Previous laboratory studies showed a

blood eosinophil count of 600 to 1,400/cu

mm. Nasal smear showed abundant eosino-

phils. Quantitative immunoglobulins were

IgG, 1,250 mg/100 ml, IgA, 225 mg/100 ml;
IgM, 190 mg/100 ml; and IgE, 2,000 IU/ml.

Paraben
James E.

Allergy

Nagel, MD; John

T. Fuscaldo, MD;

Philip Fireman,

MD

\s=b\ A

hydrocortisone preparation containing methylparaben and propylparaben provoked bronchospasm and pruritis when given intravenously to
an asthmatic patient, whereas another hydrocortisone preparation without
paraben preservative did not. Direct and passive transfer (Prausnitz-K\l=u"\stner) skin tests for immediate hypersensitivity to parabens were positive.
Parabens, frequently employed as bacteriostatic agents, are capable of producing immunologically mediated, immediate systemic hypersensitivity reactions.

(JAMA 237:1594-1595, 1977)

PARABENS, the C,-C4 alkyl esters of

p-hydroxybenzoic acid, have been

used since the 1930s as bacteriostatic

and fungistatic agents in drugs, cos
metics, and foods. Contact sensitization to this group of agents, in the
form of an intractable eczematoid
dermatitis, was first reported in
19401; since that time, numerous re
ports have appeared in the literature
describing dermatitis caused by de

layed (contact) hypersensitivity to

the paraben esters.24 In 1973, a tencenter study of 1,200 individuals by
the North American Contact Derma
titis Group found a 3% incidence of

delayed hypersensitivity

to

paraben

esters.5

Even though parabens are present

in many food products, no reports of
immediate or delayed hypersensi

tivity

to

orally ingested parabens

have been published. Many parenterally administered medications, espe

cially those in multidose packages,
also contain parabens as pre
servatives. These paraben-containing
parenterals include antibiotics, corticosteroids, local anesthetics, radio-

pharmaceuticals, vitamins, antihy-

insulin,
diuretics,
pertensives,
heparin, and chemotherapeutic
agents. Frequent use of these pre
servatives notwithstanding, only two

From the Children's Hospital, University of

Pittsburgh School of Medicine, Pittsburgh.
Reprint requests to Children's Hospital, University of Pittsburgh School of Medicine, 125
Desoto St, Pittsburgh, PA 15213 (Dr Fireman).

hyper
parenterally adminis
sensitivity
tered parabens have been docu
instances

of

immediate

to

mented.6-7

Report of a Case
A 10-year-old boy was admitted to Chil
dren's Hospital of Pittsburgh in status
asthmaticus. Past history showed that atopic dermatitis had developed when the pa
tient was 4 months of age, perennial rhi
nitis occurred during his second year, and
wheezing developed when he was 3 years
old. Four of the patient's 12 siblings also
have asthma or seasonal rhinitis or both.
In spite of medical supervision and appro
priate therapy, the boy's severe asthma re
quired numerous emergency room and hos
pital admissions. Immediately prior to the
current hospitalization, his medications in
cluded oral aminophylline (20 mg/kg/24
hr), oral prednisone (10 mg on alternate
days), cromolyn sodium inhalations four
times daily, and immunotherapy injec
tions.
Table

Chest and sinus roentgenograms were nor

mal. Pulmonary function tests demon
strated mild obstructive disease, reversible
with use of an aerosol adrenergic bronchodilator. Immediate hypersensitivity skin
tests were positive for many environmen
tal allergens including ragweed, grasses,
trees, molds, animal danders, and house
dust, and several foods, including fish and
chocolate. Historically, exposure to these
same allergens exacerbated the patient's
asthma, rhinitis, or atopic dermatitis. No

previous drug hypersensitivities

were

known.
When emergency room treatment with
subcutaneous and aerosol epinephrine
failed to improve his asthmatic symptoms,
the patient was admitted to the hospital,
where therapy with intravenous aminophylline and a hydrocortisone prepara
tion containing methylparaben and propylparaben was started. Within minutes of
receiving the dose of paraben-containing

hydrocortisone, severe generalized pruritis

and substantially increased bronchospasm
developd. No urticaria, angioneurotic
edema, or hypotension were noted.
Because the etiology of the increased
symptoms was not immediately recog
nized, a second dose of paraben-containing
hydrocortisone was administered six hours
later. This again resulted in severe pruritis
and bronchospasm. Because hypersensitivi
ty to paraben or hydrocortisone was now
suspected, the next intravenous dose of the

was given in the form of

hydrocortisone sodium succinate, a nonparaben-containing preparation; this
caused no perceivable increase in the

corticosteroid

symptoms.

the patient was

after informed
consent was obtained, intravenous chal
lenge with the hydrocortisone preparation
that contained paraben was performed un
der controlled hospital conditions. This
provocation induced bronchospasm and

Four days later, when

clinically improved and

1.Hypersensitivity Skin Testing*

Immediate
(_<._,

Delayed

_ID_PJC_Patch
+
+
Methylparaben
Ethylparaben
Propylparaben

Sodium bisulfite

Hydrocortisone with parabenf

Hydrocortisone without parabent

+
+

ND
ND
ND

ND~

Rag weed_
_+
+_
*ID indicates intradermal; P-K, Prausnitz-Kstner (passive transfer) test; and ND, not done.

tHydrocortone.

jSolu-Cortef.

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Benzoic acid

Methylparaben
Ethylparaben
Propylparaben
p-Amlnobenzoic acid
Benzocaine
Procaine

H
HO
HO
HO

NH2
NHt
NHt

generalized pruritis, reversible with subcu

taneous epinephrine. As shown in Table 1,

immediate cutaneous wheal and flare reac

tions were elicited after intradermal test
ing with methylparaben (0.15%), ethylparaben (0.15%) and propylparaben (0.02%),
as well as with the paraben-containing
hydrocortisone. Extreme pruritis occurred
at the sites of the intradermal testing with
methylparaben and the paraben-contain
ing hydrocortisone. No reactions were
noted to the other preservative, sodium bi
sulfite (0.32%), or to the non-paraben-containing hydrocortisone preparation. Pas
sive transfer (Prausnitz-Kstner) testing
demonstrated positive wheal and flare re
actions to methylparaben, propylparaben,
hydrocortisone with paraben, and rag
weed, but not to ethylparaben or hydrocortisone without paraben (Table 1). Heat
ing of the patient's serum to 56C for one
hour abolished all positive Prausnitz-Kst
ner test results. Occlusive patch tests using
individual aluminum-backed patch test
strips, were negative for contact (delayed)
hypersensitivity. (However, the patient
was receiving oral corticosteroids at the
time of patch testing).

Comment
chemicals
such as the para
Simple
bens are incapable of producing sensitization and induction of immediate
or delayed hypersensitivity without
prior conjugation to a carrier mole
cule, usually a protein. The paraben is
then considered a hapten. Although
the capacity of a simple chemical to
form in vivo covalent bonds with the
carrier molecule correlates with its
ability to induce antibody formation
and delayed hypersensitivity, this
chemical property does not neces
sarily correlate with its ability to pro
duce immediate hypersensitivity or
anaphylactic reactions. This latter
phenomenon may be related to the
number of potential reacting sites
(antigenic determinants) on the
molecule and their spatial distribu
tion.8 Chemicals with a free amino
group in the para position of a ben
zene ring are frequent sensitizers.
Representative of this group are
p-aminobenzoic acid (PABA), benzocaine, procaine, and p-phenylenediamine. As shown in Table 2, para-

C6H4
C6H4
C6H4
C6H4
C6H4
C6H4
CtH4

CO
CO

CO"
CO
CO
CO
CO

compound containing these

parabens, which were capable of
being passively transferred, we be
lieve the reaction to be immunologically mediated and caused by the
paraben esters.
The use of parabens and sodium
benzoate as preservatives in drugs,
foods, and cosmetics is widespread.
Although relatively uncommon, sensi
tization to the parabens presents a
difficult diagnostic and therapeutic
problem to the clinician. Until re
cently, federal Food and Drug Ad
ministration regulations did not re
quire precise labeling of the contents
of over-the-counter medications,
foods, cosmetics, and oral prescription
drugs. This custom made avoidance of
parabens by the sensitized patient
virtually impossible.
Recent and pending modifications
of federal regulations requiring more
complete and precise labeling of
drugs, foods, and cosmetics will facil
itate avoidance of offending agents
by sensitized patients. This case of
immediate hypersensitivity to meth
ylparaben and propylparaben demon
strates that parabens should not be
as
used indiscriminately
pre
in
not
medicines
servatives, especially
frequently given to the allergic or po
tentially allergic patient.
son

Table 2.Congeners of Benzoic Acid

OH

OCH3

OC2H5
OC3H7
OH

OC2H5
OC2H4N(C,H,),

bens differ

structurally from these

compounds only in that they have a

hydroxyl group rather than an amino

group in the para position. Cross sen
sitivity between the p-amino and phydroxyl compounds has been previ
ously demonstrated by Aldrete and

Johnson.6
The precise route and mechanism
of this patient's sensitization to the
paraben esters cannot be established
with certainty. He had intermittently
used paraben-containing topical corticosteroids and lubricating creams
for treatment of his atopic derma
titis; however, he had never experi
enced adverse cutaneous reactions to
any of these preparations. We cannot
be certain that the patient had previ
ously received intravenous paraben;
however, since many parenteral med
ications contain paraben, this is a dis
tinct probability. Sensitization by
previous oral ingestion of parabens is
possible but highly unlikely, because
of the lack of documentation of sensi
tization and development of allergic
symptoms after oral challenge.
Mendelson et al9 reported a patient
with urticaria, angioneurotic edema,,
and bronchospasm following intra

methylprednisolone or hydrocortisone therapy. Positive immediate

venous

skin test reactions were found to pure

methylprednisolone and hydrocortisone; however, passive transfer test
ing was negative. Their patient did

challenge
with a paraben-containing diluent.
As pointed out by these authors,
small changes in the chemical struc
ture of the hydrocortisone molecule
may result in negative skin tests. The
only difference between the struc
tures of hydrocortisone sodium phos
phate and hydrocortisone sodium succinate is the phosphate or succinate
not react to intravenous

group at carbon 21 of the molecule.

Because the patient described here

had positive intravenous challenges

and positive, immediate wheal and
flare reactions to methylparaben and

propylparaben and the hydrocorti-

This study was supported in part by grant HD07850 from the Public Health Service. Dr Nagel
is the recipient of grant HD-00062 from the Pub
lic Health Service.
Natalie Certo, PhD, gave technical assistance,
and Donald Kipela, MD, identified this case.

Nonproprietary Name and

Trademarks of Drug
Cromolyn sodiumAarane, Intal.
References
1. Bonnevie P: \l=O/\verfolsomhedfor aethylparaoxybenzoat (Mycocten). Nord Med 6:684-685,

1940.
2. Sarkany I: Contact dermatitis from paraben. Br J Dermatol 72:345-347, 1960.
3. Schorr WP, Mohajerin AH: Paraben sensitivity. Arch Dermatol 93:721-723, 1966.
4. Schorr WF: Paraben allergy: A cause of intractable dermatitis. JAMA 204:859-862, 1968.
5. Epidemiology of contact dermatitis in
North America: 1972. North American Contact
Dermatitis Group. Arch Dermatol 108:537-540,
1973.
6. Aldrete JA, Johnson DA: Allergy to local
anesthetics. JAMA 207:356-357, 1969.
7. Latronica RJ, Goldberg AF, Wightman JR:
Local anesthetic sensitivity: Report of a case.
Oral Surg 28:439-441, 1969.
8. DeWeck AL, Frey JR: Hypersensitivity to
simple chemical allergens. Monogr Allergy 1:5\x=req-\
41, 1966.
9. Mendelson LM, Meltzer EO, Hamburger
RN: Anaphylaxis-like reactions to corticosteroid
therapy. J Allergy Clin Immunol 54:125-131,
1974.

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