Abstract

Introduction

A possible link between exposure to mercury (Hg) and autism spectrum disorder (ASD) is a recent example of a heated debate over the association between a pervasive toxic exposure and a prevalent and devastating diagnosis. The heated debate began in the late 1990s, when it was suggested that exposure to Hg in vaccines was a risk factor for ASD (Halsey 1999). In this case, as in those before it, whenever there has been a possible link between illness and a toxic exposure, there has been heated debate characterized by adamant denial.

Denial of a toxicant in disease causation can be attributed in part and firstly, to a natural inclination to resist unpleasant theories. A historical illustration of this was acrodynia (also known as Pink Disease). This almost forgotten disease, mostly affecting infants and young children, is a well-studied example of human Hg poisoning (Bjørklund 1995). Hg as the cause of acrodynia was first suggested in 1846, and again in 1922 (Hanson and Pleva 1991). Josef Warkany and Donald M. Hubbard (1948) from the United States (US) demonstrated Hg involvement in 25 out of 28 cases of acrodynia in 1948. When Hg-containing teething powders were withdrawn from the market in Australia in 1953 (followed later by the US), there was a dramatic fall in the incidence and mortality rate from acrodynia (Bjørklund 1995). However, the role of Hg as the primary source of acrodynia was not universally accepted even as late as 1956 (Dathan and Harvey 1965). Throughout these decades of heated debate, the science indicating that acrodynia was caused by Hg exposure was resisted because, as stated by a historian studying the social and medical aspects of the illness, “poisoning was not a fashionable diagnosis” (Dally 1997).

Resistance to linking a toxic exposure to an illness can also result from a concern for liability. The responsibility for an illness or disability that results from a toxic product is borne by the industry that manufactures it, and resistance to a link between illness and an antecedent exposure is often driven by an industry that fears the consequences, since it is in their best interest to do so (Bridbord and Hanson 2009; Brownell and Warner 2009; Friedman and Richter 2005; Hayes 2004; McComas 2008; Ong and Glantz 2001; Sass 2006). As a result, conflicts of interest enter these debates and the resulting discourse is often marred by misleading information, which, unfortunately, often includes misleading assertions concerning the state of scientific research.

Historically, entities with a vested interest in a product that critics have suggested is harmful have consistently used research to back their claims that a product is safe. Kelly Brownell and Kenneth Warner (2009) reviewed the issue of conflicts of interest in research. They concluded that industry manipulates research information to buy loyalty, instill doubt about criticisms, confuse the public, give ammunition to political allies, and stall or influence government action. This practice, as noted by Brownell and Warner (2009) and many other experts on the subject, continues to the present day (Barnoya and Glantz 2006; Brownell and Warner 2009; Kessler 2001; Mars and Ling 2008; Michaels 2008; Mooney 2006; Schick and Glantz 2007). The following discussion of examples of research conflicts of interest starts with tobacco because much of what we have learned regarding the influencing or “buying” of scientists is from tobacco litigation.

Past and Current Examples of Research Conflict of Interest and Outside Influences

Conflicts of Interest in Mercury Exposure and Autism Research

Conflicts of interest in studies examining Hg exposure and the resulting risk of ASD have been noted (DeSoto and Hitlan 2010). In parallel to other historical debates over potential toxicants and their resulting adverse effects, studies examining the Hg-autism link that were sponsored and supported by entities with apparent conflicts of interest, often show no evidence of harm or no “consistent” evidence of harm from Hg exposure, even in the most vulnerable subjects, human fetuses and infants.

For example, studies on Hg exposure from coal-burning plants conducted by researchers without industry affiliation consistently show that Hg exposure from coal burning is a significant risk factor for ASD (Blanchard et al. 2011; Palmer et al. 2006, 2009; Windham et al. 2006). In contrast, Thomas Lewandowski and colleagues (2009), researchers with industry affiliation, examined the relationship between Hg release in Texas and ASD and found different results. Lewandowski works for Gradient, a product defense consulting firm that has received substantial sums from companies to write reports defending products such as cigarettes and BPA (Keim 2007). Lewandowski and colleagues (2009) concluded that Hg emissions are not “consistently” associated with ASD prevalence in Texas school districts.

Another example of such conflict of interest in research is found in studies conducted on the safety of RhoD immune globulin (RhoGAM). Different formulations of Thimerosal (49.55% Hg by weight)-containing RhoGAM were routinely administered to Rh-negative mothers in the US prior to 2002. Studies conducted by researchers without industry affiliations found significant increases in maternal Rh-negativity among children with neurodevelopmental disorders (NDs), including ASD (Geier and Geier 2007b; Geier et al. 2008; Holmes et al. 2003). However, Johnson & Johnson, a manufacturer of RhoGAM, approached Judith Miles at the University of Missouri with a significant grant to help defend the company from litigation (Evaluate™ 2012; Osterweil 2007; Wikipedia 2017). The industry-sponsored study by Miles and T. Nicole Takahashi (2007) commenced and concluded that exposure to ethylmercury (or Thimerosal) from RhoGAM was not associated with ASD (Miles and Takahashi 2007).

In ASD, the stakes for industry are particularly high, with millions of children affected globally (DeSoto and Hitlan 2010). As mentioned, more than one industry views this issue through the lens of their own potential culpability: the coal burning industry which expels mercury into the air and the pharmaceutical industry which uses Hg as a preservative in some vaccines. However, the issue of conflicts of interest in research that examines the relationship between Hg exposure and ASD is different from the typical toxic substances and products previously mentioned in that the public health sector, a powerful and influential global and governmental alliance, views this issue through the lens of its own potential culpability. According to internal documents, public health officials are concerned that negative information about Thimerosal (the Hg-based preservative used in some vaccines), if substantiated, might damage the vaccine program, in which the public health system has a vested interest as a result of its role in vaccine distribution and use (Association of American Physicians and Surgeons, Inc. 2005). As reported by the United States Congressional Report of 2003 in regard to the issue of Thimerosal and ASD, “Our public health agencies’ failure to act is indicative of institutional malfeasance for self-protection and misplaced protectionism of the pharmaceutical industry.” (Burton 2003).

Additionally, one public health entity, the US Centers for Disease Control and Prevention (CDC), receives millions of dollars in industry gifts and funding, including substantial support from the pharmaceutical industry (Lenzer 2015; Smith et al. 2012). According to Jeanne Lenzer (2015), numerous manufacturers give donations to the CDC through the CDC Foundation. For example, in 2012–2013 Janssen donated $1.5 million, and in 2011–2012 contributors included Merck ($915,149), Genzyme ($762,000), Sanofi-Aventis ($600,000), and Abbott Laboratories ($550,000) (Lenzer 2015; Smith et al. 2012). This significant financial relationship further amplifies the potential for conflict of interest on the part of the CDC.

The issue of conflict of interest in ASD can be illustrated by an examination of the published scientific literature. A systematic literature search of original studies from 1999 to August 2015 using the search terms “autism and mercury” reveals evidence of this bias. The results of this search are listed and briefly described in Tables 1 and ​and2.2. Table 1 shows the studies on Thimerosal (or mercury) and ASD which were sponsored or co-sponsored by those with public health, pharmaceutical industry, or coal-burning affiliation, that is, studies with an apparent conflict of interest. Table 2 shows the studies on Thimerosal (or mercury) and ASD that were conducted by independent researchers without public health or industry affiliation.

Similar to historical debates about other toxicants, the findings reveal, that research done with an apparent conflict of interest shows a bias toward the null hypothesis or “no effect” (i.e., no relationship between Hg and ASD). Specifically, of the studies with public health or industry affiliation, 86% (12/14) failed to reject the null hypothesis (Table 1), concluding that there was “no effect”. However, of the studies without public health or industry affiliation, only 21% (13/62) failed to reject the null hypothesis. In other words, about 80% of the studies without public health or industry affiliation found evidence of a relationship between Hg exposure and ASD (Table 2). The dramatic discrepancy in these results, 86 versus 21%, provides evidence of biased outcomes, indicative of a conflict of interest.

The Need for Transparency in Autism Research

As mentioned earlier, the stakes in the ASD debate are high. In the past two decades, there has been a dramatic increase in ASD rates. For example, in a study which examined the prevalence and characteristics of developmental disabilities over a 15–20 year time period, with specific focus on concurrent changes in ASD and intellectual disability prevalence (using data from a population-based developmental disabilities surveillance program for 8-year-olds in metropolitan Atlanta), scientists found a 269% increase from 4.2 per 1000 in 1996 to 15.5 per 1000 in 2010 (Van Naarden Braun et al. 2015). ASD is considered to have reached epidemic proportions and is an issue of high national and international concern. The critical importance of this debate only heightens the urgent need for transparency in autism research.

Transparency in autism research, including access to research datasets used, would provide for the review and evaluation of studies and the partiality or impartiality which characterized them, and encourage a system of checks and balances. When study findings are deemed inaccurate and/or biased, transparency in autism research would allow for either confirmation or correction. For instance, in 2004, Patrick Ip and colleagues published a study comparing Hg levels in the blood and hair of both children with ASD and controls, reporting that there was no difference in mean Hg levels (Ip et al. 2004). However, other scientists noted that there did appear to be a significant difference in the mean Hg levels between the groups and subsequently requested the data. Upon re-analysis, the data revealed that there was indeed a significant difference in the mean mercury levels between children with ASD and controls (DeSoto and Hitlan 2007). The authors of the re-analysis stated: “If there is any link between autism and mercury, it is absolutely crucial that the first reports of the question are not falsely stating that no link occurs.” (DeSoto and Hitlan 2007, p. 1308).

As another instance, Polly R. Sager, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Disease (NIAID), US National Institutes of Health (NIH), made a presentation entitled, “NIAID Studies on Thimerosal” to the Institute of Medicine (IOM) of the U.S. National Academy of Sciences on February 9, 2004 (Institute of Medicine, Sager 2004). In her presentation, she presented crucial evidence on the comparative distribution and persistence of Hg in brain and blood following methyl-Hg and Thimerosal administration to infant monkeys mimicking the US childhood vaccine schedule of the 1990s by other investigators (Burbacher et al. 2005). It was later discovered, following Sager’s presentation, that the data she presented did not convey the actual extent that Hg distributed and persisted in the monkey brain following Thimerosal administration. She was eventually forced to supply in her own words, “Corrected Slide Submitted to IOM May 3, 2004”. However, even with the corrections, errors remain in the “Corrected Slide” and the information did not reflect the data ultimately published by the study investigators (Burbacher et al. 2005). As a consequence, in evaluating the relationship between Thimerosal exposure and ASD risk, the IOM was unable to consider accurate and true data as to the distribution and persistence of Hg in the monkey brain following Thimerosal administration mimicking the US childhood vaccine schedule of the 1990s.

Examples of Studies that Illustrate the Importance of Transparency in Autism Research

A number of ASD and Hg studies, sponsored by entities with an apparent conflict of interest, appear to have arrived at questionable conclusions. Moreover, the authors of these studies have, unfortunately, failed to make their datasets available to others for further evaluation, exemplifying the need for transparency in autism research.

As expressed by Patricia Baskin and Robert Gross (Baskin and Gross 2015), editors of the journal Neurology, on the need for greater transparency in research in general: “The responsibility for promoting greater openness in research falls not only to the individuals performing the work, but to the funders of the work (including government, foundation, and industry sponsors), institutions where the work is being done, and to journal editors and peer reviewers, who do the final check on the quality of the research before it is released to readers.” The following examples illustrate this point.

Summary and Conclusion

Historically, entities/industries with a vested interest in a product whose safety is in dispute have consistently used research to back their claims that a product is safe. The effects of a funding source on research outcomes have been examined, and it has been shown that industry or responsible entity affiliated studies are far more likely to yield outcomes favorable to that industry/entity (Boone et al. 2014). When this conflict of interest influences research, the resulting scientific debate on products, toxicants, etc. can be confounded by misleading information. Indeed, this is precisely the outcome desired by the sponsors of such conflicted research (Brandt 2012; Bridbord and Hanson 2009; Brownell and Warner 2009).

A conflict of interest in autism research has been noted, particularly when examining Hg exposure and the risk of ASD (DeSoto and Hitlan 2010). However, conflicts of interest in this debate are different from other cases because not only industries (e.g., the coal-burning industry and the pharmaceutical industry), but also public health institutions view this issue through the lens of their own potential culpability. Further complicating the matter is the fact that public health entities often control access to the relevant datasets. Indeed, a systematic examination of the research literature in the Hg-autism debate shows that research funded by these conflicted entities is more likely to yield conclusions favorable to that industry/entity, that is, finding no relationship between Hg exposure and the risk of ASD.

Transparency in autism research is of utmost importance. The current examples of studies offering questionable conclusions clearly illustrate the need for openness and accountability. ASD is an issue of high national and international concern, where the stakes are high and researchers and policymakers need to be cognizant of the issue of conflicts of interest in autism research (DeSoto and Hitlan 2010).

One way of achieving improved openness and transparency in autism research would be for authors, journals, and funding sources to require greater openness and data sharing. As mentioned, the responsibility for promoting greater openness in research falls not just to the authors, but to the funders, institutions, and journal editors (Baskin and Gross 2015). The examples provided in this analysis suggest that some authors, journals, and institutions could improve in the area of helping to promote greater openness.

The Proceedings of the National Academy of Sciences of the United States of America (PNAS) has developed and adopted standards concerning the responsibilities of authorship in the biological sciences. It is referred to as the Uniform Principle for Sharing Integral Data and Materials Expeditiously or “UPSIDE”. In October of 2001, a National Academies committee evaluated the responsibilities of authors to share data and materials referenced in their publications, the role of journals to impose requirements for data and material sharing, and whether a common set of requirements for sharing does or should exist (Cozzarelli 2001, 2004; Cech 2003). They established that authors are obligated to release data and materials to enable others to verify or replicate published findings. They stated that one “upside” to this is it keeps science honest (Cozzarelli 2001, 2004; Cech 2003). In an article by Nicholas R. Cozzarelli, Editor-in-Chief of PNAS, he described some of the comments of the board members and these comments may be relevant to the current discussion (Cozzarelli 2001). Two of the comments are as follows:

I am one of the few people here who represents the private sector at this point, and I would love to be able to publish in prestigious journals and withhold the data. But I think it is wrong.

Scientific journals should play no role in the protection of the private interests of authors, or in shielding data from the community. Protection is far afield of the mission of journals, and shielding is antithetical to it.

Identifying causative factors for ASD is already a challenging task for the scientific community, demanding the highest standards of openness and transparency. Any departure from these standards represents a disservice to all.

Acknowledgements

Compliance with Ethical Standards

Footnotes

Contributor Information

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References