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Makalah tugas mata kuliah Kegiatan Ilmiah I
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UNIVERSITY OF INDONESIA
NAPHTHALENE EXPOSURE TOXICITY AND
OCCUPATIONAL SCREENING TESTS
SCIENTIFIC WORK
David Rudy Wibowo, dr
1006826036
MEDICAL FACULTY
OCCUPATIONAL MEDICINE SPECIALIST EDUCATION PROGRAM
JAKARTA
MARCH 2012
ii
ACKNOWLEDGEMENTS
First of all, I as the author would like to express praise and thanksgiving to Almighty
God, for blessing and mercy because of work papers for Scientific Activities Courses
can be resolved properly.
Task of this paper is made in order to meet the criteria for graduation in the course of
Scientific Activities in the Occupational Medicine Specialist Education Program at
the Faculty of Medicine, University of Indonesia.
I would also like to thank the lecturer of Scientific Activities Subject, especially to
Dr. dr. Astrid W. Sulistomo, MPH, SpOk. which gives a lot of input and guidance in
order to accomplish this paper.
Finally, this paper may bring benefits to those who read and study it.
Jakarta, March 2012
David R. Wibowo
(author)
iii
TABLE OF CONTENTS
CHAPTER I: INTRODUCTION .................................................................................. 1
I.1 Background ................................................................................................................................................ 1
I.2 Problem Statement .................................................................................................................................. 1
I.3 Objective ...................................................................................................................................................... 1
I.4 Method ......................................................................................................................................................... 2
CHAPTER II: LITERATURE REVIEW .......................................................................... 3
II.1 Chemical and physical property of naphthalene .......................................................................... 3
II.2 Naphthalene productions ..................................................................................................................... 2
II.3 Naphthalene uses ..................................................................................................................................... 3
II.3.1 As a chemical intermediate ...................................................................................................... 3
II.3.2 Wetting agent/surfactant ......................................................................................................... 4
II.3.3 As a fumigant ................................................................................................................................. 4
II.3.4 Other applications ....................................................................................................................... 4
II.4 Naphthalene as an environmental pollutant ................................................................................. 4
II.5 Occupational exposure of naphthalene ........................................................................................... 5
II.6 Naphthalene toxicokinetics .................................................................................................................. 6
II.6.1 Absorption...................................................................................................................................... 7
II.6.2 Distribution ................................................................................................................................... 7
II.6.3 Metabolism..................................................................................................................................... 8
II.7 Health effects of naphthalene .............................................................................................................. 9
II.7.1 Acute poisoning effects .............................................................................................................. 9
II.7.2 Chronic effects ............................................................................................................................ 10
II.7.2.1 Dermal effects.............................................................................................................. 11
II.7.2.2 Hematologic effects ................................................................................................... 11
II.7.2.3 Ocular effects ............................................................................................................... 12
II.7.2.4 Carcinogenic effects .................................................................................................. 12
II.8 Diagnosis of naphthalene intoxication .......................................................................................... 13
II.8.1 Blood sample collection .......................................................................................................... 13
II.9 Recommended medical surveillance .............................................................................................. 14
II.10 Biomarkers for naphthalene exposure ....................................................................................... 15
II.11 Ambient monitoring of naphthalene ........................................................................................... 18
II.12 Journal Reviews ................................................................................................................................... 18
II.12.1 Research No.1 ....................................................................................................................... 19
II.12.2 Research No.2 ....................................................................................................................... 20
II.12.3 Research No.3 ....................................................................................................................... 21
II.12.4 Research No.4 ....................................................................................................................... 22
II.12.5 Research No.5 ....................................................................................................................... 23
CHAPTER III: DISCUSSION .................................................................................... 25
CHAPTER IV: CONCLUSIONS AND RECOMMENDATIONS ...................................... 29
IV.1 Conclusions ........................................................................................................................................... 29
IV.2 Recommendations .............................................................................................................................. 30
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CHAPTER I
INTRODUCTION
I.1 Background
Naphthalene is best known as the main ingredient of traditional mothballs. It is one of
the most abundant polycyclic aromatic hydrocarbons (PAHs) found in polluted urban
environments, which are ubiquitous environmental contaminants arising from various
sources, mainly attributable to processes of incomplete combustion or pyrolysis of
organic material (fire fumes, exhaust gases from engines, incinerator fumes, tobacco
smoke, charcoal grilled food, etc). The highest work-related exposure levels are found
at workplaces where PAH-rich materials such as coke, coal tar, pitch, creosote, or
heavy oils are handled. Naphthalene, phenanthrene, and pyrene are dominant
constituents in PAH mixtures.
I.2 Problem Statement
Previous studies have shown that naphthalene can be absorbed by pulmonary,
gastrointestinal, and cutaneous routes. In animals naphthalene has been shown to
affect hematologic parameters or cause histopathological lesions of the
liver,carcinogenicity in female mice, and cataractogenicity. (1)
Exposure to high
concentrations of naphthalene may have adverse health effects, possibly causing
cancer in humans. Nevertheless, until now there is no provision governing the
implementation of periodic medical examinations on workers exposed to naphthalene
in the workplace.
I.3 Objective
The objectives of this paper are:
• To explain about the health effect of naphthalene exposure
• To establish the potential and the most relevant biomarker for occupational
naphthalene exposure.
• To provide best practice recommendations on medical examinations for workers
exposed to naphthalene
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I.4 Method
For the literature sources, the scientific literature dealing with sources, exposure
measurements, and biomonitoring of occupational naphthalene exposure was
searched. Various online databases were used, and thorough search was conducted
using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), Google Scholar
(scholar.google.com) and ProQuest (search.proquest.com). Numerous free-for-
download articles were obtained and selected, including peer reviewed journal,
dissertations, and theses which are available online as cited on the bibliography at the
end of this paper, but only the full articles were used for the journal review. Online
articles and publications from NIOSH, OSHA, ACGIH, IARC, NTP, and ATSDR
regarding naphthalene exposure, toxicity, and biomonitoring properties were also
reviewed. E-books and other internet resources, as well as the references cited in the
bibliography also take part on the review of naphthalene exposure.
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II.1 Chemical and physical
Napththalene is an organic compound with formula
polycyclic aromatic hydrocarbon
crystalline solid with a characteristic odor that is detectable a
as 0.08 ppm by mass. As an aromatic hydrocarbon, naphthalene's structure consists of
a fused pair of benzene
polycyclic aromatic hydrocarbon (PAH).
Figure 1. Naphthalene balls
Table 1. Naphthalene essential
Nomenclature
Chem. Abstr. Serv. Reg. (CAS) No.
Chem. Abstr. Name
IUPAC Systematic Name
Synonyms
Structural and molecular formulae and relative molecular mass
Molecular formula
Relative molecular mass
Physical data
Description
Boiling-point
Melting-point
Flash point
Solubility
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CHAPTER II
LITERATURE REVIEW
and physical property of naphthalene
is an organic compound with formula C10H8, and
polycyclic aromatic hydrocarbon (PAH). In purified form, naphthalene is
crystalline solid with a characteristic odor that is detectable at concentrations as low
ppm by mass. As an aromatic hydrocarbon, naphthalene's structure consists of
rings. As such, naphthalene is classified as a be
polycyclic aromatic hydrocarbon (PAH).
. Naphthalene balls
essential data (1,2)
erv. Reg. (CAS) No. 91-20-3
Naphthalene
IUPAC Systematic Name Naphthalene
Naphthalin; naphthene; tar camphor; white tar
Structural and molecular formulae and relative molecular mass
C10H8
ecular mass 128.17 g mol−1
White monoclinic prismatic plates
217.9 °C, sublimes
80.2 °C
88 °C (closed cup)
Slightly soluble in water (31–34 mg/L at 25 °C);
soluble in ethanol and methanol; very soluble in
acetone, benzene, carbon disulfide, carbon
Figure 2. Naphthalene chemical structure
Figure 3. Molecular comparison
between Benzene and Naphthalene
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, and the simplest
In purified form, naphthalene is a white
t concentrations as low
ppm by mass. As an aromatic hydrocarbon, naphthalene's structure consists of
hthalene is classified as a benzenoid
Naphthalin; naphthene; tar camphor; white tar
White monoclinic prismatic plates
34 mg/L at 25 °C);
ethanol and methanol; very soluble in
acetone, benzene, carbon disulfide, carbon
. Naphthalene chemical structure
omparison
between Benzene and Naphthalene
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tetrachloride, chloroform and diethyl ether
Volatility Vapour pressure, 0.011 kPa at 25 °C; relative
vapour density (air = 1), 4.42
Stability Volatilizes appreciably at room temperature;
sublimes appreciably at
temperatures above the melting-point
ACGIH’s Threshold Limit Value (TLV) – 2001
Conversion factor mg/m3 = 5.24 × ppm
Time Weighted Average (TWA) 10 ppm
Short Term Exposure Limit (STEL) 15 ppm
Carcinogenicity A4 (not classifiable as a Human Carcinogen)
NIOSH’s Recommended Exposure Limit (REL) – 2000
Time Weighted Average (TWA) 50 mg/m3
Short Term Exposure Limit (STEL) 75 mg/m3
OSHA’s Permissible Exposure Limit (PEL) – 2001
Time Weighted Average (TWA) 50 mg/m3
II.2 Naphthalene productions
Naphthalene is a natural constituent of coal tar and crude oil. Most naphthalene is
derived from coal tar, and in fact naphthalene is the most abundant single component
of it. From the 1960s until the 1990s, significant amounts of naphthalene were also
produced from heavy petroleum fractions during petroleum refining, but today
petroleum-derived naphthalene represents only a minor component of naphthalene
production.
Although the composition of coal tar varies with the coal from which it is produced,
typical coal tar is about 10% naphthalene by weight. In industrial practice, distillation
of coal tar yields an oil containing about 50% naphthalene, along with a variety of
other aromatic compounds. This oil, after being washed with aqueous sodium
hydroxide to remove acidic components (chiefly various phenols), and with sulfuric
acid to remove basic components, undergoes fractional distillation to isolate
naphthalene. The crude naphthalene resulting from this process is about 95%
naphthalene by weight. The chief impurities are the sulfur-containing aromatic
compound benzothiophene (<2%), indane (0.2%), indene (<2%), and
methylnaphthalene (<2%). Petroleum-derived naphthalene is usually purer than that
derived from coal tar. Where required, crude naphthalene can be further purified by
recrystallization from any of a variety of solvents, resulting in 99% naphthalene by
weight, referred to as 80 °C (melting point).
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World production of naphthalene in 1987 was around one million tonnes; about one-
fourth came from western Europe (210 thousand tonnes), one-fifth each from Japan
(175 thousand tonnes) and eastern Europe (180 thousand tonnes) and one-eighth from
the USA (107 thousand tonnes). (1)
II.3 Naphthalene uses
II.3.1 As a chemical intermediate
Naphthalene is used mainly as a precursor to other chemicals. The single largest use
of naphthalene is the industrial production of phthalic anhydride, although more
phthalic anhydride is made from o-xylene. Phthalic anhydride is used as an
intermediate for polyvinyl chloride plasticizers. Other naphthalene-derived chemicals
include alkyl naphthalene sulfonate surfactants, and the insecticide 1-naphthyl-N-
methylcarbamate (carbaryl). Naphthalenes substituted with combinations of strongly
electron-donating functional groups, such as alcohols and amines, and strongly
electron-withdrawing groups, especially sulfonic acids, are intermediates in the
preparation of many synthetic dyes. The hydrogenated naphthalenes
tetrahydronaphthalene (tetralin) and decahydronaphthalene (decalin) are used as low-
volatility solvents. Naphthalene is also used in the synthesis of 2-naphthol, a
precursor for various dyestuffs, pigments, rubber processing chemicals and other
miscellaneous chemicals and pharmaceuticals. Another new use for naphthalene is in
production of polyethylene naphthalene for making plastic beer bottles. (1)
Naphthalene sulfonic acids are used in the manufacture of naphthalene sulfonate
polymer plasticizers (dispersants), which are used to produce concrete and
plasterboard (wallboard or drywall). They are also used as dispersants in synthetic and
natural rubbers, and as tanning agents (syntans) in leather industries, agricultural
formulations (dispersants for pesticides), dyes and as a dispersant in lead–acid battery
plates.
Naphthalene sulfonate polymers are produced by reacting naphthalene with sulfuric
acid and then polymerizing with formaldehyde, followed by neutralization with
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sodium hydroxide or calcium hydroxide. These products are commercially sold in
solution (water) or dry powder form.
II.3.2 Wetting agent/surfactant
Alkyl naphthalene sulfonates (ANS) are used in many industrial applications as
nondetergent wetting agents that effectively disperse colloidal systems in aqueous
media. The major commercial applications are in the agricultural chemical industry,
which uses ANS for wettable powder and wettable granular (dry-flowable)
formulations, and the textile and fabric industry, which utilizes the wetting and
defoaming properties of ANS for bleaching and dyeing operations.
II.3.3 As a fumigant
The most familiar use of naphthalene is as a household fumigant, such as in mothballs
although 1,4-dichlorobenzene (or p-dichlorobenzene) is now more widely used. In a
sealed container containing naphthalene pellets, naphthalene vapors build up to levels
toxic to both the adult and larval forms of many moths that attack textiles. Other
fumigant uses of naphthalene include use in soil as a fumigant pesticide, in attic
spaces to repel animals and insects, and in museum storage-drawers and cupboards to
protect the contents from attack by insect pests.
II.3.4 Other applications
It is used in pyrotechnic special effects such as the generation of black smoke and
simulated explosions. In the past, naphthalene was administered orally to kill parasitic
worms in livestock. Naphthalene and its alkyl homologs are the major constituents of
creosote. Naphthalene is used in engineering to study heat transfer using mass
sublimation.
II.4 Naphthalene as an environmental pollutant
The extensive use of naphthalene as an intermediate in the production of plasticizers,
resins, insecticides and surface active agents, its presence as a major component of
coal tar and coal-tar products such as creosote and its inclusion in a wide variety of
consumer products (e.g., moth-repellents) has led to its frequent occurrence in
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industrial effluents and outdoor and indoor environments. Most of the naphthalene
entering the environment is discharged to the air (92.2%), the largest releases (more
than 50%) resulting from the combustion of wood and fossil fuels and the off-gassing
of naphthalene-containing moth-repellents and deodorants. Naphthalene and other
PAHs emitted into the air by coal-fired power plants and incinerators as the main
pollutant. (3)
Non-occupational exposure typically occurs through inhaling polluted ambient and
indoor air, and cigarette smoke. In fact, naphthalene is the most abundant PAH in
cigarette smoke (4)
, and it is present in fossil fuel smoke and exhaust fumes, especially
from diesel-fuelled vehicles and jet fuels. Another source is the use of kerosene
heaters. Forest fires also contribute to the presence of naphthalene in the environment,
as the chemical is a natural combustion product of wood. (1,3)
Naphthalene is also been
detected in ash from municipal refuse and hazardous waste incinerators. (1,3)
Vehicle
exhaust contains naphthalene both due to its presence in fuel oil and gasoline, and its
formation as a combustion by-product. In addition, there are discharges of
naphthalene on land and into water from spills during the storage, transport and
disposal of fuel oil, coal tar, etc. Another source for non occupational exposure of
naphthalene include eating contaminated food and drinking water, consuming smoked
and grilled food, ingestion of house dust, use of products containing coal-tar skin
preparations or hair shampoos, and dermal absorption from contaminated soil and
water. (3)
II.5 Occupational exposure of naphthalene
From the National Occupational Exposure Survey conducted between 1981–83, the
National Institute for Occupational Safety and Health (NIOSH) estimated that
approximately 113 000 workers, about 4.6% females, in 31 major industrial groups
were potentially exposed to naphthalene in the USA. The petroleum and coal products
and oil and gas extraction industries were among the top three industries and
comprised about 21.4% of the workers potentially exposed to naphthalene.
Naphthalene has been measured in a wide variety of workplaces for many years. At
repellents manufacturing and perfumed disinfectants, the naphthalene concentrations
can be above the limit of detection (1.0 mg/m3 for a 2-h sampling time).
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Naphthalene can be absorbed through the skin as a result of handling moth repellent
or wearing working clothes stored with moth repellent. Workers may be exposed via
inhalation or dermal absorption in settings such as naphthalene production, and other
occupational setting as described in Table 2. (3)
Table 2. Occupations in which there is exposure to naphthalene (and other PAHs)
High exposure
coke ovens
coal gasification plants
chimney sweeping
petroleum refineries (mainly exposed to naphthalene and its methyl derivatives)
impregnation of wood with creosotes (mainly exposed to naphthalene, phenanthrene, and fluorene)
handling of creosote-impregnated wood (e.g. railroad and utility workers, carpenters, mainly exposed
to naphthalene, phenanthrene, and fluorene)
Medium exposure
asphalt and pavement work
roofing
aluminium production
graphite electrode production (e.g. anode production for the aluminium industry)
foundries (processing of e.g. steel and other alloys, from coal additives in moulding sand)
smokehouses (processing of meat and fish)
Low exposure
mechanics, bus garage workers, and machinists (from diesel and spark-ignition engine exhaust gases)
mining (from diesel engine exhaust gases)
use of lubricating and cutting oils (e.g. in steel production)
cooking
II.6 Naphthalene toxicokinetics
Naphthalene and other PAHs are lipophilic compounds, therefore they can be
absorbed easily through the lungs, the gastrointestinal tract, and the skin. In the body,
naphthalene metabolism is complex, leading to biologically reactive metabolites and
other metabolites that are excreted in the urine. In studies of workers, naphthalene air
concentrations were correlated with 1-naphthol and 2-naphthol urine concentrations.
(5,6) Both naphthalene and the insecticide carbaryl are metabolized to 1-naphthol,
making it difficult to distinguish between these exposures in the general population. (7)
In contrast, only naphthalene metabolism – and not carbaryl – results in 2-naphthol in
urine.
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II.6.1 Absorption
In humans, the major routes of napthalene absorption are thought to be through: (1)
the lungs and the respiratory tract after inhalation of naphthalene-containing aerosols
or of particulates to which naphthalene, in the solid state, has become absorbed; (2)
the gastrointestinal tract after ingestion of contaminated food or water; and (3) the
skin as a result of contact with naphthalene-containing materials. Animal studies
suggest that naphthalene is readily absorbed following oral or inhalation exposure.
Nevertheless, no studies were found that quantitatively determine the extent of
absorption of naphthalene in humans following oral or inhalation exposure. (1)
ACGIH
were also designated naphthalene as “Skin” (2)
– a potential significant contribution to
the overall exposure by the cutaneous route, including mucous membranes and the
eyes (but not always iritating them), either by contact with naphthalene vapors,
liquids, and solids, even though the naphthalene airborne exposures are at or below
the TLV. ACGIH also notes the use of skin notation on naphthalene is intended to
alert the industrial hygienists that air sampling alone is insufficient to quantify
exposure accurately and that measures to prevent significant cutaneous absorption
may be required.
II.6.2 Distribution
In studies of the distribution of naphthalene and other PAHs in mice, both the parent
compounds and their metabolites were found in almost all tissues and particularly
those rich in lipids. Like many other xenobiotic substances, they would be expected to
dissolve readily in, and be transported through, the external and internal lipoprotein
membranes of mammalian cells. As a result of mucociliary clearance and
hepatobiliary excretion, naphthalene and other PAHs could present for example, in
the gastrointestinal tract even when they administered by non ingestion routes. (3)
In a
survey, naphthalene was detected in 40% of the human adipose tissue samples tested,
with concentrations up to 63 ng/g lipid. Naphthalene has also been identified in
samples of human breast milk. (1)
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Figure 4. Main metabolic pathways of naphthalene and resulting products in mammals (1)
II.6.3 Metabolism
The metabolism of naphthalene and other PAHs to more water-soluble derivatives,
which is a prerequisite for their excretion, is complex. The process follows the general
scheme of xenobiotic metabolism. The hydrocarbons are first oxidized to form phase-
I metabolites, including primary metabolites, such as epoxides, phenols, and
dihydrodiols, mainly catalysed by cytochrome P450-dependent mono-oxygenases;
and then secondary metabolites, such as diol epoxides, tetrahydrotetrols, and phenol
epoxides. The phase-I metabolites are then conjugated with either glutathione, sulfate,
or glucuronic acid to form phase-II metabolites, which are much more polar and
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water-soluble than the parent hydrocarbons. Most biotransformation leads to
detoxification products that are conjugated and excreted in the urine and faeces. (3)
The major metabolic pathways of naphthalene are illustrated in Figure 4. Naphthalene
is metabolized first to naphthalene 1,2-oxide (2, see Figure 4), which can yield 1-
naphthol (3, see Figure 4) or be converted by epoxide hydrolase to trans-1,2-dihydro-
1,2-dihydroxynaphthalene (trans-1,2-dihydrodiol) (5, see Figure 4). The hydroxyl
group of 1-naphthol may also be sulfated or glucuronidated. The 1,2-dihydrodiol can
also be converted to 2-naphthol (10, see Figure 4). The epoxide is also a substrate for
glutathione S-transferase, yielding glutathione conjugates which are eventually
eliminated as mercapturic acids.
II.7 Health effects of naphthalene
Regarding toxicological effect of naphthalene, no wonder several countries in the
world take extra caution from its usage. In China, the use of naphthalene in mothballs
is forbidden. It is due partly due to the health effects as well as the wide use of natural
camphor as a replacement.
II.7.1 Acute poisoning effects
The major toxicological responses reported in humans from acute exposure of
naphthalene is hemolytic anemia and cataracts. In 1902, a man reported to develop
cataract over 13 hours after ingestion of 5 g of naphthalene. Exposure to large
amounts of naphthalene may damage or destroy red blood cells, resulting hemolytic
anemia. The lethal oral dose is 5000-15.000 mg for adults and 2000 mg taken over
two days for a child. (3)
Poisoning from naphthalene may be accidental or suicidal and occurs as a result of
either inhalation of fumes containing naphthalene or by ingestion of mothballs. There
appears to be no cause for concern about any acute toxicity of occupational exposure
or exposure of the general population, with the exception of accidental ingestion.
Accidental ingestion of household products containing naphthalene, such as mothballs
or deodorant blocks, frequently occurs in children. (1,8)
Symptoms of naphthalene
poisoning through the gastrointestinal tract include abdominal cramps with nausea,
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vomiting and diarrhoea. Patients may have headache, profuse sweating, fatigue, and
confusion. In severe poisoning there is coma with or without convulsions.These
symptoms usually present by either inhalation or from skin exposure to clothing and
bedding treated with naphthalene moth repellents. Other mild symptoms include lack
of appetite, restlessness, and pale skin. Other symptoms of severe naphthalene
poisoning are blood in the urine, renal insufficiency, disturbances in liver function
and jaundice. Hemolysis caused by exposure to naphthalene has the potential to cause
blocking of renal tubules by hemoglobin precipitation. Hepatic necrosis may also
occur. In the absence of adequate supportive treatment, death may result from acute
renal failure in adults or kernicterus in young infants.
Excessive exposure to naphthalene vapors can irritate eyes and respiratory tract. In
some animal studies, high doses of acute exposure to the rabbit eye may cause
cataract formation. It is suggested due to one of the naphthalene metabolites,
naphthalene dihydrodiol which is produced in the liver, reaches the aqueous humour,
and penetrates the lens, where it is metabolized to naphthoquinone and causes lens
opacification. (3)
The International Agency for Research on Cancer (IARC) also stated
that acute exposure causes cataracts in humans, rats, rabbits, and mice; and that
hemolytic anemia, as described above, can also occur in children and infants after
maternal exposure during pregnancy. (1)
Treatment of acute naphthalene poisoning consists of blood transfusions and
additional alkalization of the urine. In many cases, rapid recovery, without persistent
damage, was observed. In five cases of acute haemolytic anaemia in children of about
two years of age who had eaten moth balls consisting of pure naphthalene, there was
complete recovery within one to four weeks after transfusion. (3)
II.7.2 Chronic effects
Both acute and chronic exposure of naphthalene gives similar results in terms of
cataract and hemolytic anemia. Chronic exposure of mothballs containing
naphthalene and was reported to cause peripheral neuropathy and chronic renal
failure. Chronic sniffing of naphthalene containing mothballs can cause liver necrosis.
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II.7.2.1 Dermal effects
Naphthalene can cause skin irritation and in the case of a sensitized person, severe
dermatitis can occur. Workers exposed to naphthalene may develop dermatitis on
their hands, arms, legs, and abdomen. Continuous handling of naphthalene may
produce a dermatitis characterized by itching, redness, scaling, weeping and crusting
of the skin. Lesions should clear spontaneously when the exposure is terminated.
Percutaneous absorption is apparently inadequate to produce acute systemic reactions
except in newborns.
II.7.2.2 Hematologic effects
Tests in vitro revealed that it was not naphthalene itself but its metabolites 1-
naphthoquinone and 1-naphthol that cause a decrease in reduced glutathione in
erythrocytes that can lead to hemolysis. Individuals with decreased glucose-6-
phosphate dehydrogenase activity in their erythrocytes are more sensitive to
hemolytic anemia following exposure to naphthalene. Over 400 million people in the
US have an inherited condition like that which called glucose-6-phosphate
dehydrogenase deficiency. Exposure to naphthalene is more harmful for these people
and may cause hemolytic anemia at lower doses, although toxic reactions have also
been observed in individuals without red cell defects. (1)
There are several case reports regarding naphthalene exposure on glucose-6-
phosphate dehydrogenase deficiency condition. One case report recorded by IARC
mentioned about naphthalene-induced hemolysis in a black female infant deficient in
glucose-6-phosphate dehydrogenase. Fourteen of 24 children identified as having
glucose-6-phosphatase deficiency were diagnosed with hemolysis associated with
exposure to naphthalene-containing moth-repellents. Another report mentioned acute
hemolysis with the presence of Heinz bodies and fragmented erythrocytes occurred
following inhalation of naphthalene in 21 newborn Greek infants, 12 of whom had
deficient glucose-6-phosphate dehydrogenase activity in the erythrocytes. Another
two case reports of hemolytic anaemia in newborn infants secondary to maternal
ingestion of mothballs or inhalation exposure to naphthalene have been reported. This
indicates that naphthalene and/or its metabolites can pass the placenta. (1)
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II.7.2.3 Ocular effects
Repeated exposure to naphthalene fumes or dust has led to corneal ulceration,
lenticular opacities, and cataracts; however these effects can also be seen in acute
poisoning of naphthalene. (8)
Occupational exposure to naphthalene for five years was
reported to have caused cataract, and studies in animals that are recognized by WHO
confirm the fact of the ocular toxicity of naphthalene. (3)
The effect of naphthalene in
inducing formation of cataracts in the rodent eye has been attributed to the
inducibility of the cytochrome P450 system in studies in which genetically different
mouse strains were used.
II.7.2.4 Carcinogenic effects
While other PAHs clearly reported to be carcinogenic substances by hundreds of
epidemiological studies (started about 200 years after Pott's initial finding of scrotal
cancer in chimney sweeps), no direct epidemiological evidence of an association
between occupational naphthalene exposure and cancer had been reported in human.
Early carcinogenicity studies (by various routes) of naphthalene had mostly equivocal
or non-positive results, although those studies were of low power. The data available
from epidemiological studies are inadequate to evaluate the relationship between
human cancer and exposure specifically to naphthalene.
Naphthalene was tested for carcinogenicity by oral administration in one study in rats,
by inhalation in one study in mice and one in rats and in one screening assay in mice,
by intraperitoneal administration in newborn mice and in rats, and by subcutaneous
administration in two studies in rats. Exposure of rats by inhalation was associated
with induction of neuroblastomas of the olfactory epithelium and adenomas of the
nasal respiratory epithelium in males and females. Both of these tumours were
considered to be rare in untreated rats. In the screening assay study by inhalation
using only female mice, there was an increase in lung adenomas per tumour-bearing
mouse. In the inhalation study in mice, there was an increase in the incidence of
bronchiolo-alveolar adenomas in female mice. An apparent increase in the incidence
of these tumours in male mice was not statistically significant. The studies by oral
administration in rats, intraperitoneal administration in mice and subcutaneous
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administration in rats were too limited for an evaluation of the carcinogenicity of
naphthalene.
Many international acclaimed institutions have different views about naphthalene.
The U.S. National Toxicology Program (NTP) in 1992 and 2000 conducted
researches with male and female rats and mice, exposed to naphthalene by inhalation.
After the male and female rats and mice exposed to naphthalene vapors on weekdays
for two years, they exhibited evidence of carcinogenic activity based on increased
incidences of adenoma and neuroblastoma of the nose; female mice exhibited some
evidence of carcinogenic activity based on increased incidences of alveolar and
bronchiolar adenomas of the lung, and male mice exhibited no evidence of
carcinogenic activity. (9)
These additional findings prompted IARC to re-evaluate
naphthalene, which was re-classified as Group 2B: possibly carcinogenic to humans.
(1) Under California's Proposition 65, naphthalene is listed as "known to the State to
cause cancer". In view of these new data and conclusions, it is appropriate to provide
a cancer risk estimate for naphthalene for use in the Toxic Air Contaminants program,
in addition to the Reference Exposure Level already available for the chronic non-
cancer effects. However, The American Conference of Governmental Industrial
Hygienists (ACGIH) as of 2009 has not adopted the results of NTP researches, and
still classified naphthalene as substance not classifiable as a Human Carcinogen (A4).
II.8 Diagnosis of naphthalene intoxication
Diagnosis of naphthalene acute or chronic intoxication is made from the history of
exposure and the presence of clinical manifestations and signs and symptoms of
hemolysis. Laboratory investigations may show anemia, methemoglobinemia and
elevated serum bilirubin levels.
II.8.1 Blood sample collection
Collecting blood samples should be conducted to to determine the haemoglobin
content reticulocyte count, methaemoglobin level, blood gases, blood, group and to
study the blood picture. Collect serum to determine the bilirubin level.
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Hematological findings may include a rapid fall in erythrocyte count, hemoglobin
concentration and hematocrit, followed by a temporary increase in reticulocytes and
normoblasts in the peripheral blood. During a haemolytic crisis, the fragility of the
remaining cells is increased. Haemoglobin is present in the plasma. Red cells may
contain Heinz bodies and the cells may be fragmented showing anisocytosis and
poikilocytosis. Serum bilirubin is also elevated.
The urine may be wine coloured brown or black. The colour may vary from patient to
patient or in the same patient during the course of illness. In most but not all persons
with naphthalene induced haemolysis, a deficiency of G6PD can be demonstrated.
II.9 Recommended medical surveillance
Workers who may be exposed to chemical hazards should be monitored in a
systematic program of medical surveillance that is intended to prevent occupational
injury and disease. The program should include education of employers and workers
about work-related hazards, early detection of adverse health effects, and referral of
workers for diagnosis and treatment. The occurrence of disease or other work-related
adverse health effects should prompt immediate evaluation of primary preventive
measures (e.g., industrial hygiene monitoring, engineering controls, and personal
protective equipment). A medical surveillance program is intended to supplement, not
replace, such measures. To detect and control work-related health effects, medical
evaluations should be performed (1) before job placement as initial medical
examination, (2) periodically during the term of employment, and (3) at the time of
job transfer or termination.
NIOSH (1978) has endorsed the Occupational Health Guideline for Naphthalene. The
guideline mentioned about medical surveillance of workers exposed with
naphthalene. The following medical procedures should be made available to each
employee who is exposed to naphthalene at potentially hazardous levels: (10)
1. Initial Medical Examination:
− A complete history and physical examination: The purpose is to detect pre-
existing conditions that might place the exposed employee at increased risk, and
to establish a baseline for future health monitoring. Persons with a deficiency of
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glucose-6-phosphate dehydrogenase in erythrocytes may be at increased risk
from exposure, therefore the glucose-6-phosphate dehydrogenase level should
be obtained. Examination of the eyes, blood, liver and kidney should be stressed
(baseline CBC, electrolytes, liver enzymes and renal function tests, urinalysis
and urine dipstick test for hemoglobinuria). The skin should be examined for
evidence of chronic disorders.
− A complete blood count: Naphthalene has been shown to cause red blood cell
hemolysis. A complete blood count should be performed, including a red cell
count, a white cell count, and a differential count of a stained smear, as well as
hemoglobin and hematocrit.
− Urinalysis: Since kidney damage may also occur from exposure to naphthalene,
a urinalysis should be performed, including at a minimum specific gravity,
albumin, glucose, and a microscopic on centrifuged sediment.
2. Periodic Medical Examination:
The aforementioned medical examinations should be repeated on annual basis.
II.10 Biomarkers for naphthalene exposure
Several methods have been developed to assess internal exposure to naphthalene. In
most studies, urinary biomarkers to detect naphthalene is considered the same as
biomarkers for PAH metabolites, such as urinary thioethers, 1-naphthol, b-
naphthylamine, hydroxyphenanthrenes, and 1-hydroxypyrene. The latter has been
used widely as a PAH biological index of exposure. (3)
Determination of thioethers in
urine as a biomarker for PAH is of little value, since smoking is a strong confounding
factor.
Urinary 1-hydroxypyrene has been investigated as markers for PAH in several
studies. Increased 1-hydroxpyrene excretion was found at various workplaces in coke
plants, aluminum manufacturing, wood impregnation plants, foundries, and asphalt
works. The highest exposures were those of coke-oven workers and workers
impregnating wood with creosote, who took up 95% of total of PAH through the skin,
in contrast to the general population in whom uptake via food and tobacco smoking
predominate. Although 1-hydroxypyrene is widely used to detect the presence of
PAH in the urine, but it cannot be used as a biomarker for naphthalene, for
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naphthalene metabolism in the human body does not produce 1-hydroxypyrene as one
of its metabolites.
The 1- and 2- naphthol as a urinary metabolites of naphthalene are useful biomarkers
of exposure. Seventy-five workers exposed to naphthalene while distilling
naphthalene oil excreted 7.48 mg/L (4.35 mg/g creatinine) 1-naphthol (geometric
mean values) at the end of the work shift. For 24 non-occupationally exposed
individuals, the mean urinary concentration of 1-naphthol was 0.13 mg/L. (5)
1-
Naphthol, 2-naphthol and 1,4-naphthoquinone (14, see Figure 4) were identified in
the urine of 69 coke-plant workers exposed to a geometric mean air concentration of
naphthalene of 0.77 mg/m3 during tar distillation. The end-of-work shift urinary
concentrations of 1-naphthol and 2-naphthol were 693 and 264 µmol/mol creatinine.
The correlation coefficients between the urinary excretion of naphthols and exposure
to naphthalene were 0.64 – 0.75 for 1-naphthol and 0.70 – 0.82 for 2-naphthol. There
was a linear relationship between the overall concentration of naphthols in urine and
the naphthalene concentration in air. (6)
In a further study of a coke plant, Bieniek
(1998) measured the concentrations of 1-naphthol and 2-naphthol in urine from eight
workers in coke batteries, 11 workers in the sorting department and 29 workers in the
distillation department. The mean urinary concentrations of 1-naphthol and 2-
naphthol were 294 and 89 µmol/mol creatinine for the coke-battery workers, 345 and
184 µmol/mol creatinine for the sorters and 1100 and 630 µmol/mol creatinine for the
distillation workers, respectively. (1)
Andreoli et al. (1999) examined 15 urine samples from workers in a naphthalene-
producing plant who were exposed to 0.1 – 0.7 mg/m3 naphthalene. At the end of the
work shift, the median urinary concentrations of 2-naphthyl sulfate, 2-naphthyl
glucuronide and 1-naphthyl glucuronide were 0.030 (range, 0.014 – 0.121), 0.086
(range, 0.013 – 0.147) and 0.084 (range, 0.021 – 0.448) mg/L, respectively. (1)
Since naphthalene is the most abundant component of creosote, urinary excretion of
1-naphthol was determined in three assembly workers handling creosote-impregnated
wood. (11)
The average airborne concentration of naphthalene in the breathing zone
was approximately 1 mg/m3. The average end-of-shift concentration of 1-naphthol in
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urine changed from 254 – 722 (mean, 556) µmol/mol creatinine on Monday to 1820 –
2190 (mean, 2060) µmol/mol creatinine on Wednesday and 870 – 2330 (mean, 1370)
µmol/mol creatinine on Friday. The same metabolite was measured in the urine of six
workers exposed to creosote in a plant impregnating railroad ties. (12)
As measured by
use of personal air samplers, the mean airborne concentration of naphthalene in the
workers’ breathing zone was 1.5 (range, 0.37 – 4.2) mg/m3. The mean end-of-shift
concentration of 1-naphthol was 20.5 (range, 3.5 – 62.1) µmol/L. There was a good
correlation (r = 0.745) between concentrations of airborne naphthalene and urinary 1-
naphthol. No 1-naphthol was detected (limit of detection < 0.07 µmol/L) in the urine
of five non-exposed controls. Hill et al. (1995) measured 1-naphthol and 2-naphthol
in the urine of 1000 adults without occupational exposure — a subset of the National
Health and Nutrition Examination Survey III — who may have been exposed to low
levels of naphthalene or pesticides that would yield these naphthols as metabolites. (13)
The frequency of detection was 86% for 1-naphthol and 81% for 2-naphthol. The
mean concentrations were 15 and 5.4 µg/g creatinine, respectively. Concentrations of
1-naphthol ranged up to 1400 µg/g creatinine.
Yang et al. (1999) examined the relationship between certain enzyme polymorphisms
and naphthalene metabolism in 119 men who were not occupationally exposed to
polycyclic aromatic hydrocarbons. A polymorphism in exon 7 of the CYP1A1 gene
was not related to urinary naphthol excretion. Smokers with the c1/c2 or c2/c2
genotype in CYP2E1 excreted higher concentrations of 2-naphthol in the urine than
smokers with the c1/c1 genotype. Smokers deficient in glutathione S-transferase M1
(GSTM1) showed higher urinary concentrations (without correction for creatinine) of
both 1-naphthol and 2-naphthol. (1)
Nan et al. (2001) examined the effects of occupation, lifestyle and genetic
polymorphisms of CYP1A1, CYP2E1 and the glutathione S-transferases GSTM1 and
GSTT1 on the concentrations of 2-naphthol in the urine of 90 coke-oven workers in
comparison with 128 university students. The urinary excretion of 2-naphthol was
higher in the coke-oven workers (7.69 µmol/mol creatinine) than in the students (2.09
µ mol/mol creatinine). In the control group, the excretion was higher in smokers (3.94
µ mol/mol creatinine) than in nonsmokers (1.55 µmol/mol creatinine). Urinary 2-
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naphthol concentrations were higher in coke-oven workers with the c1/c2 or c2/c2
genotypes than in those with the more common c1/c1 genotype of CYP2E1. Urinary
2-naphthol concentrations were also higher in the urine of GSTM1-null workers than
in GSTM1-positive workers. (14)
Urinary levels of 1-hydroxynaphthalene and 2-hydroxynaphthalene (1-naphthol and
2-naphthol, respectively) reflect recent exposure. Smokers typically have urinary 1-
and 2-naphthol levels that are about 2 to 3 times higher than nonsmokers in both
occupationally exposed and general populations. (15,16)
Depending on the intensity of
exposure, workers exposed to naphthalene have been found to have geometric mean
urinary 1- and 2-naphthol levels that range from around 2 to 100 times higher than
non-exposed persons. (6,17,18)
II.11 Ambient monitoring of naphthalene
Gas–liquid chromatography is used extensively to determine the naphthalene content
of mixtures. Naphthalene can be separated easily from other aromatics. Analysis of
other impurities may require the use of high-resolution capillary columns. Selected
methods for the analysis of naphthalene in various media are presented in Table 3.
Table 3. Selected methods for analysis of naphthalene in the air (1)
Sample preparation Assay procedure Limit of detection
Adsorb (charcoal); desorb
(carbon di-sulfide)
gas chromatography / flame ionization
detection
1–10 µ g/sample; 4 µ
g/sample
Adsorb (solid sorbent);
desorb (organic solvent)
high-performance liquid
chromatography / ultraviolet detection
0.6–13 µ g/sample
Adsorb (solid sorbent);
desorb (organic solvent)
gas chromatography / flame ionization
detection
0.3–0.5 µ g/sample
II.12 Journal Reviews
In order to study the most recent screening test on workers exposed to naphthalene, a
thorough search was conducted, either on PubMed, Google Scholar, or ProQuest.com.
Keyword "naphthalene exposure" AND "biomonitoring" is used. Fourteen articles of
full and free-for-download journals was found, and then selection was done on the
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journals which is published around 10 years ago (2002 and above), and found there
was 5 articles eligible enough to assess. Using the recommendation from Evidence-
Based Medicine Working Group method in appraising article on diagnosis, there are 4
questions to be answered according to the method for determining the validity of
these articles, they are: (19)
a. Was there are an independent, blind comparison with reference standard?
b. Did the patient sample include an appropriate spectrum of patients to whom the
diagnostic test will be applied in clinical practice?
c. Did the result of the test being evaluated influence the decision to perform the
reference standard?
d. Were the methods for performing the test described in sufficient detail to permit
replication?
Below is a partial summary of the journals that have been obtained using the methods
mentioned above.
II.12.1 Research No.1
Journal title: Simultaneous analysis of naphthols, phenanthrols, and 1-
hydroxypyrene in urine as biomarkers of polycyclic aromatic hydrocarbon exposure:
intraindividual variance in the urinary metabolite excretion profiles caused by
intervention with β-naphthoflavone induction in the rat. (20)
Researchers: Elovaara E, Väänänen V, Mikkola J.
Published online: February 2003
Abstract: Two fluorimetric HPLC methods are described for the quantification of
naphthols, phenanthrols and 1-hydroxypyrene (1-OHP) in urine specimens obtained
from male Wistar rats exposed to naphthalene, phenanthrene and pyrene. The
polycyclic aromatic hydrocarbons (PAHs) were given intraperitoneally, either alone
(1.0 mmol/kg body weight) or as an equimolar mixture (0.33 mmol/kg), using the
same dosages for repeated treatments on week 1 and week 2. Between these
treatments, PAH-metabolizing activities encoded by aryl hydrocarbon (Ah) receptor-
controlled genes were induced in the rats with β-naphthoflavone (βNF).
Chromatographic separation of five phenanthrols (1-, 2-, 3-, 4-, and 9-isomers) was
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accomplished using two different RP C-18 columns. Despite selective detection
(programmable wavelengths), the quantification limits in the urine ranged widely: 1-
OHP (0.18 lg/l) <phenanthrols (0.34–0.45 lg/l) <2-naphthol (1.5 lg/l) <1-naphthol (4
lg/l). The relative standard deviation of the methods was good, as also was the
reproducibility. The molar fraction of the dose excreted in 24-h urine as naphthols (≤
4.0%), phenanthrols (≤ 1.1%), and 1-OHP (≤ 2.4%) was low. Urinary disposition
increased differentially in βNF-induced rats: naphthols, 9-phenanthrol (1- to-2-fold);
2-, 3-, and 4-phenanthrols (4- to 5-fold); 1-phenanthrol and 1-OHP (over 11-fold).
The OH-metabolites were analyzed before and after enzymatic hydrolysis (β-
glucuronidase/arylsulfatase). The percentage excreted as a free phenol in urine varied
for 1-OHP (2–11%), 1-naphthol (36–51%), 2-naphthol (59–65%), and the
phenanthrols (29–94%). 1-Naphthyl- and 1-pyrenyl β-D-glucuronide served as
measures for the completeness of enzymatic hydrolysis. Characteristic differences
observed in the urinary disposition of naphthalene, phenanthrene, and pyrene are
described, as well as important factors (dose, metabolic capacity, relative urinary
output) associated with biomarker validation. This intervention study clarifies
intraindividual variation in PAH metabolism and provides useful information for the
development of new methods applicable in the biomonitoring of PAH exposure in
humans.
II.12.2 Research No.2
Journal title: Effects of genetic polymorphisms in metabolic enzymes on the
relationships between 8-hydroxydeoxyguanosine levels in human leukocytes and
urinary 1-hydroxypyrene and 2-naphthol concentrations. (21)
Researchers: Kim YD, Lee CH, Nan HM, et al.
Published: March 2003
Abstract: This study was designed to investigate the relationship between
environmental exposure to polycyclic aromatic hydrocarbons (PAHs) and oxidative
stress, and to evaluate the effects of cigarette smoking and the genetic polymorphisms
of CYP1A1, CYP2E1, GSTM1, NAT2 and UGT1A6 on the relationship. The subjects
of this study were 105 healthy Korean males without occupational exposure to PAHs.
The 8-hydroxydeoxyguanosine (8-OHdG) level in leukocytes, and urinary 1-
hydroxypyrene (1-OHP) and 2-naphthol concentrations, were measured by high-
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performance liquid chromatography. Genetic polymorphisms of CYP1A1, CYP2E1,
GSTM1, NAT2 and UGT1A6 were identified by PCR and PCR-RFLP methods. The
8-OHdG level showed a significant correlation with the 1-OHP concentration in all
subjects (p< .001) and in smokers (p< .01), and with the 2-naphthol level in non-
smokers (p< .01). The 8-OHdG level was significantly higher in smoking rapid
acetylators than in smoking slow or intermediate acetylators, and in individuals with
the UGT1A6 wild-type than in those with the UGT1A6 mutant genotype. Significant
positive correlations between 8-OHdG and 1-OHP concentrations were found in
subjects with every genotype of the CYP1A1 and CYP2E1 genes, with the GSTM1
null-type, with the NAT2 genotype of a rapid acetylator, and with the UGT1A6 wild-
type, respectively. The urinary 2-naphthol level significantly correlated with the 8-
OHdG level only in subjects with the GSTM1 null-type. In conclusion, there is a
significant correlation between the 8-OHdG level in leukocytes and the urinary 1-
OHP concentration in the population not occupationally exposed to PAHs. This
relationship is affected by genetic polymorphisms in PAH metabolic enzymes
II.12.3 Research No.3
Journal title: Occupational Exposure to Aromatic Hydrocarbons at a Coke Plant:
Part II. Exposure Assessment of Volatile Organic Compounds. (22)
Researchers: Bieniek G , Kurkiewicz S, Wilczok T, et al.
Published: January 2004
Abstract: The objective of the study is to assess the external and internal exposures
to aromatic hydrocarbons in the tar and oil naphthalene distillation processes at a coke
plant. 69 workers engaged as operators in tar and oil naphthalene distillation
processes and 25 non-exposed subjects were examined. Personal analyses of the
benzene, toluene, xylene isomers, ethylbenzene, naphthalene, indan, indene and
acenaphthene in the breathing zone air allowed us to determine the time weighted
average exposure levels to the aromatic hydrocarbons listed above. The internal
exposure was investigated by measurement of the urinary excretion of naphthols, 2-
methylphenol and dimethylphenol isomers by means of gas chromatography with a
flame ionization detection (GC/FID). Urine metabolites were extracted after
enzymatic hydrolysis by solid-phase extraction with styrene-divinylbenzene resin.
The time-weighted average concentrations of the hydrocarbons detected in the
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breathing zone air shows that the exposure levels of the workers are relatively low in
comparison to the exposure limits. Statistically significant differences between
average concentrations of aromatic hydrocarbons (benzene, toluene, xylene isomers)
determined at the workplaces in the tar distillation department have been found .
Concentrations of the naphthalene and acenaphthene detected in workers from the oil
distillation department are higher that those from the tar distillation department.
Concentrations of naphthols, 2-methoxyphenol and dimethylphenol isomers in the
urine of occupationally exposed workers were significantly higher than those of non-
exposed subjects. Concentrations of the 2-methoxyphenol and dimethylphenol
isomers in urine were significantly higher for the tar distillation workers, whereas
concentrations of naphthols were higher for the oil naphthalene distillation workers.
Operators at the tar and naphthalene oil distillation processes are simultaneously
exposed to a mixture of different hydrocarbons, mainly benzene and naphthalene
homologues.
II.12.4 Research No.4
Journal title: Urinary Biomarkers in Charcoal Workers Exposed to Wood Smoke in
Bahia State, Brazil. (23)
Researchers: Kato M, Loomis D,. Brooks LM, et al.
Published online: June 2004
Abstract: Charcoal is an important source of energy for domestic and industrial use
in many countries. Brazil is the largest producer of charcoal in the world, with
~350,000 workers linked to the production and transportation of charcoal. To evaluate
the occupational exposure to wood smoke and potential genotoxic effects on workers
in charcoal production, we studied urinary mutagenicity in Salmonella YG1041 +S9
and urinary levels of 2-naphthol and 1-pyrenol in 154 workers of northeastern Bahia.
Workers were classified into three categories according to their working location, and
information about sociodemographic data, diet, alcohol consumption, and smoking
was obtained using a standard questionnaire. Spot urine samples were collected to
evaluate urinary mutagenicity and urinary metabolites. Urinary mutagenicity
increased significantly with exposure to wood smoke and was modified by smoking.
The prevalence odds ratio was 5.31, and the 95% confidence interval was 1.85; 15.27
for urinary mutagenicity in the highly exposed group relative to the nonexposed
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group. The levels of urinary metabolites increased monotonically with wood smoke
exposure and were associated with the GSTM1 null genotype, which was determined
previously. The prevalence odds ratio (95% confidence interval) for higher levels of
2-naphtol among the highly exposed was 17.13 (6.91; 42.44) and for 1-hydroxyprene
11.55 (5.32; 25.08) when compared with nonexposed workers. Urinary 2-naphthol
was the most sensitive indicator of wood smoke exposure. This is the first reported
measurement of internal exposure to wood smoke among charcoal workers, and the
results showed that these workers receive a systemic exposure to genotoxic
compounds.
II.12.5 Research No.5
Journal title: Utility of urinary 1-naphthol and 2-naphthol levels to assess
environmental carbaryl and naphthalene exposure in an epidemiology study. (7)
Researchers: Meeker JD, Barr DB, Serdar B, et al.
Published online: May 2006
Abstract: We recently reported associations between urinary 1-naphthol (1N) levels
and several intermediate measures of male reproductive health, namely sperm
motility, serum testosterone levels, and sperm DNA damage. However, because 1N is
a major urinary metabolite of both naphthalene and the insecticide carbaryl, exposure
misclassification stemming from differences in exposure source was probable and
interpretation of the results was limited. As naphthalene, but not carbaryl, is also
metabolized to 2-naphthol (2N), the relationship of urinary 1N to 2N within an
individual may give information about source of 1N. Utilizing data from two previous
studies that measured both 1N and 2N in urine of men exposed to either carbaryl or
naphthalene, the present study employed several methods to differentiate urinary 1N
arising from exposures to carbaryl and naphthalene among men in the reproductive
health study. When re-evaluating the reproductive health data, techniques for
identifying 1N source involved exploring interaction terms, stratifying the data set
based on 1N/2N ratios, and performing an exposure calibration using a linear 1N to
2N relationship from a study of workers exposed to naphthalene in jet fuel. Despite
some inconsistencies between the methods used to distinguish 1N source, we found
that 1N from carbaryl exposure is likely responsible for the previously observed
association between 1N and sperm motility, whereas 1N from naphthalene exposure
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is likely accountable for the association between 1N and sperm DNA damage. We
demonstrate that studies of health effects associated with carbaryl should utilize a
1N/2N ratio to identify subgroups in which carbaryl is the primary source of 1N.
Conversely, studies of naphthalene-related outcomes may utilize 2N levels to estimate
exposure.
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CHAPTER III
DISCUSSION
Five journals were reviewed using the recommendation from Evidence-Based
Medicine Working Group method in appraising article on diagnosis as described in
the Table 4 below.
Table 4. Critical appraisal
Was there are an
independent,
blind comparison
with reference
standard?
Did the patient
sample include an
appropriate spectrum
of patients to whom
the diagnostic test
will be applied in
clinical practice?
Did the result of the
test being evaluated
influence the decision
to perform the
reference standard?
Were the methods
for performing
the test described
in sufficient detail
to permit
replication?
Are the
results of
the study
valid?
Elovaara E,
Väänänen V,
Mikkola J
(February 2003)
No control group
or comparison
between tests
The subjects consist
of animals and not
human
The test results were
evaluated using
reference standard
(HPLC system)
Yes, every steps
carefully recorded
so the methods
allowed to be
duplicated
restricted
Kim YD, Lee CH,
Nan HM, et al.
(March 2003)
Yes, there are
comparisons
between the
groups, but not
done before the
study begins, and
not a blind one.
Non specific human
subject
The test result were
evaluated by using
other researcher’s
method
Yes, because it
refers to the
method of
examination by
reliable
laboratories
doubtful
Bieniek G ,
Kurkiewicz S,
Wilczok T, et al.
(January 2004)
Yes, there are
comparisons
between the
groups, but the
blinding methods
did not
mentioned.
Yes, there are subject
classifications to this
type of exposure, the
workers exposed to
coal tar (naphthalene
and several other
PAH), workers
exposed to
naphthalene only, and
a control group not
exposed to both.
The test results were
evaluated using
reference standard
(HPLC system)
The procedure
involves the
examination only
in general terms
only, it seems a
lot of important
things is hidden
valid
Kato M, Loomis
D,. Brooks LM, et
al. (June 2004)
No control group
or comparison
between tests
Yes, but the selection
of subjects only done
among workers
exposed to coal tar
(naphthalene and
several other PAH),
so it represents less
relevance of the
research
The test result
evaluated by trusted
labs
The procedure is
not clear enough
to understand
doubtful
Meeker JD, Barr
DB, Serdar B, et
al. (May 2006)
No control group
or comparison
between tests
Non specific subjets;
selection of subjects
drawn from general
population, and not
from high-risk
workplaces
The test results
evaluated by reliable
test agencies (Harvard
School of Public
Health, US CDC and
trusted labs)
It is possible to
duplicate the
procedure,
because the
samples were sent
to various reliable
test agences
valid
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Based on appraised results above, only two articles are eligible to be discussed.
Bieniek et al. (2004) conducted a cross sectional research to to assess the mixed
exposure of naphthalene and other PAHs on coke-plant workers with air and
biological monitoring. Biological monitoring was conducted by the analysis of
urinary naphthols and phenols. The study group comprised of 69 workers, average
age 38 years (range 20-65) exposed to aromatic hydrocarbons in a coke plant. They
are divided into 2 groups. A group consists of workers who are involved as operators
in tar distillation department and group B consisted of operators in naphthalene oil
distillation department. The survey was performed on the 5th day of a working week,
by which time the metabolite excretion should have reached a plateau. The air and
urine samples were collected on the same day during the day shift (6:00 AM–2:00
PM). As a control, there were chosen 25 people who are not occupationally exposed
to aromatic hydrocarbons, but are actively smokers. Air samples were collected in the
breathing zone of the workers during the work shift with a charcoal tube collector.
The analysis of the charcoal extracts was performed with a gas chromatograph
equipped with a flame ionization detector. Aromatic hydrocarbons (naphthalene,
benzene, toluene, m+p-xylene and o-xylene) were analysed as previously described
by other researchers. Meanwhile, urine samples were collected rom the exposed
workers during the last 4 h of the work shift (10:00 AM to 2:00 PM). Samples were
kept at 20°C until analysis. After processed several steps, the samples were examined
by gas chromatography method. After all examination complete, the results are: for
A-group of workers, concentrations of benzene, toluene, m+p-xylene in air are higher
(p<0.05) than for B-group, whereas concentrations of naphthalene and acenaphthene
in air are higher for B-group than the A-group (p<0.05). As with urinary samples,
there are significant differences (p<0.05) between average concentrations of urinary
metabolites of non-exposed and exposed workers. The correlation between the time-
weighted average naphthalene exposure and the urinary naphthols level, during the
shift, were examined by regression analysis (as shown in figure below). The analysis
shows the correlation between the concentration of naphthalene in air and the sum of
1-naphthol and 2-naphthol concentrations in shift-end urine of operators of the
naphthalene oil distillation. The correlation between the summary concentration of
naphthols in urine and the naphthalene concentrations in the breathing zone air are
statistically significant at p<0.001. (22)
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Figure 5. Relation between naphthalene in breathing-zone air and the sum of 1-naphthol and 2-
naphthol in shift-end urine of operators of the naphthalene oil distillation
Another eligible considered research comes from Meeker et al. (2006). Previous study
by the same researcher in 2004 reported the associations between urinary 1-naphthol
levels and intermediate measures of male reproductive health, including reduced
sperm motility, increased sperm DNA damage, and reduced circulating testosterone.
Therefore, the research subjects were 370 men in subfertile couples seeking infertility
diagnosis who provided a urine sample analyzed for 1-naphthol and 2-naphthol. Of
these, 330 men without a history of medical factors for infertility were primarily
white (82%) nonsmokers (91%) with a mean (SD) age of 36 (5.5) years. A single spot
urine sample was collected from each subject. Urine samples were frozen at -20 oC
and sent to the US Centers for Disease Control and Prevention (CDC) where 1-
naphthol and 2-naphthol were measured. Urinary 1-naphthol and 2-naphthol were
isolated using liquid–liquid extraction, derivatized, and measured using gas
chromatography – chemical ionization – tandem mass spectrometry. Briefly, a semen
sample and a blood sample were collected from each subject on the same day that
urine was collected. Semen samples were analyzed for sperm count and motility, and
analyzed for DNA damage. Blood samples were centrifuged and serum stored at -80
oC until analysis. Testosterone was also measured directly with a certain test kit. As
for the statistical analysis, multiple linear regression was used to assess associations
between levels of 1-naphthol in urine and intermediate measures of male reproductive
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health. Outcome measures were chosen for this study based on researcher’s previous
work. For sperm motility and DNA damage, subjects with a history of medical risk
factors for infertility (e.g. varicocele, orchidopexy) were excluded from the analysis.
For testosterone, subjects taking hormone medication (e.g. GnRH, testosterone, or
prednisone taper) were excluded. Age, body mass index, abstinence time, smoking,
and season were considered as covariates, and were included or excluded from
models based on biologic and statistical considerations. In the case of testosterone,
sex hormone binding globulin and time of day that the blood was collected were also
included in the models. The association between urinary 1-naphthol and sperm
motility was also assessed by multiple logistic regression, where subjects were
dichotomized as either above or below 50% motile sperm based on WHO reference
levels (WHO, 1999). Some approaches were used in an attempt to separate carbaryl
and naphthalene exposure, such as 1-naphthol/2-naphthol ratio compared from
previous research. As the result, measurable levels of 1-naphthol and 2-naphthol were
found in 99.7% and 74.5% of samples, respectively. As expected, 1-naphthol and 2-
naphthol levels were higher among smokers. (median = 8.13 and 9.84 µg/l,
respectively) than among nonsmokers (median = 3.13 and 0.96 µg/l, respectively).
The correlation between 1-naphthol and 2-naphthol levels was also higher among
smokers (Spearman’s correlation coefficient - 0.89 among smokers vs. 0.42 among
nonsmokers), and the ratio of 1-naphthol over 2-naphthol was lower among smokers
as anticipated (median ratio = 3.44 among nonsmokers, 0.93 among smokers). Using
the ratio of 1-naphthol to 2-naphthol to differentiate between carbaryl and
naphthalene as sources of 1-naphthol in each subject, the researcher. Found strong
associations between 1-naphthol and sperm motility and serum testosterone when
carbaryl was the likely source of 1-naphthol. The opposite was found for DNA
damage, which was more strongly associated with 1-naphthol among men with low 1-
naphthol / 2-naphthol ratios, which is indicative of naphthalene exposure. These
results suggest that sperm DNA damage is associated with exposure to naphthalene
or, perhaps, to other PAH if naphthalene is serving as a surrogate for PAH more
generally. Results from this study indicate that sperm motility and circulating
testosterone are associated with carbaryl exposure, rather than naphthalene itself. (24)
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CHAPTER IV
CONCLUSIONS AND RECOMMENDATIONS
IV.1 Conclusions
Naphthalene is a commercially important aromatic hydrocarbon which is produced
from coal tar and petroleum. It is used mainly as an intermediate in the production of
phthalic anhydride, naphthalene sulfonates and dyes and to a lesser extent as a moth-
repellent. Human exposure to naphthalene can occur during its production, in creosote
treatment of wood, in coal coking operations, during its use as an industrial
intermediate, as a result of its use as a moth-repellent, and as a result of cigarette
smoking.
Naphthalene causes cataracts in humans, rats, rabbits and mice. Humans accidentally
exposed to naphthalene by ingestion develop haemolytic anaemia. Cases of aemolytic
anaemia have been reported in children and infants after oral or inhalation exposure to
naphthalene or after maternal exposure during pregnancy.
Regarding the possible carcinogenicity of naphthalene, there is no sufficient data to
prove that naphthalene causes cancer in humans. The IARC concluded there is
inadequate evidence in humans for the carcinogenicity of naphthalene, but there is
sufficient evidence in experimental animals for the carcinogenicity of naphthalene.
Hence, naphthalene regarded as possibly carcinogenic to humans (Group 2B).
In order to detect and control work-related health effects on naphthalene exposed
workers, medical evaluations should be performed (1) before job placement, (2)
periodically during the term of employment, and (3) at the time of job transfer or
termination. An initial or periodical medical evaluations should consist:
1. A complete history and physical examination:
a. Glucose-6-phosphate dehydrogenase level.
b. Examination of the eyes, blood, liver and kidney.
c. The skin should be examined for evidence of chronic disorders.
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2. Complete Blood Count, including a red cell count, a white cell count, and a
differential count of a stained smear, as well as hemoglobin and hematocrit,
electrolytes, liver enzymes and renal function tests
3. Urinalysis: minimum specific gravity, albumin, glucose, and a microscopic
hemoglobinuria on centrifuged sediment.
Although no data are available from human studies on absorption of naphthalene, the
determination of metabolites in the urine of workers indicates that absorption does
occur, and there is a good correlation between exposure to naphthalene and the
amount of 1-hydroxynaphthalene and 2-hydroxynaphthalene (1-naphthol and 2-
naphthol, respectively) excreted in the urine. Therefore, the most suitable
biomonitoring for naphthalene exposure is 1-naphthol and 2-naphthol. Finding a
measurable amount of 1- or 2-naphthol in the urine does not mean that the level
causes an adverse health effect, but reflect recent exposure. Smokers typically have
urinary 1- and 2-naphthol levels that are about 2 to 3 times higher than nonsmokers in
both occupationally exposed and general populations. Depending on the intensity of
exposure, workers exposed to naphthalene have been found to have geometric mean
urinary 1- and 2-naphthol levels that range from around 2 to 100 times higher than
normal.
IV.2 Recommendations
For researchers in the field of occupational medicine, further studies on biomonitoring
of urinary levels of 1 - and 2-naphthol should be done in the future. Such studies may
provide occupational physicians, industrial hygienists, and government officials with
reference values, so that they can create specific guidelines for naphthalene exposure
and biomonitoring in various industries, which are not yet available in Indonesia.
As for industries which are associated with exposure to naphthalene, an improved
industrial hygiene program should be implemented in order to protect the workers
from the danger of naphthalene exposure, such as:
• Conducting proper engineering control of industrial exhaust fumes, so they cannot
endanger the workers and people outside the industry, by providing good
ventilation.
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• Encourage the exposed workers to wear specific personal protective equipment
(PPE), such as respirators and impermeable gloves when handling naphthalene-
contained chemicals or when naphthalene exposure is present in the workplace.
• Periodic measurement of the airborne exposure levels of naphthalene in the
workplace should be performed anually, to minimize the negative health effects on
the exposed workers.
• Pre employment medical examinations and annual medical surveillance should be
performed. The annual result should be compared to the baseline level to control
the hazards from naphthalene to workers’ health.
• Workers with G6PD deficiency should not work on the working environment with
high levels of exposure to naphthalene.
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