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international journal of andrology ISSN 0105-6263

REVIEW ARTICLE

Developmental toxicity of UV filters and environmental


exposure: a review
Margret Schlumpf,* Stefan Durrer,* Oliver Faass,* Colin Ehnes,* Michaela Fuetsch,* Catherine
Gaille,* Manuel Henseler,* Luke Hofkamp,  Kirsten Maerkel,* Sasha Reolon,* Barry Timms, 
Jesus A. F. Tresguerresà and Walter Lichtensteiger*
*GREEN Tox and Institute of Anatomy, University of Zurich, Zurich, Switzerland,  University of South Dakota, Vermillion, SD, USA, and
àComplutense University, Madrid, Spain

Summary
Keywords: Several ultraviolet (UV) filters exhibit estrogenic, some also anti-androgenic
3-benzylidene camphor, 4-methylbenzylidene activity. They are present in waste water treatment plants, surface waters and
camphor, brain, cosmetics, developmental biosphere including human milk, suggesting potential exposure during devel-
toxicity, estrogenic activity, prostate, sexual
opment. Developmental toxicity was studied in rats for the UV filters 4-meth-
behaviour, uterus, UV filters
ylbenzylidene camphor (4-MBC, 0.7, 7, 24, 47 mg ⁄ kg ⁄ day) and 3-benzylidene
Correspondence: camphor (3-BC, 0.07, 0.24, 0.7, 2.4, 7 mg ⁄ kg ⁄ day) administered in chow to the
Margret Schlumpf, GREEN Tox, parent generation before mating, during pregnancy and lactation, and to the
Winterthurerstrasse 190, CH-8057 Zurich, offspring until adulthood. Neonates exhibited enhanced prostate growth after
Switzerland. 4-MBC and altered uterine gene expression after both chemicals. 4-MBC and
E-mail: margret.schlumpf@access.uzh.ch 3-BC delayed male puberty and affected reproductive organ weights of adult
offspring. Effects on the thyroid axis were also noted. Expression and oestrogen
Received 9 November 2007; revised 26
November 2007; accepted 11 December
sensitivity of oestrogen-regulated genes and nuclear receptor coregulator levels
2007 were altered at mRNA and protein levels in adult uterus, prostate and brain
regions involved in gonadal control and sexual behaviour. Female sexual behav-
doi:10.1111/j.1365-2605.2007.00856.x iour was impaired by both filters; 3-benzylidene camphor caused irregular
cycles. Classical endpoints exhibited lowest observed adverse effect levels (LOA-
ELs) and no observed adverse effect levels (NOAELs) of 7 ⁄ 0.7 mg ⁄ kg for
4-MBC and 0.24 ⁄ 0.07 mg ⁄ kg for 3-BC. Molecular endpoints were affected by
the lowest doses studied. Our data indicate that the potential risk posed by
endocrine active UV filters warrants further investigations.

chain (Balmer et al., 2005; Kupper et al., 2006; Nakata


Ultraviolet filters in environment and biosphere
et al., 2007; Schmid et al., 2007). Recent studies indicate
Ultraviolet (UV) filters are either organic molecules that chemical UV filters are present at high concentra-
(chemical UV filters) absorbing light in the UV range tions in sewage sludge (Kupper et al., 2006). Highest
(UVA 400–320 nm, UVB 320–280 nm) or physical UV levels (January, July) were observed for octocrylene [320–
filters like titanium dioxide and zinc oxide, which mainly 18740 lg ⁄ kg dry material (d.m.)] and octyltriazone (700–
scatter and reflect UV rays. Only substances listed in cos- 27700 lg ⁄ kg d.m.); levels of 4-methylbenzylidene
metics directives are allowed for use. Technical UV filters camphor (4-MBC) and ethylhexyl cinnamate (EHMC,
used in plastics and other products need not be declared, OMC) were 150–4980 lg ⁄ kg d.m. and 10–390 lg ⁄ kg
in spite of considerable structural similarities with autho- d.m., respectively. UV filters are released into surface
rized cosmetic UV filters. waters by waste water treatment plants (WWTPs) and by
With increasing use of UV filters, the possible environ- swimming (Balmer et al., 2005), and accumulate in fish
mental impact of sunscreen ingredients deserves consider- (Nagtegaal et al., 1997; Buser et al., 2006). UV filter levels
ation. There is good evidence that pharmaceuticals and in fish from rivers receiving inputs from WWTPs were
ingredients of personal care products, including chemical considerably higher (4-MBC: 1800 ng ⁄ g) than in fish
UV filters, can spread to the biosphere and reach the food from lakes with inputs from WWTPs (Buser et al., 2006),

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144 Journal compilation ª 2008 Blackwell Publishing Ltd • International Journal of Andrology 31, 144–151
M. Schlumpf et al. Developmental toxicity of UV filters

suggesting increased availability of these contaminants for very low in foetuses of both sexes in rodents (Habert
fish in rivers. & Picon, 1984) and also comparatively low in humans
Humans may be exposed to UV filters directly by use (Siler-Khodr, 1998), thus facilitating competition of
of cosmetics, or indirectly through the food chain. Expo- weak xenoestrogens for ER.
sure of populations is most reliably assessed by measuring
internal exposure levels. In a monitoring study on human
Developmental toxicity of 4-MBC and
milk conducted in collaboration with a Swiss university
3-benzylidene camphor
hospital, we detected chemical UV filters in 75% of the
samples, besides synthetic perfumes, brominated flame The potential relevance of exposure to estrogenic UV fil-
retardants and other pollutants (Schlumpf et al., unpub- ters was investigated in a mammalian model, the rat,
lished data). using 4-MBC and 3-benzylidene camphor (3-BC) (Sch-
lumpf et al., 2004b; Durrer et al., 2005, 2007; Maerkel
et al., 2005, 2007). Both compounds exhibit ER beta pref-
Endocrine activity of UV filters in vitro and
erence (Schlumpf et al., 2004a), but are also active in ER
in vivo
alpha-typical tests, 4-MBC possibly because of a hydroxyl-
Following our report on estrogenic activity of UV filters ated metabolite (Völkel et al., 2006). Male and female rats
used in sunscreens in vitro and in the uterotrophic assay of the parent generation and their offspring were exposed
(Schlumpf et al., 2001a), this finding was confirmed in to 4-MBC (47, 24, 7.0, 0.7 mg ⁄ kg ⁄ day) or 3-BC (7.0, 2.4,
a number of in vitro and in vivo test systems on mam- 0.7, 0.24, 0.07 mg ⁄ kg ⁄ day) administered in chow at least
mals and fish (Holbech et al., 2002; Schreurs et al., 2002; 10 weeks before mating, during pregnancy and lactation,
Tinwell et al., 2002; Inui et al., 2003; Mueller et al., 2003; and until adulthood of the F1 generation. 47 mg ⁄ kg
Jarry et al., 2004; Klammer et al., 2005; Kunz et al., 4-MBC corresponds to 40% of uterotrophic lowest
2006). Certain UV filters also display anti-androgenic observed adverse effect level (LOAEL), 3-BC was dosed
activity in vitro (Ma et al., 2003; Schreurs et al., 2005). according to uterotrophic potency relative to 4-MBC. The
Interactions with the thyroid axis were also observed present report focuses on data from neonatal and young
(Schlumpf et al., 2004b; Schmutzler et al., 2004; Maerkel adult (12-week-old) offspring; 13-month-old offspring
et al., 2007). Chronic studies in ovariectomized rats were also studied.
(Seidlova-Wuttke et al., 2005, 2006) and developmental
toxicity studies (below) demonstrated that different
Early postnatal period, low-dose effects, and
hormone targets are affected by UV filters.
puberty
Both UV filters reduced survival rate at higher doses
Role of oestrogens in early sexual differentiation
(Schlumpf et al., 2001b, 2004b). A decrease in thymus
Ontogenesis is a highly sensitive life stage for estrogenic weight at postnatal day (PN) 14 (day of birth = PN 1)
or anti-androgenic chemicals because sex hormones signals an impairment of the immune system. Recent
exert organizing actions on the developing organism. studies on low-dose effects in the neonate revealed that
Development of the male phenotype depends on testos- oestrogen target gene mRNA levels in early postnatal
terone (T), but is not exclusively mediated by androgen uterus (PN 6), determined by real-time reverse transcrip-
receptors (AR). In some targets such as brain, T is tion polymerase chain reaction (RT PCR) (Durrer et al.,
converted to estradiol (E2) (MacLusky & Naftolin, 2005), are affected at doses as low as 0.07 mg ⁄ kg 3-BC
1981; Lauber & Lichtensteiger, 1994), and the develop- and 0.7 mg ⁄ kg 4-MBC (Table 2). The same doses also
mental action (male sexual brain differentiation) is affected gene expression in PN 6 brain (M. Fuetsch, C.
achieved by E2 acting on oestrogen receptors (ER) Gaille, unpublished data). The changes in mRNAs encod-
(MacLusky & Naftolin, 1981). Recent observations in ing for vascular epithelial growth factor, inducible nitric
aromatase knockout mice indicate that development of oxide synthase and, in part, endothelial cell nitric oxide
the female brain also depends on E2, in contrast to the synthase suggest that angiogenesis and blood flow may be
classical theory (Bakker et al., 2002). Certain peripheral influenced. Effects on the developing prostate were dem-
male tissues such as prostate can convert T to dihyd- onstrated in the PN 1 male. 4-MBC increased number of
rotestosterone acting on AR as well as to E2 acting on ducts in dorsal prostate and duct volume in ventral pros-
ER (George, 1993; Pezzi et al., 2003), providing sites tate (Table 1, Hofkamp et al., 2007, and unpublished
of action for estrogenic as well as anti-androgenic data).
chemicals. With the exception of tissues with local Puberty was delayed in males (preputial separation),
conversion of T to E2, endogenous oestrogen levels are but unaffected in females (Tables 1 and 2, Durrer et al.,

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Journal compilation ª 2008 Blackwell Publishing Ltd • International Journal of Andrology 31, 144–151 145
Developmental toxicity of UV filters M. Schlumpf et al.

Table 1 Effect of 4-methylbenzylidene camphor and 3-benzylidene camphor on selected endpoints in male rat offspring

4-methylbenzylidene camphor 3-benzylidene camphor


(mg ⁄ kg p.o.) (mg ⁄ kg p.o.)

0.7 7 24 47 0.07 0.24 0.7 2.4 7

Puberty (preputial separation) Delayed Delayed Delayed Ø Ø Delayed Delayed


Adult body weight Ø Ø Ø Ø Ø Ø Ø Ø fl
Testis
Postnatal day 14, testis relative weight fl fl fl
Adult F1, testis relative weight Ø Ø Ø › Ø Ø Ø Ø
Prostate
Postnatal day 1, duct number (dorsal) and Ø › Ø Ø
duct volume (ventral)
Adult F1, ventral lobe relative weight- Ø fl fl fl Ø fl Ø Ø Ø
Gene expression, adult F1 prostate, mRNA ⁄ protein
Androgen receptor (AR) dorsolateral prostate (DP) Ø⁄Ø fl⁄Ø fl⁄fl fl ⁄ (fl) ›⁄fl Ø⁄fl Ø⁄) ›⁄)
Androgen receptor (AR) ventral prostate (VP) Ø⁄Ø Ø ⁄ (fl) fl⁄fl Ø⁄) ›⁄› ›⁄Ø ›⁄) Ø⁄)
AR mRNA down-regulation by estradiol in VP fl fl
N-CoR protein, DP fl fl (fl) fl fl
N-CoR protein, VP Ø (fl) fl Ø Ø
Central nervous system, adult F1, mRNA
Gene expression in ventromedial hypothalamic nucleus
Oestrogen receptor-alpha Ø fl fl › › Ø Ø
Progesterone receptor Ø Ø Ø Ø Ø › ›

Ø, no statistically significant change; blank (or) ), not analysed; PN 1, day of birth; Adult F1 offspring, 12 weeks of age, studied under baseline
conditions, females in diestrus. Data from Schlumpf et al., 2001b, 2004b, Durrer et al., 2007; Maerkel et al., 2005, 2007, Hofkamp et al., 2007;
Lichtensteiger et al., 2007; O. Faass, M. Fuetsch, C. Ehnes, C. Gaille, unpublished data.

2007; Schlumpf et al., 2004b). 4-MBC and 3-BC thus male target organs. Interactions of higher 4-MBC doses
mimic the typical effect of E2 only in males, but differ with the thyroid axis were also noted (Maerkel et al.,
from E2 in females, where E2 advances puberty (Biegel 2007).
et al., 1998). Body weight at puberty was slightly Gene expression was affected in ventral and dorsolat-
reduced in females but normal in males, indicating that eral prostate and uterus at mRNA and protein levels in
the delay of male puberty did not result from nutri- a tissue-specific manner (Durrer et al., 2005, 2007). The
tional effects. Adult body weights remained unaffected 4-MBC-induced decrease in prostate weight was accom-
by 4-MBC but slightly reduced by the highest dose of panied by a decrease in AR, ER alpha, and insulin-like
3-BC, possibly as a result of estrogenic activity (Biegel growth factor-I (IGF-I) (Table 1). In 4-MBC-exposed
et al., 1998). uterus, affected target genes include ER alpha and proges-
terone receptor (PR) (Table 2). Effect patterns differed
between the two camphor derivatives also at the molecu-
Reproductive organs of adult offspring: regula-
lar level, in spite of close structural relationship and
tion of target gene expression
similar actions in acute assays.
Exposure to 4-MBC and 3-BC affected reproductive To assess changes in sensitivity to oestrogens, adult off-
organ weights (Tables 1 and 2, Durrer et al., 2005, 2007; spring were gonadectomized and injected with a single
Schlumpf et al., 2004b). Testes of 4-MBC-exposed off- dose of E2 (10 or 50 lg ⁄ kg s.c.). 4-MBC reduced up-reg-
spring showed decreased weight at PN 14 (Schlumpf ulation of PR and IGF-I and down-regulation of ER alpha
et al., 2001b) and increased relative weight at the highest and AR mRNA in uterus 6 h after E2, and down-regula-
dose in adulthood. The adult finding is reminiscent of tion of AR and IGF-I mRNA in ventral prostate (Table 1,
neonatal administration of weak oestrogens (Atanassova Durrer et al., 2005, 2007). Decreased steroid receptor co-
et al., 2000; Putz et al., 2001). In contrast, the decrease in activator-1 (SRC-1) protein levels accompanied the
prostate weight of 4-MBC-exposed offspring resembles reduced up-regulation of oestrogen target genes in uterus,
the effect of perinatal administration of the potent ER while reduced repression of genes in prostate was paral-
agonist diethylstilbestrol (vom Saal et al., 1997; Atanass- leled by reduced nuclear receptor corepressor (N-CoR)
ova et al., 2000). This suggests a differential sensitivity of protein (Durrer et al., 2005, 2007). This identifies nuclear

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146 Journal compilation ª 2008 Blackwell Publishing Ltd • International Journal of Andrology 31, 144–151
M. Schlumpf et al. Developmental toxicity of UV filters

Table 2 Effect of 4-methylbenzylidene camphor and 3-benzylidene camphor on selected endpoints in female rat offspring

4-methylbenzylidene 3-benzylidene camphor


camphor (mg ⁄ kg p.o.) (mg ⁄ kg p.o.)

0.7 7 24 47 0.07 0.24 0.7 2.4 7

Puberty (vaginal opening) Ø Ø Ø Ø Ø Ø Ø


Adult body weight Ø Ø Ø Ø Ø Ø Ø Ø fl
Ovary
Adult F1, ovary relative weight Ø Ø › ›
Uterus
Postnatal day 6, uterus relative weight Ø Ø Ø Ø
Adult F1, uterus relative weight Ø Ø › Ø Ø Ø Ø fl
Postnatal day 6 uterus, gene expression, mRNA
Oestrogen receptor-alpha fl Ø fl fl
ecNOS Ø Ø fl (fl)
iNOS fl fl fl fl
VEGF fl Ø fl fl
Adult F1 uterus, gene expression, mRNA ⁄ protein
Progesterone receptor (PR-A protein) Ø⁄fl Ø⁄Ø fl⁄Ø fl⁄Ø Ø⁄› Ø⁄ Ø Ø⁄ Ø ›⁄Ø
PR mRNA up-regulation by estradiol Ø fl fl
SRC-1 protein fl Ø (fl) fl Ø (fl) fl Ø
Central nervous system, adult F1, mRNA
Gene expression in ventromedial hypothalamic nucleus
Oestrogen receptor-alpha fl fl fl Ø Ø › ›
Progesterone receptor fl fl fl › Ø fl fl
PR mRNA up-regulation by estradiol › Ø
Female sexual behaviour (proceptive and lordosis behaviour) fl fl fl fl
Oestrous cycle Ø Ø Ø irregular irregular irregular irregular

VEGF, vascular epithelial growth factor; iNOS, inducible nitric oxide synthase; ecNOS, endothelial cell nitric oxide synthase; SRC-1, steroid receptor
coactivator-1; Ø, no statistically significant change; blank, not analysed; PN 1, day of birth; Adult F1 offspring, 12 weeks of age, studied under
baseline conditions, females in diestrus. Data from Schlumpf et al., 2001b, 2004b, Durrer et al., 2005; Maerkel et al., 2005, 2007, Lichtensteiger
et al., 2007; O. Faass, M. Fuetsch, C. Ehnes, C. Gaille, unpublished data.

receptor coregulators as targets of endocrine receptors irregular cycles. The two functions thus are differentially
and suggests that they are involved in changes in oestro- affected.
gen sensitivity. Gene expression was analysed by real-time RT PCR in
adult male and female offspring in two brain regions
involved in the control of gonadal function and sexual
Sexually dimorphic gene expression in brain and
behaviour, medial pre-optic region (MPO) and ventrome-
female sexual behaviour
dial hypothalamic nucleus (VMH) (Tables 1 and 2, Maer-
On the basis of data on brain differentiation outlined kel et al., 2005, 2007; Lichtensteiger et al., 2007; Faass
above, we hypothesized that the female brain should be et al., unpublished data). Both compounds caused sex-
particularly sensitive to estrogenic chemicals. Sexual and region-specific changes in ER, nuclear receptor coreg-
behaviour of female offspring exposed to 4-MBC (7 ulator and target gene mRNA levels in MPO and VMH.
and 24 mg ⁄ kg) or 3-BC (2.4 and 7 mg ⁄ kg) was A drop of PR mRNA in female VMH down to male levels
strongly impaired (Table 2, Lichtensteiger et al., 2007; emerged as a common feature observed after all doses of
Faass et al., unpublished data). The treatment affected 4-MBC and after the higher two doses of 3-BC. Reduced
proceptive behaviour (jumping and ear wiggling) PR mRNA in female VMH was correlated with impaired
displayed to attract the male, as well as receptive female sexual behaviour. A similar relationship was
(lordosis) behaviour (decreased lordosis quotient observed with a brominated flame retardant, PBDE 99,
LQ = number of lordosis responses ⁄ number of and with a polychlorinated biphenyl (PCB) mixture
mounts · 100). In 4-MBC-exposed offspring, female (Lichtensteiger et al., 2004). Lordosis behaviour is directly
sexual behaviour was disturbed in the presence of nor- correlated with expression of PR mRNA in female rat
mal oestrous cycles, whereas 3-BC exposure caused VMH (Pollio et al., 1993; Ogawa et al., 1994). Loss of

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Journal compilation ª 2008 Blackwell Publishing Ltd • International Journal of Andrology 31, 144–151 147
Developmental toxicity of UV filters M. Schlumpf et al.

sexual dimorphism of PR in female VMH thus appears to estradiol is required during development in the female for
represent a signal of altered regulation of PR that is the expression of socio-sexual behaviors in adulthood.
linked with behavioural impairment across different Journal of Neuroscience 22, 9104–9112.
endocrine disrupters. Balmer, M. E., Buser, H. R., Müller, M. D. & Poiger, T. (2005)
Occurrence of some organic UV filters in wastewater, in
surface waters and in fish from Swiss lakes. Environmental
Considerations regarding human risk Science and Technology 39, 953–962.
These data indicate that pre- and postnatal exposure to Biegel, L. B., Flaws, J. A., Hirshfield, A. N., O’Connor, J. C.,
Elliott, G. S., Ladics, G. S. et al. (1998) 90-Day feeding
4-MBC and 3-BC can interfere with sexual development
and one-generation reproduction study in Crl:CD
at brain and reproductive organ levels. One approach of
BR rats with 17b-estradiol. Toxicological Sciences 44,
risk analysis is the comparison of external exposures:
116–142.
Classical endpoints exhibited lowest observed adverse
Buser, H. R., Balmer, M., Schmid, P. & Kohler, M. (2006)
effect levels ⁄ no observed adverse effect levels (LOA-
Occurrence of UV filters 4-methylbenzylidene camphor and
ELs ⁄ NOAELs) of 7 ⁄ 0.7 mg ⁄ kg for 4-MBC and octocrylene in fish from various Swiss rivers with inputs
0.24 ⁄ 0.07 mg ⁄ kg for 3-BC. Molecular endpoints were from wastewater treatment plants. Environmental Science
affected by the lowest doses studied (Tables 1 and 2). The and Technology 40, 1427–1431.
classical LOAEL and NOAEL of 4-MBC were 30 and Durrer, S., Maerkel, K., Schlumpf, M. & Lichtensteiger, W.
three times, respectively, above an estimated human expo- (2005) Estrogen target gene regulation and coactivator
sure level of 0.23 mg ⁄ kg (SCCNFP 1998). As estimates of expression in rat uterus after developmental exposure to the
external human exposure are based upon indirect calcula- UV filter 4-methylbenzylidene camphor. Endocrinology 146,
tions, a comparison of internal exposure levels from ani- 2130–2139.
mal experiments and epidemiological studies would seem Durrer, S., Ehnes, C., Fuetsch, M., Maerkel, K., Schlumpf, M.
to be more reliable. Analysis of human milk provides & Lichtensteiger, W. (2007) Estrogen sensitivity of target
information on internal exposure of mother and foetus genes and expression of nuclear receptor coregulators in rat
and on quality and magnitude of pollution of the food prostate following pre- and postnatal exposure to the UV
provided to the nursing infant. At the LOAEL dose of filter 4-methylbenzylidene camphor. Environmental Health
7 mg ⁄ kg 4-MBC, levels in rat milk (Schlumpf et al., Perspectives 115 (Suppl. 1), 42–50.
2004b) were only 13.4 times the highest value so far George, F. W. (1993) Postnatal expression of high rates of
found in our ongoing human milk monitoring study 5alpha-reductase in the female rat urogenital tract. Journal
(19 ng ⁄ g milk fat, Schlumpf et al., unpublished data). of Developmental Physiology 19, 187–191.
With both approaches, the margin of safety (MOS = NO- Habert, R. & Picon, R. (1984) Testosterone, dihydrotestoster-
one and estradiol-17 beta levels in maternal and fetal plasma
AEL ⁄ exposure · 100), normally set at 100, would not be
and in fetal testes in the rat. Journal of Steroid Biochemistry
met. This indicates that the potential risk posed by UV
21, 193–198.
filters warrants further investigations.
Hofkamp, L. E., Bradley, S., Schlumpf, M. & Timms, B. G.
(2007) Region-specific growth effects in the developing rat
Acknowledgements prostate following fetal exposure to estrogenic UV filters.
Posters on the Hill (POH), Council on Undergraduate
The studies were supported by Swiss National Research Research, Washington, DC, 24 April 2007, Abstract.
Program 50, EU 5th Framework Programme (EUR- Holbech, H., Norum, U., Korsgaard, B. & Bjerregard, P.
ISKED), Swiss Federal Office for the Environment, (2002) The chemical UV-filter 3-benzylidene camphor
Hartmann-Müller Stiftung, Olga Mayenfisch Stiftung. causes an oestrogenic effect in in vivo fish assay. Pharmacol-
ogy and Toxicology 91, 204–208.
Inui, M., Adachi, T., Takenaka, S., Inui, H., Nakazawa, M.,
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and Applied Pharmacology 218, 152–165. W. (2004a) Estrogenic activity and estrogen receptor b
Mueller, S. O., Kling, M., Firzani, P. A., Mecky, A., Duranti, binding of the UV filter 3-benzylidene camphor.
E., Shields-Botella, J., Delansorne, R., Broschard, T. & Kra- Comparison with 4-methylbenzylidene camphor. Toxicology
mer, P. J. (2003) Activation of estrogen receptor a and ERb 199, 109–120.
by 4-methylbenzylidene-camphor in human and rat cells: Schlumpf, M., Schmid, P., Durrer, S., Conscience, M.,
comparison with phyto- and xeno-estrogens. Toxicology Maerkel, K., Henseler, M. et al. (2004b) Endocrine activity
Letters 142, 89–101. and developmental toxicity of cosmetic UV filters – an
Nagtegaal, M., Ternes, T. A., Baumann, W. & Nagel, R. (1997) update. Toxicology 205, 113–122.
UV-filtersubstanzen in wasser und fischen. UWSF- Z. Um- Schmid, P., Kohler, M., Gujer, E., Zennegg, M. & Lanfranchi,
weltchem. Ökotox. 9, 79–86. M. (2007) Persistent organic pollutants, brominated flame
Nakata, H., Sasaki, H., Takemura, A., Yoshioka, M., Tanabe, S. retardants and synthetic musks in fish from remote alpine
& Kannan, K. (2007) Bioaccumulation, temporal trend and lakes. Chemosphere 67, S16–S21.

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Journal compilation ª 2008 Blackwell Publishing Ltd • International Journal of Andrology 31, 144–151 149
Developmental toxicity of UV filters M. Schlumpf et al.

Schmutzler, C., Hamann, I., Hoffmann, P. J., Kovacs, G., T. Søeborg


Stemmler, L., Mentrup, B. et al. (2004) Endocrine active
compounds affect thyrotropin and thyroid hormone levels
When you compare levels of these substances in human
in serum as well as endpoints of thyroid hormone action in and rat milk should you not expose them in the same
liver, heart and kidney. Toxicology 205, 95–112. way? I suspect that humans are exposed topically and rats
Schreurs, R., Lauser, P., Seinen, W. & van den Burg, B. (2002) orally.
Estrogenic activity of UV filters determined by an in vitro
reporter gene assay and an in vivo transgenic zebrafish assay. M. Schlumpf
Archives of Toxicology 76, 257–261.
Schreurs, R. H., Sonneveld, E., Jansen, J. H., Seinen, W. & van It is impossible to apply these substances to rats topically
der Burg, B. (2005) Interaction of polycyclic musks and UV because of their fur. Not all human exposure is through
filters with the estrogen receptor (ER), androgen receptor the skin: to some degree cosmetics are absorbed from the
(AR), and progesterone receptor (PR) in reporter gene food chain. The content of perfumes is not declared
bioassays. Toxicological Sciences 83, 264–272. because of manufacturer’s confidentiality but all contain
Seidlova-Wuttke, D., Jarry, H., Christoffel, J., Rimoldi, G. & two to four UV filters to protect the colour. Lipstick con-
Wuttke, W. (2005) Effects of bisphenol A, dibutylphthalate tains many UV filters. Some of these compounds enter
(DBP), benzophenone-2 (BP2), procymidone (Proc), and the food chain but the magnitude of this route is not
linurone (Lin) on fat tissue, a variety of hormones and known.
metabolic parameters: a 3 months comparison with effects
of estradiol (E2) in ovariectomized (ovx) rats. Toxicology
213, 13–24. A. Soto
Seidlova-Wuttke, D., Christoffel, J., Rimoldi, G., Jarry, H. &
These substances can be screened by E-screen and andro-
Wuttke, W. (2006) Comparison of effects of estradiol (E2)
gen bioassay. You measure the total xenobiotics burden
with those of octylmethoxycinnamate (OMC) and 4-meth-
in milk, but have you tried to assess the total burden by
ylbenzylidene camphor (4MBC) – 2 filters of UV light – on
activity, such as oestrogenic activity, antiandrogen activ-
several uterine, vaginal and bone parameters. Toxicology and
Applied Pharmacology 210, 246–254.
ity, either by using bioassays or estimation per level and
Siler-Khodr, T. M. (1998) Endocrine and paracrine function of relative potency?
the human placenta. In: Fetal and Neonatal Physiology, Vol.
1 (eds R. A. Polin & W. W. Fox), pp. 89–102. W.B. Saun- M. Schlumpf
ders Co, Philadelphia.
Tinwell, H., Lefevre, P. A., Moffat, G. J., Burns, A., Odum, J., This is a good suggestion for the future. At present we
Spurway, T. D., Orphanides, G. & Ashby, J. (2002) Confir- are fully occupied in the analysis of xenobiotics in milk.
mation of uterotrophic activity of 3 (4–methylbenzylidene)
camphor in the immature rat. Environmental Health Perspec-
A. Soto
tives 110, 533–536.
Völkel, W., Colnot, T., Schauer, U. M. T., Broschard, T. H. Has Dr Margaret Schlumpf in her studies on UV filters
& Dekant, W. (2006) Toxicokinetics and biotransforma- assessed human fat for the burden of these chemicals? UV
tion of 3-(4-methylbenzylidene)camphor in rats after oral filters are found in fish, and samples of human fat are
administration. Toxicology and Applied Pharmacology 216, readily available.
331–338.

M. Schlumpf
Panel discussion
We looked at the concentration of these substances in
S. Swan milk but not fat.
What is the half-life of these UV filters in the human
body?
P. Foster

M. Schlumpf The concentration of a wide variety of chemicals in addi-


tion to sunscreens, including chlorinated pesticides, are
The manufacturer’s data suggest a relatively short half life present in human milk often at a high TDI which is
of several weeks. The substances can enter the food chain. greater than the recommended exposure level. Should we
The half-life in animals is poorly documented but is therefore state that breast feeding is not recommended?
different for different animals.

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150 Journal compilation ª 2008 Blackwell Publishing Ltd • International Journal of Andrology 31, 144–151
M. Schlumpf et al. Developmental toxicity of UV filters

M. Schlumpf P. Bjerregaard
This is a difficult question to answer. It has been policy The Baltic sea in the 1970s and 1980s was heavily con-
for nurses to encourage strongly absolute breast feeding taminated with PCBs, DDT and other chemicals but these
and now we tell the mothers that there are possible dan- levels have markedly reduced in the last 20 years. In the
gers associated with breast milk. Nurses and mothers are early 1980s, a Danish committee discussed the recommen-
confused and it is now difficult to give clear guidelines dations for breast feeding and only a minority advised
and recommendations. The whole aspect of breast feeding against it because of the levels of PCBs and DDT in breast
must be considered in depth. milk. Infants breast fed at that time, especially if fish was
a large part of the diet, are now suitable for assessing
possible brain damage caused by PCBs in infancy. The
A.A. Jensen
situation is much better today now that these substances
After 3–4 months of breast feeding, the baby has the same are much less in the environment and breast milk.
serum concentration of pollutants as the mother, and
after 4 months the levels are higher in the baby than the
S. Swan
mother by a factor of up to 2–3 times. Perhaps the old
advice from WHO is best which recommends 4 months I am alarmed by the direction of this discussion. The
breast feeding. The situation is different in developing adverse effects of low level exposure to endocrine disrupt-
countries where bottle feeding is relatively very expensive, ing chemicals in breast milk are under investigation at
and the impurities in the water supply may be more dan- present. However, the nutritional, immunological and
gerous than the contaminants in breast milk. In devel- psychological benefits of breast feeding are well estab-
oped countries, it is perhaps not wise to allow the baby lished and not disputed. The alternatives to breast milk
to have higher concentrations of endocrine disrupters may not be advantageous. What is the hormonal content
than the mother. of casein-based formula milk, cow’s milk or soy formula
substitutes? This is a very complicated situation and even
water must be considered as a source of pollutants. We
A. Soto
are not yet in a position to recommend changes to breast
It is possible, therefore, that the recommendation in USA feeding which has well established health advantages.
for 6 months breast feeding is unnecessary. This recom-
mendation was brought in around 1950 when breast feed-
M. Schlumpf
ing was unusual, and no terrible consequences have been
identified. Perhaps a compromise approach is advisable. We must be very careful about assessing the data before
acting. Milk can be contaminated with cosmetics and UV
filters, but these can be controlled during lactation to
H. Leffers
reduce the exposure of the infants.
Perhaps obesity is linked to ‘‘non breast feeding’’ the chil-
dren.
H. Patisaul
Soy infant formula is used by about one third of mothers
E. Gregorasczczuk
in USA and this proportion is increasing, but this pro-
There are data to indicate that a woman clears her body duct contains phytoestrogens which can give levels in the
stores of Dioxins, PCBs and brominated compounds infant’s plasma 7,000 time greater than the endogenous
through lactation. The amount of these substances passed oestradiol level in the mother. This is much higher than
to the infant is dependent on the age of the mother, the the levels encountered in the endocrine disrupters under
rank of the baby (first or subsequent born), and the time discussion at this Workshop, and in vitro studies indicate
between pregnancies. The first child receives the entire that these phytoestrogens have much higher binding affi-
body load accumulated since the mother was born, and nity for ER. This is a complex issue. The infants must
the second baby receives the amount accumulated drink something and I do not know of anything better
between pregnancies. than breast milk.

ª 2008 The Authors


Journal compilation ª 2008 Blackwell Publishing Ltd • International Journal of Andrology 31, 144–151 151

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