Dr. Willie McKinney presents on the the importance of a toxicological risk assessment on your products before releasing them for public consumption at the Cannabis Science Conference in Providence, RI

Good morning, good afternoon everyone. I am grateful to have the opportunity to speak to you about a topic that I am very passionate about. So, I’m going to talk to you about risk assessment and toxicological evaluation programs. But before I do that, I have some disclosures. As mentioned, we’re a consulting firm and we provide scientific and regulatory advice and support to Abstract Tech, hereby referred to as Abstract, and all the studies I’m going to talk about were sponsored by Abstracts and AVD (Advanced Vapor Devices). These sponsors participated in conversations about the study design and provided product samples. We tested the products at independent laboratories. You have received the disclosure. 

So, when you have a company, there are several questions that you have to consider. How much are we going to spend on marketing? Why do we have a dip in revenue? But I think one of the most important questions you should consider, but oftentimes I find it’s the last question that, at least small companies consider, is do you have confidence that the ingredients used in your cannabis products will not cause harm to your consumer? Now, why is this an important question? Seems obvious, but I’m going to talk about it anyway. Most of you are aware, in August 2019, there were several reports of lung injury to the CDC, and the CDC classified these lung injuries as EVALI, which is E-Vapor and Vapor Associated Lung Injury. Well, there were several cases, and the cases peaked in 2019 and, ultimately, unfortunately, 2,800 people experienced lung injury and, unfortunately, 68 people died. This lung injury was linked to ingredients used in illicit products, illicit THC products to be clear, and with further study, the ingredient was vitamin E acetate and some other ingredients. 

Now, some of you may say, well, those were illicit products, illegal, they came over, how does that impact me because I’m doing things the right way? Well, let me tell you how. When something like this happens, there’s not one company that gets the blame; it’s the entire industry, and this could create a moral panic and wake regulators up and wake up the lawyers as well. All right, so that’s one thing you have to think about. The other thing is, this is a great example of innovation gone wild. These people were extremely innovative and thought they were delivering a product that the consumer wanted, and they did not do any testing. They added these ingredients, and they put these products on the market. Now, and these products caused harm. And when there’s harm in the population, I mentioned before, let’s talk about that for a moment. I’ve done a little bit of litigation support, and I can tell you, in a situation like this, you will be asked, does your product contain vitamin E acetate? And most of you know what you’re adding to your products, and you would say no. Then the plaintiff’s attorney would show some analytical data showing that your product does contain vitamin E acetate, and you would be looking like, wow, well, that’s because the product that they pulled was a year old, and there’s chemistry going on. And the chemist will challenge me on this, but somehow, vitamin E acetate is in there, or from a contaminant from manufacturing. So, the point I’m making is, it’s important to do testing. 

There’s another reason. Here’s a study that suggests that vaping CBD causes more lung injury and inflammation than vaping nicotine vape products. And the authors go on to say that adding terpenes and flavors exacerbated the response, and they conclude that there is simply a lack of robust evidence about cannabis safety when delivered from vaping products. And so, the question I have for you is, are they talking about your product? How do you distinguish whether or not your product is causing this problem if you don’t have data? Then ultimately, they may be talking about your product. 

Now, one company decided to do things differently, and that company is Abstracts. So, Abstract is a company that extracts terpenes from various sources. They put these terpenes together in a blend, or they sell isolates for their clients to use in their cannabis products. And they approached us, McKinney Regulatory Science Advisors, and asked us to help develop a regulatory science framework to support the use of their terpene blend formulation in cannabis inhalation products. And we decided, yes, we will help you. And one of the first things we did was, we need to define the product. What actually is the product? Now, for Abstracts, the product is liquids. Right? Now, if the consumer were either putting the liquids on their skin or ingesting the liquids, we would have simply looked at the ingredients, done a tox assessment or a risk assessment, and we would have been done. But that is not the case here. These liquids are then put into a device, one must look at the device independently as well, because devices have electronics. And as most of you know, devices can cause acute harm. If you’re like me, oftentimes, and you shouldn’t do this, if I need to charge something, I go find my bucket of charges, and I pull one out, and if it fits, I charge. Well, you could ultimately explode a battery that way, so I wouldn’t advise that you do that. But also, the materials used in the device may leech metals into the liquids. So, you need to understand and evaluate the materials. But ultimately, the product is these two things together, and the consumer is exposed to the aerosol. So, we really want to understand risk to the consumer when they inhale this aerosol. 

So, before I’m going to go into a little bit of detail, but the first question I have, or I’m going to try to address is, what makes a risk? What is risk? Well, a risk is hazard plus exposure. And hazard is simply something that has the ability to cause injury. And in this case, the shark represents a hazard and can cause injury. Now, I’m going to deviate from my script just a little bit and say that I know that it is rare for humans to be attacked by sharks, and most people, at least some biologists I spoke with, they told me a little joke. They said that the sea is salty because of the tears of misunderstood sharks. That still doesn’t mean I want to swim with one. So, let’s assume that this is Steven Spielberg’s shark. This is Jaws, and it is dangerous. It is a potential hazard. And now, there’s a diver in the water. The shark doesn’t seem concerned, so the likelihood of harm is low. But the next photo shows you that the human and the shark have come in contact, and the shark looks hungry. So, there’s a high probability of harm, therefore risk. There are four steps to a risk assessment: hazard identification, dose-response assessment, exposure assessment, and risk characterization. And I want to take a break down and go into detail on each one of these steps for you. 

And what we did, we created a pilot blend with Abstracts, ultimately, to evaluate these steps and develop the program for them. And the first phase is screening. And so, you want to perform a literature search and determine whether the terpene is associated with one of the priority health effects. Right? Such as, does it cause cancer? Does it lead to neurotoxicity? Does the chemical or terpene cause reproductive or developmental toxicity effects? Now, if you look and you don’t see any data, that does not mean that everything is okay. And typically, if you don’t see data, there’s a couple of things that you can do. You can generate the data, or you can look at the structure of the terpene, and if it’s similar to the structure of another molecule that has experimental data, you can leverage that experimental data and make some decisions there. Often times, I’ll just say, if a formulation contains an ingredient that is a potential carcinogen, sometimes there’s a business decision made that we really need to leave this ingredient in the formulation. I would strongly advise that you reformulate, but some people don’t want to do that. And in that case, there’s a lot of studies that you need to do to defend the use of that formulation. For example, if you’re adding a carcinogen, I would recommend you do a two-year carcinogen study, which is quite expensive and very long, and that’s before you put the product on the market, by the way. Right? It’s easier to reformulate, folks. 

The next thing we do is we look at whether or not the terpene is genotoxic. In other words, does it directly damage DNA? And does it cause lung injury, respiratory irritation, or sensitization? And we do this using predictive modeling and looking at databases and things like that. Again, if you choose to add one of these ingredients to your formulation, we would need to do testing, significant testing on your formulation, to basically say that it’s okay. 

The next step in a risk assessment is a dose-response assessment. Now, a dose-response is simply the relationship between the dose and exposure and the effect of interest. And the main thing you have to think about with a dose-response is extrapolation. Toxicologists typically expose animals or cells to high doses, then try to extrapolate to low doses. Then we also extrapolate from the animal studies to humans, and we add uncertainty factors and things like that. However, the process of extrapolation is different with the chemical and how the chemical is classified, either as a carcinogen or a non-carcinogen. Carcinogens are cancer-causing agents. It’s believed that there is no threshold, there is no level below which there is no harm. So, what you do is you do a probability assessment, or you mathematical equations, and you determine the probability of that chemical causing harm. And you usually end up with a risk of one in a million. I’m not the person that says that’s acceptable. Typically, authoritative bodies establish that as an acceptable level. For non-cancer causing agents, there is a threshold. There’s a level below which, if you are exposed for a lifetime, it is unlikely that these chemicals will cause harm to the population. And so, that’s the level that we try to find and identify for our client and the terpenes that they add. And we use the pilot blend to do that. 

So, let’s just talk about one terpene here. So, this is Nerol, which is a terpene that has a rose smell about it, and our clients like to use this. So, we evaluated it, and what we found is that it doesn’t damage DNA, it’s not carcinogenic, it’s not a neurotoxin, and there were no alerts in terms of it causing respiratory problems. So, that’s a good sign. Looks like it’s a low hazard. But we also found that there’s a level below which, if you’re exposed to Nerol, there’s a low probability or low likelihood of harm. And that is 1.09 mg per cubic meter. Well, how does that relate to what my client is adding, and are they below that level? Well, we did some conversions, and we came up with 21,800 micrograms per day is the level below which your consumers should be below. Now, so that is a maximum use level. But to determine whether or not the ingredient used in the formulation is acceptable, we needed to do an exposure assessment. How much product are people using? How much aerosol are they inhaling? What is the consumer exposed to? So, we leverage sales and survey data to estimate a daily consumption, and we made some assumptions, which are worst-case. We assumed a 100% transfer rate from e-liquid to vaping aerosol, 100% absorption, meaning everything you inhale stays in. But we know people exhale, so it’s a very conservative assumption. And in general, we found that our estimates were consistent with some general publications, so we felt good about our exposure estimates. And you can see the column in terms of milligrams per kilogram per day for exposure. 

So, now we know the maximum use level. We have an idea of what consumers are, the level that they are exposing themselves to for each ingredient in this pilot formulation. Now we have to put the two together. And when you do that, what you’re looking for is a margin of exposure. And that’s the ratio between the exposure dose over the acceptable daily intake. So, a margin of exposure less than one, okay, you’re adding the ingredient at a level below the likelihood that it would cause harm, and consumers, when you factor in exposure, you’re still okay. If the MOE (Margin of Exposure) is greater than one, you need to generate more data or reformulate. I always throw out reformulating. And so, when we looked at our pilot formulation, there were two ingredients that had a margin of exposure greater than one, Myrcene and Beta-Caryophyllene. So, we needed to do some more work. What did we do? We did studies. We did lipophilicity studies, an acute inhalation study. Well, that’s, we did finish that. We’re doing analytical chemistry analysis and biological activity analysis. So, I’m going to talk about two of these. 

Lipophilicity, what is that? Well, that’s the ability of a chemical or a compound to dissolve in fats, oils, or lipids. And what we recognize is that when I talk to you about EVALI, vitamin E acetate is highly lipophilic, easily went into cells, and caused damage. And so, there’s a scale. And what we did, we looked at all the ingredients, and we put, well, Beta-Caryophyllene and Myrcene, and we tested them. And as you can see, they fall within the green area. I include Diacetyl here because it causes lung injury, and that’s just to say that this assay alone, can you, cannot go say that an ingredient does not cause lung injury. You need to understand the mechanism as well. 

So, the terpene blend. Let me, let me make a statement here. When you look at Beta-Caryophyllene, with a lipophilicity value of 7.3, it’s getting close to the 7.5 in an area where I get a little bit uncomfortable. However, when you look at the blend, which contains Beta-Caryophyllene, it has a value of 5.7. That’s why it’s important as well to look at the formulation as well as the individual ingredients. So, they were okay there. 

We conducted an acute inhalation toxicology study, 4-hour inhalation study. And ultimately, I’ll just tell you the outcome of that. No results, everything was clean, nice. So, here we put the terpene at a maximum inhalation concentration as possible, expose them to animals, and everything is good. So, with that, we are confident that the ingredients used in the pilot terpene blend are appropriate for their intended use. We still have some additional studies to do, but I would recommend that each of you consider, if you sell products, that you consider developing a regulatory science program to understand the ingredients added to your products. With that, I’ll take a few questions. Thank you for your time.