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International

Volume   Journal
II Number 2 2011for Environmental Rehabilitation and Conservation
[23-28]
Volume III No.
[ISSN 0975 1 2012 [56 – 67]
- 6272] [ISSN 0975 - 6272] 

N-Nitrosodiethylamine and carcinogenicity: An Over review

Veena Sharma1, Pracheta Janmeda1, Lokendra Singh2

Received: November 28, 2011 ⏐ Accepted: April 22, 2012 ⏐ Online: July 28, 2012

Abstract
Cancer remains the major cause of death in the reasonably anticipated to be a human
developed, developing and underdeveloped carcinogen based on sufficient evidence of
countries next only to cardiovascular disease carcinogenicity in experimental animals. The
and hence is a major cause of morbidity and essential nature of any cancer in humans or in
mortality worldwide. N-Nitrosodiethylamine animals continues to challenge scientists and
(C4H10N2O) is the most important practitioners interested in the patho-physiology,
environmental carcinogen among the prevention and therapy of this disease. Despite
nitrosamines, present in our environment and recent advances in our understanding of the
food chain. N-Nitrosodiethylamine is present in biological processes leading to the development
a variety of Foodstuffs including milk, cheeses of cancer, there is still a need for new and
(0.5 to 30 µg/kg), meat products such as various effective agents to keep this disease under
salted and dried fishes (<1 to 147 µg/kg), cured control.
meats (up to 40 µg/kg), alcoholic beverages (0.1
µg/kg), and a few varieties of vegetables such as
Keywords: Chemoprevention ⏐ Environnemental
soybeans (0.2 µg/kg). DENA has been
impact⏐ N-Nitrosodiethylamine ⏐ Oxidative
suggested to cause oxidative stress and cellular
injury due to involvement of free radicals. It is damage

For correspondence: Introduction


1
Department of Bioscience and Biotechnology, N-nitroso compounds (NOCs) are one of the
Banasthali University, Banasthali-304022, Rajasthan, important groups of carcinogens frequently
India present in human environment and food chain
2
Department of Botany, Meerut College, Meerut (Preussmann, and Stewar 1984). NOCs, like N-
E-mail: drvshs@gmail.com
nitrosodimethylamine (NDMA), N-

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nitrosomethylethylamine (NMEA) and N- Chemical Structure


nitrosodiethylamine (DENA) are highly
C2H5
mutagenic compounds that are suspected of
N-N O
carcinogenicity (Ohkawa et al., 1979; Ohsawa C2H5
et al., 2003). The presence of nitroso
compounds and their precursors in human Properties
environment together with the possibility of N-Nitrosodiethylamine is volatile, clear yellow
their endogenous formation in human body oil that is soluble in water, alcohol, ether, other
have led to suggestions of their potential organic solvents, and lipids. The compound is
involvement in human cancers (Bartsch and sensitive to light, especially ultraviolet light,
Montesano, 1984; Kaplan et al., 1997). and undergoes relatively rapid photolytic
DENA is an N-Nitroso alkyl compound and degradation (IARC 1978, HSDB, 2002).
was chosen as a carcinogenic model because
this well-investigated, classic carcinogen is
present in our environment and suggested to Principle sources of DENA
increase the generation of reactive oxygen DENA is found in a drinking water, wide
species (ROS) resulting in oxidative stress and variety of foodstuffs such as milk products,
cellular injury (Preussmann, 1984; Bartsch et meat products, number of alcoholic beverages,
al., 1989; Bansal et al., 2000; Aiub et al., soft drinks, tobacco smoke and a few varieties
2003). There is considerable support to the of vegetables are the principal sources of
concept that oxygen free radicals and related nitroso compounds (Tricker et al., 1991;
lipid peroxides also play a key role in the Kumar and Kuttan, 2000; Liao et al., 2001;
pathogenesis of normal senescence and of age- Bansal et al., 2005).
related chronic degenerative diseases,
Uses
including cancer (Maxwell, 2000). N-
Nitrosodiethylamine is reasonably anticipated N-Nitrosodiethylamine is used primarily as a
to be a human carcinogen based on sufficient research chemical. It is used as a gasoline and
evidence of carcinogenicity in experimental lubricant additive, antioxidant, stabilizer in
animals (IARC 1978, 1982, 1987). plastics, fiber industry solvent, copolymer
softener, and starting material for synthesis of
1,1-diethylhydrazine. It is also used to increase
Synonyms dielectric constants in condensers (IARC 1972,
DEN (mutagen); NDEA; DANA; HSDB, 2002).
Diethylnitrosamine; Diaethylnitrosamin
(German); Diethylnitrosamide; Diethylnitroso-
Primary routes of exposure
amine; Ethanamine; N-ethyl-N-nitroso; N,N-
Diethylnitrosamine; N-Nitrosdi; N-Ethyl-N- The primary routes of potential human
nitroso-ethanamine; Nitrosodiethylamine. exposure to DENA are ingestion, dermal
contact, Inhalation, eye contact, skin
absorption.

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Air, diet, and smoking contribute to potential months or years: (i) N-Nitrosodiethylamine is a
human exposure at levels of a few µg per day. probable carcinogen in humans. There is some
N-Nitrosodiethylamine is present in a variety evidence that it causes liver, nose and lung
of foods, including cheeses at concentrations of cancer in humans. Further, scientists believe
0.5 to 30 µg/kg, soybeans at 0.2 µg/kg, various there is no safe level of exposure to a
fish at <1 to 147 µg/kg, cured meats at up to 40 carcinogen. (ii) N-Nitrosodiethylamine has
µg/kg, and alcoholic beverages at 0.1 µg/kg caused cancer in the offspring of animals
(IARC, 1978). N-Nitrosamines such as N- exposed during pregnancy. N-
nitrosodiethylamine are frequently produced Nitrosodiethylamine may damage the
during rubber processing and may be present developing fetus. The acute chronic hazardous
as contaminants in the final rubber product. N- effect is that, when heated to decomposition
Nitrosodiethylamine has also been detected in this compound emits toxic fumes of nitrogen
tobacco smoke condensate at concentrations of oxides (NTP, 1992).
1.0 to 28 ng/cigarette. Up to 8.3 ng/cigarette
Reactivity Profile of DENA
were found in mainstream smoke and 8 to 73
ng/cigarette were found in side stream smoke. N-Nitrosodiethylamine reacts with strong
An analysis of indoor air polluted with tobacco oxidizing agents. Incompatible with reducing
smoke indicated levels of up to 0.2 ng/L of N- agents and can be hydrolyzed by hydrogen
nitrosodiethylamine (Brunnemann et al., bromide in acetic acid (NTP, 1992).
1977). The compound has been found in high-
nitrate well water for drinking at
Human/ Animal Carcinogenicity Data
concentrations of 0.010 µg/L and in deionized
water at 0.33 to 0.83 µg/L. Wastewater from It is well known that N-Nitroso compounds act
two chemical plants contained 0.07 and 0.24 as strong carcinogens in various mammals
µg/L (IARC 1978). including primates (Leoppky and Li, 1991).
Human exposure to nitrosamines results from
contact with mixtures containing these
Chronic Health Effects and Hazard compounds (e.g., cutting oils, tobacco
identification products). Because of potential confounding by
N-Nitrosodiethylamine is on the Hazardous the other substances in these mixtures, data
Substance List because it is cited by NTP, from human exposure is of limited use in the
DEP, IARC, HHAG and EPA. The Potential evaluation of carcinogenicity of individual
symptoms are Irritation of eyes, skin, nitrosamines. Further, no adequate human
respiratory tract and liver damage. This studies of the relationship between exposure to
compound affects the different organs in N-nitrosodiethylamine and human cancer have
animals such as Liver, bladder, kidney, been reported (IARC 1978, HSDB, 2002).
esophagus, brain, nasal sinuses, stomach, and There is a large database on the carcinogenicity
lungs. of nitrosamines, most of which pertains to
The following chronic (long-term) health structure-activity relationships rather than to
effects can occur at some time after exposure dose- response. Diethylnitrosamine
to N-Nitrosodiethylamine and can last for administered by gavage, in drinking water, or

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by feeding produces liver tumors in the evidence for such inhibitory effects remains to
following species: rat, mice, hamster, guinea be demonstrated.
pig, rabbit, dog, and monkey (Druckrey et al.,
1963, 1967; Rajewsky et al., 1966; Yamamoto
et al., 1972; Tomatis, 1973; Magee et al., Environmental and Drinking water impact
1976). DENA may also form in the environment from
Tracheal and lung tumors have been observed the reaction of nitrite with Rhodamine B and
in Syrian golden hamsters upon administration Rhodamine WT tracer dyes. Because of its low
of diethylnitrosamine by gavage or inhalation estimated Koc (adsorption coefficient) value of
(Magee et al., 1976). Diethylnitrosamine 43, DENA is expected to be moderately to
administered to pregnant mice, rats, and highly mobile in soil. Volatilization from soil
hamsters has been shown to act surfaces will be rapid while volatilization of
transplacentally, inducing tumors in the DENA incorporated into the soil will be slower
progeny (Mohr, 1966; Tomatis, 1973; but may nevertheless be significant. The half-
Druckrey, 1973a, b). Dose-related increases in life for N-Nitrosodiethylamine (DENA) was
incidence of upper GI tumors and liver cell found to be about 1-2 hours in a Teflon
tumors were observed in C57-BO mice, and outdoor smog chamber irradiated with
tracheal and liver cell tumors were observed in sunlight. The primary fate mechanism for
Syrian hamsters (Peto et al., 1984). DENA in water may be photolysis

Diethylnitrosamine is mutagenic for S. In water, DENA is not expected to partition to


typhimurium, E. coli, and Neurospora crassa, sediments, suspended organic matter or biota.
and produced mitotic recombination in S. Volatilization from water is probably not
cerevisiae, recessive lethal mutations in D. significant. Hydrolysis is probably not a
melanogaster, and chromosomal aberrations in significant removal process. Estimated
mammalian cells. Positive responses in atmospheric residence time for DENA is < 0.3
bacterial cells are dependent upon the addition days with photolysis probably the primary
of a mammalian metabolic system (Montesano removal mechanism. DENA has been found in
and Bartsch, 1976). Diethylnitrosamine is the air at dye, rubber and foundry industries.
structurally related to known carcinogens. Lee DENA has also been found in Philadelphia
et al., 1989 demonstrate the Inhibition of N- drinking water, in the passenger area of new
Nitrosodiethylamine Carcinogenesis in Mice cars, in cigarette smoke, and in cheese, bacon,
by Naturally Occurring Organosulfur beer and fish. Thus, the general population
Compounds and Monoterpenes'. These results may be exposed to DENA from riding in new
provide evidence for an increasing diversity of cars, breathing cigarette smoke, drinking beer,
naturally occurring compounds having the or eating certain foods such as cheese, bacon,
capacity to inhibit nitrosoamine carcinogenesis and fish.
(Wattenberg, 1985). The impact of such Philadelphia tap water contained <0.1-0.7 ng/l
inhibitory effects on environmental exposure N-nitrosodiethylamine. EFFL: Chemical plant
of human populations to this class of effluent released to a river contained 132 ng N-
carcinogens could be of importance, but clear nitrosodiethylamine/l. In human esophageal

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mucosa, the de-ethylation of N- role in the pathogenesis of age-related chronic


nitrosodiethylamine to form acetaldehyde degenerative diseases and etiology of cancer
appears to be catalyzed by the cytochrome (Marklund and Marklund, 1974; Ray et al.,
P450, CYP2A6, but not by CYP2E1. It is also 2000).
catalyzed by human CYP2A13.
N-nitrosodiethylamine (DENA) has been
Single doses of N-nitrosodiethylamine in suggested to enhanced free radicals, disturbing
rodents have been used to initiate liver cancer the ROS status and ultimately leading to
for research on tumor promoters. Researchers oxidative stress and carcinogenesis (Ames et
may be subject to inhalational exposure to this al., 1993; Gey, 1993; Noguchi et al., 2000). It
chemical in animal rooms where animals is metabolized to its active ethyl radical
injected with it are kept. N- (CH3CH2+) metabolite by cytochrome and the
Nitrosodiethylamine constituted 5% of all reactive product interacts with DNA causing
airborne nitrosamines found in one study of the mutation and further which would lead to
vulcanized rubber industry. carcinogenesis (Anis et al., 2001).
N-Nitrosodiethylamine (DENA) released to Szatrowski and Nathan (1991) suggested that
water is expected to stay in solution and not tumor cells produce substantial amount of
partition to organic matter (Koc= 43). The hydrogen peroxide and reactive oxygen
estimated Henry's Law constant for DENA is metabolites that are released into the
1.1X10-8 atm-cu m/mol; therefore, circulation. Therefore, the increased
volatilization from water will probably not be susceptibility of plasma and red blood cells of
significant. Photolysis may be the most DENA-administered rats could be due to the
significant removal process for DENA since production of ROS during the metabolism of
89% degradation occurs in 7 hours with DENA or during the process of carcinogenesis.
sunlight. Incubation studies for 108 days in
It is widely accepted that DENA undergoes
lake water at 30°C in the dark indicate that
metabolic activation by cytochrome P450
hydrolysis and bio-concentration are not
enzyme to reactive electrophiles that are
significant processes. cytotoxic, mutagenic and carcinogenic.
Because of its relatively simple metabolic
pathway and potent carcinogenic activity,
Mechanism for DENA-induced oxidative
DENA has found widespread use as an
damage and carcinogenesis
experimental model in the field of
ROS and Oxidative stress carcinogenesis and in chemoprevention. A
Oxidative stress has recently been suggested to single administration of DENA induced liver
participate in both the metabolism (activation tumor is evidenced by the increase in liver
and detoxification) and the carcinogenic weight increased level of hepatic enzyme like
actions of nitrosamines, including DENA SGPT, SGOT, ALP, total bilirubin and
(Bartsch et al., 1989; Loeppky and Li, 1991). decrease in total proteins and increased levels
There are experimental, clinical and of GGPT, GPX, GST and LPO (oxidant
epidemiological reports that oxygen free enzymes), decrease in SOD and catalase (free
radicals and related lipid peroxides play a key radical scavengers) and morphological changes

N-Nitrosodiethylamine and carcinogenicity: An Over review


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noted by histopathological studies (Surender et Effect of DENA on Soft Tissues and their
al., 2011). Prevention
Herrold and Dunham, (1963) experiment DENA is one of the most well-known liver,
suggests three possible mechanisms for the lungs and kidney carcinogens. Tumors of the
carcinogenic effect of DENA on the liver, kidneys, and lungs have been induced in
respiratory system, liver, and ethmoturbinals. rats by the feeding diethylnitrosamine (Magee
These indude: (a) a local action of DENA; (b) and Barnes, 1956; Zak et al., 1960; Argus and
that the DENA or a metabolite present in the HochLigeti, 1961; Magee and Barnes, 1962).
circulating blood is selectively deposited in
N-Nitrosodiethylamine is a powerful and
various tissues where it is metabolized to a
potent hepatocarcinogenic dialkyl nitrosamine
carcinogen; or (c) that a carcinogenic
that has been used as an initiating agent in
metabolite is excreted via the respiratory
some 2 stage (initiation and promotion)
system.
protocols for hepatocarcinogenic studies. It is
The work of Druckrey and his colleagues metabolized to reactive electrophilic reactants
(1961 and 1962) has been considered as that alter the structure of DNA and forms alkyl
supporting a theory that the DNA adducts (Yoshiji et al., 1991).
dialkylnitnosamines are carcinogenic by virtue Sundaresan, and Subramanian (2003) showed
of their metabolic conversion to active that administration of s-allylcysteine could
alkylating agents, diazoalkanes. The theory prevent DENA-induced hepatocarcinogenesis
proposed that a specific “dealkylizing” enzyme in rats. It has been reported that DENA is
is not required for each tissue and that metabolized to alkylating reactants, which
enzymatic oxidation in the alpha carbon atom could interact with DNA molecule and initiate
is sufficient, with the result that the alkyl carcinogenesis (Anis et al., 2001).
residue is quickly split off because the
Shaarawy et al, (2009) reported the protective
oxidation products are chemically unstable,
effects of garlic and silymarin on DENA-
and the diazoalkanes are formed (Druckret and
induced rats hepatotoxicity. In this study, they
Preussmann, 1962).
demonstrated that the injection of DENA to
An estimation of lipid peroxidation products rats lead to a marked elevation in the levels of
and antioxidants has accepted them as serum AST, ALT and ALP which is indicative
significant biomarkers of cancer of hepatocellular damage, as previously
chemoprevention (Hayes and Pulford, 1995). reported (Bansal et al., 2005).
Decreased activities of GPx, SOD and CAT in
Melatonin Modulates the oxidant–antioxidant
DENA-treated rats could be due to
Imbalance during N-Nitrosodiethylamine
overutilization of these non-enzymatic and
Induced hepatocarcinogenesis in rats was
enzymatic antioxidants to scavenge the
reported by Dakshayani et al. (2005). Chodon
products of lipid peroxidation. Tumor cells
et al., (2008) find out the effect of Genistein on
have been reported to sequester essential
modulating lipid peroxidation and membrane-
antioxidants from the circulation, in order to
bound enzymes in N-Nitrosodithylamine
meet the demands of the growing tumor
induced and Phenobarbital- promoted rat liver
(Buzby et al., 1980; Corrocher et al., 1986).
carcinogenesis.
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Hydro-ethanolic extract of E. neriifolia leaves hypercholesterolemic conditions but DENA


have been observed to possess administration caused severe granular
chemopreventive effect against DENA-induced degeneration and coagulative necrosis in
renal carcinogenesis in mice (Janmeda et al., kidneys (Mittal et al., 2006).
2011). We have also reported the
chemoprotective activity of hydro-ethanolic
extract of euphorbia neriifolia Linn. leaves Chemoprevention
against DENA-induced liver carcinogenesis in Chemoprevention is a major area that has been
mice (Pracheta et al., 2011). EN extract intensively investigated in recent years. A large
restored SOD and CAT enzyme levels in the number of agents including natural and
liver and kidney. synthetic compounds have been shown to
Zak et al. (1960) demonstrated that DENA possess chemopreventive value. This warrants
produced lesions in the kidney, as well as the exploration and evaluation of effective
tumors of the trachea and bronchus. They anticancer drugs which could be easily
believe that the kidney lesions may represent available. Chemopreventive agents can be
an early stage in tumor development. This can divided into two groups: antimutagenic and
be supported by Magee and Barnes (1962). antiproliferative: Antimutagens reduce the
Dontenwill et al. (1961; 1962) reported that formation of carcinogens or mutagens there by
squamous-cell carcinoma of the trachea and preventing DNA damage through suppression
lung of Syrian hamsters followed of phase I enzymes or enhancement of Phase II
administration of DENA by each of three detoxifying enzymes and alternatively
approaches-tube feeding, inhalation, and chemopreventive agents may exert
subcutaneous injection. antiproliferative effects via induction of cell
cycle arrest or apoptosis, inhibition of terminal
In lungs, administration of DENA resulted in
differentiation and inhibition of oncogene
chronic interstitial pneumonia along with
activity or DNA synthesis (Wu et al. 2001;
infiltration of leukocytes. Under
Wu, Kassie and Mersch– Sundermann 2004).
hypercholesterolemic conditions, liver showed
The search for new chemopreventive and
vacuolar degeneration and swelling of
antitumor agents that are more effective and
hepatocytes but more severe changes were
less toxic than existing agents has kindled great
seen upon DENA administration, such as
interest in phytochemicals.
accumulation of lipid droplets in hepatocyte,
granular degeneration along with infiltration of
fibroblasts indicating chronic change. In Synthetic or Natural Approach
spleen, there was a depletion of lymphocytes
In the recent times focus on plant research has
from lymphoid follicles under
increased all over the world and a large body
hypercholesterolemic conditions.
of evidence has collected to show immense
Administration of DENA, however, also
potential of medicinal plants used in various
resulted in congestion and hemorrhage in
traditional systems (Modzelewska et al., 2005).
spleen along with severe depletion of lymphoid
One of the oldest, most effective strategies for
cells. Kidneys showed mild congestion under
developing new chemotherapeutics is the

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isolation and evaluation of chemicals of natural Bartsch, H. and Montesano, R., 1984.
origin. The importance of natural products for Relevance of nitrosamines to human
drug discovery has been impressive. cancer. Carcinogenesis, 5:1381–1393.
Chemoprevention involving the use of natural
Bartsch, H., Hietanen, E. and Malaveille, C.,
products to inhibit or reverse the carcinogenic
1989. Carcinogenic nitrosamines: free
process is an effective approach to control
radical aspects of their action. Free
cancer.
Radic Med Biol, 7:637–644.
Acknowledgement Brunnemann, K.D., Yu, L. and Hoffmann, D.,
The authors are thankful to the authorities of 1977. Assessment of carcinogenic
Banasthali University for providing support to volatile N-nitrosamines in tobacco and
the study. in mainstream and sidestream smoke
from cigarettes. Cancer Research,
37(9): 3218-22.
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