REVIEW PAPER

International Journal of Occupational Medicine and Environmental Health 2021;34(3):319 – 338

https://doi.org/10.13075/ijomeh.1896.01649

FORMALIN SAFETY
IN ANATOMIC PATHOLOGY WORKFLOW
AND INTEGRATED AIR MONITORING SYSTEMS
FOR THE FORMALDEHYDE
OCCUPATIONAL EXPOSURE ASSESSMENT
STEFANO DUGHERI1, DANIELA MASSI2,3, NICOLA MUCCI4, NICOLA BERTI5,
GIOVANNI CAPPELLI4, and GIULIO ARCANGELI4
1
Careggi University Hospital, Florence, Italy
Industrial Hygiene and Toxicology Laboratory
2
University of Florence, Florence, Italy
Department of Health Sciences
3
Careggi University Hospital, Florence, Italy
Section of Pathology
4
University of Florence, Florence, Italy
Department of Experimental and Clinical Medicine
5
Careggi University Hospital, Firenze, Italy
Health and Safety Service

Abstract
The potential carcinogenicity of formaldehyde (FA) has prompted increasing preventive measures in anatomic pathology (AP) laboratories and new
strategies aimed at innovating airborne FA monitoring systems. This review provides an updated overview of the most recent improvements in preven-
tive measures, safe practices, and exposure monitoring tools in the FA usage and handling. A computer-based search of scientific and non-scientific
sources was performed on PubMed, Web of Science, Google and Google Patents databases, querying the main topics of real-time, in-continuous
FA monitoring instruments for sale, and commercially available tools for improving preventive measures in formalin management. In order to sim-
plify the sampling process and to choose a better analytic solution to FA assessment, the main characteristics of each FA monitoring instrument were
described. The novel technical tools recently introduced on the global market, aimed at reducing FA emissions in AP laboratories, were summarized.
This review is directed at anatomic pathologists to draw their attention to the rapidly growing field of safe formalin practices. A repeated exposure
assessment is recommended to evaluate technical changes in air monitoring programs to keep FA emissions low, in compliance with the limit value;
thus, evolved monitoring devices are needed. Int J Occup Med Environ Health. 2021;34(3):319 – 38

Key words:
formaldehyde, mitigation, formalin, exposure monitoring, anatomic pathology, occupational exposure

Received: April 28, 2020. Accepted: October 5, 2020.

Corresponding author: Stefano Dugheri, Careggi University Hospital, Industrial Hygiene and Toxicology Laboratory, Viale Peraccini 15, 50134 Florence, Italy (e-mail:
[email protected]).

Nofer Institute of Occupational Medicine, Łódź, Poland 319

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INTRODUCTION exposure in >50% of the exposed population, including

In 1892, Jean Auguste Trillat observed that formaldehyde students, teachers, and laboratory staff [11–13]. Moreover,
(FA, CAS Registry No. 50-00-0) hardened soft tissues and other acute effects linked to high levels of FA in humans
triggered coagulation [1]. The following year, Ferdinand are coughing, wheezing, chest pains, and bronchitis [14].
Blum, working intensively on the use of an FA solution Concerning the chronic effects related to FA exposure,
(later to be called formalin) in antiseptic procedures, re- nasopharyngeal cancer and sensitization are the most rel-
ported that the  fingertips’ skin became visibly thickened evant diseases. In sensitized persons, FA can cause bron-
after prolonged exposure, thus becoming impregnated [2]. chial asthma [15] and contact dermatitis [16]; in persons
Blum’s results were later confirmed by Cohn, Kenyon, who are not sensitized, a prolonged inhalation of FA at
and Blum, as reported by Durig [3]. The process of for- low levels, e.g., <1 ppm, is unlikely to result in a chronic
malin fixation was extensively described in the reviews by pulmonary injury [17]. As a sensitizer, FA can cause an
Dell’Isola [4] and Blum [5,6]. The  purpose of fixation is allergic skin reaction and irritant effects on the mucosal
to preserve tissues permanently in as life-like a state as surface of the upper airways and eyes [18–20]. However,
possible. some adverse effects on the central nervous system, such
To date, there have been 5 groups of fixatives, i.e., alde- as an increased prevalence of headache, depression, mood
hydes, mercurials, alcohols, oxidizing agents, and pic- changes, insomnia, irritability, attention deficit, as well as
rates, but formalin is considered the most effective for impaired dexterity, memory, and equilibrium, have been
all uses [7]. While FA is readily available, cheap and easy reported to result from long-term exposure [21].
to store, it also allows a long-term storage, preserves Harrington et al. [22], having analyzed the cause of death
lipids well, and has been recognized as the gold standard among pathologists in the United Kingdom from the 1950s
fixative, with no clear “all-purpose” alternative found to until the late 1980s, found excessive death rates due to sui-
date [8]. In a water solution, FA allows one to rapidly cide, and higher rates of brain tumors, hematopoietic and
obtain as much histopathological information as possible lymphatic malignancies, all of which could be attributable
from a  fixed tissue. Furthermore, macroscopically, none to FA exposure.
of the  alternative fixatives was able to compete with  FA The carcinogenicity of FA and the derivation of a safe oc-
in a broad range of tissue samples [9]. The long-term use cupational exposure limit (OEL) have been the matters of
has made it the fixative of choice for almost all histo-tech- documentations by several scientific expert panels, including
niques, to the extent that, e.g., all antibody manufacturers the German Research Foundation (Deutsche Forschungsge-
have optimized their products for formalin-fixed paraffin- meinschaft), the Health Council of the Netherlands: Dutch
embedded tissues. Thus,  FA is the  standard fixative for Expert Committee on Occupational Standards, the Nordic
routine work; in fact, it is the choice in 81% of U.S. histol- Expert Group and the Scientific Committee on Occupation-
ogy laboratories and in close to two-thirds in the rest of al Exposure Limits (SCOEL) [23]. The American Confer-
the world [10]. ence of Governmental Industrial Hygienists (ACGIH) and
Acute exposure to FA via inhalation produces causes rapid the SCOEL are scientific organizations with expertise in oc-
local irritation in mucous membranes, including the eyes, cupational and environmental health. In 2016, the ACGIH
the nose, and the upper respiratory tract. Olfactory and proposed a time-weighted average (TWA) threshold limit
sensory irritations of the upper airways and eyes have been value for FA of 0.1 ppm at 8-hour, and a short-term exposure
described as acute reversible effects due to airborne FA limit (STEL) of 0.3 ppm at 15-minute [24]. The National

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Institute for Occupational Safety proposed the FA recom- have conducted a study to estimate the Italian occupational
mended exposure limits as a 10-hour TWA (0.016 ppm) exposure to FA, evaluating 1301 exposure situations (the
and a 15-minute ceiling (0.1 ppm). healthcare sector, wood industry, chemical industry, furni-
In 2015, the European Union (EU) SCOEL proposed ture manufacturing, sewage and refuse disposal, and sanita-
the FA OELs of 0.3 ppm for 8-hour exposure and 0.6 ppm tion activities). They reported that the FA concentration in
for 15-minute exposure, i.e., well above the ACGIH’s rec- Italy, observed in these scenarios, ranged 0.01–0.30 mg/m3;
ommended levels. Besides, the expert panel endorsed Di- the highest average levels of airborne FA exposure were re-
rective 2019/983 of June 5, 2019, which introduced a tran- corded in the healthcare sector, particularly among medi-
sitional period of 5 years for the healthcare sector, during cal doctors and laboratory technicians.
which the FA limit value of 0.5 ppm for 8-hour exposure To assess FA exposure, air monitoring ensures the high-
would apply. At the same time, it encouraged workplaces est correlation with occupational exposure given the fact
to meet the 8-hour 0.3 ppm limit values wherever possible. that there are no validated FA biological indicators. For
These values are only suggested guidelines, while the Oc- example, Dimenstein [30] indicated that the endogenous
cupational Safety and Health Administration, the U.S. concentration of FA in human blood does not increase
governmental institution aimed to ensure safe and health- (2.77 μg/g) after 40-minute inhalation of 1.9 ppm of FA in-
ful working conditions, established a TWA of 0.75 ppm asmuch oxidized to formate and exhaled as carbon diox-
and a STEL of 2 ppm as the mandatory permissible expo- ide. Because of its rapid metabolism in erythrocytes, no in-
sure limit [25]. At the European level, there exist no uni- crease in the tissue concentration of FA is detectable even
fied legal limit values, but the policy-agency of each coun- a  few moments after exposure  [31]. Thus, no significant
try can establish its limits; however, it is recommended to improvement can be noticed between the FA deriving from
follow the  OEL indications  [26]. The  People’s Republic exogenous exposure and its endogenous share. Moreover,
of China, New Zealand, Finland, Israel, Canada-Quebec, the urinary FA has been indicated as a marker for other
and Canada-Ontario indicate FA OEL in terms of a ceil- pathological conditions, such as prostate cancer [32,33];
ing (0.3 ppm). thus, it cannot be considered a specific marker of occupa-
Besides, FA is a ubiquitous pollutant, and the outdoor tional exposure to FA.
sources of FA may contribute to the indoor air quality in As regards environmental monitoring, numerous analyti-
houses or working environments. For example, general cal methods for determining the airborne FA values and
outdoor air pollutants may be regional sources, such as for assessing occupational exposure have been devel-
long-range transport, or heavy and light industrial vehicles, oped [34–36]. Still, no standardized recommended ap-
but also nearby sources of air pollution, such as road traf- proach has been issued for measuring real-time forma-
fic, and including emissions from parking facilities them- lin levels in exposed employees. Moreover, only a few of
selves [27,28]. Hence, to better assess the occupational the proposed methods of integrated monitoring provide
exposure and the consequent health risk, the knowledge a validated strategy for evaluating the FA risk in health-
of environmental outdoor and indoor background values care activities [37,38]. The current, validated methods for
is essential [28]. detecting gaseous FA are based on either active or pas-
The common use of FA in working activities and the related sive sampling: the former using 2,4-dinitrophenylhydra-
health effects entail the need to assess occupational expo- zine (DNPH) as a reagent on a filter, and the latter using
sure to evaluate health risks. Recently, Scarselli et al. [29] O-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine as a reagent

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on a solid sorbent [39]. These methods are standardized struments for the airborne FA occupational exposure as-
and robust, but they require skilled personnel to conduct sessment. To adopt the best practices and to lower the air-
them, and they often face the unwillingness of the moni- borne FA values, attention is paid to innovative solutions
tored operators. for the safe management of formalin, and to integrating
As mentioned before, the healthcare sector, particu- these with continuous and remotely managed monitor-
larly the anatomic pathology (AP), is characterized by ing systems. This study aims to provide a useful tool that
the highest average levels of airborne FA exposure. In AP easily consents a modern approach to the safe handling
laboratories, formalin is handled many times throughout of formalin and the related FA occupational exposure as-
the workflow: sessment.
– in operating theatres, during the immersion of biopsies
in formalin pre-filled containers, METHODS
– in the secretariat office during samples registration, In December 2019, research for scientific sources was
– in cutting operations in the grossing room [37]. conducted in bibliographic databases of peer-reviewed
The solutions widely used to minimize FA exposure in journals (PubMed, Web of Science) to provide a broad
these scenarios are benches with aspiration hoods or view of the most recent solutions to mitigate FA expo-
conventional AP fume hoods. These, on the one hand, sure and monitoring systems. This first research was
protect the operators during work activities but, on subsequently integrated from Google, Google Scholar,
the other hand, they poorly allow ergonomics of the op- and Google Patent with non-scientific sources, such as
erations and could be scarcely upgraded with techno- manufacturer datasheets and application notes, avail-
logical systems, such as a dictaphone or a digital record- able, e.g., on the  manufacturers or suppliers’ websites.
ing system. Because of these limitations, technicians Due to the vast literature available on FA occupational
employed to perform data transcription procedures are exposure and related health risks, the research focused
needed, which leads to an unnecessary cost for the lab- on some specific topics, in particular, the  latest real-
oratory and, most importantly, to an unnecessary FA time, in-continuous FA monitoring, and the modern
exposure. In addition, specimens are collected in a pre- commercially-available tools for improving preventive
filled container with  FA to reduce the  risk related to measures in formalin management. Following this pre-
the emission during specimens collection, handling, and liminary research, specific products and devices were
storage. Although it constitutes a better solution than selected, and each name of the commercially available
the holding systems (preparing and conserving bulk so- devices was entered into the previously mentioned data-
lutions of 4% FA in the AP laboratories to fill the con- bases individually.
tainers), they can represent an exposure source due to
leaks or spilling. RESULTS
In this scenario, the implementation of safe practices in The research led the authors to evaluate several sources;
AP laboratories and the adoption of new, reliable, air- most scientific articles were related to monitoring direct-
borne FA monitoring methods are crucial [29]. reading systems (notably, electrochemical instruments).
This review summarizes the trends of innovative opera- This is probably due to the fact that they are the oldest on
tive solutions to mitigate FA emissions in AP laboratories, the market and have a more widespread use than other
together with commercially-available direct-reading in- FA exposure mitigation and monitoring devices.

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Monitoring airborne FA of these initially transparent materials; the readings are per-

by portable direct-reading instruments formed in-continuous and stored in a cloud system. The de-
One effective way to assess occupational exposure to FA tection range of modern photometric instruments ranges
is by air monitoring because of the lack of any validated 0.005–5 ppm, with a sampling frequency of 3–120 min.
occupational exposure biomarkers for FA [32,40]. To sim-
plify the sampling process and analytic operations, por- Fluorimetry
table direct-reading FA monitors are of increased interest, Fluorimetry is based on the Hantzsch reaction. Fluores-
laying the bases for on-site analyses as confirmation-level cence emission of DDL occurs at 510 nm when excited
methods, with high specificity, similar to conventional with light at 410 nm. Since the reaction works in an aque-
monitoring methods (e.g., passive or active sampling with ous solution, gaseous FA must be first trapped in the aque-
dinitrophenylhydrazine cartridges) [37]. ous media. This is achieved in a stripping coil, where air
In Table 1, the main features that must be considered and a stripping solution are brought into contact, continu-
during monitoring the device choice, which allow evalu- ously, at defined flow rates and contact surfaces. The air
ating the FA levels below the mandatory occupational and liquid streams are separated afterwards, and the solu-
limit values, have been described. Target prices, based on tion is then analyzed for FA. The linear detection range of
the Italian market, have been reported, too. this technology is 0.001–3 ppm, with a sampling frequency
The experimental and field comparisons showed that di- of 2 s–2 min.
rect-reading instruments are consistent [41–44]. Further-
more, they can be easily integrated into an occupational Electrochemical devices
hygiene plan to prevent significant acute toxicity result- Formaldehyde is determined by the electrochemical
ing from FA air monitoring in the workflow connected to oxidation of FA at a metal electrocatalyst [46,47], while
the AP laboratory [38,42]. maintaining the electrode at a fixed potential and mea-
suring the current flowing through the electrode. There
Photometry are a lot of commercially-available handled electro­chem­
Photometric instruments are generally based on the chem- ical sensors. The sensitivity of conventional electro­
ical reaction between airborne FA and β-diketone that can chemical instruments can reach a maximum of 10 ppb,
be on specific supports, such as porous glass, a  tape, or and the  specificity of these sensors can be affected by
a tablet. The reaction produces a yellowing characterized other airborne organic compounds [38], especially alco-
by absorbance at 407–424 nm, which is measured via pho- hols often used in AP laboratories. To face these draw-
toelectric photometry [45]. backs, New Cosmos Electric Co., Ltd (Osaka, Japan)
The NEMo air quality monitoring station and Profil Air produces the XP-308B Formtector, which uses a DNPH-
are passive or active samplers that differ from the conven- impregnated filter to reduce the influence of volatile or-
tional photometric instruments because they are built with ganic compounds during FA measurements. Interscan
a nano-porous sensor, and they use the Hantzsch reaction Corporation (Chatsworth, CA, USA), instead, makes
(the acetyl acetone method) which entails the cyclization a voltammetric sensor (U.S. patent No. 4017373) which
of 2,4-pentanedione, ammonium acetate and FA to obtain is an electrochemical gas detector operating under dif-
dihydropyridine 3,5-diacetyl-1,4-dihydrolutidine (DDL). fusion-controlled conditions with a guaranteed limit of
The detection of FA is based on the color variation detection of 5 ppb.

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Table 1. Direct-reading instruments for formaldehyde determination currently available on the market, December 2019

Price Range Sampling

Monitoring device Producer Portable Dimensions Weight Detection mode
[EUR] [ppm] frequency

IJOMEH 2021;34(3)
FP-31: photoelectric photometry RKI Instruments + 8×15×4 cm 250 g 1000–2000 photometry 0.005–1 15–30 min
REVIEW PAPER

method with colorimetric (Union City,

tablets for detection NJ, USA)
(accumulating measurement)
FP-330: photoelectric photometry RKI Instruments – 16×19.8×26.3 cm 6.5 kg 2500–3500 photometry 0.03–5 3–10–30 min
method using a tape cassette (Union City,
    S. DUGHERI ET AL.

NJ, USA)
FM-801: reusable sensor GrayWolf Sensing + 16×19×6 cm 300 g 2000–3000 photometry <0.02–1 30 min
cartridge that employs Solutions
the chemical reaction (Shelton, CT, USA)
with β-diketone
NEMo: air quality monitoring Ethera – 19×13.5×7 cm 520 g 5000–6000 photometry 0.001–2 15–120 min
station that employs ultra- (Crolle, France)
sensitive nano-porous
materials
μF-1 analyzer: microfluidic In’Air Solutions + 32×29×15 cm 5 kg – fluorimetry 0.001–2 2–120 s
analyzer that traps FA (Strasbourg, France)
in an aqueous solution
with the Hantzsch reaction
Monitor AL4021: analyzer based Aerolaser (Garmisch- – 45×15×56 cm 20 kg 45 000– fluorimetry 0.001–3 90–300 s
on the Hantzsch reaction Partenkirchen, 55 000
Germany)
HAL-HFX205: direct real-time HAL Technology + 8×4.5×15.7 cm 200 g 500–1500 electrochemical 0.01–5 1 min
reading fast response device (Fontana, CA, USA)
Formaldemeter™ htV-M: PPM Technology + 15×8×3.5 cm 300 g 500–1500 electrochemical 0.01–10 2 min
analyzer based (Caernarfon,
on electro-oxidation of FA United Kingdom)
at the catalytically active
electrodes
FM200: handheld device Extech-FLIR + 16×6×4 cm 181.4 g 500–1500 electrochemical 0.01–5 <2 s
with a detachable probe Commercial Systems
(Nashua, NJ, USA)
 Z-300XP: electrochemical cell Environmental Sensor + 19×14.6×7 cm 900 g 1500–2500 electrochemical 0.01–30 <60 s
4-electrode type; an active Company
filter eliminates potential (Waterway, CA, USA)
interference from common
chemicals
MultiRAE: up to 6 gas sensors RAE Inc. + 19.3×9.6×6.6 cm 880 g 1500–2500 electrochemical 0.01–10 <80 s
and wireless portability (San Jose, CA, USA)
4000 Series Portable Analyzer: Interscan Corporation + 17.8×10.2×2.25 2 kg 5500–6500 electrochemical <0.005– <40–50 s
voltametric sensor operating (Simi Valley, cm 2000
under diffusion-controlled CA, USA)
conditions
PortaSens II: hand-held device PortaSense + 8.9×22.9×14 cm 2.2 kg 1000–2000 electrochemical 0.020– <60 s
that measures different gasses (Collegeville, 2000
by inserting the appropriate PN, USA)
gas sensor module
XP-308B: simplified detector; New Cosmos Electric + 17.5×14×8.6 cm 2.5 kg 500–1500 electrochemical 0.01–30 10–30 min
reduced influence of VOCs Company
with a DNPH filter (Tokyo, Japan)
Gasera One Formaldehyde: Gasera – 48×13×44 cm 13 kg 80 000– IR 0.001–10 60 s
photoacoustic detection (Turku, Finland) 90 000 spectroscopy
technology with a QCL source
ProCeas®: pre-calibrated laser Ap2e – 42×23.6×5.5 cm 20 kg 55 000– IR 0.001–10 <60 s
IR spectrometer that employs (Aix-en-Provence, 65 000 spectroscopy
a patented low-pressure France)
sampling system
G2307 Gas Concentration Picarro Inc. – 43×18×45 cm 21.3 kg 70 000– CRDS 0–30 2–10 s–5 min
Analyzer: based on CRDS (Sunnyvale, 80 000
technology CA, USA)
VOICE200ultra: real-time Syft Technologies – 100×90×80 cm 220 kg 295 000– MS 0.007–4 <2 s
analysis using SIFT-MS (Darmstadt, 305 000
FORMALDEHYDE OCCUPATIONAL EXPOSURE ASSESSMENT    

Germany)

CRDS – cavity ring-down spectroscopy; DNPH – dinitrophenylhydrazine; FA – formaldehyde; IR – infrared; MS – mass spectrometry; QCL – quantum cascade laser;
SIFT-MS – selected-ion flow-tube mass spectrometry; VOCs – volatile organic compounds.

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Infrared spectroscopy analytical data of the trace and ultra-trace of the analyte.

Infrared (IR) spectroscopy monitors the interaction of func- Mass spectrometers have become far more accessible,
tional groups in chemical molecules with IR light resulting cheaper to purchase and operate, and easier to use, as
in predictable vibrations that provide a “fingerprint” char- a consequence of the introduction of compact, bench-top
acteristic of a chemical. Gasera (Turku, Finland) has devel- instruments, coupled to gas or liquid chromatographs [48].
oped outstanding improvements to Fourier transform-IR Recently, MS has been applied to on-field air monitoring.
photoacoustic spectroscopy (PAS), reaching a sensitivity selected‑ion flow‑tube (SIFT-MS) analyzes the  air di-
for FA of 1 ppb. This new direct-reading sampler, called rectly and within seconds, using soft chemical ionization.
Gasera One Formaldehyde, is based on combining a can- This method yields exceedingly precise, real-time, quan-
tilever enhanced PAS detection technology and a quantum titative analyses, thus eliminating the phases of sample
cascade laser operating via a mid-IR fundamental spectral preparation, pre-concentration, and chromatography [49].
absorption. The Durag Group (Novara, Italy) sells the Pro- Such FA monitoring, using this technology, is achieved by
Ceas Air, in which the IR-laser technology, implemented combining the Voice 200 ultra SIFT-MS (Syft Technolo-
with optical feedback cavity-enhanced absorption spectros- gies, Christchurch, New Zealand) with a GERSTEL (Mül-
copy (WO patent No. 03031949), is used for detection. Both heim an der Ruhr, Germany) multipurpose sampler.
these 2 instruments can reach a sensitivity of 0.001 ppm, and
they guarantee a linear response of 0.001–10 ppm. Improvements of preventive measures
in formalin management in AP workflow
Cavity ring-down spectroscopy Applying mitigating measures to ensure the safe handling
Cavity ring-down spectroscopy (CRDS) is a highly sensi- and use of formalin is essential for managing AP work-
tive optical spectroscopic technique that measures abso- flow. The  following summarized technical mitigations
lute optical extinction in aerosol samples which scatter and for FA reduce formalin emissions from the operating the-
absorb light. A highly sensitive detector has been produced atres, the secretariat area and the grossing room in a pa-
by Picarro Inc. (Santa Clara, CA, USA), called the Picarro thology laboratory:
G2307 analyzer, which enables precise and stable mea- – ergonomic consoles,
surements of FA by the CRDS technology (patent No. – absorbent materials to collect any residual draining of
US7106763B2). In CRDS, the beam from a single-fre- formalin from the anatomical specimens,
quency laser diode enters a cavity created by 3 high reflec- – kits containing an FA-neutralizing agent for formalin
tivity mirrors, enabling gases to be monitored in seconds spills,
or less at the ppb level, and some gases even at the ppt – closed-circuit systems for biopsy storage.
level. Moreover, coated SilcoNert and teflon elements are Best practices for maintaining and engineering air han-
used in the G2307 gas pathway to reduce the FA adsorp- dling, and possibly for redesigning processes and systems
tion onto pathway surfaces, increasing the response time (such as equipment functions, building operations, and
and reducing the measurement bias. industry procedures), are needed to operate effectively,
in line with the new safety regulations. Attention paid to
Mass spectrometry ergonomic design, both in terms of body-friendly adjust-
Mass spectrometry (MS) is a  sensitive and specific ana- ments and streamlined workflow, contributes to these best
lytical technique, providing qualitative and quantitative practices [50].

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Grossing workstation tering problematic areas to prevent FA overexposure and

Pathologists spend long hours in front of the aspirating to help maintain a safe environment. These devices can
chemical fume hood; thus, an ergonomic console is desir- be fitted for external exhaust or with recirculating exhaust
able to provide comfort [51]. The fume cupboards/gross- systems, which safely neutralize the harmful FA fumes
ing workstations provide a multi-featured ergonomic, by chemisorption with activated carbon, impregnated
safe, and practical work area for specimen grossing: all with potassium permanganate [57] or sodium metabisul-
potential operating features linked to a standard workflow fite [58]. Indeed, FA reaction with bisulfite forms an FA
are within easy reach, while an ergonomic posture is main- sodium bisulfite adduct (sodium hydroxymethanesulfo-
tained and, at the same time, safer management of forma- nate, CAS 870-72-4), which is very stable under normal
lin is guaranteed. Recently, the main fume hood cupboard conditions. Recently, Ethera has released a  purification
manufacturers have improved the ductility of these sta- system called PureTECH which is an irreversible granu-
tions, implementing their function and their optional tools lar FA entrapment filter with an integrated saturation in-
in order to obtain multitask workstations [52,53]. dicator [59]. Ohmichi et al. [60] specifically demonstrated
The latest generation of grossing workstations is equipped the effectiveness of the photocatalyst technology in anat-
with a laminar and/or back downdraft ventilation system omy laboratories, reducing FA concentration by about
and a working surface without front glass (Table 2). 80%. A photocatalytic oxidation and manganese oxide air
The development of a high-performance and cost-effec- purification system for airborne FA is marketed by Inno-
tive digital optical console has been the goal of recent vative Labs LLC (Petaluma, CA, USA). Finally, Novaerus
years. Replacing the traditional dictation of anatomi- (Stamford, CT, USA) uses a patented atmospheric plasma
cal pathology reports by the more recent voice recogni- discharge of the dielectric barrier discharge type, whereby
tion technology (VRT) has been showing improving suc- the plasma discharge comprises electrons and ions, caus-
cess  [54,55]. Flexible and efficient console systems have ing FA neutralization [61].
recently been produced with several new features such
as modular architecture, connectivity using appropriate Closed-circuit systems for biopsies
middleware with the AP laboratory’s information system, Closed-circuit systems used for small biopsies prevent
a digital pathology system that records whole images of the user from touching FA. The market offers several
process specimens [56], and VRT. brands of pre-filled formalin containers, all consisting
of 2 containers with lids (Table 3). Using the containers
Supplemental air handling options with the lid has dramatically reduced the use of formalin
and automated FA neutralization devices in the operating theatre, along with providing a safer han-
Extra ventilation and optimized design are not always dling in the secretariat area and the grossing room [37,38].
enough to neutralize residual FA fumes or formalin in AP Another innovation has been the adoption of contain-
laboratories, especially since peak FA exposure could ers for large biopsies which employ modified atmosphere
lead to temporary shutdowns or a reduced operational packaging (MAP) or under vacuum storage (UVS)
capacity of the  ventilation system. Portable room filters, systems immediately after tissue insertion [62]. While
such as the Room Filtration Module – Pure Path – BF840 T-Filler (Combifill, Bergamo, Italy) dispenses a 4%  FA
(Mopec, Oak Park, IL, USA) or Exhale 3000 (Danaus Srl, solution into rigid containers, the Tissue Vacuum Plus
Rome, Italy), can be easily positioned in laboratories fil- and the Tissue Filling System (Kaltek, Padua, Italy) uti-

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 328
Table 2. Latest generation grossing workstations currently available on the market, and their main features, December 2019

Springkler Computer Dissection

Workstation Producer Ventilation VRT Dictaphone FA dispenser
washing system integration cutting board

IJOMEH 2021;34(3)
Grossing tables CT1BT Propath Europe D – + + – + +
REVIEW PAPER

(Ronse, Belgium)
Grossing station PMT PMT Scientific B – + + – + +
(Redford, MI, USA)
Grossing station EMEC Emec Scientific B/D – + + + + +
    S. DUGHERI ET AL.

G515 (Selangor, Malaysia)

Elevating pathology Mortech B/D – + + + + +
grossing station (Azusa, CA, USA)
Model GL100
GrossPath GP-1500 Kugel Medical D + + + – + +
ECO-line (Regensburg,
Germany)
Grossing workstation UFSK International D – + + + + +
ZT HS 455 (Regensburg,
Germany)
Grossing workstation Zenon Diagnostic B/D – + + + + +
Zenon (Istanbul, Turkey)
Grossing station Apzem Inc. B – + + – + +
Backdraft Premium (Chennai, India)
(RBi Series)
Grossing station Medimeas Instruments B + + + + + +
M-GWS (Ambala, India)
Grossing station Mopec Mopec (Madison B + + + + + +
Maestro Heaights, MI, USA)
Elevating grossing Sakura Finetek B – – – – + +
station Tissue-Tek® (Torrance, CA, USA)
Accu-Edge®
Grossing station Milestone (Milan, B/D – + + – + +
eGROSS Italy)

B/D – back and/or down draft; FA – formaldehyde; VRT – voice recognition technology.
 FORMALDEHYDE OCCUPATIONAL EXPOSURE ASSESSMENT     REVIEW PAPER

Table 3. Closed-circuit system for the safe handling of formalin in the healthcare sector, currently available on the market,
December 2019

Available volume
Closed-circuit system Producer Rigid/Non-rigid
[ml]
SafeCapsule Diapath (Martinengo, Italy) 31.7×8.3–19 rigid
Bioprotektor Kaltek (Padua, Italy) 40–90 rigid
Klessidra Bio-Optica Milano (Milan, Italy) 20–30 rigid
Tecnobilife Biopsy Box PRAXI Intellectual Property (Civitanova Marche, Italy) 20–30–60–90 rigid
Securbiop Traces (Carmagnola, Italy) 20–60–120–250–300 rigid
Zero Meccanica GM (Loreto, Italy) 20–40–60 rigid
Biopker Kerfilter (Carmagnola, Italy) 10–20–30 rigid
Furma Aquamana (Carmagnola, Italy) 30–50–100 rigid
BiopSafe Axlab Inn. (Vedbæk, Denmark) 20–60 rigid
FormSafe Menarini (Berkshire, United Kingdom) 60 rigid
T-Filler Combifill (Bergamo, Italy) 600–5700 rigid
TVP/TFS Kaltek (Padua, Italy) 250–500 rigid
Biopreserve Patholab (Selargius, Italy) 600–5000 rigid
SealSafe Milestone (Sorisole, Italy) customized non-rigid

lize MAP technology and dispense formalin into rigid workflow  [30] since they augment the  risk of formalin
containers. The Biopreserve (Patholab, Selargius, Italy) spills and the likelihood of reaching the immediately-
method, instead, adopts a rigid container, filled with for- dangerous-to-life-and-health level. Both the  scientific
malin in a UVS medium. The latter 2 devices use bags for literature and the design of many industrial products
transporting the fresh biopsy or for storing it, following (whether produced or described in patents) suggest that
the initial fixation phase in formalin inside a rigid con- some compounds can transform formalin into non-haz-
tainer. Instead, SealSafe by Milestone [63] uses a non- ardous waste [64]. In fact, for this purpose, a formalin
rigid container  – more specifically, bags with a  double- spill kit with an FA-neutralizing agent, based on sodium
barrier layer of polyamide and polyethylene – for fixation metabisulphite, is manufactured by Aldon Corporation
with FA 4% and UVS processing. As an added bonus, (Avona, CT, USA), while a mixture of trisodium phos-
these bags significantly reduce the  space occupied by phate and sodium metabisulphite, called Tissue-Tek®
the specimens so that they can be stored and transported FormaGo, is marketed by Sakura Finetek Europe (Rijn,
more easily. Furthermore, Zenon Diagnostic (Istanbul, the Netherlands) [65].
Turkey) offers Formadose, a fully automated formalin Other similar products are available on the market, but in-
preparation and dispensing device. formation regarding the composition and the reactivity of
Neutralex, patented by Scigen Inc. (Paramount, CA, USA)
Formalin spill kits with FA-neutralizing agents and certified by the California Environmental Protection
The transport of formalin-fixed specimens and the  for- Agency and PolyForm-F™ (Newcomer Supply, Middle-
malin handling itself are clearly critical phases in AP ton, USA), is not available from the manufacturers.

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 REVIEW PAPER     S. DUGHERI ET AL.

Discussion eration, data handling, and troubleshooting can be per-

The AP market was valued at USD 33 billion in 2019 and formed remotely, even by a smartphone or a tablet, with
was estimated to grow to USD 44.4 billion by 2024, very easy-to-use packages.
at a compound annual growth rate (CAGR) of 6.1% [66]. In agreement with Dimenstein [69], it is reasonable to
The increasing volume of diagnostic tests performed expect a widespread usage of quantity airborne FA moni-
in AP laboratories and the rising needs of personalized tors on a regular basis, and this paper represents an oppor-
oncology are the key factors driving this growth. Contem- tunity to challenge manufacturers to develop such devices.
poraneously, the market for direct-reading FA monitors is Notably, FA occupational exposure could be carried out
growing significantly; the  global  FA detector production by purchasing many units for various workstations, though
revenue is estimated to reach USD 103.81 million by 2022, with cheaper in-continuous monitors, while the more ex-
with a CAGR of 3.77% in 2017–2022 [67]. pensive devices can be equipped with multi-channel moni-
New regulatory provisions have been introduced for FA re- toring, with sometimes up to 12 sample inlets, enabling
garding its classification and reference or limit values; thus, a multi-point monitoring strategy.
companies have introduced new devices on the market for Indeed, modern healthcare institutions often have mul-
a safer use of formalin. Since 2013, key studies have been tiple clinics, hospitals, operating rooms, and laboratories
published, and key cancer cohorts have been updated at separate geographic locations, with consequent logistic
confirming that FA is genotoxic, causing DNA adduct for- problems related to the environmental sampling of air-
mation, with clastogenic effects. However, the exposure- borne FA. Thus, investing in remote-monitoring devices
response relationships were non-linear, and the relevant and packages will reduce the number of hours needed by
genetic polymorphisms were not identified  [18,68]. New personnel to assess workplace exposure.
updates from the U.S. National Cancer Institute cohort, Annual monitoring is mandatory, but during the year many
nevertheless, confirmed that relative risk was not in- significant events might occur, such as the  disruption of
creased if the mean air FA exposures were <1 ppm and the ventilation system or violations of formalin handling.
the peak exposures were <4 ppm [18]. These possible ef- The area monitoring approach by remote, in-continuous
fects on human health have prompted the reorganization instruments, placed within the breathing zone of the op-
of workflow processes and new FA assessment strategies erators, can eliminate human errors and reduce the per-
(Table 4). sonnel costs related to sampling. Moreover, the different
For an accurate evaluation of the occupational FA expo- systems illustrated in this review can be combined to allow
sure scenario in an AP laboratory, the use of both screen- high-throughput remote monitoring, ensuring a complete
ing- and confirmation-level airborne  FA measurement picture of workplace exposure. Recently, Mucci et al. [38]
methods is recommended. The choice of the instruments/ have described an AP workflow where FA management is
methods to be adopted will be based on various factors, confined to fume cupboard workstations located in the op-
such as the  financial resources available, the  expected erating theatres, secretariat areas and grossing rooms.
concentration and range values, etc. However, portable, Subsequently, Dugheri et al. [70] introduced an innovative
real-time monitors already exist, and the market continues ergonomic armchair – with a piezoresistive pressure sensor
to invest in the development of such devices; hence, they to detect the presence of the operator, a barcode reader
are becoming ever-more affordable. These instruments, for personnel identification, and a headrest equipped with
furthermore, are fully networkable, and instrument op- remotely-managed in-continuous measuring instruments

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Table 4. Scientific papers about innovations and processes leading to formaldehyde occupational exposure reduction, December 2019

Reference Year Theme Subject matter

Dugheri et al. [70] 2020 monitoring strategy, devices, comparison
Ogawa et al. [71] 2019 best practices ventilation system, strategy
Mastracci et al. [63] 2019 best practices UVS
Mucci et al. [38] 2019 monitoring strategy, devices, comparison
Dugheri et al. [37] 2018 monitoring strategy
Xu et al. [72] 2016 mitigation ventilation system
Zarbo et al [62] 2015 best practices UVS
Klein et al. [73] 2014 mitigation ventilation system
Di Novi et al. [74] 2010 best practices UVS
Bussolati et al. [75] 2008 best practices UVS
Ohmichi et al. [60] 2007 mitigation photocatalytic device

UVS – under vacuum storage.

within the breathing zone – placed in front of the fume determine airborne FA values of 1 ppb are recommended.
cupboard workstation. This device combines the in-con- The FA air guideline levels proposed by WHO are com-
tinuous monitoring units mounted on it with the further parable to the other limits proposed [77]. Nonetheless, all
advantages of an ergonomic workstation. efforts should be made to remain as low as possible below
A future improvement to FA occupational monitoring this value, in accordance with the as-low-as-reasonably-
could be field-portable gas or liquid chromatography cou- achievable (ALARA) principle.
pled with MS or other detectors for these specific com- At this point, how to behave when the reference values and
pound classes to evaluate DNPH, or with O-(2,3,4,5,6- the adopted limit values are very close? The airborne FA
pentafluorobenzyl)hydroxylamine samplers  [37]. How- concentrations and air exchange rates in occupational
ever, the  specificity offered by chromatographic analysis settings are inversely correlated [78,79]. Adopting venti-
systems is also guaranteed by real-time monitors, some of lation equipment with chemisorption or adsorbent filters
which can be considered instruments for confirmation-lev- is a possible alternative, but they considerably increase
el monitoring. Specifically, IR, photometric, fluorimetric, energy consumption. This gives rise to the question of
and MS techniques can eliminate the interferences given whether the technical efforts required to minimize these
by other substances, while providing a measurement cer- emissions outweigh the benefits. This would certainly not
tainty comparable to the conventional methods [38,76]. seem to be the case when these target concentrations are
Due to the FA electrochemical sensor high cross-sen- excessively below well-established guidelines.
sitivities and long recovery times after their exposure to However, a reduction of FA concentration by means of
selected compounds, these sensors are not suitable for engineering controls of the general ventilation system is
AP laboratories, where xylenes and alcohols are used in mandatory. A computer-based control system, the Build-
the same workstation as FA. Nevertheless, the detection ing Management System, must be installed to control and
limit must be considered, and real-time monitors that can monitor the  building’s mechanical and electrical equip-

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ment, such as its heating, ventilation, and air conditioning a winning solution, combining safe usage with robustness
parameters, and to interface with the extraction system and practicality [38,74]. These innovations have drastically
of the fume hoods, too. The fume cupboards must be reduced the use of FA, because closed-circuit systems are
maintained in strict accordance with all the indications pre-filled with it and do not require the manual addition
given in their mandatory technical standards, UNI EN of FA, while UVS systems can often be used in 2 operating
14175-2:2004/3:2004/4:2005/5:2007/6:2006, UNICHIM M modes: without FA or using the minimum amount of FA,
192/3:2009/2013, AFNOR NF X15-206:2005/211:2009, depending on the type of the sample. The related reduc-
and UNI/TS 11710:2018, which are the guidelines to tion of FA use in AP laboratories leads to lower expo-
guarantee both system function and user safety. In par- sure, and thus to an improvement of working conditions.
ticular, the technical standard UNI/TS 11710:2018 con- The Higher Health Council of Italy and the Italian Group
tains the  performance specifications required for fume of Mammary Pathology of the Society of Pathology have
cupboards to be used in the handling of chemicals, with called for improvements in all phases of biopsy handling,
the acceptable limit values for containment and the ro- including transportation, to prevent harm to employ-
bustness of containment, face velocity, and air exchange ees [80,81]. Moreover, adopting the UVS and/or MAP
efficiency. systems has restricted the use of FA to dedicated areas
Particular attention to the measurement of these param- in pathology laboratories since large boxes of the forma-
eters must be paid when applying them to the latest gen- lin fixative no longer have to be transported throughout
eration of pathology laboratory grossing workstations, the hospital.
equipped with a laminar and/or back downdraft ventila- The introduction of high-tech tools, such as video and
tion system. This technology pushes air from the front of photo acquisition systems or dictaphones, can also mini-
the cutting surface through the back area, creating a lami- mize errors in the workflow of AP laboratories. After sev-
nar flow pattern for each operator with their own work- eral years of a slow start, recently there has been a rise in
space preferences, and for each laboratory with its own the availability of informatics tools.
safety and workflow requirements (Mopec Inc., patent Nevertheless, a key challenge is the cost of this new tech-
No. US20060180057A1). These workstations, in addition nology; initially, setting up a high-tech system requires
to reducing airborne FA as efficiently as conventional fume significant spending. To date, a limited number of institu-
cupboard grossing workstations, simplify workflow, thus tions have adopted speech recognition and digital pathol-
lowering the operator’s exposure, by offering an open work ogy equipment because of their high costs and complexity.
surface, nozzles for in-continuous washing with water, and Prices are, however, becoming more affordable. After an
personalized ergonomic modulation. Moreover, the possi- initial capital investment, the running costs are minimal.
bility of customization (the image acquisition system, dic­ Moreover, the  Internet has simplified communications
ta­phone-VRT, towel and glove dispensers, waste bins, etc.) and overcome the problem of installing specialized lines to
allows for the further lowering of FA emissions by reduc- communication equipment. The preliminary cost of these
ing the  number of workflow actions required, which in systems is also balanced by reducing the cost of sample
the past would have had to be done outside of the fume storage and by eliminating the working hours associated
cupboard area. with transcribing and digitizing AP reports and images.
The use of the formalin closed-circuit system for pre-load- Another challenge that is usually overlooked is the re-
ed containers and UVS systems, furthermore, has been sistance of pathologists towards this change. Generally,

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a large percentage of anatomical pathologists are not in decrease turnaround time, while at the same time dealing
favor of transitioning into high-tech practices. This can be with an aging workforce, increasing financial constraints,
attributed to many factors, including the understanding and economic uncertainty. Although it is not possible to
of new technologies, with their strengths and limitations. implement total laboratory automation, great progress
Moreover, there is generally a lower level of comfort with continues to be made in workstation automation in all
the new procedures, as for any new process. However, fail- areas of the pathology laboratory.
ure to adopt technology will become a handicap and be This report highlights the technological challenges of pa-
viewed, in the future, as a shortcoming. After witnessing thology automation, showing middleware and how it facil-
successful examples in other medical disciplines (such as itates automation, as well as presents the progress made so
radiology), pathology will surely be no exception. Thus, far in the AP laboratory, introducing such newly-available
training the pathologists is essential to achieve a better un- high-tech IT tools (i.e., speech recognition and image cap-
derstanding of the nature and limitations of these new de- turing systems).
vices, in addition to benefiting future practice. Legal issues The grossing activities could be the main target for reducing
related to the archiving and protection of electronic data pollution by formalin vapors; this would, however, require
must also be thoroughly explored, and then resolved. a longer and closer examination. Namely, in-continuous air
monitoring to capture the highest levels of exposure during
CONCLUSIONS grossing activities is desirable. In contrast, the 8-hour TWA
The aim of this review was to focus on the current work levels are not always appropriate because they are influ-
practices and possible new implementations to reduce FA enced not only by the proportion of large vs. small specimens
vapor emissions in the AP workflow. Specifically, easy-to- grossed during the work shift, but also heavily by the intra-
use and economical airborne FA monitoring devices were day workload variation. For these reasons, the introduction
listed along with their main features in order to assist in of in-continuous monitoring systems during grossing activi-
improving the safety in AP workplaces, in compliance with ties should be adopted to make a fair assessment of FA ex-
national mandatory occupational limit values. The au- posure and, at the same time, to evaluate the goodness of
thors’ goal is to encourage the pinpointing of those tech- high-tech tools and FA mitigation solutions adopted.
nical changes that would mitigate emissions. Repeated
exposure assessment will help to evaluate whether tech- REFERENCES
nical changes in an air monitoring program do keep FA 1. Musiał  A, Gryglewski  RW, Kielczewski  S, Loukas  M, Waj-
emissions low. The lack of biological indicators for FA and da J. Formalin use in anatomical and histological science in
its low odor threshold suggest that air monitoring ensures the 19th and 20th centuries. Folia Med Cracov. 2016;56(3):
the highest degree of safety. 31–40.
The use of formalin in the  AP laboratories’ workflow 2. Blum F. [The formaldehyde as a hardening agent]. Microsc
has changed substantially since the years when the main Acta. 1893;10:314–5. German.
epidemiological studies were conducted; of course, it 3. During  A.  [Formalin as a  fixative instead of osmic acid in
was the monitoring of FA exposure at the workplace that the Ramòn and Cajal’s method]. Anat Anz. 1895;10:659–60.
changed the game. The practice of surgical pathology is German.
under constant pressure to deliver the highest quality of 4. Dell’Isola  G.  [On the  value of formalin in histology]. Boll
service, to reduce errors, to increase throughput, and to Acad Med Genova. 1895;10:84–94. Italian.

IJOMEH 2021;34(3) 333

 REVIEW PAPER     S. DUGHERI ET AL.

5. Blum F. [About essence and value of formaldehyde conser- Monographs on the Identification of Carcinogenic Hazards
vation]. Anat Anz. 1896;11:718–27. German. to Humans. Available from: https://monographs.iarc.fr/wp-
6. Elrich P. [Encyclopedia of microscopic technology]. Pieter- content/uploads/2018/06/mono100F-29.pdf.
len: Verlag Der Wissenschaften 1910:478–93. German. 17. Agency for Toxic Substances and Disease Registry [Inter-
7. Buesa RJ. Histology without formalin? Ann Diagn Pathol. net]. Atlanta: The Agency; 2001 [cited 2020 Jan 13]. Medical
2008;12(6):387–96, https://doi.org/10.1016/j.anndiagpath. Management Guidelines for Formaldehyde. Available from:
2008.07.004. https://www.atsdr.cdc.gov/MHMI/mmg111.pdf.
8. Hopwood D. Fixatives and fixation: a review. Histochem J. 18. Nielsen GD, Larsen ST, Wolkoff P. Re-evaluation of the
1969;1(4):323–60. WHO (2010) formaldehyde indoor air quality guideline for
9. Moelans CB, Ter Hoeve N, Van Ginkel JW, Ten Kate FJ, Van cancer risk assessment. Arch Toxicol. 2017;91:35–61, https://
Diest PJ. Formaldehyde substitute fixatives: analysis of mac- doi.org/10.1007/s00204-016-1733-8.
roscopy, morphologic analysis, and immunohistochemical 19. Hall A, Harrington JM, Aw T. Mortality study of British
analysis. Am J Clin Pathol. 2011;136(4):548–56. pathologists. Am J Ind Med. 1991;20(1):83–9, https://doi.
10. Buesa RJ. Histology safety: now and then. Ann Diagn org/10.1002/ajim.4700200108.
Pathol. 2007;11(5):334–9. 20. Flyvholm MA, Menné T. Allergic contact dermatitis from FA.
11. Onyije FM, Avwioro OG. Excruciating effect of formalde- A case study focusing on sources of formaldehyde exposure.
hyde exposure to students in gross anatomy dissection labo- Contact Dermatitis. 1992;27(1):27–36, https://doi.org/10.1016/
ratory. Int J Occup Environ Med. 2012;3:92–5. j.mrrev.2008.07.002.
12. Vimercati L, Carrus A, Martino T, Galise I, Minunni V, Ca- 21. Songur A, Ozen OA, Sarsilmaz M. The toxic effects of form-
puto F, et al. Formaldehyde exposure and irritative effects on aldehyde on the nervous system. Reviews of environmental
medical examiners, pathologic anatomy post-graduate stu- contamination and toxicology. New York: Springer; 2010.
dents and technicians. Iran J Public Health. 2010;39:26–34. p. 105–18.
13. Garzillo EM, Miraglia N, Pedata P, Feola D, Lamberti M. 22. Friis UF, Dahlin J, Bruze M, Menné T, Johansen JD. Hidden
Risk agents related to work and amyotrophic lateral sclero- exposure to formaldehyde in a swab caused allergic contact
sis: An occupational medicine focus. Int J Occup Med En- dermatitis. Contact Dermatitis. 2014;70:258–60, https://doi.
viron Health. 2016;29(3):355–67, https://doi.org/10.13075/ org/10.1111/cod.12172.
ijomeh.1896.00368. 23. Bolt HM, Degen GH, Hengstler JG. The carcinogenicity de-
14. U.S. Environmental Protection Agency [Internet]. Wash- bate on formaldehyde: How to derive safe exposure limits?
ington: The Agency; 2000 [cited 2020 Jan 15]. Formalde- Arch Toxicol. 2010;84:421–2.
hyde. Available from: https://www.epa.gov/sites/production/ 24. American Chemistry Council (ACC) [Internet]. Washington:
files/2016-09/documents/formaldehyde.pdf. The Council; 2016 [cited 2019 Dec 20]. ACGIH Decision to
15. Occupational Safety and Health Administration [Inter- Lower Formaldehyde TLVs Lacks Transparency and Scien-
net]. Washington: The Administration [cited 2020 Jul 22]. tific Basis. Available from: https://www.americanchemistry.
1910.1048 App C – Medical surveillance – Formaldehyde. com/Media/PressReleasesTranscripts/ACC-news-releases/
Available from: https://www.osha.gov/laws-regs/regulations/ ACGIH-Decision-to-Lower-Formaldehyde-TLVs-Lacks-
standardnumber/1910/1910.1048AppC. Transparency-and-Scientific-Basis.html.
16. International Agency for Research on Cancer [Inter- 25. Occupational Safety and Health Administration [Internet].
net]. Lyon: The Agency; 2018 [cited 2020 Jan 17]. IARC Washington: The Administration; 2011 [cited 2020 Jul 22].

334 IJOMEH 2021;34(3)

 FORMALDEHYDE OCCUPATIONAL EXPOSURE ASSESSMENT     REVIEW PAPER

OSHA Fact Sheet Formaldehyde. Available from: https:// 35. Dugheri S, Bonari A, Pompilio I, Colpo M, Mucci N, Mon-
www.osha.gov/OshDoc/data_General_Facts/formaldehyde- talti M, et al. Development of an innovative gas chromatog-
factsheet.pdf. raphy-mass spectrometry method for assessment of form-
26. European Chemicals Agency [Internet]. Helsinki: The Agen- aldehyde in the workplace atmosphere. Acta Chromatogr.
cy; 2019 [cited 2020 Jul 22]. Occupational exposure limits. 2017;29(4):511–4.
Available from: https://echa.europa.eu/oel. 36. Dugheri S, Mucci N, Pompilio I, Cappelli G, Bossi C, Bo­
27. Dugheri S, Mucci N, Cappelli G, Bonari A, Garzaro G, Mar­ nari A, et al. Determination of airborne formaldehyde and
rubini G, et al. Monitoring of Air-Dispersed Formaldehyde ten other carbonyl pollutants using programmed tempera-
and Carbonyl Compounds as Vapors and Adsorbed on Par- ture vaporization-large volume injection-gas chromatogra-
ticulate Matter by Denuder-Filter Sampling and Gas Chro- phy. Se Pu. 2018;36(12):1311–22, https://doi.org/10.3724/sp.j.
matographic Analysis. Int J Environ Res Public Health. 1123.2018.08050.
2019;16(11):1969–86, https://doi.org/10.3390/ijerph16111969. 37. Dugheri S, Bonari A, Pompilio I, Colpo M, Mucci N, Arcange-
28. Salthammer T. The formaldehyde dilemma. Int J Hyg Environ li G. An Integrated Air Monitoring Approach for Assess-
Health. 2015;218(4):433–6, https://doi.org/10.1016/j.ijheh. ment of Formaldehyde in the Workplace. Saf Health Work.
2015.02.005. 2018;9(4):479–85, https://doi.org/10.1016/j.shaw.2018.05.002.
29. Scarselli  A, Corfiati  M, Di Marzio  D, Iavicoli  S. National 38. Mucci N, Dugheri S, Rapisarda V, Campagna M, Garzaro G,
Estimates of Exposure to Formaldehyde in Italian Work- Farioli A, et al. Occupational exposure to airborne formal-
places. Ann Work Expo Health. 2017;61(1):33–43, https:// dehyde in hospital: setting an automatic sampling system,
doi.org/10.1093/annweh/wxw004. comparing different monitoring methods and applying them
30. Dimenstein IB. A pragmatic approach to formalin safety in to assess exposure. Med Lav. 2019;110(6):446–58, https://
anatomical pathology. Lab Med. 2009;40(12):740–6. doi.org/10.23749/mdl.v110i6.8038.
31. Heck HDA, Casanova-Schmitz M, Dodd PB, Schachter EN, 39. Associazione per l’Unificazione nel Settore dell’Industria
Witek TJ, Tosun T. Formaldehyde (CH2O) concentra- Chimica (Unichim). [Official Method n. 2237:09: Work envi-
tions in the blood of humans and Fischer-344 rats exposed ronments – Determination of airborne aldehydes – Method
to CH2O under controlled conditions. Am Ind Hyg As- for solid phase microextraction (SPME) and analysis by
soc J. 1985;46(1):1–3. gas chromatography coupled with mass spectrometry (GC-
32. Španěl  P, Smith  D, Holland  TA, Singary  WA, Elder  JB. MS)]. Milan: The Association; 2009. Italian.
Analysis of formaldehyde in the headspace of urine from 40. Pala M, Ugolini D, Ceppi M, Rizzo F, Maiorana L, Bolog-
bladder and prostate cancer patients using selected ion flow nesi C, et al. Occupational exposure to formaldehyde and
tube mass spectrometry. Rapid Commun Mass Spectrom. biological monitoring of Research Institute workers. Can-
1999;13(14):1354–9, https://doi.org/10.1002/(SICI)1097-0231 cer Detect Prev. 2008;32(2):121–6, https://doi.org/10.1016/
(19990730)13:14<1354::AID-RCM641>3.0.CO;2-J. j.cdp.2008.05.003.
33. Takeuchi A, Takigawa T, Abe M, Kawai T, Endo Y, Yasugi T, 41. Hak C, Pundt I, Kern C, Platt U, Dommen J, Ordóñez C,
et al. Determination of formaldehyde in urine by headspace et al. Intercomparison of four different in-situ techniques for
gas chromatography. B Environ Contam Tox. 2007;79(1):1–4. ambient formaldehyde measurements in urban air. Atmos
34. Szulejko JE, Kim KH. Derivatization techniques for de- Chem Phys Discuss. 2005;5(3):2897–945.
termination of carbonyls in air. TRAC-Trend Anal Chem. 42. Hirst D, Gressel MG, Flanders W. Short-term monitoring of
2015;64:29–41. formaldehyde: comparison of two direct-reading instruments

IJOMEH 2021;34(3) 335

 REVIEW PAPER     S. DUGHERI ET AL.

to a laboratory-based method. J Occup Environ Hyg. 2011;8(6): from: https://bio-optica.it/ftp/technical_datasheet/Trimming

357–63, https://doi.org/10.1080/15459624.2011.578499. tech130_en.pdf.
43. Wisthaler A, Apel EC, Bossmeyer J, Hansel A, Junker- 54. Suvalsky S, Boelman V. Voice recognition technology vs.
mann W, Koppmann R, et al. Intercomparison of formal- manual transcription: Is voice recognition technology supe-
dehyde measurements at the atmosphere simulation cham- rior to manual transcription for surgical pathology – in terms
ber SAPHIR. Atmos Chem Phys. 2008;8(8):2189–200. of return on investment? A formal study says the answer is
44. Chevallier E, Caron T, Belon C, Karpe P, Tran-Thi TH, Co- no. MLO: Med Lab Obs. 2012;44(9):36–8.
lomb S, et al. Development of a formaldehyde chemical sen- 55. Al-Aynati MM, Chorneyko K. Comparison of voice-auto-
sor for indoor air quantification: application in health and mated transcription and human transcription in generating
safety at work. In: Ventilation 2012; 2012 September; Paris, pathology reports. Arch Pathol Lab Med. 2003;127(6):721–5.
France. Paris: REHVA; 2012. p. 1–6. 56. Chow JA, Törnros ME, Waltersson M, Richard H, Kusoff-
45. Maruo YY, Nakamura J, Uchiyama M. Development of sky M, Lundström CF, et al. A design study investigating
formaldehyde sensing element using porous glass impreg- augmented reality and photograph annotation in a digi-
nated with β-diketone. Talanta. 2008;74(5):1141–7. talized grossing workstation. J Pathol Inform. 2017;8(31).
46. Zhou ZL, Kang TF, Zhang Y, Cheng SY. Electrochemical 57. Hu SC, Chen YC, Lin XZ, Shiue A, Huang PH, Chen YC,
sensor for formaldehyde based on Pt–Pd nanoparticles and et al. Characterization and adsorption capacity of potassium
a Nafion-modified glassy carbon electrode. Microchim Acta. permanganate used to modify activated carbon filter media
2009;164(1–2):133–8. for indoor formaldehyde removal. Environ Sci Pollut Res.
47. Baez-Gaxiola MR, Fernández-Sánchez C, Mendoza E. Gold 2018;25(28):28525–45, https://doi.org/10.1007/s11356-018-2681-z.
cluster based electrocatalytic sensors for the detection of 58. Warner CR, Daniels DH, Fitzgerald MC, Joe Jr FL, Diachen-
formaldehyde. Anal Methods. 2015;7(2):538–42. ko GW. Determination of free and reversibly bound sulphite
48. Mellon FA. Mass Spectrometry, Principles and Instrumenta- in foods by reverse-phase, ion-pairing high-performance
tion. Cambridge: Academic Press; 2003. liquid chromatography. Food Addit Contam. 1990;7(5):575–
49. Španěl  P, Smith  D. Selected ion flow tube mass spectrom- 81, https://doi.org/10.1080/02652039009373922.
etry for on-line trace gas analysis in biology and medicine. 59. Ethera [Internet]. Crolle: The Institute; 2019 [cited 2020
Eur J Mass Spectrom. 2007;13(1):77–82, https://doi.org/ Jan 15]. Air filtration pellet  – Puretech, Purification with
10.1255%2Fejms.843. PureTECH® (Granular). Available from: http://www.ethera-
50. Jones RL, Eagleson D. Ergonomic considerations in the de- labs.com/en/air-filtration-pellet-puretech/.
velopment of a class II, type A/B3 biological safety cabinet. 60. Ohmichi K, Matsuno Y, Miyaso H, Yamamoto H, Toriuchi M,
Am Clin Lab. 2001;20(4):37–42. Shimane M, et al. Pilot study of a dissection table for gross
51. Suvarna  K, Layton  C, Bancroft  J.  Bancroft’s Theory and anatomy laboratory equipped with a photocatalytic device
Practice of Histological Techniques. Elsevier; 2018. that decomposes formaldehyde. J Occup Health. 2007;49(6):
52. Diapath [Internet]. Bergamo: The Institute; 2019 [cited 2020 499–503, https://doi.org/10.1539/joh.49.499.
Jan 3]. Cappa aspirante Zefiro 180 ci18xx 380. Available from: 61. Start-up Europe [Internet]. Bruxelles: The Institute; 2019
https://www.diapath.it/it/prodotto/cappa-aspirante-zefiro- [cited 2020 Feb 10]. Novaerus uses power of plasma to im-
180-ci18xx-380. prove air quality and patient outcomes. Available from:
53. Bio-optica [Internet]. Milan: The Institute; 2018 [cited 2020 https://startupeuropenews.eu/novaerus-uses-power-of-plas-
Jan 3]. Technical Datasheet Trimmingtech130. Available ma-to-improve-air-quality-and-patient-outcomes/.

336 IJOMEH 2021;34(3)

 FORMALDEHYDE OCCUPATIONAL EXPOSURE ASSESSMENT     REVIEW PAPER

62. Zarbo RJ. Histologic validation of vacuum sealed, formalin- 70. Dugheri S, Massi D, Mucci N, Cappelli G, Arcangeli G.
free tissue preservation, and transport system. In: Dietel M, Changes in airborne formaldehyde concentrations after
Wittekind C, Bussolati G, von Winterfeld M, editors. Pre- safer use improvements: the 20-year experience of an Italian
Analytics of Pathological Specimens in Oncology. Springer; university hospital. Arh Hig Rada Toksikol. 2020;71(3):178–
2015. p. 15–26. 88. https://doi.org/10.2478/aiht-2020-71-3406.
63. Mastracci L, Gambella A, Bragoni A, Pigozzi S, Pastorino L, 71. Ogawa M, Kabe I, Terauchi Y, Tanaka S. A strategy for
Vanni I, et al. Coping with formalin banning in pathology: the reduction of formaldehyde concentration in a hospital
under vacuum long-term tissue storage with no added for- pathology laboratory. J Occup Health. 2019;61(1):135–42,
malin. Histochem Cell Biol. 2019;151(6):501–11, https://doi. https://doi.org/10.1002/1348-9585.12018.
org/10.1007/s00418-018-1765-7. 72. Xu W, Stewart EJ. A comparison of engineering controls for
64. Masters  AL. A  review of methods for detoxification and formaldehyde exposure during grossing activities in health
neutralization of formalin in water. N Am J Aquacult. care anatomic pathology laboratories. J Occup Environ Hyg.
2004;66(4):325–33, https://doi.org/10.1577/A03-060.1. 2016;13(7):529–37, https://doi.org/10.1080/15459624.2016.1
65. Prakash R, Carmichael ST. Evaluation of two eco-friendly 149182.
neutralizers for a spectrum of tissue fixatives for biomedical 73. Klein RC, King C, Castagna P. Controlling formaldehyde ex-
applications. Future Sci OA. 2018;4(8):FSO329, https://doi. posures in an academic gross anatomy laboratory. J Occup
org/10.4155/fsoa-2018-0035. Environ Hyg. 2014;11(3):127–32, https://doi.org/10.1080/154
66. MarketsandMarkets Research Private Ltd [Internet]. Pune: 59624.2013.816432.
The Company; 2019 [cited 2019 Dec 21]. Anatomic pathology 74. Di Novi C, Minniti D, Barbaro S, Zampirolo MG, Cimino A,
market by product & service (instruments (tissue processing Bussolati G. Vacuum-based preservation of surgical speci-
systems, microtomes), consumables (antibodies), histopa- mens: an environmentally-safe step towards a formalin-free
thology), application (disease diagnosis (cancer (gastroin- hospital. Sc Total Environ. 2010;408(16):3092–5, https://doi.
testinal)), end user (hospital, lab) – global forecast to 2024. org/10.1016/j.scitotenv.2010.04.022.
Available from: https://www.marketsandmarkets.com/Mar- 75. Bussolati  G, Chiusa  L, Cimino  A, D’Armento  G. Tissue
ket-Reports/anatomic-pathology-market-137323145.html. transfer to pathology labs: under vacuum is the safe alterna-
67. The Market Reports [Internet]. Pune: The Company; 2019 [cit- tive to formalin. Virchows Arch. 2008;452(2):229–31, https://
ed 2019 Dec 21]. Global formaldehyde detectors market status doi.org/10.1007/s00428-007-0529-x.
and trends research report 2017. Available from: https://www. 76. Kaiser J, Li X, Tillmann R, Acir I, Holland F, Rohrer F, et al.
themarketreports.com/report/global-formaldehyde-detectors- Intercomparison of Hantzsch and fiber-laser-induced-fluo-
market-status-and-trends-research-report-2017. rescence formaldehyde measurements. Atmos Meas Tech.
68. International Agency for Research on Cancer [Internet]. 2014;7(6):1571–80.
Lyon: The Agency; 2018 [cited 2019 Dec 10]. IARC mono- 77. Salthammer T. Formaldehyde in the ambient atmosphere:
graphs. 100F Formaldehyde. Available from: https://mono- from an indoor pollutant to an outdoor pollutant? Angew
graphs.iarc.fr/wp-content/uploads/2018/06/mono100F-29.pdf. Chem Int Ed. 2013;52(12):3320–7, https://doi.org/10.1002/
69. Dimenstein IB [Internet]. Gross Pathology; 2009 [cited 2020 anie.201205984.
Feb 21]. Formalin Safety in the Surgical. Available from: 78. Institute of Medicine (IOM) of the National Academies. Cli-
https://grossing-technology.com/formalin-safety-in-the-sur- mate Change, the Indoor Environment, and Health. Wash-
gical-pathology-laboratory/. ington, DC: The National Academies Press; 2011.

IJOMEH 2021;34(3) 337

 REVIEW PAPER     S. DUGHERI ET AL.

79. Gammage RB, Gupta K. Formaldehyde. In: Walsh PJ, Dab- tissues for diagnostic investigations of pathological anatomy.
ney CS, Copenhaver ED, editors. Indoor Air Quality. Boca Available from: http://www.salute.gov.it/imgs/C_17_pubbli-
Raton: CRC Press; 1984. p. 109–42. cazioni_2504_allegato.pdf.
80. Ministry of Health Higher Health Council [Internet]. Roma: 81. Fiocca R, Marchetti A, Massi D, Truini M, Zanin T. [Note
The Ministry; 2016 [cited 2020 Feb 25]. Guidelines Tracking, on the use of formalin, re-classified “carcinogenic”]. Milan:
Collection, Transport, Preservation and Storage of cells and SIAPEC-IAP Divisione Italiana; 2016. Italian.

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