Understanding Sources of Heavy Metals in Cannabis and Hemp: Benefits of a Risk Assessment Strategy – Part 2

Part 2: Can a risk assessment strategy be applied to the cannabis industry?

Part 1 of this series of articles highlighted pharmaceutical risk assessment from an historical perspective and what we learned from this process. Part 2 will focus on whether a well-established risk assessment strategy could be adapted by the cannabis industry and, in particular, how it could help industry members to better understand all the potential sources of elemental contaminants that are derived from cannabis cultivation, extraction, manufacturing, packaging and delivery.

What does a ‘heavy metals in cannabis’ risk assessment approach look like?

It’s difficult to fully comprehend how the cannabis industry can implement a comprehensive risk analysis strategy for elemental contaminants in consumer and medicinal products in a similar way to what the pharmaceutical industry began in the mid-1990s. Pharma realized that the compendial methodology (sulfide precipitation visual observation) was inadequate to protect public health and in an effort to maintain global harmonization on this initiative joined in and expanded upon the United States Pharmacopeia’s (USP’s) update process with the initiation of the ICH Q3D initiative. There is very little incentive for the cannabis industry to do this at this present time. Since there is no national regulatory body driving uniformity or regulation, the industry is basically regulating itself with some oversight from the individual state regulators.

Most states regulate the big four heavy metals, but there is evidence in the public domain that at least another ten are worthy of consideration. It’s likely that the momentum for change will come from consumers and consumer advocates and the desire to have safer products. Product recalls and certificates of analysis (COAs) that are vague and, in some cases, intentionally falsified will in the long run likely drive the need for a unified approach with consequences for noncompliance. However, there could be a better way to scrutinize the different aspects of cannabis manufacturing through a root cause analysis process similar to the fishbone approach used by the pharmaceutical industry. But who would be responsible for driving it is uncertain at the moment? The global pharmaceutical industry had the International Council for Harmonisation of Technical Requirements for Pharmaceuticals (ICH) to carry out the risk assessment study, but no such regulatory bodies exist in the cannabis industry. So, it would have to be determined what standards organizations and interested stakeholders outside the federal government would be willing to take on this responsibility. Only time will tell. In the meantime, it is important to have a basic understanding of how the problem could be approached!

Breakdown of the cannabis production process

In parallel with the fishbone diagram shown in Figure 1 in Part 1 of the series, we can identify six different processes in the production of cannabinoids that can lead to the introduction of elemental impurities in the final product:

• Cultivation and growing of cannabis and hemp.
• Extraction and purification of cannabinoids.
• Processing of specific cannabis/hemp consumer products.
• Manufacturing of infused products.
• Product packaging.
• Consumer delivery.

These could be represented by a modified fishbone approach shown in Figure 2, by using many of the guidelines and suggestions enummerated in the pharmaceutical version.

Figure 2: Possible Fishbone approach for the cannabis industry.

 
Let’s take a closer look at each of these processes, particularly how they can impact elemental contaminants in the final medicinal/consumer products and recommendations on how to reduce them.

Potential sources of heavy metals

Considerations about where to grow cannabis and hemp are going to be critically important because it could have serious implications on the level of heavy metals that are absorbed by the plant and its resulting safety for human consumption of cannabinoids. Historically, apart from the western and southern regions of the US, much of the cannabis in the US has been grown indoors in greenhouses under controlled growing environments, so the absorption of heavy metals into the plant has been kept in check reasonably well.

But in 2020 it became legal to grow hemp for CBD production anywhere in the US. As a result, it became more challenging to keep the levels low, because most of the hemp plants are grown outdoors on farms where the soil might be an additional source of contamination¹.

So, let’s first look at potential sources of elemental contaminants in cannabis and hemp from a growing and cultivation perspective and then we’ll focus on the impact of the extraction, processing, production, and packaging and delivery processes.

Cultivation and growing sources

Plant-based phytoremediation is emerging as a cost-effective technology to concentrate and remove elements, compounds, and pollutants from the environment². And within this field, the use of cannabis and hemp plants to concentrate metals from the soil into the harvestable parts of roots and above-ground shoots (phytoextraction) has great potential as a viable alternative to traditional contaminated land remediation methods³. However, the natural inclination of these plants to absorb heavy metals from the soil could potentially limits its commercial use for the production of medicinal cannabinoid-based compounds. A number of studies provide convincing evidence that cannabis is an active accumulator of heavy metals such as lead, cadmium, arsenic, mercury, magnesium, copper, chromium, nickel, manganese, and cobalt^{4, 5, 6, 7}.

Main factors for metal uptake

The health and growth of all plants rely on essential nutrients and minerals being available in dissolved, ionic forms in the soil. To maintain enough water to survive and thrive, the plant’s primary means of facilitating the movement of water is through transpiration, which is a highly efficient means of drawing a concentrat­ed solution of minerals and nutrients out of the soil. Transpi­ration works by the evaporative loss of water from the shoots, which is controlled by the opening and closing of specialized pores (known as stoma­ta) embedded in the surface of the leaves that initiate gas exchange. When the stomata are open, the pressure potential of the plant becomes very negative, creat­ing a vacuum effect that draws water and nutrients into the plant, moving it from the roots to the shoots. Unfortunately, this is also the mechanism that the plant draws in heavy metal contaminants in addition to the nutrients.

The rhizosphere is the region of soil in the vicinity of plant roots. Its chemistry and microbiology is influenced by the roots’ growth, respiration, and nutrient exchange⁸. Unfortunately, under certain conditions, the plant’s root system will preferentially absorb heavy metals over other minerals, which cannot be explained exclusively by passive ion uptake. The hyper-accumulating properties of cannabis and hemp aren’t fully understood, but are partially dependent upon other factors, including soil pH, availability of other metal/mineral ions in solution, the nitrogen/phosphorus/potassium (NPK) ratio and the ability of the plant’s natural metalloproteins, which act as chelating compounds to bind with the heavy metals to reduce the rate of absorption and overcome their toxic effects.

It should also be noted that the plant’s natural polyamine compounds will strengthen the defense response of plants and enhance their defense against diverse environmental stressors, including toxicity and oxidative stress. Bode wrote an excellent article on the underlying mechanisms of heavy metal uptake by cannabis plants, which should be essential reading for any cannabis grower ⁹.

Based on evidence in the public domain, there are approximately 15-20 heavy metals found in polluted ecosystems that could be potential sources of contaminants, including lead, arsenic, mercury, cadmium, nickel, vanadium, cobalt, copper, selenium, boron, thallium, barium, antimony, silver, gold, zinc, tin, manganese, molybdenum, tungsten, iron, and uranium. Many of these elements exist as different species (metalloids, for example) based on their oxidation state, organic/inorganic/ionic form¹⁰, or as engineered nanoparticles that could find their way into wastewater streams¹¹. Their levels of toxicity would need to be investigated further, but there is a compelling case to be made that the many of these elements, metalloids, and speciated forms could be the future basis of a federally regulated panel of metal-based contaminants in cannabis and hemp.

Outdoor growing sources

Let’s take a closer look at some of the “real-world” sources of elemental contaminants that are supported by evidence in the public domain. It’s only when cannabis and hemp cultivators and growers have a good understanding of this problem can they hope to reduce or even eliminate them. This isn’t an exhaustive list, but it offers some suggestions and a good starting point to begin investigating them:

• Water is a critically important nutrient for cannabis plants. Ensure that only the highest quality water is used and test on a regular basis for common pollutants. Refer to ICH Q3D guidelines for water quality used in pharmaceutical manufacturing¹².
• When grown outdoors, if possible, the soil chemistry should be characterized to make sure that the elemental contaminants are at acceptable levels. In particular, the acidity (pH) of the soil should be optimized to minimize the amount of heavy metal ions in solution. Explore the use of natural chelating agent, such as humic acid or a soil amendment medium like biochar (any biomass heated in an oxygen-lean atmosphere), to bind with the harmful metallic contaminants to minimize their uptake by the plant’s root system¹³.
• In areas where gold and silver mines are found, there is the potential for high mercury levels in the soil, as mercury amalgamation is a well-accepted extraction method. These mines are particularly prevalent in the growing states of California, Oregon, and Washington, which have some of the highest density of outdoor cannabis farms in the US^{14, 15}.
• Metal smelting plants will experience heavy metal contamination in surrounding areas. Lead and copper ores in particular contain high levels of arsenic¹⁶.
• Environmental Protection Agency (EPA) superfund sites, especially those involved in the manufacture of weapons, could have high levels of radionuclides such as uranium in the soil and the groundwater¹⁷.
• Fly ash waste from coal-fired power plants is extremely high in heavy metals from the coal combustion process. Surrounding areas where the fly ash has been dumped into ponds will likely seep out and contaminate the soil and ground water¹⁸.
• Decades of leaded gasoline usage has contaminated much of the soil close to and around major highways and roads¹⁹.
• Many industries are known to emit elemental mercury into the atmosphere, including coal-fired power plants, metal refineries/smelters, petrochemical plants, and cement works. It’s well documented by the Clean Air Act that up to 100 tons of mercury are emitted by US industries annually, much of it being converted into the highly toxic methyl mercury by the process of bioaccumulation²⁰.
• Try to avoid planting hemp in fields that were once apple orchards. Spraying apple trees with fungicides containing lead arsenate was a common practice, so it is inevitable high levels of arsenic and lead will have polluted the soil^{21, 22}.
• Wood preservation chemicals contain high levels of copper, arsenic, and chromium. Areas around these plants are likely contaminated²³.
• Low-grade fertilizers/nutrients made from phosphate rocks contain significant amounts of elemental impurities²⁴.
• Nickel has been promoted as a cannabis flower/bud-enhancer and silicon as a way of increasing shoot size, which means that higher levels of nickel and silicon will invariably end up in the cannabis product. These elements are typically not required by the vast majority of states, so they would escape the scrutiny of most state regulators^{25, 26, 27}.
• Some glyphosate-based herbicides are rich in heavy metals²⁸.
• Although there is no speciation requirement in the current state-based limits for heavy metals, both dietary supplement and pharmaceutical regulators have shown that inorganic and organic forms of arsenic and mercury should be monitored if the maximum limits for the total amount of the element is exceeded. In addition, depending on where the cannabis/hemp plants are grown, the location will also dictate whether other speciated forms should be monitored. Examples of this might include the highly toxic hexavalent chromium (CrVI) compared to the relatively innocuous trivalent species (CrIII)²⁹.
• At some point in the future, nanoparticle characterization in the soil and uptake by the cannabis plant may be required, particularly when there are regulated methods for environmental and food-based nanoparticle assays¹¹.

Indoor growing sources

Although an indoor growing environment is far more controlled than cultivating plants outdoors, there are still many opportunities for picking up elemental contaminants. Nutrients, fertilizers, and potable water are three of the potential sources of metal contamination. As a result, indoors plants cultivated in a synthetic soil, grow bags, Rockwool medium, or hydroponically grown are highly dependent on the nutrients, minerals, and water used. For that reason, high quality fertilizers and a source of clean water are essential for healthy plants. Here are three potential areas of concern when growing plants indoors.

• Last year the EPA estimated that 30 million people in the US live in areas where drinking water violated safety standards. The EPA defines a list of primary and secondary elemental maximum contaminants levels (MCLs) in drinking water and overseas all local water authorities/municipalities in the US to ensure compliance. It’s important to know these levels in your region to make sure they are well below the limits for metal impurities (they will be posted online by your local water authority). Also keep in mind that these are levels for samples taken at the water treatment plant and not the levels measured at your home or growing site. EPA mandates that a municipality only has to measure water quality at its customers’ sites every two years and has to take remedial action only if ten percent of those sampled are above the MCL. A recent example of what can go wrong is provided by the lead-contaminated drinking water in Flint, Michigan. The source was changed from lake water (Lake Huron) to the local Flint River without understanding the chemistry and its corrosion properties. As a result, the water partially dissolved the inside of the old lead pipes and ended up contaminating the drinking water supply ^{30, 31}.
• Decades of using lead-based pigments in residential and commercial paint has meant that many of the older homes and buildings still contain these types of paints, which have often been painted over, but still produce dust/particles that can potentially be problematic³².
• Some plasterboard used in the construction industry is made from gypsum-based flue gas desulfurization (FGD) waste products mixed with a silicate material known as clinker. FGD is produced by scrubbing particulate emissions from coal-fired power plants, which are notoriously high in heavy metals³³.

Final thoughts

Part 2 of this series of articles on heavy metals risk assessment explored how the cannabis industry could use a similar approach to how the pharmaceutical industry carried out the risk assessment to better understand sources on heavy metal contaminants in drug products. In particular, it looked at the cultivation of cannabis and hemp and where the likely sources of metal uptake from the soil and growing environment come from. Part 3 of this white paper examines the critically important step of extracting cannabinoids from the biomass, the flower, and other parts of the plant.

References

1. Global Impact of Trace Non-essential Heavy Metal Contaminants in Industrial Cannabis Bioeconomy. L. Bengyella, Toxin Reviews, October 2021, https://doi.org/10.1080/15569543.2021.1992444
2. The Use of Plants for the Removal of Toxic Metals from Contaminated Soil; M. Lasat, AAAS Report, Washington, DC, 2004, https://clu-in.org/download/remed/lasat.pdf
3. Phytoremediation Potential of Hemp (Cannabis sativa L.): Identification and Characterization of Heavy Metals Responsive Genes, R. Ahmad et. al., CLEAN - Soil Air Water, Volume 44, Issue 2, Pages 195-201, August, 2015, https://www.alchimiaweb.com/blogfr/wp-content/uploads/2016/08/Phytoremediation-Potential-of-Hemp-Cannabis-sativa-L.-Identification-and-Characterization-of-Heavy-Metals-Responsive-Genes-2015.pdf
4. A Budding Cannabis Cottage-Industry has set the stage for an Impending Public Health Crisis, Gauvin D.V. et.al., Pharmaceutical Regulatory Affairs Vol 7(1): 199, 2018, https://www.hilarispublisher.com/open-access/abuddingcannabis-cottageindustry-has-set-the-stage-for-an-impending-public-health-crisis-2167-7689-1000199.pdf
5. Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “La Fee Verte”, D. Gauvin et.al., Pharmaceutical Regulatory Affairs, 7:1, 2018, https://www.hilarispublisher.com/open-access/marijuana-toxicity-heavy-metal-exposure-through-statesponsored-accessto-la-fee-verte-2167-7689-1000202.pdf
6. Effect of Soil Contamination on Some Heavy Metals Content of Cannabis Sativa, M. Khan, Journal of Chemical Society of Pakistan Pak., Vol. 30, No.6, 2008, https://www.votehemp.com/wp-content/uploads/2018/09/Effect-of-Soil-Contamination-on-Some-Heavy-Metals-Content-of-Cannabis-sativa.pdf
7. Environmental Contamination by Heavy Metals; V. Masindi and K. L. Muedi, Intech open access, https://www.intechopen.com/chapters/60680
8. Rhizosphere engineering: Enhancing sustainable plant ecosystem productivity, A.H. Ahkami et. al., Rhizosphere, Volume 3, Part 2, June 2017, Pages 233-243, 2017, https://doi.org/10.1016/j.rhisph.2017.04.012
9. Back to the Root—The Role of Botany and Plant Physiology in Cannabis Testing, Part I: Understanding Mechanisms of Heavy Metal Uptake in Plants, G. Bode, Cannabis Science and Technology, Vol 3, No 2, March 2020, https://www.cannabissciencetech.com/view/back-root-role-botany-and-plant-physiology-cannabis-testing-part-i-understanding-mechanisms
10. Heavy Metals in Soils: Trace Metals and Metalloids in Soils and their Bioavailability; Editor, B. J. Alloway, Department of Soil Science, University of Reading, UK; Springer Science, Dordrecht, 2013, ISBN: 978-94-007-4469-1, https://link.springer.com/book/10.1007/978-94-007-4470-7
11. Single-Particle ICP-MS: A Key Analytical Technique for Characterizing Nanoparticles; C. Stephan, R. Thomas, Spectroscopy Magazine, 32(3) March 2017, https://www.spectroscopyonline.com/view/single-particle-icp-ms-key-analytical-technique-characterizing-nanoparticles
12. ICH Guideline Q3D on Elemental Impurities (R1), European Medicine Agency Website: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-32.pdf

13.   Using Biochar for Remediation of Soils Contaminated with Heavy Metals and Organic Pollutants; X Zhang et. al., Environmental Science Pollution Research, DOI 10.1007/s11356-013-1659-0, Springer Verlag, 2013, https://www.academia.edu/27819557/Using_biochar_for_remediation_of_soils_contaminated_with_heavy_metals_and_organic_pollutants

14.   The Impact of Illegal Artisanal Gold Mining on the Peruvian Amazon: Benefits of Taking a Direct
Mercury Analyzer into the Rain Forest to Monitor Mercury Contamination, R. J. Thomas, AP Column, Spectroscopy Magazine, March, 2019, Volume 34, Issue 2, pg 22–32 https://www.spectroscopyonline.com/view/impact-illegal-artisanal-gold-mining-peruvian-amazon-benefits-taking-direct-mercury-analyzer-rain-fo

15.   Global mercury emissions from gold and silver mining, L.D. Lacerda, Water, Air, and Soil Pollution, volume 97, 209–221, (1997), https://link.springer.com/article/10.1007/BF02407459

16. Heavy metals and living systems: An overview, R. Singh et. al., Indian J Pharmacol, May-June; 43 (3): 246–253, (2011), https://pubmed.ncbi.nlm.nih.gov/21713085/
17. Common Radionuclides found at Superfund Sites, The U.S. Environmental Protection Agency (EPA), https://www.epa.gov/radiation/which-radionuclides-are-found-superfund-sites
18. Coal Ash Basics, The U.S. Environmental Protection Agency (EPA), https://www.epa.gov/coalash/coal-ash-basics
19. Urban children are playing in toxic dirt, Yvette Cabrera, Think Progress, July 12, 2017, https://archive.thinkprogress.org/urban-children-are-playing-in-toxic-dirt-41961957ff23/
20. Mercury and Air Toxics Standards (MATS): Clean Air Act, The U.S. Environmental Protection Agency (EPA), https://www.epa.gov/mats
21. New Hampshire Apple Orchards as a Source of Arsenic Contamination, C.K. Wong et.al., ResearchGate, May, 2002, https://www.researchgate.net/publication/253725992_New_Hampshire_Apple_Orchards_as_a_Source_of_Arsenic_Contamination
22. Impact of Land Disturbance on the Fate of Arsenical Pesticides. C.E. Renshaw, Environmental. Quality, 35:61–67 (2006), https://www.researchgate.net/publication/253725992
23. Chromated copper arsenate–treated wood: a potential source of arsenic exposure and toxicity in dermatology, A. Yuntzu-Yen Chen and T. Olsen, Int. J. Women’s Dermatol., March; 2(1): 28–30, 2016, https://pubmed.ncbi.nlm.nih.gov/28491998/
24. Heavy metal pollution from phosphate rock used for the production of fertilizer in Pakistan, T. Mamoud et. al., Microchemical Journal 91(1), September 2008, https://doi.org/10.1016/j.microc.2008.08.009
25. Essential Roles and Hazardous Effects of Nickel in Plants, M. Ahmad, M. Ashraf,  Review of Environmental Contamination Toxicology, Springer, New Yok, 2011;214:125-67, https://doi.org/10.1007/978-1-4614-0668-6_6
26. Role of Nickel in Plant Culture, T. Buechel, Promix Website, November, 2021, https://www.pthorticulture.com/en/training-center/role-of-nickel-in-plant-culture/
27. How To Use Silica To Grow Healthier Cannabis Plants, Marijuana Growing Forum, Royal Queen Seeds, https://www.royalqueenseeds.com/blog-using-silicon-supplements-to-cultivate-healthier-cannabis-plants-n199
28. Toxicity of formulants and heavy metals in glyphosate- based herbicides and other pesticides, N. Defarge, J. Spiroux de Vendômoisb, G. E. Séralinia, Toxicology Reports Volume 5, 2018, 56-163, https://doi.org/10.1016/j.toxrep.2017.12.025
29. Hexavalent Chromium, The National Institute for Occupational Safety and Health (NIOSH), https://www.cdc.gov/niosh/topics/hexchrom/default.html
30. America’s Clean Water Crisis Goes Far Beyond Flint. There’s No Relief in Sight. J. Moorland, Time Magazine, Feb 20, 2020, https://time.com/longform/clean-water-access-united-states/
31. Flint Drinking Water Response, EPA Continues to Oversee State and City Action to Protect Public Health, The U.S. Environmental Protection Agency (EPA), https://www.epa.gov/flint
32. Learn about Lead: Factsheet about the hazards of lead paint, The U.S. Environmental Protection Agency (EPA), https://www.epa.gov/lead/learn-about-lead
33. Influence of Flue Gas Desulfurization Gypsum Amendments on Heavy Metal Distribution in Reclaimed Sodic Soils, Q. Chan et. al., Environmental Engineering Science. 1; 32(6): 470–478, June 2015, https://pubmed.ncbi.nlm.nih.gov/26064038/