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ACIP 2025
BusinessThimerosal as a Vaccine Preservative
Prepared for the
Advisory Committee for
Immunization PracticesLyn Redwood RN, MSN, FP (Retired)
2The Food and Drug Administration
Modernization Act of 1997
•Compiled list of drugs and foods that contained intentionally introduced
mercury compounds
•Provided quantitative and qualitative analysis of mercury compounds
•Report included 219 products which included 11 biologics and immunoglobulin
therapies
Ref: U.S. Congress. (1997, November 21). Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105 -115, 111 Stat. 2296.
31999 Joint Statement by US Public Health Service
(PHS) and American Academy of Pediatrics (AAP)
Thimerosal in Vaccines: A Joint Statement of the American Academy of Pediatrics and the Public Health
Service. MMWR Weekly. July 09, 1999 / 48(26);563 -565.•On July 9th , 1999, a joint statement issued by PHS and AAP called for the immediate
reduction and elimination of the mercury based preservative thimerosal from infant
vaccines based on the findings that infants and children who received vaccines
preserved with thimerosal could be exposed to mercury in excess of federal safety
guidelines.
•“because any potential risk is of concern, the Public Health Service (PHS), the
American Academy of Pediatrics (AAP), and vaccine manufacturers agree that
thimerosal -containing vaccines should be removed as soon as possible.”
4 Institute of Medicine
Immunization Safety Review of Thimerosal Containing Vaccines
and Neurodevelopmental Disorders (October 2001)
•The committee “supported prior decisions made by the ACIP and AAP to call for the removal of
thimerosal from vaccines that are part of the recommended childhood immunization schedule.”
But they noted that “vaccines that are not part of the recommended childhood immunization
schedule still contain thimerosal as a preservative and may be given to some children” and a
lingering concern that there remains “on the shelf” an unknown quantity of thimerosal -containing
Hib, hepatitis B, and DTaP vaccines.
•Recommended: “the use of thimerosal free DTaP , HiB and Hepatitis B vaccines despite the fact that
there might be remaining supplies available” and “full consideration be given by appropriate
professional societies and government agencies to removing thimerosal from vaccines
administered to infants, children or pregnant women in the united States. ”
Institute of Medicine (US) Immunization Safety Review Committee; Stratton K, Gable A, McCormick MC, editors. Immunization Saf ety Review: Thimerosal -
Containing Vaccines and Neurodevelopmental Disorders. Washington (DC): National Academies Press (US); 2001. Immunization Safe ty Review, Thimerosal -
Containing Vaccines and Neurodevelopmental Disorders. Available from: https://www.ncbi.nlm.nih.gov/books/NBK223724/
5Safety Studies
Prior to Marketing Thimerosal as Vaccine Preservative
(1) Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines Pediatrics. 2001;(107)5:1147 -1153.
(2) Powell HM, Jamieson WA. Merthiolate as a germicide. Am J. Hyg. 1931;(13):296 -310.
(3) Department of Health and Human Services. 21 Code of Federal Regulations: 601.25. 1985•In 1997, FDA Modernization Act prompted assessment of thimerosal use in vaccines.
•FDA was unable to find any clinical studies formally evaluating the use of thimerosal
before its initial marketing in 1930’s. (1)
•Single study published in 1931 where thimerosal administered to individuals suffering
from meningitis. (2)
-Not designed to specifically examine toxicity and no clinical assessments or laboratory
studies reported.
•FDA grandfathered in the use of thimerosal and did not require the typical animal safety
data for finished biological products, including active and inactive ingredients. (3)
6 Thimerosal use in vaccines
Ref: 1. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines Pediatrics. 2001;(107)5:1147 -1153.
2. Powell HM, Jamieson WA. Merthiolate as a germicide. Am J. Hyg. 1931;(13):296 -310.
3. Department of Health and Human Services. 21 Code of Federal Regulations: 601.25. 1985 •Thimerosal was first introduced as a preservative in vaccines in the 1930’s after being
developed and patented in 1927 and subsequently marketed by Eli Lilly under the trade
name “Merthiolate” in 1928.
•After a deadly incident of bacterial contamination of vaccines in Australia where 12
children died from staphylococcal -contaminated diphtheria vaccine, the FDA began
enforcing safety standards which led to regulations requiring that all multidose vaccines
contain a preservative to prevent contamination.
•Thimerosal was used during the manufacturing process and in multi -dose vials to
prevent bacterial and fungal contamination. By the 1930’s thimerosal became widely
used as a preservative in vaccines and other medical products.
7 Thimerosal Not Generally Recognized
as Safe and Effective (GRASE) in OTC Drugs
Ref: Federal Register, Department of Health and Human Services, Food and Drug Administration. Mercury -Containing Drug Products for Topical
Antimicrobial Over -the-Counter Human Use; Establishment of a Monograph. (January 5, 1982);47(2):436 -442. 47 FR 436 [Docket No. 75N -0183(1)
Federal Register, Department of Health and Human Services, Food and Drug Administration. Status of Certain Additional Over -the-Counter Drug
Category II and III Active Ingredients. (April 22, 1998);63(77):19799 -19802. 21 CFR Part 310 [Docket No. 75N -183F, 75N -183D, and 80N-0280. •In 1975, FDA convened panel of experts to evaluate the use of mercury -containing over -the-counter (OTC). The panel
found evidence that thimerosal was “35.3 times more toxic for embryonic chick heart tissue than for Staphylococcus
aureus” and “was no better than water in protecting mice from potential fatal streptococcal infections.”
•The FDA issued a report of the panel’s findings in the Federal Register in 1982 which concluded that “thimerosal was
not safe for OTC topical use because of its potential for cell damage if applied to broken skin and its allergy potential,
not effective “because bacteriostatic action could be reversed.”
• In response to the expert panels report, the FDA published final rules in the Federal Register in 1998 that concluded
the use of thimerosal in over -the-counter products is not “generally recognized as safe or effective.” (GRASE)
8
Evidence of Thimerosal
Ineffectiveness as a Preservative
Stetler HC, Garbe PL, Dwyer DM, Facklam RR, Orenstein WA, West GR, Dudley KJ, Bloch AB. Outbreaks of group A streptococcal ab scesses following diphtheria -
tetanus toxoid -pertussis vaccination. Pediatrics. 1985 Feb;75(2):299 -303. PMID: 3881728.
Smith S. Safety fears cut vaccine for flu. Priority urged for the aged, frail. Boston Globe . (October 6, 2004).
http://www.boston.com/news/globe/health_science/articles/2004/10/06/safety_fears_cut_vaccine_for_flu?mode=PF•In 1982, clusters of disease from Group A streptococcus infections were traced back to multi -dose vials of
diphtheria toxoid, pertussis, and tetanus toxoid (DPT) vaccine which were contaminated after being
opened. Thimerosal was present in acceptable limits in unopen vials of vaccine from the same lot. The
authors concluded that “Preservatives in multidose vials do not prevent short term bacterial
contamination ” and the “only feasible and cost -effective preventative measure now available is careful
attention to sterile technique when administering vaccines from multidose vials.”
•In 2004, a Chiron plant that manufactured Fluvirin vaccine preserved with thimerosal was forced to close
because its vaccine was contaminated with Serratia marcescens. The closure created shortages in the
vaccine supply and caused concern among providers and patients. In this case and others, thimerosal
failed to prevent bacterial growth.
9 Current Research
Thimerosal safety and effectiveness
•A more current in vitro investigation into the cytotoxic effects and
antimicrobial activity of thimerosal was published in 2023. The authors
reported that thimerosal should be present in culture media at 100 μg/ml
concentration to achieve effective antimicrobial activity. But all tested cell
lines lost viability completely at 4.6 µg/ mL.
•“Overall, our study revealed Thimerosal was 333 -fold more cytotoxic to
human and animal cells as compared to bacterial and fungal cells . Our results
promote more study on Thimerosal toxicity and its antimicrobial effectiveness
to obtain more safe concentrations in biopharmaceuticals.”
Rahimian A, Lakzaei M, Askari H, Dostdari S, Khafri A, Aminian M. In vitro assessment of Thimerosal cytotoxicity and antimicr obial activity. J Trace Elem Med
Biol. 2023 May;77:127129. doi: 10.1016/j.jtemb.2023.127129. Epub 2023 Jan 4. PMID: 36630761.
10Evidence of Thimerosal
Developmental Neurotoxicity
Wallin, M. (1993). Effects of potential aneuploidy -inducing agents on microtubule assembly in vitro.
*Mutation Research. Fundamental and Molecular Mechanisms of Mutagenesis*, 287(1), 17 –22. https:// doi.org /10.1016/0027 -5107(93)90141 -2•In 1987 the Commission of the European Communities initiated a research project on 10
known or suspected spindle poisons. Thimerosal was found to cause significant
interference with microtubule polymerization destabilizing the spindle machinery that
ensures accurate chromosome separation during cell division.
•This mechanistic disruption suggests direct mutagenic potential via structural
chromosomal abnormalities, which is a known pathway to carcinogenesis or congenital
defects.
•By affecting fundamental cellular structures at the molecular level, thimerosal revealed
“strong mechanistic evidence for mutagenicity and developmental toxicity”.
11
Thimerosal has been recognized as a Prop 65 chemical since 1990.CALIFORNIA EPA Proposition - 65
•California’s Proposition 65, requires identification of chemicals known to cause cancer, birth
defects or other reproductive harm, and to ensure public warnings when people might be
exposed to them. Thimerosal has been on the Prop -65 list since 1990.
•In 2003 a petition was filed on behalf of the Bayer Corporation “for reconsideration of the
determination that mercury and mercury compounds (thimerosal) as reproductive toxicants.”
•The CA EPA responded that “The scientific evidence that thimerosal cause reproductive
toxicity is clear and voluminous. Thimerosal dissociates in the body to ethyl mercury. The
evidence for its reproductive toxicity includes severe mental retardation or malformations
in human offspring who were poisoned when their mothers were exposed to ethyl mercury
or thimerosal while pregnant, studies in animals demonstrating developmental toxicity after
exposure to either ethyl mercury or thimerosal, and data showing interconversion to other
forms of mercury that also clearly cause reproductive toxicity.”
12
Evidence From Human Research (1)
•A study published in Pediatrics in 2000 measured blood mercury levels in preterm and
term infants after administration of the Hepatitis B vaccine containing 12.5 µg ethyl
mercury.
•The investigation documented elevated post -immunization concentrations relative to
pre-immunization levels in all neonates studied. Levels of blood mercury after exposure
in low -birth -weight infants were 7.36 ( ± 4.99) µg/L.
•One infant was found to have developed a mercury level of 23.6 µg/L, thus meeting the
CDC criteria as a case of chemical poisoning from mercury 10µg /L. The study subjects
had measurable blood Hg concentrations prior to immunization, indicating that risk
assessment must include background mercury levels from other sources.
Stajich GV, Lopez GP , Harry SW, Sexson WR. Iatrogenic exposure to mercury after Hepatitis B vaccination in preterm infants. J .Pediatrics. 2000;136 (5):679 -81.
Centers for Disease Control and Prevention. (2005, January 14). Case Definitions for Chemical Poisoning. MMWR Recommendations and Reports, 54(RR -1), 1 –
24. Retrieved from https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5401a1.htm
13
Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal mod els. Environ Health Perspect .
2000;108 Suppl 3:511 -33.•Experts contend that there are “windows of vulnerability” which occur during neurological
development and that specific types of developmental outcomes may have separate
windows of vulnerability. These critical periods of development have not been established
and may be relatively short in duration.
•The fact that thimerosal from vaccines has been documented to raise blood mercury levels
over known thresholds where developmental effects have been documented to occur
during the first few months of life, means that particular "windows of vulnerability" may
have been breached. Even minor neurological impairment can have profound societal
effects when amortized across the entire population and life span.Evidence From Human Research (2)
14 Exposure To Vaccine Level Thimerosal
Crosses the Blood Brain Barrier and Results in Significant
Deposition of Mercury in the Brain
•A 2005 study funded by NIH compared brain mercury levels in infant Macaca fascicularis
primates exposed to: 1) injected ethyl mercury (thimerosal) and 2) equal amounts of
ingested methylmercury.
•Ethyl mercury more rapidly converted to inorganic mercury in the brains of the primates
which resulted in increasing levels of inorganic mercury.
•Primates exposed to ethyl mercury retained much higher levels of inorganic mercury in
their brains, up to 71% vs. 10% compared to primates exposed to methyl mercury.
•Once organic mercury compounds reach the brain tissue and dealkylate, Hg2+ (toxic
inorganic mercury) the mercury cannot cross the blood brain barrier and becomes
trapped, resulting in neuroinflammation.
Burbacher TM, Shen DD, Liberato N, Grant KS, Cernichiari E, and Clarkson T. Comparison of blood and brain mercury levels I in fant monkeys exposed to
methylmercury or vaccines containing thimerosal. Environmental Health Perspectives. 2005;113(8):1015 -1021.
15 Inorganic Mercury and the Developing Brain
Thimerosal is ~49.6%
mercury by weight•A recent review outlined evidence from human and animal studies which estimated the
inorganic mercury half -life in human brains of at least five to 27 years. (1)
•The impact of mercury exposure to the developing brain interferes with neuronal
proliferation, migration, differentiation, synaptogenesis, tightly regulated apoptosis, and
other processes vital to the formation and functioning of the nervous system which can
result in lifelong neurodevelopmental impacts.
•Exposure during the first trimester of pregnancy may result in deficits or defects very
different from those developed by someone who is exposed during the third trimester of
pregnancy. “There may never be a safe level of mercury exposure, especially for an
unborn child.” (2)
1.Rooney JP . The retention time of inorganic mercury in the brain --a systematic review of the evidence. Toxicol Appl Pharmacol. 2014 Feb 1;274(3):425 -35.
2. Pletz J, Sánchez -Bayo F, Tennekes HA. Dose -response analysis indicating time -dependent neurotoxicity caused by organic and in organic mercury -Implications
for toxic effects in the developing brain. Toxicology. 2016 Mar 10;347 -349:1 -5. doi: 10.1016/j.tox.2016.02.006. Epub 2016 Mar 2. PMID: 26945727.
16 Mercury Content In
Thimerosal -containing Flu Vaccines
•Thimerosal is ~49.6% mercury by weight with a concentration of 0.01% thimerosal in
vaccines. This equates to 100 µg/mL of thimerosal and 50 µg/mL of ethyl mercury per ml.
•The EPA’s Toxicity Characteristic Leaching Procedure (TCLP) determines whether a
substance is considered hazardous waste based on its potential to leach toxic chemicals
into groundwater.
•According to EPA TCLP Mercury Threshold (40 CFR § 261.24) the regulatory threshold for
mercury (D009) under TCLP is: 0.2 mg/L (200 parts per billion, or 200 µg/L).
•Flu vaccine mercury concentration (~50,000 µg/L) is 250 times greater than the TCLP limit.
Therefore, thimerosal -containing vaccines exceed the TCLP threshold by orders of
magnitude and are classified as D009 Hazardous Waste
17 Vaccine Mercury: Disposal Guidelines
18
Population Susceptibility Factors
Fetus / Developing InfantRapid neurodevelopment, immature blood -brain barrier, low glutathione,
high brain accumulation
Pregnant Women Placental transfer, fetal susceptibility, breast milk transfer
Young Children Higher exposure per kg, immature detoxification systems
Older Adults Reduced renal clearance, pre -existing neurodegenerative conditions
Genetically Susceptible Impaired detox (e.g., GST, MTHFR, APOE4), mitochondrial dysfunction
High Fish Consumers Bioaccumulation through predatory fish, dietary exposure
Occupationally Exposed Workers Inhalation exposure, chronic accumulation (e.g., dentists, miners)Susceptible Populations
19 Summary (1)
•Mercury is the third most toxic element on earth, behind polonium and plutonium,
and has no physiological role in the human body.
•Thimerosal was grandfathered for use without adequate safety testing by the FDA.
•Thimerosal is not “generally recognized as safe or effective” (GRASE) by the FDA OTC
Division since 1998.
•There is evidence that thimerosal is not an effective preservative at vaccine levels.
•Thimerosal can cross the placenta and blood brain barriers and converts to inorganic
mercury in the brain at higher levels that methyl mercury.
•Studies have identified infants with blood levels after exposure to thimerosal that
breach CDC guidelines for a case of mercury chemical poisoning.
20 Summary (2)
•Thimerosal is recognized as a developmental and reproductive toxicant and is listed as
a chemical on the California Proposition 65 list since 1990.
•Unused doses of thimerosal preserved flu shots must be disposed of as hazardous
waste.
•Tremendous progress has been made in removing thimerosal, but more than 60,000
pregnant mothers receiving Medicaid in the 2019 -2020 flu season received TCVs.
•We currently have enough thimerosal free flu vaccines to recommend that all
pregnant women, infants and children receive only thimerosal free vaccines.
•After a critical appraisal of this issue almost 25 years ago, the prestigious Institute of
Medicine made this same recommendation.
•Removing a known neurotoxin from being injected into our most vulnerable
populations is a good place to start with Making America Healthy Again.