Toxicological evaluation and limit values for Methyl-tertiary-butyl ether (MTBE), Formaldehyde, Glutaraldehyde, Furfural

3. Human toxicity

An immense amount of data exists concerning acute effects from formaldehyde exposure. However, there is a variability in the quality of the studies and reportings and due to big differences in individual sensitivity and in the effect concentrations observed from the different studies, it is from several expert groups deemed almost impossible to point out single studies for identifying the absolute NOAEL and LOAEL value, from which recommendations can be made. Thus a more overall view of the data has been used to establish dose-response and dose-effect relationships (IPCS 1989, ACGIH 1991, WHO 1998, Paustenbach 1997). This is reflected in the following description of the effects of formaldehyde which more focuses on the conclusions from the expert groups rather than detailed evaluation of the specific studies and reportings.

Vapour exposure odour

IPCS (1989) indicates a level between 0.06 mg/m³ and 0.22 mg/m³ as odour threshold, while levels of 0.031-0.177 mg/m³ (non-smokers) and 0.025-0.58 mg/m³ (smokers) were reported by IARC (1995). In the WHO (1998) evaluation, 0.03, 0.18, and 0.6 mg/m³ were reported as the 10-, 50- and 90-percentiles for the odour detection threshold.

Irritative effects on the respiratory tract and eyes

The common effects related to formaldehyde exposure are various symptoms caused by irritation of the mucosa in the eyes and the upper airways. The symptoms reported are headache, irritation/ burning sensation of the eyes, sore throat and annoyance because of smell. In the non-industrial indoor environment the sensory reactions are typical effects, but there appear to be large individual differences in the normal population and among hyper-reactive people.

In the evaluation of IPCS (1989) it was concluded that no absolute irritation threshold could be set for formaldehyde. It was acknowledged that sensory irritation for the eyes were reported at 0.06 mg/m³ and for the respiratory tract at 0.12 mg/m³. Overall it was recommended that the level of formaldehyde in ambient air should not exceed 0.1 mg/m³. To account for hypersensitive people without immunological signs it was further recommended that formaldehyde concentrations should not exceed 0.01 mg/m³.

ACGIH (1991) concluded that formaldehyde levels of 0.25-0.5 ppm (0.3-0.6 mg/m³) would be troublesome for up to 20% of a population and that 10-20% would react acutely to levels below 0.25 ppm as some studies have reported mucous membrane irritation at concentrations as low as 0.1 ppm (0.1 mg/m³). On the overall data ACGIH recommended a threshold limit value (as ceiling value) for formaldehyde of 0.3 ppm (0.37 mg/m³) in the occupational environment.

WHO (1998) tabulates the following dose effect relationship:

In the overall evaluation of WHO (1998) an irritation threshold of 0.1 mg/m³ after short term exposure for the general population is noticed, while a progression of symptoms and effects occur at levels above 1.2 mg/m³. To prevent significant sensory irritation an air quality guideline of 0.1 mg/m³ is proposed.

Paustenbach et al. (1997) in a recent evaluation of a panel of experts (The Industrial Health Foundation Panel) re-evaluated the scientific basis for a formaldehyde dose-response relationship and for the setting of an occupational exposure limit. The panel found that the most reliable data in which effects and response rates were related to specific formaldehyde exposure levels were human data from laboratory chamber exposure. From these studies ten key studies were identified by the panel. Furthermore, six studies with occupational exposure and two studies from community surveys were considered important for the setting of an occupational exposure limit.

The panel concluded that eye irritation is the most sensitive effect related to formaldehyde exposure. From the dose-response relationship obtained by linear least-square regression of the data from the key studies, the panel estimated that 1-5% of a population would feel transient eye irritation at a level of 0.3 ppm (0.37 mg/m³) and 5-25% at a level of 0.5-1.0 ppm (0.6-1.2 mg/m³). A level of 0.1 ppm (0.12 mg/m³) was judged to prevent irritation in virtually all persons. Furthermore, it was stated that significant irritation due to formaldehyde exposure in most studies does not occur until an exposure level of 1.0 ppm (1.2 mg/m³) is reached. Based on this the panel recommended an occupational exposure limit of 0.3 ppm (0.37 mg/m³) as an 8-hour average and a ceiling value of 1 ppm (1.2 mg/m³) to avoid irritation.

pulmonary effects

Inhalation studies using formaldehyde levels up to 2.4 mg/m³ did not cause any effects on lung function parameters in human volunteers, however, at higher levels (above 6 mg/m³) pulmonary effects and effects from the lower airway are likely to occur (IPCS 1989).

sensitivity

Experimental data indicate great variability between individuals in sensitivity towards the effects of formaldehyde exposure. However, the data do not indicate that asthmatic persons seem to be more sensitive compared to the non-asthmatic persons (Paustenbach et al. 1997, IARC 1995, IPCS 1989). Nevertheless, asthma-like symptoms have been reported at irritant concentrations from occupational studies (IPCS 1989).

Oral intake

Ingested formaldehyde solution has resulted in corrosive injury in the stomach. Lethal outcome after formaldehyde ingestion has occurred after the ingestion of a few drops to 89 ml of concentrated solution (i.e. about 40% aqueous solution). The largest quantity survived is reported to 120 ml. After ingestion of 60-90 ml of a 40% solution death was associated with pronounced injury in the oesophagus and the gastrointestinal tract: all organs and tissues in contact with the stomach were dark (chocolate brown) and hardened to a depth of about 8 mm (IPCS 1989).

Dermal contact

Contact may cause burns to skin (HSDB 1996).

The concentration of aqueous formaldehyde solution causing irritant reactions has not been specifically determined but a 1% solution applied under occlusive dressing is considered to produce irritant response in approximately 5% of the population. Cosmetics containing a formaldehyde concentration of 0.2% as a preservative and nail hardeners containing at least 5% formaldehyde did not provoke toxic or irritative reactions on normal skin (IPCS 1989).

Eye contact

Contact with the eye may cause burns. Depending on the formaldehyde concentration, aqueous solutions in contact with the eye have caused injuries ranging from severe, permanent corneal opacification and loss of vision to minor transient injury or discomfort (Grant 1986).

A splash of 0.2% solution of formaldehyde has been reported to cause irritation with stinging and hyperaemia, but without permanent injury. One drop of a 40% solution in an eye which was instantly washed resulted in pain after 6 hours and corneal opacity that still lasted after 6 months. Other cases with eye splash of 40% formaldehyde solution have resulted in blindness and loss of the eye (Grant 1986).

(With respect to eye irritation from vapour exposure see the section vapour exposure).

There are only few reports on sensitisation associated with inhalational exposure to formaldehyde. In one report including 230 persons with asthma like symptoms inhalational provocation test with formaldehyde identified 12 persons with specific positive response. Several other studies, however, with less persons involved, also report of positive provocation tests with formaldehyde (IPCS 1989). Patterson et al. (1989) and Grammer et al. (1991) from their studies with persons suffering from respiratory symptoms in relation to formaldehyde exposure found no evidence for immunologically mediated asthma from formaldehyde exposure. Patterson et al. (1989) concluded that there is no evidence for formaldehyde being an inhalational antigen, while Grammer et al. (1991) judged respiratory sensitisation from formaldehyde to be extremely rare, if at all existing.

Also Bardana & Montanaro (1991) in their review on immunologic effects concluded that no data until now have proven the induction of IgE-mediated respiratory tract symptoms caused by inhalational exposure to formaldehyde. Only on rare occasions were formaldehyde at high exposure levels found to induce bronchial asthma.

- dermal contact

Formaldehyde solution is a primary skin-sensitising agent inducing allergic contact dermatitis (type IV, T-cell mediated delayed hypersensitivity reaction); it may induce immunological contact urticaria (type I, perhaps IgE mediated, immediate hypersensitivity reaction). Patch tests with different concentrations have shown that concentrations below 0.05% rarely elicit an allergic response in sensitised persons. However, patch-tests using concentrations of 2% or more are often unreliable, as a positive response may be due to a direct irritant response (IPCS 1989, IARC 1995). IPCS (1989) states that skin sensitisation do only occur at exposure to formaldehyde solutions with a higher concentration than 2% (no reference given in the text), and sensitisation from cosmetic products e.g. shampoos is considered unusual.

A Nordic expert group found that data from human experiments suggested that the threshold for sensitisation induced by formaldehyde would lie in a formaldehyde concentration range of 0.037-0.37%. This was the result from a study in which persons were induced with ten epicutaneous applications of different concentrations of formaldehyde (Draize procedure). At 0.037% none of 45 test persons developed sensitisation, whereas at 0.37% 4 out of 85 persons (4.5%) were sensitised (Marzulli & Maibach 1974). In a human maximisation study 72% of the test persons induced with 1.85% formaldehyde solution were sensitised (Nord 1991).

In a series of patch tests the lowest formaldehyde concentration for provocation of allergic response in sensitised persons was found to a formaldehyde content of 150 ppm, and the no effect concentration was found to 80 ppm. In another study where formaldehyde were applied in the axilla a 30 ppm solution elicited positive response in four of nine sensitised persons (Nord 1991).

In a recent study, Flyvholm et al. (1997) found a 250 ppm formaldehyde solution under occlusive dressing as the lowest concentration that caused positive response in a provocation test with formaldehyde sensitised persons. No persons responded at 50 ppm. Using non-occluded exposure no reaction was found at the highest concentration tested at 10000 ppm.

The possibility that formaldehyde may induce pathological or cytogenetic changes in the nasal mucosa has been examined in several occupational studies. In these studies from the wood, furniture and resin industry the workers were exposed to formaldehyde at average levels up to 2.4 mg/m³. Examination of nasal biopsies from the workers more frequently revealed signs of inflammation and histological changes (hyperplasia, metaplasia and dysplasia) compared to non-exposed groups. However, the findings were not always statistically significant and no firm relation between the adverse findings and exposure level or duration could be found. (IARC 1995).

Also pulmonary function has been assessed in several studies with formaldehyde exposed workers. The formaldehyde levels were <0.02 - >6.0 mg/m³ and in most of the studies formaldehyde alone or in combination with other agents caused transient, reversible declines in lung function, but with no evidence of a chronic decrement in lung function (IARC 1995).

In a recent evaluation of an expert panel it was concluded based on the epidemiological data from the occupational environment that no long term effects such as emphysema or chronic obstructive pulmonary disease could be found from occupational data with formaldehyde exposure in the range 0.4-2.0 ppm, while at higher levels (above 2 ppm) reductions in pulmonary function have been recorded (Paustenbach et al. 1997).

No conclusive study results are reported regarding formaldehyde and toxicity to reproductive system or to developing foetuses in humans (IARC 1995, IPCS 1989).

A series of studies on cytogenetic effects (chromosomal aberrations, sister chromatid exchange in peripheral lymphocytes) of formaldehyde in humans has been published. Both positive and negative results were obtained, but interpretation of the data was found to be difficult because of small number of subjects studied and inconsistencies in the findings. (IARC 1995).

A significant excess of micronucleated cells in nasal scrapes from the mucosa was found in formaldehyde exposed workers from the wood industry. However, no dose-response relation could be found and mixed exposure to wood dust occurred. (IARC 1995).

3.5 Carcinogenic effects

More than 30 epidemiological studies have been performed for determining the relationship between exposure to formaldehyde and cancer in humans. From two recent meta-analyses of these studies a causal relationship was suggested for occupational exposure to formaldehyde and elevated risk for the development of sinonasal and nasopharyngeal cancers (Blair et al. 1990, Partanen et al. 1993).

On the overall human data the International Agency for Research on Cancer (IARC 1995) concluded that there was only limited evidence for carcinogenic effects of formaldehyde in humans. nevertheless, the suggested relationship between formaldehyde exposure and cancer of the nasopharynx and the nasal cavities was noticed. It was found that industrial cohorts showed low or no increased risk for lymphatic or haematopoietic cancer, and cohort studies of embalmers and anatomists tended to show excess risks for cancers of the brain, however, based on small numbers. Based on the overall human and animal data IARC placed formaldehyde in group 2A "probably carcinogenic to humans".

More recent epidemiological data adds further support to a causal relationship between formaldehyde exposure and nasal cancer. Hansen & Olsen (1995) identified 265 Danish companies in which formaldehyde was used. From the Danish Cancer Register 3304 cancer patients having worked more than 10 years in these companies were registered (2041 men and 1263 women). Among these cancer patients the only increased cancer risk was found for nasal cancer (RR for men: 2.3 (1.3-4.0, 95% confidence limit); RR for women: 2.4 (0.6-6.0, 95% confidence limit). In a subgroup of blue-collar workers with no probable wood-dust exposure (a major confounder for nasal cancer) the relative risk for nasal cancer was 3.0 (1.4-5.7).