title: Pharmacokinetic modeling as an approach to assessing the safety of residual formaldehyde in infant vaccines.
abstract: 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 μg, 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 μg/L, which is equivalent to a body burden of 66 μg 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.
authors.affiliation: Office of Biostatistics and Epidemiology, USFDA Center for Biologics Evaluation and Research, 1401 Rockville Pike, HFM-210, Rockville, MD 20852, USA. Robert.Mitkus@fda.hhs.gov
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mitkus
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Hess
authors.forename: Sorell L
authors.initials: SL
authors.lastname: Schwartz
mesh_terms: D003432:Cross-Linking Reagents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000737:chemistry; D005557:Formaldehyde / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018073:Haemophilus Vaccines / Q000737:chemistry; D017325:Hepatitis B Vaccines / Q000737:chemistry; D006801:Humans; D007223:Infant; D007273:Injections, Intramuscular; D008954:Models, Biological; D011054:Poliovirus Vaccine, Inactivated / Q000737:chemistry; D018570:Risk Assessment
chemical_list: D003432:Cross-Linking Reagents; D015721:Diphtheria-Tetanus-Pertussis Vaccine; D018073:Haemophilus Vaccines; D017325:Hepatitis B Vaccines; D011054:Poliovirus Vaccine, Inactivated; D005557:Formaldehyde