J. theor. BioL (1985) 114, 223-241
Speculations on the Origin of the Ill-Effects Associated With the Use of Visual Display Terminals ANTHONY R.
MAWSON
Section of Rheumatology and Rehabilitation, Department of Medicine, Louisiana State University Medical Center, 1542 Tulane Avenue, New Orleans, Louisiana 70112, U.S.A. (Received 26 September 1984) There are increasing reports of a wide variety of unexplained ill-effects associated with the occupational use of visual display terminals (VDTs) ; these include psychological complaints such as headache, irritability, and fatigue, musculoskeletal pains, dry or burning eyes, deteriorating eyesight, cataracts, facial dermatitis, and pregnancy abnormalities. Many VDTs emit near-ultraviolet (UV-A) radiation in amounts ranging from 200 to 1500 times less than the present U.S. safety standard of 1.0xl0-3W/cm 2. Although the possibility of a radiation hazard from VDTs is widely discounted, various points of circumstantial evidence are marshalled in this paper in support of the hypothesis that prolonged exposure to even these low amounts of UV-A radiation may result in progressive increases in sensitivity to UV-A and in cumulative biologic damage. It is further proposed that UV-A produces the ill-effects by catabolizing vitamin A in skin and plasma into highly active metabolites, the gradual accumulation of which results in an endogenous form of vitamin A intoxication. In addition to producing the skin and systemic effects of hypervitaminosis A, these metabolites presumably enter the fetal circulation, leading to pregnancy abnormalities similar to those associated with high doses of the vitamin for the treatment of skin disorders.
In recent years, coinciding with the widespread adoption of visual display terminals (VDTs) in the United States and elsewhere, there have been increasing reports of a variety of ill-effects associated with their use. These effects, the causes of which are completely unknown, include s y m p t o m s of headache, fatigue, and irritability, to musculoskeletal aches and pains, diffuse itching, skin rashes, and erythema. Most alarming have been reports of deteriorating eyesight, cataracts, and pregnancy abnormalities (Gilbert, 1978; Gunby, 1981; Morris, 1982; 9-to-5, 1983; Slesin & Zybko, 1983; Donoghue, 1983; Australian Postal and Telecommunications Union Federal Executive, [APTU] 1983; Deiman, 1983; Bennett et al., 1984). The intent here is briefly to review these effects and the hypotheses p r o p o s e d thus far 223
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to explain them. Evidence will then be presented implicating a specific physical agent in the causation of many of the effects, and a possible physiochemical mechanism of action will be outlined. The Phenomena
A wide range of mental and physical symptoms have been reported by VDT operators, including eye strain, irritation and dryness of the eyes; blurred or double vision; temporarily impaired accommodation (Brown, Dismukes & Rinalducci, 1982; Frank, 1984), deteriorating eyesight (APTU, 1983; 9-to-5, 1984; Frank, 1984), and cataracts (APTU, 1983; Australian Council of Trade Unions--Victorian Trades Hall Council, 1982). With regard to cataracts, a 1980 survey by the U.S. National Institute for Occupational Safety and Health (NIOSH) found that one in 100 VDT operators reported being diagnosed or treated for a cataract within the previous 5 years, whereas no such cases were found among non-VDT operators (NIOSH, 1981). According to a recent report of the National Research Council (1983), however, there have been no well-designed studies linking VDT work with cataracts or other ocular abnormalities. Other symptoms associated with VDT use include extreme fatigue, dizziness, severe headaches (Canadian Labor Education and Studies Center [CLESC], 1982; Frank, 1984), nausea, stomach pains, muscle pain, tendon and joint symptoms (Hunting, Laubli & Grandjean, 1980; Frank, 1984), and other muscuoskeletal symptoms; tension or anxiety, irritability, anger, depression, insomnia (APTU, 1983); tightness in the chest and difficulty breathing; menstrual problems; diffuse itching, often associated with erythema of the cheeks, forehead and chin that develops during the day and disappears after work; and other skin rashes (Slesin & Zybko, 1983). Several studies indicate that VDT workers complain more about visual, musculoskeletal and psychological problems related to their work than non-VDT workers (Grandjean & Vigliani, 1980; Murray, Moss & Parr, 1981; CLESC, 1982). For instance, a study of 257 VDT operators and 124 controls in New Zealand (Coe et al., 1980) indicated that visual complaints, seating complaints, and muscular discomfort of the arms, shoulders, and neck, were greater among VDT operators than among the controls. Few differences were reported between cases and controls regarding job dissatisfaction and job demands. It should, however, be noted that not all studies have found differences between VDT and non-VDT workers in terms of postural complaints (Arndt, 1983, for review). In addition to visual, musculoskeletal, and skin complaints, 11 confirmed "clusters" of abnormal pregnancies have been reported among VDT
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operators in U.S. and Canadian offices (Slesin & Zybko, 1983; Microwave News, 1984; VDT News, 1984) ; 12 additional clusters are as yet unconfirmed (VDT News, 1984, p. 8). These abnormal pregnancies consist mainly of spontaneous abortions, but major and minor birth defects, premature deliveries and still births have also been reported. For instance, it was reported recently that 50% of the 48 pregnancies occurring among VDT workers at the United Airlines" San Francisco Office since 1970 were abnormal. There were 15 miscarriages, 1 stillbirth, 1 neonatal death, 2 premature births, and 2 children with birth defects (The VDT Coalition, 1984). The rate of spontaneous abortion in the general population averages about 15%, and the rate of serious birth defects about 2-3% (Hemminki et al., 1983). The overall rate of adverse pregnancy outcomes in eight of the VDTassociated clusters reported thus far, not including the United Airlines case, averages 66% (range, 53-87%) (9-to-5, 1983). In the absence of well-designed epidemiologic studies the significance of these clusters is difficult to evaluate (Smith, 1982). However, the rapid increase in the numbers of reported clusters, and the high rate of abnormalities in the various groups, suggest that the incidence of pregnancy abnormalities among VDT operators may indeed be higher than chance expectation. It is unclear at this time whether the adverse effects described above are caused by direct exposure to the VDTs themselves, by some aspect or aspects (e.g. sociopsychological, ergonomic) of the immediate working environment, or a combination of factors. The two main types of explanations suggested thus far are radiation emissions and adverse working conditions. With regard to radiation, several studies have detected both ionizing and non-ionizing emissions from VDTs (e.g. Murray et al., 1981 ; U.S. Bureau of Radiological Health, 1981). However, the levels of radiation measured are so much lower than existing U.S. safety limits that, to quote one investigator (Weiss, 1983, p. 100), "it is the unanimous conclusion of all studies conducted thus far that VDTs do not represent a health hazard from any radiation exposure caused by their use". Recently, it has been suggested that non-ionizing radiation in the very low frequency (VLF) range of 3 to 30 kHz, emitted by the so-called "'flyback" transformer in the visual display terminal, may be responsible for some of the ill-effects (Canadian Center for Occupational Health and Safety, 1983), especially as much of the non-ionizing radiation emitted by VDTs occurs in this range (9-to-5, 1983, p. 4). There have so far been no systematic studies on the possible biological effects of exposure to such emissions from VDTs. With regard to the working environment, several factors have been suggested as playing a role in some of the reported ill-effects; namely,
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environmental design--including improper illumination, glare, and improper contrasts in luminescence; extreme fluctuations in temperature or humidity; machine and work station design;job d e m a n d s - - b o t h physical and psychological; administrative problems, including lack of worker participation in VDT implementation; inadequate employee training; job security issues; performance monitoring; and incentive schemes (Donoghue, 1983; Arndt, 1983; Deiman, 1983; Smith, 1984). It remains uncertain whether VDT workers in general, or those assigned to specific tasks, experience more job dissatisfaction than non-VDT workers. One difficulty with the work-environment hypothesis is that VDT workers report more severe visual symptoms than traditional office workers whose jobs are also visually demanding (Smith, 1984, p. 202).
Hypothesis Most investigators believe that VDTs pose no threat in terms of radiation since the measured emissions are well below existing safety standards. Here it is suggested that chronic exposure to low levels o f one type o f radiation emitted by VDTs may nevertheless be responsible for many o f the reported ill-effects; namely, ultraviolet A (UV-A) or near-ultraviolet radiation.t It is proposed that chronic exposure to subliminal amounts of UV-A radiation results in increasing sensitivity to its biological influence; moreover, UV-A produces the VDT-associated ill-effects by catabolizing vitamin A in skin and plasma into highly active metabolites, the gradual accumulation of which results in an endogenous form of vitamin A intoxication. In addition to producing the skin and systemic effects o f hypervitaminosis A, these metabolites may also cross the placenta and cause pregnancy abnormalities, just as does ingestion of excessive amounts o f vitamin A. It should be noted that several of the ill-effects attributed to the occupational use of VDTs, e.g. musculoskeletal symptoms and pregnancy abnormalities, have no known connection with UV-A. Furthermore, the mechanism of UV-A damage is uncertain even for effects which are known to be associated with UV-A, e.g. sunburn erythema. Thus, the hypothesis proposed herein assumes that UV-A has effects that have not been described hitherto; it also suggests a novel explanation of biological phenomena that have been linked to exposure to ultraviolet light. t The UV portion of the electromagneticspectrum is commonlysubdivided into three groups of wavelengths, measured in nanometers (nm). They are, in order of decreasing wavelength, UV-A (320-400 nm), UV-B (290-320 nm), and UV-C (200-290 nm)(Parrish et al., 1978,Ch. 1).
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VDTs and Ultraviolet Radiation (UVR) Almost all existing VDTs employ a picture tube (cathode ray tube) that operates by electron beams that strike a phosphor-coated screen at a high rate of acceleration. The kinetic energy so produced is converted mostly into visible light. Some phosphors also emit small amounts o f radiation in the near ultraviolet spectrum (Weiss, 1983). For instance, the U.S. Bureau of Radiological Health (1981) evaluated a cross-section o f representative VDT models of all known VDT manufacturers, 51 models in all. About half were found to emit some radiation in the near-UVR range (320-400 nm) at the user distance. The maximum near-UV irradiance at a user distance of 40 to 50 cm from the screen was estimated at about 5 x 10 -6 W/cm2; that is, about 200 times less than the U.S. maximum standard or recommended level of 1.0 × 10 -3 W / c m 2 (NIOSH, 1972). The U.S. Bureau of Radiological Health admits that some o f the VDTs examined emitted near-UVR and that delayed injury cataracts can result from UVR over-exposure; however, "no effects on eyes or skin have been observed at optical radiation levels comparable to those measured from VDTs" (U.S. Bureau of Radiological Health, 1981, p. 23). A radiation survey was also carried out by N I O S H (Murray et aL, 1981) on some 136 terminals among 530 in use at three different sites (i.e. slightly over 25%). Measurements were made at contact with the VDT screen face. Emissions in the near-UV ranged from not detectable to 6 . 5 × 1 0 - T W / c m 2, i.e. 1500 times less than the N I O S H standard. Although UV-A emissions from VDTs are considerably less than existing U.S. safety limits permit, there are several reasons for suggesting that even these low emissions could have adverse biological effects as a result of chronic exposure. 1. UVR in the 320-400 nm range produces many of the same sorts of ill-effects as are associated with VDTs, which also emit UV-A. The ill-effects of UV-A include erythema, skin rashes, eye pains, decreased visual acuity, and cataracts (Parrish et aL, 1978). Similarities between the effects o f UV-A exposure, particularly on the eye, and those associated with VDTs, have been explicitly noted (Zaret, 1980; ACTU-VTHC, 1982). According to Zaret (1984, p. 58) lenticular cataracts that have every sign of being radiation energy cataracts (that is involving capsular opacification at the posterior surface of the l e n s - - o r the refringement end of the lens when viewed by slit-lamp biomicroscopy) have been observed in dentists and dental technicians exposed to levels of UVR 1000 times lower than the US safety standard.
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UV-B and UV-C radiation are absorbed by the cornea and conjunctiva, but most UV-A enters the pupil and is absorbed by the crystalline lens. Hence, the lens may be particularly prone to biological ill-effects, including cataract formation, due to UV-A radiation (Parrish et aL, 1978, pp. 79-80). The harmful effects of UV-A may also be amplified by certain foods and drugs. One suggestion is that UV exposure and the consumption of yoghurt may have synergistic effects, producing an increased risk of cataract formation (Sliney, 1980). 2. Two reports from Norway sought to disprove UVR as the cause o f facial rash in VDT operators. In one study (Nilsen, 1982), it was stated anecdotally that some o f the V D T operators at the National Telephone C o m p a n y in Bergen, suspecting radiation, mounted window glass in front of the screens. This, however, had no effect on the rash (6/94 operators were affected). In the other report (Linden & Rolfsen, 1981), 1 0 V D T operators were described as having facial dermatitis and intense pricking sensations on the face and other uncovered parts of the body. The sensation began after a 1-8 h exposure and was usually followed by erythema and by "small circumscribed areas of superficial solid elevation" (p. 62) at the same sites. The rash usually disappeared during the weekend, although a few individuals had to be absent for 1-2 weeks before s y m p t o m s disappeared completely. Most had experienced the s y m p t o m s for years, often after c o m m e n c i n g work with VDTs. The authors visited m a n y offices and used provocation tests to establish an association between VDTs and the rash. In two sensitive individuals the rash developed in 6 and 8 h, respectively. During the testing, in order to exclude UVR, "the terminal was placed TABLE 1
Health survey of visual display terminal operators in Australiat Percentage of operators reporting symptoms
Symptom Headache and eye pain Fatigue, overall tiredness, dizziness Muscle pain
Part-time or shift up to 12 months contact with VDTs
All operators over 2 years contact
% increase
8
76
+68
5 !1
41 32
+36 +21
t Source: adapted from ACTU-VTHC (1982, p. 13). No information was provided on the numbers of operators contacted nor on the methodology of the survey.
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behind an ordinary sheet of window glass. This procedure did not prevent the skin reaction in question. On the contrary, in some cases it seemed to encourage it". (p. 62). While the authors themselves believed that static electricity was responsible for the rashes, UVR cannot be considered ruled out by their procedure since UV-A is transmitted by most window glass (Parrish et al., 1978, pp. 6, 151), but in reduced amounts, as well as by many plastics that do not transmit UV-B (ibid., p. 6). 3. Phototoxic damage by UV-A is cumulative; that is, sensitivity increases with duration of exposure. For instance, repeated exposure to subliminal doses of UVR results in a lowering of the erythema threshold dose. In one study (Kaidbey & Kligman, 1981), the threshold dose for delayed erythema for UV-C and UV-A solar-simulated radiation was determined by administering exposures in 25% increments to 42 healthy male and female Caucasian volunteers aged t 8-28 years. The smallest dose required to produce erythema 24 h later was defined as the minimum erythema dose (MED). Repeated exposures to subliminal doses at 24 h intervals resulted in a lowering of the erythema threshold dose, providing evidence of the cumulative nature of acute UVR damage in human skin. Repeated exposures of 0.25 MED of UV-A (but neither UV-B nor UV-C) produced erythema in about 30% of the individuals after exposure (cumulative dose, 1-25 MEDs). The frequency of erythema plotted against the total cumulative dose for each waveband showed the response to be clearly dose-related in an almost linear fashion. Since UV-A damage is not as efficiently repaired as that produced by other wavelengths, longer time-periods may be needed to repair damage from single subthreshold exposures to UV-A. 4. Another argument supporting the possibility of UVR involvement in the VDT ill-effects is that just as the effects of UV-A are cumulative, so too are the phenomena associated with VDTs. Thus, in the survey of VDT operators in Australia, the Australian Council of Trade Unions (ACTUVTHC, 1982) found a very large increase in the proportion of operators who experienced symptoms and clusters of symptoms after more than two years of working with VDTs (Table 1). 5. Existing U.S. safety standards for UVR are of dubious validity. The American Conference of Government and Industrial Hygienists (ACGIH) and NIOSH safety standard for UV irradiance is 1-0 mW/cm 2 for UV-A for periods greater than 1000 seconds, a standard based on threshold doses to monochromatic radiation for skin erythema. If, however, prolonged daily exposures are anticipated, cumulative effects should be taken into consideration in order to limit possible deleterious effects. Based on the ACGIH and NIOSH standard, the total accumulated dose for a 7-h work day would
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be about 25 J / c m 2 for UV-A. Such a daily exposure is about l M E D and could therefore result in cumulative effects.t Based on their finding that repeated doses of 0.25 M E D produced erythema in about 30% of the subjects, Kaidbey & Kligman (1981) r e c o m m e n d that daily exposure to UV-A should be reduced to about 15% of the M E D , or about 4 J / c m 2 per day, a dose level which would fail to produce cumulative erythema. Given the m a x i m u m UV-A emission of 5 x l 0 -6 W / c m 2 from VDTs observed by the U.S. Bureau of Radiological Health (1981), the cumulative dose of UV-A after 8 h would be 0.144J/cm2; after five 8-h days it would be 0-72 J / c m 2, and after 20 8-h days it would be 2-88 J / c m 2. Kaidbey & Kligman (1981) add, however, that more studies o f cumulative injury are necessary before safety limits can be firmly established; moreover, the dosages needed to produce cumulative d a m a g e to epidermal cells, D N A , cell m e m b r a n e s , and enzymes are most probably lower than those needed to produce erythema. Thus, although the UV-A emissions from V D T terminals are very low even in comparison to Kaidbey & Kligman's p r o p o s e d safety standard, it is not inconceivable that chronic daily exposure to such emissions could result in increasing sensitivity to UV-A radiation and increasingly severe biologic damage.
Other Possible Effects of VDT-induced UVR In addition to its postulated role in cataract formation, VDT-induced UV-A is also hypothesized to produce several other ill-effects that have been reported by V D T operators: namely, musculoskeletal symptoms, skin rashes, and abnormal pregnancies. UV-A is known to produce erythema but it does so less efficiently than UV-B, and the mechanism of action remains uncertain (Epstein, 1983).$ UV-A has also been implicated in various skin disorders (Parrish et al., 1978, pp. 141-153). There is no evidence, as far as I am aware, that UV-A produces musculoskeletal symptoms or pregnancy abnormalities. However, UV-A is known to induce cutaneous lupus erythematosus and to exacerbate systematic lupus erythematosus (SLE) (Tuffanelli, 1981); SLE is also associated both with musculoskeletal s y m p t o m s and an increased risk of teratogenesis and fetal t Parrish et al. (1978) have similarly pointed out that "'for a source emitting UV-Airradiance, the maximum allowed exposure would be ( 1.0 mW/cm2) x (8 h) x (3600 sec/h), or 28.8 J/cm 2. This UV-A exposure dose may be sufficient to cause delayed erythema in some fair skinned individuals .... In any case, the UV-A exposure standard was recommended by NIOSH in the absence of adequate biologic data and therefore reflects some uncertainty". (p. 245). :l:This could explain why facial erythema is one of the less common symptoms reported by VDT operators.
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wastage (Smolen & Steinberg, 1981). Here it is suggested that UV-A causes musculoskeletal symptoms and pregnancy abnormalities by breaking down vitamin A into metabolites that are more biologically active, and hence more toxic, than the vitamin itself, thereby inducing an endogenous form of hypervitaminosis A. Could UV-A Induce An Endogenous Vitamin A Toxicity Reaction? Vitamin A (retinoi) fulfils a number of physiological functions, including the stimulation of growth and skeletal development, reproduction, the maintenance of rod vision, and the differentiation of mucus-secreting epithelial tissue (Weber, 1983). Its role in the vision cycle is especially wellknown (Wald, 1968). Retinol is first metabolized to all-trans-retinal and then isomerized to 11-cis-retinal; the latter in turn interacts with the protein opsin to form rhodopsin, the visual pigment of the rods and cones. In response to light energy, retinol is released from the rhodopsin molecule as the all-trans-isomer, and the cycle repeats itself. The suggestion here is that functional and dysfunctional interactions of UVR and vitamin A also occur in skin and in other tissues. The vitamin is extremely sensitive to photooxidation, the absorption maxima of most retinoids (natural and synthetic forms of vitamin A) ranging from 280 to over 400 nm (DeLuca, Zile & Neville, 1969). Thirty-five to 50% of incident UV-A radiation is transmitted through Caucasian epidermis (Everett et al., 1966) and absorbed directly by blood in the capillaries of the papillary dermis. UV-A radiation probably produces histologic changes in skin at greater depths than the shorter UV-B (290-320 nm) or UV-C (200-290 nm) wavelengths (Parrish et al., 1978, p. 68). One early study (Findley & van der Merwe, 1965) showed that UVR had a biphasic effect on human blood vitamin A levels; first, an increase which peaked at 7 h following irradiation, and then a fall 24-48 h later. Epidermal assays of the vitamin carried out on one subject before and after the induction of a second degree erythema reaction indicated a "slight lowering" of vitamin A in the irradiated patch compared to the control patch. Instead of being destroyed completely by UVR, however, vitamin A is metabolized to several highly active derivatives. Vitamin A circulates and is delivered to the target tissues as retinol bound to a retinol-binding protein. Retinol is oxidized to retinoic acid (RA); all-trans-RA is then isomerized to 13-cis-RA (Sundaresan & Bath, 1982). Both of these metabolites are highly active, judging by in vitro studies of the response of keratinizing tracheas of vitamin A-deficient hamsters to the compounds. Reversal of keratinization at a low concentration indicates vitamin A-like activity in a
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target tissue (Newton, Henderson & Sporn, 1980). Further metabolic steps include 5,6-epoxidation and 4-hydroxylation of the cyclohexene ring of RA, and glucuronidation of RA and the ring-oxides of RA, all giving rise to what appear to be elimination metabolites, since their capacity for biologic activity is low. Oxidation probably takes place in the target organs (Nutr. Rev., 1983). Recent studies have also shown that all-trans-RA and the 5,6-epoxy derivative are present in substantial amounts as normal oxidative metabolites of retinyl palmitate or retinol in rats on a normal diet (McCormick & Napoli, 1982). The technique of high pressure liquid chromatography has led to the identification in human skin of two main forms of vitamin A: (all-trans)retinol (A~) and 3-dehydroretinol (A2) (Vahlquist, 1982). Two-thirds of the retinol forms esters with fatty acids (Vahlquist, 1982). Dermal retinol may be derived in part from the adjacent subcutis, which contains 10-20 times more of the vitamin than both skin and blood (Vahlquist, 1982). 3-dehydroretinol, an endogenous retinoid, occurs mainly in the epidermis and may be an epidermal metabolite of retinol (Vahlquist et al., 1982). Small amounts of retinoic acid, the major metabolite of retinol, are found in human skin, and appear to represent a mixture of 13-cis/transisomers of retinoic acid (Vahlquist, 1982). The hypothesis that UV-A radiation photooxidizes vitamin A to various toxic metabolites which are in thrn responsible for sunburn erythema, musculoskeletal symptoms, and pregnancy abnormalities, has not yet been investigated. In a recent study, two patients with dermatologic disorders were treated daily with 25 mg and 50 mg etretinate (Ro10-9359), the ethyl ester of an aromatic analog of retinoic acid (Rollman & Vahlquist, 1983). Epidermal retinoids were analyzed before and after whole-body UVR (380320 nm: 1.9 mW/cm2; 320-300 nm: 2.6 mW/cm2). Retinol concentrations were reduced 60-70% by the irradiation. By contrast, the etretinate concentrations before (94 and 274 ng/g wet weight) and after irradiation (86 and 365 ng/g) were described as "similar" (Rollman & Vahlquist, 1983, p. 445). However, inspection of the actual numbers indicates that after 10 minutes of UVR the epidermal concentration of etretinate in the patient on 50 mg etretinate had increased by approximately one-third. I predict that with more prolonged exposure to UVR the epidermal concentration of etretinate and its metabolites would increase further. Three additional aspects of the metabolism of vitamin A in the skin are pertinent to the toxicity hypothesis: their strength, their tendency to accumulate, and their prolonged duration in skin. Strength. Retinoic acid is the most biologically-active metabolite of retinoi (DeLuca, 1979); however, smaller quantities of several highly potent polar
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metabolites of retinoic acid have been identified in peripheral tissues, including 13-cis-retinoic acid (isotretinoin) (DeLuca, 1979). A l l - t r a n s - R A is an order of magnitude more active than retinol in terms of its ability to stimulate growth and the differentiation of epidermal tissue (DeLuca, 1979). Retinoic acid also induces hypervitaminosis A much more effectively than retinol (Pitt, 1983). The major metabolite of etretinate in plasma, Ro 10- ! 670, a free carboxylic acid, is also more active than etretinate itself at the target level (Aoyagi et al., 1981). This metabolite binds to cellular retinoic acid binding protein and several of its functions are similar to those of retinoic acid (Jetten, 1981). Accumulation. During prolonged treatment, etretinate accumulates in the body and its plasma half-life increases to at least 100 days (Paravicini, 1981). Drug concentrations in the subcutis are 10-30 times higher in the first month of therapy than in the dermis or epidermis (Rollman & Vahlquist, 1983). Duration. Following withdrawal of etretinate there is a rapid clearance of the drug from epidermis, a less rapid clearance from dermis, but virtually none from the subcutis for the first 7 weeks (Rollman & Vahlquist, 1983). In one patient the drug was detected in the subcutis 18 months after discontinuation (Rollman & Vahlquist, 1983). There is also an older literature indicating that vitamin A clearance from the body can take months or years (Neiman & Obbink, 1954). In line with our hypothesis, one may wonder if the slow clearance and tendency of vitamin A to accumulate in the tissues is related to the decrease in the minimal erythema dose following successive exposures to UVR. A further point linking UVR radiation and toxic vitamin A metabolites is the striking similarity between the effects of UVR and of hypervitaminosis A on the skin. UV-B in particular and UV-A to a considerably lesser extent is known to produce the "sunburn" reaction which comprises erythema, itching, and desquamation of the skin (Sams, 1974; Gilchrest et al., 1981). It is of interest that vitamin A intoxication likewise causes erythema, itching, and skin peeling (Windhorst & Nigra, 1982; Olson, 1983). The pathogenesis of the UV-induced delayed sunburn reaction is poorly understood (Sams, 1974; Parrish et al., 1978; Gilchrest et al., 1981; Epstein, 1983). None of the endogenous substances suggested so far, including histamine and prostaglandins and their metabolites, satisfactorily explain the erythema reaction to UVR. The possible involvement of vitamin A in UVR-induced erythema is further suggested by the response of both erythema and vitamin A to antioxidants. It was reported that a diet supplemented with the antioxidants ascorbic acid, butylated hydroxytoluene (BHT), vitamin E, and glutathione,
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produced a marked protective effect against UVR-mediated erythema in hairless mice. BHT was most effective; the others afforded negligible protection (DeRios et al., 1978). BHT and several other antioxidants were likewise reported as being potent inhibitors of retinyl palmitate hydrolase (Napoli et al., 1984). Total vitamin A (retinol and retinyl esters), liver stores of vitamin A and plasma retinol are reduced during alpha-tocopherol deficiency (vitamin E, another antioxidant) and increased during alphatocopherol supplementation (Yang & Desai, 1977). The catabolism of vitamin A into its metabolites is likewise prevented by antioxidants (e.g. Roberts, Lamb & Sporn,1980). According to the present hypothesis, antioxidants inhibit the erythema reaction by preventing the oxidation of vitamin A to its more active polar metabolites. The above arguments are pertinent to the suggestion that UV-A causes a vitamin A toxicity reaction. But what evidence is there to connect such reactions with VDTs? There is, as far as I know, no direct evidence as yet. The possibility of such a connection, however, is suggested by the close similarity between the various complaints of VDT operators, on the one hand, and the symptoms of hypervitaminosis A, on the other. Both sets of reactions are summarized in Table 2. Let us consider the various signs and symptoms in groups: (i) Skin. Just as erythema and skin rashes, itching and dry mucous membranes are reported by VDT operators, so these same symptoms are prominent in hypervitaminosis A. (ii) Musculoskeletal. Muscle, joint, and tendon pains are common among VDT operators. Likewise, arthralgias, bone tenderness and restricted movement are symptoms of vitamin A toxicity. Vitamin A palmitate administered intra-articularly into the knees of rabbits also causes regressive and proliferative changes in the articular cartilage which closely resemble the lesions of human arthrosis (Boni et al., 1977). (iii) Visual. Dry, burning eyes, blurred or double vision, and cataracts have been reported among the complaints of VDT operators. Similar effects, including corneal opacities, are associated with the therapeutic use of isotretinoin for severe acne (FDA Drug Bull., 1983). (iv) Central Nervous System. The complaints of VDT operators include anxiety, tension, irritability, depression, insomnia, extreme fatigue, severe headaches, dizziness, and nausea. The effects of hypervitaminosis A similarly include hyperirritability, sleep disturbance, fatigue, headache, anorexia, dizziness, and nausea. (v) Menstruation. Menstrual problems are reported by VDT operators. Increased menstrual bleeding is also seen in hypervitaminosis A.
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TABLE 2
VDT-associated ill-effects and the symptoms of hypervitaminosis A compared t VDT-associated effects Eye irritation Dry eyes Blurred or double vision Impaired accomodation Deteriorating eyesight Cataracts Extreme fatigue Dizziness Headache Nausea Stomach pains Muscle pain Tendon/joint symptoms Tension, anxiety Menstrual problems Diffuse itching Erythema Facial dermatitis Pregnancy abnormalities, esp. miscarriages
Findings in hypervitaminosis A Conjunctivitis Dry eyes Double vision ? ? Corneal opacities Fatigue Dizziness Headache Nausea, vomiting Abdominal pain Myalgia Arthralgias, bone pain Depression, hyperirritability Increased menstrual bleeding Itching Erythema Facial dermatitis Pregnancy abnormalities, esp. miscarriages
Other clinical findings in hypervitaminosis A Alopecia Hemorrhages Dry mucous membranes Edema, painful feet Skin desquamation Hepatomegaly Psychosis Splenomegaly Thirst Hyperostosis Papilledema Hypercalcemia Anorexia Hyperlipemia Weight loss t Sources: VDTs: Slesin & Zybko (1983); APTU (1983); Deiman (1983); Frank (1984): Hunting et aL, (1980); CLESC (1982); The VDT Coalition (1984); VDT News (1984); Bennett et aL, ( t 984); 9-to-5 (1983). Hyperoitaminosis A: Windhorst & Nigra (1982); Olson (1983); FDA Drug Bull. (1983); Stern et al. (1983); Benke (1984).
(vi) Abnormal Pregnancy. E l e v e n c o n f i r m e d a n d 12 u n c o n f i r m e d " c l u s t e r s " o f s p o n t a n e o u s a b o r t i o n s , b i r t h defects, a n d o t h e r signs o f a b n o r m a l p r e g n a n c y , i n c l u d i n g p r e n a t a l d e l i v e r y a n d stillbirths h a v e b e e n r e p o r t e d a m o n g V D T o p e r a t o r s . B e t w e e n 53% a n d 87% o f p r e g n a n c i e s a m o n g the different g r o u p s o f w o m e n w e r e a b n o r m a l (940-5, 1983), figures that are very m u c h h i g h e r t h a n the c o r r e s p o n d i n g rate in the g e n e r a l
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population (Hemminki et al., 1983). Teratogenesis is also a well-known effect of vitamin A toxicity, both in animals and humans (Olson, 1983). Recent reports indicate that isotretinoin (13-cis-RA), taken orally for severe acne, is strongly associated with spontaneous abortions and congenital malformations (Stern, Rosa & Baum, 1983; FDA Drug Bull., 1983; Benke, 1984). Comparison of VDT-associated pregnancy abnormalities and vitamin A-related abnormalities suggest, first, that fetotoxicity rather than malformation of a live infant is the most frequent type of adverse outcome in both sorts of exposures, given the large percentage of spontaneous abortions. Secondly, there is some overlap in the types of observed birth defects. Of nine severe birth defects among the offspring of VDT operators, one had a "foot deformity", another a club foot, one needed eye surgery, another had an underdeveloped eye, one had an undisclosed heart defect, three had neonatal respiratory disease, and one had a cleft palate (Beauchamp, 1983). All such defects have been reported in infants born to women exposed to isotretinoin during the first trimester (Stern et al., 1983; Benke, 1984). Conclusion
They purpose of this article has not been to suggest that psychological factors, mechanical a n d / o r work-station design aspects of VDT work have no bearing on the ill-effects reported by operators. More research is clearly indicated in these areas, although it is difficult to account for all of the reported ill-effects, especially the pregnancy abnormalities, in terms of such factors. Instead, the aim has been to suggest that the majority of ill-effects can be explained in terms of chronic exposure to low levels of nearultraviolet (or UV-A) radiation. Most VDTs emit UV-A radiation in amounts ranging from 200 to 1500 times less than the currently-accepted NIOSH safety standard. The suggestion is that prolonged exposure to even these low amounts induces an increasing sensitivity to UV-A, eventually resulting in biological damage. It is further speculated that UV-A exposure produces the various ill-effects by catabolizing vitamin A in skin and plasma into highly active polar metabolites, the acculation of which results in an endogenous form of hypervitaminosis A. These metabolites presumably enter the fetal circulation, leading to pregnancy abnormalities similar to those associated with excessive use of the vitamin for the treatment of skin disorders. While the theory is speculative, it provides a parsimonious explanation of VDT-associated disease and suggests hypotheses which can be tested by
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further research. Retrospective and prospective studies could be undertaken in humans, correlating plasma and tissue levels of vitamin A metabolites, duration of exposure to VDTs, and disease symptomatology, including miscarriages and birth defects; laboratory and clinical studies could also be undertaken to detect other evidence of hypervitaminosis A such a hyperlipemia and hel6atomegaly. One group of small mammals could be exposed to fully-lit VDT screens and allowed to breed, while other groups would be assembled to control for potential confounding factors. Serial measurements of vitamin A metabolites and evidence of teratogenesis could then be obtained for both the experimental and control groups. If, as a result of such studies, the UV-A radiation emitted from VDTs is found to have the adverse effects reported by VDT operators, the implication in terms of prevention would be to install special screens on VDTs that selectively block emissions in the UV-A range.
Summary The occupational use of visual display terminals (VDTs) appears to be associated with numerous unexplained ill-effects, ranging from psychological complaints such as headache and fatigue, to musculoskeletal pains, eye disorders, facial dermatitis, and pregnancy abnormalities. The hypothesis is proposed that many if not most of these symptoms result from long-term exposure to low levels of near-ultraviolet (UV-A) radiation, and that UV-A achieves these effects by catabolizing vitamin A in skin and plasma into toxic metabolites which accumulate in the tissues and produce an endogenous form of hypervitaminosis A. This hypothesis is based on the following points: (I) Most VDTs emit UV-A radiation in amounts ranging from 200 to 1500 times less than the existing U.S. safety standard of 1-0 × 10-3 W/cm 2. (2) The effects of UV-A overlap with those associated with VDTs (exceptions are musculoskeletal complaints and pregnancy abnormalities, which are not known to be associated with UV-A). (3) Sensitivity to UV-A increases with duration of exposure and UV-A phototoxic damage is not as efficiently repaired as that produced by other UV wavelengths. (4) Just as the effects of UV-A are cumulative, so too are the ill-effects associated with VDTs. (5) The U.S. safety standard is based on threshold doses to monochromatic radiation for skin erythema. It does not take cumulative effects into account; moreover, the doses of UV-A needed to produce cumulative
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damage to epidermal cells, DNA, cell membranes, and enzymes, are probably lower than those needed to produce erythema. (6) Vitamin A is extremely sensitive to photooxidation, the absorption maxima of most retinoids (vitamin A and its synthetic derivates) ranging from 280 to over 400 nm. (7) From 35% to over 50% of UV-A is transmitted through Caucasian epidermis and is directly absorbed by blood in the capillaries; UV-A also penetrates more deeply than the shorter UV wavelengths. (8) Vitamin A and its metabolites are present in the skin. (9) Certain vitamin A metabolites are more biologically active and hence more toxic than the vitamin itself. (10) Vitamin A tends to accumulate during prolonged treatment and clearance from the body may take years. (11) There is a striking similarity between the effects of UV radiation and hypervitaminosis A on the skin (erythema, itching, desquamation). (12) Antioxidants have a marked protective effect against UV radiationmediated erythema and likewise prevent the catabolism of vitamin A into its metabolites. (13) There is a close similarity between the various complaints of VDT operators and the symptoms of hypervitaminosis A. I thank Dr K. W. Jacobs, Dr R. Gregory and Dr Hugh McGrath for their helpful suggestions, Ms Virginia Howard for editorial assistance, and Ms Bronwyn Williams for typing the manuscript.
Note added in proof It should be noted that two recent studies have failed to detect an increased risk of psychophysiological symptoms (Starr, S., 1984 Human Factors 26, 347) or birth defects (Kurppa, K. et aL, 1984--Lancet ii, 1339) among VDT operators compared to well-matched controls.
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