Chapter 8 Toxic effects Toxic and other adverse effects studies of tens or hundreds of patients spectrum to which the skin is exposed of sunscreens (Thune, 1984; English et al., 1987; (Gasparro et al., 1998). Since UVB is the In order for a sunscreen to have a toxic Lenique et al., 1992; Szczurko et al., primary stimulus for adaptation of the effect on living tissues, it must penetrate 1994; Trevisi et al., 1994; Gonçalo et al., skin to sunlight, less adaptation might be the skin. There is some evidence that 1995; Ang et al., 1998) and reviews expected to develop in individuals who this can occur (see p. 63 et seq.). (Dromgoole & Maibach, 1990; Gonzalez use sunscreens regularly. The adaptive & Gonzalez, 1996; Schauder & Ippen, responses include thickening of the epi- Human studies 1997). In the past, PABA and its esters dermis and transfer of melanin-contain- No published studies of toxic effects in were the most commonly reported ing granules to keratinocytes (tanning) humans were available to the Working contact and photoallergens in sun- (Fig. 44), which reduces the trans- Group. screens (Funk et ai., 1997), and this find- parency of the skin to UVA and UVB ing contributed to a reduction in their use (Fusaro et al., 1966; Olson et al., 1973). Contact sensitivity in sunscreens. The contact or photocon- Several reports showed that UVR- There are numerous reports of cases of tact allergen in sunscreens most induced injury, such as dermal connec- allergic reactions and photoreactivity to frequently cited today is benzophenone- tive tissue damage and sunburn cell for- sunscreens, but the prevalence of this 3, followed by dibenzoyl methanes. mation, can occur in human epidermal problem among sunscreen users is diffi- There have also been a few reports of cells in the absence of erythema and at cult to estimate. Since sunscreens are contact allergy to excipients included in doses that are far below the SPF of the becoming more complex, with multiple the formulations (Jeanmougin et al., sunscreen (Kaidbey, 1990; Kligman, active ingredients, fragances and other 1988; Nishioka et al., 1995; Silvestre et 1997). Furthermore, prevention of sun- compounds, this problem could increase al., 1996). in a longitudinal, population- burn by sunscreens may create a false in the future. Reactions to sunscreens based study to reactions to sunscreens sense of security, while allowing were found to be reasonably common carried out in Australia, of the 603 people prolonged exposure to sunlight. An among patients referred to a clinic tested with a commonly used sunscreen increasing number of studios indicate because of suspected photosensitivity. formulation, 114 developed an adverse that, although UVB is the most damaging Such patients are heavily exposed to reaction (e.g. skin irritation). When they component of sunlight, UVA is responsi- sunscreen products and are thought to were patch tested, however, none was ble for numerous morphological, molecu- become more sensitive to chemicals allergic to the active ingredients. A higher lar and biochemical events which may than others (Green et aI., 1991; Bilsland than expected proportion of the subjects contribute to photodamage of the skin & Ferguson, 1993; Stitt et al., 1996; who developed an adverse reaction had (Kiigman & Gebre, 1991; Scharffetter et Berne & Ros, 1998). a personal history consistent with atopy al., 1991; Wlaschek et al., 1993; Lavker The published reports of adverse (Foley et al., 1993). et al., 1995b; Lavker & Kaidbey, 1997). effects range from case histories in one or several subjects (Schauder & Ippen, Overexposure to UVA Vitamin D depletion 1986; Knobler et al., 1989; Motley & An obvious but not readily recognized Vitamin D is produced when UVB Reynolds, 1989; Murphy et al.. 1990; adverse effect of sunscreens is interfer- absorbed by the epidermis causes Torres & Correia, 1991; Buckley et al., ence with accommodation by the skin to 7-dehydroxycholesterol to form previta- 1993; Collins & Ferguson, 1994; Kimura UVR. Because most sunscreens absorb min D3, which isomerizes spontaneously & Katoh, 1995; Parry et al., 1995; Silva primarily UVB and, in some cases, short- to vitamin D3 before entering the circula- et al., 1995; Marguery etal., 1996; Ricci wavelength IJVAII (315-340 nm), the tion, where it is metabolized by the liver et al., 1997; Zhang et al., 1998) to use of sunscreens changes the UVR into 25-hydroxyvitamin D3 and by the 133 IARC Handbooks of Cancer Prevention, Vo une 5: Sunscreens normal range. Nevertheless, the serum calcium concentration was within the normal range, as was that of parathyroid hormone, which might have been ;ROW doftw. expected to be increased if the vitamin D level was low (Sollitto et al., 1997). - ... .... A randomized double-blind controlled _ ... 491, trial of 113 healthy adults over 40 years q f , of age who used a sunscreen or a placebo cream included analyses of serum vitamin D concentrations over 7 months, including summer (Marks et ai., 1995). The broad-spectrum sunscreen had an 8FF of 17 and contained 8°I ethylhexyl methoxycinnamate and 2% butyl meth oxydibenzoylmethane and was applied to the head and neck, fore- arms and dorsum of each hand at least once a day. The concentrations of 25- ' - ..... hydroxyvitamin D3 rose to a similar Figure 44 Increased melanin deposition Induced by repeated exposure to the sun can be visu- extent in the groups given sunscreen alized throughout the epidermis by Fontana Masson staining and placebo over the summer period, whereas those of 1 ,25-dihydroxyvitamin kidneys into I ,25-dihydroxyvitamin D3. D was measured in groups of four D. increased in the group given the The Latter is the most biologically active healthy subjects 1 h before and 24 h placebo but not in those given the sun- form. Vitamin D can also be supplied by after exposure to 0.8 MED from the screen, although they did not fall below the diet. With parathyroid hormone, it same UVR source (Matsuoka et al., the normal range. This suggests that regulates calcium homeostasis. There 1990). The volunteers received either no although vitamin D synthesis was has been concern that reduction of UVB sunscreen or sunscreen applied to reduced by the sunscreen it was not absorption by the epidermis by sun- increasing areas of the body. Whole- reduced sufficiently to cause deficiency. screen use could suppress vitamin D body protection completely prevented Th!s finding is in agreement with that production, thus affecting calcium the UVR-induced increase in serum vita- of another study (Farrerons et al., 1998) metabolism. min D, and selective protection of in which serum vitamin D, parathyroid In one study, six women and two men increasing skin areas correlated with the hormone and bone biological markers received whole-body exposure to 1 MED serum vitamin D concentration. were assessed in 24 users of a sun- UVR (Westinghouse sunlamps FS72T1 2, Twenty persons with a history of skin screen (SPF 15) and compared with 260-360 nm) with or without protection cancer (mean age, 64.6) who had been those in 19 controls over 2 years. from 5% PABA (SPF 8). The serum con- using PABA-based sunscreens for more Whereas significantly lower levels of vit- centration of vitamin D in unprotected than 1 year had a significantly lower amin D were observed in the sunscreen subjects increased from 1.5 ± 1.0 to 26 ± serum vitamin D concentration (40 ± 3.2 users, there were no changes in parathy- 6.7 ng/ml 24 h after exposure to UVR. In nmol/L) than 20 healthy controls roid hormone or bone biological markers. the sunscreen-protected volunteers, matched for age and exposure to sun- serum vitamin D was unaltered by expo- light (91 ± 6.2) (Matsuoka et al., 1988). Experimental studies sure, with values of 5.6 ± 3.0 and 4.4 ± In a study of eight patients with xero- Whole animals and cells 2.4 ng/ml before and 24 h after expo- derme pigmentosum who took extreme All UVR filters used in over-the-counter sure, respectively. PABA also completely measures to protect themselves from sunscreen products are subjected to inhibited previtamin D3 production from light, including minimizing the time spent extensive testing for toxicity and safety, 7-dehydroxycholesterol in triplicate sam- in sunlight, protective clothing and con- and the results are evaluated by regula- ples of human skin exposed to UVR in stant sunscreen use, the serum vitamin tory bodies, including the Scientific vitro (Matsuoka et aI., 1987). D concentration monitored over 6 years Committee on Cosmetics and Non-food In a subsequent study, serum vitamin was found to be at the lower end of the Products for the Commission of the 134 Toxic effects European Union (Loprieno, 1992) and bate dermal damage caused by chronic growth and DNA synthesis, retarding cell the Food and Drug Administration n the exposure to long-wavelength UVA (> 340 cycle progression from G when added USA (Food & Drug Administration, nm) (Kligman & Zheng, 1994). to cultured cell lines at doses of 50-100 1999). Only compounds proven to be lsoamyl-para-methoxycinnamate admini- pg/mi. As these doses could be achieved safe and without significant toxicological stered to pregnant Wistar rats on days in vivo in sunscreen-treated skin, these effects receive approval for use in sun- 6-15 of gestation caused the death of effects may be of biological relevance screens. This information is supplied to 10% of the animals due to gastrointestinal (Xu & Parsons, 1999). PABA at a dose of the regulatory bodies by manufacturers erosion and haemorrhage when given at a 328 pmol/L was reported to inhibit but is not publicly available and could dose of 2.25 but not 0.75 or 0.25 g/kg bw platelet aggregation in vitro (Barbieri et therefore not be reviewed by the per day by intragastric instillation.