British Journal of Dermatology (1975) 93, 721.
Comment P-CAROTENE AND THE PHOTODERMATOSES Classification of the photodermatoses is unsatisfactory because the aetiology of so many is obscure but Ramsay (1975) has suggested four groups: (i) idiopathic; (ii) drug or chemical induced; (iii) due to metabolic disease; (iv) sunlight precipitated or aggravated. Group (i) includes polymorphic light eruption, solar urticaria, actinic reticuloid and photosensitive eczema; group (iii) erythropoietic protoporphyria (EPP). EPP was first clearly described by Magnus et al. (1961); it is an inborn error of porphyrin metabolism characterized by an excess of red cell and perhaps faecal protoporphyrin but with normal urinary porphyrin excretion. The cardinal symptom is photosensitivity, often beginning in childhood, frequently manifesting as a severe burning sensation after only brief exposure to sunlight. The responsible wavelength is around 400 nm. It has long been known that carotenoid pigments could protect photosynthetic bacteria from lethal photosensitivity (Sistrom, Griffiths & Stanier, 1956) but it was not until 1969 that the carrot pigment, ^-carotene, was shown to be successful in the treatment of three patients with EPP (Mathews-Roth et al., 1970 a, b). Reports of its value in the management of EPP and some other photodermatoses have appeared regularly since then, and last year a small group of physicians met in London under the chairmanship of Dr Ian Sneddon to discuss their results and experiences since ^-carotene became available in the U.K. in 1971. Among the many reports which have appeared (Fitzpatrick et al., 1971; Mathews-Roth et al., 1972; Lewis, 1972; Baart de la Faille et al., 1972; Ippen, 1972; Moynahan & Leppard, 1973; Krook & Haeger-Aronson, 1974; Mathews-Roth et al., 1974) controlled trials have been conspicuously absent. The conventional 'double-blind' technique is impossible because of the unavoidable skin staining which results from the hypercarotenaemia during treatment with ^-carotene. In some individuals carotenoderma is quite striking but the majority find it cosmetically acceptable. Replacing some of the ^-carotene with another synthetic carotenoid pigment, canthaxanthin, modifies the carotenoderma in such a way that the appearance is much more like natural sun-tan. Inevitably, both in EPP and in other photodermatoses the effectiveness of treatment must rest on subjective assessment, together with the physician's judgment, hopefully reinforced by measurement of relatively objective parameters such as the determination of changes in reactivity of the skin to artificial radiation. Nevertheless, because ofthe wide variability in this reactivity not only between subjects but also according to time of day, skin temperature, humidity and so on, assessment of effect by such artificial means is of limited value. Consequently, results of'trials' with jS-carotene must be assessed principally on single case reports rather than on formal trial groups. Donaldson (Stoke-on-Trent) has treated five EPP patients (4 female, i male) with oral doses of j5-carotene (Roche) of between 150-200 mg daily, in divided doses, over a period of 3^ years. Three were improved, one reported no change and one was lost to follow-up. Wide fluctuations in RBC porphyrin were noted whether patients were on treatment or not. However, two ofthe three improved patients were shown to have a io-fold increase in tolerance to Xenon Lamp exposure (400-600 nm) while on jS-carotene. Serum carotene levels ranged from 100-520 /(g/ioo ml; one patient clearly showed a dose-related response. Although Fitzpatrick et al. (1971) have suggested that plasma levels of at least 400 ^g/ioo ml are necessary to achieve any therapeutic effect, Donaldson found improvement in some of his patients to be associated with low serum concentrations. 721
722
Comment
Others at the meeting reported similar or better results in EPP, both in children and adults. In all, some forty-four patients have been treated with ^-carotene in the U.K. in the last 3 or 4 years and forty-two have reported benefit ranging from merely 'improved' to 'transformed life'. Two patients with congenital porphyria (Gunther) are also reported to have benefited but one patient with porphyria cutanea tarda has not responded. The situation in other light sensitive dermatoses is not so clear. Between 40 and 60% of patients with photosensitive eczema, polymorphic light eruptions or solar urticaria appear to respond to a varying extent. In the last 2 years Holti and his colleagues (Newcastle-upon-Tyne) have treated twenty-one patients in the 'idiopathic' group and, in contrast to the experience of Kobza, Ramsay & Magnus (1973), have had encouraging results. Only one of eight and two of nine patients with solar urticaria and light provoked eczema respectively, completely failed to respond. The others showed varying degrees of benefit from this treatment but none was rendered symptom-free. This, however, also applies to patients with erythropoietic protoporphyria. An objective test of therapeutic effectiveness is badly needed. One of Holti's patients with severe solar urticaria, a bell-ringer, volunteered that his change-ringing sessions left him with intact palms while on treatment, whereas previously he could not handle the ropes for more than 15 min without blistering. Could ;6-carotene have an epidermal thickening effect ? To try to answer that question, and at the suggestion of Comaish, suction blister times (Comaish & McVittie, 1973) were measured in the bell-ringer and fifteen other patients before, during and after treatment. Significantly increased times were demonstrated during treatment compared with those before and 6 weeks after treatment. In three patients whose blister times did not alter significantly jS-carotene had conferred no benefit. On the other hand, one patient who claimed a 50% improvement on ^-carotene had no change in blister times. The suction blister test is not easily standardized and results are dependent on other variables such as site, skin temperature, humidity and so on. Consequently it is difficult to know how much reliance can be placed on these results; more data are obviously needed. i?-carotene is, of course, a provitamin A; indeed it is the most important ofthe precursors in the animal world with a theoretical potential for conversion to retinol in gut mucosa in the ratio 1:2. However, man is a very inefficient converter and it is doubtful if more than 10% of dietary ^-carotene is converted to the vitamin in normal circumstances. Plasma retinol levels may rise in only a small number of patients during treatment with ^-carotene but remain within the normal range. Daily intakes of 100 mg ^-carotene would normally raise plasma carotene levels to between 600 and 2000 A(g/ioo ml in 3 months; plasma retinol levels would average about 250 iu/ioo ml ( = 75 ^g/retinol). There is therefore no real risk of inducing hypervitaminosis A in patients during oral ^-carotene treatment although, because of biological variability in conversion rates, it is probably wise to monitor vitamin A levels during treatment (Nieman & Obbink, 1954; Bagdon, Zbinden & Studer, i960; Lewis, 1972). Canthaxanthin, mentioned earlier, is a synthetic carotenoid with no provitamin A activity. On its own in oral doses of the same order as ^-carotene, it produces an unpleasant and unacceptable deep salmon-pink skin colour. With added j8-carotene, however, the effect is modified and resembles natural tanning. A combination of 10 mg )3-carotene and 15 mg canthaxanthin appears to be as effective in EPP as 25 mg of pure j6-carotene but therapeutic trials with the mixture have not been as extensive as with the latter alone. There are many unanswered questions in the jS-carotene story. Individual case reports from U.S.A., U.K. and Europe provide circumstantial evidence that 90% of patients with EPP benefit, so that many dermatologists are sufficiently convinced of its value and see no need for more scientific assessment by controlled clinical trial. In EPP no other treatment has so far been found as effective;
Comment
723
nevertheless, Ramsay and others feel that a controlled study should at least be attempted, although not even a 'single blind' trial is possible. If j3-carotene has an effect in these conditions how is it mediated ? Because it apparently accumulates in skin is it acting simply as a sunscreen ? In fact, monochromator studies in protected patients give no support to that idea; further, there is no evidence that j9-carotene even reaches the epidermis and indeed topical application is singularly unsuccessful. A more elegant hypothesis is based on the fact that ^-carotene is, in vitro, an effective singlet excited oxygen quencher. There is some evidence that photosensitivity in EPP and indeed in other types of porphyria is due to the presence of an excited state of oxygen. There is some experimental in vitro work to support this hypothesis (Davies et al., 1975) but the lack of a suitable animal model hampers further research in this field. A porphyrin-like photosensitivity occurs in sheep in some areas but these animals convert their ingested J?-carotene in toto to vitamin A. Gardiner (ICI, Pharmaceuticals Division, Macclesfield) has carried out a controlled trial of ficarotene in thirteen healthy volunteers rendered photosensitive by contact with an anthraquinonebased dye. Disperse Blue 35 (Gardiner, 1974). Photo-contact dermatitis in this situation is to visible light (500-650 nm) but in other respects the model parallels the postulated system for porphyria. In that trial, however, 175 mg ^-carotene daily was ineffective as judged by patch and photopatch testing in spite of an average io-fold increase in plasma carotene levels. However, it was only given for 3 weeks and this, together with an insufficient range of exposure to light, may not have been sufficient for any demonstrable benefit. The trial was carried out in 1974 in ICI Organics Division. Other in vitro studies have purported to demonstrate an inhibitory effect of ^-carotene on protoporphyrin-induced photohaemolysis which cannot be explained as a pure 'filter effect' (Swanbeck & Wennerstein, 1973) but their results are open to criticism and the work has not so far been repeated. Those dermatologists with patients who have shown a response will continue to treat them with j3-carotene or ^-carotene and canthaxanthin combined simply because these compounds afford relief and make management of otherwise intractable conditions that much easier. The academics are not so happy. As Ramsay pleaded at the meeting ' . . . we must be careful about it (using j3-carotene), otherwise we will be feeding this drug to our patients for many years and, unless we obtain positive evidence of benefit now, we are not going to know in 10 years' time if we have been right or not'. I would like to thank Dr Colin Ramsay for helpful suggestions in the preparation of this article and Drs Donaldson, Gardiner and Holti for allowing me to report their results. Roche Products Ltd., Welwyn Garden City, Herts. AL7 3AY
NORMAN POLLITT
REFERENCES BAART DE LA FAILLE, H . , SUURMOND, D . , WENT, L.N., STEVENINCK, J. VAN & SCHOTHORST, A.A. (1972) y?-carotene
as a treatment for photohypersensitivity due to erythropoietic protoporphyria. Dermatologica, 145, 389. BAGDON, R.E., ZBINDEN, G . & STUDER, A. (i960) Chronic toxicity studies of jS-carotene. Toxicology and Applied Pharmacology, 2, 225.
COMAISH, S. & MCVITTIE, E. (1973) Suction blisters in bullous pemphigoid and other dermatoses. British Journal of Dermatology, 89, 127.
DAVIES, A.K., HAMBLETT, I., MCKELLAR, J.F. & PHILLIPS, G . O . (1975) Mechanism of photocontact dermatitis due
to an anthraquinone disperse dye. Journal of Applied Chemistry and Biotechnology, 25, 195. FiTZPATRiCK, T.B., PATHAK, M.A., PARRISH, J.A. & MATHEWS-ROTH, M.M. (1971) Topical and systemic approaches to photoprotection. Proceedings of the Royal Society of Medicine, 64, 861. GARDINER, J . S . (1974) Personal communication. IPPEN, H. (1972) Beta-carotin als Lichtschutz bei Porphyria cutanea tarda. Hautarzt, 23, 47.
724
Comment
KoBZA, A., RAMSAY, C.A. & MAGNUS, I.A. (1973) Oral j9-carotene therapy in actinic reticuloid and solar urticaria. British Journal of Dermatology, 88, 157. KROOK, G . & HAEGER-ARONSON, B. (1974) Erythropoietic protoporphyria and its treatment with j9-carotene. Acta dermato-venereologica, 54, 39. LEWIS, M.B. (1972) The effect of ^-carotene on serum vitamin A levels in erythropoietic protoporphyria. Australian Journal of Dermatology, 13, 75. MAGNUS, I.A., JARRETT, A., PHANKARD, T . A . J . & RIMINGTON, C . (1961) Erythropoietic protoporphyria: a new
porphyria with solar urticaria due to protoporphyrinaemia. Lancet, ii, 448. MATHEWS-ROTH, M.M., PATHAK, M.A., FITZPATRICK, T.B., HARBER, L.C. & KASS, E . H . (1970a) fl-carotene as a
photoprotective agent in erythropoietic protoporphyria. Nezu England Journal of Medicine, 282, 1231. MATHEWS-ROTH, M.M., PATHAK, M.A., FITZPATRICK, T.B., HARBER, L.C. & KASS, E.H. (1970b) ^-carotene as a
photoprotective agent in erythropoietic protoporphyria. Transactions ofthe Association of American Physicians, 83, 176. MATHEWS-ROTH, M.M., PATHAK, M.A., FITZPATRICK, T.B., HARBER L . C , KASS, E.H., TODA, K . & CLEMENS, W .
(1972) A clinical trial of the effects of oral ;8-carotene on the responses of human skin to solar radiation. Journal of Investigative Dermatology, 59, 349. MATHEWS-ROTH, M.M., PATHAK, M.A., FITZPATRICK, T.B., HARBER, L.C. & KASS, E.H. (1974) ;8-carotene as an
oral photoprotective agent in erythropoietic protoporphyria. Journal of the American Medical Association, 228, 1004. MOYNAHAN, E.J. & LEPPARD, B. (1973) Erythropoietic protoporphyria. Proceedings ofthe Royal Society of Medicine, 66, 51. NiEMAN, C. & OBBINK, H . J . K . (1954) The biochemistry and pathology of hypervitaminosis A. Vitamins and Hormones, 12, 69. RAMSAY, C. (1975) Photosensitivity and the skin. Hospital Medicine, 13, 536. SISTROM, W.R., GRIFFITHS, M . & STANIER, R.Y. (1956) The biology of a photosynthetic bacterium which lacks colored carotenoids. Jowrna/ of Cellular and Comparative Physiology, 48, 473. SwANBECK, G. & WENNERSTEIN, G . (1973) Effect of y?-carotene on photohaemolysis. Acta dermato-venereologica, 53. 283.
Comment P-CAROTENE AND THE PHOTODERMATOSES Classification of the photodermatoses is unsatisfactory because the aetiology of so many is obscure but Ramsay (1975) has suggested four groups: (i) idiopathic; (ii) drug or chemical induced; (iii) due to metabolic disease; (iv) sunlight precipitated or aggravated. Group (i) includes polymorphic light eruption, solar urticaria, actinic reticuloid and photosensitive eczema; group (iii) erythropoietic protoporphyria (EPP). EPP was first clearly described by Magnus et al. (1961); it is an inborn error of porphyrin metabolism characterized by an excess of red cell and perhaps faecal protoporphyrin but with normal urinary porphyrin excretion. The cardinal symptom is photosensitivity, often beginning in childhood, frequently manifesting as a severe burning sensation after only brief exposure to sunlight. The responsible wavelength is around 400 nm. It has long been known that carotenoid pigments could protect photosynthetic bacteria from lethal photosensitivity (Sistrom, Griffiths & Stanier, 1956) but it was not until 1969 that the carrot pigment, ^-carotene, was shown to be successful in the treatment of three patients with EPP (Mathews-Roth et al., 1970 a, b). Reports of its value in the management of EPP and some other photodermatoses have appeared regularly since then, and last year a small group of physicians met in London under the chairmanship of Dr Ian Sneddon to discuss their results and experiences since ^-carotene became available in the U.K. in 1971. Among the many reports which have appeared (Fitzpatrick et al., 1971; Mathews-Roth et al., 1972; Lewis, 1972; Baart de la Faille et al., 1972; Ippen, 1972; Moynahan & Leppard, 1973; Krook & Haeger-Aronson, 1974; Mathews-Roth et al., 1974) controlled trials have been conspicuously absent. The conventional 'double-blind' technique is impossible because of the unavoidable skin staining which results from the hypercarotenaemia during treatment with ^-carotene. In some individuals carotenoderma is quite striking but the majority find it cosmetically acceptable. Replacing some of the ^-carotene with another synthetic carotenoid pigment, canthaxanthin, modifies the carotenoderma in such a way that the appearance is much more like natural sun-tan. Inevitably, both in EPP and in other photodermatoses the effectiveness of treatment must rest on subjective assessment, together with the physician's judgment, hopefully reinforced by measurement of relatively objective parameters such as the determination of changes in reactivity of the skin to artificial radiation. Nevertheless, because ofthe wide variability in this reactivity not only between subjects but also according to time of day, skin temperature, humidity and so on, assessment of effect by such artificial means is of limited value. Consequently, results of'trials' with jS-carotene must be assessed principally on single case reports rather than on formal trial groups. Donaldson (Stoke-on-Trent) has treated five EPP patients (4 female, i male) with oral doses of j5-carotene (Roche) of between 150-200 mg daily, in divided doses, over a period of 3^ years. Three were improved, one reported no change and one was lost to follow-up. Wide fluctuations in RBC porphyrin were noted whether patients were on treatment or not. However, two ofthe three improved patients were shown to have a io-fold increase in tolerance to Xenon Lamp exposure (400-600 nm) while on jS-carotene. Serum carotene levels ranged from 100-520 /(g/ioo ml; one patient clearly showed a dose-related response. Although Fitzpatrick et al. (1971) have suggested that plasma levels of at least 400 ^g/ioo ml are necessary to achieve any therapeutic effect, Donaldson found improvement in some of his patients to be associated with low serum concentrations. 721
722
Comment
Others at the meeting reported similar or better results in EPP, both in children and adults. In all, some forty-four patients have been treated with ^-carotene in the U.K. in the last 3 or 4 years and forty-two have reported benefit ranging from merely 'improved' to 'transformed life'. Two patients with congenital porphyria (Gunther) are also reported to have benefited but one patient with porphyria cutanea tarda has not responded. The situation in other light sensitive dermatoses is not so clear. Between 40 and 60% of patients with photosensitive eczema, polymorphic light eruptions or solar urticaria appear to respond to a varying extent. In the last 2 years Holti and his colleagues (Newcastle-upon-Tyne) have treated twenty-one patients in the 'idiopathic' group and, in contrast to the experience of Kobza, Ramsay & Magnus (1973), have had encouraging results. Only one of eight and two of nine patients with solar urticaria and light provoked eczema respectively, completely failed to respond. The others showed varying degrees of benefit from this treatment but none was rendered symptom-free. This, however, also applies to patients with erythropoietic protoporphyria. An objective test of therapeutic effectiveness is badly needed. One of Holti's patients with severe solar urticaria, a bell-ringer, volunteered that his change-ringing sessions left him with intact palms while on treatment, whereas previously he could not handle the ropes for more than 15 min without blistering. Could ;6-carotene have an epidermal thickening effect ? To try to answer that question, and at the suggestion of Comaish, suction blister times (Comaish & McVittie, 1973) were measured in the bell-ringer and fifteen other patients before, during and after treatment. Significantly increased times were demonstrated during treatment compared with those before and 6 weeks after treatment. In three patients whose blister times did not alter significantly jS-carotene had conferred no benefit. On the other hand, one patient who claimed a 50% improvement on ^-carotene had no change in blister times. The suction blister test is not easily standardized and results are dependent on other variables such as site, skin temperature, humidity and so on. Consequently it is difficult to know how much reliance can be placed on these results; more data are obviously needed. i?-carotene is, of course, a provitamin A; indeed it is the most important ofthe precursors in the animal world with a theoretical potential for conversion to retinol in gut mucosa in the ratio 1:2. However, man is a very inefficient converter and it is doubtful if more than 10% of dietary ^-carotene is converted to the vitamin in normal circumstances. Plasma retinol levels may rise in only a small number of patients during treatment with ^-carotene but remain within the normal range. Daily intakes of 100 mg ^-carotene would normally raise plasma carotene levels to between 600 and 2000 A(g/ioo ml in 3 months; plasma retinol levels would average about 250 iu/ioo ml ( = 75 ^g/retinol). There is therefore no real risk of inducing hypervitaminosis A in patients during oral ^-carotene treatment although, because of biological variability in conversion rates, it is probably wise to monitor vitamin A levels during treatment (Nieman & Obbink, 1954; Bagdon, Zbinden & Studer, i960; Lewis, 1972). Canthaxanthin, mentioned earlier, is a synthetic carotenoid with no provitamin A activity. On its own in oral doses of the same order as ^-carotene, it produces an unpleasant and unacceptable deep salmon-pink skin colour. With added j8-carotene, however, the effect is modified and resembles natural tanning. A combination of 10 mg )3-carotene and 15 mg canthaxanthin appears to be as effective in EPP as 25 mg of pure j6-carotene but therapeutic trials with the mixture have not been as extensive as with the latter alone. There are many unanswered questions in the jS-carotene story. Individual case reports from U.S.A., U.K. and Europe provide circumstantial evidence that 90% of patients with EPP benefit, so that many dermatologists are sufficiently convinced of its value and see no need for more scientific assessment by controlled clinical trial. In EPP no other treatment has so far been found as effective;
Comment
723
nevertheless, Ramsay and others feel that a controlled study should at least be attempted, although not even a 'single blind' trial is possible. If j3-carotene has an effect in these conditions how is it mediated ? Because it apparently accumulates in skin is it acting simply as a sunscreen ? In fact, monochromator studies in protected patients give no support to that idea; further, there is no evidence that j9-carotene even reaches the epidermis and indeed topical application is singularly unsuccessful. A more elegant hypothesis is based on the fact that ^-carotene is, in vitro, an effective singlet excited oxygen quencher. There is some evidence that photosensitivity in EPP and indeed in other types of porphyria is due to the presence of an excited state of oxygen. There is some experimental in vitro work to support this hypothesis (Davies et al., 1975) but the lack of a suitable animal model hampers further research in this field. A porphyrin-like photosensitivity occurs in sheep in some areas but these animals convert their ingested J?-carotene in toto to vitamin A. Gardiner (ICI, Pharmaceuticals Division, Macclesfield) has carried out a controlled trial of ficarotene in thirteen healthy volunteers rendered photosensitive by contact with an anthraquinonebased dye. Disperse Blue 35 (Gardiner, 1974). Photo-contact dermatitis in this situation is to visible light (500-650 nm) but in other respects the model parallels the postulated system for porphyria. In that trial, however, 175 mg ^-carotene daily was ineffective as judged by patch and photopatch testing in spite of an average io-fold increase in plasma carotene levels. However, it was only given for 3 weeks and this, together with an insufficient range of exposure to light, may not have been sufficient for any demonstrable benefit. The trial was carried out in 1974 in ICI Organics Division. Other in vitro studies have purported to demonstrate an inhibitory effect of ^-carotene on protoporphyrin-induced photohaemolysis which cannot be explained as a pure 'filter effect' (Swanbeck & Wennerstein, 1973) but their results are open to criticism and the work has not so far been repeated. Those dermatologists with patients who have shown a response will continue to treat them with j3-carotene or ^-carotene and canthaxanthin combined simply because these compounds afford relief and make management of otherwise intractable conditions that much easier. The academics are not so happy. As Ramsay pleaded at the meeting ' . . . we must be careful about it (using j3-carotene), otherwise we will be feeding this drug to our patients for many years and, unless we obtain positive evidence of benefit now, we are not going to know in 10 years' time if we have been right or not'. I would like to thank Dr Colin Ramsay for helpful suggestions in the preparation of this article and Drs Donaldson, Gardiner and Holti for allowing me to report their results. Roche Products Ltd., Welwyn Garden City, Herts. AL7 3AY
NORMAN POLLITT
REFERENCES BAART DE LA FAILLE, H . , SUURMOND, D . , WENT, L.N., STEVENINCK, J. VAN & SCHOTHORST, A.A. (1972) y?-carotene
as a treatment for photohypersensitivity due to erythropoietic protoporphyria. Dermatologica, 145, 389. BAGDON, R.E., ZBINDEN, G . & STUDER, A. (i960) Chronic toxicity studies of jS-carotene. Toxicology and Applied Pharmacology, 2, 225.
COMAISH, S. & MCVITTIE, E. (1973) Suction blisters in bullous pemphigoid and other dermatoses. British Journal of Dermatology, 89, 127.
DAVIES, A.K., HAMBLETT, I., MCKELLAR, J.F. & PHILLIPS, G . O . (1975) Mechanism of photocontact dermatitis due
to an anthraquinone disperse dye. Journal of Applied Chemistry and Biotechnology, 25, 195. FiTZPATRiCK, T.B., PATHAK, M.A., PARRISH, J.A. & MATHEWS-ROTH, M.M. (1971) Topical and systemic approaches to photoprotection. Proceedings of the Royal Society of Medicine, 64, 861. GARDINER, J . S . (1974) Personal communication. IPPEN, H. (1972) Beta-carotin als Lichtschutz bei Porphyria cutanea tarda. Hautarzt, 23, 47.
724
Comment
KoBZA, A., RAMSAY, C.A. & MAGNUS, I.A. (1973) Oral j9-carotene therapy in actinic reticuloid and solar urticaria. British Journal of Dermatology, 88, 157. KROOK, G . & HAEGER-ARONSON, B. (1974) Erythropoietic protoporphyria and its treatment with j9-carotene. Acta dermato-venereologica, 54, 39. LEWIS, M.B. (1972) The effect of ^-carotene on serum vitamin A levels in erythropoietic protoporphyria. Australian Journal of Dermatology, 13, 75. MAGNUS, I.A., JARRETT, A., PHANKARD, T . A . J . & RIMINGTON, C . (1961) Erythropoietic protoporphyria: a new
porphyria with solar urticaria due to protoporphyrinaemia. Lancet, ii, 448. MATHEWS-ROTH, M.M., PATHAK, M.A., FITZPATRICK, T.B., HARBER, L.C. & KASS, E . H . (1970a) fl-carotene as a
photoprotective agent in erythropoietic protoporphyria. Nezu England Journal of Medicine, 282, 1231. MATHEWS-ROTH, M.M., PATHAK, M.A., FITZPATRICK, T.B., HARBER, L.C. & KASS, E.H. (1970b) ^-carotene as a
photoprotective agent in erythropoietic protoporphyria. Transactions ofthe Association of American Physicians, 83, 176. MATHEWS-ROTH, M.M., PATHAK, M.A., FITZPATRICK, T.B., HARBER L . C , KASS, E.H., TODA, K . & CLEMENS, W .
(1972) A clinical trial of the effects of oral ;8-carotene on the responses of human skin to solar radiation. Journal of Investigative Dermatology, 59, 349. MATHEWS-ROTH, M.M., PATHAK, M.A., FITZPATRICK, T.B., HARBER, L.C. & KASS, E.H. (1974) ;8-carotene as an
oral photoprotective agent in erythropoietic protoporphyria. Journal of the American Medical Association, 228, 1004. MOYNAHAN, E.J. & LEPPARD, B. (1973) Erythropoietic protoporphyria. Proceedings ofthe Royal Society of Medicine, 66, 51. NiEMAN, C. & OBBINK, H . J . K . (1954) The biochemistry and pathology of hypervitaminosis A. Vitamins and Hormones, 12, 69. RAMSAY, C. (1975) Photosensitivity and the skin. Hospital Medicine, 13, 536. SISTROM, W.R., GRIFFITHS, M . & STANIER, R.Y. (1956) The biology of a photosynthetic bacterium which lacks colored carotenoids. Jowrna/ of Cellular and Comparative Physiology, 48, 473. SwANBECK, G. & WENNERSTEIN, G . (1973) Effect of y?-carotene on photohaemolysis. Acta dermato-venereologica, 53. 283.
