Yaqin Pan, MD, Dept. Of Allergy, Peking Union Medical College Hospital, Beijing, China, Research Fellow, Environmental Health Center-Dallas

William J. Rea, MD, FACS, Director, Environmental Health Center-Dallas, First World Chair in Environmental Medicine, Robens Institute, The University of Surrey, Guildford, England

Abstract: Many patients have been found to be sensitive to formaldehyde. This paper gives the results both of formaldehyde inhalation challenges and intracutaneous skin tests in 49 chemically sensitive patients and 14 normal controls under environmentally controlled formaldehyde-free conditions, with the patients having a reduced total body load in the deadapted state. All patients had negative reactions to normal saline and to a weak solution of methyl alcohol given intradermally. All had positive reactions to intradermal histamine. Forty-eight of the 49 patients had positive reactions to formaldehyde given intradermally, and 31 (63%) had positive reactions to double-blind formaldehyde inhalation challenges. Only one control subject had a positive formaldehyde intradermal test; none had positive inhalation challenges.

Of the 48 patients with positive formaldehyde intradermal tests, 31 had positive inhalation challenges. Nineteen of the patients had histories indicating a sensitivity to formaldehyde, and all these had positive intradermal tests; 11 had positive inhalation challenges.

Both intradermal tests and inhalation challenges with formaldehyde solutions are helpful in the investigation of patients though to be sensitive to formaldehyde.

Formaldehyde Allergy Intradermal skin testing Inhalant challengeCwhat is this?
  INTRODUCTION

There is increasing concern over the number of patients who develop symptoms after exposure to formaldehyde. Randolph,¹ Breysse,² and Rea³ have demonstrated that formaldehyde can induce a variety of reactions, including cardiovascular, neurological, respiratory, gastrointestinal, skin, and ocular symptoms. Formaldehyde is a ubiquitous air contaminant found both in the outside and indoor environments.¹ In this study, we carried out formaldehyde skin tests (FST) and formaldehyde inhalation tests (FIT) to determine their prevalence in 49 chemically sensitive patients with predominantly neurovascular involvement, and we compared our findings with those 14 healthy controls.

MATERIALS AND METHODS

Patients

The subjects were 49 selected patients who, from their histories and symptoms, were thought to be very sensitive to formaldehyde. All had food, inhalant, and chemical sensitivities. Twenty-two were treated as outpatients, 27 as inpatients; 13 were male and 36 female. Their ages ranged from 14 to 69 years, with an average of 48 years.

The controls were 14 nonsmoking, healthy volunteers with no history of formaldehyde sensitivity; 3 were male and 11 female. Their ages ranged from 16 to 52 years, with an average of 31 years. The study was conducted between October 1983 and December 1988 in a formaldehyde-free (below analytical detection limit) chemically less polluted environment constructed of porcelain steel. The patients were in the deadapted state with a reduced total body load when the tests were carried out.

Formaldehyde Skin Tests (FST)

An intracutaneous injection test was given. Four types of extract were used:

Initially, the test dose was 0.01 cc of the #4 dilution, to make a wheal of approximately 5 mm x 5 mm. After 10 minutes, if no signs or symptoms had developed and there had been no growth in the size of the wheal, 0.05 cc of #4 dilution was injected, creating a 7 mm x 7 mm wheal. If after 10 minutes both parameters were again negative, 0.01 cc of #3 dilution was injected. If after 10 minutes there were no signs or symptoms or wheal growth, 0.05 cc of #3 dilution was injected. If after 10 minutes both parameters were again negative, 0.01 cc of #2 dilution was injected. If after ten minutes both parameters were negative, 0.05 cc of #2 dilution was injected. If after 10 minutes both parameters were negative, 0.01 cc of #1 dilution was injected. If after 10 minutes both parameters were negative, the test was considered negative. If wheal growth occurred and/or symptoms and signs developed, the test was considered positive. Delayed onset of wheal growth was also considered positive.

All injections were single-blinded. Neither patients nor controls knew what they were being tested with until all tests had been completed. All patients were taken off antihistamines 48 to 72 hours before testing.

The growth in wheal size was assessed by measuring the average diameter, this being the sum of the width and height divided by two.

Formaldehyde Inhalation Tests (FIT)

Inhalation tests were carried out double-blind in a steel and glass airtight booth, free from formaldehyde and other toxic volatile organic chemicals.

An open four ounce glass jar with 30 ml of 0.74% formalin was put in the booth. After 10 minutes, the challenge concentration of formaldehyde in the air, measured by gas chromatography/mass spectrometry (GS/MS), was <0.2 ppm. This was below the reported odor threshold.⁴ No patient could tell what he/she was being exposed to. There was no detectable level of methyl alcohol in the air of the booth as measured by GC/MS. The placebo was spring water in a glass bottle with the lid open. Patients and controls were stabilized before testing by means of four days of deadaptation in a formaldehyde-free environment. The interval between placebo testing and FIT was at least 24 hours.

The patients and controls sat in the booth with the bottle closed for five minutes before testing. If no symptoms occurred, they were then exposed to formaldehyde for 15 minutes.

Patients and controls were attached to cardiac monitors while in the booth. Blood pressure and Peak Flow Rates (PFR) were taken before and after tests. Pulse rates and symptoms and signs were monitored at five minute intervals. Symptoms and signs were noted prior to the start of the FIT and for the next 24 hours. Scores were kept for these.

Depending on the severity of the patient=s reaction, various treatments were used to try to curtail symptoms. These methods included neutralization of symptoms by means of neutralizing doses of histamine (0.05 ml of 0.004% or 0.05 ml of 0.0008%, 0.10 ml of 0.004%, 0.10 ml of 0.0008%, etc.) given subcutaneously, or of serotonin given in the same manner. Vitamin C, 15 gm in 200 ml normal saline, was also given intravenously, and, if necessary, oxygen was given by mask for 15 minutes at 3-4 L/min was administered.
 
 

RESULTS

A. Formaldehyde Skin Tests

B. Formaldehyde Inhalation Test

C. The relationship between past history, FST, and FIT.

D. The relationship between FST and FIT

DISCUSSION

Formaldehyde is the simplest of the aldehydes (HCHO). It is a gas at room temperature. It is obtainable in crystalline form or as a liquid. Formalin, dissolved in water in a concentration of 35 to 40% formaldehyde with methyl alcohol used as a polymerization inhibitorCfragment: what about formalin?.

There are two major sources of formaldehyde: direct commercial manufacture and indirect production. Commercial formaldehyde is used mainly in the synthesis of disinfectants, cosmetics, deodorants, paper, dyes, photographic materials, textiles, inks, wood products, synthetic resins, preservatives, leather, fertilizers, and insecticides.⁵ Indirect production of formaldehyde may occur through the photochemical oxidation of airborne hydrocarbons from vehicle exhausts, the incomplete combustion of hydrocarbons in fuels, and other sources.⁶ Other sources in the atmosphere include cigarette smokingClevels over 0.2 ppm have been observed⁷ and anaerobic decomposition of methane by microbes.⁸

In 1961, Randolph¹ pointed out that formaldehyde, both in inside and in outside air, can cause a variety of serious reactions. Breysse² reported that eye, nose, and throat irritation were apparently associated with formaldehyde emissions from chipboard. The commonest symptoms were irritation of the eyes and upper respiratory tract, headaches, and nausea and drowsiness. In 1978, Rea³ reported that formaldehyde could also trigger cardiac problems usually associated with neurological, muscular, respiratory, or dermal symptoms. All these symptoms are commonly associated with environmental sensitivities.⁹ Formaldehyde-induced disease is closely linked to building-related illness¹⁰ or the tight building syndrome.¹¹

Studies to evaluate formaldehyde sensitivity have been done by several investigators over the past 80 years, starting in 1909.¹² In the 1909 study, subjects developed stomach or intestinal pains, headaches, and itchy rashes on the chest and thigh after drinking milk that contained formaldehyde.¹² In 1934, Horsfall¹³ reported an experimental study using intradermal injections of 0.02 cc formalin in a dilution of 1:10,000 to 1:8,000,000. He recorded as positive those reactions where a papule greater than 3 mm in diameter developed within 5 to 20 hours. In his study, four normal individuals showed no reaction to a 1:10,000 dilution.

More recently, in two separate studies assessing formaldehyde skin tests, Morris⁹ and Rogers¹⁴ described the serial dilutions used by them. Their #1 dilution was a 1:10 (3.17%) dilution of formalin USP, their #2 was 0.74%, their #3 was 0.148%, and their #4 was 0.0296%. These were five-fold dilutions. Morris performed intradermal tests using 0.01 to 0.02 cc of the appropriate dilution of formaldehyde. He never used solutions stronger than 0.148% (#3) because they caused nonspecific skin irritation. Most patients were screened with 0.0296% or 0.148% concentrations.⁹ Rogers used an intradermal injection of 0.01 cc of the #3 dilution. If a negative reaction was obtained, 0.05 cc of the #3 was then injected. She never gave more than 0.05 cc of the #3 dilution.¹⁴ Morris⁹ also administered the solution sublingually using a 1:250 dilution (0.148%) of formalin. This route of administration also seemed efficacious.

The concentrations of formaldehyde that we have used are similar to the above. We believe it is safe for sensitive patients to be given the #3 or #4 dilutions (0.00592%) or 0.001184%). We never use solutions stronger than 0.148% (our #1 dilution). This is equivalent to Morris= and Rogers= #3. Two patients sensitive to formaldehyde by history had positive FSTs to the#1 dilution (0.148%). Reactions triggered by this concentration are, therefore, significant. Most patients (83%) reacted to 0.00592% or 0.001184% concentrations of formaldehyde.

Epstein and Maibach,¹⁵ instead of giving injections, performed patch tests with 2% formalin. In a series of 156 patients, they found that six formaldehyde-sensitive patients had 2+ reactions (erythema with papules) or 3+ reactions (erythema and papules and small vesicles); two patients had a 1+ reaction (erythema only). This was considered a false-positive irritant reaction. These tests seem to be accurate only if they are positive; they have the disadvantage that one does not know if there are skin penetration reactions.

Some reports regarding formaldehyde inhalation challenges have also been published but, unfortunately, the tests were not standardized. In 1957, Sim and Pattle¹⁶ reported on 12 male subjects who were exposed in a chamber to 13.8 ppm of formaldehyde for 30 minutes. No mention was made as to whether the chamber itself was free from formaldehyde. All the subjects initially had considerable eye and nose irritation, but none had severe effects after 30 minutes. The eye irritation subsided after ten minutes; it was felt that this was due to short-term human adaptation to what would be considered very strong concentrations of formaldehyde. In 1959, Bourne and Seferian¹⁷ reported burning and stinging of the eyes and nose, with headaches and throat irritation by customers and employees in several dress shops. Air samples in the stores contained between 0.13 and 0.45 ppm of formaldehyde. These studies illustrate the wide variety of reactions to formaldehyde in humans.

In 1977, the National Institute for Occupational Safety and Health (NIOSH) used a whole-body chamber constructed of materials not likely to emit formaldehyde. However, again it wasn=t noted if the chamber was formaldehyde-free. Formaldehyde was generated by heating paraformaldehyde and measured by use of a standard method. Individuals were exposed to 1 to 3 ppm for up to one hour.¹⁸ The use of the heating apparatus in the study probably introduced many more variables; the significance of the results is therefore debatable. In 1978, Anderson¹⁹ reported that short-term formaldehyde exposures in the range of 0.5 to 1.5 ppm induced symptoms which included irritation and dryness of the nose and throat, decreased mucous flow, moderate eye irritation, and increased eye blinking. Some test subjects experienced symptoms at a concentration as low as 0.25 ppm. In 1982, Hendrick et al.²⁰ used a method attempting to stimulate the working conditions of his patients by having them paint an aqueous solution of formaldehyde on cardboard. This, or course, introduced new variablesCthe open room and the cardboard emissions. In 1984, Frigas et al.²¹ used a Dynacalibrator (model 340-23-X, Metronics, Santa Clara, CA) to administer formaldehyde by face mask in concentrations of 0.1, 1.0 and 3 ppm, single or double-blinded, for 20 minutes, with a placebo of air. This technique may have introduced new variables coming from the materials in the face mask. Moreover, it is important to note that the above studies do not report if patients were in the deadapted state, with reduced total body load. We suspect they were not, which would tend to make the data suspect.

The concentration of formaldehyde for inhalation provocation testing in our studies was <0.2 ppm. This is lower than the perceptible odor level of 1 ppm noted by NIOSH.⁴ In our opinion, a concentration below the odor limit with the patient in the deadapted state with a reduced total body load is both adequate and safe for double-blind challenges.

In 1981, the Committee on Toxicology of the National Research Council estimated that as much as 10% of the total United States population may be hypersensitive to the irritant effects of formaldehyde.²² In our highly selected group of patients, 63% reacted to FITS and 98% to FSTs. Only one control (7.1%) had a positive FST; none had a positive FIT. The patient with a positive FST had been passively exposed to cigarette smoke for an extended period of time. She may have had a potential formaldehyde sensitivity and may develop clinical symptoms in the future.

In this study, 65% of patients with positive FSTs and 58% of patients with a history suggestive of formaldehyde sensitivity had positive FITs. All had positive skin tests. This discrepancy may be because the patients were only exposed to low concentrations of formaldehyde and then only for 15 minutes.

An FST is a useful specific test, due to the fac that (a) all the patients with an obvious history of formaldehyde sensitivity had a positive FST; (b) all those with positive FITs also had positive FSTs; 8 and only one normal control had a positive FST. Local burning and a stinging sensation in the skin may be induced by the irritant effect of formaldehyde and should not be considered a reaction, since the controls also experienced this phenomenon. In addition, FITs can be considered valid because the symptoms, which appeared originally when the patients were exposed to formaldehyde, were triggered by FSTs but not by the placebo.

In conclusion, our results suggest that under environmentally controlled formaldehyde-free conditions, with the patient in the deadapted state and with reduced total body load, reactions induced by FSTs and FITs are indicative of a true formaldehyde sensitivity. We also conclude that, under environmentally controlled formaldehyde-free conditions, the FSTs and FITs are useful methods for the assessment and diagnosis of formaldehyde sensitivity.