cancers

Systematic Review
The Carcinogenic Effects of Formaldehyde Occupational
Exposure: A Systematic Review
Carmela Protano 1 , Giuseppe Buomprisco 2 , Vittoria Cammalleri 1 , Roberta Noemi Pocino 1 , Daniela Marotta 1 ,
Stefano Simonazzi 2 , Francesca Cardoni 2 , Marta Petyx 3 , Sergio Iavicoli 3 and Matteo Vitali 1, *

1 Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.le Aldo Moro 5,
00185 Rome, Italy; carmela.protano@uniroma1.it (C.P.); vittoria.cammalleri@uniroma1.it (V.C.);
robertanoemi.pocino@uniroma1.it (R.N.P.); daniela.marotta@uniroma1.it (D.M.)
2 Department of Human Anatomy, Histology, Forensic Medicine and Orthopedics,
Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy; giuseppe.buomprisco@uniroma1.it (G.B.);
stefano.simonazzi@uniroma1.it (S.S.); francesca.cardoni@uniroma1.it (F.C.)
3 Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, INAIL,
Via Fontana Candida 1, 00078 Monte Porzio Catone, Rome, Italy; m.petyx@inail.it (M.P.);
s.iavicoli@inail.it (S.I.)
* Correspondence: matteo.vitali@uniroma1.it

Simple Summary: Formaldehyde is a chemical compound present in many working activities and
indoor workplaces. Occupational exposure occurs primarily by inhaling airborne formaldehyde,
but it can also be absorbed through the skin or ingested. The International Agency for Research
on Cancer (IARC) classified formaldehyde as a Group 1 carcinogen for humans in 2004, based on



toxicological data and epidemiological evidence obtained in workplaces, all published before that year.


Over the last two decades, many new studies in this field have been published, providing updated
Citation: Protano, C.; Buomprisco, findings. The aim of the present systematic review was to synthetize the results of epidemiological
G.; Cammalleri, V.; Pocino, R.N.;
studies in occupational settings carried out in the last 20 years and to evaluate whether the IARC
Marotta, D.; Simonazzi, S.; Cardoni,
classification was confirmed by further studies. Our results show that the evidence of correlation
F.; Petyx, M.; Iavicoli, S.; Vitali, M.
between formaldehyde occupational exposure and the occurrence of cancer is limited.
The Carcinogenic Effects of
Formaldehyde Occupational
Abstract: Background: Formaldehyde, classified as a carcinogen in 2004, as of today is widely
Exposure: A Systematic Review.
Cancers 2022, 14, 165. https://
used in many work activities. From its classification, further studies were performed to evaluate
doi.org/10.3390/cancers14010165 its carcinogenicity. The aim of the systematic review is to update the evidence on occupational
exposure to formaldehyde and cancer onset. Methods: The review, in accordance with the PRISMA
Academic Editors: Venerando
statement, includes articles in English reporting original results of studies conducted on workers
Rapisarda and Caterina Ledda
exposed to formaldehyde, considering all types of cancer, published from 1 January 2000 to 30 July
Received: 12 November 2021 2021 and selected from the Pubmed and Scopus databases. The studies’ quality was assessed by
Accepted: 28 December 2021 the Newcastle–Ottawa Scale. Results: A total of 21 articles were included, conducted in different
Published: 29 December 2021 European, American, and Asian countries. The most investigated occupational areas are those
Publisher’s Note: MDPI stays neutral characterized by a deliberate use of formaldehyde. Some studies evaluated all types of cancer,
with regard to jurisdictional claims in whereas others focused on specific sites such as thyroid and respiratory, lymphohematopoietic,
published maps and institutional affil- or central nervous systems. The results showed weak associations with lung cancer, nasopharyngeal
iations. cancer, leukemia, and non-Hodgkin’s lymphoma. Conclusions: The results demonstrate the need for
further original studies carried out on representative samples of workers exposed to measured levels
of FA. These studies should be designed to reduce the bias due to co-exposure to other carcinogens.

Copyright: © 2021 by the authors.

Keywords: formaldehyde; carcinogenicity; occupational exposure; cancer risk
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
1. Introduction
creativecommons.org/licenses/by/ Formaldehyde (FA) is a chemical compound naturally occurring in the atmosphere,
4.0/). in some foods, and in the organisms of mammals as a product of oxidative metabolism and,

Cancers 2022, 14, 165. https://doi.org/10.3390/cancers14010165 https://www.mdpi.com/journal/cancers

Cancers 2022, 14, 165 2 of 12

thus, is considered a ubiquitous pollutant. In addition to these sources, FA can be released

in the environment through combustion processes or by degradation of some hydrocarbons
such as methane. Besides, due to its chemical–physical characteristics, FA is widely applied
in many productive processes, such as the construction materials industry, the chemical
industry (resins, paintings, etc.), the wood-processing and furniture industry, the food
industry, biomedical laboratories, gross anatomy rooms, handicrafts, etc. [1]. Consequently,
many types of occupational activities determine FA exposure. Driscoll et al. [2] conducted
a study based on data obtained from the Australian Workplace Exposures Study about the
prevalence and patterns of exposure to 38 known or suspected carcinogens, including FA,
among the Australian working population. As a result, 2.5% of the workers were likely to
have been exposed to FA. The main working activities that exposed them to this chemical
were the processing of chipboards or plywood panels for carpentry, building maintenance,
and sanding before painting. The other workers most exposed were firefighters [3–5],
healthcare workers [6], and beauticians. FA has also been detected in restaurants [7,8] when
grilling dishes and adding sauces, in copy shops [9,10], in gardening [11], in the agri-food
sector [12,13], in veterinary clinics, in embalming laboratories, in industrial launderings,
etc. Besides, FA is frequently found in building environments, posing at potential risk of
exposure to all indoor workers [14–19].
Exposure occurs primarily by inhaling airborne FA, but it can also be absorbed through
the skin or ingested. The International Agency for Research on Cancer (IARC) in 2004
concluded that there was sufficient evidence of the carcinogenicity of FA for humans to
reclassify FA from Group 2A (probably carcinogenic to humans) to Group 1 (carcinogenic
to humans) [20]. In the subsequent monograph n. 100 of 2012, in summary, the IARC
confirmed that there was sufficient epidemiological evidence that FA causes tumors of the
nasopharynx, insufficient evidence of a causal relationship with leukemia, and limited
epidemiological evidence for nasal sinus cancer [21]. EU Regulation 2015/491 also imposed
the reclassification of FA from suspected carcinogen to carcinogen for humans in category
1B (i.e., it can cause cancer) on the basis of sufficient evidence both in humans [22,23]
and in experimental animals [24,25]. However, all the scientific evidence that led to these
classifications date back to before 2005. Besides, most of the studies on the relationship
between FA and cancer were in vitro experiments demonstrated the effects on culture cells.
Researchers have found many cellular damages, like DNA and RNA alterations [26,27],
the onset of DNA–protein crosslinks, changes in p53 protein expression [28], and histone
modifications [29]. On the other hand, epidemiological studies have not been able to
confirm this association. In addition, several previous reviews investigated the relation-
ship between occupational FA exposure and the onset of specific cancers, often obtaining
conflicting conclusions [30–34]. However, no recent systematic review has looked into the
relationship between occupational exposure to FA and the occurrence of cancer, except one
published 15 years ago that concluded that there was no appreciable excess risk for cancers
of the oral cavity and pharynx, sinus and nasal cavity, nasopharynges, and lung [35].
The aim of this systematic review is to update the scientific evidence on the relationship
between occupational exposure to FA and the occurrence of all kinds of cancer evaluated
by epidemiological studies performed on humans. The results of the review might help
to confirm the evidence already produced by previous studies, or to highlight the need to
review the current classification and/or to carry out new studies.

2. Materials and Methods

The presentation of this systematic review is in accordance with the latest version of the
PRISMA statement [36]. We started the review process before the publication of the PRISMA
Statement 2020; for this reason, the first steps of the review were conducted following
the old version (PRISMA Statement 2009), which was less stringent in the “protocol and
registration” item, reporting the following sentence “Indicate if a review protocol exists,
if and where it can be accessed (e.g., Web address), and, if available, provide registration
information including registration number)”. Thus, initially we did not register the protocol
Cancers 2022, 14, 165 3 of 12

in any database and, then, it was too late to do it because the protocol registration must
be performed before the start of the review process. Zotero citation management software
(RRID:SCR_013784) was used to identify any duplicates and to manage and screen the
identified records.

2.1. Literature Research

The review includes articles published in the last 20 years, from 1 January 2000 to
31 July 2021, on the databases Pubmed and Scopus. The search strategy used a combination
of controlled vocabulary and free text terms based on the following keywords: “formalde-
hyde”, “cancer”, “tumor”, “neoplasm”, “occupational”, and “exposure”. Additionally,
a hand search of the reference lists of the selected articles was carried out for a wider
analysis. Four independent reviewers (V.C., R.N.P., D.M. and G.B.) performed the search,
reading the titles and abstracts of the articles identified by the search strategy.
During the multi-step exclusion process, any disagreement on the studies was dis-
cussed until consensus. The process was supervised by other investigators (C.P. and M.V.).
Figure S1 (Supplementary Materials) shows the flow chart summarizing the selection
steps for the systematic review.

2.2. Inclusion and Exclusion Criteria

The review included only studies in which the participants were classified as “exposed
to formaldehyde.” The exposure assessment was considered acceptable if performed by di-
rect (personal or environmental) sampling of FA, occupational history data, or job exposure
matrix. Cancers were classified using the International Classification of Diseases, Tenth
Revision (ICD-10).
Only studies involving humans (men and/or women) exposed to FA in occupational
settings, reporting results for any kind of cancer and published in peer-reviewed journals,
were selected. Searches providing no information about the exposure assessment method
or with a self-assessment by the participants were excluded. Besides, we excluded reviews,
editorial articles, individual contributions (i.e., conference speeches), and purely descrip-
tive studies published in scientific conferences without any quantitative or qualitative
conclusions. Finally, articles published in languages other than English were excluded.

2.3. Data Analysis

From each study included in the review, the following data were extracted: publication
year, exposure time period, study design, working population studied, cancer type (ICD-10
classification), exposure assessment, and main conclusions.

2.4. Quality Evaluation

Four different reviewers (V.C., R.N.P., D.M. and G.B.) assessed the methodological
quality of the selected studies with a specific rating tool, the Newcastle–Ottawa Scale
(NOS), adapted for evaluating case-control, cross-sectional, and cohort studies [37]. It is
divided into eight categories checking three quality aspects: selection, comparability and
outcome/exposure; scores range from 0 to 9. The quality of a study was considered to be
high if the NOS score was 7 to 9, intermediate if the NOS score was 4 to 6, and low if it was
0 to 3.

3. Results
In total, we recovered 1029 studies from all searched databases (n = 629 from Scopus
and n = 400 from Pubmed) and, after applying filters by automation tools, 390 articles
remained. Out of the remaining 390 papers, 350 were excluded after removing duplicates.
Successively, one more paper was removed after reading the abstract. Then, the full texts of
39 studies were checked and evaluated considering the inclusion/exclusion criteria. A total
of 14 papers were then excluded because they did not fit the inclusion criteria. Besides,
eight articles were based on the same studied cohort; thus, we considered only the most
Cancers 2022, 14, 165 4 of 12

recent, excluding those previously published. Six articles were found via citation search
and four were included after checking their eligibility, whereas two were discarded due
to the difficulty of extrapolating FA exposure. At the end of the process, 21 articles were
included in the systematic review [38–58]. The PRISMA Flow Diagram is available as
Supplementary Materials (Figure S1).
Table 1 shows the characteristics of the studies included, with reference to coun-
try, workers’ gender, sample size, working context, study period, smoking adjustment,
exposure assessment, cancer type, and main conclusions.

3.1. Characteristics of the Included Studies

The studies included were conducted on almost all continents, with six from Europe,
nine from North America, four from Asia, one from South America, and one multicen-
ter study. Most (11 studies) involved both sexes, seven involved only males, and three
only females. In total, 11 case-control studies, eight cohort studies, and two case-cohort
studies were considered. Industry and manufacturing were the most examined working
contexts, in particular the sectors of chemical, plywood, and textile production. Therefore,
the majority of the studies included (n. 11) regarded workers exposed to FA in several
working contexts and workplaces. Twelve studies considered smoking a confounding
factor and adjusted the results accordingly. Only three research groups performed the
direct exposure assessment through personal or environmental sampling; the others as-
sessed the exposure level indirectly by job exposure matrix or occupational history data.
Five studies looked for the relationship between FA exposure and the onset of any cancer,
seven evaluated the onset of upper airway cancers, four focused on lung cancer, two fo-
cused on lympho-hematopoietic cancers, one focused on thyroid cancer, and one focused
on meningioma. The sample size was very variable, ranging from two cases and five
controls in the smallest case-cohort study to a cohort of 1.2 million workers in the study by
Siew et al. [51].

3.2. Scoring Results

The median NOS score of the included studies was 7, thus indicating a high average
quality level. Table 2 shows the results of the scoring method applied to each study included
in the review, with reference to publication year, study design, and main statistical results
achieved (expressed as odds ratio, hazard ratio, relative risk, or standardized mortality
ratio and with a 95% confidence interval).
Cancers 2022, 14, 165 5 of 12

Table 1. Characteristics of the studies (n = 21) included in the systematic review.

Risk—Adjusted
Reference Workers’ Study Exposure Cancer Type
Sample Size * Working Context for Smoking Main Conclusions
[n.]—Country Gender Period Assessment (ICD-10)
Habits
49 cases, Chemical, plywood, and Nasopharyngeal No association was found between nasopharyngeal
[38]—Malaysia Both 1990–1992 Yes Air sampling **
49 controls textile industries cancer (C11.9) carcinoma and FA.
Results from this study support the hypothesis that
79 cases, Occupational Nasopharyngeal occupational exposure to FA increases risk of NPC.
[39]—USA Both Various 1987–1993 Yes
79 controls history data cancer (C11.9) The association between risk of NPC and potential
exposure to FA was stronger among cigarette smokers.
Laryngeal: 102 cases,
85 controls Laryngeal and Exposure to FA was associated with an increased risk
Job exposure
[40]—France Men Hypopharyngeal: Various 1987–1991 Yes hypopharyngeal of hypopharyngeal cancer. No association with
matrix
83 cases, cancer (C10.9) laryngeal cancer was found.
85 controls
There was some evidence of increasing risk of NPC
74 cases, Occupational Nasopharyngeal
[41]—Taiwan Both Various 1991–1994 Yes with increasing years of exposure to FA, but the
41 controls history data cancer (C11.9)
observed trend did not achieve statistical significance.
[42]—Northern Vitreous fiber-producing Occupational Lung cancer This study provides no evidence of a carcinogenic
Men 108 cases, 398 controls 1971–1996 Yes
Europe plants history data (C34) effect on the lungs from FA exposure.
Personal Results support a possible relation between FA
sampling among All cancers exposure and myeloid leukemia mortality.
[43]—USA Both 11,039 Various 1955–1998 Not
workers (1981 (C00–C97) Non-significant excesses in mortality were observed
and 1984) ** among FA-exposed workers for several other cancers.
Agricultural workers,
32 cases, histology technicians, Occupational Lung cancer Constant exposure to FA was significantly associated
[44]—Uruguay Men 1994–2000 Yes
65 controls medical personnel, history data (C34) with an increased OR of adenocarcinoma of the lung.
and foundry workers
Laryngeal cancer
[45]—Central (C32)
Occupational No overall association
and Eastern Men 18 cases, 30 controls Various 1999–2002 Yes Hypopharyngeal
history data was found between FA and laryngeal cancer.
Europe cancer (C12,
C13)
Historical Associations were observed between thyroid cancer
2 cases, Thyroid cancer
[46]—China Women Textile industries 1989–1998 Not measurements and employment in jobs with 10 or more years of FA
11 subcohort non-cases (C73)
data exposure.
Overall, the pattern of findings suggests that the large,
persistent nasopharyngeal and other PC excesses
Occupational Nasopharyngeal
[47]—USA Both 7345 Plastic-producing plants 1979–2003 Yes observed were not associated with FA exposure.
history data cancer (C11.9)
Interaction models suggest that NPC and AOPC risks
were not elevated in subjects exposed only to FA.
Cancers 2022, 14, 165 6 of 12

Table 1. Cont.

Risk—Adjusted
Reference Workers’ Sample Working Study Exposure
for Smoking Cancer Type (ICD-10) Main Conclusions
[n.]—Country Gender Size * Context Period Assessment
Habits
201 cases, Exposure to FA was found to be associated
Job exposure Non-Hodgkin lymphoma
[48]—USA Women 203 Various 1996–2000 Yes with an increased risk of NHL in our study, but the risk
matrix (C85.90)
controls was mainly for those with a low exposure intensity or probability.
2 cases, Exposures to silica and FA may have increased lung cancer
Textile Job exposure
[49]—China Women 11 subcohort 1989–1998 Yes Lung cancer (C34) risk. This observation was based on very small numbers of
industries matrix
non-cases exposed workers.
Nasopharyngeal cancer (C11.9)
Funeral Historical Lympho-hematopoietic cancers The duration of embalming practice and related FA exposure in
144 cases,
[50]—USA Men industry 1960–1986 Yes measurements (C81–C96) the funeral industry were associated with statistically
210 controls
workers data Myeloid leukemia (C92.90) significantly increased risk for mortality from myeloid leukemia.
Brain cancer (C71)
Job exposure Nasopharyngeal cancer (C11.9) The results are inconclusive, but FA did not appear to increase risk
[51]—Finland Men 1, 2 mln Various 1971–1995 Yes
matrix Lung cancer (C34) in any way whatsoever for nasal, nasopharyngeal, or lung cancer.
347 cases, Job exposure No marked increases in lung cancer risk related to workplace
[52]—Canada Both Various 1979–2002 Yes Lung cancer (C34)
325 controls matrix FA exposure were observed.
We continue to see limited evidence of an association between
Garment-
Personal FA and leukaemia. We did not find solid evidence of increased
[53]—USA Both 11,043 manufacturing 1985–2008 Not All cancers (C00–C97)
sampling ** mortality from other lympho-hematopoietic cancers and a
facilities
priori solid cancers with FA exposure.
For all cancer, solid tumors, and lung cancer, the mortality
Historical among exposed workers was high, but internal analyses
[54]—USA Both 25,619 Various 1950–2004 Not measurements All cancers (C00–C97) revealed no positive associations with FA exposure. Consistent
data with previous analyses of this cohort, this update continues to
suggest a link between FA exposure and nasopharyngeal cancer.
Our results provide no support for an increased hazard of
myeloid leukemia, nasopharyngeal carcinoma, or other upper
Chemical Occupational
[55]—UK Men 14,008 1941–2012 Not All cancers (C00–C97) airway tumors from FA exposure. These results indicate that
industries history data
any excess risk of these cancers, even from relatively high
exposures, is at most small.
Laminated We found no meaningful excess mortality from any
Occupational
[56]—Italy Both 2750 plastic 1947–2011 Not All cancers (C00–C97) lymphohematopoietic nor other neoplasms, except possibly for
history data
factories nasopharyngeal cancer.
Historical Lympho-hematopoietic cancers No association between cumulative FA exposure and mortality
[57]—USA Both 25,619 Various 1930–2004 Not
measurements data (C81–C96) from all leukemias combined was observed for the entire cohort.
This study shows an increased risk in relation to FA based
[58]—
116 cases, Job exposure mainly in women in relation to a duration of exposure of more
Multicenter Both Various 1945–2003 Not Meningioma (D32.9)
278 controls matrix than 15 years and highest cumulative exposure, although
study
neither of the trends was statistically significant.
* Both cases and controls exposed to formaldehyde; ** direct exposure assessment.
Cancers 2022, 14, 165 7 of 12

Table 2. Scoring results of the included studies in relation to study design, year of publication, and
statistical results achieved.

Reference [n.]—Year Study Design Statistical Results NOS Score

[38]—2000 Case-control Nasopharyngeal cancer: OR: 0.88 (CI: 0.70–1.12) 7
[39]—2000 Case-control Nasopharyngeal cancer: OR: 1.3 (CI: 0.80–2.1) 7
Hypopharyngeal cancer: OR: 1.35 (CI: 0.86–2.14)
[40]—2000 Case-control 6
Oropharyngeal cancer: OR: 1.14 (CI: 0.76–1.70)
[41]—2001 Case-control Nasopharyngeal cancer: OR: 1.4 (CI: 0.93–2.2) * 6
[42]—2002 Case-control Lung cancer: OR: 1.33 (CI: 0.76–2.34) 7
All cancers: SMR: 0.89 (CI: 0.82–0.97)
[43]—2004 Cohort 7
Myeloid leukemia: SMR: 1.44 (CI: 0.80–2.37)
[44]—2005 Case-control Lung cancer: OR: 1.7 (CI: 1.1–2.8) 6
[45]—2006 Case-control Laryngeal cancer: OR 1.68 (CI: 0.85–3.31) * 6
[46]—2006 Case-cohort Thyroid cancer: HR: 8.33 (CI: 1.16–60) 7
Nasopharyngeal cancer: SMR: 4.43 (CI: 1.78–9.13)
[47]—2007 Cohort 7
Other pharynx cancers: SMR: 1.71 (CI: 1.01–2.72)
[48]—2008 Case-control Non-Hodgkin lymphoma: OR: 1.3 (CI: 1.0–1.7) 7
Nasopharyngeal cancer: OR: 0.1 (CI: 0.01–1.2)
Lympho-hematopoietic cancers: OR: 0.9 (CI: 0.4–2.1) *
[49]—2009 Case-cohort
Myeloid leukemia: OR: 3.9 (CI: 1.2–12.5)
Brain cancer: OR: 1.9 (CI: 0.7–5.3) *
[50]—2011 Case-cohort Lung cancer: HR: 2.10 (0.40–11.00) 8
Nasopharyngeal cancer: RR: 0.87 (CI: 0.34–2.20)
[51]—2012 Cohort 8
Lung cancer: RR: 1.18 (CI: 1.12–1.25)
[52]—2013 Case-control Lung cancer: OR: 1.06 (CI: 0.89–1.27) 7
[53]—2013 Cohort All cancers: SMR: 0.96 (CI: 0.90–1.02) 7
[54]—2013 Cohort All cancers: SMR: 1.08 (CI: 1.05–1.12) 7
[55]—2014 Cohort All cancers: SMR: 1.10 (CI: 1.06–1.15) 7
[56]—2014 Cohort All cancers: SMR: 79.8 (CI: 67.5–93.6) 6
[57]—2016 Cohort Lymphohematopoietic cancers: SMR: 2.07 (CI: 1.22–3.49) 8
[58]—2018 Case-control Meningioma: OR: 1.02 (CI: 0.80–1.29) 7
*: Not statistically significant; CI: 95% confidence interval; OR: odds ratio; HR: hazard ratio; RR: relative risk; SMR:
standardized mortality ratio.

4. Discussion
We performed a systematic review on the association between FA occupational expo-
sure and the occurrence of cancer in potentially exposed workers.
Previous studies about FA and cancer risk suggested a modest excess of risk for
nasopharyngeal cancer [59], but the studied cohort of workers was co-exposed to several
other chemicals, resulting in additive and/or synergic effects or misleading results. Despite
this, the findings were included by the IARC in its evaluation, even if subsequent analysis
revealed no statistical significance of these results and highlighted the inappropriateness of
the adopted exposure assessment approach [60].
Among the studies included in our review, we found a direct assessment of the
exposure levels of FA only in three papers. In the other cases, the exposure assessment
was indirectly extrapolated considering the length of exposure and the type of activities
performed (e.g., job exposure matrix). Most of the studies included in this review dealt
with occupational settings, characterized by a deliberate use of FA as a component of the
production cycle. Those were mainly represented by chemical industries dedicated to
the production of plastics, fiberglass, paints, etc.; it is reasonable to imagine that in such
contexts the levels of exposure to FA were particularly high. Three studies were carried
out in textile-/garment-producing plants, where FA is used to give resistance to the folds
of clothing fabrics and for the processing of leathers. Another sector where this substance
is widely used is that of woodworking and furniture making. In fact, FA, together with
resins, gives strength and resistance to chipboard panels. FA is also widely used in the
medical field: in the operating room it was used to disinfect instruments because of its high
antibacterial power, and even today, it is used to avoid the deterioration of human tissues
Cancers 2022, 14, 165 8 of 12

that must undergo histopathological analyses. Despite that, very few studies concerned
the health sector, or the agri-food industry, where FA is used as a preservative. That is
quite surprising, considering that there is much research about the occupational exposure
to FA in pathological anatomy settings and sector rooms [61–63] that stress the needing for
adequate preventive measures for workers [64].
Although the genotoxicity and immunotoxicity of FA is well known and has been
demonstrated by several studies regarding its influence on DNA and pro-oxidative ef-
fects on cells [28,65–72], the evidence from human studies and diagnosed cancers is much
less consistent [73]. Most of the studies included in this review focus on upper-airway
neoplasms (ICD-10 codes: C10–C14 and C30–C33), as mentioned previously. In fact,
the main way of entry of this substance into the body is by inhalation. Five studies explored
the relationship between FA occupational exposure and the onset of lung cancer (ICD-10
code: C34). Their findings contrasted with each other: some did not provide evidence of
a carcinogenic effect on the lungs [42,51,52], whereas others found a correlation [44,49].
These last studies, however, were performed on a very small sample and present sev-
eral limitations (e.g., self-reported data on exposure levels). A recent meta-analysis by
Kwak et al. [31] concluded no significant increase in the risk of lung cancer, even consid-
ering only groups of highly exposed workers. The small study sample of the study by
Checkoway et al. about lung cancer was also checked for thyroid cancer, with some relation-
ships found but with the same, considerable, limitations [46]. In 2012, the IARC affirmed
that there was strong but insufficient evidence of a causal relationship with leukemia.
Two studies included in our review regarded the relationship between FA exposure and
lympho-hematopoietic cancers (ICD-10 codes: C81–C96), but no association was observed
for all leukemias [56], except for a small and weak association with non-Hodgkin lym-
phoma [48] and myeloid leukemia [50]. This is consistent with the results of other previous
studies [30,33]. Five of the included publications evaluated the effects of FA occupational
exposure on the onset of any kind of cancer. These were large cohort studies, carried out in
Europe and the USA in industrial contexts, and almost all concluded no positive association
with FA exposure and the mortality from any cancer, and very limited evidence with NPC
and leukemia [43,53–56]. The most recent research included, published in 2018, was a
multicenter study about FA and meningioma. Meningiomas are tumors that develop from
the meninges, tissues that surround the outside of the brain and account for about 30% of
brain tumors. Although benign, they are dangerous because dysphagia, dysarthria, ocular
motility disorders, and facial numbness can occur. Intracranial hypertension, focal seizures,
lack of strength, and balance and gait disturbances may also sometimes occur. The study
concluded that FA did not provoke excess risks of meningioma [58].
The present systematic review has some limitations. First of all, we considered only
papers published in the last 20 years, but this choice was driven by the aim of the present
systematic review. Secondly, we considered only articles published in the English language,
excluding a priori potentially useful results published in other languages. Finally, we
did not perform a formal meta-analysis because the studies included in the review were
different in terms of exposure assessment methodologies, kind of cancers considered,
and study design. For this reason, statistical heterogeneity and publication bias were not
evaluated. Our choice is well supported by a very recent official statement by Cochrane
on the opportunity for performing a meta-analysis when data are heterogeneous: “Meta-
analysis should only be considered when a group of studies is sufficiently homogeneous in
terms of participants, interventions and outcomes to provide a meaningful summary. It is
often appropriate to take a broader perspective in a meta-analysis than in a single clinical
trial. A common analogy is that systematic reviews bring together apples and oranges,
and that combining these can yield a meaningless result” [74].

5. Conclusions
FA has been classified by the IARC as a Group I carcinogen since 2004; this clas-
sification was based on evidence obtained in preceding years. Reviewing the scientific
Cancers 2022, 14, 165 9 of 12

literature published in the last 20 years, we found at least 21 additional epidemiological

studies on the association between occupational exposure to FA and cancer onset. This
finding indicates the need for an update of the FA classification based on the new evidence.
On the other hand, the results of the examined papers do not completely confirm the IARC
classification of FA and give contrasting results. Thus, it is essential to perform further
original studies carried out on representative samples of workers exposed to measured
levels of FA. These studies should be designed to reduce bias as much as possible due to
co-exposure to other carcinogens.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10

.3390/cancers14010165/s1, Figure S1: PRISMA flow diagram.
Author Contributions: Conceptualization, C.P. and M.V.; methodology, C.P.; formal analysis, G.B.,
V.C., R.N.P. and D.M.; investigation, G.B., V.C., R.N.P. and D.M.; data curation, S.I., M.P., S.S. and
F.C.; writing—original draft preparation, G.B.; writing—review and editing, S.I., M.P., C.P. and M.V.;
supervision, C.P., S.S., F.C. and M.V.; project administration, F.C. and M.V. All authors have read and
agreed to the published version of the manuscript.
Funding: This research was funded by INAIL, BRiC-2018, project number B86C19000070001.
Data Availability Statement: Data are provided as tables and figures directly within the manuscript,
and raw data are available via e-mail upon request to the corresponding author.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript,
or in the decision to publish the results.

References
1. Cammalleri, V.; Pocino, R.N.; Marotta, D.; Protano, C.; Sinibaldi, F.; Simonazzi, S.; Petyx, M.; Iavicoli, S.; Vitali, M. Occupational
scenarios and exposure assessment to formaldehyde: A systematic review. Indoor Air, 2021, in press. [CrossRef]
2. Driscoll, T.R.; Carey, R.N.; Peters, S.; Glass, D.C.; Benke, G.; Reid, A.; Fritschi, L. The Australian Work Exposures Study: Prevalence
of Occupational Exposure to Formaldehyde. Ann. Occup. Hyg. 2016, 60, 132–138. [CrossRef] [PubMed]
3. Reisen, F.; Brown, S.K. Australian firefighters’ exposure to air toxics during bushfire burns of autumn 2005 and 2006. Environ. Int.
2009, 35, 342–352. [CrossRef] [PubMed]
4. Laitinen, J.; Makela, M.; Mikkola, J.; Huttu, I. Fire fighting trainers’ exposure to carcinogenic agents in smoke diving simulators.
Toxicol. Lett. 2010, 192, 61–65. [CrossRef] [PubMed]
5. Jankovic, J.; Jones, W.; Burkhart, J.; Noonan, G. Environmental study of firefighters. Ann. Occup. Hyg. 1991, 35, 581–602.
[CrossRef] [PubMed]
6. Vecchio, D.; Sasco, A.J.; Cann, C.I. Occupational risk in health care and research. Am. J. Ind. Med. 2003, 43, 369–397. [CrossRef]
[PubMed]
7. Que, D.E.; Chao, H.R.; Hsu, Y.C.; Cui, K.; Chen, S.; Tayo, L.L.; Arcega, R.D.; Tsai, Y.I.; Lu, I.C.; Wang, L.C.; et al. Emission of
carbonyl compounds from cooking oil fumes in the night market areas. Aerosol. Air Qual. Res. 2019, 19, 1566–1578. [CrossRef]
8. Jung, J.H.; Youn, S.U.; Kwon, E.; Im, S.; Akiyama, Y.; Arashidani, K.; Yang, W. Emission rates of air pollutants from portable gas
ranges and nitrogen dioxide exposure assessment in restaurants. J. UOEH 2009, 31, 13–22. [CrossRef]
9. Su, M.; Sun, R.; Zhang, X.; Wang, S.; Zhang, P.; Yuan, Z.; Liu, C.; Wang, Q. Assessment of the inhalation risks associated with
working in printing rooms: A study on the staff of eight printing rooms in Beijing, China. Environ. Sci. Pollut. Res. Int. 2018, 25,
17137–17143. [CrossRef]
10. Vicente, E.D.; Ribeiro, J.P.; Custódio, D.; Alves, C.A. Assessment of the indoor air quality in copy centers at Aveiro, Portugal.
Air Qual. Atmos. Health 2017, 10, 117–127. [CrossRef]
11. Baldauf, R.; Fortune, C.; Weinstein, J.; Wheeler, M.; Blanchard, F. Air contaminant exposures during the operation of lawn and
garden equipment. J. Expo. Sci. Environ. Epidemiol. 2006, 16, 362–370. [CrossRef] [PubMed]
12. Voorhees, J.M.; Barnes, M.E. Airborne Formaldehyde Levels during Simulated Formalin Egg Treatments in Vertical-Flow Tray
Incubators at a Production Fish Hatchery. J. Agric. Saf. Health 2016, 22, 199–207. [CrossRef] [PubMed]
13. Doane, M.; Sarenbo, S. Exposure of farm laborers and dairy cattle to formaldehyde from footbath use at a dairy farm in New York
State. Sci. Total Environ. 2014, 487, 65–71. [CrossRef] [PubMed]
14. Kim, W.J.; Terada, N.; Nomura, T.; Takahashi, R.; Lee, S.D.; Park, J.H.; Konno, A. Effect of formaldehyde on the expression of
adhesion molecules in nasal microvascular endothelial cells: The role of formaldehyde in the pathogenesis of sick building
syndrome. Clin. Exp. Allergy 2002, 32, 287–295. [CrossRef] [PubMed]
Cancers 2022, 14, 165 10 of 12

15. Ho, S.S.H.; Cheng, Y.; Bai, Y.; Ho, K.F.; Dai, W.T.; Cao, J.J.; Lee, S.C.; Huang, Y.; Ip, H.S.S.; Deng, W.J.; et al. Risk assessment
of indoor formaldehyde and other carbonyls in campus environments in northwestern China. Aerosol. Air Qual. Res. 2016, 16,
1967–1980. [CrossRef]
16. Pośniak, M.; Makhniashvili, I.; Koziel, E. Volatile organic compounds in the indoor air of Warsaw office buildings.
Indoor Built Environ. 2005, 14, 269–275. [CrossRef]
17. Salonen, H.J.; Pasanen, A.L.; Lappalainen, S.K.; Riuttala, H.M.; Tuomi, T.M.; Pasanen, P.O.; Back, B.C.; Reijula, K.E. Airborne
concentrations of volatile organic compounds, formaldehyde and ammonia in Finnish office buildings with suspected indoor air
problems. J. Occup. Environ. Hyg. 2009, 6, 200–209. [CrossRef] [PubMed]
18. Hui, P.S.; Mui, K.W.; Wong, L.T. Influence of indoor air quality (IAQ) objectives on air-conditioned offices in Hong Kong.
Environ. Monit. Assess. 2008, 144, 315–322. [CrossRef]
19. Kaden, D.A.; Mandin, C.; Nielsen, G.D.; Wolkoff, P. Formaldehyde. In WHO Guidelines for Indoor Air Quality: Selected Pollutants;
World Health Organization: Geneva, Switzerland, 2010; Available online: https://www.ncbi.nlm.nih.gov/books/NBK138711
(accessed on 10 September 2021).
20. International Agency for Research on Cancer (IARC). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans:
Formaldehyde, 2-Butoxyethanol and 1-Tert-Butoxypropan-2-ol. 88; International Agency for Research on Cancer: Lyon, France, 2006.
21. International Agency for Research on Cancer (IARC). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Chemical
Agents and Related Occupations, Vol 100 F, A Review of Human Carcinogen; WHO, International Agency for Research on Cancer:
Lyon, France, 2012.
22. Cogliano, V.J.; Grosse, Y.; Baan, R.A.; Straif, K.; Secretan, M.B.; El Ghissassi, F. Working Group for Volume 88. Meeting report:
Summary of IARC monographs on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol. Environ. Health Perspect. 2005,
113, 1205–1208. [CrossRef]
23. Blair, A.; Saracci, R.; Stewart, P.A.; Hayes, R.B.; Shy, C. Epidemiologic evidence on the relationship between formaldehyde
exposure and cancer. Scand. J. Work Environ. Health 1990, 16, 381–393. [CrossRef]
24. Kerns, W.D.; Pavkov, K.L.; Donofrio, D.J.; Gralla, E.J.; Swenberg, J.A. Carcinogenicity of formaldehyde in rats and mice after
long-term inhalation exposure. Cancer Res. 1983, 43, 4382–4392.
25. Swenberg, J.A.; Kerns, W.D.; Mitchell, R.I.; Gralla, E.J.; Pavkov, K.L. Induction of squamous cell carcinomas of the rat nasal cavity
by inhalation exposure to formaldehyde vapor. Cancer Res. 1980, 40, 3398–3402.
26. Ye, X.; Yan, W.; Xie, H.; Zhao, M.; Ying, C. Cytogenetic analysis of nasal mucosa cells and lymphocytes from high-level long-term
formaldehyde exposed workers and low-level short-term exposed waiters. Mutat. Res. 2005, 588, 22–27. [CrossRef] [PubMed]
27. Gonzalez-Rivera, J.C.; Sherman, M.W.; Wang, D.S.; Chuvalo-Abraham, J.C.L.; Hildebrandt Ruiz, L.; Contreras, L.M. RNA
oxidation in chromatin modification and DNA-damage response following exposure to formaldehyde. Sci. Rep. 2020, 10.
[CrossRef]
28. Shaham, J.; Bomstein, Y.; Gurvich, R.; Rashkovsky, M.; Kaufman, Z. DNA-protein crosslinks and p53 protein expression in relation
to occupational exposure to formaldehyde. Occup. Environ. Med. 2003, 60, 403–409. [CrossRef] [PubMed]
29. Lu, K.; Boysen, G.; Gao, L.; Collins, L.B.; Swenberg, J.A. Formaldehyde-induced histone modifications in vitro. Chem. Res. Toxicol.
2008, 21, 1586–1593. [CrossRef]
30. Catalani, S.; Donato, F.; Madeo, E.; Apostoli, P.; De Palma, G.; Pira, E.; Mundt, K.A.; Boffetta, P. Occupational exposure to
formaldehyde and risk of non-hodgkin lymphoma: A meta-analysis. BMC Cancer 2019, 19, 1245. [CrossRef] [PubMed]
31. Kwak, K.; Paek, D.; Park, J.T. Occupational exposure to formaldehyde and risk of lung cancer: A systematic review and
meta-analysis. Am. J. Ind. Med. 2020, 63, 312–327. [CrossRef]
32. Collins, J.J.; Esmen, N.A.; Hall, T.A. A review and meta-analysis of formaldehyde exposure and pancreatic cancer. Am. J. Ind Med.
2001, 39, 336–345. [CrossRef]
33. Checkoway, H.; Boffetta, P.; Mundt, D.J.; Mundt, K.A. Critical review and synthesis of the epidemiologic evidence on formalde-
hyde exposure and risk of leukemia and other lymphohematopoietic malignancies. Cancer Causes Control 2012, 23, 1747–1766.
[CrossRef]
34. Kang, D.S.; Kim, H.S.; Jung, J.H.; Lee, C.M.; Ahn, Y.S.; Seo, Y.R. Formaldehyde exposure and leukemia risk: A comprehensive
review and network-based toxicogenomic approach. Genes Environ. 2021, 43, 13. [CrossRef]
35. Bosetti, C.; McLaughlin, J.K.; Tarone, R.E.; Pira, E.; La Vecchia, C. Formaldehyde and cancer risk: A quantitative review of cohort
studies through 2006. Ann. Oncol. 2008, 19, 29–43. [CrossRef] [PubMed]
36. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.;
Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J. Clin. Epidemiol. 2021,
134, 178–189. [CrossRef] [PubMed]
37. Wells, G.A.; Shea, B.; O’Connell, D.; Peterson, J.; Welch, V.; Losos, M.; Tugwell, P. The Newcastle-Ottawa Scale (NOS) for Assessing
the Quality of Nonrandomised Studies in Meta-Analyses; Ottawa Health Research Institute: Ottawa, ON, Canada, 2014.
38. Armstrong, R.W.; Imrey, P.B.; Lye, M.S.; Armstrong, M.J.; Yu, M.C.; Sani, S. Nasopharyngeal carcinoma in Malaysian Chinese:
Occupational exposures to particles, formaldehyde and heat. Int. J. Epidemiol. 2000, 29, 991–998. [CrossRef] [PubMed]
39. Vaughan, T.L.; Stewart, P.A.; Teschke, K.; Lynch, C.F.; Swanson, G.M.; Lyon, J.L.; Berwick, M. Occupational exposure to
formaldehyde and wood dust and nasopharyngeal carcinoma. Occup. Environ. Med. 2000, 57, 376–384. [CrossRef]
Cancers 2022, 14, 165 11 of 12

40. Laforest, L.; Luce, D.; Goldberg, P.; Bégin, D.; Gérin, M.; Demers, P.A.; Brugère, J.; Leclerc, A. Laryngeal and hypopharyngeal
cancers and occupational exposure to formaldehyde and various dusts: A case-control study in France. Occup. Environ. Med.
2000, 57, 767–773. [CrossRef] [PubMed]
41. Hildesheim, A.; Dosemeci, M.; Chan, C.C.; Chen, C.J.; Cheng, Y.J.; Hsu, M.M.; Chen, I.H.; Mittl, B.F.; Sun, B.; Levine, P.H.;
et al. Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma. Cancer Epidemiol.
Biomark. Prev. 2001, 10, 1145–1153.
42. Kjaerheim, K.; Boffetta, P.; Hansen, J.; Cherrie, J.; Chang-Claude, J.; Eilber, U.; Ferro, G.; Guldner, K.; Olsen, J.H.; Plato, N.; et al.
Lung cancer among rock and slag wool production workers. Epidemiology 2002, 13, 445–453. [CrossRef]
43. Pinkerton, L.E.; Hein, M.J.; Stayner, L.T. Mortality among a cohort of garment workers exposed to formaldehyde: An update.
Occup. Environ. Med. 2004, 61, 193–200. [CrossRef]
44. De Stefani, E.D.; Boffetta, P.; Brennan, P.; Deneo-Pellegrini, H.; Ronco, A.; Gutiérrez, L.P. Occupational Exposures and Risk of
Adenocarcinoma of the Lung in Uruguay. Cancer Causes Control 2005, 16, 851–856. [CrossRef]
45. Shangina, O.; Brennan, P.; Szeszenia-Dabrowska, N.; Mates, D.; Fabiánová, E.; Fletcher, T.; t’Mannetje, A.; Boffetta, P.; Zaridze, D.
Occupational exposure and laryngeal and hypopharyngeal cancer risk in central and eastern Europe. Am. J. Epidemiol. 2006, 164,
367–375. [CrossRef]
46. Wong, E.Y.; Ray, R.; Gao, D.L.; Wernli, K.J.; Li, W.; Fitzgibbons, E.D.; Feng, Z.; Thomas, D.B.; Checkoway, H. Reproductive history,
occupational exposures, and thyroid cancer risk among women textile workers in Shanghai, China. Int. Arch. Occup. Environ.
Health 2006, 79, 251–258. [CrossRef]
47. Marsh, G.M.; Youk, A.O.; Buchanich, J.M.; Erdal, S.; Esmen, N.A. Work in the metal industry and nasopharyngeal cancer mortality
among formaldehyde-exposed workers. Regul. Toxicol. Pharmacol. 2007, 48, 308–319. [CrossRef] [PubMed]
48. Wang, R.; Zhang, Y.; Lan, Q.; Holford, T.R.; Leaderer, B.; Zahm, S.H.; Boyle, P.; Dosemeci, M.; Rothman, N.; Zhu, Y.; et al.
Occupational exposure to solvents and risk of non-Hodgkin lymphoma in Connecticut women. Am. J. Epidemiol. 2009, 169,
176–185. [CrossRef] [PubMed]
49. Checkoway, H.; Ray, R.M.; Lundin, J.I.; Astrakianakis, G.; Seixas, N.S.; Camp, J.E.; Wernli, K.J.; Fitzgibbons, E.D.; Li, W.;
Feng, Z.; et al. Lung cancer and occupational exposures other than cotton dust and endotoxin among women textile workers in
Shanghai, China. Occup. Environ. Med. 2011, 68, 425–429. [CrossRef] [PubMed]
50. Hauptmann, M.; Stewart, P.A.; Lubin, J.H.; Beane Freeman, L.E.; Hornung, R.W.; Herrick, R.F.; Hoover, R.N.; Fraumeni, J.F., Jr.;
Blair, A.; Hayes, R.B. Mortality from lymphohematopoietic malignancies and brain cancer among embalmers exposed to
formaldehyde. J. Natl. Cancer Inst. 2009, 101, 1696–1708. [CrossRef] [PubMed]
51. Siew, S.S.; Kauppinen, T.; Kyyrönen, P.; Heikkilä, P.; Pukkala, E. Occupational exposure to wood dust and formaldehyde and risk
of nasal, nasopharyngeal, and lung cancer among Finnish men. Cancer Manag. Res. 2012, 4, 223–232. [CrossRef]
52. Mahboubi, A.; Koushik, A.; Siemiatycki, J.; Lavoué, J.; Rousseau, M.C. Assessment of the effect of occupational exposure to
formaldehyde on the risk of lung cancer in two Canadian population-based case-control studies. Scand. J. Work Environ. Health
2013, 39, 401–410. [CrossRef]
53. Meyers, A.R.; Pinkerton, L.E.; Hein, M.J. Cohort mortality study of garment industry workers exposed to formaldehyde: Update
and internal comparisons. Am. J. Ind. Med. 2013, 56, 1027–1039. [CrossRef]
54. Beane Freeman, L.E.; Blair, A.; Lubin, J.H.; Stewart, P.A.; Hayes, R.B.; Hoover, R.N.; Hauptmann, M. Mortality from solid tumors
among workers in formaldehyde industries: An update of the NCI cohort. Am. J. Ind. Med. 2013, 56, 1015–1026. [CrossRef]
55. Coggon, D.; Ntani, G.; Harris, E.C.; Palmer, K.T. Upper airway cancer, myeloid leukemia, and other cancers in a cohort of British
chemical workers exposed to formaldehyde. Am. J. Epidemiol. 2014, 179, 1301–1311. [CrossRef]
56. Pira, E.; Romano, C.; Verga, F.; La Vecchia, C. Mortality from lymphohematopoietic neoplasms and other causes in a cohort of
laminated plastic workers exposed to formaldehyde. Cancer Causes Control 2014, 25, 1343–1349. [CrossRef] [PubMed]
57. Checkoway, H.; Dell, L.D.; Boffetta, P.; Gallagher, A.E.; Crawford, L.; Lees, P.S.; Mundt, K.A. Formaldehyde Exposure and
Mortality Risks from Acute Myeloid Leukemia and Other Lymphohematopoietic Malignancies in the US National Cancer Institute
Cohort Study of Workers in Formaldehyde Industries. J. Occup. Environ. Med. 2015, 57, 785–794. [CrossRef] [PubMed]
58. McElvenny, D.M.; van Tongeren, M.; Turner, M.C.; Benke, G.; Figuerola, J.; Fleming, S.; Hours, M.; Kincl, L.; Krewski, D.;
McLean, D.; et al. The INTEROCC case-control study: Risk of meningioma and occupational exposure to selected combustion
products, dusts and other chemical agents. Occup. Environ. Med. 2018, 75, 12–22. [CrossRef] [PubMed]
59. Hauptmann, M.; Lubin, J.H.; Stewart, P.A.; Hayes, R.B.; Blair, A. Mortality from solid cancers among workers in formaldehyde
industries. Am. J. Epidemiol. 2004, 159, 1117–1130. [CrossRef] [PubMed]
60. Youk, A.O.; Marsh, G.M.; Stone, R.A.; Buchanich, J.M.; Smith, T.J. Historical cohort study of US man-made vitreous fiber
production workers: III. Analysis of exposure-weighted measures of respirable fibers and formaldehyde in the nested case-control
study of respiratory system cancer. J. Occup. Environ. Med. 2001, 43, 767–778. [CrossRef]
61. Aung, W.Y.; Sakamoto, H.; Sato, A.; Yi, E.E.; Thein, Z.L.; New, M.S.; Shein, N.; Linn, H.; Uchiyama, S.; Kunugita, N.; et al. Indoor
Formaldehyde Concentration, Personal Formaldehyde Exposure and Clinical Symptoms during Anatomy Dissection Sessions,
University of Medicine 1, Yangon. Int. J. Environ. Res. Public Health 2021, 18, 712. [CrossRef]
62. Waschke, J.; Bergmann, M.; Bräuer, L.; Brenner, E.; Buchhorn, A.; Deutsch, A.; Dokter, M.; Egu, D.T.; Ergün, S.; Fassnacht, U.; et al.
Recommendations of the working group of the Anatomische Gesellschaft on reduction of formaldehyde exposure in anatomical
curricula and institutes. Ann. Anat. 2019, 221, 179–185. [CrossRef]
Cancers 2022, 14, 165 12 of 12

63. Jalali, M.; Moghadam, S.R.; Baziar, M.; Hesam, G.; Moradpour, Z.; Zakeri, H.R. Occupational exposure to formaldehyde, lifetime
cancer probability, and hazard quotient in pathology lab employees in Iran: A quantitative risk assessment. Environ. Sci. Pollut.
Res. Int. 2021, 28, 1878–1888. [CrossRef]
64. Bhat, D.; Chittoor, H.; Murugesh, P.; Basavanna, P.N.; Doddaiah, S. Estimation of occupational formaldehyde exposure in cadaver
dissection laboratory and its implications. Anat. Cell Biol. 2019, 52, 419–425. [CrossRef]
65. Bouraoui, S.; Mougou, S.; Brahem, A.; Tabka, F.; Ben Khelifa, H.; Harrabi, I.; Mrizek, N.; Elghezal, H.; Saad, A. A combination of
micronucleus assay and fluorescence in situ hybridization analysis to evaluate the genotoxicity of formaldehyde. Arch. Environ.
Contam. Toxicol. 2013, 64, 337–344. [CrossRef]
66. Teng, S.; Beard, K.; Pourahmad, J.; Moridani, M.; Easson, E.; Poon, R.; O’Brien, P.J. The formaldehyde metabolic detoxified on
enzyme systems and molecular cytotoxic mechanism in isolated rat hepatocytes. Chem. Biol. Interact. 2001, 130–132, 285–296.
[CrossRef]
67. Saito, Y.; Nishio, K.; Yoshida, Y.; Niki, E. Cytotoxic effect of formaldehyde with free radicals via increment of cellular reactive
oxygen species. Toxicology 2005, 210, 235–245. [CrossRef]
68. Jiang, S.; Yu, L.; Cheng, J.; Leng, S.; Dai, Y.; Zhang, Y.; Niu, Y.; Yan, H.; Qu, W.; Zhang, C.; et al. Genomic damages in peripheral
blood lymphocytes and association with polymorphisms of three glutathione S-transferases in workers exposed to formaldehyde.
Mutat. Res. 2010, 695, 9–15. [CrossRef]
69. Aydin, S.; Canpinar, H.; Ündeğer, Ü.; Güç, D.; Çolakoğlu, M.; Kars, A.; Başaran, N. Assessment of immunotoxicity and
genotoxicity in workers exposed to low concentrations of formaldehyde. Arch. Toxicol. 2013, 87, 145–153. [CrossRef] [PubMed]
70. Viegas, S.; Ladeira, C.; Nunes, C.; Malta-Vacas, J.; Gomes, M.; Brito, M.; Mendonca, P.; Prista, J. Genotoxic effects in occupational
exposure to formaldehyde: A study in anatomy and pathology laboratories and formaldehyde-resins production. J. Occup.
Med. Toxicol. 2010, 5, 25. [CrossRef] [PubMed]
71. Costa, S.; Coelho, P.; Costa, C.; Silva, S.; Mayan, O.; Santos, L.S.; Gaspar, J.; Teixeira, J.P. Genotoxic damage in pathology anatomy
laboratory workers exposed to formaldehyde. Toxicology 2008, 252, 40–48. [CrossRef]
72. Burgaz, S.; Erdem, O.; Cakmak, G.; Erdem, N.; Karakaya, A.; Karakaya, A.E. Cytogenetic analysis of buccal cells from shoe-
workers and pathology and anatomy laboratory workers exposed to n-hexane, toluene, methyl ethyl ketone and formaldehyde.
Biomarkers 2002, 7, 151–161. [CrossRef]
73. Duhayon, S.; Hoet, P.; Van Maele-Fabry, G.; Lison, D. Carcinogenic potential of formaldehyde in occupational settings: A critical
assessment and possible impact on occupational exposure levels. Int. Arch. Occup. Environ. Health 2008, 81, 695–710. [CrossRef]
[PubMed]
74. Deeks, J.J.; Higgins, J.P.T.; Altman, D.G. Chapter 10: Analysing Data and Undertaking Meta-Analyses. In Cochrane Handbook for
Systematic Reviews of Interventions; Version 6.2 (updated February 2021); Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li,
T., Page, M.J., Welch, V.A., Eds.; Cochrane: London, UK, 2021; Available online: www.training.cochrane.org/handbook (accessed
on 15 December 2021).