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Vaccine 31 (2013) 2738–2743

Contents lists available at SciVerse ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Pharmacokinetic modeling as an approach to assessing the safety of residual
formaldehyde in infant vaccines
Robert J. Mitkus a,∗ , Maureen A. Hess b , Sorell L. Schwartz a,c
a
b
c

Office of Biostatistics and Epidemiology, USFDA Center for Biologics Evaluation and Research, 1401 Rockville Pike, HFM-210, Rockville, MD 20852, United States
Office of Vaccines Research and Review, USFDA Center for Biologics Evaluation and Research, 1401 Rockville Pike, HFM-405, Rockville, MD 20852, United States
Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Rd NW, Washington, DC 20057, United States

a r t i c l e

i n f o

Article history:
Received 25 July 2012
Received in revised form 5 March 2013
Accepted 31 March 2013
Available online 11 April 2013
Keywords:
Formaldehyde
Inactivating agent
Safety
Pharmacokinetics
Modeling

a b s t r a c t
Formaldehyde is a one-carbon, highly water-soluble aldehyde that is used in certain vaccines to inactivate
viruses and to detoxify bacterial toxins. As part of the manufacturing process, some residual formaldehyde can remain behind in vaccines at levels less than or equal to 0.02%. Environmental and occupational
exposure, principally by inhalation, is a continuing risk assessment focus for formaldehyde. However,
exposure to formaldehyde via vaccine administration is qualitatively and quantitatively different from
environmental or occupational settings and calls for a different perspective and approach to risk assessment. As part of a rigorous and ongoing process of evaluating the safety of biological products throughout
their lifecycle at the FDA, we performed an assessment of formaldehyde in infant vaccines, in which
estimates of the concentrations of formaldehyde in blood and total body water following exposure to
formaldehyde-containing vaccines at a single medical visit were compared with endogenous background
levels of formaldehyde in a model 2-month-old infant. Formaldehyde levels were estimated using a
physiologically-based pharmacokinetic (PBPK) model of formaldehyde disposition following intramuscular (IM) injection. Model results indicated that following a single dose of 200 ␮g, formaldehyde is
essentially completely removed from the site of injection within 30 min. Assuming metabolism at the
site of injection only, peak concentrations of formaldehyde in blood/total body water were estimated to
be 22 ␮g/L, which is equivalent to a body burden of 66 ␮g or <1% of the endogenous level of formaldehyde. Predicted levels in the lymphatics were even lower. Assuming no adverse effects from endogenous
formaldehyde, which exists in blood and extravascular water at background concentrations of 0.1 mM,
we conclude that residual, exogenously applied formaldehyde continues to be safe following incidental
exposures from infant vaccines.
Published by Elsevier Ltd.

1. Introduction
Formaldehyde is an effective cross-linking agent that is used
in certain vaccines to inactivate viruses and to detoxify bacterial
toxins while not materially affecting antigenicity [1]. Formaldehyde may also contribute to the preservation of these vaccines and
help ensure that there is no reversion of the biological components
back to an active or toxic state [2,3]. As part of the manufacturing process, residual free formaldehyde can remain behind at
levels of 0.4–100 ␮g per 0.5 mL (0.00008–0.02%), depending on
the vaccine product; 2.5 ␮g per 0.5 mL dose (0.0005%) is a typical
level of residual formaldehyde measured in some yearly influenza
vaccines by FDA chemists [Alfred Del-Grosso, personal communication]. Formaldehyde has not been associated with local or systemic

∗ Corresponding author. Tel.: +1 301 827 6083.
E-mail address: Robert.Mitkus@fda.hhs.gov (R.J. Mitkus).
0264-410X/$ – see front matter. Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.vaccine.2013.03.071

adverse effects following vaccine administration other than a single case of exacerbation of eczema reported in an adult healthcare
worker who received a formalin-containing hepatitis B vaccine
[4–6].
In humans and other mammals, formaldehyde is produced normally in all cells of the body by oxidative N-demethylation of
endogenous metabolic intermediates [7,8]. Accordingly, formaldehyde exists naturally at relatively constant levels of about 0.1 mM
in both blood and extravascular tissues, and almost completely in
its hydrated form, methanediol, given the predominantly aqueous nature of those compartments [9–11,14,54,55]. Predictably,
with a water solubility of 400 g/L, exogenous formaldehyde, like
methanol, should distribute in total body water, i.e. in a volume of distribution of about 0.7 L/kg, and the plasma half-life
of exogenously administered formaldehyde is extremely short,
approximately 1.5 min [12,13,36]. Assuming a volume of distribution of approximately 50 L for a 70-kg individual, this implies a
total body formaldehyde turnover rate of approximately 69 mg per
minute, based on body water distribution.

R.J. Mitkus et al. / Vaccine 31 (2013) 2738–2743

2739

Fig. 1. The metabolism of formaldehyde. FDH: formaldehyde dehydrogenase. Modified from [51]. Reproduced with permission.

Both endogenous and exogenous formaldehyde are scavenged
by glutathione (GSH) and metabolized in a two-step reaction
(Fig. 1) involving formaldehyde dehydrogenase (FDH) and Sformylglutathione hydrolase [17]. Formaldehyde may also be
metabolized by aldehyde dehydrogenase 1A1 and 2, or catalase;
however, FDH, with an ∼200-fold lower Michaelis–Menten constant, Km , is the predominant metabolizing enzyme [15,16]. Studies
on the distribution of FDH and S-formylglutathione hydrolase in
rats and humans indicate that both are present ubiquitously in tissues and at similar levels or activity across tissue [15,18–22]. This
reflects the tight homeostatic regulation of formaldehyde in mammalian tissues, especially muscle, blood, and blood vessels [23–25].
Studies have failed to demonstrate significant differences in FDH
expression in the human population [17,26,27].
Environmental and occupational exposure to formaldehyde,
principally by inhalation, has been and is a continuing risk assessment focus and area of debate and research [10,28,29,65]. This
arises from the high reactivity of formaldehyde with small and
large biological molecules, as well as from animal and epidemiological data indicating that formaldehyde is a human carcinogen
by that route. Exposure to formaldehyde via vaccine administration, however, is qualitatively and quantitatively different from
environmental and occupational settings and calls for a different
perspective and approach to risk assessment.
There are stark differences in exposure amounts and duration, as
well as time factors in absorption and distribution, that distinguish
vaccine-source formaldehyde from occupational and environmental sources of exogenous formaldehyde. For example, exposure to
formaldehyde in vaccines is parenteral, acute, and infrequent, with
a dosing interval in infants of one month or more, compared to
occupational exposures which are often daily via the inhalation
route, continuous throughout a working day, or chronic. These differences, combined with the understanding that formaldehyde is
an endogenous molecule that exists in the body at high background
levels, imply that risk assessments relevant to occupational and
environmental formaldehyde exposures are not applicable to exposure by the vaccine route. Furthermore, while regulatory limits for
both oral and inhalational exposures exist for formaldehyde, those

thresholds are primarily for repeat long-term, rather than singledose, exposures [28,56,57]. Given the significant uncertainty that
results from route-to-route as well as intermediate-/long-term to
single-dose extrapolations based on those regulatory values, they
are not considered relevant for assessing risk from episodic exposures to residual formaldehyde in vaccines.
While several studies have been published in either animals following experimental treatment or in humans following iatrogenic
exposures to formaldehyde by the intravenous, intraperitoneal,
or intradental route [58–62], we found no published data on
the fate of intramuscular formaldehyde in any species of any
age. In the absence of relevant experimental or clinical data on
levels of formaldehyde in the body via the IM route, we developed a physiologically-based pharmacokinetic (PBPK) model that
estimates both local and systemic levels of vaccine formaldehyde following IM administration. We then compared our model
estimates with known steady-state levels of endogenous formaldehyde and utilized that comparison as the basis of an assessment
of the safety of formaldehyde in infant vaccines. Our assessment is based on a plausibility argument: it is neither deductive,
wherein the conclusion logically derives from the premise; nor
inductive, wherein the conclusion is probabilistically derived from
the premise. Plausibility has been subsumed, in some descriptions, under abduction; and Walton cites Rascher in stating that
“[P]lausibility. . . evaluates propositions in relation to the standing and solidity of their cognitive basis by weighing available
alternatives” [37]. It is beyond the scope of this assessment,
however, to proffer a complete exposition of the philosophical
underpinnings of plausibility arguments.
2. Methods
2.1. Pharmacokinetic modeling
The model used for pharmacokinetic estimations was based on
a hypothetical 2-month-old, 4.2 kg infant who, by these parameters is in the lower 10th percentile (United States) for age-weight
relationship [30]. This age was chosen because a low-birth-weight,

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Table 1
Physiological inputs for the PBPK model of formaldehyde disposition in infants.
Compartment

Volume (ml)

Blood flow (mL/min)

Blood
Body water reservoir
Quadriceps zone 1
Quadriceps zone 2

330
2670
545

987 (cardiac output)
985.5
1.9 (total)

2-month old infant could receive the highest maximum exposure to formaldehyde-containing vaccines per unit body weight.
Specifically, this would obtain in the 4.2-kg infant receiving 208 ␮g
formaldehyde from Tripedia® (DTaP, diphtheria tetanus and acellular pertussis), ActHIB® (Hib, Haemophilus B conjugate), IPOL®
(IPV, inactivated polio), and Recombivax HB® (HepB, hepatitis B)
products at a single office visit, according to the 2012 vaccination
schedule published by the Advisory Committee on Immunization
Practices of the Centers for Disease Control and Prevention [31,52].
A 6-month-old infant could receive a higher combined dose of
formaldehyde (∼250 ␮g from the four vaccines mentioned above
plus 50 ␮g from the Fluzone® influenza vaccine at a single office
visit; however, since a 6-month-old weighing 6.8 kg (lower 10th
%ile) is larger than a 2-month-old, s/he would actually receive a
lower dose per unit body weight. In addition, because some healthcare providers may use alternative immunization schedules and
some vaccine products contain lower amounts of formaldehyde
than others, it is unclear how typical either of those formaldehyde exposures would be. For example, Pediarix® , a combined
DTaP/IPV/Hep B vaccine that an infant might receive at 2 months of
age, contains less than or equal to 100 ␮g formaldehyde per dose.
Therefore, we assumed a maximum single dose of 200 ␮g as an
upper estimate of formaldehyde exposure in our model.
The anatomical and physiological parameter values for our
model are summarized in Table 1 and were derived as follows: total
body water, 0.7 L·kg (bw)−1 [32]; blood volume, 80 mL·kg (bw)−1
[32]; quadriceps femoris muscle volume, 12 mL·kg (bw)−1 , which
was based on adult volume [33] corrected for infant/adult body
composition difference (0.55) and infant/adult muscle distribution between the upper and lower extremities (0.55) [32];
cardiac output, 235 mL·min−1 ·kg (bw)−1 [34]; quadriceps blood

flow, 38 mL·min−1 ·kg (tissue)−1 [35]; Km of FDH in rat respiratory/olfactory tissue, 0.09 ␮g/mL (based on [16], in absence of a
value in humans); Vmax of FDH in muscle, 189 ␮g/min (derived from
[22]). A physiologically-based pharmacokinetic model was developed that related the quadriceps muscle to rest of the body (Fig. 2).
The quadriceps muscle was divided into two zones, an administration zone (qf1) and a metabolic zone (qf2). This was to account
for the time delay in formaldehyde distribution among the muscle
fibers and intracellular entry. The proportion of space allotted to the
qf1 zone was an estimate, the accuracy of which is not consequential, as is discussed below. Estimates of formaldehyde in blood and
total body water and at the site of injection post dose were made
using the physiologically-based pharmacokinetic (PBPK) modeling
software, CMATRIX [53]. Distribution into these media following
injection was based on its very high water solubility (400 g/L [36]).
The purpose of the PBPK model was also to focus on administered
formaldehyde as it is distributed within and leaves the muscle,
physically or metabolically. Consequently (as a nod to the principle
of parsimony – Occam’s razor), extra-muscle metabolism was not
included in the model, although it can be assumed to occur given
the ubiquitous presence of FDH in mammalian tissues.
3. Results and discussion
As a first, and understandably rudimentary, approximation, a
classical one-compartment pharmacokinetic model was employed.
Irrespective of cross-link formation, the endogenous formaldehyde
blood concentration of 0.1 mM reflects the concentration in total
body water, almost exclusively as methanediol, save for corrections
for cellular and protein blood components. The total body water in
the model infant is 3 L, so that the total endogenous formaldehyde
in body water is 9 mg (30 mg·mmol−1 × 0.1 mM × 3 L). Continuing the starting-point analysis, the administration of 200 ␮g of
formaldehyde would increase the total body water content of
formaldehyde by approximately 2%, or 2 ␮M.
Clearly, the estimate of formaldehyde concentration in total
body water after a one-compartment distribution is inaccurate; it
ignores the metabolism of formaldehyde and its distribution from
an intramuscular site. Therefore it is an overestimate of additional

Fig. 2. PBPK model of formaldehyde disposition in infants (a) and differential equations (b). Model differential equations were generated and solved using the software
CMATRIX. Cbld : arterial blood concentration; C[compartment] : physiological compartment concentration, which, in this model, is equal to the effluent venous blood concentration; Q[compartment] : physiological compartment blood flow; V{compartment] : physiological compartment volume; k1,2 : diffusion constant between qf1 and qf2; Vmax and Km :
Michaelis–Menten kinetics parameters.

R.J. Mitkus et al. / Vaccine 31 (2013) 2738–2743

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Fig. 3. PBPK model estimates of the time course of formaldehyde in blood and total body water and as a fraction of administered dose at the site of injection following a
single intramuscular injection of 200 ␮g in infants. Metabolism by FDH modeled only at site of injection.

distributed formaldehyde provided by the 200 ␮g dose. The essential question is whether or not the administered formaldehyde
gains access to tissue sites distinct from endogenous formaldehyde.
This was assessed by using the physiologically-based pharmacokinetic model shown in Fig. 2a and b.
Fig. 3 shows the blood and body reservoir formaldehyde concentrations and total muscle formaldehyde content over the 30-min
post administration period based on our PBPK model. The peak
body water concentration of formaldehyde in the model infant is
just under 22 ␮g/L following a 200 ␮g dose. This is equivalent to a
body burden of approximately 66 ␮g formaldehyde, or <1% of the
endogenous level of formaldehyde, which we consider more plausible than the 2% estimate from the one-compartment model. This
body burden would have been even lower had we included the contribution of extra-muscular metabolism by the ubiquitous enzyme,
formaldehyde dehydrogenase, to the elimination of formaldehyde
in the model. Model results also indicate that formaldehyde is
almost completely removed from muscle within 30 min of a single
dose.
We started our analysis with the premise that the vaccinerelated exogenous formaldehyde is pharmacokinetically indistinct
from endogenous formaldehyde, and, as mentioned, determined
that it is not. It is initially concentrated in a section of muscle. It leaves the site of injection by two well-known means that
are represented in our PBPK model: (1) circulating blood and (2)
metabolism. There is another possible route of departure from
the muscle that is not represented in the PBPK model, i.e. entry
into lymphatics. Lymph production is the means of maintaining an
iso-volumetric and iso-gravimetric interstitial space. Conceivably,
an intramuscular injection could increase interstitial fluid hydrostatic pressure, resulting in bulk fluid movement from the muscle
lymphatic capillaries. The flux of water would carry with it the
molecules in that water, including formaldehyde. Lymphatic flow

is reported to be 50–100 times less than blood flow [38]. Using a
PBPK model wherein a 0.5 mL lymph compartment was included
in the quadriceps muscle, and in direct contact with qf zone 1
(Fig. 2a), and a lymph flow of 0.04 mL/min, it is estimated that,
if any formaldehyde at all leaves the muscle via lymph drainage,
it is not more than 0.3% of the dose. This loss would also occur
within 30 min after dose administration. This is consistent with
the findings by Navas et al. [39] on the removal of intramuscularly administered 99m Tc-labeled albumin from at-rest muscle via
lymphatic flow, i.e. 0.06 ± 0.05% min−1 , and taking into account
that unlike formaldehyde, there is no muscular metabolism of
the injected albumin. Accordingly, insignificant formaldehyde content is added to the lymph, when compared with the endogenous
concentration (equal to body water concentration). Specifically,
endogenous formaldehyde levels (9 mg) are likely to be at least
four orders of magnitude higher than any exogenous formaldehyde
that might “escape” into the lymphatics following a 200 ␮g dose of
formaldehyde.
We do not expect adverse effects from vaccine formaldehyde
for several reasons. First, the background levels of formaldehyde in
an infant are 136× (9000 ␮g/66 ␮g) higher than peak systemic levels of formaldehyde following vaccine administration. To expect an
adverse effect from such a small amount of exogenous formaldehyde would necessarily imply adverse effects from endogenous
formaldehyde, which is present at much higher levels. We could
find no experimental or clinical evidence in the biomedical literature that demonstrated any adverse effect from endogenous
formaldehyde. In fact, human cells are exposed to ∼1000 endogenous formaldehyde-DNA adducts, among many other forms of DNA
damage, at any given time [7,43]. Importantly, glutathione (GSH)
and other electrophile and free radical scavengers, metabolizing
enzymes, and DNA repair mechanisms work to keep the levels
of reactive endogenous compounds and their adducts under tight

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R.J. Mitkus et al. / Vaccine 31 (2013) 2738–2743

homeostatic control [45–47,50]. Lutz [44] has shown that even
when endogenous hepatic formaldehyde production was pushed
to maximal levels in rats following single oral exposures to an
extremely high dose of methanol (1000 mg/kg bw), there was no
corresponding increase in DNA–protein crosslinks.
Second, as described above, our PBPK model indicates that a
maximum of only a third of the dose (66 ␮g) will be distributed
systemically following a 200-␮g dose of exogenous formaldehyde;
the remainder would be expected to be dispatched rapidly at the
site of injection through GSH scavenging and metabolism (primarily) and tissue binding [40]. Considering the normal range of
formaldehyde in tissues related to its role in glycine, methionine,
choline, and serine metabolism, and in nucleic acid synthesis, we
do not consider it plausible that a <1% change (66 ␮g/9000 ␮g) in
the systemic level of formaldehyde would create a disease condition where none existed prior to the change [41,42]. Such an
effect would imply endogenous formaldehyde under homeostatic
control having heretofore unknown sensitivity, one more finely
tuned than that for other endogenous compounds including calcium, sodium, and potassium, to name a few. Had we included the
activity of formaldehyde dehydrogenase in blood and tissues distant to the site of injection, our estimate of systemically distributed
formaldehyde would have been even lower.
We have also considered the possibility that exogenous
formaldehyde levels might be “additive to background” (i.e.,
endogenous) levels and lead to systemic toxicity. We find this possibility to be untenable, since the additivity to background hypothesis
assumes an adverse effect from endogenous levels of formaldehyde
to begin with [48]; as mentioned earlier, there is no evidence for any
adverse effect from endogenous levels of formaldehyde, including
tumors. Moreover, we found no evidence in the published literature
of an association between vaccination or formaldehyde-containing
vaccines and childhood skeletal muscle tumors (rhabdomyoma or
rhabdomyosarcoma), both of which are rare in children and adolescents [63,64]. To summarize using language from the National
Academy of Sciences (2009) in their most recent guidance document on risk assessment practice, therefore, we would expect
no “chemical additivity” [48] of vaccine formaldehyde to endogenous levels of formaldehyde, since, as our model demonstrates,
the level of formaldehyde in the body at a single vaccination is
a tiny fraction (<1%) of the endogenous level and so short-lived
in plasma (t1/2 = 1.5 min) as to be inconsequential. And we would
also expect no “biologic additivity” to background [48], since there
are no known systemic toxicities in the general population associated with endogenous formaldehyde to which vanishingly small
amounts of vaccine formaldehyde could contribute.
Finally, Zhang et al. [49], attempting to “bridge the gap” between
the epidemiologic evidence of hematologic malignancies “due to
[occupational] formaldehyde exposure” and “possible mechanistic routes” conjectured that inhaled formaldehyde could cause
leukemia by “inducing DNA damage and chromosome aberrations
in hematopoietic stem or early progenitor cells in the bone marrow
or circulating in the blood”. Placing the debatable and speculative
aspects of this proposition aside [65], we do not think it is plausibly applicable to the circulating formaldehyde originating from
vaccine administration for all of the reasons stated thus far, as well
as the significant differences in rate and duration of exposure to
formaldehyde that are known to exist between the occupational
and iatrogenic exposure scenarios.

4. Conclusion
Formaldehyde is an effective cross-linking agent that is used
in certain vaccines to inactivate viruses and to detoxify bacterial toxins while not materially affecting antigenicity. As a result

of the manufacturing process, some residual formaldehyde can
remain behind in certain vaccines at low levels. Vaccine formaldehyde has not been associated with local or systemic adverse
effects other than a single case of exacerbation of eczema reported
over 25 years ago in an adult healthcare worker who received a
formalin-containing hepatitis B vaccine. As part of a rigorous and
ongoing process of evaluation of the safety of biological products
throughout their lifecycle, we developed a physiologically-based
pharmacokinetic model of vaccine formaldehyde disposition following intramuscular injection of a model 2-month-old infant. Our
model indicated that following a single dose of 200 ␮g, formaldehyde is essentially completely removed from the site of injection
within 30 min. Under the conservative assumption of metabolism
at the site of injection only, peak concentrations of formaldehyde
in blood/total body water were estimated to be 22 ␮g/L, which
is equivalent to a body burden that is <1% of the endogenous
level of formaldehyde. Predicted levels in the lymphatics were
even lower. In the absence of any known adverse health effects
from endogenously produced formaldehyde, which exists in blood
and extravascular water at steady-state concentrations that are
more than 100-fold higher, we consider vaccine-related, exogenous formaldehyde to be a miniscule part of the daily formaldehyde
turnover by the body, and, therefore, do not find it plausible that
vaccine-related formaldehyde represents an unsafe component of
infant vaccines.
Acknowledgment
We thank Dr. Agnieszka Sulima for assistance with her translation of reference 58 from Polish.
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