Formaldehyde Exposure and Neuropsychiatric Disorders

Abstract

Formaldehyde is getting more widely used in modern industrial and information society. Exposure to ambient air pollution is a serious and common public health concern. The high risk of formaldehyde exposure often occurs in the occupational settings, including scientific laboratories in hospitals and universities, particle board/plywood plants, fire sites, etc. Despite the data showing workplace formaldehyde exposures well below those typically considered risks to health, workers complained psychiatric disorders more frequently, and the syndromes could be rescued after leaving the workplace for a period of time. In addition to the occupational formaldehyde exposure sites, urea-formaldehyde resins in building and furnishing materials contributes to the major component of indoor air pollution where people act and live in newly decorated houses and rooms. More people are at high risk of long-term and low-level formaldehyde exposure because of the low ventilation rate indoor. Epidemiological studies show that people complain a series of neuropsychiatric symptoms, such as depression, anxiety, sleep disorders, malaise, balance dysfunctions, headache, indigestion, lethargy, decrease in motor activity and loss of appetite. All those further confirmed that the neuropsychiatric symptoms are highly related to the long-term formaldehyde exposure in the air. In the case of long-term formaldehyde exposure, the victims (17 males, 20 females; average age of 38 years old) mainly showed anxiety symptoms. Around 60.7% of them had elevated levels of urine formaldehyde compared with the normal control. In other words, it is necessary to determine and monitor endogenous formaldehyde for the victims suffering a long-term exposure. Although exogenous formaldehyde causes depression, anxiety and circadian rhythm disorders, whether endogenous formaldehyde induces those symptoms is still unclear. Here, we discuss the effects of formaldehyde exposure on psychosomatic behaviours such as rhythm disorders, depression, anxiety and other behavioural disorders except for cognitive impairment.

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191© Springer Science+Business Media B.V. 2017
R. He, Formaldehyde and Cognition, DOI 10.1007/978-94-024-1177-5_10
Chapter 10
Formaldehyde Exposure andNeuropsychiatric
Disorders
XiumeiWang andRongqiaoHe
Abstract Formaldehyde is getting more widely used in modern industrial and
information society. Exposure to ambient air pollution is a serious and common
public health concern. The high risk of formaldehyde exposure often occurs in the
occupational settings, including scientic laboratories in hospitals and universities,
particle board/plywood plants, re sites, etc. Despite the data showing workplace
formaldehyde exposures well below those typically considered risks to health,
workers complained psychiatric disorders more frequently, and the syndromes
could be rescued after leaving the workplace for a period of time. In addition to the
occupational formaldehyde exposure sites, urea-formaldehyde resins in building
and furnishing materials contributes to the major component of indoor air pollution
where people act and live in newly decorated houses and rooms. More people are at
high risk of long-term and low-level formaldehyde exposure because of the low
ventilation rate indoor. Epidemiological studies show that people complain a series
of neuropsychiatric symptoms, such as depression, anxiety, sleep disorders, mal-
aise, balance dysfunctions, headache, indigestion, lethargy, decrease in motor activ-
ity and loss of appetite. All those further conrmed that the neuropsychiatric
symptoms are highly related to the long-term formaldehyde exposure in the air.
Inthe case of long-term formaldehyde exposure, the victims (17 males, 20 females;
average age of 38years old) mainly showed anxiety symptoms. Around 60.7% of
them had elevated levels of urine formaldehyde compared with the normal control.
In other words, it is necessary to determine and monitor endogenous formaldehyde
for the victims suffering a long-term exposure. Although exogenous formaldehyde
causes depression, anxiety and circadian rhythm disorders, whether endogenous
formaldehyde induces those symptoms is still unclear. Here, we discuss the
effects of formaldehyde exposure on psychosomatic behaviours such as rhythm
X. Wang
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese
Academy of Sciences, Beijing 100101, China
R. He (*)
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese
Academy of Sciences, Beijing 100101, China
University of Chinese Academy of Sciences, Beijing 100049, China
e-mail: rongqiaohe@163.com

192
disorders, depression, anxiety and other behavioural disorders except for cognitive
impairment.
Keywords Formaldehyde • Exposure • Neuropsychiatric disorder • Anxiety •
Depression • Circadian rhythm
1 Introduction
Formaldehyde is ubiquitous, which enters the human body through different ways
such as respiratory tract, skin absorption and food intake. Due to the high water
solubility and reactivity, the airborne formaldehyde is absorbed mainly in the upper
airways (>90%) (Nielsen etal. 2013). Low level of chronic formaldehyde exposure
in the airborne environment mainly induces disorders of respiratory symptoms such
as rhinitis and anaphylaxis, as well as the effects on neurological, musculoskeletal,
dermatological, gastrointestinal, cardiac and endocrinological systems (Gibson and
Vogel 2009). High-level exposure has the potential risk to cause tumours in the
upper respiratory tract (Kilburn etal. 1985a) and leukaemia (Cogliano etal. 2005).
The International Agency for Research on Cancer (IARC) has evaluated: “There is
sufcient evidence in humans for the carcinogenicity of formaldehyde. Formaldehyde
causes cancer of the nasopharynx and leukaemia” (IARC2012).
Generally speaking, exposure to formaldehyde is higher indoors than outdoors.
This is mainly due to the multiple formaldehyde sources and low air exchange rates
in the indoor environment. Persistent central nervous system (CNS) symptoms and
impairments have been reported in occupationally or nonoccupationally
formaldehyde- exposed humans (Sparks etal. 1990; Lu etal. 2008). Epidemiological
studies have shown that work-related exposure to formaldehyde results in head-
aches, anxiety, depression, panic, fatigue, sleep disorders, cognition and memory
decline (Kilburn etal. 1987). Formaldehyde exposure to murine has effect on anxi-
ety, depression, cognitive ability, exhibiting the same behaviour symptoms like
humans (Bhatt and Panchal 1992; Aslan etal. 2006; Li etal. 2016a).
Because occupational formaldehyde places have protective measures, the people
could reduce the risk of high-concentration formaldehyde exposure in working
place except for accident. But materials containing formaldehyde resin are widely
used in house decoration, and more and more people are subjected in low-level and
long-term formaldehyde exposure environment. Coincidentally, clinical patients
with melatonin (MT) deciency also complain cognitive problems associated with
the mental disorders discribed above. Age-related cognitive impairment is often
accompanied with neuropsychiatric disorders such as sleep disorders, depression,
anxiety and aggression. The indoor symptom, named sick building syndrome (SBS),
affects the normal life and work on people. Mental disorders should be paid atten-
tion to and deserved research (Hu etal. 2016), in order to avoid cell dysfunction,
substantive organ damage and even cancer caused by formaldehyde. We have
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193
reviewed cognitive dysfunction and formaldehyde in Chap. 8. Here, we are going to
discuss the effects of formaldehyde exposure on psychosomatic behaviours such as
biological rhythm, depression, anxiety and the other behavioural disorders except
for cognitive impairment.
2 Formaldehyde andCircadian Rhythm
2.1 Formaldehyde Exposure Disturbing Sleep
It is known that there is disturbed circadian rhythm in Alzheimer’s patients, which
is related to the declined cognitive function. In 1985, Kilburn and colleagues
recruited the women working in histology who had daily exposure to formaldehyde,
xylene and toluene and the unexposed female clerical workers working in the same
hospitals. They compared the disturbances of sleep, memory, mood and equilibrium
that occurred simultaneously with headache and indigestion. They found that form-
aldehyde exposure correlated better with neurobehavioural symptoms and with
respiratory and mucous membrane symptoms than did exposure to xylene/toluene
or to other agents (Kilburn etal. 1985a). Weber and colleagues reported a family
with chronic exposure to formaldehyde in a renovated apartment. The family mem-
bers suffered from sleeping disturbances, malaise, headache and nausea, besides
eye and upper airway irritation and lack of appetite (Weber etal. 1988). In fact,
formaldehyde has long been used as a pain agent for disturbance on sleeping
(Coderre et al. 1984; Park et al. 2011). Zaman and collaborators performed
formaldehyde- induced paw oedema with pain to disturb sleeping in the study of
Nidrakar Bati, an herbal remedy used to cure somnifacient (sleeping aid) in South
Asia as Ayurvedic medicinal system (Zaman etal. 2015). To mimic the occupational
formaldehyde exposure environment, Mei and collaborators employed 16 healthy
adult male mice which were exposed to gaseous formaldehyde (3mg/m3) for 7 con-
secutive days. Formaldehyde exposure elicits an intensive oxidative stress by reduc-
ing systemic glutathione levels, in particular, decreasing the concentrations of brain
melatonin (MT), accompanied with the impairment of spatial memory associated
with hippocampal neuronal death (Mei et al. 2016). Zhou and colleagues have
reported the disturbance of circadian rhythm and melatonin levels as an early event
in the process of AD, which is accompanied with the progression of AD neuropa-
thology. They employed melatonin asa drug to treat AD patients combined with
light regulation, and delayed the impairment of their cognitive function (Zhou and
Liu 2012). So far, however, evidence should be obtained to support the hypothesis
that formaldehyde is involved in circadian rhythm. Whether MT ameliorates the
disorders in circadian rhythm through regulation of the metabolism of endogenous
formaldehyde needs to be investigated.
10 Formaldehyde and Neuropsychiatry

194
2.2 Formaldehyde Exposure Affecting Water Intake Habit
In order to investigate the relationship between formaldehyde and circadian rhythm,
Li and her colleagues rst compared the water-intake frequency and volume of
1-month-old mice with 10-month-old mice. The water intake of old mice decreased
in both the frequency and volume (Li etal. 2012). Then, they intraperitoneally
injectedthe mice with formaldehyde (0.5mg/kg, once daily) for a week, and then
they monitored the mice in their water-intake frequency and volume (Li et al.
2016c). Both the frequency and volume of water intake signicantly decreased
compared with those of mice injected with saline as control. Furthermore, changes
in the frequency of water intake per hour were also observed in the formaldehyde-
treated group. In other words, administration with formaldehyde could change the
daily rhythm of the mice in their water intakehabit. Furthermore, Mei and col-
leagues’ work shows that formaldehyde affects endogenous MT metabolism and
intraperitoneal injection of MT markedly attenuated formaldehyde-induced hippo-
campal neuronal death, restored brain MT levels and reversed memory decline.
Formaldehyde directly inactivates MT in vitro and in vivo (Mei et al. 2016).
Melatonin supplementation could contribute to the rescue of the biological rhyth-
mic disorders and age-related cognitive impairment (Maurizi 1987; Skene etal.
1990). These data support the hypothesis that endogenous formaldehyde is involved
in daily biological rhythm of animals’ behaviours (Li etal. 2016c).
3 Changes inNeuropsychological Behaviours
3.1 Formaldehyde andDepression
Formaldehyde exposure causes emotional and behavioural symptoms. In a case
series study of composite-material workers who were in the phenol-formaldehyde
exposure condition, ~19% of them had antecedent depression disease (Parks and
Pilisuk 1991). The hippocampus is in situ at the limbic area involved in emotion,
memory and learning. It is known to possess the greatest levels of adrenocorticoste-
roid receptor binding and mRNA expression (Reul and de Kloet 1985; Aronsson
etal. 1988; Reul etal. 1989), which more likely underlie the deleterious effects of
glucocorticoids on learning and memory and long-term potentiation (Diamond and
Rose 1994; Bodnoff etal. 1995).
Formaldehyde exposure can activate the hypothalamic-pituitary-adrenal gland
(HPA) axis and subsequently increase levels of glucocorticoids (Dallman etal. 2003;
Makino etal. 2002; Sorg etal. 2001a) that regulate the HPA response via negative
feedback of glucocorticoid receptors (GRs) binding in the hippocampus (Raone etal.
2007). Repeated stress exposure and long-term glucocorticoid treatment downregu-
late levels of brain GRs, in particular of the hippocampus (Huot etal. 2004; Kitraki
etal. 2004). Li and colleagues used open-eld tests (OFT), elevated plus-maze tests
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195
(EPM) and forced swimming tests (FST) to assess levels of anxiety- and depression-
like behaviours following repeated formaldehyde exposure. They observed that
repeated formaldehyde exposure reduces levels of GRs in the hippocampus (Li etal.
2016a). As we know, low levels of GRs in the hippocampus induce less negative
feedback to regulate levels ofcorticosterone (CORT) (Kitraki etal. 2004), subse-
quently increase levels of CORT and lead to higher levels of anxiety and depression.
Acute formaldehyde (5ppm) exposure resulted in decreased motor activity and
increased levels of dopamine (DA) together with its enzymatic metabolites in the
hypothalamus of rats (Boja et al. 1985). Inhalative formaldehyde treatment
(13.5±1.5ppm) for 2 weeks enhances aggressive behaviour and increases DA in
the frontal cortex synaptosome (Liu etal. 2009). In other words, changes in behav-
iour induced by formaldehyde exposure could be associated with alteration in DA
levels because DA plays a role in the control motor activity and emotional behav-
iour (Gainetdinov etal. 1999; Rodgers etal. 1994; Zhuang etal. 1999; Zhou and
Palmiter 1995). Tyrosine hydroxylase (TH), a rate-limiting enzyme for DA synthe-
sis, as an indicator of DA production, is distributed in many areas of the rat brain. Li
and her colleagues found that different concentrations of gaseous formaldehyde
exposure result in different effects on anxiety, depression-like behaviour and cogni-
tion ability, which may be associated with alterations in hippocampal glucocorti-
coid receptors and brain tyrosine hydroxylase levels (Li etal. 2016a).
3.2 Formaldehyde andAnxiety
Though anxiety, another nervous disorder, is different from depression, many peo-
ple who develop depression have a history of an anxiety disorder earlier in their
lives. It is usual for someone with an anxiety disorder toalso suffer from depression.
The two psychosomatic disorders are often co-occurrence. Actually, the anxiety-
like behaviour was also observed in the 1 week formaldehyde-exposed mice. The
data from open-eld test and elevated plus-maze test supported the relation between
formaldehyde exposure and anxiety. Even if mice were exposed to the formalde-
hyde vapour (1.1, 2.3 and 2.5ppm) for 2h, their locomotor and explorative activity
in the open eld would be affected (Malek etal. 2004). They could still observe the
effects on the mice after 24h. These data suggested that formaldehyde can induce
emotional and mood changes, even disorders.
Formaldehyde has been used as an inducer in pain-associated anxiety (Rahman
etal. 1994a), namely, the animal model of experimental pain/anxiety (Rahman etal.
1994b). In the study of chemical intolerance, Sorg and colleagues observed that
repeated low-level formaldehyde exposure produces and increases anxiety, besides
sleep disturbance and/or fatigue (Sorg etal. 2001b). Li and her colleagues intraperi-
toneally injected mice with formaldehyde (once daily) for 7 days, leading to a
decrease of brain 5-hydroxytryptamine (5-TH) compared with the control group.
Simultaneously, the formaldehyde-treated mice became markedly sensitive and eas-
ily irritated, besides slower learning in “Shuttle box” behaviour assay than those fed
10 Formaldehyde and Neuropsychiatry

196
with water as controls (Li etal. 2016a, b, c ). Behavioural sensitization occurred
after the mice were injected with formaldehyde for 7 days, suggesting anxiety
induced by formaldehyde, similar to the results reported by Sorg and colleagues
previously (Sorg etal. 2001b). Behavioural sensitization, easy irritation and anxiety
also were observed in monkey trials after the animal had drunk 3% methanol for
3months.
Herewith is an unpublished data about a case of about 37 staffs (17 males, 20
females; 28–55years old, average age of 38years old) who worked in a company
complaining of the air pollution with formaldehyde or other organic compounds in
their workplace. They were worried about their health in the presence of formalde-
hyde odour. Some of them showed anxiety-like behaviours such as headache, ver-
tigo, nausea, indigestion, dry mouth, fatigue and itchy skin (World Health
Organization 2009; Testa etal. 2013). The authors collected their urine (28 of them)
and measured the concentrations of urine formaldehyde by using HPLC coupled
withdinitrophenylhydrazone (DNPH). Seventeen (60.7%) of them had high levels
of urine formaldehyde compared with the age-matched normal control
(5.9±0.62μM). Among the participants with high formaldehyde levels, 73.33%
(11/15) were males, and 46.15% (6/13) were females. The most irrational and
excessively worried person who had the highest concentration of endogenous form-
aldehyde (18.28μM) was working in the same ofce with the other two persons
whose formaldehyde levels were 15.13μM and 12.26μM.They complained of the
formaldehyde odour in their ofce and felt agitated and restless. It was possible that
the wood desk they sat at contained excess formaldehyde released into the ofce air.
However, it was difcult to make a conclusion that their anxious symptoms are
directly resulted from the formaldehyde toxicosis because their behaviours were
also affected by improper emotions. The urine samples were only 28, too small to
get a solid conclusion. Referred to the reports by Kilburn and colleagues (1985a, b,
1998), these data suggested that a long-term exposure to formaldehyde affects
human’s mood including anxiety and sensitization. In addition, determination of
endogenous formaldehyde should be recommended for the victims who have long
been exposed to a polluted environment.
4 Changes inNeurobiological Behaviours
4.1 Olfaction Impairment
Formaldehyde is colourless, with a particular pungent smell of gas. Even in very
low concentrations, it can be smeltout and induce lesions in the nasal area. It has
been previously established that the low-level formaldehyde exposure (0.25ppm for
130days) can inuence odour sensitivity (Apfelbach and Weiler 1991). Zhang and
his colleagues found that in the higher concentration for short time (13.5±1.5ppm,
twice 30minutes/day for 14days), the rat olfactory function was impaired by buried
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197
food pellet test (Zhang etal. 2014). As described by Lang and colleagues, olfactory
symptoms occurred at concentrations as low as 0.3ppm. Long-term formaldehyde
inhalation can change cellular morphologies in the olfactory bulb (Lang etal. 2008).
Therefore, we suggest the effects of formaldehyde on the olfactory system should
be urgently paid attention to.
MicroRNA (miRNA) is a small non-coding RNA molecule involved in a wide
range of biological processes such as cell cycle control, apoptosis and several devel-
opmental and physiological processes includingthe differentiation of olfactory pre-
cursors, olfactory neuron morphogenesis and neurogenesis. Recently, Li and
coworkers have tried to study the molecular mechanisms of formaldehyde-induced
olfactory dysfunction (Li et al. 2015). They found that formaldehyde inhalation
markedly alters the miRNA expression prole of olfactory bulb. With high-
throughput microarray technology, 18 upregulated miRNAs and 7 downregulated
miRNAs were identied (Li etal. 2015). Among them, miR-199a, miR-146b and
miR-200a were changed most. A long-termformaldehyde exposure resulted in an
increase in the number of tyrosine hydroxylase-immunopositive periglomerular cells
of the main olfactory bulb (Hayashi etal. 2004). As we know, tyrosine hydroxylase
uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to dopamine. The
olfactory bulb of mammals has a large population of dopaminergic neurons within
the glomerular layer. Dopamine has been proved to modulate olfactory information
processing. Synaptosomal-associated protein 25 (SNAP25) is a presynaptic plasma
membrane protein involved in the regulation of neurotransmitter release. The olfac-
tory bulbs exhibit high levels of SNAP25. After formaldehyde exposure, the protein
expression decreased (Zhang etal. 2014). These results show that formaldehyde may
impact the olfaction by affecting neurotransmitter system.
4.2 Algesthesia
Formalin, an aqueous solution of formaldehyde, is commonly employed to study
algesthesia. The rodent formalin model is utilized for evaluating the effects of pain
and analgesic compounds in laboratory animals (Tajolsen etal. 1992). When forma-
lin is injected into the paw of a rodent, it will induce biphasic nociceptive behav-
ioural responses including early and late phases. The early-phase response seems to
be caused by direct activation of the small primary afferents, while the late phase is
dependent on the combination of an inammatory reaction in the peripheral tissue
and functional changes in the dorsal horn of the spinal cord. It is a valuable test
available to study nociception. A lot of research has been done to uncover the mech-
anisms. Transient receptor potential cation channel, subfamily A, member 1
(TRPA1) is identied as the principal site of formalin’s pain-producing action
(McNamara et al. 2007). The activation of this excitatory channel underlies the
10 Formaldehyde and Neuropsychiatry

198
physiological and behavioural responses associated with this model of pain
hypersensitivity.
The other pain-associated molecules play roles in the model of nociceptive and
inammatory pain and inammatory oedema (Dutra etal. 1994; Godin etal. 2015).
Mogil has reviewed animal pain models and considered pain is so complicated that
the researchers should carefully pay attention to the models and must take into
account when using an animal model (Mogil 2009). One interesting discovery is
that the cancer tissues can directly secrete endogenous formaldehyde and so forth.
Formaldehyde at low concentration induces metastatic bone cancer pain through
TRPV1 activation especially under tumour acidic environment (Tong etal. 2010).
4.3 Effect onMotor Activities
Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease involving
the death of upper and lower motor neurons. It causes muscle weakness and impacts
physical function. At the late stages, the condition affects nerves that control breath-
ing and other vital bodily functions, resulting in death. Currently, experts do not
know what cause ALS precisely.
The neurotoxic effects of formaldehyde from animal models and in vitro experi-
ments indicate that it may be relevant for ALS. Several epidemiological researches
were performed to determine the relationship between ALS and formaldehyde
exposure. Weisskopf assessed the association between exposure to chemicals and
risk of ALS in a prospective cohort study including over 1 million participants in the
American Cancer Society’s Cancer Prevention Study II.A strongly signicant dose-
response relation with increasing years of formaldehyde exposure was concluded
(Weisskopf et al. 2009). It was reported that certain occupations and workplace
exposures may be associated with increased risk of ALS (Fang etal. 2009). A cohort
research of formaldehyde-exposed garment workers does not suggest that ALS is
associated with formaldehyde exposure (Pinkerkon etal. 2013). In 2015, Roberts
and colleagues examined the association of ALS mortality with job-related formal-
dehyde exposure in the National Longitudinal Mortality Study (NLMS). The results
indicated that workers like funeral directors, with a high probability of exposure to
formaldehyde, have an almost threefold greater rate of death related to ALS (Roberts
etal. 2016).
4.4 Primary Open-Angle Glaucoma
Primary open-angle glaucoma (POAG) is a leading cause of irreversible blind-
ness worldwide. Growing evidence indicates a relation between POAG and
Alzheimer’s disease (Bayer etal. 2002). Recently, an increased occurrence rate of
POAG could be found in AD patients (Tislis etal. 2014). In order to reveal the
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199
risk factor of POAG, Cui and his colleagues investigated the correlation of the
level of endogenous formaldehyde with POAG by high-performance liquid chro-
matography (HPLC) to detect the endogenous aldehyde in a double-blind man-
ner(Cui etal. 2016). They found that endogenous formaldehyde level is positively
correlated with the neuronal defects of POAG.This suggests again that endoge-
nous formaldehyde is involved in neurodegenerative diseases.
5 The Other Psychosomatic Behaviours
Besides those effects on CNS functions, as mentioned above, formaldehyde can
also cause some other nervous symptoms such as seizures, autism and amnesia.
Three patients were evaluated for effects of formaldehyde on CNS function by
Kilburn. All were disabled, and two had developed seizures (Kilburn 1994).
Tracking a case of epilepsy caused by formaldehyde exposure, Perna and colleagues
suggested that chronic formaldehyde exposure resulted in heightened sensitivity to
formaldehyde, three tonic-clonic seizures and dramatic amnesia as well as other
cognitive dysfunction (Perna etal. 2001). Utero exposure of ambient toxics includ-
ing formaldehyde is considered as a risk of childhood autism (von Ehrenstein etal.
2014). Complaints of headache, nosebleeds and stomachache were observed in the
villagers who live in the trailers built with particleboard which have been found
contaminated with formaldehyde (Madrid et al. 2008). Of course formaldehyde
affects the other sensory organs; for instance, indoor formaldehyde exposure stimu-
lates nasal mucosa. Temporary abnormalities in the olfaction test and increased
nasal mucosal hypersensitivity to histamine were observed in a few students with
preexisting allergic rhinitis after environmental exposure of high concentrations of
formaldehyde though these effects appeared to be transient (Hisamitsu etal. 2011).
6 Potential Mechanisms inMultiple Ways
Over the years, neurotoxicity and cognitive dysfunction have separately been asso-
ciated with endogenous formaldehyde and reduction of acetylcholine signals. 0.024
to 0.74ppm formaldehyde-exposed workers with increased alcohol dehydrogenase
III ADH32–2 genotype had higher AChE (acetylcholinesterase) than controls, sug-
gesting that the neurotoxic effects of formaldehyde depend on the AChE activity
(Zendehdel etal. 2016). Potential chronic and debilitating effects of solvents and
formaldehyde have been attributed to the formation of biologically active epoxides
near axons. Such epoxides bind to neurolamental proteins. These proteins swell
and neurolaments proliferate that are believed to result in demyelination (Kilburn
etal. 1987; Savolarnin 1977). Using an animal study of acute low-level formalde-
hyde exposure with rats, Boja and colleagues have found that formaldehyde expo-
sure resulted in decreased motor activity and neurochemical changes in dopamine
10 Formaldehyde and Neuropsychiatry

200
and serotonin (5-TH) neurons (Boja etal. 1985). Administration of formaldehyde
also decreases norepinephrine(NE) levels in the brain of rodents. Tong and his col-
leagues provided evidence that accumulated formaldehyde is a critical endogenous
factor for ageing-associated NE depletion and cognitive decline (Mei etal. 2015).
These neurotransmitters (dopamine, 5-TH and norepinephrine) are involved not
only in cognitive function but also in mood and emotion.
Reactive aldehydes have been implicated in the aetiology of several neurological
and psychiatric disorders, and increased formaldehyde and upregulation of
semicarbazide- sensitive amine oxidase, which forms formaldehyde from methyl-
amine, have been implicated in disorders such as cerebrovascular disorders, alcohol
abuse, diabetes and Alzheimer’s disease. Glutamate pathway may be the key point,
because formaldehyde can reduce the alteration of the second messengers, AKT and
p38 (Song et al. 2010). As mentioned above, formaldehyde affects anxiety,
depression- like behaviour and cognition ability, through association with alterations
in hippocampal glucocorticoid receptors and brain tyrosine hydroxylase levels (Li
etal. 2016b).
Chemical modications of proteins have been well documented to play impor-
tant roles in the pathophysiology of many human diseases such as cancer, age-
related pathology and neurodegenerative disorders. Endogenous and exogenous
formaldehydes have a reaction with cysteine residues in proteins, and cysteine resi-
dues may serve as a biomarker of formaldehyde exposure (Liu etal. 2016). In addi-
tion, most of mechanistic studies related to formaldehyde toxicity have been
performed in cytotoxic concentrations enough to trigger cell death. To mimic daily-
life formaldehyde exposure level, 200μM formaldehyde exposed normal human
keratinocytes to induce pro-inammatory responses (Lee et al. 2016). Thus,
formaldehyde- induced inammatory may be another cause to impair neurons and
brain function. About these contents, please see Chap. 8.
7 To Clarify Formaldehyde Toxicosis Is aCareful Work
As with many potentially cerebrotoxic chemicals, there are few studies of the effects
of chronic formaldehyde exposure on cognitive functioning as described by Pern
and collaborators. Williams and Lees-Haley (1998) noted that some research on
formaldehyde exposure has often been criticized due to “selection bias in recruit-
ment of research participants and unreliability of participant recall for obtaining
data on important background variables and exposure levels”. Criticisms such as
these are often inherent in the study of any toxic chemical exposure. The difcult
situation is that cases involved in litigation may represent more severe outcomes and
must be examined critically, with consideration of symptom magnication (Perna
etal. 2001). In order to clarify the health impairment resulted from formaldehyde
exposure, measures of symptom validity may help clarify this issue and should be
included and reported when possible. The second difculty in eld studies and case
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201
reports of formaldehyde or other exposure to toxic substances is that individuals are
rarely exposed to a single toxin, either because multiple toxins are in the work envi-
ronment or because toxins are often present in complex solutions or compounds.
Another relevant, yet variable, factor isthe degree and duration of exposure. The
literature provides mixed support regarding potential effects of formaldehyde (Perna
etal. 2001). To face these situations, the measurement of endogenous formaldehyde
(in blood or urine) may be suggested to clarify some of the cases which are resulted
from the formaldehyde exposure as mentioned above. The elevated concentrations
of formaldehyde may provide some useful information to support the diagnosis. As
with many other toxins, there appears to be large individual differences in reactivity
and symptomatology. In fact, psychological factors can worsen the symptoms,
which should not be ignored. Neuropsychological symptoms are related to the
social psychological factor indicators (spirit) (Sparks et al. 1990). Therefore,
although the victim has really exposed to high concentrations of formaldehydein
the air, the effect of psychological factors on the symptoms should be considered. A
series of appraisal methods found that the subjects resorted to the formaldehyde
concentration have no obvious symptoms and correlation. Because patients exposed
to toxic substances recognize themselves in danger, and they may have some physi-
cal characterization of discomfort as well, the resulting anxiety depression, insom-
nia and a series of mental neurological symptoms may not be caused by exposure to
pollutants. Application of neurophysiology and neuropsychological assessment of
chemical exposure on neurobehavioural damage, age and education level of the
synergistic effect should be considered and analysed (Kilburn and Warshaw 1992).
8 Debate andNotable Matters
Hippocampus plays important roles in the consolidation of information from short-
term memory to long-term memory and spatial learning in human and other animals
(Lieberwirth etal. 2016). Formaldehyde has been found in the cerebrospinal uid
(authors’ unpublished data) and thus affects the neuroglia and nerve cell because it
can pass easily through the blood-brain barrier (Malek etal. 2003a, b). Exposure to
exogenous formaldehyde has been reported to be associated with increased formal-
dehyde levels in the brain (Tulpule and Dringen 2013; Tulpule etal. 2012). Several
recent inhalation studies using labelled formaldehyde (13CD2) did not nd DNA
adducts outside the nasal tissue in rats and monkeys. Thus, formaldehyde was not
considered to reach the internal organs or the blood compartment (Lu etal. 2010; Lu
etal. 2011; Swenberg etal. 2011). Formaldehyde accumulation in the brain is con-
sidered to come from endogenousness, especially dysmetabolism of formaldehyde.
But ultrane particles matters < 2.5 nanometre (PM2.5) can enter the vessel and
blood-brain barrier (Ailshire and Clarke 2015; Ailshire and Crimmins 2014).
Formaldehyde maybe absorbed onto the particles, which may target the receptor
tissues and cells.
10 Formaldehyde and Neuropsychiatry

202
The results from animals and cells to humans need to be extrapolated carefully
(Worek etal. 2002), although epidemiological studies and experimental research are
enough to alert us to avoid formaldehyde exposure and reduce exposure levels.
There are many factors including the way, concentrations and duration of
formaldehyde exposureand different metabolism pathways of formaldehyde in dif-
ferent species signicantly inuence the outputs of the behavioural components
tests. The transport and metabolism in the body gradually become clear. Even though
formaldehyde comes from different pathways and goes in different metabolisms,
lysosome shows its role as a central organelle to accommodate and transfer formal-
dehyde in and out of cells (Chen etal. 2017; Xiong and Zhu 2016) (see Chap. 8). Of
course, further investigation of neurotoxic mechanisms is required.
9 Precautionary Measures
Formaldehyde isa main compound of the air pollution in workplace and home, and
epidemiological and experimental data showthat formaldehyde has risks to health.
Some precaution should be taken to reduce the risks, such as an increase of ventila-
tion to dilute the levels of formaldehyde and the use of air cleaners to remove form-
aldehyde. Lime was found to be an efcient reagent to lower the concentration of
formaldehyde in highly concentrated efuents (Moussavi etal. 2002). Planting trees
reduces formaldehyde pollution in air and water (Su and Liang 2015). Toxics use
reduction (TUR) is one part of a comprehensive cancer prevention strategy. TUR
emphasizes reducing the use of cancer-causing chemicals by improving manufac-
turing processes and identifying and adopting safer alternatives. Daily intake of
antioxidant food such as grapeseed (resveratrol) reduces formaldehyde level in
body to protect health. In fact, disengagement of formaldehyde is the most effective
method of protection. More information is described about drug usages to treat the
formaldehyde toxicosis in Chap. 12.
10 Conclusion
Excess formaldehyde has multiple harmful effects on different human organs
such as kidney, liver, lung and blood vessels, especially CNS.Epidemiological
and experimental data support the role of formaldehyde as a risk factor for neuro-
psychiatric disorders such as depression, anxiety and circadian rhythm dysfunc-
tion, including cognitive impairment, though the mechanisms of formaldehyde
exposure causing mental disorders still are unclear. Recent studies showed that
formaldehyde induces β-amyloid deposition, Tau hyperphosphorylation, dys-
metabolism of neurotransmitters and neuronal death. All those may be related to
the impairment of brain and neuropsychiatric disorders. It is necessary to
X. Wang and R. He

203
strengthen the research and studies on the effects of air pollution on neuropsycho-
logical disorders and highly sensitive monitoring methods for formaldehyde and
effective protective measures for people’s health. Further and more work should
be carried out to clarify the relationship between long-term formaldehyde expo-
sure and neuropsychiatric disorders. At the same time, whether endogenous form-
aldehyde can be used as a biomarker to identify anxiety or depression needs
further investigating.
Acknowledgements This project was supported by grants from the National Key Research and
Development Program of China (2016YFC1306300), the National Basic Research Program of
China (973 Program) (2012CB911004), the Beijing Municipal Science and Technology Project
(Z161100000217141; Z161100000216137), the National Natural Science Foundation of China
(NSFC 31270868), the Foundation of Chinese Academy of Sciences (CAS-20140909) and the
Queensland-Chinese Academy of Sciences Biotechnology Fund (GJHZ201302).
Competing Financial Interests The authors declare no competing nancial interests.
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