Formalin is intentionally placed in the article’s title. Laboratory practice employs 10% formalin, or 4% formaldehyde water solution that is important when safety issues are in consideration. Formaldehyde will remain the “universal” fixative in anatomical pathology practice for a good long time.
Numerous experimental, epidemiological, and clinical studies of formaldehyde exposure morbidity and mortality convinced governmental organizations and institutional facilities in implementing measures for monitoring formaldehyde exposure. There are calls for restriction and even elimination of formaldehyde use. Formaldehyde’s apparent deleterious effect (smell, irritation, tearing) helps to win public support for these measures.
This article does not dispute institutional policies and governmental regulations of formaldehyde use. The goal is to present a sober assessment of safety issues related to formalin fixation in anatomical pathology, especially in its surgical pathology division. The formaldehyde carcenogenity will have a disproportional length of presentation due to its significance as the main safety concern.
We are not going to repeat well known OSHA Safety Mandates for Formaldehyde Exposure that are described in official materials (1, 2), in the comprehensive manual on this subject by Janet & Richard Dapson “Hazardous Material in the Histopathology Laboratory” (3) , as well as in local institutional safety manuals. Our goal is to offer a pragmatic approach to formalin use which stems from long time experience through numerous mistakes.
This article has an unusual pattern of presentation. The literature data will be interspaced with personal observations as a bench pathologist, pathologists’ assistant and grossing technologist. The author considers himself as “soaked” by formalin during many decades of work in anatomical pathology.
Let’s start with an introductory personal story to bring some credibility to the “soaked” word. Many years ago, I had an embarrassing experience. After working a half of the day on surgical pathology grossing and autopsy, I went to a different facility by catching a crowded bus. A woman told quietly to her companion: “It smells like somebody left a hospital.” I modestly refused recognition.
Formaldehyde/ formalin background
History of formaldehyde is well presented in many publications to name a recent of them (4). Formaldehyde’s fixative features were serendipitously discovered during its studies as a disinfectant at the end of 19th century (Ferdinand Blum) when few antiseptic reagents were available (5). Formalin, as formaldehyde’s water solution, became the prevalent fixative in anatomical pathology laboratory and embalming in 20th century.
Let us discuss formaldehyde/ formalin’s physical and chemical features as far as safety issues are concerned. This background can help comprehend some prevention measures of its harmful effects.
There are two aspects of formaldehyde’s exposure: local at the place of the initial contact (respiratory and digestive tracts, skin, etc.) and general as a result of absorption. More than 90% of inhaled formaldehyde is absorbed in the upper respiratory tract and mixes with the endogenous formaldehyde pool. Endogenously produced, formaldehyde is a metabolic intermediate in all cells. The endogenous concentration of formaldehyde in human blood does not increase (2.77 microgram/gram) after inhalation for 40 minutes of 1.9 ppm formaldehyde. Because of its rapid metabolism in erythrocytes, no increase in tissue concentration of formaldehyde is detectable even moments after exposure (6). Absorbed formaldehyde can be oxidized to formate and exhaled as carbon dioxide. This data suggest that local exposure has the most significance from the safety approach.
Formaldehyde HCHO, a colorless gas, is rarely found in its original state because it had a short half-life in air due to its decomposition in light. Formaldehyde (methanal) is manufactured as a product of catalytic oxidation of methanol (CHOH). The concentrated water solution (37%-40%) of formaldehyde is called Formalin by its German trade name. The anatomical pathology practice uses Neutral Buffered Formalin (NBF) to prevent acidification due to formaldehyde’s tendency to be oxidized to formic acid. The buffer solution also enhances formation monomeric formaldehyde (methylene hydrate), as a fixation reagent. Methanol (7-10%) is added to prevent polymerization in paraformaldehyde (7).
As a small light molecule, formaldehyde evaporates easily from the formalin surface. The kinetic energy of evaporation depends on temperature, humidity, and air flow (8). The thinner the layer of the liquid where formaldehyde is dissolved, the easier formaldehyde molecules can overcome the intermolecular boundaries, including Van der Waals force, and escape to gas phase. The kinetic theory also explains the well- known observation that evaporation depends on the temperature, the higher the more intensive. Everyone who had to open a working VIP processor during formalin phase can remember irritation of eyes and throat. Another condition that determines evaporation is humidity of the space, or water vapor. Humidity, as it is well known from our every day life, prevents evaporation, and thus limits formaldehyde gas escape from liquid phase. Air flow increases escaping of formaldehyde of the formalin surface as well. Physics of formaldehyde gas should be in consideration in organization of laboratory working place and in emergencies of formalin spills.
As far as safety considerations are concerned, some chemical features of formaldehyde behavior in water solution (formalin) are important to discuss. Formaldehyde in water forms methylene glycol (methylene hydrate). The equilibrium between methilene glycol and formaldehyde in water solution lies in favor of methylene glycol. Formaldehyde requires conversion from methylene glycol to be able for actual covalent chemical reaction. This feature has a well known, especially to histotechlogists, name as fixation. Formaldehyde behaves as a fast penetrating, but slow fixative. Fast penetration is due to diffusion of methylene glycol. The slow fixative feature depends on covalent chemical reaction of carbonyl formaldehyde with proteins, glycoproteins, nucleic acids, and polysaccharids for intra-and intermolecular cross-linking of macromolecules. Slow fixation rate is positive from safety perspective because it buys time for formaldehyde elimination from upper respiratory and digestive tracts before the fixation damage is done. Formaldehyde’s high solubility in water causes fast absorption in mucus of the upper respiratory tract, predominately in nose cavity and sinuses. Mucus blanket is the first line of the body’s defense in formaldehyde exposure. This issue will be discussed more detailed in preventive measures section.
The physical and chemical characteristics of formalin are presented in some detail to provide a background for safety considerations. Safety concerns can be breaking up in three unequal groups: carcinogenicity, general medical problems, and acute harmful effect.
Carcinogenicity as the main safety concern
Among objections to formalin use, the major is formaldehyde’s carcinogenicity. “Carcinogen.” writes RW Dapson in the “Safety in the Laboratory” section of the Bancrofts’s histology techniques manual (9).
In 1989, American Medical Association summarized literature data through 1985 on formaldehyde occupational exposure. By mentioning that regulatory agencies as OSHA, regard formaldehyde as a possible human carcinogen, AMA noticed that “this is a controversial opinion in the view of many industry and academic scientists.” During the 80th, there was a politically charged dispute between EPA, OSHA, CAP, Formaldehyde Institute, DuPont and labor unions on evaluation of occupational exposure risk (10) that was based at that time on formaldehyde assessment as “probable carcinogen.”
The main organization that influences the assessment of reagents as carcinogenic is the World Health Organization’s (WHO) International Agency for Research on Cancer (IARC) based inLyon,France. IARC summarizes literature data predominately epidemiological research, as well as some experimental studies.
According to IARC Press Release No 153, 15 June 2004 (11) formaldehyde is placed in Group I – known carcinogens- along with such substances as asbestos and benzene.
It is reasonable to quote excerpts from Summary of Data Reported and Evaluation (in italic, with main points in bold) of the IARC Monographs Programme on Formaldehyde 2006. The complete text is 496 pages. Comments will accompany main conclusions, as well as some relevant anatomical data. The IARC’s text is in red italics.
5.2 Human data
“Overall, the Working Group concluded that the results of the study of industrial workers in the USA, supported by the largely positive findings from other studies, provided sufficient epidemiological evidence that formaldehyde causes nasopharyngeal cancer in humans.”
The Monograph Programme presents cohort and case-control epidemiological studies predominately manufacturing and garment industries, as well as mobile homes exposure to formaldehyde containing materials. The data are very much contradictory due to misclassification and inadequate methodology of dose-response relationship. Some dissent studies were partially included (13, 14), but some analyses were left out completely (15).
Nasopharyngeal cancer is rare; even one case that was misclassified on the death certificate (main source of statistic data) can change the entire statistical equation. A simple methodological failure in cohort epidemiological studies cannot be dismissed. A recent analysis of literature data with a title “The enigmatic epidemiology of nasopharyngeal carcinoma” found association of formaldehyde exposure with nasopharyngeal cancer risks unconvincing (16).
Nasopharynx, or the nasal part of the pharynx, is a small anatomical area behind the nasal cavity; it is bonded by five walls and borders the oropharynx at the level of lower margin of the uvula. Before formaldehyde reaches the nasopharynx area, it has to go with the inhaled air a long way that is designed to contain any “intruder”. The nasopharynx and nasal cavity communicate through the conches. It is doubtful that formaldehyde specifically targets this relatively small area living alone nasal cavity and pharynx. However, if (IF remains) the IARC conclusion is correct, this location can have some explanation and most importantly open some opportunities for prevention which will be discussed in prevention measures section of this article.
“In summary, there is strong but not sufficient evidence for a casual association between leukemia and occupational exposure to formaldehyde. Increased risk for leukemia has consistently been observed in studies of professional workers and in two of three of most relevant studies of industrial workers.”
Most recent epidemiological studies (17) completely ignore leukemia as a formaldehyde exposure related cause of death among industrial workers. For lymphhematopoietic neoplasm there were modestly elevated risks in professional group as pathologists and anatomist (18). The professional group required special discussion that will be presented below.
“Almost all of the formaldehyde-exposed cases in the case -control studies were also exposed to wood dust, which resulted in a high relative risk, particularly for adenocarcinoma. Thus, there is only limited epidemiological evidence that formaldehyde causes cancer in humans.”
The nasal cavity and sinuses are the formaldehyde exposure frontiers. Formaldehyde rarely reaches even sinuses staying on turbinate which have a great square due to curves. It is a puzzle why the frontiers of formaldehyde exposure do not develop cancer.
Cancer at other sites
A number of studies have found associations between exposure to formaldehyde and cancer at other sites, including the oral cavity, oro- and hypopharynx, pancreas, larynx, lung and brain. However, the Working Group considered that overall balance epidemiological evidence did not support a causal role for formaldehyde in relation to these other cancers.”
The controversies on this issue reflect a debate in cancer epidemiology literature (19, 20)
Experimental cancer remains the important convincing issue in assessing formaldehyde as carcinogen. The IARC animal carcenogenity data summary noted that inhalation of formaldehyde by rats . Studies showed that administration of formaldehyde in drinking-water to rats showed increased evidence of neoplasm. As the main conclusion: “There is sufficient evidence in experimental animals for the carcenogenity of formaldehyde.”
Perhaps, the experimental data require some reservations in application to formalin exposure in anatomical pathology
First, the dose of exposure (up to 14 ppm) was completely incomparable with laboratory levels. Tumor incidence was 0% at 2 ppm ((21, 22). Neoplastic cells proliferation might occur as a result of extreme chronic irritation.
Second, there is difference in neoplasm development even between species (mice and hamsters are resistant). Rats and rabbits are obligate nose breathers.
Third, the nostrils, which the air passes through into the nasal cavity, of all animals, including primates, are directed to the front, while the nostrils of man, in distinction, are directed downward. As a result, the current of inspired air instead of passing straight to the back, like in monkeys, flows upward to the olfactory region and follows a long and arched path to the nasopharynx.
Epidemiologic studies have the strengths of numbers and years of duration but limitations of misclassification and unintentional biases. The main weakness of these studies is that they use mortality data. However, in formaldehyde exposure more interesting and promising would be morbidity analysis. In modern society, equipped with advancements medicine, a death, for example, from a nasal cavity cancer is a health care failure.
Formaldehyde exposure in cohorts epidemiological studies in professional groups are of most interest for anatomical pathology. This group includes pathologists, anatomists, and embalmers. It is predictable, that data in this group regarding formaldehyde’s carcenogenity are inconclusive as heterogeneous and amorphous in regard to formaldehyde exposure is selection of the group. Actually, no further epidemiological study on these professionals groups exposed to formaldehyde has been published since 1994 (15) that was justified owning the substantial changes in type of work as far as formaldehyde exposure is concerned. Only embalmers in this heterogenic group can be considered as true formaldehyde prone professionals.
No neoplasms were reported statistically significant increase of nasal cavity or sinus (23), although a statistically significant increase in proportionate mortality rates from neoplasm of the hypopharynx was found. The death rates for brain tumors and leukemia were also higher than in a control groups. There was no nasal cavity or sinus neoplasm among surveyed embalmers inNew YorkandCaliforniabut increase in neoplasm of lymphathic/hemopoietic system and buccal cavity (24).
No excess risk for cancers of the oral cavity and pharynx, sinus and nasal cavity and lung were found with some excess risk for brain cancer (24, 25, 26) and lymphoid/hematopoietic neoplasm that was interpreted as unrelated to formaldehyde exposure (18).
The review of literature data regarding formaldehyde exposure carcenogenity is remarkable that there is a discrepancy between epidemiological statistic data and minimal clinical observation from physicians who observed particular or groups of patients. Neither otolaryngology, nor other surgical manuals even mention formaldehyde as a possible ethological or contributing factor of cancer in their clinical observations. The fundamental “Cancer Principles and Practice of Oncology” (27) haven’t mentioned formaldehyde either in carcenogenity or in other clinical chapters (head and neck, lung).
Pathologists haven’t observed higher morbidity and mortality of colleagues and technical staff connected with formalin.
However, in practical sense the dispute about formaldehyde carcenogenity is meaningless at this time. TheUSA regulatory agencies, the EPA and the OSHA assume formaldehyde as a potential occupational carcinogen with appropriate regulations (1). OSHA mandated a notice in any laboratory or industrial area where formaldehyde mixtures or solutions capable of releasing formaldehyde into the air at concentrations reaching exceeding 0.1 ppm are used: “Danger: Formaldehyde: irritant and potential cancer hazard.”
We have to accept until it is proved wrong the conclusion of IARC. We need to extract data relevant to conditions of anatomical pathology. Especially, there are other issues of safety concerns when dealing with formalin in every day histology laboratory practice.
General medical problems after formaldehyde exposure
Formaldehyde has apparent deleterious effect that everyone experiences with different degree of tolerance. Eye irritation, tears, some sensations of irritants smell is common in most individuals.
There can be adverse reaction of hypersensitivity. Relatively low concentrations have provoked symptoms in some individuals. It has been suggested that long-term inhalation of formaldehyde may trigger classic IgE-meditated nasal allergy in atopic individuals (28)
A study of 34 workers in a gross anatomy laboratory with an exposure to formaldehyde ranging from 0.07 t0 2.94 ppm during dissecting operations reviled decreased forced vital capacity (FVC) and forced expiratory volume in 3 seconds (FEV3) (29)
There are documented cases of skin hypersensitivity by contact with formalin. Some studies present changes in pulmonary function after long term formaldehyde exposure although there are studies which haven’t noticed any general medical problem.
The upper part of the internal nose is called the olfactory region. The peripheral endings of the olfactory nerve, the olfactory cells composing the receptor of the olfactory analyzer, are embedded here. Surprisingly this area is left out from formaldehyde exposure studies although the damage of this function is easy detectable and can give some clues for preventive measures.
Formalin exposure in histology laboratory
Main epidemiological studies left out histotechnologists although they were formed as an organized professional group since NSH and definitely outnumber pathologists and anatomists. This group has an established system of monitoring. There are scarce studies of histotechnologists about formaldehyde exposure. Most of them are inconclusive.
One of the studies presented results of chronic workplace exposure to formaldehyde among other solvents in 280 non-smoker histology technicians studied during national workshops for four years (30). The study found a small difference in steeper decrement in vital capacity and flows in comparison with a control population.
A group of fifteen histology technicians who worked in three different pathology departments had though subclinical statistically significant increase in nasal resistance. A chronic cumulative effect of formaldehyde exposure has been excluded in this study (31).
Although personal experience does not have any statistical thus scientific value, it is a truism that statistic is a summarization of individual experience., I am glad to state that for many years of work in anatomical pathology I haven’t seen or heard about any of coworker with formaldehyde related general health problem never mind neoplasm.
Ironically, the anatomical pathology manager I worked with tried to escape any presence in histology laboratory for good reasons. While entering the laboratory, she immediately developed a face rush with eye, nose and throat irritation. She never worked in a histology laboratory before.
The Formalin Standard was passed in 1987 (Federal Register 52 (233): 46168-46312, December 4, 1987 29 CFR 1910.1048). This standard was revised in 1992 to include lower exposure limits and new monitoring procedures.
It is the law. There is no any reason to discuss minimal exposure and preventable damaging effects. In the same way, common sense dictate preventing burn in the kitchen cuts while working with sharp instruments.
Preventive measures in the surgical pathology laboratory
For the most part, the relatively low threshold of response and the disagreeable, irritating pungent suffocating odor of formaldehyde prevent one from breathing intolerable amounts of gas. Although in rare massive acute exposures, victims have suffered pulmonary edema and even death, such situation cannot happen in anatomical pathology practice.
Some anatomy and physiology data relevant to formaldehyde exposure in laboratory practice might support understanding of damage prevention methods. They should be considered in connection with physical and chemical features of formalin.
The nasal mucosa of the lateral, inferior and medial walls of the nose, paranasal sinuses, and conches is covered with ciliated pseudostratified, columnar epithelium whose cilia form a carpet on which dust settles. The vibration of the cilia in the direction of the conches drives out the settled dust. The mucous membrane contains mucous glands (Goblet cells) whose secretions produces mucus 1 liter per day. It wraps around the dust and makes its expulsion easier and also humidifies the air. The mucous blanket, which is mowed by the cilia, flows to the sinus ostia and then to the nasopharynx where it is expectorated or swallowed. Serous glands within the lamina propria, deep to the mucous membrane, contribute fluid to the thinner periciliary layer of the blanket.
Water is 97% of mucus. Formaldehyde has absolute solubility in water. Formaldehyde is diluted and absorbed. It does not reach the pharynx under non extreme exposure. However, formaldehyde can damage the cilia, the most vulnerable structures. All preventive measures should be concentrating on minimizing this damage.
The use of formalin has been changed substantially since the years when the main epidemiological studies were conducted. Now most laboratories are using prefilled containers for biopsies which are opened for a short time just to take out the specimen. Material of large specimens is received in fresh state and even processed before fixation. There are different models of laboratory stations equipped with exhaust engineering devices. Of course, monitoring of formaldehyde exposure at the working place changed the game.
The threshold for subjective effects varies considerably from 0.1 to 2.5 ppm; most people feel symptoms in the throat first (32). According to OSHA odor threshold is 0.8-1 ppm.
The limit for airborne exposure to formaldehyde set by OSHA the Formaldehyde Standard (TWA) is 0.75 ppm in an 8-hour time-weighted average (officially 1 ppm) and 2 ppm for a 15-minute Short-Term Exposure Limit (OSHA STEL). By the way, in 1987 TWA was 3 ppm.
OSHA requires monitoring by the employer of the exposure to formaldehyde exceeds the 0.5 ppm (the Action Level) or the 2.00ppm STEL. A “representative employee” is asked to wear a sampling passive badge device to collect formaldehyde (industrial monitoring uses a different methodology). Determination time-weighted average (TWA) collected from the employee’s breathing zone air during full shift is considered as optimal. Usually monitoring is done on annual basis.
Two personal stories reflect the relative value of this monitoring.
Being “soaked” by formalin for many years, my annual monitoring had never reviled any abnormal reading. I left once by accident a monitoring badge on my coat near buckets with formalin overnight, but somebody for some reasons had opened the lid. I do not have any explanation why the reading came normal. I always resisted temptation to repeat intentionally this “experiment.” I haven’t done this for good reasons that the second story shows.
Recently, during annual monitoring, personal samples at two grossing stations collected on the same day near each other came back with different readings. One was 10 ppm while another showed 0.055 ppm. Nobody at this day reported any odors that would be consistent with high formaldehyde exposures. It was a simple explanation as splashing that could contaminate the sample badge, but the management became so agitated that a special consulting firm was invited, with many days of monitoring performances, meetings, and papers. Nobody wants to take chances to deal with the regulatory governmental institutions. Unfortunately the right idea of formaldehyde exposure monitoring collides with fear that is not the best adviser to common sense.
Usually histology laboratories use a passive badge monitor containing bisulfite-impragnated paper with chromotropic acid analysis with TWA validation range from 0.2 to 4.9 ppm and overall error +/_ 18.6%.
Annual monitoring is mandatory, but during the year many events might occur with disruption of ventilation system and other violations of formalin handling. An established monitoring system that includes passive monitoring, hood vaneometers, filtering system, hand held formalin monitors, even oximeter, might be beneficial (Rene Buesa personal communication).
Perhaps in addition, it is reasonable to have quantity monitors on a regular basis, like canaries in the old coal mines for methane and carbon monoxide overconcentration detection. Some reagents like well known in histology laboratory Schiff reagent (red)) or reticulin diamine silver solution (black) in contact with aldehydes can provide a warning that will alert that there are some signs of formaldehyde overexposure at different areas of the histology laboratory. The bisulfate indicator that is a reagent in the standard monitor badge might be used for quantity monitoring. I am using this opportunity to challenge manufacturers in developing such quantity monitors. The market can be sufficient for a commercial return investment for the development of such device. Meanwhile, a Schiff reagent would be useful to have handy in every surgical pathology laboratory to prevent from sniffing containers with formalin in question. This popular habit is obviously unhealthy.
Formalin spills are the real challenge. They are not so rare and require attention, training, and understanding. It makes sense to discuss this unfortunate situation in detail.
Formaldehyde gas evaporation depends on the square surface but not of the volume spilled fluid. Formalin in the 50 ml container is relatively harmless but the same amount that has been spread on the board or floor immediately irritates. The principle of handling the spill is to contain minimizing the surface of the spill.
Every institution has their policies and protocols regarding handling chemical hazards spills. This article provides the author’s approach to handling specifically formalin spills based on personal experience and physical and chemical features described in formalin/formaldehyde background section.
An article about laboratory safety had a section titled: “What To Do if Formaldehyde Is Spilled” (32). In histology laboratory formalin is spilled. This distinction is substantial for cleaning actions when the goal is to prevent evaporation of formaldehyde from its water solution, namely formalin.
How much formalin constitutes a spill as far as safety is concerned? OSHA has an “informative” definition as “appreciable quantity”. For example, OSHA recommends “if a spill of appreciable quantity occurs, leave the area quickly unless you have specific emergency duties” to wait for designated person to stop the leak. This is, probably, for industrial situations.
Histology laboratory rarely manipulates at the same time quantities more than one gallon (3.8 liters). Usually, spills which can be a safety concern range from 50 ml to 2 liters. Of course, there is a difference where the spill occurs: on the grossing station’s table or on the laboratory floor.
Who supposed to handle formalin spill? To call or not to call for outside help in case of large spill? What constitutes a large spill for histology laboratory?
If the institutional policies definitely determine the amount of the spilled formalin that requires Hazardous Materials Response Department involvement, of course, the call is obligatory to be in compliance. However, often it is useless and even contra productive. Deficit of time is a substantial factor. As a rule spills are not planned but occur suddenly. Hopefully, there is a spill kit in every laboratory that uses formalin.
The working rooms where spills occur are not empty and completely flat floor surfaces. Formalin should be containing as much as possible otherwise it spreads everywhere, including under the tables and equipment with gradual evaporation. The clean up in the laboratory should start immediately with or without call for outside help.
First and foremost an appropriate PPE as disposable gown, gloves, safety glasses (nonvented goggles are difficult to handle while cleaning), and a wet mask, preferably Kimberly-Clark Face Shield type. The wet mask is reasonable because the evaporating formaldehyde goes through even the multi layers of dry mask, but a wet mask partially absorbs formaldehyde due to high solubility in water. What about a full-face respirator with formaldehyde-absorbing cartridges, as is usually recommended? Yes, if it is on hand, fit the face, and a person is trained to use it. In practice all three conditions are not in place.
The spill should be contained by building around a dike like wall of wet paper/cloth to absorb formalin as much as possible preventing formaldehyde from evaporation from thin layer of formalin on the floor. The absorbing material is moved from the periphery to the center. The soaked paper/cloth should be collected in sealable plastic waste bags that are placed in a closed container and replaced by dry paper/cloth. While moving the wet paper/cloth towels to the center, the floor can be covered by a neutralizer, like Spill-X-FP), if it is on hand. Absorption and polymerization requires some time, at least 10-15 minutes.
Simultaneously it is necessary to enhance ventilation as the grossing stations and other areas, as well as open running water facets to increase humidity in the room that diminish evaporation. It is reasonable to change many times the wet face mask because it becomes saturated with formalin. In this situation the wet mask becomes also an obstacle to breath under conditions of intensive physical labor during cleaning up operation.
If the outside help cleaning team arrives, it will not be in a moment anyway, let them finish the job according to institutional policies. If the outside help team is not involved, make sure to put neutralizer into containers with clean up materials soaked with formalin. Anyway, the entire area of the cleanup up requires a moping with generous amount of soup water.
It would not a bad idea to take care of the participants of the spills clean up. Of course, if somebody feels not well, medical help must be provided. In an acute exposure, when the dose of formaldehyde excises the absorption and dilution by nose cavity mucus layer, most people feel irritation of the throat first. This is especially true under conditions of emergency intensive work and communications. Milk or alkaline drinks, for people who cannot tolerate milk, is optimal for immediate drinking, keeping in mouth, and gargling.
Some years ago, late in the evening my coworker dropped on the floor a bucket with cassettes collected for processing and around 2 liters of formalin. In agitation of collecting of the dispersed around cassettes and cleaning up formalin, we violated every rule of safety. As a result, I had a painful sore throat and lost my voice for almost a week.
Table 1 summarizes individual action, engineering measures and personal protective equipment in formalin spill
Formalin spill management
|Personal Protective Equipment
|Contain to minimize evaporation
|Intensify local and general ventilation
|Absorb in wet paper/fabric towels
|Humidify the space of the room
|Safety glasses/ goggles
|Dilute with water
|Wet mask (many changes during procedure)
|Eliminate absorbed formalin towels in closed bags
|Gloves (nitrile better than latex)
|Neutralize absorbed formalin
|Respirator if individually tested before the accident
|Mop the floor
|Water resisted shoes
Formalin spills often are accompanied by splashes that are another safety concern in the laboratory and require a different sat of precaution.
Of course, splashes occur without spills also. They are always a result of poor working practices or negligence.
Just as a final confession, I had formalin splashes twice (silly, isn’t it?) many years ago when the pathologists grossed by themselves and the specimens arrive in the laboratory from surgery always in formalin. While opening ovarian cysts, the formalin fixed content burst during cut. Intolerable pain, treatment in emergency, and some time of persistent sore in the eye were the punishment for working without glasses. Clouded vision lasted for a week. This happened before the time of eye washing station, and before my understanding how to handle such injury. Since then, the first thing for me, while entering the histology laboratory, is safety glasses on.
Safety glasses with above and side shields completely protect from splashes. Some recent models though are fashionable but unreliable because the modern design leaves to mush open space for formalin splashes. Goggles are unpractical for every day work because they are uncomfortable, irritation periorbital skin, and… really ridiculous. A shield mask, like Kimberly-Clark does not provide a reliable protection and it is inconvenient for long work. Personal glasses obviously cannot be substituted for safety glasses that require wearing them both.
Eye washing after a formalin splash is obligatory, and every histology laboratory has an eyewash station. However, 15 minutes recommendation is not only practically unsustainable but wrong. It is completely enough to wash a couple minutes. The tap water is obviously not sterile; it contains chemical substances which irritate the sclera and conjunctiva. Formaldehyde cannot penetrate deep. Though uncomfortable, the water should be cold because warm formalin remnants penetrate faster but the goal is the opposite. It is more reasonable to allow the sterile tears to wash away the remnants of formalin. Though this sounds not seriously enough, I wish I had in my accidents an onion, which emanates bactericidal ethers that provide healing tears in abundance instead of irritation by tap water.Medical help would be highly recommended if the person were uncomfortable after eye rinsing.
Safe Working Practices
Some working habits of prevention splashes and appropriate equipment can contribute to prevention of splashes. This brings us to a question of general safety culture at the work place related to safety issues.
Safety culture at the working place includes engineering controls and simple reasonable working practices of all participants to lower short-term exposure levels.
The engineering controls for histology, pathology, and anatomy laboratories are mandated by OSHA at the level of local exhaust ventilation. Histology laboratory uses hoods, for example at grossing workstations. The optimal choice is back-vented station. Laboratory hoods have face velocities (the flow rate at the front of the hoods) in the 60-100 fpm range. The velocity should be certified and periodically tested.
The optimal working place is near the back-vented area with horizontal or angled backward sashes.
Proper work practices can diminish short term formaldehyde exposure. Every detail counts. Here are some examples.
Even how the container with prefilled formalin is opened, the specimen taken out, and how carefully the lid is placed back, everything can make a difference. Storage of containers with wet specimens and after biopsies processing should be carefully monitored to prevent formalin evaporation.
Formalin in the bucket with grossed cassettes to the end of the day warms up by continued tissue metabolism before fixation is completed and by chemical reaction during fixation. The lid is constantly opened to put new cassettes and for other cassetting manipulations. Placing the bucket with cassettes on a cold plate can decrease formaldehyde evaporation.
After formalin fixation, brains washing (literally) for post autopsy cut up should be carried out carefully. Preferably, the procedure should be done under the hood. The same applies to additional cut up of previously fixed surgical pathology specimens like colon (often additional search for lymph nodes), breast, etc. In practice, this requirement is often violated.
Fixed in formalin bones require special attention. Bone dust during sawing makes formaldehyde inhalation more traumatic due to injury of the upper respiratory tract by small sharp bone particles loaded with formalin. This is somehow similar to work with formaldehyde in the metal plants where the nasopharyngeal cancer was revealed disproportionately high frequency in cohort epidemiological studies.
While opening a working tissue processor in the formalin phase protective mask and safety glasses are obligatory (goggles are preferable). The warm formaldehyde vapor and possible splash can be harmful. Of course, any heating of formalin for fixation in a non-laboratory microwave oven is dangerous. Fortunately, modern microwave processors make this bad working practice more and more obsolete.
Formalin recycling, besides questionable economical benefits, might be a source of saturation of laboratory air with formaldehyde vapor. The formalin neutralization practice in laboratories is controversial. Areas of formalin neutralization should be provided with effective ventilation that is not easy to achieve if large quantities are collected. The limited amount of formalin in use in modern surgical pathology laboratory due to prefilled containers make the big poorly closed capacities with formalin for neutralization out of date. The laboratory must comply with local EPA regulations whether or not formalin can be dumped in the wastewater system gradually in small increments by flow of water without any damage the biology of waste treatment.
The processing cassettes should we washed off from formalin during time consuming count of the material after grossing. It does not make any harm to the material because the already penetrated formaldehyde is bound with the tissues, but only the evaporating from formaldehyde is harmful.
A list of working practices rationalization that decrease formaldehyde exposure can be endless. For example, smaller stock formalin boxes, absorbing neutralization pads, collection of soaked by formalin waste, soiled soaked by formalin towels, etc.
The common sense safety motto: use formalin preventing formaldehyde evaporation.
Formaldehyde overexposure and traumatic application to upper respiratory tract mucosa, eyes, and skin are bad sides of formalin use in anatomical pathology practice. But in the end of the day keeping in mind the level of every day housekeeping; it would not hurt some formaldehyde disinfection in the laboratory environment.
Fortunately for surgical pathology laboratories, as well as in some industries which make use of formaldehyde, there will not be any convincing proof or substantiate objection of virtual epidemiological statistical studies about formaldehyde’s human carcinogenicity. However, it does not make any sense to ignore reasonable protective protocols, nor to fail to use equipment to minimize formaldehyde’s damaging effects. Sensible steps can be taken without exaggeration and overreaction. Monitoring and taking measures to limit exposure to formaldehyde substantially diminish its harmful effects in the workplace. As far as issues of safety are concerned, formalin can remain for the foreseeable future as the ubiquitous fixative reagent in surgical pathology laboratories.
1.USDept of Labor: Occupational exposure to formaldehyde: Final rule. Federal register 1987; 52 (Dec 4): 46168-46312
2. OSHA. 29 CFR 1910.1048
3. Dapson JC, Dapson RW Hazardous Materials in the histopathology Laboratory. Regulation, Risks, Handling and Disposal, Fourth Edition, 2005, Anatech LTD
4. Buesa RJ: Histology without formalin? Ann Diag Pathol; Vol 12 (6):387-396, 2008
5. Fox C H. Johnson FB, Whiting J, Roller PP Formaldehyde Fixation The Journal of Histochemistry and Cytochemistry Vol 33, No. 8, pp. 845-853, 1985)
6. Heck HD, Casanova-Schmitz M, Dodd PB, et al. Formaldehyde (CH2O) concentrations in the blood of humans and Fischer-344 rats exposed to CH2O under controlled conditions. AmIndHyg Assoc J (1985) 46:1-3
7. Kiernan JA Histological and Histochemical Methods, 2008, 4th ed.Oxford: Butterworth-Heimann.
8. Giancoli DC: Physics. Principles with Application, 1998, Fifth Ed. Prentice Hall, pp 405-408
9. Bancroft JD, Gamble M: Theory and Practice of Histological Techniques. 5th Ed.New York,NY, Churchill -Livingstone, 2002. Page 28
10. Council Report. Formaldehyde. Council on Scientific Affairs. JAMA 1989; 261:1183-1187
11. IARC Press Release No 153, 15 June 2004
12. World Health Organization International Agency for Research on Cancer IARC Monographs on the Evaluation Carcinogenic Risks on Humans Volume 88 , 2006 Formaldehyde Monographs Programme http://monographs.iarc.fr/ENG/Monographs/Vol88/index.php
13. Collins JJ, Acquavella JF, Esmen NA: An Updated Meta-Analysis of Formaldehyde Exposure and Upper Respiratory Tract JOEM, Vol 39, Number 7, July 1997: 639-651
14. Gardner MJ, Pannett B., Winter PD, Crudas AM. A cohort study of workers exposed to formaldehyde in the British chemical industry: an update British Journal of Industrial Medicine 1993; 50: 827-834
15. McLaughlin JK. Formaldehyde cancer: a critical review. Int Arch Occup Environ Health (1994) 66: 295-301
16. Chang ET. Adami HO The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol. Biomarkers Prev, 2006; 15 (10); 1765-1977
17. Hauptman M, Lubin JH, Stewart PA, Hayes RB, Blair A: Mortality from solid cancers among Workers in Formaldehyde Industries. American Journal of Epidemiology, 159; (12): 1117-1130
18. C. Bosetti C, McLaughlin JK, Tarone RE, Pira E and La Vecchia C: Formaldehyde and cancer risk: a quantative review of cohort studies through 2006. Annals of Oncology 2008; 19; (1): 29-43
19. Torone RE, McLaughlin JK. Re: “Mortality from Solid Cancers among Workers in Formaldehyde Industries.” Am J Epidemiol 2005 Vol 161, (11): 1089-1090.
20. Hauptman M., Lubin JH, Stewart PA, et al. The Authors Reply. Am J. Epidemiol, 2005; 161 (11): 1090-1091.
21. Kerns WD, Pavkov KL, Donofrio DJ, et al: Carcenogenity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res 1983; 43: 4382-4392.
22. Rusch GM, Clary JJ, Rinehart WE, et al: A 26-week inhalation toxicity study with formaldehyde in the monkey, rat, and hamster. Toxicol Appl Pharmacol 1983; 68: 329-343.
23. Harrington JM, Oakes D: Mortality study of British pathologists 1974 to 1980. Br JIndMed 1984; 41: 188-191.
24. Walrath J, Fraumeni JF Jr: Mortality patterns among embalmers Cancer Res 1984; 44: 4638-4641.
25. Hayes RB., Blair A, Stewart PA, et al Mortality of U.S. embalmers and funeral directors. Am JIndMed 1990; 18: 641-652.
26. Levine RJ, Andjelkovich DA, Shaw LK. The mortality ofOntarioundertakers and a review of formaldehyde related mortality studies. J Occup Med 1984, 26:760-6.
27. DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology. Lippincott Williams & Wilkins 7th Ed, 2008.
28. Wilhelmsson B., Holmstrom M.: Positive formaldehyde-RAST after prolonged
formaldehyde exposure by inhalation. Lancet 1987; 2:164.
29. Akbar-Khanzadeh F, Vaquerano, MU, Akbar-Khanzadeh M, Bisesi MS: formaldehyde exposure, acute pulmonary response, and exposure control options in gross anatomy laboratory American Journal of Industrial Medicine, 2007; 26 (1): 61-75.
30. Kilburn KH, Warshaw R, Thornton JC Pulmonary function in histology technicians compared with women fromMichigan: effects of chronic low formaldehyde on a national sample of women British Journal of Industrial Medicine 1989; 46: 468-472.
31. Giardano C, Siccardi E, Fedrigini B, et al. Nasal patency patterns observed during working hours in a group of technicians habitually exposed to formaldehyde. Acta Otorhinolaryngol Ital 1995 15 (5): 335-44.
32. Goris J, Ang S, Navarro C. Minimizing the toxic effects of formaldehyde. LabMedicine1998; 29 (1): 39-42.
Dimenstein IB: A Pragmatic Approach to Formalin Safety in Anatomical Pathology. LabMedicine, 2009 Vol 40 (12):740-746.