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Formaldehyde has a pungent odour detectable at low concentrations, and its vapour and solutions are known skin and eye irritants in human beings. The common effects of formaldehyde exposure are various symptoms caused by irritation of the mucosa in the eyes and upper airways. In the non-industrial indoor environment, sensory reactions are typical effects, but there are large individual differences in the normal population and between hyperreactive and sensitized people.
There are a few case reports of asthma-like symptoms caused by formaldehyde, but none of these demonstrated a sensitization effect (neither Type I nor Type IV) and the symptoms were considered to be due to irritation. Skin sensitization is induced only by direct skin contact with formaldehyde solutions in concentrations higher than 20 g/litre (2%). The lowest patch test challenge concentration in an aqueous solution reported to produce a reaction in sensitized persons was 0.05% formaldehyde.
The available human evidence indicates that formaldehyde does not have a high carcinogenic potential. While some studies have indicated an excess of cancer in exposed individuals or populations, only nasal or nasopharyngeal tumours are likely to be causally related to formaldehyde exposure.
Formaldehyde does not have any adverse effects on reproduction and is not teratogenic.
Formaldehyde in vitro interferes with DNA repair in human cells, but there are no data relating to mutagenic outcomes.
Formaldehyde is naturally formed in the troposphere during the oxidation of hydrocarbons. These react with OH radicals and ozone to form formaldehyde and/or other aldehydes as intermediates in a series of reactions that ultimately lead to the formation of carbon monoxide and dioxide, hydrogen, and water (Zimmermann et al., 1978; Calvert, 1980).
Of the hydrocarbons found in the troposphere, methane occurs in the highest concentration (1.18 mg/m3) in the northern hemisphere. Thus, it provides the single most important source of formaldehyde (Lowe et al., 1981).
Terpenes and isoprene, emitted by foliage, react with the OH radicals, forming formaldehyde as an intermediate product (Zimmermann et al., 1978). Because of their short life-times, this potentially important source of formaldehyde is only important in the vicinity of vegetation (Lowe et al., 1981). The processes of formaldehyde formation and degradation are discussed in section 4.
Formaldehyde is one of the volatile compounds formed in the early stages of decomposition of plant residues in the soil (Berestetskii et al., 1981).
Indoor air levels of formaldehyde in various countries were presented during the International Conference on Indoor Air Quality in Stockholm (Berglund et al., 1984).
A survey of indoor air quality under warm weather conditions, in a variety of residences in Houston, Texas, USA, not selected in response to occupant complaints, revealed a distribution of indoor formaldehyde concentrations ranging from < 0.01 to 0.35 mg/m3, with an arithmetic mean of 0.08 mg/m3 (Stock & Mendez, 1985). Levels in approximately 15% of the monitored residences exceeded 0.12 mg/m3. Formaldehyde levels depended on the age and structural type of the dwelling. These factors were not independent and reflected the influence of more fundamental variables, i.e., the rate of exchange of indoor and outdoor air and the overall emission potential of indoor materials. The results of this survey suggested that considerable population exposure to excess (>0.12 mg/m3) formaldehyde concentrations might have occurred in the residential environment, indicating the need for improved control strategies.
Hawthorne et al. (1984) measured formaldehyde levels in 40 East Tennessee homes. Levels in older houses averaged 0.048 mg/m3 while those in houses less than 5 years old averaged 0.096 mg/m3.
The effects of foliage plants on the removal of formaldehyde from indoor air in energy-efficient homes is discussed in section 7.3.
Measurements made in living areas, schools, hospitals, and other buildings are listed in Table 17 to 19.
Table 15. Migration of formaldehyde from melamine and urea-resin tableware (mg/litre) into
different solvents. Detection limit 0.4 mg/litrea.
——————————————————————————————– Resin Temperature Water 4% Acetic acid 15% Ethanol 35% Ethanol
30 minb 30 minc 30 minb 30 minc 30 minb 30 minc 30 minb 30 minc
——————————————————————————————–
25 °C n.d.d n.d. n.d. n.d. n.d. n.d. n.d. n.d.
60 °C n.d. n.d. 0.5 n.d. 0.4 n.d. n.d. n.d.
Melamine 70 °C n.d. n.d. resin 80 °C 0.5 1.4 0.6 3.0 0.5 1.6 0.5 1.4
90 °C 2.2 2.6 100 °C 2.6 5.2 0.8 8.9 0.5 4.6 0.5 4.8
——————————————————————————————–
25 °C 0.4 0.4 0.4 0.5 0.5 0.5 0.4 0.5 60 °C 2.9 4.3 3.1 8.3 3.1 3.8 2.9 4.1
Urea 70 °C 5.0 13.0 resin 80 °C 9.1 23.4 9.6 126.0 7.4 30.0 8.6 28.2
90 °C 13.0 39.2 100 °C 18.0 48.2 27.6 648.0 19.0 54.0 18.5 50.4
——————————————————————————————– a From: Homma (1980). b Standing at room temperature. c Maintained at a definite temperature. d Not detected. Table 16. Migration from melamine cups with 4% acetic acid
concentration in the migration solutiona
——————————————————————- Conditions Melamine Formaldehyde
mg/litre mg/litre
——————————————————————-
60 °C, 30 min 0.5 ± 0.6 ndb
Microwave oven 1.5 min (90 °C) and stood at room temperature for 30 min (60 °C) 1.7 ± 1.2 (1.1 ± 0.4)
95 °C, 30 min
repetition 1 9.5 ± 3.1 (4.1 ± 0.8) 2 28.1 ± 6.0 (12.0 ± 2.6) 3 37.7 ± 10.3 (17.3 ± 3.4) 5 46.4 ± 13.9 (19.4 ± 2.8) 7 50.4 ± 3.6 (22.2 ± 2.2)
——————————————————————- a From: Ishiwata et al. (1986). b Not detected.
Tobacco smoke contains an average of 48 mg formaldehyde/m3 and is an important source of formaldehyde in indoor air. Two cigarettes smoked in a 30 m3 room increased the formaldehyde level to more than 0.1 mg/m3 (Jermini et al., 1976). Formaldehyde from tobacco smoke is absorbed by furniture, carpets, and curtains, and only slowly desorbed if the formaldehyde concentration in the indoor air decreases. Particle boards and, to a lesser extent, urea-formaldehyde-foam insulation (UFFI) were also listed as causes of increased indoor exposure. Disinfectant products may cause high exposure. These sources of emission are described in Table 17, 18, and 19.
Formaldehyde concentrations in 49 Dutch houses and 3 old peoples' homes where no UF-foam or particle board had been used were analysed by Cornet (1982). The houses were of different construction types and periods, in which it could be established that no particle board as construction material nor UF-foam had been used. However, several of these houses had particle board furniture. Overall, construction types and conditions of use were typical for Dutch circumstances. Average formaldehyde concentrations were 65 µg/m3, ranging mainly from 30 to 100 µg/m3. Ventilation rates ranged usually from 0.3-1.5 air changes per hour in living rooms and 0.2-1.2 in bedrooms. During the measurements no smoking took place.
No clear correlations could be established between the amount of particle board present in furnishings, ventilation rates, and formaldehyde concentrations.
Table 17 (partial).
Country No. Average Room Air Humidity HCHO Comments Reference (Year) of age of volume temp. (% relative (mg/m3)b
homes homes (m3) (°C) humidity or gH2O/kg air)
——————————————————————————————————— USA (1982) 40 0-30 years 0.076 ± 0.095 5903 Hawthorne
18 0-5 years 0.103 ± 0.112 measurements et al. 11 5-15 years 0.052 ± 0.052 (1983) 11 >15 years 0.039 ± 0.052 18 0-5 years 0.107 ± 0.114 spring 0.136 ± 0.125 summer 0.058 ± 0.068 autumn
USA (1981) 41 0.04 homes without Ulsamer
(0.012-0.098) UFFI et al. (1982) 636 0.15 homes with UFFI (0.012-4.2)
USA 244 UFFI homes Breysse
>1.23 2.8% of samples (1984) 0.61-1.22 1.9% of samples 0.12-0.60 24.1% of samples <0.12 71.2% of samples
non-UFFI homes and
apartments 59 >1.23 1.8% of samples 0.61-1.22 1.8% of samples 0.12-0.60 36.3% of samples <0.12 60.1% of samples
USA 13 building 0.12 (median) Dally (1978-79) material et al.
3-92 months (1981) (5.2 months median)
USA (1979) 1 0.098 energy Berk et
(0.04-0.15) efficient al. (1980) house (0.01 mg HCHO/m3 outdoors) 1 0.081 unoccupied without ±0.007 furniture
0.225 unoccupied with
±0.016 furniture 0.263 ± 0.026 occupiedh, daytime
0.141 ± 0.044 occupiedh,
nighttime
USA 9 2 years 445 0.044 ± 0.022 airtight Offermann (1980/81) (total) construction et al.
(half had (1982) gas appliances) 0.033 ± 0.020 mechanical venti- lation
1 6 years 441 0.017 “loose” construc-
(total) tion
USA (1983) 20 <6 0.076 energy- Grimsrud
years efficient et al. new homes (1983)
16 0.037 low ventilation
modernized homes
———————————————————————————————————
a Modified from: Meek et al. (1985). Where blanks appear, relevant information not provided by authors. b Means, ranges or standard deviations, unless otherwise specified. c Ventilation = 0.8 air changes/h. d Loading (ratio of unit area of formaldehyde source to room volume) = 1.2 m2/m3. e Standard conditions were: 23 °C, 7 g H2O/kg air, 1 air change/h. f Ventilation = 0.32 air change/h. g Ventilation = 1 air change/h. h House had a gas stove and 3 occupants, no cigarette smokers.
Foam made from specific aminoplastic resins is used for the thermal insulation of spaces in walls or other elements of construction. In this process, an acidic surfactant solution is foamed by compressed air and continuously mixed with aqueous UF resin. Formaldehyde is emitted during and after completion of the hardening process. The resulting in- door exposure depends, among other factors, on the age of the building, type of resin, the application and the care taken, the amount of excess formaldehyde, the amount and rate of emission, the prevailing tempera- ture, humidity, and rates of ventilation.
Most of the studies performed on UFFI and mobile homes have been carried out in Canada and the USA (Table 18), but they are currently of less importance.
Studies by Everett (1983) showed that there is some increase in formaldehyde levels in dwellings, directly after foaming, but that this decays over a period of a few weeks. Everett (1983) noted that, though there were isolated high values up to 1.2 mg/m3, 70% of the results after foaming were below 0.1 mg/m3.
Girman et al. (1983), conducting the 40-home East Tennessee study, obtained formaldehyde measurements that led to the following major conclusions:
The average formaldehyde levels exceeded 0.12 mg/m3 (0.1 ppm) in 25% of the homes;
Formaldehyde levels were positively related to temperature levels in homes. In houses with UFFI, a temperature-dependent relationship with measured formaldehyde levels frequently existed;
Formaldehyde levels generally decreased with increasing age of the house. This is consistent with decreased emission from materials due to aging;
Formaldehyde levels were found to fluctuate significantly both during the day and seasonally.
Popivanova & Beraha (1984) carried out a study on phenol- formaldehyde penoplast in order to establish the amount and dynamics of formaldehyde migration into the indoor air in relation to three major factors, i.e., age of the material, air temperature, and air exchange rate. Age of the material was found to be the most important factor influencing formaldehyde migration, followed by temperature elevation. The rate of air exchange was inversely related to formaldehyde migration level. A mathematical model of these processes has been developed and a regression equation proposed. A review of factors influencing formaldehyde migration from formaldehyde resins was published by Popivanova (1985).
As with all other incomplete combustion processes, formaldehyde is emitted in the smoke from cigarettes. About 1.5 mg of formaldehyde was found in the total smoke from one cigarette, which was distributed between the main and side stream in the ratio of 1:50, i.e., 30 µg in the main stream (= inhaled smoke) and 1526 µg in the side stream (Jermini et al., 1976; Klus & Kuhn, 1982). Other investigators measured up to 73 µg of formaldehyde per cigarette in the main stream (Newsome et al., 1965; Mansfield et al., 1977). Concentrations of 60-130 mg/m3 were measured in mainstream smoke. For an individual smoking 20 ciga- rettes per day, this would lead to an exposure of 1 mg/day (Weber- Tschopp et al., 1977). Exposure to sidestream smoke (or environmental tobacco smoke) can be estimated from chamber measurements. Thus, in a 50-m3 chamber with one air exchange per hour, 6 cigarettes smoked in 15 min yield over 0.12 mg/m3 (WKI, 1982). Weber-Tschopp et al. (1976) measured the yield of 5-10 cigarettes in a 30-m3 chamber with 0.2-0.3 air exchanges per hour as 0.21-0.35 mg/m3, which would be about 0.05-0.07 mg/m3 at one air exchange per hour. This concentration is in the same range as that likely to be found in the rooms of most conventional buildings where there is no smoking (section 5.2). Levels of formaldehyde emitted from combustion sources other than cigarette smoke are presented in Table 20.
Table 20. Formaldehyde levels from combustiona
Source Comments Emission rate Air change HCHO Reference
(g fuel/min) per h (mg/m3)
——————————————————————————————————–
Gas stove in test ventilation conditions: kitchen, 27 m3 no stove vent or hood 0.25 0.40 Hollowell
hood vent (without fan) above stove 1.0 0.26 et al. hood vent, fan at low speed (1979) (1.4 m3/min) 2.5 0.14 hood vent, fan at high speed (4 m3/min) 7.0 0.035 outdoor concentration during test 0.010
Undiluted exhaust gases: 10 Schmidt &
Götz (1977)
Household natural gas appliances 6 Altshuller Cooking range (oven) 4 et al. Floor furnace 1.5 (1961)
Kerosine heaters: 27 m3 environmental chamber, 0.4
temp. < 26 °C
radiant (new) fired in chamber 3.13 5.1 5.1b Traynor
10-min warm-up outside chamber 3.16 4.0 et al. (1983)
radiant (1 year old) 10-min warm-up outside 2.54 0.67 convection (new) fired in chamber 3.03 0.36
10-min warm-up outside chamber 3.0 1.3
convection fired in chamber 2.1 6.7 (5 years old) 10-min warm-up outside chamber 2.2 5.6
Table 20 (contd).
Radiant heater 21 m3 room, closed door, 3.6 0.5 0.025 Caceres Radiant heater 3.6 1.0b et al. Convection heater 2.7 0.9b (1983)
0.4b
Cigarette smoke 30 m3 climate chamber, 0.3
1 cigarette (1 min) 0.06 Weber- 3 cigarettes (2 min) 0.16 Tschopp 5 cigarettes (3 1/2 min) 0.29 et al. 10 cigarettes (7 min) 0.55 (1976) 15 cigarettes (10 1/2 min) 0.76
Cigarette smoke 45.8 m3 room, 5 subjects, Sundin
20 cigarettes smoked over 30 min: (1978) original background level level after 30 min 0.01 0.33
Cigarette smoke undiluted smoke 40-140 Auerbach
et al. (1977)
——————————————————————————————————–
a From: Dept National Health Welfare Canada (1985). b mg/h.
5.3 General Population Exposure
The possible routes of exposure to formaldehyde are inhalation, ingestion, dermal absorption, and, rarely, blood exchange, as in dialysis.
The daily inhalation exposure for an average adult can be estimated by assuming a respiratory volume of 20 m3/day, given the exposures mentioned above, and making different assumptions about the duration of exposure periods (Table 21). Average time estimates lead to the conclusion that people spend 60-70% of their time in the home, 25% at work, and 10% outdoors. If it is assumed that normal work exposures are similar to home exposures, the daily exposure resulting from breathing is about 1 mg/day, with a few exposures of > 2 mg/day, and a maximum of 5 mg/day; this compares favourably with the estimated range of 0.3-2.1 mg/day, based on the work of Kalinic et al. (1984), with estimated weighted average exposures of 0.02-0.14 mg/m3.
Matsumura et al. (1985) determined the levels of exposure to formaldehyde of housewives by using personal air sampling apparatus (Sampler: silica gel impregnated with triethanolamine, Hydrazine method). The highest exposure level was 0.311 mg/m3 (0.259 ppm) (3.73 mg/day), while the lowest was 0.011 mg/m3 (0.009 ppm) (0.13 mg/day). The usual exposure range was 0.018-0.030 mg/m3 (0.015-0.025 ppm) (0.22-0.36 mg/m3). The highest exposure level was that of a housewife living in a newly constructed house, where irritation of the eyes and throat, lachrymation, and cough were observed in the family.
Chemical toilet fluids, used in caravans, on camping sites, in aeroplanes, and in boats often include formaldehyde. In an experiment, a 10% formaldehyde solution (normally found on the market) was applied in a 2 m3 toilet room (Reus, 1981a). The toilet bowl was filled with 1 1/2 litres of water and 110 ml of the disinfectant, giving a solution of 0.75% formaldehyde. The ventilation rate was not determined, but estimated to be 3-5 air changes per hour, temperature 20-22 °C. Air concentrations of formaldehyde, which rose to 150-350 µg/m3 during the filling of the toilet, gradually decreased within 1 h to 60-90 µg/m3 and then remained constant. Closing the lid caused a further decrease to < 20 µg/m3.
Concentrations of 60-130 mg/m3, measured in mainstream smoke, would lead to an average daily intake of 1 mg formaldehyde per day (daily consumption: 20 cigarettes; WHO, 1987).
Formaldehyde produced by cigarettes can also mean considerable exposure for the non-smoker through passive smoking, the more so since it has been reported that the effects of gaseous formaldehyde are potentiated by smoke particles and aerosols (Rylander, 1974; Weber-Tschopp et al., 1977; WHO, 1987).
Table 21. Contribution of various atmospheric environments to average exposurea
Source | Average exposure (mg/day) |
---|---|
Air | |
Ambient air (10% of the time) | 0.02 |
Indoor air | |
Home (65% of the time) | |
- Conventional | 0.5-2 |
- Prefabricated (particle board) | 1-10 |
Work-place air (25% of the time) | |
- Without occupational exposureb | 0.2-0.8 |
- Exposed occupationally to 1 mg/m3 | 5 |
- Environmental tobacco smoke | 0.1-1.0 |
Smoking | |
20 cigarettes/day | 1.0 |
b Assuming the normal formaldehyde concentration in conventional buildings.
Concentrations in drinking-water are normally less than 0.1 mg/litre, which means that, except for accidental ingestion of formaldehyde-contaminated water, intake is negligible (below 0.2 mg/day; WHO, 1987).
The daily formaldehyde intake depends on the composition of the meal and may range between 1.5 and 14 mg for an average adult (see Table 14, section 5.1.4).
In a residue study of the Food Inspection Service in The Netherlands, it was found that 53% of 162 samples of soft drinks, alcoholic beverages, sugar-containing foodstuffs, such as marmalade, and meat and meat products contained formaldehyde at levels exceeding 1 mg/kg. Up to 20% of samples contained levels exceeding 2 mg/kg; levels in 15 samples of meat and meat products even exceeded 10 mg/kg, with some reaching about 20 mg/kg. The source of the formaldehyde could not be established for any of the cases (Nijboer, 1984). In an additional study, the formaldehyde contents of meat and meat products were analysed (Nijboer, 1985) and, in 62 out of 86 samples, were found to exceed a level of 1 mg formaldehyde/kg. Levels in 50% of samples were between 1 and 2 mg/kg and 22% exceeded 2 mg/kg with some levels as high as 14-20 mg/kg. Again, no source for the formaldehyde residue could be established.
Dermal exposure and absorption occur through contact with cosmetics, household products, disinfectants, textiles (especially of artificial origin) and orthopaedic casts. Most of these exposures are likely to remain localized (though gaseous formaldehyde will be available for inhalation). The estimates of the systemic absorption of formaldehyde through the entire epidermal layer and across the circulatory layer, are negligible (Jeffcoat, 1984; Robbins et al., 1984; Bartnik et al., 1985). Contact with liquid barriers, as in the eyes does not appear to lead to absorption. There have been case reports of newborn infants being exposed to formaldehyde-containing disinfectants in incubators.
In certain rare events, formaldehyde in aqueous solution enters the blood stream directly. These events are most likely to occur during dialysis or in circulation-assisted surgery in which the dialysis machine and tubes that have been disinfected with formaldehyde, still contain the compound because of adsorption or back wash, and it is then introduced into the patient's bloodstream (Beall, 1985).
==== 8.3 Short-term Exposures ====
Inhalation studies are summarized in Table 28.
Table 28. Short-term formaldehyde inhalation studies
Species Exposure Concentration Effect Reference
mg/m3 (ppm)
——————————————————————————————————–
Nose-only inhalation
Rat 6 h/day, 5 days/week, 3.6 (3) no adverse findings AIHA
for 4 weeks (1983)
6 h/day, 5 days/week, 19, 73, (16, 61, antibody inhibition AIHA
for 4 weeks 120 99) (1983)
Inhalation
Rat 8 h/day (continuous), 6, 12 (5, 10) slightly increased prolifer- Wilmer
5 days/week, for (equivalent to ation of nasal epithelium; et al. 4 weeks 40 ppm x h or slight hypermetaplasia of (1987) 80 ppm x h) nasal epithelium
8.5 h/day (interrupted), 12, 24 (10, 20) strongly increased prolifer- Wilmer
5 days/week, for (equivalent to ation of nasal epithelium; et al. 4 weeks 40 ppm x h or moderate hypermetaplasia of (1987) 80 ppm x h) nasal epithelium
Rat 22 h/day, for 90 days 1.9 (1.6) no adverse findings Dubreuil
et al. (1976) 22 h/day, for 45 days 5.4 (4.55) decreased weight gain Dubreuil et al. (1976) 22 h/day, for 60 days 9.6 (8.07) decreased liver weight; Dubreuil eye irritation et al. (1976) 6 h/day, 5 days/week, 4.8 (4) no adverse effect Mitchell for 13 weeks et al. (1979)
Rat 6 h/day, 5 days/week, 15 (12.7) nasal erosion Mitchell
for 13 weeks et al. (1979) 6 h/day, 5 days/week, 48 (40) nasal ulceration Mitchell for 2 weeks et al. (1979) 8 h/day (continuous), 1.2 (equivalent no adverse effects Wilmer 5 days/week, for 9.6 to 8 ppm x h) et al. 13 weeks (1986)
8.5 h/day (intervals), 2.4 (equivalent no adverse effects Wilmer
5 days/week, for 9.6 to 8 ppm x h) et al. 13 weeks (1986)
8 h/day, 5 days/week, 2.4 (equivalent no adverse effects Wilmer
for 13 weeks 19.2 to 16 ppm x h) et al. (1986) 8.5 h/day, 5 days/week, 4.8 (equivalent hyper- and metaplasia of Wilmer for 13 weeks 19.2 to 16 ppm x h) nasal respiratory epithelium et al. (1986) 6 h/day, 5 days/week, 0.36 (0.3) transient, slight increase Zwart for 13 weeks in cell turnover rate of the et al. nasal respiratory epithelium (1987)
6 h/day, 5 days/week, 1.2 (1) transient, slight increase Zwart
for 13 weeks in cell turnover rate of et al. the nasal respiratory (1987) epithelium
6 h/day, 5 days/week, 3.6 (3) 5- to 10-fold increase in Zwart
for 13 weeks cell turnover rate and et al. squamous metaplasia of the (1987) nasal respiratory epithelium
Rat 6 h/day, 5 days/week, 1.2 (1) questionable hypermetaplasia Woutersen
for 13 weeks of the nasal respiratory et al. epithelium (1987)
6 h/day, 5 days/week, 12 (10) squamous metaplasia of nasal Woutersen
for 13 weeks respiratory epithelium et al. (1987) 6 h/day, 5 days/week, 24 (20) transient excitation and Woutersen for 13 weeks uncoordinated locomotion; et al. growth retardation; de- (1987) creased level of plasma- protein; increased activity of several plasma enzymes; squamous metaplasia of the nasal respiratory and olfac- tory epithelium; squamous metaplasia of laryngeal epithelium
6 h/day, 5 days/week, 2.4-48 (2-40) 12-48 mg/m3: histological Maronpot
for 13 weeks lesions in the upper respira- et al. tory system; 48 mg/m3: death (1986)
22 h/day, 7 days/week, 1.2 (1) no adverse findings Rusch et
for 26 weeks al. (1983)
22 h/day, 7 days/week, 3.6 (3) squamous metaplasia; depres- Rusch et
for 26 weeks sion in body weight gain al. (1983)
Mouse 6 h/day, 5 days/week, 4.8 (4) no adverse findings Mitchell
for 13 weeks et al. (1979) 6 h/day, 5 days/week, 15 (12.7) no adverse findings for 13 weeks
6 h/day, 5 days/week, 48 (40) nasal ulceration in males
for 2 weeks
Hamster 22 h/day, 7 days/week, 1.2 and (1 and no adverse findings Rusch et
for 26 weeks 3.6 3) al. (1983)
Guinea-pig 6 h/day, 5 days/week, 1.2 (1) hyperkeratosis in the cavity Marshall
for 8 weeks (reversible after 30 days); (1983) mucus flow elevated; foci of squamous metaplasia of res- piratory epithelium
Monkey 22 h/day, 7 days/week, 1.2 (1) metaplasia in nasal turbin- Rusch et (cynomolgus) for 26 weeks ates in 1/6 exposed al. (1983)
22 h/day, 7 days/week, 3.6 (3) metaplasia in nasal turbin- Rusch et
for 26 weeks ates in 6/6 exposed al. (1983)
Monkey 6 h/day, 5 days/week, 7.2 (6) mild degeneration and early Monticello (rhesus) for 1 or 6 weeks squamous metaplasia of nasal et al.
passages, trachea and bronchi (1989) in 6/6 exposed. Percentage of nasal surface area affected was greater in 6-week exposure group
———————————————————————————————————
Table 29. Summary of carcinogenicity studies of formaldehyde on animals
Species/ Number of Route of Dosage Findings Reference Strain animals exposure
(sex)
———————————————————————————————————
Mouse 42-60 inhalation 0, 50, 100, or 200 mg/m3; no pulmonary tumours at Horton
three l-h periods/week, 0-100 mg/m3 et al. for 35 weeks (1963)
Mouse 36 inhalation 50 mg/m3 for 35 weeks no pulmonary tumours Horton
+ 150 mg/m3 for 29 weeks; et al. three l-h periods/week (1963) in addition
Mouse 26 inhalation 100 mg/m3; three 1-h formaldehyde did not modify Horton
periods/week for 35 weeks the pulmonary carcinogenesis et al. followed by a coal-tar of coal-tar (1963) aerosol for 35 weeks
Mouse: 119-121 inhalation 0, 2.4, 6.72, or 17.16 mg/m3; squamous cell carcinoma of Kerns B6C3F1 (male) 6 h/day, 5 days/week, for the nasal cavity in 2 males et al.
119-121 up to 24 months; 6-month (at high exposure only) (1983) (female) follow-up
Mouse: 29-99 ingestion 0 or 0.5 HMT in drinking- no increased tumour Della CTM, SWR (male) water for 60 weeks or 5% incidence Porta +C3Hf 27-100 for 30 weeks (CTM only); et al.
(female) follow-up for 110-130 weeksa (1968)
Mouse: 39 subcutaneous 5 g/kg on alternate days, no increased tumour Della CTM (male) for 110-130 weeksa incidence Porta
44 et al. (female) (1968)
Mouse 60 Injection µl “formol oil” 50 times no tumoursd Klenitzky
(route not to the cervix uteri (dose (1940) described) not defined)
———————————————————————————————————-
Table 29 (contd).
Mouse: 30 topical, 3.7% formaldehyde formaldehyde is probably Spangler SENCAR (female) back skin in acetone not a complete carcinogen & Ward
once a week, 48 weeks or an initiator (1983) (preliminary findings only)
Mouse: 30 subcutaneous 0.1-1.0 mg, no incidence of initiator/ Krivanek CD-1 (female) 3 times a week promotor activity et al.
for 180 days (preliminary findings) (1983a)
Mouse 16 topical, 200 µg 1% or 10% no tumours Iversen
(male) back skin sol., twice a week, (1986) 16 60 weeks (female)
Rat: 100 inhalation 17 mg/m3 (14.2 ppm); 382 10 squamous cell carcinomas Albert Sprague (male) exposures over a 588-day of the nasal cavity et al. Dawley period; 6 h/day, 5 days/week (significantwith regard (1982)
to controls (preliminary findings only)
Rat: 99 inhalation 16.80 mg/m3 (14.7 ppm) 25/99 squamous cell Albert Sprague formaldehyde + 14.80 mg/m3 carcinomas of the nasal et al. Dawley (10.6 ppm) HCl (BCME estima- cavity and 3 papillomas (1982)
ted 1 µg/m3), 6 h/day, 5 days/week, for life
Rat: 100 inhalation 17.16 mg/m3 (14.3 ppm) 12 squamous cell carcinomas Albert Sprague (male) formaldehyde + 14 mg/m3- of the nasal et al. Dawley (10 ppm) HCl (pre-mixed); cavity (significant (1982)
378 exposures over 588 days; with regard to controls) 6 h/day, 5 days/week (preliminary results only)
Rat: 100 inhalation 16.92 mg/m3 (14.1 ppm) for- 6 nasal (significant with Albert Sprague (male) maldehyde + 13.30 mg/m3 (9.5 regardto controls) et al. Dawley ppm) HCl (not pre-mixed); (5 squamous cell (1982)
378 exposures over 588 days; carcinomas, 1 adenocarcinoma) 6 h/day, 5 days/week (preliminary results only)
———————————————————————————————————————-
Table 29 (contd).
Species/ Number of Route of Dosage Findings Reference Strain animals exposure
(sex)
———————————————————————————————————————-
Rat: 119-121 inhalation 0, 2.4, 6.72, or 17.16 mg/m3; non-significant polypoid Kerns F-344 (male) for up to 24 months; 6 h/ adenoma at all doses; 2/235 et al.
119-121 day, 5 days/week; 6-month (non-significant) and 103/232 (1983) (female) follow-up (significant) squamous cell carcinomas of nasal cavity, at the medium and high doses, respectively (see also Table 30)
Rat: 32 inhalation 0.36, 2.4, or 17 mg/m3; rhinitis; epithelial cell Tobe F-344 6 h/day, 5 days/week, for hyperplasia; squamous et al.
28 months metaplasia at 17 mg/m3, 14/ (1985) 32 squamous cell carcinomas (P < 0.01) and 5/32 papillomas (P < 0.05)
Rat: 100 inhalation 18.24 mg/m3 (15.2 ppm) for- 13 polyps/papillomas; 45 Sella- Sprague (male) maldehyde + 13.86 mg/m3 (9.9 squamous cell carcinomas; kumar Dawley ppm) HCl (pre-mixed) (BCME, 1 adenocarcinoma et al.
0.1-0.4 µg/m3); 6 h/day, 1 fibrosarcoma; esthesic (1985) 5 days/week, for life neuroepithelioma resp
Rat: 100 inhalation 17.88 mg/m3 (14.9 ppm) for- 27 squamous cell carcinomas; Sella- Sprague (male) maldehyde + 13.58 mg/m3 (9.7 2 adenocarcinomas; 11 kumar Dawley ppm) HCl (not pre-mixed);6 h/ polyps/papillomas et al.
day, 5 days/week for life (1985)
Rat: 100 inhalation 17.76 mg/m3 (14.8 ppm) for- 38 squamous cell carcinomas; Sella- Sprague (male) maldehyde; 6 h/day, 5 days/ 1 fibrosarcoma; 1 mixed car- kumar Dawley week, for life cinoma et al.
(1985)
Rat 30 stomach tube 0.4 g/daya, for 333 days no treatment-related tumours Brendel
(1964)
———————————————————————————————————
Table 29 (contd).
Rat: 48 ingestion 1% HMT in drinking-water no increased tumour Della Wistar (male) for 104 weeks, for 3 yearsa incidence Porta
48 et al. (female) (1968)
Rat: 280 ingestion 0, 1.2, 15, or 81 mg/kg bw no tumours (except 1 skin Til Wistar (male) (males); 0, 1.8, 21, or 109 mesenchymoma in high-dose et al.
280 mg/kg bw (females) male) (1988) (female) (drinking-water, 2 years)
Rat: 80 ingestion 0, 10, 50, or 300 mg/kg bw; no significant increase in Tobe Wistar (male) (drinking-water, 2 years) tumours et al.
80 (1988) (female)
Rabbit 6 oral tank 3% formalin, 90 min, 2/6 leukoplakiasb Mueller
5 times/week for 10 months et al. (1978)
Syrian 88 inhalation 12 mg/m3, 5 h/day, no increase in Dalbey golden 5 day/week, lifetime tumour incidence (1982) hamsters
Syrian 50 inhalation 36 mg/m3, 5 h/day, no increase in nasal Dalbey golden 5 day/week, lifetime tumour incidence (1982) hamsters (with diethylnitrosamine)
Rat 10 subcutaneous 1 ml/week for 15 months 4/10 injection-site sarcomas Watanabe
0.4% solution et al. (1954)
Rat 20 subcutaneous 1-2 ml/week till tumour 7/20 injection-site sarcomas; Watanabe &
development 9-40%a 1/20 injection-site adenoma Sugimoto (1955)
Rat: 20 subcutaneous 5 g/kg on alternate days, no increased tumour Della Wistar (male) for 2 yearsa incidence Porta
20 et al. (female) (1968)
——————————————————————————————————— a Hexamethylenetetramine (HMT) (from which formaldehyde is liberated in vivo). b Showed “histological features of carcinoma in situ” (Mueller et al., 1978). c Aspartame (sweetener) was administered to rats at a dosage level of 8 g/kg body weight, which
has been assumed to biodegrade (10%) in the animals yielding 800 mg formaldehyde/kg.
d No tumours, even after treatment with dibenzpyrene and coal tar.
Table 30. Neoplastic changes in the nasal cavities of Fischer 344 ratsa
Formaldehyde Sex Number of Squamous Nasal Undifferen- Malignant Polypoid Osteo- mg/m3 (ppm) nasal cell carcinomas tiated sarcomas adenomas chondromas
cavities carcinomas carcinomas/ evaluated sarcomas
———————————————————————————————————
0 (0) male 118 0 0 0 0 1 1
female 114 0 0 0 0 0 0
2.4 (2) male 118 0 0 0 0 4 0
female 118 0 0 0 0 4 0
6.7 (5.6) male 119 1 0 0 0 6 0
female 116 1 0 0 0 0 0
17.2 (14.3) male 117 51c 1b 2b 1 4 0
female 115 52d 1 0 0 1 0
———————————————————————————————————
a From: Kerns et al. (1983) and BGA (1985). b One animal also exhibited a squamous cell carcinoma. c 36 of these animals were among the 57 that died prematurely. d 15 of these animals were among the 67 that died prematurely.
The general population may be exposed to formaldehyde in tobacco smoke, automobile emissions, from materials used in buildings and home furnishings, in consumer and medicinal products, and in nature (section 3).
. . . . The most predominant effects of formaldehyde exposure usually reported in human beings are various kinds of physical symptoms emanating from the irritation of the mucosa in the eyes and upper airways as well as the sensitivity of the skin. Sensory reactions are apparently the most typical effects in the non-industrial indoor environment. Most human beings are exposed to low concentrations of formaldehyde (less than 0.06 mg/m3) in the environment and sensory effects (odour and irritation) are by far the most common response; symptoms of hyperactivity in the lower respiratory tract may also be produced.
It should be realized that extrapolation from animal studies to estimate human response is dubious in most cases and, for some effects, impossible. Although some effects, e.g., skin reactions may be comparable between animals and human beings, other effects, such as pulmonary function reactions, are more questionable and others, such as sensory irritation, cannot be compared.
No cases of death from formaldehyde inhalation have been published. There are numerous reports that exposure to formaldehyde vapour causes direct irritation of the respiratory tract. However, precise thresh- olds have not been established for the irritant effects of inhaled formaldehyde but, within the range of 0.1-3.1 mg/m3, most people experience irritation of the throat (Table 35).
The effects of formaldehyde on ciliary movement and mucociliary clearance were studied by Andersen & Mölhave (1983). They measured nasal mucociliary flow by external detection of the motion of a radio- labelled resin particle placed on the surface of the inferior turbi- nate. The nasal mucous flow rate in the nose decreased during exposure to formaldehyde, but the response did not increase at concentrations ranging from 0.5 mg/m3 to 2 mg/m3 or on prolongation of the exposure period from 3 h to 5 h.
The potential of formaldehyde to produce chronic respiratory tract disease was studied by Yefremov (1970). At a wood-processing plant, the incidence of chronic upper respiratory disease was higher in 278
workers exposed to formaldehyde than in 200 controls. However, formal- dehyde concentrations were not measured, and possible confounders were not evaluated.
Forty-seven subjects exposed to formaldehyde (mean air concen- tration 0.45 mg/m3) and 20 unexposed subjects, all of whom were employed at a carpentry shop, were studied by Alexandersson et al. (1982) with regard to symptoms and pulmonary function. Symptoms involving the eyes and throat as well as chest oppression were signifi- cantly more common in the exposed subjects than in the unexposed controls. Spirometry and simple breath nitrogen washout were normal on the Monday morning, before exposure to formaldehyde. A reduction in forced expiratory volume in 1 second by an average of 0.2 litres (P = 0.002), percent forced expiratory volume by 2% (P = 0.04), maximum mid-expiratory flow by 0.3 litre/second (P = 0.04) and an increase in closing volume in percentage of vital capacity by 3.4% (P = 0.002) were seen after a day of work and exposure to formal- dehyde, suggesting bronchoconstriction. Smokers and nonsmokers displayed similar changes in spirometry and nitrogen washout.
Schoenberg & Mitchell (1975) performed standardized respiratory questionnaire and pulmonary function tests (FVD, FEV1, MEF 50%) on 63 employees in an acrylic-wool filter department (40 production line workers, 8 former production line workers, and 15 employees who had never been on the production line). Formaldehyde levels in the work environment were between 0.5 and 1 mg/m3, and phenol levels, between 7 and 10 mg/m3; particles and fibres were not well suppressed. In spite of the high proportion (85%) of subjects reporting acute respir- atory symptoms, only small and insignificant changes in pulmonary function were found.
Andersen & Mölhave (1983), in a study of 16 healthy volunteers in a chamber, could not find any increase in airway resistance or any effects on vital capacity and maximum expiratory flow volume from exposure to formaldehyde levels of up to 2.0 mg/m3 in a 5-h study.
To study pulmonary function during and after exposure to formal- dehyde, Schachter et al. (1986) exposed 15 non-smoking healthy volun- teers (mean age, 25.4 years) in a double-blind random manner to 0 or 2.4 mg formaldehyde/m3, for 40 min on one day and again on a second day but with the subjects performing moderate exercise (450 kpm/min) for 10 min. No significant bronchoconstriction was noted (FEV1 test), and subjective complaints following such exposure were confined to irritative phenomena of the upper airways. Post-exposure symptoms (up to 24 h following exposure) were infrequent and confined to headache. Another study by the same group (Witek et al., 1986, 1987) on 15 healthy and 15 asthmatic volunteers resulted in similar findings.
Main & Hogan (1983) examined 21 subjects exposed to formaldehyde (0.14-1.9 mg/m3) in a mobile home trailer. Eighteen unexposed con- trols were included. No differences in lung function were found between the 2 groups. However, there were significantly more complaints of eye and throat irritation, headache, and fatigue among the exposed.
In controlled studies, Day et al. (1984) exposed 18 volunteers to a formaldehyde concentration of 1.2 mg/m3. Nine subjects had pre- viously complained of various non-respiratory adverse effects from the urea formaldehyde foam insulation (UFFI) in their homes. Pulmonary function was assessed before and after exposure in a laboratory. Each subject was exposed, on separate occasions, to formaldehyde at 1.2 mg/m3 in a environmental chamber for 90 min and to UFFI off-gas yielding a formaldehyde concentration of 1.4 mg/m3 in a fume hood for 30 min. None of the measures of pulmonary function used showed any clinically or statistically significant responses to the exposure either immediately or 8 h after, commencement of exposure. There were no statistically significant differences between the responses of the group that had previously complained of adverse effects and of the groups that had not. There was no evidence that either formaldehyde or UFFI off-gas behaved as a lower airway allergen or important broncho- spastic irritant in this heterogeneous population but, because of the small number of persons under study, it cannot be excluded.
Fifteen non-smoking volunteers (mean age, 25.1 years) who suffered from substantial bronchial hyperreactivity, were studied by Harving et al. (1986). The mean provocation concentration of histamine producing a 20% decrease (PC20) in peak expiratory flow rate was 0.37 g/litre (standard deviation (SD) = 0.36). All except one patient regularly required bronchodilator treatment. None used methylxanthines or corticosteroids. They were exposed to formaldehyde once a week for 3 consecutive weeks. The studies were carried out in a double-blind random fashion, under controlled conditions, in a climate chamber with particle-free air. All underwent the same 3 treatments, being exposed to mean formaldehyde concentrations of 0.85 mg/m3 (SD = 0.07), 0.12 mg/m3 (SD = 0.07), and zero. The mean exposure time at a steady- state concentration was 89.4 min (SD = 9.5). Bronchodilator drugs were withheld for 4 h before the studies. During the exposure, each par- ticipant rated his symptoms of asthma every 15 min on a visual analogue scale, and forced expiratory volume in one second was measured on a spirometer every 30 min.
Before and after exposure to formaldehyde, functional residual capacity and airways resistance were determined in a body plethys- mograph, and flow-volume curves were measured. Immediately after exposure, a histamine challenge test was performed.
No significant changes in forced expiratory volume in one second, airways resistance, functional residual capacity flow-volume curves, or subjective ratings of symptoms of asthma were found in the group as a whole, or among the 9 participants with high histamine reactivity (PC20 < 0.50 mg/ml). Histamine challenge tests were highly reproduc- ible and were unaffected by exposure to formaldehyde. No appreciable symptoms were reported after exposure.
Asthma-like symptoms have been elicited by irritant concentrations of formaldehyde. Precise thresholds have not been established for the irritant effects of inhaled formaldehyde. However, lower airway and pulmonary effects are likely to occur between 6 and 36 mg/m3, inde- pendent of confirmed sensitization.
Several studies have addressed the problem of the mobile home situation, especially in Canada and the USA, without measurements of other confounders (section 9.2.8).
Formaldehyde is a known sensitizer for the skin (DFG, 1987), but no thresholds for induction of dermal, respiratory tract, or systemic sensitization have been reliably determined.
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