What data is needed to prepare an occupational health categorization report?
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An occupational health categorization (OHC) request is typically for a compound that is in an earlier stage of development. As such, it is expected that there will be gaps in the available toxicology data. However, it is important to recognize that the more missing data the greater the uncertainty in assigning a control band, and the more conservative the toxicologist needs to be in order to protect worker health. This naturally results in a higher control band assignment.
What data should be supplied to the toxicologist for an OHC assessment and what is the impact of different data types?
The ideal answer is that the occupational toxicologist should be provided with all available toxicology data. Original reports are not necessary, in fact submittal of dozens of reports is not helpful, but clear and complete summaries of study findings facilitate the process and avoids unnecessary back-and-forth questioning. If an investigator’s brochure (IB) is available, there is a good chance that the IB will contain the needed information. The reality is that often clients do not share all the available data with the contract development and manufacturing organization (CDMO). This is unfortunate as this can stand in the way of setting the correct band and a band that is too high is not only too conservative, but expensive for all concerned.
Clearly identify your compound! It is very important to clearly identify your compound.
The client may have changed the name of your compound during development, or you may have in-licensed it from another company and assigned a new designation to the compound. In order to avoid costly confusion as we evaluate the data on the compound, we are dependent on you to provide us with this information.
What toxicology information in particular can influence the control band assignment?
Genotoxicity Information: Genotoxicity is one of the first pieces of information that we look for in determining a control band. Genotoxic compounds can result in cancer and birth defects. Without genotoxicity information, the assumption is that the compound could be genotoxic and that immediately contributes to a higher band. Sometimes in the early stages, only a screening Ames study will have been performed. Ultimately, almost every pharmaceutical will need to have genotoxicity information available and, except for special cases, no pharmaceutical company wants to discover they have a genotoxic compound late in development. Should no genotoxicity information be available, with a chemical structure and for an additional fee, the occupational toxicologists at Affygility Solutions can perform an in silico prediction of whether or not the compound is expected to be genotoxic. In some cases, this can help guide our classification.
Mechanism of Action: The mechanism of action is what the compound is designed to do. For some therapeutic approaches there are known hazards. For example, an anti-androgen, which is a treatment for prostate cancer, will have both reproductive (sterilization) and developmental effects that the OHC needs to be protective for just by virtue of what it is designed to do. Even at an early stage, all clients will know what are the intended biological targets and effects.
Oral Dosing Studies in Animals: These studies will most likely be in rats, but may include dogs, rabbits or monkeys as a compound goes forward in development, and the duration can vary from a single dose to determine the median lethal dose (LD50) to 90 days with daily dosing or beyond. The purpose of the OHC is to protect worker health; workers who may be repeatedly exposed over a long period. Therefore, the longer the animal study, the more relevant the information is to determining the OHC. The single dose LD50 is not considered useful for establishing an OHC, while a 90-day study can be very informative. We are interested in no observed effect levels (NOEL) or no observed adverse effect levels (NOAEL). Pharmaceuticals are all designed to have effects on humans, but we don’t want the pharmaceutical to have any effect on a healthy worker. Sometimes we are provided maximum tolerated doses (MTD). These are commonly determined in pharmaceutical development but are of little value for the OHC determination. Remember, we want to be at no effect levels for workers; not anywhere near what can be maximally tolerated. Sometimes all that is available is the lowest observed effect level (LOEL). While this data point is not ideal, but can be used, but the occupational toxicologist will need to apply an additional uncertainty factor to extrapolate a LOEL to NOEL. In all cases, we want to know what the adverse effect was that established the NOEL/NOAEL as this tells us what is the origin of toxicity.
Cancer and Developmental/Reproductive Effects: Since these studies are long in duration and expensive, it is unlikely that this information will be available for an early stage compound. When a compound is known to not be genotoxic, the concern regarding cancer is reduced. These factors are, however, typical unknowns for compounds requesting OHCs.
Sensitization: Sensitization is an allergic response and one that is unique to individuals and has the potential to be severe. Once sensitized to a compound it is permanent. For early stage compounds, it is unlikely that sensitization information will be available for a compound. However, if the client is aware that their compound has sensitization potential, it is important that they reveal this information.
Bioavailability: Most drugs are targeted for oral delivery and therefore have a reasonable bioavailability. In establishing an OHC, often the occupational toxicologists have to consider toxicology results from oral dosing. However, in a manufacturing setting, the most likely route of occupational exposure is inhalation. The standard assumption is that inhalation bioavailability is 100%. This is conservative, but widely practiced. If the oral bioavailability is low, an adjustment may result that could affect the OHC.
Metabolic Clearance: It is important that any worker exposure be cleared from their system by the time they return to work the following day. If the compound has a long metabolic half-life, an adjustment may need to be made to the OHC to ensure that there is not an ever-increasing systemic accumulation to the worker throughout the week.
What about toxicology information on similar structures? The problem with information on “similar structures” is that everyone has a different definition of similar. For some, it’s the second compound that we have been working on against the same target, for others there are details about the chemical structure that determine similarity. However one defines similar, it is well known that small structural changes in a molecule can result in significant differences in toxicology. So, how is it possible to use information on a similar compound? Toxicologists look for what are called bridging studies. When both compounds have been in the same types of studies (e.g., both in 28-day oral studies in the rat) and show similar results (e.g., similar NOELs), an ever-increasing case can be made for the compounds being similar in their toxicologies. With enough bridges, one can comfortably build a scientific-based case that it is likely that the two compounds will behave similarly. This supports the suggestion that the new compound will behave like the more mature derivative did in studies that have yet to be performed.
Completion of accurate onboarding questionnaires
Finally, it is common practice that environmental, health, and safety (EHS) groups at CDMOs will have on-boarding questionnaires that clients are required to completed prior to working on a compound. It is important that your client complete these documents accurately – unknown is a completely acceptable answer. Clients should not check boxes corresponding to hazards in an attempt to be conservative if the client doesn’t have evidence to support that the hazard do, indeed, exist. The occupational toxicologist will need to assume that the client knows that these hazards are associated with the compound and that may inappropriately raise its classification.
Conclusion
Always remember, accurate, complete toxicology information provided up front allows for an efficient and appropriate OHC determination that will protect worker health. As always, the experts at Affygility Solutions are here to support your OHC needs and are always available to address your questions along the way.
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