Another day, another junk science study published by our anti-vaccine scientists. This time, former scientist James Lyons-Weiler teamed up with a notorious anti-vaccine pediatrician.
As in mathematics, adding two negative values results in additive effects. Here too, the combination of two science deniers made an already flawed set of claims even weaker than it was initially.
With a certain cynicism, I would question why Lyons-Weiler refused to publish in the journal created by his own organization, IPAK – the new journal named Science, Public Health Policy and Law. I guess having two authors (JLW and PA) sitting in the editorial board would make the lack of meaningful review too obvious.
But something more sinister is folding, the predation of peer-reviewed journals with decent impact factors by anti-vaccine (AV) scientists. Historically, the Journal of Inorganic Biochemistry has been a safe haven for AV scientists for years – until one paper from Christopher Shaw (University of British Columbia) got flagged at the end of 2017 for blatant data manipulations (spliced immunoblots and agarose gels).
Since then, the journal apparently revved up the review process to ensure a more rigorous review, especially when it comes from authors with questionable quality in their publication.
Here comes the Journal of Trace Elements in Biology and Medicine. As Lyons-Weiler’s new safe haven, the journal seems to give a free and unfiltered pass to several scientists publishing low-quality anti-vaccine work – Christopher Exley (three papers), James Lyons-Weiler (two papers including this one), or a climate denialist named Albert Parker (writing under a pseudonym, his real name is Alberto Boretti), who, according to this website, writes from his garage.
These papers were published despite major methodological flaws, or sometimes comments close to libel (see the comment letter written by Christopher Exley targeting the Chair of the UK Joint Committee on Vaccination and Immunization which was critiqued here).
Seeing such blatant “studies” that do not fit a rigorous standard for publication-quality and yet got approved by a panel of reviewers suggest a breach in the peer-review of this journal is troubling.
Considering that these publications will be used as a cannon fodder by the anti-vaccine movement which will claim these are legit studies (spoiler: they are not, and I will show why in the rebuttal below), this journal is de-facto contributing in the spread of “fake news” and fuels vaccine hesitancy, bringing more fuel to fires already burning. Just look at the number of measles outbreaks that occurred this year, setting us to record levels never seen since the publication of the fraudulent paper by Wakefield, and the honor of the AV movement identified as one of the top 10 global health threats in 2019.
To keep it rigorous and respectful, I have written my rebuttal as a hypothetical letter to the Editor. I wish I could submit such a letter, but given my particular situation in my life, I prefer to not make waves that could capsize my tiny sloop.
Response to James Lyons-Weiler junk science
I am writing to you following the recent study published by Grant McFarland, Elaine La Joie, Paul Thomas, and James Lyons-Weiler entitled “Acute exposure and chronic retention of aluminum in three vaccine schedules and effects of genetic and environmental variation”.
Although the authors’ are within their rights to question the safety of aluminum levels in vaccines, the way this was done here is inaccurate, inappropriate, and directly contributes to anti-vaccine efforts.
The flaws include ignoring the extensive literature and retrospective amount of data showing no increased risk posed by aluminum adjuvants (since its initial use in two clinical trials for pertussis and diphtheria vaccines by Bell and colleagues [1, 2]), as well as the flawed methodology and logical reasoning used by the senior author (JLW) (already present in his previous publication ) to make his point. Considering that the anti-vaccine movement has been labeled by the World Health Organization (WHO) as one of the Top 10 global health threats in 2019, this is especially alarming.
In order to assess the relationship between the dose administered and safe levels of aluminum in the central compartment (commonly referring to the systemic circulation, which can be sampled by plasma/serum levels), it is important to understand, master and respect basic principles of pharmacokinetics.
Unfortunately, none of the authors hold any degrees or credentials to address these key points necessary to provide an accurate and sound pharmacokinetic/pharmacodynamic (PK/PD) modeling.
The article’s authors are Grant McFarland as lead author, Elaine La Joie, Paul Thomas, and James Lyons-Weiler. Grant McFarland holds a BS in Electrical Engineering and a Ph.D. in electrical engineering from Stanford University. Elaine La Joie holds a BS in physics and an MS in Applied Physics. Paul Thomas is a family medicine physician, and James Lyons-Weiler holds a BS in Zoology and a Ph.D. in evolution and conservation biology.
With all due respect to the authors, none of them have credentials to claim mastery of PK/PD related questions, and this is, unfortunately, undermining the whole premise and experimental method of the study.
1. The limitation of Clark’s rule
The central point of the study (and its preceding study from the same senior author) is to question the “safe limit” of aluminum in vaccines, as most non-live vaccines contain aluminum adjuvants (mostly present as aluminum hydroxide and/or aluminum phosphate). To address the hypothesis, James Lyons-Weiler claims that the FDA safe levels are wrong and uses a modified Clark’s equation to support the claim.
The whole purpose of the Clark formula is aimed to quickly and easily allow any healthcare professional to adjust therapeutic dosing from a dose recommended for an adult into a patient from the pediatric population, using a dose based on weight (e.g. mg/kg or µg/kg).
Clark’s rule is commonly referred to in the literature as the following (assuming a dose in mg):
This formula can be used when a patient is prescribed a certain dosing regimen and we know the dose in adults necessary to maintain a certain drug concentration in blood/plasma (we commonly refer it as “average concentration at steady state”) within a range we consider therapeutic.
To give an example, let’s assume we put a 7-year old Caucasian male (weight 60lbs) on an antibiotic (let’s assume amoxicillin). In adults, amoxicillin is known to work well in an average adult at 500mg every 8 hours. Using the Clark formula, we can adjust the amoxicillin dose to 200mg every 8 hours ((60/150)*500) and we should be able to achieve a blood concentration of amoxicillin that will cure this little boy of the infection he is suffering.
But you cannot use this formula to determine the average plasma concentration of amoxicillin in this boy just by knowing the dose administered. It needs a completely different formula that accounts for important PK parameters such as the bioavailability (if you give the medication outside an IV route), the dosing interval (how many times a day you give that boy the antibiotics) and the clearance of the drug (how fast the antibiotic is removed from the body).
In order to establish a direct link between a dose and an average plasma concentration at steady-state (Cave), the use of an equation commonly used in the multiple-dosing regimen should be instead be applied, such equation is commonly displayed in most pharmacokinetic textbooks as (using mg as dose):
Knowing the dose, the dosing interval (Tau), and the total clearance (Cl), we can associate a certain dose to an average plasma concentration (Cave) and therefore determine if a dose is deemed below or over the minimum toxic concentration (MTC).
It is also important to factor in the bioavailability of a drug (F) for the determination of Cave. By default, F=1 for injection via a vascular route (commonly via intravenous route), whereas F<1 for any extravascular route (including oral (PO) and intramuscular administration (IM) route). In other words, the only situation where you can assume all the substance goes into the bloodstream is when the substance is given directly into the vein – any other form of administration, including intramuscular administration (the common way vaccines are given), leads to less of the substance ending in the bloodstream (see discussion below).
For information, the F values for aluminum via IM and PO routes are considered approximatively as F=0.006 and F=0.003 according to Yokel and McNamara  – in other words, only 0.3-0.6% of the injected substance would end in the blood. We will use these F values in the following stipulation. None of these parameters are accounted for in the Clark formula, making it unsuitable for its use outside therapeutic dosing.
Therefore, the use of the Clark formula as a methodology to support the claim that the FDA is wrong in setting aluminum limits is wrong and shows a lack of competence and sophistication by the authors to appropriately assess the toxicity of aluminum using a PK/PD approach.
2. A failure to discern differences between vascular and extra-vascular routes
The second important issue encountered in this study is the blatant failure of the authors to acknowledge that their whole premise, built on their previous publication, does not account for the important differences between vascular routes and extravascular routes.
In his previous study published in your journal , James Lyons-Weiler stated the following:
If infants were given 850μg of aluminum (injected), the exposure would vastly exceed the only available CFR/FDA 4–5μg/kg/day safety limit (Fig. 2). Compared to an adult whose body weight is 60kg, a male child at birth receives 254μg/kg, 152.7μg/kg at 2 months, 121.4μg/kg at 4 months, 107.1μg/kg at 6 months, 92.8μg/kg at 1year, and 69.9μg/kg at 2 years as compared to 12.5-14.2μg/kg in an adult.
The FDA safety limit is pretty clear and applies to parenteral aimed for total parenteral nutrition products (TPN, including IV bags):
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 [micro]g/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
This safety value is likely originating from the work of Bishop and colleagues , in which the authors demonstrated a better neurological outcome in premature newborns fed by TPN via IV route.
You cannot directly compare safety values set for administration via IV route to the dose administered via extravascular routes (in the case of vaccines, via IM route).
Unlike vascular administration routes, extravascular routes have additional challenges to overcome before a drug can reach the systemic circulation (commonly referred as the central compartment), mostly inherent to the absorption process (involving both pharmaceutical and physiological events), evasion of the first-pass hepatic extraction (oral administration) and distribution into the systemic circulation.
Commonly, the determination of a drug concentration in the central compartment via administration by extravascular route can be calculated using the following formula:
At the timepoint indicative of the peak concentration (tmax), this formula can be simplified to calculate the peak concentration (Cmax), like the following:
According to the initial work of Flarend and colleagues following the injection of 26Al (stable radioisotope) via IM route in healthy rabbits , the tmax values reported were approximately occurring 10-12 hours after injection, whereas the Cmax reported was about 2*10-6mg/g blood (or approximately 2µg/L blood).
Considering each rabbit received 850µg of aluminum adjuvants, and approximating the blood volume in these rabbits at the day of injection to about 180mL (source: ), we can estimate that such Cmax value represents about 0.042% of the injected dose ([0.360/850)*100].
Yet, the author failed to account for important parameters to calculate the exposure via IM route, as he failed to provide experimental data from his own study or from the existing literature, to accurately account the exposure level to aluminum. Indeed, the author assumed a 100% bioavailability and a peak concentration occurring quasi -instantaneously at the injection time.
Indeed, when factored in the bioavailability of aluminum adjuvants, an 850µg injection in a 2 months-old female infant following the CDC schedule and falling at the 5th percentile curve would yield to a weight of approximately 4kgs (8lbs). This would put the safe limit of the FDA by about 16-20µg/day.
Assuming an average bioavailability of 0.6% per day , the burden of 850µg dose of aluminum at the day after the injection would equate to 5.1µg/day.
We still have to account for the average exposure to aluminum from food (in that case from formula milk/breast milk), which also contributes to the burden. Nevertheless, the burden of food is much lesser than vaccines at this age. If we combine the WHOLE amount of aluminum burden that day, we will still be way below (60% below at the very least) the limit set by the FDA.
What is really concerning and should have been an immediate rejection of the study was the inability of the authors to integrate that IV routes and non-IV routes have distinct features when it comes to absorption. You cannot immediately compare them unless you integrate the bioavailability for oral and injections (I refer here to IM and SC routes). You have to consider the fraction that is bioavailable (in other words, the amount that reached the whole blood circulation) and only then you can compare such fraction to values obtained from IV data.
This callousness of the author to compare IV and IM routes as is, assuming that the amount of aluminum injected from vaccines was delivered instantaneously all at once into the bloodstream is reflective of a severe deficiency in understanding basic concepts of pharmacokinetics, making them unfit to run such study.
The second mistake made by the author is that the safety limit set by the FDA was set based on the work made by Bishop and colleagues on premature infants. Therefore, the need for the Clark formula to adjust a dose from an adult population to an infant population is completely useless: the source is already in infants.
Further, the authors also omitted to cite relevant literature, both from preclinical and clinical studies, that shown no increase in aluminum plasma levels in infants and toddlers [7-10] following immunization with aluminum adjuvants-containing vaccines, or following IM injections of aluminum adjuvants in rodent models at doses reflective or significantly higher than humans.
This omission of citing published literature (preceding the submission of the revised manuscript) contradicting the author claims suggests the presence of a certain maliciousness from the authors, commonly referred to as “literature cherry-picking”.
Because the whole mathematical model in which the authors build Figure 1 has not been built on a reliable model, the result is invalid, and so are any subsequent figures built on the data initially generated with Figure 1.
3. The inability of the author to account for the E in ADME (E is for elimination)
The PK/PD of aluminum is relatively known although its modeling remains complex and occurs via a multi-compartment model . However, there is a consensus that aluminum present in vaccine adjuvants is found in the systemic circulation as Al3+ ions bound to transferrin and to citrate.
The elimination of aluminum, according to Priest and others, is considered to occur mostly via the renal route (>95%) . Although the elimination rate of aluminum from peripheral tissues (e.g. bone tissue, brain tissue) can be very long, the terminal elimination rate using the same study by Priest as cited by the author has been documented [12, 13].
The elimination rate in PK/PD studies is commonly referred as the terminal half-life (or elimination half-life). The terminal half-life (t1/2) is the amount of time (usually referred as hours) by which 50% of a drug has been eliminated from the body. The determination of t1/2 can be obtained experimentally, by determining the elimination rate (k in hour-1) from experimental data and using the following equation:
In PK/PD, we estimate a drug completely eliminated after 4 half-lives (which equates for ~93% eliminated or 7% of the initial dose administered remaining).
According to the study by Priest , less than 3% of aluminum remained in the blood by 24 hours. Such observation would account that the approximate half-life of aluminum in the blood is about 6 hours (t1/2=6 hours).
Despite citing the same study as me, the authors underwent an intense, yet deeply flawed, mental gymnastics by estimating the total amount of aluminum exposed from birth to the 18 months time point, comparing the CDC schedule to its modified version and a “Vaccine-friendly Plan” (VFP) version established by PT that has yet to demonstrate an efficacy and safety (as of today, there is no peer-reviewed study published about this alternative immunization schedule).
The authors summarized such exposure in Table 1 by giving the total values of aluminum exposed as 4925µg, 3070µg and 1820µg for the recommended CDC schedule, modified CDC schedule and VFP respectively.
This summation of doses administrated has little relevance for the PK/PD, unless the goal is misleading the reader. As it reads, the authors are trying to claim that under no circumstances aluminum is eliminated from the body and that the aluminum injected will accumulate in the body during the first 18 months of life.
This serves as an argument to favor the VFP (which has 1/3 of aluminum than the recommended CDC schedule) as a “safer” schedule. Yet, the authors blatantly ignored the elimination half-life provided by Priest and the very transient nature of aluminum in the central compartment, as seen by its rapid elimination by the renal route.
To justify the presence of accumulation, the authors have to show that the dosing interval (Tau) between two immunization rounds is shorter or equal to the terminal half-life of these adjuvants. In the case of multiple dosing, the dosing interval (Tau) has to be equal or shorter than the elimination half-life (t1/2) to reach an accumulation, as defined by the formula:
If we assume a dosing interval (Tau) between two rounds of 2 months (60 days = 1440 hours), and a terminal half-life of 6 hours (according to Priest), the ratio obtained is 6/1440 = 0.004. It is impossible mathematically to achieve an accumulation of aluminum in the central compartment with the recommended CDC schedule.
This invalidates the claim made by the VFP protocol. Further, to really compare these schedules there is a need for experimental data (from a randomized clinical trial) assessing levels of aluminum in plasma from patients on the recommended schedule versus patients on the VFP protocol. The VFP protocol has yet to be validated and documented by its publication in a peer-review journal and shows no rationale in terms of increased “safety” through different aluminum exposure.
Indeed, by spacing out the immunization, patients are at higher risk of contracting vaccine-preventable diseases (VPD) compared to patients on the recommended CDC schedule, thus increasing the risk with little or no benefits.
If the authors want to make their argument valid, it is their obligation to support their mathematical model with experimental data showing a statistically significant difference in aluminum plasma levels between these groups. Considering the poor record of Paul Thomas in terms of experimental design and the use of statistics, I would recommend they ask the involvement of a biostatistician and full public access to the raw data to allow scientists to determine the accuracy of such data.
This gross omission and negligence make Table 1 unreliable and invalidates subsequent data figures relying on this table.
3. Concluding remarks and recommendation
Considering the fatal flaws identified in Figure 1 and Table 1, reconsideration of the validity of the data subsequently presented in the study is essential, as all of them are relying in one form or another on these two elements.
This study required the presence of qualified personnel and authors with established credentials in PK/PD. Yet, none of the authors have the credentials to do so, resulting in a study that has little merit and has such gross experimental mistakes, failure in data interpretations and signs of scientific dishonesty (omission of relevant experimental data validating the model, “cherry-picking” of the literature, failure to acknowledge the literature contradicting the study), that makes this study heavily biased, and factually wrong.
As a peer and reviewer, I raise important concerns about the quality of the review of this study, and question if such a study has been reviewed adequately by reviewers holding expertise in PK/PD. This study shows the failure of an adequate and objective peer-review that is critical for the validity of the results and the conclusions made.
I, therefore, recommend, dear editor, that these issues require an additional round of reviews by qualified reviewers with experience in PK/PD modeling. By allowing such publication to be published, we are allowing the spreading of “junk studies” that directly feed the anti-vaccine movement by giving them a false sense of equivalency and fuel the flames of the record outbreaks of VPD ignited and maintained by the anti-vaccine activism.
Considering the record-breaking number of measles associated cases and death this year since the publication of the now-retracted Lancet study by Wakefield and colleagues , I implore that studies questioning the scientific consensus on vaccines to be treated with the same rigor and criticism as the majority of the studies in favor of vaccines.
This article is by VaultDwellerSYR, a pseudonym used by a faculty member of a School of Pharmacy within a large medical school. They have significant research and publications in the effect of certain chemicals on the brain. Although we are opposed to all arguments from authority, the author has a substantial record of actual, published research in this field of brain cell biology and biochemistry.
The author has stated that he has no conflict of interest to disclose.
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