Thiomersal

From Wikipedia, the free encyclopedia

Thiomersal

Names
IUPAC name Ethyl(2-mercaptobenzoato-(2-)-O,S) mercurate(1-) sodium
Other names Mercury((o-carboxyphenyl)thio)ethyl sodium salt
Identifiers
CAS Number	54-64-8
ChEBI	CHEBI:9546
ChEMBL	ChEMBL508338
ChemSpider	10772045
ECHA InfoCard	100.000.192
EC Number	200-210-4
PubChem CID	16684434
RTECS number	OV8400000
UNII	2225PI3MOV
Properties
Chemical formula	C9H9HgNaO2S
Molar mass	404.81 g/mol
Appearance	White or slightly yellow powder
Density	2.508 g/cm3
Melting point	232 to 233 °C (450 to 451 °F; 505 to 506 K) (decomposition)
Solubility in water	1000 g/l (20 °C)
Pharmacology
ATC code	D08AK06 (WHO)
Hazards
Safety data sheet	External MSDS
GHS pictograms
GHS signal word	Danger
GHS hazard statements	H300, H310, H330, H373, H410
GHS precautionary statements	P260, P273, P280, P301, P310, P330, P302, P352, P310, P304, P340, P310
NFPA 704	1 3 1
Flash point	250 °C (482 °F; 523 K)

Thiomersal (INN), or thimerosal (USAN, JAN), is an organomercury compound. This compound is a well-established antiseptic and antifungal agent.

The pharmaceutical corporation Eli Lilly and Company gave thiomersal the trade name Merthiolate. It has been used as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks. Its use as a vaccine preservative was controversial, and it was phased out from routine childhood vaccines in the European Union, and a few other countries in response to popular fears. As of 2019, scientific consensus is that these fears are unsubstantiated.

History

Morris Kharasch, a chemist then at the University of Maryland filed a patent application for thiomersal in 1927; Eli Lilly later marketed the compound under the trade name Merthiolate. In vitro tests conducted by Lilly investigators H. M. Powell and W. A. Jamieson found that it was forty to fifty times as effective as phenol against Staphylococcus aureus. It was used to kill bacteria and prevent contamination in antiseptic ointments, creams, jellies, and sprays used by consumers and in hospitals, including nasal sprays, eye drops, contact lens solutions, immunoglobulins, and vaccines. Thiomersal was used as a preservative (bactericide) so that multidose vials of vaccines could be used instead of single-dose vials, which are more expensive. By 1938, Lilly's assistant director of research listed thiomersal as one of the five most important drugs ever developed by the company.

Structure

Thiomersal features mercury(II) with a coordination number 2, i.e. two ligands are attached to Hg, the thiolate and the ethyl group. The carboxylate group confers solubility in water. Like other two-coordinate Hg(II) compounds, the coordination geometry of Hg is linear, with a 180° S-Hg-C angle. Typically, organomercury thiolate compounds are prepared from organomercury chlorides.

Uses

Thiomersal's main use is as an antiseptic and antifungal agent, due to the oligodynamic effect. In multidose injectable drug delivery systems, it prevents serious adverse effects such as the Staphylococcus infection that, in one 1928 incident, killed 12 of 21 children vaccinated with a diphtheria vaccine that lacked a preservative. Unlike other vaccine preservatives used at the time, thiomersal does not reduce the potency of the vaccines that it protects. Bacteriostatics such as thiomersal are not needed in single-dose injectables.

In the United States, countries in the European Union and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood vaccination schedules. In the U.S., the only exceptions among vaccines routinely recommended for children are some formulations of the inactivated influenza vaccine for children older than two years. Several vaccines that are not routinely recommended for young children do contain thiomersal, including DT (diphtheria and tetanus), Td (tetanus and diphtheria), and TT (tetanus toxoid); other vaccines may contain a trace of thiomersal from steps in manufacture. The multi-dose versions of the influenza vaccines Fluvirin and Fluzone can contain up to 25 micrograms of mercury per dose from thiomersal. Also, four rarely used treatments for pit viper, coral snake, and black widow venom still contain thiomersal. Outside North America and Europe, many vaccines contain thiomersal; the World Health Organization has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on safety grounds to change to more expensive single-dose administration. The United Nations Environment Program backed away from an earlier proposal of adding thiomersal in vaccines to the list of banned compounds in a treaty aimed at reducing exposure to mercury worldwide. Citing medical and scientific consensus that thiomersal in vaccines posed no safety issues, but that eliminating the preservative in multi-dose vaccines, primarily used in developing countries, will lead to high cost and a requirement for refrigeration which the developing countries can ill afford, the UN's final decision is to exclude thiomersal from the treaty.

Toxicology

Thiomersal is very toxic by inhalation, ingestion, and in contact with skin (EC hazard symbol T+), with a danger of cumulative effects. It is also very toxic to aquatic organisms and may cause long-term adverse effects in aquatic environments (EC hazard symbol N). In the body, it is metabolized or degraded to ethylmercury (C₂H₅Hg⁺) and thiosalicylate.

Cases have been reported of severe mercury poisoning by accidental exposure or attempted suicide, with some fatalities. Animal experiments suggest that thiomersal rapidly dissociates to release ethylmercury after injection; that the disposition patterns of mercury are similar to those after exposure to equivalent doses of ethylmercury chloride; and that the central nervous system and the kidneys are targets, with lack of motor coordination being a common sign. Similar signs and symptoms have been observed in accidental human poisonings. The mechanisms of toxic action are unknown. Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a half-life of about 18 days in adults by breakdown into other chemicals, including inorganic mercury. Ethylmercury is eliminated from the brain in about 14 days in infant monkeys. Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury. Methylmercury and ethylmercury distribute to all body tissues, crossing the blood–brain barrier and the placental barrier, and ethylmercury also moves freely throughout the body. Concerns based on extrapolations from methylmercury caused thiomersal to be removed from U.S. childhood vaccines, starting in 1999. Since then, it has been found that ethylmercury is eliminated from the body and the brain significantly faster than methylmercury, so the late-1990s risk assessments turned out to be overly conservative. Though inorganic mercury metabolized from ethylmercury has a much longer half-life in the brain, at least 120 days, it appears to be much less toxic than the inorganic mercury produced from mercury vapor, for reasons not yet understood.

Allergies

Patch test

 

Thiomersal is used in patch testing for people who have dermatitis, conjunctivitis, and other potentially allergic reactions. A 2007 study in Norway found that 1.9% of adults had a positive patch test reaction to thiomersal; a higher prevalence of contact allergy (up to 6.6%) was observed in German populations. Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization, though there have been no large sample sized studies regarding this matter to date. In real-world practice on vaccination of adult populations, contact allergy does not seem to elicit clinical reaction. Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there. In a recent study of Polish children and adolescents with chronic/recurrent eczema, positive reactions to thiomersal were found in 11.7% of children (7–8 y.o.) and 37.6% of adolescents (16–17 y.o.). This difference in the sensitization rates can be explained by changing exposure patterns: The adolescents have received six thiomersal-preserved vaccines during their life course, with the last immunization taking place 2–3 years before the mentioned study, younger children received only four thiomersal-preserved vaccines, with the last one applied 5 years before the study, while further immunizations were performed with new thiomersal-free vaccines.

Autism

Following a review of mercury-containing food and drugs mandated in 1999, the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics asked vaccine manufacturers to remove thiomersal from vaccines as a purely precautionary measure, and it was rapidly phased out of most U.S. and European vaccines. Many parents saw the action to remove thiomersal—in the setting of a perceived increasing rate of autism as well as increasing number of vaccines in the childhood vaccination schedule—as indicating that the preservative was the cause of autism. The scientific consensus is that there is no evidence supporting these claims, and the rate of autism continues to climb despite elimination of thiomersal from routine childhood vaccines. Major scientific and medical bodies such as the Institute of Medicine and World Health Organization, as well as governmental agencies such as the Food and Drug Administration and the CDC reject any role for thiomersal in autism or other neurodevelopmental disorders. This controversy has caused harm due to parents attempting to treat their autistic children with unproven and possibly dangerous treatments, discouraging parents from vaccinating their children due to fears about thiomersal toxicity, and diverting resources away from research into more promising areas for the cause of autism. Thousands of lawsuits have been filed in a U.S. federal court to seek damages from alleged toxicity from vaccines, including those purportedly caused by thiomersal.

Thiomersal and vaccines

From Wikipedia, the free encyclopedia

Thiomersal (or Thimerosal) is a mercury compound used as a preservative used in some vaccines. Anti-vaccination activists promoting the incorrect claim that vaccination causes autism, have asserted that the mercury in thiomersal is the cause. There is no scientific evidence to support this claim. The idea that thiomersal in vaccines might have detrimental effects originated with anti-vaccination activists and was sustained by them and especially through the action of plaintiffs' lawyers.

 

The potential impact of thiomersal on autism has been investigated extensively. Multiple lines of scientific evidence have shown that thiomersal does not cause autism. For example, the clinical symptoms of mercury poisoning differ significantly from those of autism. In addition, multiple population studies have found no association between thiomersal and autism, and rates of autism have continued to increase despite removal of thiomersal from vaccines. Thus, major scientific and medical bodies such as the Institute of Medicine and World Health Organization (WHO) as well as governmental agencies such as the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) reject any role for thiomersal in autism or other neurodevelopmental disorders. In spite of the consensus of the scientific community, some parents and advocacy groups continue to contend that thiomersal is linked to autism and the claim is still stated as if it were fact in anti-vaccination propaganda, notably that of Robert F. Kennedy, Jr., through his group Children's Health Defense. Thiomersal is no longer used in most children's vaccines in the United States, with the exception of some types of flu shots. While exposure to mercury may result in damage to brain, kidneys, and developing fetus, the scientific consensus is that thiomersal has no such effects.

This controversy has caused harm due to parents attempting to treat their autistic children with unproven and possibly dangerous treatments, discouraging parents from vaccinating their children due to fears about thiomersal toxicity and diverting resources away from research into more promising areas for the cause of autism. Thousands of lawsuits have been filed in the U.S. to seek damages from alleged toxicity from vaccines, including those purportedly caused by thiomersal. US courts have ruled against multiple representative test cases involving thiomersal. A 2011 journal article described the vaccine-autism connection as "perhaps, the most damaging medical hoax of the last 100 years".

Outside of the United States, worries about thiomersal had not gained any significant traction as of 2009.

History

Thiomersal (also spelled thimerosal, especially in the United States) is an organomercury compound used as a preservative in vaccines to prevent bacterial and fungal contamination. Following a mandated review of mercury-containing food and drugs in 1999, the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) asked vaccine makers to remove thiomersal from vaccines as quickly as possible as a precautionary measure, and it was rapidly phased out of most US and EU vaccines, but is still used in multi-dose vials of flu vaccines in both jurisdictions. In the context of perceived increased autism rates and increased number of vaccines in the childhood vaccination schedule, some parents believed the action to remove thiomersal was an indication that the preservative caused autism.

It was introduced as a preservative in the 1930s to prevent the growth of infectious organisms such as bacteria and fungi, and has been in use in vaccines and other products such as immunoglobulin preparations and ophthalmic and nasal solutions. Vaccine manufacturers have used preservatives to prevent microbial growth during the manufacturing process or when packaged as "multi-dose" products to allow for multiple punctures of the same vial to dispense multiple vaccinations with less fear of contamination. After the FDA Modernization Act of 1997 mandated a review and risk assessment of all mercury-containing food and drugs, vaccine manufacturers responded to FDA requests made in December 1998 and April 1999 to provide detailed information about the thiomersal content of their preparations.

A review of the data showed that while the vaccine schedule for infants did not exceed FDA, Agency for Toxic Substances and Disease Registry (ATSDR), or WHO guidelines on mercury exposure, it could have exceeded Environmental Protection Agency (EPA) standards for the first six months of life, depending on the vaccine formulation and the weight of the infant. The review also highlighted difficulty interpreting toxicity of the ethylmercury in thiomersal because guidelines for mercury toxicity were based primarily on studies of methylmercury, a different mercury compound with different toxicologic properties. Multiple meetings were scheduled among various government officials and scientists from multiple agencies to discuss the appropriate response to this evidence. There was a wide range of opinions on the urgency and significance of the safety of thiomersal, with some toxicologists suggesting there was no clear evidence that thiomersal was harmful and other participants like Neal Halsey, director of the Institute of Vaccine Safety at Johns Hopkins School of Public Health, strongly advocating removal of thiomersal from vaccines due to possible safety risks. In the process of forming the response to this information, the participants attempted to strike a balance between acknowledging possible harm from thiomersal and the risks involved if childhood vaccinations were delayed or stopped.

Upon conclusion of their review, the FDA, in conjunction with the other members of the US Public Health Service (USPHS), the National Institutes of Health (NIH), CDC and Health Resources and Services Administration (HRSA), in a joint statement with the AAP in July 1999 concluded that there was "no evidence of harm caused by doses of thimerosal found in vaccines, except for local hypersensitivity reactions."

Despite the lack of convincing evidence of toxicity of thiomersal when used as a vaccine preservative, the USPHS and AAP determined that thiomersal should be removed from vaccines as a purely precautionary measure. This action was based on the precautionary principle, which assumes that there is no harm in exercising caution even if it later turns out to be unnecessary. The CDC and AAP reasoned that despite the lack of evidence of significant harm in the use of thiomersal in vaccines, the removal of this preservative would increase the public confidence in the safety of vaccines. Although thiomersal was largely removed from routine infant vaccines by summer 2001 in the U.S., some vaccines continue to contain non-trace amounts of thiomersal, mainly in multi-dose vaccines targeted against influenza, meningococcal disease and tetanus.

In 2004 Quackwatch posted an article saying that chelation therapy has been falsely promoted as effective against autism, and that practitioners falsified diagnoses of metal poisoning to "trick" parents into having their children undergo the process. As of 2008, between 2–8% of children with autism had undergone the therapy.

Rationale for concern

Reports of autism cases per 1,000 children grew dramatically in the U.S. from 1996 to 2007. It is unknown how much, if any, growth came from changes in autism's prevalence.

 

Although intended to increase public confidence in vaccinations, the decision to remove thiomersal instead led to some parents suspecting thiomersal as a cause of autism. This concern over a vaccine-autism link grew from a confluence of several underlying factors. First, methylmercury had for decades been the subject of widespread environmental and media concern after two highly publicized episodes of poisonings in the 1950s and 1960s in Minamata Bay, Japan from industrial waste and in the 1970s in Iraq from fungicide contamination of wheat. These incidents led to new research on methylmercury safety and culminated in the publication of an array of confusing recommendations by public health agencies in the 1990s warning against methylmercury exposure in adults and pregnant women, which ensured a continued high public awareness of mercury toxicity. Second, the vaccine schedule for infants expanded in the 1990s to include more vaccines, some of which, including the Hib vaccine, DTaP vaccine and hepatitis B vaccine, could have contained thiomersal. Third, the number of diagnoses of autism grew in the 1990s, leading parents of these children to search for an explanation for the apparent rise in diagnoses, including considering possible environmental factors. The dramatic increase in reported cases of autism during the 1990s and early 2000s is largely attributable to changes in diagnostic practices, referral patterns, availability of services, age at diagnosis, and public awareness, and it is unknown whether autism's true prevalence increased during the period. Nevertheless, some parents believed that there was a growing "autism epidemic" and connected these three factors to conclude that the increase in number of vaccines, and specifically the mercury in thiomersal in those vaccines, was causing a dramatic increase in the incidence of autism.

Advocates of a thiomersal-autism link also relied on indirect evidence from the scientific literature, including analogy with neurotoxic effects of other mercury compounds, the reported epidemiologic association between autism and vaccine use, and extrapolation from in vitro experiments and animal studies. Studies conducted by Mark Geier and his son David Geier have been the most frequently cited research by parents advocating a link between thiomersal and autism. This research by Geier has received considerable criticism for methodological problems in his research, including not presenting methods and statistical analyses to others for verification, improperly analyzing data taken from Vaccine Adverse Event Reporting System, as well as either mislabelling or confusing fundamental statistical terms in his papers, leading to results that were "uninterpretable".

Publicity of concern

Several months after the recommendation to have thiomersal removed from vaccines was published, a speculative article was published in Medical Hypotheses, a non-peer-reviewed journal, by parents who launched the parental advocacy group SafeMinds to promote the theory that thiomersal caused autism. The controversy began to gain legitimacy in the eyes of the public and gained widening support within certain elements in the autism advocacy community as well as in the political arena, with U.S. Representative Dan Burton openly supporting this movement and holding a number of Congressional hearings on the subject.

Further support for the association between autism and thiomersal appeared in an article by Robert F. Kennedy, Jr. in the magazines Rolling Stone and Salon.com alleging a government conspiracy at a CDC meeting to conceal the dangers of thiomersal to protect the pharmaceutical industry, and a book written by David Kirby, Evidence of Harm, dramatizing the lives of parents of autistic children, with both authors participating in media interviews to promote their work and the controversy. Although the allegations by Kennedy were denied and a US Senate committee investigation later found no evidence to substantiate the most serious allegations, the story had already been well publicized by leveraging Kennedy's celebrity. Salon magazine subsequently amended Kennedy's article five times due to factual errors and later retracted it completely on January 16, 2011, stating that the works of critics of the article and evidence of the flaws in the science connecting autism and vaccines undermined the value of the article to the editors.

Meanwhile, during this time of increased media publicity of the controversy, public health officials and institutions did little to rebut the concerns and speculative theories being offered. Media attention and polarization of the debate has also been fueled by personal injury lawyers who took out full-page ads in prominent newspapers and offered financial support for expert witnesses who dissented from the scientific consensus that there is no convincing evidence for a link between thiomersal and autism. Paul Offit, a leading vaccine researcher and advocate, has said that the media has a tendency to provide false balance by perpetually presenting both sides of an issue even when only one side is supported by the evidence and thereby giving a platform for the spread of misinformation.

Despite the consensus from experts that there is no link between thiomersal and autism, many parents continue to believe that such a link exists. These parents share the viewpoint that autism is not just treatable, but curable through "biomedical" interventions and have been frustrated by the lack of progress from more "mainline" scientists in finding this cure. Instead, they have supported an alternative community of like-minded parents, physicians and scientists who promote this belief. This mindset has taught these parents to challenge the expertise from the mainstream scientific community. Parents have also been influenced by an extensive network of anti-vaccination organizations such as Robert F. Kennedy Jr.'s Children's Health Defense and a large number of online anti-vaccination websites that present themselves as an alternative source for evidence using pseudoscientific claims. These websites use emotional appeals to gather support and frame the controversy as an adversarial dispute between parents and a conspiracy of doctors and scientists. Advocates for a thiomersal-autism link have also relied on celebrities like model Jenny McCarthy and information presented on Don Imus' Imus in the Morning radio show to persuade the public to their cause, instead of relying only on "dry" scientific papers and scientists. McCarthy has published a book describing her personal experience with her autistic son and appeared on The Oprah Winfrey Show to promote the hypothesis of vaccines causing autism. Bitterness over this issue has led to numerous threats made against the CDC as well as researchers like Offit, with increased security placed by the CDC in response to these threats.

Scientific evaluation

Rationale for doubting link

Various lines of evidence undermine a proposed link between thiomersal and autism. For example, although advocates of a thiomersal-autism link consider autism a form of "mercury poisoning," the typical symptoms of mercury toxicity are significantly different from symptoms seen in autism. Likewise, the neuroanatomic and histopathologic features of the brains of patients who have mercury poisoning, both with methylmercury as well as ethylmercury, have significant differences from the brains of people with autism. Previous episodes of widespread mercury toxicity in a population such as in Minamata Bay, Japan would also be expected to lead to documentation of a significant rise in autism or autism-like behavior in children should autism be caused by mercury poisoning. However, research on several episodes of acute and chronic mercury poisoning have not documented any such rise in autism-like behavior. Although some parents cite an association between the timing of onset of autistic symptoms with the timing of vaccinations as evidence of an environmental cause such as thiomersal, this line of reasoning can be misleading. Associations such as these do not establish causation as the two occurring together may be only coincidental in nature. Also, genetic disorders that have no environmental triggers such as Rett syndrome and Huntington's disease nevertheless have specific ages when they begin to show symptoms, suggesting specific ages of onset of symptoms does not necessarily require an environmental cause.

Although the concern for a thiomersal-autism link was originally derived from indirect evidence based on the known potent neurotoxic effects of methylmercury, recent studies show these feared effects were likely overestimated. Ethylmercury, such as in thiomersal, clears much faster from the body after administration than methylmercury, suggesting total mercury exposure over time is much less with ethylmercury. Currently used methods of estimating brain deposition of mercury likely overestimates the amounts deposited due to ethylmercury, and ethylmercury also decomposes quicker in the brain than methylmercury, suggesting a lower risk of brain damage. These findings show that the assumptions that originally led to concern about the toxicity of ethylmercury, which were based on direct comparison to methylmercury, were flawed.

Population studies

Multiple studies have been performed on data from large populations of children to study the relationship between the use of vaccines containing thiomersal, and autism and other neurodevelopmental disorders. Almost all of these studies have found no association between thiomersal-containing vaccines (TCVs) and autism, and studies done after the removal of thiomersal from vaccines have nevertheless shown autism rates continuing to increase. The only epidemiologic research that has found a purported link between TCVs and autism has been conducted by Mark Geier, whose flawed research has not been given any weight by independent reviews.

In Europe, a cohort study of 467,450 Danish children found no association between TCVs and autism or autism spectrum disorders (ASDs), nor any dose-response relationship between thiomersal and ASDs that would be suggestive of toxic exposure. An ecological analysis that studied 956 Danish children diagnosed with autism likewise did not show an association between autism and thiomersal. A retrospective cohort study on 109,863 children in the United Kingdom found no association between TCVs and autism, but a possible increased risk for tics. Analysis in this study also showed a possible protective effect with respect to general developmental disorders, attention-deficit disorder, and otherwise unspecified developmental delay. Another UK study based on a prospective cohort of 13,617 children likewise found more associated benefits than risks from thiomersal exposure with respect to developmental disorders. Because the Danish and UK studies involved only diphtheria-tetanus-pertussis (DTP) or diphtheria-tetanus (DT) vaccines, they are less relevant for the higher thiomersal exposure levels that occurred in the U.S.

In North America, a Canadian study of 27,749 children in Quebec showed that thiomersal was unrelated to the increasing trend in pervasive developmental disorders (PDDs). In fact, the study noted that rates of PDDs were higher in the birth cohorts with no thiomersal when compared to those with medium or high levels of exposure. A study performed in the US which analyzed data from 78,829 children enrolled in HMOs taken from the Vaccine Safety Datalink (VSD) did not show any consistent association between TCVs and neurodevelopmental outcomes, noting different results from data in different HMOs. A study performed in California found that removal of thiomersal from vaccines did not decrease the rates of autism, suggesting that thiomersal could not be the primary cause of autism. A study on children from Denmark, Sweden and California likewise argued against TCVs being causally associated with autism.

Scientific consensus

In 2001 the Centers for Disease Control and Prevention and the National Institutes of Health asked the U.S. National Academy of Science's (NAS) Institute of Medicine to establish an independent expert committee to review hypotheses about existing and emerging immunization safety concerns. This initial report found that based on indirect and incomplete evidence available at the time, there was inadequate evidence to accept or reject a thiomersal-autism link, though it was biologically plausible.

Since this report was released, several independent reviews have examined the body of published research for a possible thiomersal-autism link by examining the theoretical mechanisms of thiomersal causing harm and by reviewing the in vitro, animal, and population studies that have been published. These reviews determined that no evidence exists to establish thiomersal as the cause of autism or other neurodevelopmental disorders.

The scientific consensus on the subject is reflected in a follow up report that was subsequently published in 2004 by the Institute of Medicine, which took into account new data that had been published since the 2001 report. The committee noted, in response to those who cite in vitro or animal models as evidence for the link between autism and thiomersal:

"However, the experiments showing effects of thimerosal on biochemical pathways in cell culture systems and showing abnormalities in the immune system or metal metabolism in people with autism are provocative; the autism research community should consider the appropriate composition of the autism research portfolio with some of these new findings in mind. However, these experiments do not provide evidence of a relationship between vaccines or thimerosal and autism. In the absence of experimental or human evidence that vaccination (either the MMR vaccine or the preservative thimerosal) affects metabolic, developmental, immune, or other physiological or molecular mechanisms that are causally related to the development of autism, the committee concludes that the hypotheses generated to date are theoretical only."

The committee concludes:

"Thus, based on this body of evidence, the committee concludes that the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism." [bold in original]

Further evidence of the scientific consensus includes the rejection of a causal link between thiomersal and autism by multiple national and international scientific and medical bodies including the American Medical Association, the American Academy of Pediatrics, the American College of Medical Toxicology, the Canadian Paediatric Society, the U.S. National Academy of Sciences, the Food and Drug Administration, Centers for Disease Control and Prevention, the World Health Organization, the Public Health Agency of Canada, and the European Medicines Agency.

A 2011 journal article reflects this point of view and described the vaccine-autism connection as "the most damaging medical hoax of the last 100 years".

Consequences

The suggestion that thiomersal has contributed to autism and other neurodevelopmental disorders has had a number of effects. Public health officials believe fear driven by advocates of a thiomersal-autism link has caused parents to avoid vaccination or adopt "made up" vaccination schedules that expose their children to increased risk from preventable diseases such as measles and pertussis. Advocates of a thiomersal-autism link have also helped enact laws in six states (California, Delaware, Illinois, Missouri, New York and Washington) between 2004 and 2006 to limit the use of thiomersal given to pregnant women and children, although later attempts in 2009 in twelve other states failed to pass. These laws can be temporarily suspended, but vaccine advocates doubt their utility given the lack of evidence for danger with thiomersal in vaccines. Vaccine advocates are also concerned that passage of such laws help fuel a backlash against vaccination and contribute to doubts about the safety of vaccines that are unwarranted.

During the period of time of removal of thiomersal, the CDC and AAP asked doctors to delay the birth dose of hepatitis B vaccine in children not at risk for hepatitis. This decision, though following the precautionary principle, nevertheless sparked confusion, controversy and some harm. Approximately 10% of hospitals suspended the use of hepatitis B vaccine for all newborns, and one child born to a Michigan mother infected with hepatitis B virus died of it. Similarly, a study found that the number of hospitals who failed to properly vaccinate infants of hepatitis B seropositive mothers rose by over 6 times. This is a potential negative outcome given the high probability that infants who acquire hepatitis B infection at birth will develop the infection in a chronic form and possibly liver cancer.

The notion that thiomersal causes autism has led some parents to have their children treated with costly and potentially dangerous therapies such as chelation therapy, which is typically used to treat heavy metal poisoning, due to parental fears that autism is a form of "mercury poisoning". As many as 2 to 8% of autistic children in the U.S., numbering as many as several thousand children per year, receive mercury-chelating agents. Although critics of using chelation therapy as an autism treatment point to a lack of any evidence to support its use, hundreds of doctors prescribe these medications despite possible side effects including nutritional deficiencies as well as damage to the liver and kidney. The popularity of this therapy caused a "public health imperative" that led the U.S. National Institute of Mental Health (NIMH) to commission a study about chelation in autism by studying DMSA, a chelating agent used for lead poisoning, despite worries from critics that there would be no chance it would show positive results and it would be unlikely to convince parents to not use the therapy. Ultimately, the study was halted due to ethical concerns that there would be too much risk to children with autism who did not have toxic levels of mercury or lead due to a new animal study showing possible cognitive and emotional problems associated with DMSA. A 5-year-old autistic boy died from cardiac arrest immediately after receiving chelation therapy treatment using EDTA in 2005.

The notion has also diverted attention and resources away from efforts to determine the causes of autism. The 2004 Institute of Medicine report committee recommended that while it supported "targeted research that focuses on better understanding the disease of autism, from a public health perspective the committee does not consider a significant investment in studies of the theoretical vaccine-autism connection to be useful at this time." Alison Singer, a senior executive of Autism Speaks, resigned from the group in 2009 in a dispute over whether to fund more research on links between vaccination and autism, saying, "There isn't an unlimited pot of money, and every dollar spent looking where we know the answer isn't is one less dollar we have to spend where we might find new answers."

Court cases

From 1988 until August 2010, 5,632 claims relating to autism were made to Office of Special Masters of the U.S. Court of Federal Claims (commonly known as the "Vaccine Court") which oversees vaccine injury claims, of which one case has received compensation, 738 cases have been dismissed with no compensations made, and with the remaining cases pending. In the one case which received compensation, the U.S. government agreed to pay for injury to a child that had a pre-existing mitochondrial disorder who developed autism-like symptoms after multiple vaccinations, some of which included thiomersal. Citing the inability to rule out a role of these vaccinations in exacerbating her underlying mitochondrial disorder as the rationale for payment, CDC officials cautioned against generalizing this one case to all autism-related vaccine cases as most patients with autism do not have a mitochondrial disorder. In February 2009, this court also ruled on three autism-related cases, each exploring different mechanisms that plaintiffs proposed linked thiomersal-containing vaccines with autism. Three judges independently found no evidence that vaccines caused autism and denied the plaintiffs compensation. Since these same mechanisms formed the basis for the vast majority of remaining autism-related vaccine injury cases, the chance for compensation in any of these cases has significantly decreased. In March 2010, the court ruled in three other test cases that thiomersal-containing vaccines do not cause autism.

What’s Wrong with Moral Foundations Theory, and How to get Moral Psychology Right

By Oliver Scott Curry

March 26, 2019

Original link:  http://behavioralscientist.org/whats-wrong-with-moral-foundations-theory-and-how-to-get-moral-psychology-right/?fbclid=IwAR2FMsH20-sGW1WIoirXrNG8nmuw1miG4_o7rtigArM_l7i4tSe6Uw-_25c

 

Image: Antonio Marín Segovia/Flickr

Once the exclusive preserve of philosophy and theology, the study of morality has now become a thriving interdisciplinary endeavor, encompassing research in evolutionary theory, genetics, biology, animal behavior, psychology, and anthropology. The emerging consensus is that there is nothing mysterious about morality; it is merely a collection of biological and cultural traits that promote cooperation.

Best known among these accounts is Jonathan Haidt’s Moral Foundations Theory (MFT). According to MFT: “Moral systems are interlocking sets of values, virtues, norms, practices, identities, institutions, technologies, and evolved psychological mechanisms that work together to suppress or regulate selfishness and make cooperative social life possible.” And MFT proceeds to argue that, because humans face multiple social problems, they have multiple moral values—they rely on multiple “foundations” when making moral decisions. These foundations include: Care, Fairness, Loyalty, Authority, and Purity.

• Care: “The suffering of others, including virtues of caring and compassion.”
• Fairness: “Unfair treatment, cheating, and more abstract notions of justice and rights.”
• Loyalty: The “obligations of group membership” including “self-sacrifice, and vigilance against betrayal.”
• Authority: “Social order and the obligations of hierarchical relationships, such as obedience, respect, and the fulfillment of role-based duties.”
• Purity: “Physical and spiritual contagion, including virtues of chastity, wholesomeness, and control of desires.”

These moral foundations have been operationalized, and measured, by the Moral Foundations Questionnaire (MFQ; you can complete it here).

MFT and the questionnaire have had an enormous impact on moral psychology. The central papers have been cited hundreds of times. And there is now a huge literature applying MFT to bioethics, charity, environmentalism, psychopathy, religion, and especially politics. However, MFT has some serious problems, both theoretical and empirical.

The main theoretical problem is that MFT’s list of foundations is not based on any particular theory of cooperation, or on any explicit theory at all. Indeed, Haidt, has explicitly argued against taking what he calls an “a priori or principled” approach to moral psychology, and instead has advocated taking an “ad hoc” approach. The shortcomings of this ad hoc approach, however, are all too plain to see.

First, MFT’s list of foundations has critical omissions. Despite claiming to be an evolutionary-cooperative account of morality, MFT fails to include the four most well-established types of evolved cooperation: kin altruism, reciprocal altruism, competitive altruism, and respect for prior possession.

• Kin altruism has no dedicated foundation in MFT. Although MFT argues that Care originally motivated investment in offspring, it is now applied to nonkin; and MFT treats “family” as just another type of “group.” The questionnaire (MFQ) does have two items pertaining to family, but they appear under Fairness and Loyalty, not Care.
• Reciprocal altruism has no dedicated foundation in MFT. Instead, MFT conflates reciprocity—a solution to iterated prisoners’ dilemmas—with fairness—a solution to bargaining problems. And the MFQ has no items pertaining to reciprocity.
• Competitive altruism—that is, costly signals of status, such as bravery or generosity—has no dedicated foundation in MFT, and no items in the MFQ.
• Respect for prior possession—that is, property rights and the prohibition of theft—has no dedicated foundation in MFT. The MFQ’s only mention of property occurs in an item about inheritance, under Fairness.

Second, in addition to these omissions, MFT includes two foundations that are not distinct types of evolved cooperation: Care and Purity.

• Care—like “altruism” or “benevolence”—is a generic category, not a specific type of cooperation. It doesn’t distinguish between the various distinct types of cooperation—kin altruism, mutualism, reciprocal altruism, competitive altruism and their corresponding psychological mechanisms—all of which involve caring for different people (including family, friends, strangers) for different reasons.
• Purity is supposed to stem from the need to avoid “people w/ diseases, parasites [&] waste products.” But “avoiding pathogens” is not itself a cooperative problem, any more than, say, “avoiding predators.” And, indeed, MFT offers no connection between purity and cooperation. On the contrary, Purity is described as an “odd corner” of morality because it is not “concerned with how we treat other people.” Hence, categorizing Purity as a moral foundation is anomalous.

Thus, MFT’s theory-free approach results in egregious errors of omission, conflation, and commission. It misses some candidate moral domains, combines others, and includes noncooperative domains. Most egregiously, the lack of theory means that MFT cannot rectify these errors; it cannot make principled predictions about what (other) foundations there might be, thus it cannot make progress toward a cumulative science of morality.

MFT also has empirical problems. The main problem is that MFT’s five-factor model of morality has not been well supported by studies using the MFQ. Some of the original studies, as well as replications in Italy, New Zealand, Korea, Sweden, and Turkey, and also a 27 country study using the short-form MFQ, have found that MFT’s five-factor model falls short of the conventionally acceptable degree of model fit (CFIs less than 0.90). These studies typically find that a two-factor model—“Care-Fairness” and “Loyalty-Authority-Purity”—is a better fit. And so despite MFT promising five moral domains, the MFQ typically delivers only two. The MFQ does not distinguish domains dedicated to Fairness, Loyalty, or Authority; nor does it establish that Care and Purity are distinct moral domains. Simply put, it does not establish that there are five moral foundations. Other research has taken issue with specific foundations, especially Purity and the link between disgust and morality; but that’s a story for another time.

To their credit, proponents of MFT acknowledge these problems. They accept that the original list of foundations was “arbitrary,” based on a limited review of only “five books and articles,” and never intended to be “exhaustive.” And they have positively encouraged research that could “demonstrate the existence of an additional foundation, or show that any of the current five foundations should be merged or eliminated.”

And so that is what my colleagues and I have done. But we have not done so by making yet more “ad hoc” suggestions. We have gone back to first principles, to the theory that can provide a rigorous, systematic foundation for a cooperative theory of morality—the mathematics of cooperation, the theory of non-zero-sum games. We call this approach Morality-as-Cooperation (MAC).

According to MAC, morality consists of a collection of biological and cultural solutions to the problems of cooperation recurrent in human social life. For 50 million years humans and their ancestors have lived in social groups. During this time, they faced a range of different problems of cooperation, and they evolved and invented a range of different solutions to them. Together, these biological and cultural mechanisms provide the motivation for cooperative behavior; and they provide the criteria by which we evaluate the behavior of others. And, according to MAC, it is precisely this collection of cooperative traits—these instincts, intuitions, and institutions—that constitute human morality.

Which problems of cooperation do humans face? And how are they solved? That’s where game theory comes in. Game theory makes a principled distinction between zero-sum and non-zero-sum games. Zero-sum games are competitive interactions that have a winner and a loser; one’s gain is another’s loss. Non-zero-sum games are cooperative interactions that can have two winners; they are win-win situations. Game theory also distinguishes between different types of non-zero-sum games and the strategies used to play them. Thus, it delineates mathematically distinct types of cooperation.

A review of this literature suggests that there are (at least) seven well established types of cooperation: (1) the allocation of resources to kin; (2) coordination to mutual advantage; (3) social exchange; and conflict resolution through contests featuring (4) hawkish displays of dominance and (5) dove-ish displays of submission; (6) division of disputed resources; and (7) recognition of prior possession.

In my research, I have shown how each of these types of cooperation can be used to identify and explain a distinct type of morality.

(1) Kin selection explains why we feel a special duty of care for our families, and why we abhor incest. (2) Mutualism explains why we form groups and coalitions (there is strength and safety in numbers), and hence why we value unity, solidarity, and loyalty. (3) Social exchange explains why we trust others, reciprocate favors, feel gratitude and guilt, make amends, and forgive. And conflict resolution explains why we (4) engage in costly displays of prowess such as bravery and generosity, why we (5) express humility and defer to our superiors, why we (6) divide disputed resources fairly and equitably, and why we (7) respect others’ property and refrain from stealing.

Our research has shown that examples of these seven types of cooperative behavior—help your family, help your group, return favors, be brave, defer to your superiors, be fair, and respect others’ property—are considered morally good all around the world and are probably cross-cultural moral universals.

And we have used MAC’s framework to develop a new measure of moral values that promises, and delivers, seven moral domains: (1) Family, (2) Group, (3) Reciprocity, (4) Heroism, (5) Deference, (6) Fairness, and (7) Property. This new Morality-as-Cooperation Questionnaire (MAC-Q) introduces the four moral domains that were missing from MFT: Family, Reciprocity, Heroism, Property. And unlike the MFQ, it distinguishes Family from Group (Loyalty), Group (Loyalty) from Deference (Authority), and Reciprocity from Fairness.

So this principled approach to morality, grounded firmly in the underlying logic of cooperation, outperforms an unprincipled approach. MAC explains more types of morality than MFT. It can generate novel principled predictions about morality’s content and structure—predictions that have thus far been supported by psychological and anthropological research. And it leads to a more comprehensive and reliable measure of moral values.

Equipped with this new map of the moral landscape, we can now examine familiar ground in greater detail and survey previously unexplored territory. We can take a fresh look at the genetic basis, and the psychological architecture, of morality. We can reassess the relationship between morals and politics. And we can investigate how and why moral values vary around the world. Above all, by using a theory to generate new testable predictions, we can pave the way for a genuine science of morality.

Oliver Scott Curry

Oliver Scott Curry is a senior researcher at the Institute of Cognitive and Evolutionary Anthropology, University of Oxford. His research investigates the nature, content, and structure of human morality, using a range of techniques from philosophy, experimental and social psychology, and comparative anthropology.

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Understanding gene interactions holds key to personalized medicine

by University of Toronto

March 25, 2019 

Original link: https://medicalxpress.com/news/2019-03-gene-interactions-key-personalized-medicine.html?fbclid=IwAR3MxlnKkFlr5XNwwR0QYkxqgSaz0kU2-k4__w-suZUSBH34Ivc9HJjbQFk

When the Human Genome Project was completed, in 2003, it opened the door to a radical new idea of health—that of personalized medicine, in which disease risk and appropriate treatment would be gleaned from one's genetic makeup. As more people had their genomes sequenced, disease-related genes would start coming into view— and while this is true in many ways, things also turned out to be much more complicated.

Sixteen years on, tens of thousands of people have had their genomes sequenced yet it remains a major challenge to infer future health from genome information. Part of the reason may be that genes interact with each other to modify trait inheritance in ways that aren't totally clear, write Donnelly Centre researchers in an invited perspective for the leading biomedical journal Cell.

"All the genome sequencing data is highlighting the complexity of inheritance for the human genetics community," says Brenda Andrews, University Professor and Director of U of T's Donnelly Centre for Cellular and Biomolecular Research and a senior co-author, whose lab studies interactions between genes. "The simple idea of a single gene leading to a single disease is more likely to be an exception than a rule," she says.

Andrews and Charles Boone, who is also a senior co-author, are professors in U of T's Donnelly Centre and the Department of Molecular Genetics, as well as Senior Fellows of the Genetic Networks program at the Canadian Institute for Advanced Research, which Boone co-directs.

Genome wide association studies, or GWAS, which scan the genomes of patient populations and compare them to healthy controls, have unearthed thousands of mutations, or genetic variants, that are more prevalent in disease. Most variants are found in common diseases that affect large swathes of the world's population but their effects can be small and hard to see. Instead of there being a single gene for heart disease or schizophrenia, for example, there may be many combinations of subtle genetic changes scattered across the genome that tune up or down a person's susceptibility to these diseases.

Vast genetic diversity in the human population further influences trait inheritance while environmental effects, such as diet and upbringing, further complicate matters.

In some cases, a single gene variant can be extremely potent and cause a disease, as seen in cystic fibrosis, heamophilia and other inherited disorders. But even two people with the same disease variant can experience a wildly different disease severity which, presently, cannot be gleaned from their genomes. Even more astonishing, sequencing studies have identified people who carry damaging mutations but remain perfectly healthy, presumably protected by other, as yet unknown gene variants within their genomes.

"It would be a simpler problem if one particular mutation resulted in Disease X all of the time, but that's often not the case," says Michael Costanzo, Senior Research Associate in Boone's lab and one of the authors on the paper. "To understand the effect of combinations of variants is really difficult. We suspect it's particular sets of mutations that really impact what the disease outcome is going to be in a personal genome" says Costanzo. "How genes interact with each other is important and, given our current understanding of gene-gene interactions, it's not a problem that's easily solved by reading individual genome sequences."

It's a numbers game as most genome analysis methods lack the statistical power to confidently uncover multiple genes behind a disease. An often-cited calculation, by researchers at the Broad Institute in Boston, states that to identify a single pair of genes underlying a disease, on the order of half a million patients would have to have their genomes sequenced, with another half a million of healthy people as controls. "If most genetic diseases involve gene combinations, collecting enough patient data to find these interactions is a huge challenge," says Costanzo.

Genetic interactions—what are they and how can they be identified?

"The concept of genetic interaction is simple, but the physiological repercussions can be profound," write the authors. Two genes are said to interact if a combined outcome of their defects is bigger or lesser than expected from their individual outcomes. For example, a person carrying a mutation in either gene A or in gene B can be healthy, but if both A and B don't work, disease occurs.

Research in simple model organisms—most notably yeast—has mapped genome-wide genetic interactions revealing how thousands of genes organize into functional groups within a network. From this, basic principles emerged, allowing researchers to predict a gene's function and its relative importance for the cell's health based on its position in the network. Studies also revealed the identity of so-called "modifier genes" which can suppress the effect of damaging mutations and how genetic background influences trait inheritance.

These types of studies rest on the researchers' ability to switch off genes in precise combinations to find the ones that work together. For human genes, however, such tools did not exist until very recently.

That's all changed now thanks to the gene editing tool CRISPR with which human genes can be turned off in any combination with ease. Although no genome-wide map is yet available, early work indicates that the same principles uncovered in model organisms also apply to human genes. This is already helping reveal function of the less studied human genes and how they relate to disease. And with new computational approaches, it is becoming possible to integrate findings from model organisms with incoming human data to achieve an emerging glimpse of more meaningful insights about health from genome information.

Genetic interactions and cancer therapy

Freed from normal checks and balances, cancer cells stockpile mutations in their genomes and this sets them apart from healthy cells in a way that can be exploited for therapy. Knowing how genes interact in cancer holds promise for the development of selective drugs that kill only sick cells and leave healthy ones unharmed.

"Cancer is a genetic disease and ultimately the genetic wiring of a cancer cell is a product of mutations that occur its genome and we want to understand that," says Jason Moffat, a co-author on the paper and a professor of molecular genetics in the Donnelly Centre whose lab uses CRISPR to map genetic interactions in cancer cells. "With CRISPR, we can start to systematically map how genes interact in cancer cell lines in a similar fashion to how geneticists have mapped genetic interactions in yeast," he says.

This work has the potential to reveal distinct drug targets for different forms of disease. The goal is to find a drug that synergizes with a mutation that's only found in a type of cancer. The drug would then kill sick cells more precisely and with fewer side effects than chemotherapy or radiotherapy.

The knowledge of genetic interactions will also help shed light on why so many approved cancer drugs only work in some patients and not others.

"We can't think about genes in isolation anymore," says Boone. "We have to start looking at variants of multiple genes as a major component of genetic disease, because those combinations are going to be different for different people and these specific combinations may not only profoundly affect disease susceptibility, but they will likely dictate new personalized therapies."