From my perspective, most OELs are set these days by taking a No Observed Adverse Effect Level in a repeat dose toxicology study (NOAEL or NOEL) and dividing it by an uncertainty or safety factor (SF). Last week’s blog was about NOELs. This week it is about uncertainty/safety factors.
As we discussed last week, NOELs are in reality typically frank effect levels for the adverse health effects from exposure. The portion of any tested animal population having a frank ill effect from a NOEL exposure has been shown to range from 2-21% depending on the experimental design and shape of the dose-response curve. Assuming people are as sensitive as rodents, an exposed population of 100,000 workers and a 2-21% response results in 2,000-21,000 workers whose health has been adversely effected by exposure to the NOEL. Clearly, the NOEL would not make a good OEL and some adjustment needs to be made. Thus, an uncertainty or safety factor is applied to bring the OEL down to be a fraction of the NOEL.
Various schemes have been forwarded to size these factors. A paper is available online that does a reasonable job of providing the details and the references for the standard OEL/Safety Factor approach written in 2000 by Dr. Robert H. Ku, Ph.D.,CIH.: http://www.safebridge.com/pdf_docs/overview_of_setting_oel.pdf
Here is an excerpt from that paper dealing specifically with safety factors:
The number and magnitude of these safety factors depend on the quality of the data. In general, some of these safety factors may include: (1) a factor from 1 to 10 for animal-to human (interspecies) extrapolation (if the NOEL is based on animal data), (2) a factor from 1 to 10 for human-to-human intraspecies variability in response, (3) a factor from 1 to 10 to consider study duration (a long-term study being more helpful than a short-term study), (4) a factor to consider the persistence of the drug in the body (or elimination half-life), and (5) a factor to accommodate for absorption efficiency by different routes of exposure.
Thus, it appears that the overall safety factor can range from close to 1 to a factor larger than 1000. In my experience, they typically come out to be significantly less than 100.
As a range, I have seen safety factors as low as 3 for fully reversible, local tissue irritation response effects and greater than 1000 when considering highly uncertain data for a dreaded health effect (i.e., cancer).
From viewing it for many years, my sense is that the entire process is somewhat subjective and, in my estimation, to a certain degree driven by the practical ability to control the exposure at whatever limit is decided upon.
Indeed, one of the pioneers in our field, Dr. Stanley Roach along with his coauthor Dr. Stephen Rappaport published a paper on this subject in 1990. The title of this paper and its reference: But they are not thresholds: A critical analysis of the documentation of threshold limit values, American Journal of Industrial Medicine, Volume 17, Issue 6, pages 727–753, 1990.
Their primary observations and conclusion:
• “Upon analysis it was found that, where the exposure was at or below the TLV, only a minority of studies showed no adverse effects (11 instances) and the remainder indicated that up to 100% of those exposed had been affected (8 instances of 100%)”
• “…a surprisingly strong correlation was found between the TLVs and the (workplace) exposures reported in the corresponding studies cited in the Documentation [of the TLVs](emphasis added).”
Perhaps a new study should be done to see how much this situation has changed in the last 24 years.
That fact remains, however, that in most cases the size of the safety factors are driven by guidelines and are not subject to stringent rules. We are often advised that this is necessary to allow for “professional judgment”. I think we can all see how such a subjective system can potentially lead to somewhat unconscious bias in which the resulting OELs might become strongly correlated with workplace exposures as the study by Drs. Roach and Rappaport found.
In recent years there has been a scheme to strictly apply safety factors to toxicology data put forward by the REACh regulations in Europe. This is done in the determination of the recently devised OEL class known as DNELs. In the interest of time and space I am not going into the details of the DNELs and the safety factors here but suffice it to say that the process in general has cause a lot of consternation primarily because of its prescriptive nature.
So where are we with all of this? My sense is that the current system is clearly in need of some improvement. The National Academy of Sciences seems to agree and has forwarded a rational modeling scheme for determining or estimating the amount of risk that exists at any exposure including the exposure limit for both carcinogens and non-carcinogens. This is Chapter 5 of the so called “Silver Book” which you can download for free (You can download just Chapter 5 or the entire book) at: http://www.nap.edu/download.php?record_id=12209
Even though this book has been out since 2009, the OEL setting community has not embraced the recommendations. Some folks in our community including this blogger are asserting that it should now become an increasingly prominent topic of discussion within our world.