A search was done in PubMed by IP on 21 February 2012. Search strategy

• 23 Add Search (#22) AND #21 35
• 22 Add Search hospital[Title/Abstract] 550947
• 21 Add Search (#20) AND #17 1505
• 20 Add Search (#19) OR #18 546515
• 19 Add Search work[Title/Abstract] 483270
• 18 Add Search occupational[Title/Abstract] 79830
• 17 Add Search (#16) OR #15 39041 04:41:15
• 16 Add Search formaldehyde[Title/Abstract] 14641
• 15 Add Search formalin[Title/Abstract] 24748

The search yielded 35 articles {Appendix SAF-3}. The National Toxicology Program Final Report on Carcinogens 2010 was taken as the basis for carcinogenicity information. As there are sufficient EU sources for safety epidemiology and safety management, all guidelines prepared for non-European contexts were excluded.

Information was also retrieved from web pages of manufacturers, from the European Agency for Safety and Health at Work (EU-OSHA), the draft NICE report 2012, the European Commission Joint Research Centre’s European Chemical Substances Information System (ESIS), and the WHO International Programme on Chemical Safety (IPCS). As there is no free database for Material Safety Data Sheets (MSDS), the best way to find the data sheets is to Google for MSDS and formaldehyde.

Preparation of the tissues samples for each of the three tests under review is different. Before sending the test kit to the manufacturers’ laboratories (or recommended laboratory) preparation of samples for Oncotype DX requires formalin fixation (11). In MammaPrint this is optional; as of January 2012, the manufacturer accepts formalin-fixed paraffin-embedded samples (12). In uPA/PAI-1 formalin fixation is not used.

Risks of formalin fixation

The concentrated water solution (37–40%) of formaldehyde (CAS registry number 50-00-0) is known as formalin (its German trade name). In laboratory practice, 10% and 4% formaldehyde water solutions are used. Formaldehyde evaporates easily from the formalin surface. Formaldehyde (HCHO, methanal) is a colourless gas, which has a short half-life in air due to its decomposition in light. Due to its high solubility in water formaldehyde is fast absorbed in the mucus of the upper respiratory tract, predominantly in the nasal cavity and sinuses, where it can damage the cilia (13). It does not reach the pharynx under non-extreme exposure. Formaldehyde exposure can occur locally, at the place of the initial contact (respiratory or digestive tract, skin etc) and generally, as a result of absorption (14).

Formaldehyde concentrations that have been associated with various toxic effects in humans show wide inter-individual variability and are route dependent. Symptoms are rare at concentrations below 0.5 ppm; however, upper airway and eye irritation, changes in odour threshold, and neurophysiological effects (e.g., insomnia, memory loss, mood alterations, nausea, fatigue) have been reported at concentrations ≤ 0.1 ppm. The odour threshold is 0.8–1 ppm. The most commonly reported effects include eye, nose, throat, and skin irritation. Other effects include allergic contact dermatitis, histopathological abnormalities (e.g., hyperplasia, squamous metaplasia, and mild dysplasia) of the nasal mucosa, occupational asthma, reduced lung function, altered immune response, and haemotoxicity (15).

Formalin has been used for decades and the amounts used in hospitals and laboratories are substantial. Concerns about carcinogenicity and other health hazards have changed its use in past years. Pre-filled containers are used for small biopsies that need to be opened only for a short time, just to remove the specimen, exhaust devices have been developed and formaldehyde exposure is monitored. It has been noted that hospital workers underestimate their levels of exposure to formaldehyde (16).

Carcinogenicity of formaldehyde

The International Agency for Research on Cancer (IARC) concluded in 2006 that there is sufficient evidence of the carcinogenicity of formaldehyde in humans, and placed formaldehyde in Group I—known carcinogens, along with asbestos and benzene (15). This was reinforced in the eleventh Report of Carcinogens based on limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in laboratory animals (13).

A large number of epidemiological studies have been conducted to evaluate the relationship between formaldehyde exposure and carcinogenicity in humans. There are cohort studies and nested case-control studies of health professionals, including physicians, pathologists and laboratory nurses. They generally report mortality or incidence of cancer for ever-exposed workers in analyses using standardised mortality ratios or proportionate mortality ratios. Some of the studies attempted indirect measures of exposure, such as length of professional membership as a proxy for exposure duration.

Cancer risk in healthcare workers exposed to formaldehyde (13):

• cancers of the buccal cavity and pharynx: elevated but statistically non-significant risk (based on three cohort studies: Hayes 1990; Walrath 1983, 1984)
• lung cancer: no association observed in six cohort studies (Hall 1991, Hayes 1990, Stroup 1986, Levine 1984, Walrath 1983 and 1984)
• lymphohaematopoietic cancers: elevated mortality risk based on six cohort studies (Hall 1991, Hayes 1990, Stroup 1986, Levine 1984, Walrath 1983 and 1984);statistically significant risk: RR 1.31 (1.16, 1.47)(Bosettti 2008)
• leukaemia: RR 1.39 (1.15, 1.68)
• brain and central nervous cancers: meta-analysis by Bosetti 2008 reported statistically significant increase in risk, RR 1.56 (1.24, 1.96); excessive mortality reported in six cohort studies, with statistically significant difference in three studies: SMRs/PMRs 1.94 to 2.7 (Stroup 1986, Walrath 1983, 1984)
• pancreatic cancer: two meta-analyses identified borderline significant increase among pathologists and anatomists (Ojajärvi 2000, Collins 2001)

Other medical problems related to formaldehyde exposure

Eye irritation, tears and sensation of odour are common in most individuals. There can be an adverse reaction of hypersensitivity, even at low concentrations. It has been suggested that long- term inhalation of formaldehyde may trigger classic immunoglobulin E-mediated nasal allergy in atopic individuals (17). Clinical data has revealed dermatitis and skin sensitisation among histotechnologists after chronic exposure to formalin (18). A group of 15 histology technicians had subclinical statistically significant differences in nasal resistance. EU directives list sensitising substances. Respiratory sensitizers are required to be labelled with their R-phrases. Formaldehyde has an R-phrase R43 which means that it may cause sensitisation by skin contact. Significantly elevated odds of work-related asthma have been observed for exposure to formalin/formaldehyde in hospitals (19). A study of 34 workers in an anatomy laboratory revealed decreased pulmonary function (FVC and FEV₃) at formaldehyde exposures in the range 0.07– 2.94 ppm. Another study with 280 non-smoker histotechnologists with formaldehyde exposure showed small differences in the reduction of vital capacity during 4 years compared with non-exposed controls (20).

In 1997 the Industrial Health Foundation experts’ panel identified the occupational exposure limit for formaldehyde that would prevent irritation. The panel concluded that there was sufficient evidence to show that persons with asthma do not respond differently from healthy individuals following exposure to concentrations of up to 3.0 ppm. The panel could not identify a group of people who were hypersensitive, nor was there evidence that anyone could be sensitised (develop an allergy) following inhalation exposure to formaldehyde. Although cancer risk did not receive exhaustive evaluation, the panel agreed with other scientific groups who have concluded that the cancer risk of formaldehyde is negligible at airborne concentrations that do not produce chronic irritation (21). More details about the occupational exposure limits are presented in {SAF11}.

Higher rates of spontaneous abortion and low birth weight have been reported among children of women occupationally exposed to formaldehyde (15, 22).

A relatively low threshold of response and the disagreeable, irritating pungent suffocating odour of formaldehyde prevent one from breathing intolerable amounts of gas. Although in rare massive acute exposures victims have suffered pulmonary oedema and even death, such a situation is unlikely in the surgical theatre or pathological laboratory due to the relatively limited amount of formalin that is used.