Apologies for the long blog absence. I’ve been busy PhD-ing (including preparing for and passing my oral general exam!) and working on various side projects.
One of those side projects has been focused on glyphosate. Glyphosate, the active ingredient in Monsanto’s (now owned by Bayer) Roundup, is the most widely used herbicide in the world. First marketed in 1974, its usage skyrocketed after the introduction of “Roundup-ready” (i.e.: Roundup resistant) crops in 1996 and the practice of “green-burndown” (i.e.: using the chemical as a desiccant shortly before harvest) in the mid-2000s. In 2014, global usage was estimated to be 1.8 billion pounds.
But these staggering statistics are not the only claim to fame for glyphosate. It has also been the subject of intense international regulatory and scientific scrutiny in recent years, for its possible link to cancer. The stakes are high (billions of dollars for Monsanto, related to sales of both the herbicide itself and its line of herbicide-resistant crops), and the conclusions are controversial.
Carcinogenic or not, that is the question.
In 2015, the International Agency on Cancer (IARC) declared that glyphosate was a “probable human carcinogen” (relevant links: explanation of IARC classifications; official summary for glyphosate; IARC webpage with follow-up links). However, that same year, the European Food Safety Authority (EFSA) concluded that “glyphosate is unlikely to pose a carcinogenic hazard to humans, and the evidence does not support classification with regard to its carcinogenic potential.” In 2016, the US Environmental Protection Agency (EPA) determined that glyphosate was “not likely to be carcinogenic to humans at doses relevant for human health risk assessment.”
Ok, so that’s confusing. How did these agencies, all of which are supposed to conduct unbiased reviews of all of the evidence come to such different conclusions? There have been several recent publications that explain these inconsistencies (for example, see here and here). In essence, it boils down to: 1) differences in how the agencies weighed peer-reviewed, publicly available studies (most show adverse health effects) versus unpublished regulatory studies submitted by manufacturers (most do not show adverse health effects); 2) whether the agencies focused on studies of pure glyphosate or the final formulated glyphosate-based product that is used in agricultural applications (which is known to be more toxic); and 3) whether the agencies considered dietary exposures to the general population only or also took into account elevated exposures in occupational scenarios (i.e. individuals who apply glyphosate-based herbicides in agricultural settings).
Meanwhile, as the debate continues… 27 countries (as of November 2018) have decided to move forward with implementing their own bans or restrictions. And, Monsanto/Bayer faces more than 9,000 lawsuits in the US from individuals who link their cancer to the herbicide. (The courts ruled the first case in favor of the plaintiff, though Monsanto is appealing the decision).
This highly contentious area is outside the topic of my dissertation research, but I got involved because my advisor was a member of the EPA scientific advisory panel that reviewed the agency’s draft assessment of glyphosate in 2016. The panel’s final report raised a number of concerns with EPA’s process and conclusions, including that the agency did not follow its own cancer guidelines and made some inappropriate statistical decisions in the analysis.
Because of their dissatisfaction with EPA’s report, my advisor and two other panel members decided to pursue related research to dig further into the issues. I enthusiastically accepted the invitation to join.
Our collaborative group recently published two review papers on glyphosate. I’ll provide brief highlights of both below.
Reviewing our reviews, part 1: exposure to glyphosate
In January 2019, we published a review of the evidence of worldwide exposure to glyphosate. Even though glyphosate-based products are the most heavily used herbicides in the world, we were surprised (and dismayed) to find less than twenty published studies documenting exposure in only 3721 individuals.
So, our paper mostly serves to highlight the limitations of the existing data:
- These studies sampled small numbers of individuals from certain geographic regions, mostly in the US and Europe, and therefore are not representative of the full scope of global exposures
- Most studies relied on a single urine spot sample, which does not represent exposure over the long term and/or in different agricultural seasons
- The occupational studies only covered 403 workers in total, a serious deficiency given its widespread agricultural use. Few assessed exposure before and after spraying; and no studies evaluated patterns related to seasonality, crop use, etc.
- Only two small studies evaluated how population exposure has changed over time. So, we definitely don’t know enough about whether the dramatic increases in global usage have resulted in similarly dramatic increased concentrations in our bodies. (Presumably, yes).
In addition to highlighting the need to address the points above, we specifically recommended incorporating glyphosate into the National Health and Nutrition Examination Survey (NHANES), a national survey that monitors exposure to many chemicals – including other common pesticides. This is an obvious and fairly straightforward suggestion; in reality, it’s quite bizarre that it has not already been incorporated into NHANES. Testing for glyphosate would allow us to better understand exposure across the US – which is not reflective of global levels, of course, but an important start.
Reviewing our reviews, part 2: glyphosate & non-Hodgkin Lymphoma (NHL)
Our second paper, published earlier this week, was a meta-analysis of the link between glyphosate exposure and non-Hodgkin Lymphoma (NHL). Yes, diving right in to the controversy.
There had already been several prior meta-analyses that showed an association between glyphosate and NHL, but ours incorporates new research and applies a method that would be more sensitive to detecting an association.
A meta-analysis combines results from separate studies to better understand the overall association. While they technically do not generate any “new” data, meta-analyses are essential in the field of public health. A single study may have certain weaknesses, focus only on selected populations, or reflect a chance finding. In drawing conclusions about hazards (especially in this scenario, affecting millions of people and billions of dollars), we want to look across the collection of data from many studies so we can be confident in our assessment.
We were able to include a newly published follow-up study of over 54,000 licensed pesticide applicators (part of the Agricultural Health Study (AHS)). Compared to an earlier paper of the same cohort, this updated AHS study reports on data for an additional 11-12 years. This extension is important to consider, given that cancer develops over a long period of time, and shorter studies may not have followed individuals long enough for the disease to arise.
We conducted this meta-analysis with a specific and somewhat unusual approach. We decided to focus on the highly exposed groups in order to most directly address the question of carcinogenicity. In other words, we would expect the dangers (or, proof of safety: is it safe enough to drink?) to be most obvious in those who are highly exposed. Combining people who have low exposure with those who have high exposure would dilute the association. IMPORTANT NOTE: this approach of picking out the high exposure groups is only appropriate because we are simply looking for the presence or absence of a link. If you were interested in the specific dose-response relationship (i.e.: how a certain level of exposure relates to a certain level of hazard), this would not be ok.
Our results indicate that individuals who are highly exposed to glyphosate have an increased risk of NHL, compared to the control/comparison groups. This finding itself is not entirely earth-shattering: the results from prior meta-analyses were similar. But, it adds more support to the carcinogenic classification.
More specifically, we report a 41% increased risk. For comparison, the average lifetime risk of NHL is about 2%. However, I want to emphasize that because our analytical method prioritized the high exposure groups, the precise numerical estimate is less important than the significant positive correlation. Basically, the purpose of this and other related assessments (like IARC’s) is to understand whether glyphosate is carcinogenic or not: this is a yes/no question. It is up to regulatory agencies to judge the scale of this effect and decide how to act on this information.
As with any scientific project, there are several limitations. In particular, we combined estimates from studies that differed in important ways, including their design (cohort vs. case-control), how they controlled for confounding by exposure to other pesticides, and which reference group they chose for the comparison (unexposed vs. lowest exposed). When studies are very different, we need to be cautious about combining them. This is another reason to focus more on the direction of the effect rather than the exact numerical estimate.
Beyond the headlines
The news coverage of this work has focused on the overarching results (especially the 41% statistic), as expected. But I want to highlight a few other aspects that have been overlooked.
To better understand the timing of these studies in relation to glyphosate usage, we put together a timeline of market milestones and epidemiological study events.
Of note is that all of the studies conducted to date evaluated cancers that developed prior to 2012-2013, at the latest. Most were much earlier (80s, 90s, early 00s). As illustrated in the timeline, we’ve seen a huge increase in glyphosate usage since green burndown started in the mid-2000s. Yet none of these studies would have captured the effects of these exposures, which means the correlation should be easier to see in newer studies if/when they are conducted.
Also, as I mentioned above, we included the newly published AHS cohort study in our meta-analysis. One might expect the old and new AHS studies to be directly comparable, given that they were conducted by the same research group. However, our deep dive into both papers elucidated important differences; consequently, they are not directly comparable (see Table 8 of our paper). An in-depth discussion of these issues (and some of their potential implications) is a topic for a separate post, but there’s a clear lesson here about how important it is to carefully understand study design and exposure assessment methods when interpreting results.
Finally, two brief points on the animal toxicology studies, which we also reviewed in our paper because they provide complementary evidence for assessing hazard in humans. We discuss these data but did not conduct a formal pooled analysis (to combine results from separate but similarly designed animal studies), which would allow us to better understand overarching results from the animal studies. Anyone ready for a project?
Additionally, in future animal toxicology studies, researchers should use the formulated glyphosate product that is actually used around the world rather than the pure glyphosate chemical that has been the focus of prior testing. There is growing evidence to suggest that the final formulated product is more toxic, perhaps due to the added adjuvants and surfactants. And this would allow for better comparisons to the human epidemiological studies, which assess effects of exposure to the formulated product.
Reflecting on the process
I had followed the evolving story on glyphosate with great interest for several years, so it was exciting to be part of these projects. Contributing to research with a real-world public health impact has always been a priority for me, and this high-profile research (affecting millions of people, billions of dollars) certainly fits the bill.
That being said, it was not an easy process. These two papers represent years of work by our group, which we did on top of our regular commitments. Collaborating with three researchers whom I had never met also proved challenging, since we did not have established rapport or an understanding of each other’s work and communication styles. So, in addition to gaining skills in conducting literature reviews and meta-analyses, I learned valuable lessons in group dynamics. 🙂
Given the high-stakes and high-profile nature of this work, we were extra meticulous about the details of this project. We knew that it would be scrutinized carefully, and any error could damage our credibility (especially worrisome for me, since I’m just establishing myself in my career). It took many, many rounds of review and editing to get everything right. A good lesson in patience.
Speaking of patience, I know that scientific research and related policy decisions take time. But I hope that these two projects can contribute to moving forward in a direction that protects public health.