gov/
Clinical
Resources
•
American College of Occupational and
Environmental Medicine (ACOEM)
http://www.acoem.org/
o ACOEM is the nation's largest medical society
dedicated to promoting the health of workers
through preventive medicine, clinical care,
research, and education.
o ACOEM members include physicians in a variety
of medical practices who are united via the
college to develop positions and policies on vital
issues relevant to the practice of preventive
medicine within and outside the workplace.
61
•
American College of Medical Toxicologists (ACMT)
http://www.acmt.net
o ACMT is a professional, nonprofit association of
physicians with recognized expertise in medical
toxicology.
o The college is dedicated to advancing the
science and practice of medical toxicology
through a variety of activities.
• Association of Occupational and Environmental
Clinics http://www.aoec.org
o The Association of Occupational and
Environmental Clinics (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.
o Pediatric Environmental Health Specialty Units
(PEHSUs) http:www.pehsu.net
PEHSUs form a respected network of experts
in children's environmental health.
The PEHSUs were created to ensure that
children and communities have access to,
usually at no cost, special medical knowledge
and resources for children faced with a health
risk due to a natural or human-made
environmental hazard.
Located throughout the United States,
Canada, and Mexico, PEHSU professionals
provide quality medical consultation for
health professionals, parents, caregivers, and
patients. The PEHSUs are also dedicated to
increasing environmental medicine knowledge
among health care professionals around
children’s environmental health by providing
consultation and training.
• Poison Control Center
62
o
Contact the American Association of Poison
Control Centers for questions about poisons and
poisonings. The website provides information
about poison centers and poison prevention.
AAPC does not provide information about
treatment or diagnosis of poisoning or research
information for student papers.
o American Association of Poison Control Centers
(1-800-222-1222 or http://www.aapcc.org
General
Environmental
Health
Information
Please refer to the following Web resources for general
information on environmental health.
• Agency for Toxic Substances and Disease Registry
https://www.atsdr.cdc.gov
o To view the complete library of Case Studies in
Environmental Medicine series (CSEMs)
https://www.atsdr.cdc.gov/csem/
o Taking an Exposure History CSEM
https://www.atsdr.cdc.gov/csem/csem.asp?cse
m=33&po=0
The Exposure History Form is available for
download in a "fillable" PDF format form that
can be printed and saved
Exposure History Form [PDF - 455 KB
• Centers for Disease Control and Prevention (CDC)
https://www.cdc.gov
o CDC works to protect public health and the
safety of people, by providing information to
enhance health decisions, and promotes health
through partnerships with state health
departments and other organizations.
o The 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.
63
•
National Center for Environmental Health (NCEH)
https://www.cdc.gov/nceh/
o NCEH works to prevent illness, disability, and
death from interactions between people and the
environment. NCEH is especially committed to
safeguarding the health of populations
particularly vulnerable to certain environmental
hazards: children, the elderly, and people with
disabilities.
o NCEH works to achieve its mission through
science, service, and leadership.
• National Institutes of Health (NIH)
http://www.nih.gov
o 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) https://www.cdc.gov/niosh/
o NIOSH is in the U.S. Department of Health and
Human Services. NIOSH provides research,
information, education, and training in the field
of occupational safety and health to help assure
safe and healthful working conditions for
working men and women.
Posttest
Posttest
For each question, select the one best choice
1. Which of the following statements about carbon
tetrachloride (CCl
4
) is INCORRECT?
A. CCl
4
is a manufactured chemical.
B. Its chemical instability results in an atmospheric
half-life of 24–48 hours.
64
C.
CCl
4
is a clear, nonflammable, heavy liquid
producing an odor similar to chloroform.
D. Because of CCl
4
’s toxicity, consumer uses of this
chemical have been discontinued in the United
States.
To review relevant content, please see “What is
Carbon Tetrachloride?”
2. All of the following statements about exposure
sources are correct EXCEPT:
A. U.S. public can be exposed to small amounts of
CCl
4
through ambient air.
B. Across the U.S., overall ambient air
concentrations are slowly declining.
C. Household cleaning products containing bleach
can produce volatile organic compounds,
including chloroform and carbon tetrachloride.
Use of these common agents might, in part,
explain elevated indoor CCl
4
concentrations.
D. It is not permitted in products intended for
home use; however, chemicals containing CCl
4
can still be purchased online.
To review relevant content, please see “Where is
Carbon Tetrachloride Found?”
3. Today, the U.S. general public is most commonly
exposed to CCl
4
through
A. Use of consumer products that contain CCl
4.
B. Ingestion of contaminated food.
C. CCl
4
-contaminated ambient air and drinking
water.
D. All of the above.
To review relevant content, please see “What Are
Routes of Exposure to Carbon Tetrachloride?”
4. Of the following occupations in the United States
today, which is most likely to be at increased risk
for exposure to CCl
4
?
65
A.
Pesticide applicators.
B. Dry cleaners.
C. Hazardous waste workers.
D. All of the above.
To review relevant content, please see “Who is at
Risk for Exposure to Carbon Tetrachloride?”
5. Which of the following statements about CCl
4
is
NOT TRUE?
A. Most inhaled CCl
4
is excreted unchanged in the
urine.
B. Metabolism of CCl
4
is required for toxicity.
C. The •CCl
3
radical is the key metabolite
responsible for ultimate plasma membrane
disruption and death of the cell.
D. Alcoholic patients are far more susceptible to
hepatotoxic effects of CCl
4
than are others.
To review relevant content, please see “What is the
Biologic Fate of Carbon Tetrachloride in the Body?”
6. All of the following statements are true EXCEPT
A. Liquid CCl
4
is not easily absorbed through the
human skin.
B. Metabolism of CCl
4
is required for toxicity.
C. Mixed function oxidase inducers can increase the
toxicity of CCl
4
.
D. Unmetabolized CCl4 is eliminated primarily in
exhaled air.
To review relevant content, please see “What is the
Biologic Fate of Carbon Tetrachloride in the Body?”
7. Which of the following statements regarding U.S.
guidelines and regulations for CCl
4
is FALSE?
A. EPA classifies CCl
4
as a hazardous air pollutant.
B. NIOSH has determined an air level of CCl
4
that
might be immediately dangerous to life and
health.
66
C.
Use of pesticide products containing CCl
4
is a
major source of exposure in the general public
in the United States today.
D. EPA has set a maximum contaminant level for
CCl
4
in drinking water.
To review relevant content, please see “What are
Guidelines and Regulations for Carbon
Tetrachloride Exposure?”
8. Which of the following statements regarding signs
and symptoms in patients exposed to a high dose
of CCl
4
is INCORRECT?
A. They will likely exhibit CNS and gastrointestinal
effects.
B. Symptoms that persist beyond 24 hours are
most likely psychophysiologic in nature.
C. Patients with acute and chronic exposures might
exhibit some of the same symptoms.
D. Hepatic and renal injury might manifest in 48
hours.
To review relevant content, please see “What are
the Toxicological Effects of Carbon Tetrachloride
Exposure?”
9. In general, patients over-exposed to CCl
4
by any
route PREDOMINANTLY exhibit which of the
following symptoms?
A. Hepatomegaly.
B. CNS depression.
C. Nephritis.
D. Pulmonary edema.
To review relevant content, please see “Clinical
Assessment – History and Physical Exam.”
10. Which of the following is a direct biomarker of
exposure to carbon tetrachloride?
A. Kidney function tests.
B.
Blood CCl
4
67
C.
Liver function tests.
D. None of the above.
To review relevant content, please see “Clinical
Assessment — Laboratory Tests.”
11. Treatment for a patient with acute exposure to CCl
4
might include all of the following EXCEPT
A. Administration of a free-radical scavenger such
as N-acetylcysteine.
B. Hyperbaric oxygen therapy.
C. Irrigation of eyes and skin.
D. Induced emesis for patients who have ingested
CCl
4.
To review relevant content, please see “How
Should Patients Exposed to Carbon Tetrachloride
be Treated and Managed?”
12. Patients should be advised on ways to avoid CCl
4
exposure and educated about possible health
effects from exposure to CCl
4.
Which of the
following should be discussed with a patient
exposed to CCl
4
?
A. The use of safer alternatives to products with
CCl
4
.
B. The use of CCl
4
-appropriate personal protective
equipment (PPE), such as gloves, goggles, and
respiratory protection.
C. Increased area air ventilation when using
products containing CCl
4
.
D. All of the above.
To review relevant content, please see “What
Instructions Should be Given to Patients Exposed
to Carbon Tetrachloride?”
68
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