Vaccine 31 (2013) 2738–2743 Contents lists available at SciVerse ScienceDirect Vaccine j our nal homep ag e: 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 Office of Biostatistics and Epidemiology, USFDA Center for Biologics Evaluation and Research, 1401 Rockville Pike, HFM-210, Rockville, MD 20852, United States b Office of Vaccines Research and Review, USFDA Center for Biologics Evaluation and Research, 1401 Rockville Pike, HFM-405, Rockville, MD 20852, United States c 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 formalde- hyde 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 assess- ment. 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 intramus- cular (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 formalde- hyde. 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]. Formalde- hyde 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 manufac- turing 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 communica- tion]. 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). adverse effects following vaccine administration other than a sin- gle 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 nor- mally in all cells of the body by oxidative N-demethylation of endogenous metabolic intermediates [7,8]. Accordingly, formalde- hyde 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 aque- ous 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 vol- ume 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 distribu- tion 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. 0264-410X/$ – see front matter. Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.vaccine.2013.03.071