Good morning, everyone. I'm going to go and get started because I got a few housekeeping notes that ACOM wanted me to present. So just for everyone's awareness, if you haven't already, please download the AOHC 2023 event app called Swapcard. It'll tell you everything you need to know about the meeting. If you need assistance, please go to the ACOM membership booth in the foyer here. You can evaluate and claim credit by navigating to this session in the Swapcard app. There is a link in neon green towards the bottom left within the session. If you need them, restaurants are located on either side of the main foyer outside this ballroom. Please do not forget to silence your phones and other devices. And then be aware that ACOM staff have red lanyards and buttons identifying them as such. Let them know if you need assistance. There's also the membership booth on the fifth floor for assistance. All right. So without further ado, I'm going to go ahead and begin. Welcome this morning to our talk. It's called Glyphosate, Public Health Menace or Agrochemical Miracle. I am Ross Mullinax. My counterpart here is Dr. John Downs. He's in Army. I'm Navy. I see both in the crowd. But no worries. Today we're working together. So all right. We have no conflicts of interest. Of course, our views are our own. So just up front, I want to be clear on who we are and who we are not. So we are both practicing OCMED docs. We are not at all involved in Glyphosate litigation, advocacy, corporate interests or defense. We're not. We don't do Glyphosate research. We're basically interested observers who find this a fascinating topic. And we think it's important for OCMED docs to be knowledgeable about these kind of controversial topics. So here are our objectives. I'm essentially going to give the first half where I'm going to give some of the story and the history and the background of the Glyphosate saga. It's quite interesting with a number of it's just very multifaceted. Dr. Downs is a medical toxicologist, also board certified medical toxicologist. So he's going to come in and bring a little bit more of the hard science and the data at the end. So the issue of course, as all of you are aware, is there's increasing concern worldwide about chronic low-level toxic exposures and the potential impact that has on human health. Glyphosate is of particular concern because it's the most widely used herbicide or weed killer, in this case, in world history. Recent data indicates that probably about 2 million tons of Glyphosate is used globally every year in recent years. So it's quite a lot of Glyphosate in use. So a little bit of history. So Glyphosate was created by the chemical company Monsanto back in 1970. It was marketed and put in commercial use in 74, although the last Monsanto patent expired quite some time ago in 2000. So there's a lot of Glyphosate products on the market now, all with of course slightly different formulations. Most of these are made outside of the U.S. Of course, in recent years with your genetic engineering of crops, a number of products have been engineered specifically to be Glyphosate resistant, which has somewhat increased the concern in that more Glyphosate can be used directly on the product that ends up being our food because it kills the weeds but doesn't kill the crop, right? So we'll talk in some detail about the IARC decision which came in 2015, which is an important milestone. And then just of note, Monsanto no longer exists. It was acquired by Bayer in 2018, which is the large German conglomerate. The IARC decision in 2015 is kind of where this story, I think, begins. The interesting part begins, right? Previously it was group 2B, which is possibly a carcinogen. IARC upgraded that in 2015 to group 2A. And that was based on their finding of limited evidence in humans, but sufficient evidence in animals of carcinogenicity. This had a really significant impact, I would say, as really the primary driver of the cycle of litigation that started against, you know, Roundup manufacturers. So one really, really critically important point that I want to make sure everyone understands, right, is it's really important to understand how IARC does, makes their determinations, right? What's their goal? What are they looking at, right? So a lot of, I would say, most scientific regulatory bodies look at carcinogenicity for more of a risk standpoint, right? Risk implies a function of probability or likelihood. The IARC does not, okay? So this is straight from their website, right? So they specifically do not measure the likelihood that cancer will occur at any particular level, right? So what IARC is looking at, right, is can cancer be caused really in any conceivable situation, right, with this particular exposure, regardless of whether the risk of that exposure in humans is high or low or nearly impossible. Just a quick review of the IARC groups, right? So there's four groups. Group 1, carcinogens, which we're familiar with many of those. Group 2A, where glyphosate falls. And then Group 2B, which is possibly carcinogenic, lower level of certainty. And then Group 3, which is basically we don't have enough data to make a determination. I will note that Group 3 is quite large compared to the other groups. It does include atrazine, which happens to be the second most used herbicide in the world. Atrazine has its own issues, and it's already been banned in some parts of the world, particularly in Europe, because it seeps into the groundwater. There were concerns of that. There used to be also a Group 4, probably not carcinogenic. They got rid of Group 4 a couple years ago, probably in part because they never really put anything in it. There was only one thing ever put in Group 4. It's now back in Group 3. So it's not even on the list of options anymore. So I just wanted to point out, right, Group 1, it includes the usual suspects, right, things we normally think of, ionizing radiation, tobacco smoke, cadmium, asbestos. But there's a lot of other stuff that we don't normally think of as being cancer-causing, necessarily, like alcohol, being a firefighter, bacon, and other processed meats, or even prescription drug medications like tamoxifen, or oral, I'm sorry, combined, or combination, rather, oral contraceptive pills, which, of course, are prescribed by the millions in the United States, right? And then Group 2A, which is where glyphosate falls, includes things like red meat, shift work, very hot beverages, work as a barber. So the point I'm trying to make is that I think when you're looking at regulatory and policy decisions, you can't just point to an IR determination and say, this substance is bad, or this substance should be banned, right? You have to look at the total risk, number one, and you have to look at the benefit as well, right, and weigh the risk-benefit. And it's different for every exposure. And that's important in the case of glyphosate. So let's look at, now, the regulatory perspective. So there's a number of regulatory bodies all over the world that have analyzed glyphosate in great detail. I will sum it up by saying that to our knowledge, no pesticide regulatory agency anywhere in the world currently considers glyphosate to be a cancer risk to humans at the level which humans are currently exposed. My favorite is, in 2016, this is after the IARC decision, right? So IARC is a subsidiary of the World Health Organization, right? So is the Food and Agriculture Organization. So the FAO looked at this and put out a joint statement with WHO in 2016 stating that it's unlikely to be a carcinogen. So the WHO is somewhat in disagreement with itself, or at least disagreement with its own IARC on this. I'll also note that the US EPA created a new interim decision in 2020 on glyphosate. They put it out for public comment. It was immediately met with a large number of lawsuits from various groups. And then in June of last year, a three-judge panel in San Francisco, I think it's the Ninth Circuit Court, threw out EPA's decision in a fairly, I would say, stunning move. They said, you know, EPA's science is no good. You guys need to redo it. They gave them, and that was particularly with respect to two things. One was human health and the carcinogenicity question. The other one was a threat to endangered species in the environment. They gave the EPA three months to redo it. EPA came back later and said, hey, you know, three months is a pretty tight turn on this sort of big analysis, so we're not going to be able to meet that. So they withdrew their interim decision altogether, and I guess they'll presumably have to start over from scratch at some point in the future. And then there's the state of California. So as far as we know, California is the only place, the only HHA specifically, that puts glyphosate out as a known carcinogen. This was listed in 2017, although it was later, there was a lawsuit that stopped this, and it was, you know, an injunction was made permanent, so it's not currently listed. So the question is why, right? Does California have data that no one else does? Are there researchers that are just smarter? And the answer is no, of course. It's really just the way that the state code is written, right? So it's essentially automatic, because the California Code of Regulations requires OEHHA to list chemicals under Prop 65 when it's determined to be IARC Group 2A based on sufficient evidence of carcinogenicity in animals, which is what IARC had determined. So from some of the public documents that OEHHA put out, this is, in particular, what they call their initial statement of reasons. This is kind of providing some of the justification for listing glyphosate as a carcinogen. They note this one study, which they say, quote, is the most sensitive study of sufficient quality. This is a rodent study. You can see it's fairly straightforward. Four groups of rodents that were fed different amounts of glyphosate for a long time frame. The highest concentration group there had a number of instances of cancer. So a compelling finding academically. The potential issue with this study, right, is the rodents were fed a thousand milligrams per kilogram per day for two years straight, right? The EPA reference dose for oral intake is two milligrams per kilogram per day, and the high-end estimates are only about eight milligrams per day. So this is several, is a couple orders of magnitude greater than any estimated human health exposure, right? So, okay, what do you do with that? You know, what should we really do with that? What is the average person, you know, what's their risk based off this sort of study? Well, the EPA looks at it a little differently. So to contrast the way that the IARC looks at it from the hazard standpoint, the EPA is explicit about including risk in their assessment, right, from their own guide to cancer risk assessment. They look not only at the data on cancer, but they look at the conditions under which these cancer causing effects are expressed. So in their last still standing, I guess, glyphosate paper, they looked at rodent studies like the one on the previous slide, and they made a number of comments. Among them things like, you know, a lot of the rodent studies, about half don't show an association with cancer, and of the half that do, they're often different cancers, so there's not necessarily a lot of agreement within the data. But furthermore, based on these really high exposures, which are far higher than human estimated exposures, right, they consider these studies essentially not relevant for human health risk assessment. So it's an important distinction from the way that IARC looks at it, right, the hazard versus the risk assessment. So it gets interesting with when politics comes into place. So this is one of the interesting facets of this case, right. So you have now the U.S. EPA essentially saying it doesn't cause cancer. You have a state, California, saying, yes, it does. How do you resolve that? Well, the EPA, this is in 2019, okay, it's under a prior government administration. They basically sent a letter, kind of a cease and desist letter to California saying, you know, because we've already made our call on this, if you're going to go 180 degrees the other way, then we consider that a false and misleading statement. Fairly, you know, harsh language, I think. However, the story gets more interesting because last May, you know, different administration now, during one of Bayer's appeals to the Supreme Court, the U.S. Solicitor General filed a brief that basically said, hey, look, just because the EPA says one thing, it doesn't mean that states can't add their own stuff in addition. So now we have, you can see how politics can really throw some uncertainty on the situation. I will touch briefly on lawsuits because this is important and the lawsuits are many and the numbers are large. So the first one really, the first big verdict was in August of 2018, a California school groundskeeper who used glyphosate regularly and developed cancer, won a $280 million verdict against Bayer. This was later reduced significantly. But then in May 2020, a California jury awarded $2 billion, and that's not a typo, that is billion with a B, to a single couple. I don't have the details of that one, but it was also later reduced. But these kind of things hit the headlines in the newspaper and as you would expect, that opened up the floodgates. As of May of last year, Bayer had paid out over $11 billion to settle over 100,000 roundup lawsuits, and there were still 26,000 cases active. I'm sure that number has grown since then. They did try to make a bid, it went all the way to the Supreme Court to kind of force the settlement to close the cycle of litigation last year. That did not go in their favor. And then I think it's important to understand the impact of advocacy and activism on the narrative and the public opinion on glyphosate. This is one example that I just picked because it was big in the headlines when it happened. I was still a resident in 2019 when this was in mid-headline news, right? So a group that's fairly well known, the Environmental Working Group, that particularly is engaging advocacy on sunscreens and pesticides, but also did some work on glyphosate. So they pulled some common food products off the shelf, things like Cheerios, Quaker oatmeal. They tested them all for glyphosate and found glyphosate in all of them. That's not particularly surprising, I think, given how widely used glyphosate is. But I think where it gets complicated is then they tested them against their healthy benchmark level and found that 26 and 28 were elevated, right? So the headline, the implication from the headline is most of your food is unhealthy to eat because of glyphosate, right? But we've got to be clear that EWG's healthy benchmark is a number that they created, that they made up, right? And it's substantially lower, right, than the kind of numbers that scientific regulatory bodies such as the EPA use in these kind of calculations. Yeah, but you can't underestimate the impact, I think, when this is in the headlines that it has on the public perception of risk. One more thing along these lines. So the CDC put out some data last summer from their long-running NHANES study, right? So the data was from about 2,000 people. They tested their urine for glyphosate. They detected glyphosate in about 80 percent, okay? Again, I think not particularly surprising. As we know, just the mere presence of a toxicant is not necessarily meaningful, right? It's the dose that makes the poison. And our instruments in detecting these sort of things are very, very good nowadays. The technology is excellent. So the limit of detection in this case is a fraction of a nanogram per milliliter, right? That's 0.0000002 milligrams per milliliter. We're talking very, very tiny amounts, right? So it doesn't really speak to whether or not this is a health hazard or a risk to human health. But the news article that came across to me, this is the first that I became aware of this data. It was an article in the lay press that had a very fearful tone. It really emphasized the cancer risk, the impact to kids, that sort of thing. And I found it interesting at the bottom that it said the story was co-published with basically the collaboration with a prominent activist group. So there's definitely a blurring of the lines, I think, between kind of classic journalism and activism, at least in this case. So as I wrap up my part, I'll leave you with a couple of questions to ponder. What is the alternative to glyphosate? Glyphosate plays a very critical role in agriculture worldwide, right? It's an important product and there's a great benefit to society, right? It's a weed killer, right? So the whole point of this product is to kill living organisms. So as a rule, these are not healthy and safe products. And most really are far more toxic than glyphosate. Paraquat, anyone? Right? So some of the advantages of glyphosate are that mostly it's not absorbed. The part that is absorbed is excreted rapidly. It doesn't the part that is absorbed is excreted rapidly. It doesn't bioaccumulate in animal tissues. And furthermore, I know we talked about atrazine earlier. So glyphosate binds to the soil very tightly, so it does not seep down into the groundwater and contaminate potentially the drinking water supply. It's broken down by bacteria naturally in the soil. I think the half-life is about two to three months in soil. So there's some quite favorable characteristics of glyphosate that are often not found in other weed killers. Right? But, you know, there's a lot of calls to ban things like this, right? Glyphosate, it's group 2A, it's bad, we should get rid of it. Well, in fact, one country has actually tried that. Sri Lanka was the first country to ban glyphosate completely in 2015. It did not go well for Sri Lanka. It was about two and a half years until they reversed course and brought glyphosate back. And that was really because they had an adverse impact on their agricultural production, right? The problem is there's not a great replacement necessarily for glyphosate that is as effective and also as low in terms of toxicity. A number of other countries have banned it or tried to ban it and have either reversed course or kind of tabled it indefinitely or they've exempted the agricultural sector which is like 90 plus percent of all use. I think it's particularly interesting that Mexico has banned glyphosate that's supposed to take effect next year. My suspicion is that won't happen, I've already read even the Mexican president himself has backpedaled pretty furiously on this. I think they're it's likely not going to go through but we'll see. All right my last slide just to give you kind of an idea of the the level of polarization on this controversial topic right so I've got two quotes on this slide one is from an actual sitting US senator who wrote a kind of pointed letter to the EPA when they were finally removed their interim decision said we're going to start over last fall. He said given the serious risks associated with glyphosate I urge the EPA to closely follow its its own guidelines for carcinogen risk assessment in its current review of glyphosate in order to protect our nation's public health from this dangerous chemical. Contrast that with Mr. Steven Pals who's a scientist with the USDA he said glyphosate is quote a virtually ideal herbicide. He said glyphosate is a one in a hundred year discovery that is important for reliable global food production as penicillin is for battling disease. Quite a statement and quite a contrast. So with that I'm going to turn it over to Dr. Downs and thank you very much. Good morning. Wow there are a lot of you here more than I was expecting to be entirely honest. I'm probably gonna walk right in front of the light because I'm too full of coffee right now and typically when I give talks I run around the room anyway. So I'll try to stay out of the out of the immediate camera light there. So I've got so about 35 ish minutes now 20 25 ish minutes to summarize the science on a controversy that's continued for at least the last 20 plus years so no pressure yeah easy easy day but we'll we'll try to go through that. I am a medical toxicologist of the I'm associate program director for our occupational environmental medicine residency at the Uniformed Services University. Like Ross said I'm not involved in any of this it was just kind of question for for debate and we thought that you all would want to hear a little bit of each side of things some of the the legal and regulatory as well as some of the science. Disclaimer not a PhD epidemiologist not about a PhD biostatistician. You say well John if you're not that why are you even up here talking to us about about this? Well because I guess that the most of you are not PhD epidemiologists or PhD biostatisticians either. Like Ross said we're practicing OEM physicians so we wanted to give you a little bit more perspective at kind of our level you know what do epidemiologists like to do aside from design studies? Anybody? Argue about the methods of said studies right forever endeavor endeavor so I'm gonna try to limit how much I get into to that just understand where I'm coming from here. And a lot of what's going to follow is somewhat mathematical and what I say what mean by that is depending on how you want to set up your study design how you whether you want to use a random effects model for your meta-analysis or a fixed effects model or it it can change things which we all know depending on your exposure assessments your outcome assessments there's bias that can occur with with studies for sure. So again I'm not going to dig way down into the the weeds of that I'm sure most of you all would fall asleep and I probably would while I was discussing it and I still wouldn't entirely understand it so I'll I'll just give that disclaimer too. I'm going to try to stay away from mudslinging and allegations. Once you get to reading some of the material about this controversy it very quickly goes down into ad hominem attacks and even the individual papers that are written somewhat go to that degree. I'm talking like peer-reviewed literature at times and you know you can very easily Google and find all sorts of lay press reporting of improprieties on both sides of this discussion and even when you you try to read the papers that I'll reference you'll go through the paper and then at the bottom where there's like you know disclaimers listed it will be you know one of our co-authors works primarily for XYZ advocacy organization or one of our co-authors was funded by Monsanto as part of this this study so there's there's clearly some issues with that from a from an ethical scientific standpoint. Okay I'm going to talk mostly about human health effects and I'll tell you specifically about non-Hodgkin's lymphoma because that's where in most of the issue lies but I do want to bring up not to gloss this over but there are other other pesticides that that we have banned or controlled the use of more specifically because of their environmental impact right humans do not live on the earth in a vacuum we're part of an ecosystem there. Aside from what I'm going to discuss today there are definitely concerns about the environmental impact of the use of glyphosate. There is some literature to say that it's probably more acutely toxic to to aquatic life than it is to mammals. You'll see some references to collapsing bee colony disorder whether that's a contribution of neonicotinoid insecticides and or glyphosate. You'll also see mention of alteration of gut microbiome not only in humans but also in animals. I did not know this until I was digging around. Although Monsanto discovered this compound in the 1970s apparently it was discovered prior to that even and originally was created to be like an anti-parasitic agent. It has some antimicrobial activity so there's been some discussion as to whether or not this contributes also to multi-drug resistance around the around the world. If you like monarch butterflies, monarch butterflies have a symbiotic relationship with milkweed plants. Milkweed plants have a cardiac glycoside in them sort of like digoxin that helps monarch butterflies not be eaten by predators or if one of them does get eaten by predators then another one won't be eaten by predators. The use of glyphosate has eliminated milkweeds in some areas and reduced the monarch butterfly population. There can be health effects outside of humans and the role of POEA or polyoxylated ethyl amine, say that five times fast, is a surfactant and diluent that is used in some of the Roundup compounds and the older glyphosate formulations that is thought to enhance toxicity of glyphosate in certain settings because of its surfactant properties and ability to cross mitochondrial membranes. So that's also a question for another day. Non-Hodgkin lymphoma, that's where the the crux of this debate for carcinogenicity lies in, specifically on this cancer for the most part. I think most of us in an occupational medicine and when we were taught IARC1 chemicals we tend to think about specific cancers that are associated and not only that but even specific subtypes or histologic types of those cancers. Non-Hodgkin's lymphoma is interesting in that it's not actually a single histologic type. The definition of non-Hodgkin's lymphoma is just that, that it's not a Hodgkin's lymphoma. So Hodgkin's, if you go way back to medical school, is anything that has a Reed-Sternberg cell in the pathology. These are all B-cell and T-cell cancers that don't have a Reed-Sternberg cell. So it's sort of a group together that isn't necessarily genetically the same or originates the same etiology or even treated exactly the same. But in the studies for not just glyphosate but other pesticides, they're lumped together. And also often for epi-reporting purposes, they're lumped together as well. Also as a lump, very common cancers. So you'll see different lists as many between 15 and 40 different subtypes of non-Hodgkin's lymphoma listed. And I think number seven on the top ten list of cancers within the United States. So I'll very briefly go through some kinetics on this. Some of us may remember ADME, absorption, distribution, metabolism, elimination, from tox class way back. Most of this is taken in orally, but actually even if you get an ingested dose, there's about two-thirds of it that just passes out with your feces, doesn't actually get systemically absorbed. So that's sort of reassuring there. It has a fairly low volume of distribution, so mostly stays in the blood, doesn't particularly accumulate in any organs. At least most of this is based off of the ATSDR tox profile and that's a combination of human and animal data. Very little, if any, in vivo metabolism on the order of a single digit percent, which seems to be some phase one reactions that will metabolize this, but most of it is excreted without metabolism in the urine or in the feces with an elimination half-life that's pretty quick on the order of a couple of hours. So even in studies that have been done of farmers that were exposed and had either blood or urine values of glyphosate and it's one metabolic derivative AMPA, they tend to clear out within a day or two. So pretty quick there with four to five elimination half-lives. Often we're concerned about similar mechanisms of toxicity between, excuse me, I got to get a sip of coffee here to add to my continued trimethylxanthine intoxication this morning. We're often concerned about toxic mechanisms of action and activity that are similar between a particular pesticide, be it an insecticide or an herbicide or a denticide, and what can happen in a mammal. Part of the reason that some folks have referred to glyphosate as an ideal herbicide is that it actually has no, its mechanism of action is unique to plants. So it inhibits the shikimic acid pathway. Humans have no analogous shikimic acid pathway or anything like that for glyphosate to act upon. Interestingly, we get our tryptophan, phenylalanine and tyrosine through plants essentially. I am contractually obligated by as being a medical toxicologist to include chemical structures in any talk. You guys are lucky that I didn't include the Krebs cycle, the electron transport chain, but I did at least mention mitochondrial membranes so I can maintain my board certification as a result of that. This is a uniquely an organophosphorus compound. Some people have been concerned about that because it looks like what? Organophosphorus insecticide, which we know inhibits acetylcholinesterase and results in cholinergic crisis. This does not, though, and that's been shown in multiple intentional overdoses with glyphosate in humans. There's no real cholinergic activity to it. These folks don't have a cholinergic crisis as if they had been hit with a nerve agent or sprayed with chlorpyrifos or something of that nature. The acute LD50 is sort of somewhere in the range of 5,000 milligrams per kilogram. That's generated off of animal data, which is pretty doggone high. If you add one of those surfactants to that, it might drop down to like 1,200 mg per kg, which is probably a little closer to what we see in humans. Just to give you some context for that to be at 1,200 mg per kg, and I'll show this on some animal studies as well, for a human to get that in you would have to be drinking concentrated glyphosate, which is a 40 to 50% glyphosate product, in about 100 to 150 mLs, which for context is somewhere in the order of a third to a half of a Coke can of a very concentrated substance, which is fairly corrosive to the GI tract if you drink that. At that dose of very concentrated, this is a problem just because of its acute corrosive effects to our system. I'll start talking here about animal and meta-analyses here, but I always remind my residents when I talk to them that animal studies are great. They get the right answer, but they ask the wrong question. Epi studies are great too. They ask the right question, but they get the wrong answer because we've got all these other confounding aspects going on with them, the biases it plays in. Again, like Dr. Molenak's mentioned, we're talking about animals giving them doses that are multi-fold higher than what a human might ever receive. These are the IARC by their preamble criteria for how they grade things, and I think particularly when we're in residency, we were taught IARC is kind of the black and white. Learn the IARC ones because those are declared known human carcinogens and those will be on your boards and there's no more argument about it. If you actually start reading down into the monographs, it's a little more nuanced than that. This is how they're supposed to set it up, but you'll find even they don't necessarily even follow that final determination. There are a couple of chemicals that we will describe as well-known IARC ones. Ethylene oxide is kind of the one I always bring up, for which IARC says there isn't sufficient evidence of human carcinogenicity, but still they declare it as a group one, which is kind of interesting there. For representative animal studies, and I'm only going to throw up a few particularly for lymphoma, but there are a litany of animal studies, particularly in rodents, for various different cancers that glyphosate or its compounded versions of glyphosate are associated with. Renal tubular cancers, skin cancers, pancreatic cancers. There are review articles that have these all combined, but what we're really again concerned about is lymphoma. There's no rat equivalent of non-Hodgkin's lymphoma, so the studies were done basically to look at the incidence of malignant lymphoma over the course of a rat lifetime. So when animal studies are done for cancer, they're usually done over a year and a half to two years. That's the thought to be the lifetime of a rodent, and that over the course of their lifetime, if given a particular dose, what will they result in cancer? And I know this is a little bit hard to read, but we're looking, highlighted in blue here, doses in the 800 to 1,500 milligram per kilogram per day over the course of the rat's life. I mean, there are some pretty concerning finds here. So if you look at the incidence of malignant lymphoma in this group of albino rats, if you give them 1,500 a day, 50% of them will develop malignant lymphoma. I mean, that's pretty concerning. However, if we put that a little bit in context, 1,500 milligram per kilogram per day, again, is probably like a half to two-thirds of a Coke can of concentrated glyphosate product, essentially every day over the course of your life. Or if you're using the residential product, that would be, that's about a 2% to 5% blend. That's something on the order of intentionally drinking about two and a half to maybe three liters of Roundup a day. Now, you know, we're always more conservative than animal models. Typically, with cancer studies, there may or may not be some uncertainty factors pulled in, as there are, as opposed to acute toxicity. But still, it seems a little unrealistic there. And then it seems like, to me, that everyone has a meta-analysis. And they're all using almost the same data. There's like five or six case control studies and a cohort study or two that sort of gets ground up in a different manner and popped out again as a meta-analysis. And then we get a little bit different results, depending upon which way that they do it. So there are probably a good, I think, seven or eight different meta-analysis now, with a couple of cohort studies that, at times, get included in said meta-analysis, at times get excluded from the meta-analysis. Again, sort of depends on how you do your magical math and, you know, which side of the epidemiology argument that you're on for methods. I'm just going to do a quad chart here, quickly. So these are probably the four meta-analyses that get referenced the most. And a couple of notes on these, again, I'm not going to go way down into methods on this. This 2014 was the first one that really reported an increased relative risk for non-Hodgkin's lymphoma and maybe diffuse large B-cell lymphoma as well. That one is, was essentially done by IARC, or people that were on the IARC panel. The preceding meta-analysis had found no association with any cancer at all in humans. Before we go further, some people ask, well, how's the exposure assessment done on these studies? So a lot of them were, as I said, were based off case controls. So it's, you know, somewhat potential for recall bias there in those case control studies. And then in their exposure assessment, most of these did ever, never. So it was a dichotomous variable, either you had some exposure to glyphosate ever in your life, you ever used it, or you used it. So there was not really an ability to set out a dose response within a human in that regard. It was just an all or none kind of analysis there. 2016 blatantly stated, this is funded by Monsanto, the corporation that was making glyphosate in response, or was the recipient of all the litigation. They did their own meta-analysis. Even they found about a 30 percent increased risk. Statistically significant for non-Hodgkin's lymphoma. And then probably the one that caught the press the most recently was this Zhang study from 2009, which included all of the same studies that Chang did in 2016, but then also added the National Agricultural Study, and I'm gonna speak a little bit specifically about that in a moment. But the Zhang study was a little bit different in that they wanted to try to get the folks who had the highest exposure received in the prior case control studies, if they could tease that out. The thought being that if there was a signal for a cancer in human, that it would be amongst the people who had received the most dose. And so they thought that they could actually show an even potentially higher risk ratio in their meta-analysis if they only focused on the people who had received the highest dose, which kind of makes sense. However, they excluded a lot of data as a result of that, and they did come up with this meta-risk ratio of 1.4, which also was statistically significant. This met quite a bit of criticism by the EPA. They actually, Dr. Mullenix had sent me this in our preparation. It sent out like an 18-page letter from the EPA specifically kind of replying what would have been like a letter to the editor kind of thing, but it would have been way too long for any journal to accept as a letter to the editor sort of rebutting point by point this particular study's methods. The National Ag Study is probably the largest cohort that's been done, and we're generally taught a good cohort study sort of is high on the tier of evidence and would trump all of these other case control studies with their issues of recall bias and whatnot there. The National Ag Study really followed folks going back as far as about 1993. This was predominantly in North Carolina and Ohio, so folks that were farmers in that area, industrial-level agriculture. They were surveyed in the early 1990s and then surveyed again around the late 1990s, early 2000s, as I recall. So about 54,000 people enrolled in this spanning over a decade and a half. They actually stratified people out by use of glyphosate, by quartiles. So it was a good way to actually see a dose response if there is going to be, and they did that by cumulative lifetime days of glyphosate use. So basically, if you applied this to your crops, how many days did you do that a year? How many years did you do that? I found it interesting, their median number of days was about 48 days, which I'm assuming that's because if you're doing industrial-level agriculture, this is like a big operation that you're gonna do for a couple of days out of the year, as opposed to, I guess, if I went around with my residential supply and I squirt the dandelions a couple of times a year, that's not really even approximating the same exposure. But with this, and I would say the big critique here is that they had to impute about a third of the exposure data, which again, there's all sorts of epi-magic you can do with Stata and SAS to impute data that you don't really have. With that, for any cancer, they found no dose response at all. I mean, you can see there those hazard ratios all across one. So, pretty compelling in this regard. There's another French study, or excuse me, European study that combined this and two other cohorts that ended up finding similar data. So we're left here, I'm finishing up a little earlier than I expected, that's good, with some remaining questions. When we're looking at questions of causality, general causality for a chemical, typically we look for biological plausibility as well. What's the primary mechanism that this would happen by? How does this actually occur? That's still a bit of a question. There have been proposals of a general concept of oxidative stress resulting in carcinogenicity. There was a study, I believe done as part of the Ag study in CDC earlier this year, that checked metabolic byproducts of, quote, oxidative stress in humans, and found that farmers who used glyphosate might have something on the order of 20-ish percent higher oxidative stress metabolites, but the confidence intervals on that were pretty wide. They didn't cross one as a ratio, but they were pretty wide there. So that's the primary question at the moment. There's not been anything that's really shown a definitive route of genotoxicity or a mechanism of carcinogenicity. And if we go back to things like the Ames test and other mammalian cells being exposed in a petri dish to glyphosate, most of those found no evidence of mutagenicity or genotoxicity unless it was at doses that would be grossly toxic to a human, like you would have acute effects and be unable to sustain said dose. There's several questions about other exposures and combined exposures that are still not entirely ironed out. If you're a farmer, likely glyphosate is not the only thing that you utilize or even if you're doing this as a groundskeeper is probably not the only herbicide that you use. There's been questions of contributions of organophosphate insecticides combined with glyphosate. How does that affect the potential for cancer developing? There's also a lot of questions about human exposure assessment. So like I said, a lot of those meta-analyses and the case controls that the meta-analyses were based off of are kind of ever and ever exposure. And they're really based off of agricultural settings. So I think in the general public, the general public's not necessarily concerned about what happens to a farmer, but is more concerned about what happens to them as a, particularly as a consumer, either from ingestion of glyphosate residual in a food crop or just that they use the spray around their home for control of weeds and whatnot. There's really not much in terms of exposure assessment amongst general population. I see Dr. Baker in the back of the room a few decades ago. Now she did some exposure assessments in farmers that showed even with farmers, the uptake was fairly minimal and when you compare that to the EPA reference dose for day-to-day intake. And I certainly haven't seen anything that is looking at an observational study for just human general public intake in food and the risk for cancer as a result of that. And I don't, I haven't seen that. Maybe it's just out there. I haven't stumbled across it yet, but I would think if it were based off what we have for farmers and the association being fairly weak there, that there probably wouldn't be much in terms of humans. The, again, the dose that, if you go back and kind of back calculate that limit of detection dose that Dr. Mullinax talked about was reported in the NHANES data. We're talking something of like ingestion of 0.1%. So like a 10th of a percent, even the highest group in there, a 10th of a percent of the EPA reference dose. And that would be what the general US population were ingesting. So I guess take home points for us to finish up. It's important to appreciate methodology for any scientific bodies analysis and recommendations, particularly when IARC is coming from a hazard approach as opposed to risk specifically. So a little different than most other agencies do. Some of the human epi studies do show a bit of an increased risk, particularly for non-Hodgkin's lymphoma. But I would say that that is a fairly weak association. You know, typically when we're talking about things that have sort of solidified as stronger evidence, we're talking risk ratios and five, 10 higher, a 1.3 is pretty minimal. And again, a lot of those are very close approximating one. Even with that though, we can be as educated as we want to be. And a lot of these decisions still boil down to policy level and what the public wants their lawmakers to put in place. But we just feel like we as occupational and environmental physicians need to know some of the context for that so that we can help, you know, from a public health standpoint, the populations that we may serve understand. And then the workers specifically who may be using this and have some concerns about its health effects as well. And so I'll stop there, but before I take questions, and I said I wasn't gonna walk in front of that darn lamp and I did. We do, Dr. Baker and I were able to stand up a occupational and environmental toxicology interest section for the ACOM. It's the first that I'm aware of that we have had within the ACOM. Our first in-person meeting will be Monday evening at 1730 in room 405. So even if you're not signed up for the section, I'm not gonna hold it against you because we're not serving dinner anyway. So it's not gonna, you know, it doesn't really matter. You wouldn't be stealing it from food from anybody. But if you're interested in talking about things like this or how they might affect individual patients or populations of people, we would, you know, love to have you and engage in those discussions and talk about ways to reinvigorate the field of toxicology within occupational environmental medicine. And thank you all. Happy to take questions. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Recording, thank you. Yes, I just had a question. From a medical toxicology perspective, do you interpret a study differently if the animal cancer risk goes from zero out of 50 to five out of 50, than if it goes from 20 out of 50 to 25 out of 50? Well, again, I deal with humans for the most part. So I'm not setting up a lab studies, but in general, my understanding is that if you're being very sensitive, any increase in incidence that's considered statistically significant is considered evidence. And if it's replicated multiple times, then yes. Now, whether or not, going from a percentage of 20 to 25 would kind of depend on how many, whether or not that was significant would sort of depend upon how many population that you had in the study. But yes, there should be some consideration for underlying incidence, if that's what you're getting at, and then over and above said background incidence. What I found for the most part in animal studies is that's just not considered quite as much with a few exceptions, I think. Thank you for a very good presentation. My question, taking this home, is that my wife forbids the use of Roundup in our yard. And so the question is, has there been evaluation of the teratogenic potential or the potential of development with this? Yeah, I didn't hit on that for sake of time. I didn't specifically look along those lines. I don't think, as I read across, for animal studies there were, but I'm happy to take your information and get back to you, because I've got like a bank of papers now on this. Thank you, excellent presentation. I have a question about the Zhang meta-analysis, and you included the National Ag, and you spent some time talking about that, which was very interesting, and I take it that we're North Carolina and Ohio? North Carolina and Iowa. Yeah, and Iowa, oh, okay. Can you explain, though, that the meta-analysis showed an increase? Yeah, that was kind of like the $50,000 question when that study came out, and the reason that the EPA wrote a sort of scathing report back. The explanation, in part, is that they only used about 12% of the data that was included in the National Ag study. How they cherry-picked that, but I basically said the same thing. If you've got a fairly robust cohort study, comparing that to some kind of a near-equivocal case control studies, how do you come out still with an elevated risk ratio there? And the best that I can tell is that they sort of, they said that they were coming from an a priori standpoint, that the highest exposures would induce cancer, so they went with basically the highest 15 or so percent that they could come out. That was the way that it was explained to me, but I had the same question. It's not entirely clear. That was a very good presentation. Thank you both. Early on, there was mention of the Environmental Working Group, and the benchmark level, they said, of 160 parts per billion. Where did they get that? Good question. So I did look into this. It was not that easy to determine how they reached that benchmark, and as I recall, I'd have to review to be 100%, but I believe they found the most, or the lowest kind of official number out there, which was the one that California uses, and then they added a couple of additional safety factors. I think they basically divided by 100, and that's what they came up with. So it was substantially lower than anything you would see by an actual scientific. For comparison, EPA standards for glyphosate residual and food products varies by food product, but is typically on the order of 10 part per million to maybe a couple of hundred part per million, so versus 160 part per billion, so several orders of magnitude lower than that, so it's a pretty radically different number than what the EPA food allowances in the United States have. Yeah, but that point is lost on the public when the headline says almost 100% above the healthy level. Please. Morning. So my question is, a lot of the studies, they either look at it causes cancer or it doesn't cause cancer, and a lot of the policy is kind of based, or the hierarchy is based on whether it causes it or not, but kind of like the EWG website and through my toxicology rotation, there's a lot of other effects that can affect the public health that don't cause death, so it's known that high fructose corn syrup doesn't cause cancer if you drink a bottle of syrup, if you can choke it down, but it also, we know that it doesn't break down the same as the body, it causes obesity, it causes other kind of human suffering and issues, but there's no regulations or there's nothing done about that, and it's only done if it kills you, so if we have a lot of these chemicals that aren't necessarily killing you, but are contributing to multiple other comorbidities, how can there be a system kind of set up to look at those issues, not just the binary dead cancer, not dead kind of breakdown? I think there is some of that, so I mentioned briefly the potential for environmental impact there, again, those things are, those are topics in and of themselves, and there are week-long, month-long workshops on glyphosate, I specifically chose to focus on carcinogenicity because that is what, when you're sitting at home on television at 10 o'clock at night, is what they're saying, call your lawyer today if you have non-Hodgkin's lymphoma and you use Roundup, you may be entitled to compensation. But, so I think two things in response to that, one is, somewhat to Dr. Mullinax's point early on, it is the most widely used herbicide in the world, there actually are implications for feeding the world if glyphosate were not used, so there's that aspect. The dose that is actually received in food products by humans, even with fairly wide use in agriculture, is really, really small in comparison to what's shown in any of these studies, way, way off from acute toxicity levels for sure. The question of other health effects, like does it lead to obesity, what's the contribution of diabetes, I haven't even looked in all of that, but that comes into the area of single-hit hypothesis versus multi-hit hypothesis versus genetics and all of this, which is, again, the things that epidemiologists spend their entire careers focused on, you know, one little aspect of causality for a particular disease. But at this point, based off glyphosate not really having any known direct mechanism of toxicity in a human, considering that it was focused on a plant metabolism pathway, I'm not aware of other things that have come up, and I think that's probably the last question that we can take for time. Yeah, I'll add one thing. I've given a couple versions of this talk to residents in the past, and I often get the question at the end, well, what do you think, you know, is the IARC right or is the EPA right, you know, because they're saying different things, and what I tell them is, you know, you gotta look at the questions that they're asking, because they're not actually asking the same question. They're looking at things just slightly differently, right? One looking at the hazard standpoint and one looking at the risk standpoint, and I think it's entirely possible that they're both right, actually. You know, if you drink, you know, three gallons of Roundup a day, and you get cancer years down the road, okay, that may well be the case, but what's the relevance for human health at normal exposures, right? I think the EPA does a robust analysis as well. So anyway, I'll leave you with that, but thank you all for attending, and have a great rest of your conference. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you.

glyphosate

herbicide

health effects

chronic low-level toxic exposures

non-Hodgkin's lymphoma

animal studies

meta-analysis

National Agricultural Study

carcinogenic potential

risk assessment