Summary
This paper reports results from a series of four PROSPERO-registered systematic reviews examining US infant exposure to arsenic, cadmium, lead, mercury, and per- and polyfluoroalkyl substances (PFAS) from human milk (HM) and infant formula (IF). It is relevant to the ready-to-feed formula page because it identifies the Ryu et al. 1983 study as the only RTF-specific blood lead dataset in the US infant literature and because it provides the most recent evidence on arsenic biomarker concentrations in US formula-fed infants from the New Hampshire Birth Cohort.
Key numbers
Arsenic (urinary biomarker, New Hampshire Birth Cohort, N=4 articles):
From Pikounis et al. 2024 (summarized in Table 1 of this paper):
- All infants at 6 weeks (n=462): total urinary arsenic geometric mean 0.23 µg/L (95% CI 0.21-0.25)
- Exclusively breastfed (n=338): 0.17 µg/L (0.15-0.18)
- Exclusively formula-fed (n=44): 0.85 µg/L (0.66-1.09)
- Combination fed (n=80): 0.42 µg/L (0.35-0.5)
Formula-fed infants had approximately 5-fold higher urinary arsenic than breastfed infants. This reflects combined exposure from formula product plus any reconstitution water.
Lead (blood, US infant studies, N=3 articles summarized in Table 2):
From Ryu et al. 1983 — the only RTF-specific dataset identified in this systematic review series:
- Infants fed ready-to-feed formula (67 kcal/dL, glass bottles): n=23 at each time point
- Blood lead by flameless atomic absorption spectrophotometry:
- 8 days old: mean 8.9 µg/dL (SD 3.2)
- 23 days: 5.8 µg/dL (SD 2.2)
- 56 days: 5.1 µg/dL (SD 1.7)
- 84 days: 5.4 µg/dL (SD 2.8)
- 112 days: 6.1 µg/dL (SD 1.7)
- Combined data (infants receiving HM or IF cans at later ages):
- 140 days (n=7): 9.3 µg/dL (SD 4)
- 168 days (n=7): 12.1 µg/dL (SD 4)
- 196 days (n=7): 14.4 µg/dL (SD 4.4)
Ryu et al. was conducted in Iowa City, Iowa, 1975-1976, with birth weights >2450 g. 100% White. The paper rated analytic method as “acceptable.” Data collected in 1975-1976; contemporary formula lead concentrations are substantially lower. These are blood biomarker values, not product concentration measurements.
From Rabinowitz et al. 1985 (Boston, 1979-1981):
- Formula-fed infants (n=NR, formula = Similac, Enfamil, and Isomil): blood lead mean 5.6 µg/dL (SE 0.5)
- Human milk-fed: 7.6 µg/dL (SE 0.6)
- All infants (n=22): mean 6.2 µg/dL (SE 0.5)
Cadmium: N=2 US articles reported urinary cadmium from the New Hampshire Birth Cohort. Geometric mean urinary cadmium at 6 weeks was 0.14 µg/L (IQR 0.13-0.15) for all infants (n=462, Pikounis 2024). No significant difference by feeding mode (P=0.065).
Mercury: N=1 US article reported total mercury (Signes-Pastor 2023 from NHBC). No feeding-mode comparison was performed.
Bioavailability findings: No articles meeting inclusion criteria were identified for bioavailability of arsenic, cadmium, lead, mercury, or PFAS from HM or IF in the US. No evidence on bioavailability was found in this series.
Key gaps identified by the authors: Lack of contemporary, geographically and demographically diverse US infant biomonitoring data; no data on methylmercury or PFAS in US infant biospecimens from HM/IF; evidence largely from one cohort (New Hampshire Birth Cohort); most studies are >30 years old for lead.
Methods (brief)
Series of four systematic reviews developed with a Technical Expert Panel (TEP), registered a priori on PROSPERO. Databases searched: CAB Abstracts, CENTRAL, CINAHL, Embase, MEDLINE through 2 April 2025. Studies required to report contaminant concentrations in relation to infant feeding on HM only, IF only, or HM and IF; studies in US populations plus global HDI high/very-high countries for bioavailability questions. Risk of bias assessed with ROBINS-E (observational) or ROB 2 (randomized). Narrative synthesis; no meta-analysis performed because “small and unrepresentative samples” did not support pooling. This SR is companion to Thoerig et al. 2025 (PMC12674019) which covers contaminant concentrations in HM and IF.
Implications
- Certification: Provides the most recent US evidence on formula-associated arsenic biomarker exposure. The 5-fold higher urinary arsenic in formula-fed versus breastfed US infants at 6 weeks (Pikounis 2024, extracted in this SR) is the most defensible recent number for US formula-exposed infant arsenic burden. The Ryu 1983 RTF blood lead data are historical (1975-1976 formulation) and not appropriate for contemporary product benchmarks but illustrate RTF-specific exposure.
- Courses: Useful for teaching the distinction between product concentration (which this SR did not find contemporary data for) and biomarker-based exposure evidence.
- App: Supports arsenic exposure estimates for formula-fed US infants at 6 weeks.
- Microbiome: No direct microbiome endpoint.
Provenance notes
Open-access CC BY article. PDF retrieved from PMC (PMC13156631). SHA256 verified against MANIFEST.csv for HMI-PROD-ready-to-feed-formula-1.
Update history
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