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Sunscreens containing physical UV blockers can increase transdermal absorption of pesticides

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People are encouraged to wear sunscreens because of their effectiveness at reducing the risk of skin cancer. The dermal penetration of the herbicide 2,4-D can be enhanced by commercial formulations containing chemical ultraviolet (UV) absorbers, the absorbers themselves and the insect repellent DEET. This work has been extended to determine whether commercially available sunscreens containing the physical UV absorbers titanium dioxide (TiO2) or zinc oxide (ZnO) enhance the transdermal absorption of pesticides. Hairless mouse skin was pretreated with either commercially available sunscreens or the UV absorbers themselves, dissolved in phenyl trimethicone. In vitro permeability studies were performed with the pesticides 2,4-D, paraquat, parathion or malathion. The data demonstrate that pretreatment with five of the nine sunscreens tested increased the transdermal absorption of 2,4-D (P<0.05). Transdermal studies using paraquat, parathion and malathion pretreated with a representative sunscreen all demonstrated significant penetration enhancement when compared to controls (P<0.05). Repeated 2,4-D and sunscreen applications resulted in either no change between pulses or an increase in absorption after the second pulse depending on the washing regimen. Examining penetration of individual UV absorbers formulated in phenyl trimethicone showed that that ZnO can impede 2,4-D penetration and TiO2 had no effect. Combining UV absorbers in the presence of trimethicone resulted in 'sunscreens' that could actually inhibit 2,4-D penetration. Inert ingredients therefore control the increased absorption seen in commercial sunscreen products and this enhancement can be eliminated by substituting phenyl trimethicone as the solvent. Sunscreen use must still be encouraged even with the undesirable side effect of increased penetration through the skin.
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Sunscreens containing physical UV blockers can increase transdermal
absorption of pesticides
Rhonda M Brand, James Pike, Roselyn M Wilson and Anna R Charron
Department of Internal Medicine, Ev anston Northwestern Healthcare and Feinberg School of Medicine at Northwestern
University, Evanston, IL, USA
People are encouraged to wear sunscreens because of their effectiveness at reducing the risk of skin
cancer. The dermal penetration of the herbicide 2,4-D can be enhanced by commercial formulations
containing chemical ultraviolet (UV) absorbers, the absorbers themselves and the insect repellent
DEET. This work has been extended to determine whether commercially available sunscreens
containing the physical UV absorbers titanium dioxide (TiO
2
) or zinc oxide (ZnO) enhance the
transdermal absorption of pesticides. Hairless mouse skin was pretreated with either commercially
available sunscreens or the UV absorbers themselves, dissolved in phenyl trimethicone. In vitro
permeability studies were performed with the pesticides 2,4-D, paraquat, parathion or malathion.
The data demonstrate that pretreatment with five of the nine sunscreens tested increased the
transdermal absorption of 2,4-D (PB
/0.05). Transdermal studies using paraquat, parathion and
malathion pretreated with a representative sunscreen all demonstrated significant penetration
enhancement when compared to controls (PB
/0.05). Repeated 2,4-D and sunscreen applications
resulted in either no change between pulses or an increase in absorption after the second pulse
depending on the washing regimen. Examining penetration of individual UV absorbers formulated in
phenyl trimethicone showed that that ZnO can impede 2,4-D penetration and TiO
2
had no effect.
Combining UV absorbers in the presence of trimethicone resulted in ‘sunscreens’ that could actually
inhibit 2,4-D penetration. Inert ingredients therefore control the increased absorption seen in
commercial sunscreen products and this enhancement can be eliminated by substituting phenyl
trimethicone as the solvent. Sunscreen use must still be encouraged even with the undesirable side
effect of increased penetration through the skin. Toxicology and Industrial Health 2003; 19: 9
/16.
Key words: multiple applications; pesticides; sunscreens; transdermal; UV absorbers
Introduction
Sunscreens are quite effective at preventing most
skin cancers; and therefore their use is critical when
outdoors. Exposure to ultraviolet (UV) radiation
above a threshold level can cause damage to the
barrier properties of the skin and has been shown
to increase the dermal penetration of small hydro-
philic chemicals (Gelis et al., 2002). This is a
problem because dermal absorption is a major
source of chemical exposure in occupational and
agricultural (Fenske and Elkner, 1990; Nielsen and
Nielsen, 2000; Nomiyama et al., 2001) as well as
recreational settings (Lindstrom et al., 1997;
Moody and Chu, 1995; Xu et al., 2002). Sunscreen
Address all correspondence to: Rhonda Brand, Department of Internal
Medicine, Evanston Northwestern Healthcare and Feinberg School of
Medicine at Northwestern University, 1001 University Place, Evan-
ston, IL 60201, USA
E-mail: rhbrand@enh.org
Toxicology and Industrial Health 2003; 19: 9 /16
www.tihjournal.com
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use should, therefore, help prevent this damage and
reduce the absorption of undesirable penetrants.
A number of commercially available sunscreens,
containing chemical UV absorbers, however, have
been shown to act as transdermal penetration
enhancers for the herbicide 2,4-D (Brand et al.,
2002). A follow-up study demonstrated that the
most commonly used chemical UV absorbers are
penetration enhancers; but, the increase may be
blocked by the inert ingredients in commercial
formulations (Pont et al., 2004a). The insect repel-
lent, DEET can act synergistically with the UV
absorbers to enhance the penetration of 2,4-D to an
even greater level (Pont et al., 2004b). One of the
formulations tested in the original work that did
not increase absorption was a broad spectrum
sunscreen offering both UVA and UVB protection
that contained the physical UV blocker titanium
dioxide (TiO
2
). This raised the question of whether
commercially available sunscreens containing phy-
sical blockers, such as TiO
2
and zinc oxide (ZnO),
can prevent the penetration enhancement that
occurs with formulations containing chemical UV
absorbers.
UV radiation can be subdivided into UVB (290
/
320 nm) and UVA (320/400 nm). UVB delivers
energy to the stratum corneum and superficial
layers of the epidermis and is primarily responsible
for sunburns and a variety of skin disorders
including actinic keratoses and nonmelanoma skin
cancers (Ley and Reeve, 1997). UVA, in contrast,
reaches deeper into the skin and causes oxidative
damage to the guanine bases in DNA. It is almost
20 times more common than UVB and, because of
its wavelength, each photon is five times more likely
to reach the dermis, thereby resulting in a 100 fold
greater risk than for UVB (Lim et al., 2001). UVA
is thought to have a larger role in melanoma than
other forms of skin cancer (Garland et al., 2003;
Ley and Reeve, 1997; Zhang and Rosdahl, 2003).
There is a correlation between severe sunburn at an
early age and later development of melanoma (Lim
et al., 2001) and some indications that there is a
relationship between use of UVA tanning devices
and the occurrence of malignant melanoma in
young adults (Ley and Reeve, 1997).
For many years, most sunscreens contained
principally UVB absorbers, which may explain
why there is some controversy as to the effectiveness
of sunscreens in preventing melanoma. The use of
broad spectrum sunscreens should therefore be
encouraged to reduce the risk of both melanoma
and nonmelanoma skin cancers. Recent formula-
tion advances have improved the ability to incor-
porate the UVA absorbers TiO
2
and ZnO into
commercial sunscreens, and these broad spectrum
products are becoming more common. These new
sunscreens should, in theory, eventually decrease
the lifetime risk of developing melanoma, which has
the fastest rate of increase of any type of cancer in
the USA (Dennis et al., 2003).
The purpose of this work was to determine the
effect of broad spectrum commercial sunscreens
containing physical UV absorbers on the transder-
mal absorption of the pesticides 2,4-D, paraquat,
parathion and malathion and to determine the
effect of sunscreen reapplication on 2,4-D penetra-
tion. Furthermore, the impact of inert ingredients
on 2,4-D absorption was demonstrated by devel-
oping an inhibiting ‘sunscreen’ using the solvent
phenyl trimethicone and the UV absorbers TiO
2
,
ZnO and octyl methoxycinnamate (OM).
Methods
Chemicals and reagents
The following UVA/UVB sunscreens were tested:
Neostrata Daytime Protection Cream SPF15,
Obagi Nu Derm Sunblock SPF24, Ti-Silc Untinted
SPF45, Skin Medica Daily Sun Protection SPF20,
Solbar Zinc SPF38, Pre-Sun Sensitive Skin Sun-
block Titanium Dioxide SPF28, Pevonia Sunblock
Body Shield SPF15, Vanicream Sunscreen SPF15
and Revision SPF50 Sunscreen (all purchased from
www.SkinCareWorldWide.com).
The barrier formulations tested contained TiO
2
(www.SkinCareWorldWide.com), transparent ZnO,
USP powder (BASF, Wyandotte, MI), or OM
(RONA, EM Industries, Hawthorne, NY) with
phenyl trimethicone (HV) (SilCare
TM
15M30, Clar-
iant Corporation, Charlotte, NC) as the solvent.
The following concentrations, all of which are
within USFDA regulatory limits, were used for
each of the sunscreen ingredients: TiO
2
(9.0% v/v),
OM (7.5% v/v), and ZnO, USP (9% w/v).
The donor solutions consisted of either 2,4-D
amine (Agriliance, St. Paul, MN), paraquat (Gra-
Sunscreens with physical UV absorbers as penetration enhancers
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moxone Extra, ZenecaAg/Syngenta, Greenboro,
NC), malathion (PS-86, Chem Service, Inc., West
Chester, PA) or parathion (PS-95, Chem Service,
Inc., West Chester, PA), each of which were diluted
1:40 in either deionized water (2,4-D and paraquat)
or ethanol (malathion and parathion). The solution
was then spiked with the appropriate radiolabelled
chemical (Sigma, St. Louis, MO), either [
14
C] 2,4-D
(specific activity 92.6 mCi/mg), [
14
C] paraquat/
methyl
14
C dichloride (specific activity 125.7 mCi/
mg), [
14
C] malathion (specific activity 16.9 mCi/mg),
or [
14
C] parathion (specific activity 31.5 mCi/mg).
The receiving solution was Hanks balanced
saline solution (HBSS) supplemented with 4%
(w/v) bovine serum albumin (BSA) (Fisher Chemi-
cals, Pittsburgh, PA). The BSA supplement in-
creases the hydrophobicity of the solution, thus
improving the partitioning of lipophilic molecules
into the receiver compartment, with viable skin
maintenance and metabolism, for more than 24
hours (Collier and Bronaugh, 1991).
Diffusion studies
Female hairless mice (CRL:SKH1, Charles River
Laboratories, Wilmington, MA), aged 6
/16 weeks,
were used for all experiments and were treated
according to the NIH Guide for the Care and Use
of Laboratory Animals. Each mouse was eutha-
nized with carbon dioxide gas and cervical disloca-
tion and the full-thickness dorsal skin was removed.
The excised hairless mouse skin was placed into a
Kel-F Bronaugh-style flow-through diffusion
chamber with an exposed surface area of
0.785 cm
2
(Permegear, Rieglesville, PA) with the
epidermal side facing the donor chamber. The
chamber was maintained at 328C.
After an initial one-hour background, approxi-
mately 1.6 mg of sunscreen (2 mg/cm
2
) was added
to the donor wells of the chambers followed by a
30-minute incubation period. A 100 mL aliquot of
the donor solution was added to each donor well.
Additional 90-minute fractions were collected for
24 hours (ISCO Retriever IV, ISCO, Lincoln, NE).
The amount of pesticide present in each fraction
was then determined via liquid scintillation count-
ing (Model LS 6500, Beckman Coulter, Inc., Full-
erton, CA).
Study design
Four different studies were performed using these
methods. The first examined the effect of commer-
cial sunscreens containing physical UV absorbers
on the transdermal penetration of 2,4-D. This was
determined by pretreating the skin with the nine
previously described sunscreens and following the
protocol listed above. The goal of the second study
was to determine if an inhibiting ‘sunscreen could
be formulated using the solvent phenyl trimethi-
cone and the UV absorbers TiO
2
, ZnO and OM.
The next study modelled the repeated application
of sunscreen recommended by manufacturers. The
diffusion study was performed using Ti-Silc Un-
tinted SPF45 as a representative sunscreen, how-
ever, with a second dose of both the sunscreen and
2,4-D amine applied 4.5 hours later. The last study
examined the ability of the model sunscreen Ti-Silc
Untinted SPF45 to enhance the transdermal pene-
tration of other pesticides.
Analytical methods
Data were analysed by computing cumulative
percent flux (per cent penetrated versus time) and
lag time (defined as the x-intercept of the linear
portion of this curve). The total amount penetrated
and lag times for each pretreatment were then
compared to the control via ANOVA followed by a
Dunnett’s Multiple Comparison Test (PB
/0.05).
Statistical significance between paired treatments,
as determined by Student’s t-tests, was used when
necessary (GraphPad Prism, GraphPad, San Diego,
CA). In the repeated application study the data are
presented as per cent flux, and statistical compar-
isons as described above were performed on the
peak height.
Results
The cumulative penetration and lag times are
presented in Table 1. Five of the nine sunscreens
led to significantly enhanced transdermal penetra-
tion of 2,4-D through hairless mouse skin. These
included Neostrata Daytime Protection Cream,
Obagi Nu Derm, Ti-Silc Untinted, Solbar Zinc at
PB
/0.01 and Revision at PB/0.05. The remaining
four sunscreens, Skin Medica, Pevonia, Body
Sunscreens with physical UV absorbers as penetration enhancers
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Shield, Vanicream and Presun all increased the 2,4-
D absorption, but at a nonsignificant level
(P
/0.05). The lag times of Skin Medica, Neostrata
Daytime Protection Cream, Ti-Silc Untinted, Sol-
bar Zinc and Revision were significantly decreased
at PB
/0.01, resulting in faster absorption, while
Obagi Nu Derm and Presun led to faster penetra-
tion, at PB
/0.05 when compared to the control.
Only Vanicream had longer lag times, albeit not
significantly greater than control (P
/0.05).
The results of the first experiments described are
consistent with the hypothesis that inert ingredients
in cosmetic formulations have an impact on the
penetration-enhancing properties of sunscreens. To
test this hypothesis, inert formulations were re-
placed by the solvent phenyl trimethicone. The UV
absorbers found in the commercial formulations
tested, 9% TiO
2
, 9% ZnO or 7.5% OM, were
suspended in the trimethicone prior to 2,4-D
application. Table 2 demonstrates that the trimethi-
cone solvent itself as well as all three UV absorbers
were able to inhibit 2,4-D transdermal penetration
when compared with the control (PB
/0.01). OM, a
known penetration enhancer (Pont et al., 2004a),
increased the penetration compared to the solvent
itself (PB
/0.01), whereas pretreatment with TiO
2
had no effect (P/0.05) and ZnO caused absorption
inhibition (PB
/0.01).
Multiple UV absorbers were then combined
in trimethicone to mimic the commercial formula-
tions discussed previously (Table 2). All of these
combinations inhibited the 2,4-D penetration when
compared to the control (P B
/0.01). The mixture of
ZnO and TiO
2
significantly reduced 2,4-D absorp-
tion compared to the trimethicone (P B
/0.01).
Replacing the TiO
2
with OM reversed this inhibi-
tion (P B
/0.05). Combining TiO
2
and OM led to
enhanced 2,4-D absorption versus the solvent alone
(P B
/0.05). The ZnO/TiO
2
(15.59/2.4) combina-
tion was closer to ZnO (18.09
/2.0) than to TiO
2
(23.59/2.7). The same held for the ZnO/OM
combination (23.29
/2.4), which followed the ZnO
pattern instead of OM’s (37.59
/3.7). In contrast,
the OM
/TiO
2
(30.09/2.4) combination had a
penetration that approximated the average of the
Table 1. 2,4-D absorption after pretreatment with sunscreens containing physical absorbers.
Formulation Active ingredient Cumulative (% dose/24 hours)
mean9
/SEM
Lag time (hours)
mean9/SEM
Skin Medica ZnO 47.79
/3.9 3.09/0.1
#
OM
Neostrata Daytime Protection Cream TiO
2
57.29/7.6
#
2.79/0.3
#
OM
Obagi Nu Derm ZnO 63.79
/5.2
#
4.19/0.6*
TiO
2
Ti-Silc Sheer TiO
2
62.79/4.4
#
3.29/0.4
#
OM
Solbar Zinc ZnO 54.69
/1.0
#
1.89/0.4
#
OM
Homosalate
Pevonia Sunblock Body Shield TiO
2
43.39/4.5 4.29/0.3
Revision ZnO 52.99
/3.7* 3.29/0.5
#
TiO
2
OM
Vanicream ZnO 39.79
/3.3 5.99/0.3
TiO
2
Presun TiO
2
47.69/6.2 4.19/0.4*
Control 36.89
/2.4 5.49/0.2
*P B
/0.05,
#
P B/0.01.
Table 2. Effect of phenyl trimethicone and physical UV absorbers on
transdermal delivery of 2,4-D.
UV absorber Cumulative
(% dose/24 hours)
Mean9
/SEM
Lag time (hours)
Mean9
/SEM
TiO
2
23.59/2.7
c
4.79/0.2
ZnO 18.09
/2.0
b,c
5.29/0.4
OM 37.59
/3.7
b,c
4.79/0.3
ZnO
/TiO
2
15.59/2.4
b,c
6.59/0.2
a
ZnO/OM 23.29/2.4
c
6.69/0.3
a
TiO
2
/OM 30.09/2.4
a,c
5.99/0.3
ZnO
/TiO
2
/OM 23.89/3.2
c
6.29/0.4
Trimethicone 24.59
/0.9
c
5.09/0.3
Control 45.99
/1.3
b
5.39/0.2
a
P B/0.05 versus trimethicone,
b
P B/0.01 versus trimethicone,
c
P B/0.01
versus control.
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individual ingredients (30.5) as did the three-
ingredient combination (23.89
/3.2 versus 26.1).
Lag times were then determined to see if these
compounds inhibit the initial rate of absorption.
Table 2 demonstrates that no significant differences
were found between any of the individual ingredi-
ents and either the trimethicone or control treat-
ments (P
/0.05). Combining multiple UV
absorbers, however, resulted in significantly slower
lag times for ZnO
/TiO
2
, ZnO/OM (P B/0.05).
The studies described so far were performed to
represent a long-term continuous exposure. A third
experiment was done to examine the effect of
repeated sunscreen applications on 2,4-D absorp-
tion. Ti-Silc Untinted was chosen as a model
sunscreen for this work because it was an effective
enhancer in an earlier study, and 2,4-D was applied
in ethanol to ensure a finite dose. Figure 1
demonstrates that when the skin is not washed
after either the first or second application, there is a
significant increase in the peak penetration of the
second pulse compared to the first (P B
/0.01).
If the wash was performed only after the second
dose, there was also significantly greater peak
penetration of the second pulse compared to the
first (P B
/0.001). However, if the skin was washed
with water after both applications, there was no
difference in the peak 2,4-D penetration between
the two applications (P
/0.05).
The transdermal absorption of three additional
pesticides was examined in order to determine
whether sunscreens can enhance the penetration
of pesticides other than 2,4-D. These pesticides
were selected for their wide range of octanol water
partition coefficients and water solubilities. Para-
quat is very hydrophilic and water soluble
(log K
ow
/ /4.5, water solubility/700 000 mg/L).
Malathion is moderately hydrophobic (log K
ow
/
2.3, water solubility/130 mg/L) like 2,4-D
(log K
ow
/2.8, water solubility/900 mg/L), but
unlike 2,4-D has very low water solubility. Para-
thion is quite hydrophobic with extremely low
water solubility (log K
ow
/3.8, water solubility /
55 mg/L). The penetration of the three pesticides
was determined after a 30-minute pretreatment
with the Ti-Silc sunscreen (Figure 2). All three
pesticides, like 2,4-D, had significantly increased
absorption after Ti-Silc application as compared
with their respective controls (P B
/0.05).
Discussion
The data demonstrate that commercially available
sunscreens containing the UV absorbers TiO
2
and
ZnO increase the transdermal absorption of the
pesticides 2,4-D, paraquat, malathion and para-
thion. An additional study confirmed that inert
ingredients are modulators of this enhanced pene-
tration. Substituting phenyl trimethicone for all
Figure 1. Impact of multiple applications of Ti-Silc sunscreen and
2,4-D with and without washing between applications. First pulse of
2,4-D was applied at 1.5 hours and the second at 6 hours; pretreatment
with TiSilc was applied 30 minutes prior to the herbicide. \
/no
washes 1.5 hours after either 2,4-D application (P B
/0.01 versus
control), ^
/washing 1.5 hours only after the second 2,4-D applica-
tion (P B
/0.01 versus control), I /washing 1.5 hours after both 2,4-D
applications (P
/0.05 versus control), " /no 2,4-D application.
Figure 2. Penetration of pesticides after pretreatment with Ti-Silc
sunscreen. ^
/paraquat control, ' /paraquat/sunscreen, k/ma-
lathion control, m
/malathion/sunscreen, \ /parathion control,
%
/parathion/sunscreen. Sunscreen pretreatment significantly in-
creases transdermal absorption versus control for all pesticides tested
(P B
/0.05).
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other inert ingredients reversed the penetration
enhancement caused by the commercial formula-
tions.
Inorganic sunscreens use TiO
2
and ZnO and
work primarily by reflecting and scattering light.
ZnO offers better UVA protection than TiO
2
(Lim
et al., 2001), although both compounds can be
classified as a broad-spectrum agent. Avobenzone
offers the best UVA protection of the chemical
absorbers. Inorganics have traditionally been un-
popular because they tend to leave a haze or white
film. Recently, newer formulations of the physical
absorbers have been made which have reduced the
particle size, making these compounds easier to
incorporate into useable sunscreen formulations
(Reisch, 2002). Studies have demonstrated that
TiO
2
microparticles do not readily penetrate the
skin, with almost all of it remaining in the outer-
most layers of the stratum corneum (Pflucker et al.,
2001). Only one percent was found in the hair
follicles and none in the viable tissues (Lademann
et al., 1999). The lack of absorption into the skin
demonstrates that the penetration enhancement
(for Presun) is not due to the TiO
2
microparticles
interacting with the 2,4-D.
The variations in 2,4-D absorption after pre-
treatment with different sunscreen formulations
containing similar active ingredients indicate that
the inert ingredients have a major effect on the
penetration enhancement. The most dramatic effect
could be seen with Vanicream and Obagi Nu Derm.
Both formulations contain ZnO and TiO
2
as their
active ingredients. Vanicream caused no significant
changes in the level of 2,4-D absorption when
compared to control; however, Obagi significantly
increased the penetration and decreased the lag
time. These results are consistent with similar
studies performed using commercially formulated
sunscreens containing chemical penetration enhan-
cers (Brand et al., 2002; Nakai et al., 1997) as well
as individual (Pont et al., 2004a) and combinations
of active sunscreen ingredients (Pont et al., 2004b).
Substituting the phenyl trimethicone for the inert
ingredients in the commercial formulations resulted
in a barrier cream with UV absorbing capabilities
which successfully reduced the quantity of 2,4-D
through the skin. The trimethicone itself acts as a
barrier to 2,4-D; and this barrier is maintained even
when the UV absorbers TiO
2
or ZnO were added.
Mixing the known enhancer OM (Pont et al.,
2004a) with the phenyl trimethicone significantly
increased the 2,4-D absorption. These results
indicate that neither TiO
2
nor ZnO are penetration
enhancers. Furthermore, the reduced penetration
associated with ZnO demonstrates that this UV
absorber can actually act as a penetration inhibitor.
It is the only UV absorber either physical or
chemical tested that was able to inhibit 2,4-D
penetration levels (Pont et al., 2004a).
There were no significant differences in 2,4-D lag
time for any of the individual substances. The fact
that OM did not significantly alter lag time,
however, was somewhat surprising because it has
been shown to decrease 2,4-D lag time when
applied in ethanol and in the commercial formula-
tions that contained OM. This UV absorber is
known to alter the dermal barrier, as demonstrated
by its ability to increase
3
H
2
O permeability (Pont
et al., 2004a). It is possible that OM interacts with
the trimethicone so that its absorption into the skin
is slowed, thereby delaying its penetration enhance-
ment capabilities. Taken together, these results
indicate that inert ingredients influence lag times
as well as total penetration levels.
A systematic study was then performed to
determine if combinations of these UV absorbers
would demonstrate interactions that could influ-
ence pesticide penetration in a manner similar to
that described earlier (Pont et al., 2004b). Combin-
ing ZnO with TiO
2
or OM resulted in absorption
similar to ZnO alone. The TiO
2
and OM combina-
tion, as well as the three-ingredient formulation,
had a final value resting at approximately the
average of the total absorption of the individual
ingredients. None of the combinations resulted in
synergistic interactions as found with DEET (Pont
et al., 2004b). The lag times for the combinations
were significantly slower than any of the individual
values or the solvent, indicating that the mixtures
can actually retard the initial flux.
Repeating the sunscreen application after thor-
oughly washing results in a similar absorption
profile as the original 2,4-D pulse. This indicates
that rinsing the skin with water removed the 2,4-D
without damaging the stratum corneum, causing
the second pulse to be similar to the first. When the
skin was either not cleaned at all or was washed
thoroughly with water, the second application
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of 2,4-D had greater penetration than the first. This
is consistent with the concept of a reservoir effect
from the first pulse. Earlier work involving multiple
dosing studies found either no effect on subsequent
pulses, as seen with benzoic acid, parathion and
salicylic acid (Bucks et al., 1990), or increased
absorption after repeated applications of hydro-
cortisone (Wester et al., 1977), malathion (Bucks et
al., 1985) and benzoyl peroxide (Courtheoux et al.,
1986). The differences between these studies are
that in the former there was no washing between
applications, whereas the latter studies included a
wash with soap and water between the pulses. The
authors hypothesized that the different results were
due to the soap extracting stratum corneum lipids,
thereby reducing the efficacy of the barrier. The
studies presented here are slightly different in that
no soap was used in the wash because the experi-
ment was designed to model sunscreen reapplica-
tion after swimming.
The universality of sunscreens as penetration
enhancers was determined by examining the ab-
sorption of several pesticides with different physical
properties. Lipophilicity is a major factor in
determining transdermal absorption (Potts and
Guy, 1992), as well as the effectiveness of penetra-
tion enhancers (Kitagawa et al., 1997). The percu-
taneous absorption of the different pesticides
presented here was designed to determine the effect
of lipophilicity and water solubility on the penetra-
tion enhancement properties of a representative
sunscreen, when compared to its untreated control.
Neither parameter correlated with the increased
absorption, indicating that the greater penetration
seen for these four pesticides would be expected to
occur for many others.
These studies were performed in vitro using
hairless mouse skin. This model is widely used
even though it has been reported that penetration
enhancement across hairless mouse skin is not
predictive of human skin for some chemicals
(Bond and Barry, 1988). A comparison was there-
fore made of the 2,4-D absorption through hairless
mouse and human skin in the presence of chemical
UV absorbers. Penetration enhancement was con-
sistent between human and mouse skin, although
mouse skin was more permeable allowing for
greater amounts of herbicide to pass (Pont et al.,
2004a). This indicates that the results presented in
this study for physical UV absorbers using hairless
mouse skin should be consistent in human skin.
Overall the data show that commercial sunsc-
reens containing physical UV absorbers can act as
penetration enhancers for pesticides with varied
physical properties. The increase is dependent on
the inert ingredients and this enhancement can be
eliminated by substituting phenyl trimethicone as
the solvent. Interestingly, this substitution can lead
to the prevention of 2,4-D penetration, thereby
creating a barrier cream which is also a sunscreen.
Even with the undesirable side effect of penetration
enhancement, it is still essential that people are
encouraged to wear sunscreens, as the risk of
developing skin cancer is probably larger than the
increased toxicity from a two-fold greater pesticide
absorption.
Acknowledgements
This project was funded by a joint grant from the
Association of American Medical Colleges and the
Centers for Disease Control. The authors acknowl-
edge the Clarion Corporation for donating phenyl
trimethicone and want to thank Dr E Jeffrey
Metter for his assistance with the statistical analy-
sis.
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at MCMASTER UNIV LIBRARY on March 10, 2016tih.sagepub.comDownloaded from
... Like other chemicals, it also has harmful effects. It acts as a potential endocrine disruptor and is linked with hormone disruption [41]. Along with direct health concern, homosalate exposure can enhance pesticide absorption in the body [42,43]. ...
... Along with direct health concern, homosalate exposure can enhance pesticide absorption in the body [42,43]. It is not readily degraded and persistent in our environment [41,44]. ...
... It is one of the most widely used physical sunblocks present in sunscreens and is found in sun protection factor (SPF) makeup products, lotions, and skin lightening products. TiO 2 is generally considered safe and effective, although several studies show that oral consumption could be carcinogenic to humans [41,59]. ...
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... Limited studies can be found on the interactions between sunscreen constituents and other pollutants [28]. In the work of Brand et al. [29], scientists confirmed enhanced penetration of selected pesticides (e.g., 2,4-D (2,4-Dichlorophenoxyacetic acid), DEET (N,N-diethyl-m-toluamide), paraquat, parathion and malathion) when hairless mouse skin was co-exposed to titanium and zinc oxides [29]. In the work of Marrot [30], the possible explanation for elevated atopy or eczema during periods of increased pollution exposure (heavy metals or polycyclic aromatic hydrocarbons (PAHs)) include oxidative stress, inflammation and metabolic impairments correlated to more frequent use of sunscreens. ...
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... Only limited information is available in the literature regarding toxicological effects of nanocomposites. At high doses, nano-ZnO was found to be toxic [79,80]. Al 2 O 3 particles of 20 nm induce an inflammatory reaction in rat lungs [79]. ...
... At high doses, nano-ZnO was found to be toxic [79,80]. Al 2 O 3 particles of 20 nm induce an inflammatory reaction in rat lungs [79]. Ag NPs are toxic in living organisms at high concentrations [81] and chronic exposure to silver has been reported to cause argyria and/or argyrosis in humans [82]. ...
Chapter
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... Therefore, sunscreen should be used to prevent skin damage. Most sunscreens are chemical and have the ability to penetrate the skin that causes DNA damage [248,249]. By filtering ultraviolet rays and absorbing reactive oxygen species (ROS), melanin reduces UV radiation damage in the body, thus protecting the cell nucleus and DNA damage [250,251]. ...
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Melanin is a complex group of natural pigment substance, and it shows excellent biological and biomedical applications which is commonly present in algae, fungi, bacteria, cephalopoda, and sea cucumber. From the past few decades, great attention has been given to melanin and its derivative for the product development in the area of medical, industrial, food and cosmetic industries. In addition, melanin plays an important in pharmaceutical product development in antioxidant, anti‐inflammatory, immunomodulatory, radioprotective, and gastrointestinal benefits. In this review, we focus on melanin production from various marine species, summarized Purification and extraction strategies of various marine melanin with their analyzes and also their application in medical and industries.
... Sunscreens are classified as chemical filters or physical barriers based on their protection mechanism (Maier and Korting, 2005). The chemicals used in chemical filters and minerals used in physical barriers have skin penetration ability that causes unfavorable conditions such as DNA damage (Dunford et al., 1997;Brand et al., 2003). Thus, there is an emerging demand for safer, chemically inert, and effective sunscreen. ...
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... 63 A laboratory study of sunscreen found that those containing the physical UV absorbers titanium dioxide or zinc oxide enhance the transdermal absorption of parathion. 64 Therefore, another possibility of the increased risk seen among subjects exposed to both sun and pesticides is the use of sunscreen. ...
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... However, OMC is highly lipophilic, and so that bioaccumulation may occur in wildlife and humans (Hagedorn-Leweke and Lippold, 1995; plasma, urine and breast milk after topical administration (Hagedorn-Leweke and Lippold, 1995;Hany and Nagel, 1995;Hayden et al., 1997;Jiang et al., 1999;Janjua et al., 2004;Sarveiya et al., 2004). Agricultural workers have been encouraged to use sunscreen to reduce their risk of skin cancer, but UV absorbers, including OMC, may increase dermal absorption of pesticides (Brand et al., 2002(Brand et al., , 2003Pont et al., 2004). In addition, some adverse reactions, such as photoallergic reactions in patients with suspected clinical photosensitivity, have been reported (Schauder and Ippen, 1997). ...
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... Nano-engineered materials also have the potential to increase the bioavailability of those chemicals, such as toxins. One study found that micronized titanium dioxide in sunscreens increases the skin's absorption of several pesticides (Brand et al., 2003). ...
Chapter
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To clarify the potential for dermal absorption of N,N-dimethylformamide (DMF) (CAS No. 68-12-2) vapor, and the appropriate adjustment method and the half-lives of urinary concentrations of N-methylformamide (NMF) as the biological exposure item of DMF. Thirteen healthy male volunteers (mean age: 22.7 years, range: 20-27) were exposed to DMF vapor twice, via both the skin and the lung, for 4 h at concentrations below 10 ppm, the recommended occupational exposure limit set by the Japan Society for Occupational Health, the American Conference of Governmental and Industrial Hygienists, and Deutsche Forschungsgemeinschaft, under conditions of 27 degrees C and 44% humidity. Each volunteer was exposed to DMF via the skin in a whole-body type exposure chamber and outside the chamber, via the lung by a respirator connected to the chamber. Exposure levels were 6.2 +/- 1.0 ppm in dermal exposure and 7.1 +/- 1.0 ppm in inhalation exposure. Urine samples were collected at every opportunity until 72 h after exposure; and NMF, as well as volume, creatinine, and specific gravity were measured. Dermal and inhalation intakes were compared after adjusting concentrations. DMF vapor absorptions via the skin and the lung were estimated to be 40.4 and 59.6%, respectively. Workers need to be aware of the risk of dermal absorption of DMF vapor as well as of the liquid. Though NMF concentrations adjusted by creatinine, specific gravity, and urinary volume showed good correlation with total NMF excretion and the absolute amount of NMF at each sampling time, creatinine-adjusted NMF concentration correlated better than the others. The biological half-life of urinary NMF after dermal exposure, 4.75 +/- 1.63 h, was longer than that after respiratory exposure, 2.42 +/- 0.63 h.
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Background: Originally developed to protect against sunburn, sunscreen has been assumed to prevent skin cancer. However, conflicting reports include claims that sunscreen increases risk for melanoma. Objective: To examine the strength and consistency of associations between melanoma and sunscreen use in the published literature. Data Sources: A comprehensive MEDLINE search of articles published from 1966 to 2003 that reported information on sunscreen use and melanoma in humans. Study Selection: Analytic studies reporting data on sunscreen use before diagnosis of melanoma. Data Extraction: Two independent reviewers extracted data. Inconsistencies were rereviewed until agreement was achieved. When necessary, a third party resolved discrepancies. Data Synthesis: Odds ratios were pooled across studies by using standard meta-analytic techniques. Pooled odds ratios for ever use among 18 heterogeneous studies did not support an association between melanoma and sunscreen use. Variation among odds ratios was explained by studies that did not adjust for confounding effects of sun sensitivity. The lack of a dose-response effect with frequency of use (never, sometimes, or always) or years of use provided further evidence of a null association. Conclusions: No association was seen between melanoma and sunscreen use. Failure to control for confounding factors may explain previous reports of positive associations linking melanoma to sunscreen use. In addition, it may take decades to detect a protective association between melanoma and use of the newer formulations of sunscreens.
Article
Alveolar breath sampling was used to assess trihalomethane (THM) exposures encountered by collegiate swimmers during a typical 2-hr training period in an indoor natatorium. The breath samples were collected at regular intervals before, during, and for 3 hr after a moderately intense training workout. Integrated and grab whole-air samples were collected during the training period to help determine inhalation exposures, and pool water samples were collected to help assess dermal exposures. Resulting breath samples collected during the workout demonstrated a rapid uptake of two THMs (chloroform and bromodichloromethane), with chloroform concentrations exceeding the natatorium air levels within 8 min after the exposure began. Chloroform levels continued to rise steeply until they were more than two times the indoor levels, providing evidence that the dermal route of exposure was relatively rapid and ultimately more important than the inhalation route in this training scenario. Chloroform elimination after the exposure period was fitted to a three compartment model that allowed estimation of compartmental half-lives, resulting minimum bloodborne dose, and an approximation of the duration of elevated body burdens. We estimated the dermal exposure route to account for 80% of the blood chloroform concentration and the transdermal diffusion efficiency from the water to the blood to in excess of 2%. Bromodichloromethane elimination was fitted to a two compartment model, which provided evidence of a small, but measurable, body burden of this THM resulting from vigorous swim training. These results suggest that trihalomethane exposures for competitive swimmers under prolonged, high-effort training are common and possibly higher than was previously thought and that the dermal exposure route is dominant. The exposures and potential risks associated with this common recreational activity should be more thoroughly investigated.
Article
• This study determines the percutaneous absorption of hydrocortisone when applied as a single dose or on a repetitive basis. Application was to the shaved ventral forearm of the rhesus monkey, an animal model in which some relevance to man has been shown. Absorption was quantified by measuring14C in aliquots of urine over five days. There was no substantial difference in total absorption when 13.3 μg/sq cm was applied as a single dose or when the 13.3 μg/sq cm was applied three times, totaling 40 μg/sq cm. However, when 40 μg/sq cm was applied as a single dose, absorption was substantially increased over 13.3 μg/sq cm applied either once or three times. Additionally, when the skin was washed between applications to remove previously applied material in the three application experiment, there was a statistically significant increase over not washing the skin. The clinical importance of these results to man will await appropriate clinical studies. (Arch Dermatol 113:620-622, 1977)
Article
This study determines the percutaneous absorption of hydrocortisone when applied as a single dose or on a repetitive basis. Application was to the shaved ventral forearm of the rhesus monkey, an animal model in which some relevance to man has been shown. Absorption was quantified by measuring 14C in aliquots of urine over five days. There was no substantial difference in total absorption when 13.3 microng/sq cm was applied as a single dose or when the 13.3 microng/sq cm was applied three times, totaling 40 microng/sq cm. However, when 40 microng/sq cm was applied as a single dose, absorption was substantially increased over 13.3 microng/sq cm applied either once or three times. Additionally, when the skin was washed between applications to remove previously applied material in the three application experiment, there was a statistically significant increase over not washing the skin. The clinical importance of these results to man will await appropriate clinical studies.
Article
Published permeability coefficient (K p) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (K oct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physicochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of K p upon MV (or MW) and K oct. It is found that the existence of an “aqueous-polar (pore) pathway” across the SC is not necessary to explain the K p values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected K p. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to >750, and log K oct ranging from −3 to + 6), the postulated upper limiting value of K p for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal K p values. Overall, then, we present a facile interpretation of a considerable body of skin permeability measurements that (a) very adequately describes the dependence of K p upon permeant size and lipophilicity, (b) generates parameters of considerable physicochemical and mechanistic relevance, and (c) implies that the SC lipids alone can fully characterize the barrier properties of mammalian skin.
Article
A preliminary study of dermal and respiratory exposure to chlorpyrifos (Dursban TC) during structural treatments was conducted with eight workers from a commercial pest control company. The compound was applied by sub-slab and soil injection to four houses, with each application involving two workers. Crawl space applications were included in three of the jobs. Field sampling extended over the entire workday, and included personal air samples and dermal exposure evaluation with patches and handwashes. A fluorescent tracer was added to the formulation for qualitative determination of skin deposition patterns. Pre-exposure and complete 72 hour urine samples were also collected. Total dermal exposure averaged 5.94 mg/hr. The major contributors were the upper legs (38%) and the forearms (34%). Accidents occurred during two of the four applications observed, and the two workers involved in the accidents were the most highly exposed individuals. The mean estimated absorbed daily dose was 9.5 ug/kg/day, with approximately 73% contributed by the dermal route. Thus, under these work conditions the Threshold Limit Value is not an appropriate guide for worker safety. The principal urinary metabolite of chlorpyrifos, 3,5,6-trichloro-2-pyridinol, was found in measurable quantities in all urine samples. Urinary metabolite levels collected 24-48 hr postexposure were highly correlated (R2 = 0.86) with total absorbed dose estimates. The high variability among individual excretion patterns suggests against the use of urine spot sampling, but longer collections may prove useful in the development of a Biological Exposure Index for chlorpyrifos.
Article
The effect of daily topical application on the in vivo percutaneous absorption of benzoic acid, parathion and salicylic acid in rhesus monkeys has been investigated. The study was designed to test further the hypothesis that topical bioavailability, or body burden, of a chemical following chronic exposure may be accurately predicted from the result of a single acute-dose experiment. No significant change in percutaneous absorption from that following the initial dose was observed following the eighth daily dose of a 14-day multidose regimen for each of the three penetrants considered. The results are consistent with those of recent experiments in humans with malathion and steroids, but not entirely consistent with the results of other animal studies.