Neurotoxicity

The Hidden Biopesticide on Your Produce

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Few would argue that consuming ample quantities of fruits and vegetables in the diet is a good idea, right? Fresh produce may be the only food on the planet that all diet gurus agree on, but did you know that you may be getting a chemically-applied dose of a known carcinogen every time you eat a piece of “fresh” fruit?

If you have been eating lots of produce as part of a healthy diet, it may shock you to learn that more than forty countries, including the United States, have promoted the use of a genotoxic, carcinogenic “freshness preserver,” applied to extend the shelf-life of fruits and vegetables. And despite vehement denials of any danger to the public, health concerns regarding the expanding use of this substance continue to mount.

Sold by U.S.-based company AgroFresh Solutions, Inc. under three different trade names, this patented preservation process applies a synthetic pesticide to fruit before it has ripened. The active ingredient in the pesticide, 1-methylcyclopropene (1-MCP), retards ripening by blocking ethylene receptors in the fruit from receiving the phytohormone ethylene – the plant’s chemical cue to ripen.[1] The trade names under which this rapidly expanding practice are operating are SmartFresh™ Technology, which is applied to produce post-harvest; Harvista™, applied to apple and pear orchards; and RipeLock™, applied to bananas after picking to retard ripening. Once applied, 1-MCP can retard ripening for up to one year.[2]

Per the manufacturer, SmartFresh technology is sold as a way to “reduce fruit waste” (marketing-speak for “increase profits”) and “maintain texture, firmness, taste and appearance of fruits by warding off negative ethylene effects.” In short, applying 1-MCP allows produce distributors to keep fruits and vegetables in storage much longer after harvest, while maintaining a fresh-looking and -tasting product to sell. Heralded as a breakthrough technology, it preserves profits for growers by allowing them to sell in-demand produce varieties during off-seasons.

Why it Matters

Marketed as “non-toxic”, the manufacturer states that SmartFresh “poses no risk to humans, animals or the environment, when used as recommended.” This marketing campaign has been very effective. Perceived as being low-risk to consumers, SmartFresh is approved for use on apples, pears, persimmons, plums, cherimoyas, kiwis, tomatoes, peaches, melons, mangoes, limes, and avocados, with more uses planned.[3] It is interesting to note that a “non-toxic” substance that “poses no risk to humans” is accompanied by safe handling instructions that specify anyone involved in application of the chemical “Wear long-sleeved shirt, long pants, shoes, socks, chemical-resistant gloves and safety glasses or goggles” while handling.[4] Nothing screams “safety” like a hazmat suit! Image credit: http://agrofresh.octochemstore.com/wp-content/uploads/2015/02/ProTabs_Pink_Use-Recommendations.pdf

The commercial implications of preserving the saleability of a produce harvest for an entire year are so significant, use of these technologies has spread across agricultural nations like a wildfire. 1-MCP has even penetrated the organic standards of several countries, with legislation knocking on the door of organic farming in the U.S. As of this writing, it is not allowable under the United States’ National Organic Program, however in mid-2016, a change was proposed to organic standards that would allow SmartFresh to be applied to tree fruits. The outcome of this proposal has not yet been announced.

With treated fruits lasting up to three times longer than non-treated fruits, the economic incentive is obvious. Organic standards are currently the only safeguard in place
to protect consumers from unknowingly ingesting toxic herbicides and pesticides. Organic standards should also strive to represent more localized, sustainable, and environmentally conscious agricultural practices. Are the organic standards in the United States strong enough to protect the public from the aggressive lobbying being done on behalf of these economic interests?

The most recent estimate available for the prevalence of this pesticide application comes from 2006, when approximately 60 percent of apples sold in the United States were treated with SmartFresh.[5] In 2018, this percentage has undoubtedly increased. And while it is not approved for use under current organic standards, there is only one test for 1-MCP, devised by the U.S. Environmental Protection Agency, and it is rarely employed. The test, which uses a radioisolated analytical method, detects 1-MCP residue on fruits and vegetables for up to 90 days post-treatment.[6] This test is considered expensive in the industry, as well as limited in effectiveness. As a result, testing for 1-MCP residue is rarely performed, helping foster conditions under which its use can go undetected. Testing is further hindered by an extraordinary EPA exemption from a set legal limit or tolerance level on surface residues.[7]

A new testing method is being pioneered that may help safeguard against unscrupulous agricultural practices that attempt to pass off chemically-treated produce as organic. The new test checks genetic activity, rather than surface residues of produce. According to the test developer, “Fruit treated with 1-MCP shows little or no genetic activity,” thus setting it apart from truly organic fruit. This test can also be used to predict the optimum time for picking fruit, allowing for greater control over quality without jumping into the toxic pesticide pool.[8]Whether this test will voluntarily be adopted is yet to be determined. Pressure from consumers for organic watchdogs to maintain the integrity of these standards is essential on local, state, and federal levels.

There are at least two groups of individuals who must take note of this issue: agricultural workers who are routinely exposed to high doses of this pesticide, and health-conscious individuals who strive to eat an optimized diet, comprised of multiple servings of fresh fruits and vegetables each day. Research into the health implications for both groups of people presents serious challenges. Despite there being nearly 300 abstracts on 1-MCP on PubMed, the US National Institutes of Health’s database of scientific studies, research on human and environmental effects is scant. A 2005 peer review and meta-analysis by the European Union (EU) and the European Food Safety Authority that was published in EFSA Journal, highlighted the difficulties in making a thorough determination of the health and safety implications of 1-MCP. First, there are actual physical challenges: “At high concentrations, [1-MCP] is energetically self-reactive and becomes explosive if it is allowed to warm in a closed container. These properties present practical difficulties when conducting studies.” Perhaps most noteworthy is a deep-seated presumption of safety around this substance, which has created a climate in which testing is simply not done.  Despite requests from the aforementioned researchers for a thorough review of studies on 1-MCP, submissions were not available on the effects of feeding 1-MCP-treated foods to animals. Nor were studies submitted on long-term human exposure, neurotoxicity or reproductive toxicity. In addition, according to the researchers, “No analytical methods for the determination of residues in soil and water have been required, since 1-methylcyclopropene is a gas and it is unlikely to reach these compartments.” Kind of like how mustard gas doesn’t reach the soils and waters around exposure sites?

Human reactivity data were only available from inhalation studies, which showed that 10% of 1-MCP inhaled into the lungs on each breath was absorbed into the bloodstream. Results of blood analysis determined that “1-MCP is not acutely toxic. Based on available data, 1-MCP gave negative results in in-vitro and in-vivo genotoxicity assays. However, two impurities, 1-chloro-2-methylpropene (1-CMP) and 3-chloro2-methylpropene (3-CMP)…are reported to give positive results in genotoxicity studies and are carcinogenic. Thus, a classification of 1-MCP as T-R46 is proposed.” Let’s break down what this means. The substance, in stable form, is not “acutely toxic.” Reference the hazmat suit and extremes of caution outlined in the safe handling guidelines if you believe this claim! Once the substance is activated, the real cautionary tale begins. 1-CMP, which is emitted during activation, is defined as “a clear, colorless, highly volatile and flammable liquid chlorinated hydrocarbonthat emits highly toxic fumes of hydrochloric acid and other chlorinated compounds when heated to decomposition.” This substance literally becomes a chemical weapon on par with hydrogen chloride gas! 3-CMP is the other chlorinated compound that is released, also believed to be a human carcinogen. When heated, 3-CMP emits toxic fumes of hydrochloric acid and other chlorinated compounds.[9] Regarding the researchers proposed T-R46 classification, according to the International Chemical Safety Classification, T=Toxic, while R signifies “Harmful by inhalation” and “Dangerous for the ozone layer.” The number 46 spans a range between 20-59, denoting degree of risk. It is noteworthy that once a chemical reaches 40, humans can experience “Possible risks of irreversible effects” due to exposure.[10] Besides the cumulative, long-term risks of exposure to these carcinogenic, chlorinated compounds, researchers noted “In the short-term toxicity studies that were peer-reviewed, effects on red blood cells were also observed.”

The fallback argument for the EPA and FDA to allow these chemicals into our food supply, is the “allowable limits” clause. Allowable limits are set for our air quality, water purity, soil contamination levels, and even our food chain. 1-MCP levels that have previously been detectable on produce, if tests were performed, have fallen under the hypothetically-derived safety levels set for health and human safety. However, absence of data does not denote zero risk. When 1-MCP binds to the ethylene receptors in fruits and vegetables, the bond is permanent. This means we are ingesting this pesticide, in quantities that vary based on how many days post-treatment when the produce is consumed. Another factor being how much treated produce we are consuming. AgroFresh’s proliferating 1-MCP technologies have been in use in the United States fruit market for more than 15 years. With the limited amount of research into human and animal exposures over what is now the long-term, consumers who care about food safety enough to buy organic cannot afford to lose these critical protections.

Our levels of unwitting exposure will continue to increase as new ways to use these technologies are developed. Many of the current laws regarding 1-MCP were developed when the substance was only approved for use inside well-sealed containers, an effort to mitigate environmental risk. However, Harvista technology, also based on 1-MCP, is sprayed directly onto fruit orchards and vegetable fields.[11] As use spreads globally, and environmental protections wane, our organic food standards may be all that stand between the health-conscious consumer and questionable farming practices. 1-MCP may be the trojan horse that is already inside the city gates.

Endothelial Activation Linked to Increased Risk of Severe Neurotoxicity

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Biomarkers may help identify patients at increased risk of neurotoxicity from chimeric antigen receptor (CAR) T-cell therapy.

New potential biomarkers and a novel algorithm could help identify patients at increased risk of developing severe neurotoxicity after receiving CD19 CAR T-cell therapy.

 “The first-generation of CD19 CAR T-cells show promise, but they do have toxicities — most often cytokine-release syndrome [CRS] and neurotoxicity,” the senior author of a new study, Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, said in an interview. “There seems to be an overlap between the two, although neurotoxicity is rare in the absence of CRS. There is understandable anxiety about some of the side effects of CD19 CAR T-cell therapy, but these treatments have been very effective for a subgroup of patients with resistant disease.”

So far, two CAR T-cell products have received FDA approval for patients who have limited or no therapeutic options, and “these therapies will become more widely used,” he continued. “Understanding how to minimize the risk of neurotoxicity will be important as we move forward. We need to devise assays to determine who will develop severe toxicity as a trigger to allow us to intervene and ‘cool off’ CAR T-cells and limit neurotoxicity.”

Turtle and colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from CD19 CAR T-cell therapy. They used data from 133 adult patients with relapsed/refractory CD19 B-cell acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, or chronic lymphocytic leukemia who were treated with lymphodepletion chemotherapy followed by infusion of JCAR014, a type of CD19 CAR T-cell therapy developed at the cancer center.

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events. Of these, 28 patients (21%) had grade 3 or higher neurotoxicity; alterations in neurologic status completely resolved in a majority of cases. Four of the 133 patients (3%) developed fatal neurotoxicity.

Patients with an early onset of CRS were at increased risk of subsequently developing severe neurotoxicity, the team noted. Tocilizumab, an interleukin-6R antagonist approved by the FDA to treat CRS, ameliorated CRS-related fever and hypotension in most patients, but the role in preventing or treating neurotoxicity was less clear.

Patients who had neurotoxicity were mostly younger and had B-cell ALL, a higher tumor burden, and more CD19-positive cells in the bone marrow as compared with those who did not develop this side effect. Data also revealed that those with severe neurotoxicity had endothelial activation, which could contribute to the capillary leak, blood coagulation abnormalities, and disruption of the blood-brain barrier observed in patients with severe CRS and neurotoxicity.

“This is the most comprehensive description of what neurotoxicity looks like when clinicians come across it in the clinic,” said Turtle. “Others have found that high cytokine levels increase the risk of neurotoxicity, but ours is the first association with endothelial activation. We need to work out whether this is due to focal endothelial activation in neurotoxicity or just a systemic manifestation.”

Turtle and colleagues also developed a predictive classification tree algorithm based on the side effects — including fever, high serum IL-6, and MCP-1 — to identify patients within the first 36 hours after CAR T-cell infusion who are at increased risk for severe neurotoxicity. This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity, the team reported. Eight patients were misclassified; one of the eight patients did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Using algorithms may help identify patients who have an increased risk of severe neurotoxicity and who could benefit from early intervention: “If a patient develops seizure 24 to 36 hours after receiving CAR T-cell therapy, then it’s time to worry about neurotoxicity, if there is no other obvious cause,” said Turtle. “CRS may be occurring aggressively and early. Watch the patient closely and, if need be, intervene therapeutically.”

He cautioned that the cytokine thresholds and seizures outlined in the study apply only to the CD19 CAR T-cell product at Fred Hutchinson — i.e., other CAR T-cell products may lead to different toxicity rates and clinical kinetics. “These biomarkers can’t be applied to other CAR T-cells, and other biomarkers for other CAR T-cells will have to be validated. Ultimately, when an algorithm triggers therapy, clinicians can give steroids or cytokine-directed therapy to mitigate toxicity to ‘cool off’ cytokine secretions.”

The next step in this research, he said, is to look at early intervention in high-risk patients and determine whether the effects of shutting down CAR T-cell response affects efficacy. Turtle’s team and others are currently working on these trials.

Turtle said that most toxicity appeared early in treatment during dose escalation, and the risk of toxicity of CAR T-cell therapy has dropped over the past few years with more experience with this gene-directed immunotherapy. “The potential for severe toxicity still exists with CAR T-cell therapy, but moving forward this will become less frequent. We can optimize CAR T-cell regimens to reduce toxicity. If we can predict how many patients will develop severe toxicity, we may be able to intervene at early time points,” he said.

Enormous improvements have been made in the last few years in strategies to minimize the risk of toxicity, he added. “Because CAR T-cell therapy is so new, we are still learning how to improve the delivery and reduce the side effects.”