Vaccinations Part 2 : Mercury & Thiomersal

Continued from Part 1 - MMR

In the US, the major vaccine fear has been around the use of a preservative called thiomersal (US spelling: Thimerosol), although this hasn't been as much of an issue over here, with the roll-out of the new thiomersal-preserved swine flu vaccine, people have started to voice concern. Here's Henry for example.

So lets talk about mercury in vaccines, shall we?

In 1998, U.S. legislation required the measurement of mercury in all food and drugs. By 1999 the FDA had learned that infants could get as much as 187.5 μg of mercury from the thiomersal in all their vaccines. They were concerned because mercury is toxic, which it is. Horribly so. But the thing is, toxicity is all about dose - lots of things are toxic, but you don't notice because your exposure to them is negligible.
Similarly with mercury, it's EVERYWHERE: in the soil we grow our vegetables in (and therefore in the veg itself), in fish, in meat(which at some point ate the veg), in tap-water (about 2 parts in a billion), but we don't notice, why is that? Because we have a tolerance to a greater or lesser extent to everything. You don't notice the arsenic in your table salt, do you? I'll come back to this, let's get back to the narrative:

Thimerosal is a preservative that allows vaccines to be sold in multi-dose vials. It contains ethylmercury. It was tested and found to be safe before it was added to vaccines and animal studies showed no adverse effects. In 1929 in Indiana it was tested as a treatment in a meningitis outbreak(they weren't big on ethics back then) — adults injected with 2 million μg (10,000 times the total amount in all children’s vaccines) didn’t develop symptoms of mercury poisoning.

In 1999 the U.S. removed thiomersal from vaccines. The decision was not based on evidence but was due to the opinion of Neal Halsey, the FDA committee member who threatened to hold his own press conference if they didn’t do what he wanted.
His passion convinced the other committee members to invoke the precautionary principle — essentially bending over backwards to prevent any possible harm from a high total body burden of mercury from a combination of diet, environmental and vaccine sources. He didn’t even consider autism: he was only concerned about possible neurologic damage.
They announced their decision in words guaranteed to confuse the public and create suspicion:

“current levels of thimerosal will not hurt children, but reducing those levels will make safe vaccines even safer.”

Yeah, they could've phrased that better.

Similarly to the MMR scare, a fair proportion of US parents became very worried, and it wasn't long before some were drawing the connection between mercury and autism. There is no longer any serious scientific debate about this, mainly due to the lack of a plausible mechanism and lack of evidence. Evidence isn't everything? Get in the feckin sack.

Whenever you see ongoing public debate on this issue it is inevitably driven by ideological groups who have an anti-vaccine agenda. These groups rely upon increasingly implausible and desperate rationalisations, conspiracy mongering, and simply bad logic.
But they have also based many of their arguments on a separate line of scientific evidence, that of toxicology – studying the effects of mercury and thiomersal on cells and in the body. In fact it is increasingly looking as if toxicological evidence will be the last stand for these groups on this issue.

The reason for this is simple – mercury is a neurotoxin, as we've already said. No one denies that. Proponents of the thiomersal-autism relationship essentially argue that we can know that thiomersal causes autism because it is toxic to the brain, or at least we should assume that until we prove beyond doubt that it is not toxic.
This is called proving a negative, and if you paid attention in science class, you know that this is an impossible standard. And it is irrelevant because we already know that mercury is a toxin. But this arguments misses two key points:
The first is that toxicological evidence can never answer the question of whether or not a substance actually did cause harm. In this respect epidemiological evidence trumps toxicological evidence – and all (and I mean ALL) the epidemiological evidence says that thiomersal is not linked to any harm.

A brief aside for the blessed uninitiated, some definitions:

Toxicology = study of poisons on living organisms
Epidemiology = study of effects of stuff (eg. diseases and medicines/side-effects) on large groups of people.

The second point is that toxicity is all about dose – any substance is safe in a small enough dose and anything is toxic (even oxygen, even water) in a high enough dose. What the anti-vaccine crowd has not demonstrated is that the mercury found in thiomersal is toxic at the doses given in vaccines.
Related to the question of dose is that of access – is the toxin in question getting exposed to brain cells in a sufficient dose to cause neurotoxicity? Sure, mercury damages brain cells when you pour it on top of neurons in a petri dish, but this does not necessarily mean that thiomersal in vaccines has the capability to cross the blood-brain barrier in order to cause toxicity. Because the epidemiological evidence shows no connection to autism, the assumption has been that the dose of mercury in vaccines is too small and it is cleared too quickly from the body for it to cause any measurable toxicity.

This brings us to a recent study, which looked at blood, stool, and urine levels of mercury in children following their newborn, 2 month old, and 6 month old vaccinations.
(The study was performed in Argentina because thiomersal has been removed from all routine childhood vaccines in the US and the UK.)
They calculated the half-life of mercury in the blood of 72 healthy children in each age group and found that the mean half-life (the time it takes for half of remaining mercury to be cleared from the blood) is 3.7 days, without a significant difference between the age groups. Levels of mercury in the blood returned to pre-vaccination levels in about 30 days. These results are significant for various reasons.

First we need to know that there are various types of organic mercury, the two most important being:
methyl mercury (the type found in certain fish)
and ethyl mercury (the type found in thiomersal ).

Methyl mercury is more toxic than ethyl mercury and is cleared more slowly, but data on the exact clearance rate for ethyl mercury was lacking. For this reason when calculating safety limits for human exposure the higher toxicity and slower clearance rates for methyl mercury were assumed. The half life of methyl mercury is about 30 days. This means that ethyl mercury (at least in young children - it is probably slower for adults) is cleared about 10 times more quickly than was previously assumed.

This is critical because the argument made for the potential toxicity of thiomersal was based upon the cumulative dose of ethyl mercury of all childhood vaccines. The argument was that ethyl mercury was building up from vaccine to vaccine, and that even if the dose from a single vaccine were safe, the cumulative dose is what was toxic. This new study shows fairly conclusively that all the ethyl mercury given in one vaccine will be cleared by the time the next vaccine is due to be given – so their is no build-up, no cumulative dose. This effectively shoots down the last remaining scientific argument of the mercury= autism crowd.

The authors also noted that the levels of mercury they measured in the blood were generally low, writing:

We also observed that the highest levels in samples that were taken from children shortly after vaccination were <=8 ng/mL. The importance of blood levels of ethyl mercury for assessing toxicity is unknown, but blood levels have been shown to be a predictor of toxicity for methyl mercury exposure. The low levels of mercury detected in this study suggests relatively low risk for toxicity from this exposure.

so we find ourselves with toxicological evidence moving in line with the epidemiological and other independent lines of evidence toward the conclusion that thiomersal given in childhood vaccines is not a contributor or cause of autism or other neurological disorder.
There are more studies to be done, but there always are – science is a messy and complex business. But it is reassuring to know that children clear ethyl mercury 10 times more quickly than was previously assumed, and that levels do not build up from vaccine to vaccine.
At least it is reassuring to those of us who look at all the evidence to formulate our opinions.

There was no thiomersal in any vaccine except the flu vaccine after 2002. The mercury=autism crowd expected autism rates to drop, thereby proving the mercury connection. Autism rates rose. Instead of relinquishing their belief, they made implausible attempts to implicate new sources of atmospheric mercury, from cremations of bodies with mercury amalgam fillings or from pollution wafted across the Pacific from China.

They'll never be happy, because their position is not a rational one; they have committed themselves so totally and invested so much of their time and effort in this fruitless and medieval belief system that I could have tablets written by God telling them that vaccines are safe, and they would say he was in the pocket of big Pharma.

Anyway, now you know what I know.


Key Research and summaries courtesy of ScienceBasedMedicine.org

Thiomersal and Autism
Andrews N, et al., Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics, 2004;114:584-591.
Summary: From the methods of this study: “A retrospective cohort study was performed using 109,863 children who were born from 1988 to 1997 and were registered in general practices in the United Kingdom that contributed to a research database.” And the results: “Only in 1 analysis for tics was there some evidence of a higher risk with increasing doses. Statistically significant negative associations with increasing doses at 4 months were found for general developmental disorders, unspecified developmental delay, and attention-deficit disorder. For the other disorders, there was no evidence of an association with thimerosal exposure.”
In other words – the researchers found a random scattering of mild positive and negative correlations between thimerosal exposure and a few neurodevelopment outcomes, with most outcomes showing no correlation. This is consistent with other studies and is essentially what we expect if thimerosal does not cause neurodevelopmental disorders. Some in the anti-vaccine camp have cherry-picked the weak association with tics, but there is no more reason to think that correlation is anything other than random noise than there is to believe that thimerosal protects against ADHD based upon this data.
___________________________________________________________
Fombonne E., et. al., Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links with Immunizations. Pediatrics. 2006;118:139-150.
Summary: This is a population based study involving 27,749 children born from 1987 to 1998. The researchers calculated the total exposure to thimerosal, which dropped to zero after 1996 as thimerosal was removed from childhood vaccines in Canada at that time. They found:

The prevalence of pervasive developmental disorder in Montreal was high, increasing in recent birth cohorts as found in most countries. Factors accounting for the increase include a broadening of diagnostic concepts and criteria, increased awareness and, therefore, better identification of children with pervasive developmental disorders in communities and epidemiologic surveys, and improved access to services. The findings ruled out an association between pervasive developmental disorder and either high levels of ethylmercury exposure comparable with those experienced in the United States in the 1990s or 1- or 2-dose measles-mumps-rubella vaccinations.

___________________________________________________________
Heron J, Golding J, and ALSPAC Study Team. Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United Kingdom does not support a causal association. Pediatrics. 2004;114:577-583.
Summary: This study is similar to the Andrews study, except this was prospective rather than retrospective. They followed > 14,000 children with neurological assessments from 6 to 91 months of age. As with the Andrews study they found a random scattering of mild correlations, mostly negative (meaning that thimerosal exposure was associated with a decreased risk of neurological signs or disorders) and only one positive correlation with poor pro-social behavior. These results are consistent with chance, i.e. no cause and effect between thimerosal and neurodevelopmental disorders.
The researchers conclude: “We could find no convincing evidence that early exposure to thimerosal had any deleterious effect on neurologic or psychological outcome.”
___________________________________________________________
Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between thimerosal-containing vaccine and autism. Journal of the American Medical Association 2003;290:1763-1766.
Summary: This is yet another population-based study looking at a large number of children – this one is a Danish study comparing children vaccinated with a thimerosal-containing vaccine and the same vaccines but without thimerosal. The methods indicate:

Population-based cohort study of all children born in Denmark from January 1, 1990, until December 31, 1996 (N = 467,450) comparing children vaccinated with a thimerosal-containing vaccine with children vaccinated with a thimerosal-free formulation of the same vaccine.

The results are pretty straight-forward and entirely negative:

The risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine.

___________________________________________________________
Madsen KM, Lauritsen MB, Pedersen CB, Thorsen P, Plesner AM, Andersen PH, Mortensen PB. Thimerosal and the Occurrence of Autism: Negative Ecological Evidence From Danish Population-Based Data. PEDIATRICS Vol. 112 No. 3 September 2003, pp. 604-606
Summary: Madsen et al evaluated autism rates in Denmark from 1971 – 2000. From 1961 – 1970 children received 400 micrograms of thimerosal. From 1971-1992 they received 250 micrograms of thimerosal. After 1992 all thimerosal was removed from childhood vaccines in Denmark. The study identified 962 children with autism over this period. They found that from 1970 to 1990 there was no change in the incidence of autism. After 1990 autism rates began to increase, which was attributed to expanding diagnosis and surveillance. These numbers generally match the experience in other Western nations. (See here and here for further discussion.)
___________________________________________________________
Miles JH, and Takahashi TN. 2007. Lack of association between Rh status, Rh immune globulin in pregnancy and autism. American Journal of Medical Genetics, Part A1. 143(13):1397–407.
Summary: Given the lack of association between vaccine exposure, thimerosal exposure, and autism spectrum disorder (ASD), proponents of the mercury- autism hypothesis have blamed possible exposure by the mother to thimerosal exposure during pregnancy. Rh- mothers may be treated with Rhig which may be preserved with thimerosal. This study looked at 305 mothers with children on the autism spectrum and compared them to general population. They found so significant difference in the risk of being Rh- or having been exposed to thimerosal in mothers with ASD children compared to the general population. Therefore exposure to thimerosal during pregnancy does not appear to be associated with ASD.
___________________________________________________________
Schechter R, Grether JK. Continuing Increases in Autism Reported to California’s Developmental Services System: Mercury in Retrograde. Arch Gen Psychiatry. 2008;65(1):19-24.
Summary: The data presented in this study is the most definitive evidence against an association between thimerosal in vaccines and autism. It shows that after all but trace amounts of thimerosal were removed from the routine childhood vaccine schedule (although remaining in some optional flu vaccines), the rate of autism diagnoses did not decrease, as predicted by vaccine-autism proponents. This is especially significant because this is the same database used by proponents to argue that the increase in the rate of autism in the 1990s correlated with an increase in the vaccine schedule and the total thimerosal exposure.
The graph below shows the steady increase in the rate of autism diagnoses (by birth year) long after the removal of thimerosal from the vaccine schedule was completed – by the end of 2002.

___________________________________________________________
Thompson WW et al. Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years. N Engl J Med. 2007 Sep 27;357(13):1281-92.
Summary: This study enrolled 1047 children and compared their thimerosal exposure based upon immunization records to outcomes on standardized neurological testing. They found: “Among the 42 neuropsychological outcomes, we detected only a few significant associations with exposure to mercury from thimerosal. The detected associations were small and almost equally divided between positive and negative effects.” This is the expected statistical noise, occurring by chance alone. This study therefore lends strong support to a lack of association between thimerosal exposure from vaccines and neurodevelopmental disorders. (Further discussion here, here, and here.)
___________________________________________________________
Tozzi AE, Bisiacchi P, Tarantino V, De Mei B, D’Elia L, Chiarotti F, Salmaso S. Neuropsychological Performance 10 Years After Immunization in Infancy With Thimerosal-Containing Vaccines. PEDIATRICS Vol. 123 No. 2 February 2009, pp. 475-482 (doi:10.1542/peds.2008-0795)
Summary: This study analyzed data from a vaccine safety study performed in 1993. They were able to compare two groups randomized to different pertussis vaccines with either low dose (62.5 µg) or a higher dose (137.5 µg) of thimerosal ten years later. They found no difference in autism rates between the two groups. When they did multiple comparisons for other neurological conditions they found only two minor correlations, less than predicted by chance – so essentially the study found no significant correlation between two doses of thimerosal and neurological outcome. This evidence contradicts the belief that a similar increase in the dose of thimerosal in the US in the 1990s caused an increase in the incident of autism. (See here for further discussion of this study.)
___________________________________________________________
Verstraeten T, et al., Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics 2003;112:1039-1048.
Summary: This is a 2-phase retrospective cohort study looking at a large database of children from three HMOs. The first phase looked at 124,170 children from 1992-1999 from two HMOs and found an association between thimerosal exposure and tics in the first HMO and an association between thimerosal and language delay (but not tics) at the second HMO. The second phase was of 16,717 children from 1991-1997 at a third HMO and found no significant associations. The strength of this study is that it used three independent data sets to confirm any chance associations. It found no consistent associations between thimerosal and any neurodevelopmental disorder, and it found no association at all with autism or ADHD. This is most consistent with a lack of association between thimerosal exposure and neurodevelopmental disorders, but the authors call for follow up of the inconsistent association with tics and language delay.
___________________________________________________________