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Indian J Occup Environ Med. 2011 Sep-Dec; 15(3): 8792.

doi: 10.4103/0019-5278.93195

PMCID: PMC3299103

Oxidative stress effects of thinner inhalation


Minerva Martnez-Alfaro, Yolanda Alcaraz-Contreras, Alfonso Crabez-Trejo, and Guillermo E. Leo-
Amador1

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299103/
Abstract
Thinners are chemical mixtures used as industrial solvents. Humans can come into contact
with thinner by occupational exposure or by intentional inhalation abuse. Thinner sniffing
causes damage to the brain, kidney, liver, lung, and reproductive system. We discuss some
proposed mechanism by which thinner induces damage. Recently, the induction of oxidative
stress has been suggested as a possible mechanism of damage. This paper reviews the current
evidence for oxidative stress effects induced by thinner inhalation. Early ideas about the
effects of thinner on lipids are discussed in one section. We discuss several studies that have
shown the oxidative effects of thinner inhalation on: lipid peroxidation, levels of antioxidant
enzymes, glutathione depletion, and oxidation of proteins and DNA. We have also included
studies about oxidative stress effects induced by toluene, the principal component (60-70%)
of thinner. Finally, work describing the effects of oxidative stress induced by thinner
inhalation on different organs is discussed.

Keywords: Organ effects, oxidative stress, thinner inhalation


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INTRODUCTION
Intentional inhalation is a health problem throughout the world. The majority of drug users
are children or adolescents, and most of them get are initiated as drug abuser with thinner.
One of the reasons of this is that it is easily available and inexpensive compared to other
drugs.[13] Conversely, toxicology mechanism of thinner inhalation as mix is not frequent
studied. Oxidative stress effects on these organs by thinner inhalation are reviewed. A
systematic review was carried out in PubMed using the word thinner inhalation 96 articles
were reviewed only 12 describes oxidative stress effect of thinner inhalation considering
thinner as mix.

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THINNER COMPOSITION
Thinner is a solvent mixture used in both household products and industrial settings; it has a
highly variable composition, displaying both temporal and geographic differences. In
addition, thinner components vary depending on regulatory specifications or processing
techniques. Toluene and acetone were the most abundant compounds in commercial thinner
samples from Mexico City analyzed in 1997. These samples were analyzed by gas
chromatography, and the toluene content varied from 7% to 77%;[4] benzene was identified
in 62% of the samples, and it accounted for 0% to 2.2% (average 0.3%, v/v). In Japan,
Saito[5] analyzed four thinner preparations by capillary gas chromatography. Acetone and
methyl isobutyl ketone, together with toluene, were the most common solvents found;
chlorinated hydrocarbons and ethylene glycol derivatives were seldom detected.

Proportions of ingredients vary significantly; current regulatory laws have greatly reduced the
inclusion of benzene, and in Mexico, there is a commercial thinner without benzene. This is
important, since benzene is classified as genotoxic by the IARC.[6]

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EARLY IDEAS ABOUT MECHANISM OF TOXICITY


The major component of thinner is toluene, a well-known neurotoxic agent. Acute and
chronic effects of toluene on neurons have been well documented.[7] The first ideas to
explain the mechanism of the neurotoxic effects of solvents such as toluene were based on the
lipid hypothesis, which proposed that perturbation of the lipid bilayer would result in
dysfunctional membrane proteins. Solvents were thought act on lipids in the cell membrane,
because toluene and other solvents have lipophilic properties that allow them to reach high
concentrations in the CNS. In this review, we include some studies about the effect of toluene
on lipids. Lipid changes were observed in rat brain exposed to toluene (320 ppm) for 30 days.
Total phospholipids were reduced in the cerebral cortex, where a slight increase in
phosphatidic acid was also observed. No changes were observed in the brainstem. The
mechanism for these changes is uncertain.[8] Studies of the effects of toluene on membrane
fluidity demonstrated that in vivo administration of toluene in rat (1 g/kg, 1 h, i.p.) increased
the synaptosomal membrane fluidity. The authors proposed a specific toluene-phospholipid
interaction in synaptosomes that resulted in altered membrane composition and fluidity.[9]
The same authors showed later that toluene increased phospholipid methylation and
stimulated Na and K adenosine triphosphatase (ATPase) activity in synaptosomes both in
vivo and in vitro.[10]

Inhibition of the integral enzymes acetylcholinesterase (AChE) and ATPase of rat


synaptosomal membrane after incubation with 3 mM toluene was observed in vitro.
Disruption of lipidprotein interactions was suggested as a mechanism of inhibition.[11]

Recently, biophysical studies of the protein-lipid interface, curvature elasticity, and the
polymorphic potential of lipid assemblies have shown the dynamics of the lipid membrane,
which can influence the function of membrane proteins. Changes in membrane lipids have an
effect on elastic fluctuations of the lipid bilayer that influence protein insertion and
conformational changes in the protein structure that are important for protein function.[12]

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OXIDATIVE STRESS
Oxidative stress is a cellular state characterized by an excess of oxidants (reactive oxygen and
nitrogen species) that overwhelms the antioxidant capacity. Oxidants are constituted by free
radical species containing reactive oxygen and nitrogen species. The presence of unpaired
electrons makes them unstable and highly reactive. DNA, RNA, proteins, and lipids are the
targets of these radicals. Reactive oxygen species (ROS) include oxygen-derived free
radicals: the superoxide anion radical and the hydroxyl radical or its derivates, such as
hydrogen peroxide. ROS are the result of the aerobic environment, and the superoxide anion
radical arises during mitochondrial respiration. Coenzyme Q (CoQ) sporadically loses an
electron in the transfer of reducing equivalents through the electron chain. This electron is
transferred to dissolve O2 producing superoxide. It is estimated that 1-2% of the O2 consumed
by mitochondria is converted to the superoxide anion radical.[13] Oxidative stress induces
oxidation of lipids, proteins, and DNA in cells and a response of a variety of cellular
detoxification systems: superoxide dismutase (SOD), glutathione peroxidase (GPX), and
glutathione (GSH).

Thinner inhalation induces oxidative stress. Activation of free radical processes underlies the
effect of many toxic substances like: ethanol, toluene, ionizing radiation, lead, arsenate, etc.
[14] In the case of thinner, there are some proposed mechanisms:

One of them is the oxidative metabolism of benzene, toluene, xylene, ethanol,


acetone, and tri-methylbenzene which generates cytosolic NADH. NADH is oxidized
indirectly by mitochondria electron transport depending on hydrogen shuttling
mechanism that involve carriers in the mitochondrial inner membrane. This condition
that increases mitochondrial NADH and enhance the reducing pressure on the
electron transport chain without increasing the rate of respiration promotes the
formation of O2 in the electron transport chain.[15]

The production of quinones by cytochrome P450, particularly during toluene, and


benzene metabolism is another mechanism proposed. These quinones are able to
establish a futile redox cycle (quinones and semiquinone radicals), during which
cytotoxic ROS are accumulated.[16]

Another mechanism is non-mitochondrial which increase ROS formation. Metabolism


of thinner's components results in activation of cytochrome P450 isoforms like
CYP2E1 which is prone to radical formation.[17]

In addition, toxic substances exposures cause inflammation. In the case of thinner,


inhalation induces inflammatory response in lungs. Considerable evidence supports a
role of inflammatory mediators released by phagocytic leukocytes and infiltrating
macrophages in the generation of reactive oxygen and nitrogen species in lung.
Macrophages produce NO (nitric oxide) via an inducible form of the enzyme, NO
synthase. This enzyme is up-regulated by inflammatory mediators such as cytokines
like tumor necrosis factor alpha (TNF-). Moreover, rapid and persistent activation of
nuclear factor B (NF- B) in alveolar macrophages induce the expression of an
inducible form of the enzyme NO synthase (iNOS) and the TNF- receptor. The
highly reactive O2-(superoxide anion) is released by stimulated leukocytes including
monocytes, macrophages, and polymorphonuclear leukocytes by the action of
NADPH oxidase.[18,19] There are many different methods to evaluate oxidative
stress.[20] The indices based on the composition of various biological specimens are
the most used. Most publications used at least two methods to assay oxidative stress,
evaluation of promoters and peroxidation products induced by oxidative,[21] oxidized
proteins,[22] and DNA oxidation.[23]

We review the different assays for evaluating oxidative stress induced in different organs by
inhalation of thinner and its principal component, toluene.

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EFFECTS ON ORGANS
Brain

Some studies about the oxidative stress showed induction of ROS caused by intraperitoneal
toluene exposure (1 g/kg, 1 h) in crude, synaptosomal, and microsomal fractions of cortex.
[24] In vivo exposure to various doses (0.5, 1.0, and 1.5 g/kg, ip) of toluene elicited elevated
ROS in crude mitochondrial fractions obtained from rat lung and kidney and synaptosomal
fractions from striatum and hippocampus. Hippocampus had the highest induced levels of
ROS.[25] Prenatal exposure of rats to toluene (1800 ppm, 6 hr/day on days 7-20 of
pregnancy) induces longlasting changes in the oxidative status and membrane fractions of
the fetal brains.[26]

Chronic inhalation of toluene produces oxidative stress in the brain. Increased activities of
glutathione peroxidase and the free radical process were observed with a dose of 10 times the
maximum permissible concentration (MPC, 500 mg/m3 of toluene) and showed free radical
activation (421 70) in comparison to the control value (26136).[27] Free radicals were
measured directly using a chemiluminescent probe that forms fluorescent products upon
interaction with free radicals. Partial spectral analysis of the chemiluminescence showed a
predominance of red-light-emitting species arising from the singlet oxygen dimol emission
peaks; a side reaction derived from the complex free radical sequence of lipid peroxidation
probably leads to light emission.[28]

More recently, the effect of chronic toluene exposure (15, 30, and 45 days) on oxidative stress
was investigated. Increases in the levels of the thiobarbituric acid reactive substance
(TBARS), glutathione reductase (GR), glutathione disulphide (GSSG), and superoxide
dismutase (SOD) were observed in various organs of the rat. Furthermore, the cortex and
cerebellum showed the greatest increase in an apoptotic marker (caspase 3), indicating that
apoptosis may play a role in toluene neurotoxicity.[29]

In the experimental studies performed on rats, levels of inhaled exposure are 3000 ppm
toluene at various durations of exposure. This level of exposure in experimentation is
comparable to the inhaled exposure which produces euphoria in humans[30] [Table 1].

Table 1
Oxidative stress effects of toluene on different organs

There are not many studies about the effects on brain of thinner inhalation. One case with
pathological and tomography analyses was reported by Escobar.[32] The patient was a 27-
year-old male who had been addicted for 12 years to glue and thinner inhalation and had
developed neurological and behavioral disturbances and finally died. Computed tomography
showed cerebral and cerebellar atrophy and dilated lateral ventricles that were confirmed by
pathological examination. There was a decrease in neuron density replaced by a diffuse
gliosis, demyelination, and thinning of both the cortex and corpus callosum. Giant axonal
degeneration was evident in long ascending and descending tracts in the spinal cord. Another
pathological and magnetic resonance study describes cerebellar and cerebral demyelination as
well as atrophy in humans as a result of toluene abuse.[33] Table 2 shows experimental
studies of thinner inhalation on rats all these studies toluene concentrations are more than
3000 ppm, this level is comparable to the inhaled exposure which produces euphoria in
humans [Table 2].

Table 2
Oxidative stress effects of toluene on different organs

More recently, oxidative stress effects of thinner inhalation (45 days) have been demonstrated
in brain. Neuronal damage induced by thinner inhalation generates glial reactivity in the
hippocampus, cortex, and cerebellum. This reactivity is demonstrated by a marked elevation
of glial fibrillary acidic protein (GFAP). Melatonin, a pineal hormone, is a free radical
scavenger, and it prevents oxidative damage to lipids, proteins, and nucleic acids induced by
thinner inhalation; it also prevents the increase of GFPA and decreases the oxidative effects
induced by thinner inhalation.[37]

Chronic exposure to thinner inhalation (45 days) induced oxidative stress in brain; the lipid
peroxidation level was increased, and the expression of neural cell adhesion molecules
(NCAM) 140 and NCAM 180 in hippocampus and the cortex was reduced. The mechanism
postulated was the interference with the synthesis of NCAM by thinner-induced oxidative
stress. NCAM proteins are crucial for the stabilization of cell binding at synaptic sites. In
addition, rats showed learning and memory deficits in the passive avoidance and Morris
water maze tasks.[38]

Oxidative stress effects in the brain of rats exposed to chronic thinner inhalation (16 weeks)
were an increase of MDA and a decrease of GSH. These effects correlate well with oxidative
DNA damage in lymphocytes over the course of the treatment.[39]

Normal brain consumes a large quantity of oxygen, naturally forms oxidants for auto-
oxidation of some neurotransmitters, and is relatively poor in antioxidant capacity, which
makes it particularly vulnerable to oxidative damage[40] and might help to explain the
neurotoxic effects of thinner. Nevertheless, additional knowledge is needed about the
interaction of oxidative stress with other pathological mechanisms, such as apoptosis or
necrosis.

Lung

Oxidative stress effects were observed on lung tissues of rats exposed for 5 weeks to thinner
inhalation. MDA levels significantly increased between the second and the fifth weeks of
thinner inhalation. A decrease in superoxide dismutase activity was observed from the third
week until the end of the treatment. Glutathione levels increased in the first 2 weeks of
exposure, and then decreased from the third until the fifth week of inhalation treatment.
Chronic inflammatory changes, alveolar epithelial proliferation, collapse, emphysematous
changes, and interstitial fibrosis were detected in the lung.[34]

In a long-term study, rats were exposed for 12 weeks to high concentrations of thinner. An
increase in MDA values was observed, whereas GSH values decreased until 6 weeks and then
increased again. SOD levels did not change significantly. Emphysema similar to chronic
obstructive disease was observed in the lung.[35]

In a recent study, N-acetylcysteine (NAC), which is a precursor of GSH and can replenish the
intracellular GSH stores, was found to act also as a scavenging agent by itself. When
administered to rats concomitantly with thinner inhalation, NAC significantly lowered the
tissue MDA levels throughout the 8-week treatment, as compared to the rats exposed to
thinner only. In addition, tissue GSH levels of the rats given NAC while inhaling thinner
were significantly higher than those of rats that inhaled thinner without NAC treatment.
However, although the MDA and GSH levels indicated that oxidative stress caused by thinner
inhalation was reduced by NAC, no beneficial effect on lung morphology was observed by
light microscopy.[36]

Kidney

Epicutaneous administration of toluene in pigs caused progressing nuclear pyknosis and


junctional separation between the basement membrane and the basal cells; it also induced
spongiosis before the junctional separation.[41] Renal function was measured in workers
exposed to a mixture of toluene and xylene. Renal function impairment indicators included
total proteinuria, albuminuria, and urinary excretion of muramidase; the levels of these
parameters suggested mild tubular lesions.[42]

Acute renal failure induced by toluene-containing adhesive was reported. Histopathological


changes induced by thinner inhalation were tubular damage in the form of patches and severe
tubulointersticial nephrits in kidneys.[43]

The effects of thinner inhalation and smoking on rat kidney were studied for 6 weeks, and
evidence of interstitial cell infiltration and interstitial nephritis characterized by fibrosis was
observed. In addition, focal necrosis in the epithelium of proximal tubules was seen in the
kidney of rats that were exposed to thinner fumes and cigarette smoke.[44]

Blood

There have been a few studies about the oxidative DNA damage caused by toluene.[16]
Studies have shown the oxidative effects of thinner inhalation on lipid peroxidation, levels of
antioxidant enzymes; in addition, glutathione depletion was observed in the plasma of
adolescents with inhalant abuse and people working with paint thinner.[2,45]

Thinner inhalation induced oxidative damage in the DNA of rat lymphocytes. This oxidative
damage was correlated with the other, widely used biomarkers of oxidative stress, increased
MDA and decreased GSH levels in brain and liver.[39] Inhalation of thinner induces
oxidative stress in the plasma of rats. Nevertheless, thinner inhalation does not damage DNA
by inducing single- or double-strand breaks; moreover, thinner does not alter DNA repair.
This may indicate that oxidative stress, a well-documented effect of thinner inhalation, does
not induce genotoxic effects.[46]
Toluene exposure increased oxidative stress parameters (MDA and protein carbonyl levels) in
human erythrocytes after in vivo and in vitro exposure. Osmotic fragility in erythrocytes was
altered only after in vitro exposure to toluene, and new synthesis of membrane components is
important. The erythrocytes tested were from individuals exposed to toluene in the work
place.[47]

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DISCUSSION
The aim of this review has been to describe oxidative stress effects of thinner inhalation in
animal models of solvent abuse. The current evidence suggests that oxidative stress is a
common mechanism of many toxic substances. Many pathways play a key role in how
thinner induces oxidative stress. We have discussed some of these pathways: metabolism of
thinner components, enzymes (P450), metabolites (quinones), inflammatory reactions or
indirectly via its solvent-like actions affecting lipid membranes. These pathways are not
exclusive of one another indeed, all mechanisms contribute to the ability of thinner to induce
oxidative stress. This mechanism plays a major role by which thinner induces brain damage.
The evidence that thinner-induced oxidative stress plays a role in cell injury is showed in two
studies. Administration of antioxidant can prevent or ameliorate the toxic action of thinner in
the nervous system. In rats, learning and memory deficits induced by thinner inhalation are
reversed by melatonin.[37] Melatonin administration significantly reduced lipid peroxidation
and elevated glutathione levels in brain in this study. In contrast, N-acetylcystein (an oxygen
radical scavenger) administration reduces the level oxidative stress effects on lungs.
Nevertheless, pathological examinations did not show any beneficial effect of N-acetylcystein
application. On the other hand, oxidative stress is related to apoptosis in only one study.[36]

Thinner consists of a large numbers of components in a complex mixture, widely used in


home and industry. Real life always involves simultaneous exposures to multiple solvents,
indicating the need for experimental work with combinations of substances. However,
assessing the effects of chemical mixtures is a complex topic. In the case of studying thinner,
problems like: the variability of its composition among the different types on the market and
the complex toxicokinetics chemical interactions between thinner components. Future studies
are required to further clarify thinner metabolic interactions.

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ACKNOWLEDGEMENT
The authors thank Dr. Dorothy Pless for her language assistance.

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Footnotes
Source of Support: PROMEP- SEP Project 103.5/10/7310

Conflict of Interest: None declared


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