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Currently in the life cycle of the cannabis industry, it is not obvious where the heavy metal regulatory landscape will end up. Clearly, the big four are not enough, but what is a realistic panel that reflects the real world of cannabinoid production?
The lack of federal oversight with regard to heavy metals in consumer cannabis products in the US has left individual states to regulate its use. Cannabis is legal in 37 states, while 18 states and Washington, D.C. allow its use for adult recreational consumption (1). However, the cannabis plant is known to be a hyper-accumulator of heavy metals in the soil, so it is critical to monitor levels of elemental contaminants to ensure cannabis products are safe to use. Unfortunately, there are many inconsistencies with heavy metal limits in different states where cannabis is legal. The vast majority of these states define the “big four” heavy metals as lead (Pb), arsenic (As), cadmium (Cd), and mercury (Hg). New York State also requires the testing for chromium (Cr), nickel (Ni), copper (Cu), antimony (Sb), and zinc (Zn), while Michigan requires inorganic As (not total) and also adds Cr, Ni, and Cu to the big four. Maryland and a few other states also include Cr as well as the big four. Some states base their limits directly in the cannabis, while others are related to human consumption per day. Others take into consideration the body weight of the consumer, while some states do not even have heavy metal limits. To complicate the situation, certain states only require heavy metals in the cannabis plant or flower, while some give different limits for the delivery method such as oral, inhalation, or transdermal (2).
These inconsistencies and the fractured nature of state-based limits would make it extremely complicated to implement at the federal level unless there was a completely fresh assessment of the regulations. For example, why does New York State currently have action limits for nine elemental contaminants whereas the vast majority of the other states only require the big four. In other words, what do New York regulators know about the toxicological impact of the five additional elements, compared to say California that only regulates four. Or why does Michigan require inorganic arsenic (iAs) while every other state just lists total arsenic. Furthermore, how can some states justify no heavy metal action limits at all? It might all become a moot point when federal regulators have oversight of the industry, but what will that regulatory panel look like? The disparity in state-based limits can be a good indicator, but there might also be clues in the way federally approved cannabidiol (CBD) drug formulations have historically been regulated, together with an understanding of how national standards and testing organizations have approached writing standardized methods and the development of reference materials.
To highlight the disparity between state-based limits and federal guidelines for pharmaceutical formulations, the Food and Drug Administration’s (FDA) Botanical Review Team in the Office of New Drug Products recently publisheda study entitled “Quality Standards in State Programs Permitting Cannabis for Medical Uses,” which compared the maximum allowable limits of the big four heavy metals for states that had medical cannabis programs (MCP) with United States Pharmacopeia USP Chapter <232> permitted daily exposure (PDE) concentrations in inhalation and oral drug formulations (3). Although the actual states are not mentioned, it can be seen from Table I that in the majority of cases, the eight medical programs reported are very different to the USP limits. In fact, it can be seen by the data in red that they are significantly higher than the federal limits.
There is no obvious reason as to why the state programs action limits are so different, but the researchers’ overall conclusion was three-fold:
Clearly, there is a need for more consistency across state lines, particularly as the industry inevitably moves in the direction of federal oversight. This is further compounded by the fact that there is compelling evidence in the public domain that only monitoring the big four heavy metals is not enough to ensure consumer safety. But how many metals should there be in an expanded panel, particularly as there is no comprehensive understanding of the sources of elemental contaminants in the cannabinoid production processes. Moreover, besides the big four, there is no consensus on the toxicity impact of other heavy metals in cannabis and hemp, as there have been no risk studies carried out regarding heavy metal contaminants and for that reason, consumer health is likely being compromised.
At a recent American Society for Testing and Materials (ASTM) workshop dedicated to the measurement of heavy metals in cannabis and hemp consumer products, compelling evidence was presented by several researchers that suggested 10–15 elemental contaminants are worthy of consideration (4). Moreover, the National Institute of Standards and Technology (NIST) is developing a 13-toxic element hemp certified reference material (CRM) through its Cannabis Quality Assurance Program (CannaQAP) to include Pb, Cd, As, Hg, beryllium (Be), cobalt (Co), Cr, manganese (Mn), molybdenum (Mo), Ni, selenium (Se), uranium (U), and vanadium (V) (5). In addition, ASTM International’s D37 Cannabis Committee has recently developed and approved a standardized inductively coupled plasma-mass spectrometry (ICP-MS) method for up to 24 different elemental contaminants in cannabis. As a result, it is going to offer testing laboratories the flexibility to select the heavy metals that are important in their jurisdiction and, in particular, to encourage state regulators to expand the panel beyond the big four to those additional metals that are worthy of regulatory scrutiny.
The only solid evidence we have at this current time for what could be a federally regulated panel is with the FDA approved CBD-based drug Epidiolex, which is available in the US to treat childhood seizures. Manufactured by UK-based GW Pharmaceuticals, it went through the regulatory process four years ago to get it approved in the US and had to show compliance by meeting PDE limits for up to 24 elemental impurities as defined in USP Chapter 232 (6) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3D guidelines (7).
Moreover, the USP recently published a draft monograph for CBD as an active pharmaceutical ingredient (API) for a federally approved drug formulations which stated that (8): “Elemental impurities in official drug products are controlled according to the principles defined and requirements specified in Elemental Impurities—Limits 232, as presented in the General Notices 5.60.30.”
In the long term, this could possibly indicate that the FDA will regulate CBD products for up to 24 elemental contaminants when it eventually has oversight of the cannabis industry. But more importantly, in the short term it implies that CBD being manufactured in the US for recreational or medicinal purposes does not meet the purity requirements for federally-approved drugs, because currently it only has to comply with the state’s maximum limits for heavy metal contaminants, which in most US states is typically only Pb, Cd, As, and Hg.
However, it’s important to stress that a panel generated by pharmaceutical regulators isn’t necessarily one that should be used by the cannabis industry, as the process for manufacturing cannabinoids is very different to drug products. At some point, the cannabis industry needs to carry out a comprehensive risk assessment study to provide evidence as to what metals are worthy of consideration similar to what the pharmaceutical regulators did to characterize elemental impurities in drug products and formulations (9). To better understand this risk assessment process and how it might have a bearing on a cannabis panel of heavy metal contaminants, let’s take a closer look at how pharmaceutical regulations for elemental impurities came into existence.
The pharmaceutical industry began the process to overhaul regulations and methodology for elemental impurities more than 20 years ago when it updated its 100-year-old semi-quantitative sulfide precipitation colorimetric test for a small suite of heavy metals to eventually arrive at a method to monitor 24 elemental impurities in drug products using plasma spectrochemistry. Moreover, they completely reassessed the toxicological impact of these elemental contaminants based on well-established animal models and defined them by PDE limits according to the mode of administration (oral, parenteral, inhalation, and transdermal) and classified them by toxicity and the probability of finding them in the drug manufacturing process.
These limits were described in USP 232 - Elemental Impurities (6) together with ICH Q3D Guidelines (7). While the measurement procedures were defined in USP Chapter 233 which describes the plasma spectrochemistry methodology (inductively coupled plasma-optical emission spectrometry [ICP-OES] or ICP-MS), a microwave digestion procedure, and a full set of validation protocols (10). Table II represents the full list of USP and ICH elemental PDE limits in microgram per day (µg/day) per delivery method and toxicological classification, which are explained in greater detail in Table III.
It’s also important to emphasize that the data in Table II are maximum limits per day. So, for a suggested daily dosage of 10 g, these limits should be divided by 10 to calculate the maximum allowable limits in the drug products in microgram per gram (µg/g). However, even though 10 g is a typical maximum dosage for drugs, we have no way of knowing in what quantities consumers use cannabis products. So, if larger quantities are being consumed these PDE limits will be even lower. Furthermore, the mode of administration will also impact the regulated limit, so inhalation PDEs in most cases are significantly lower than the oral ones. In addition, the classification number will impact the frequency of testing with the Class 1 and 2A metals of higher priority that the Class 2B and 3 metals. In fact, the classification can offer clues as to what elements from this list would be worthy of consideration for an expanded panel to regulate cannabis and hemp consumer products. For example, Class 1 and 2A would warrant inclusion in any regulated panel, whereas Class 2B metals would likely not be required at all, because they are not used in the manufacturing process. On the other hand, Class 3 metals may not be required for oral products but would be required for inhalation products such as vaping devices.
Currently in the life cycle of the cannabis industry, it is not obvious where the heavy metal regulatory landscape will end up. Clearly, the big four are not enough, but what is a realistic panel that reflects the real world of cannabinoid production? New York and Michigan states are leading the charge with an additional five and four metals respectively, with a few other states like Maryland and Missouri adding chromium to the big four. But it’s clear from the recent study carried out by the FDA’s Botanical Review Team that they view the efforts of the states to regulate heavy metals as being inadequate. However, recent activity from the USP has sent signals to the industry that if they want to produce CBD as an API for use as a federally approved drug formulation, they are going to have to monitor up to 24 elemental contaminants to meet the quality attributes. And it’s encouraging that standards organizations are developing standardized methods to meet these demands with NIST developing a 13-toxic element hemp CRM and ASTM approving an ICP-MS method for up to 24 different elemental contaminants in a wide variety of cannabis and hemp related samples. The evidence is clearly going in that direction, and it should be only a matter of time before the industry moves beyond the big four and has an expanded regulated panel that is more in line with the pharmaceutical industry, and better reflects consumer safety concerns.
Robert (Rob) Thomas is the principal of Scientific Solutions, an educational consulting company that serves the needs of the trace element user community. He has worked in the field of atomic and mass spectroscopy for almost 50 years, including 24 years for a manufacturer of atomic spectroscopic instrumentation. He has served on the American Chemical Society (ACS) Committee on Analytical Reagents (CAR) for the past 20 years as leader of the plasma spectrochemistry, heavy metals task force, where he has worked very closely with the United States Pharmacopeia (USP) to align ACS heavy metal testing procedures with pharmaceutical guidelines. Rob has written more than 100 technical publications, including a 15-part tutorial series on ICP-MS. He is also the editor and frequent contributor of the "Atomic Perspectives" column in Spectroscopy magazine, as well as serving on the editorial advisory board of Analytical Cannabis. In addition, Rob has authored five textbooks on the fundamental principles and applications of ICP-MS. His most recent book is a new paperback version of Measuring Heavy Metal Contaminants in Cannabis and Hemp published in December, 2021. Rob has an advanced degree in analytical chemistry from the University of Wales, UK, and is also a Fellow of the Royal Society of Chemistry (FRSC) and a Chartered Chemist (CChem).
R. Thomas, Cannabis Science and Technology® Vol. 5(9), 12-17 (2022).