Safety and Adjustment Factors

Double Duty Numbers

Ever since the concept was formally introduced to food safety in 1954, safety factors (or Uncertainty Factors as the EPA calls them) have played a dual role.  One has a scientific basis, the other does not.  The scientific role is to correct for known inaccuracies.  For example, began to answer the question “Why a Factor of Safety?, Lehman and Fitzhugh (1954) started with: “Animals for the most part are more resistant to toxic chemicals than man”.  The policy role is to add an element of precaution.  This notion is also given by Lehman and Fitzhugh in a concluding argument: “The application of simple statistical rules indicates that the probability of human injury decreases with each increase in the margin of safety”.  These two roles are separable, but in the Safety Assessment paradigm they usually are not.

However, the rationale for the original 100 fold safety factor was soon segregated into two factors of 10.  One safety factor  of 10 is to be applied when an ADI is based on studies with laboratory animals.  If an ADI or TDI is based on human data, as is often the case for contaminants, then the animal factor can be dispensed with.  The other factor of is intended to account for human variability.  Since naturally occurring chemicals that are judged under a standard where susceptible subpopulation don’t count, the difference between “ordinarily injurious” and “may be injurious” is often interpreted as a factor of 10. 

The EPA often uses additional Uncertainty Factors as well (Barnes and Dourson, 1988).  The two most common are an additional factor for generating a standard for chronic (long-term) exposure (i.e. an RfD) based on short-term data, and an additional factor when there are database deficiencies.  The latter factor is justified as a means of encouraging companies to provide better data; this justification clearly does not apply for chemical contaminants that have no sponsor.

Safety Factors are obviously somewhat arbitrary.  However, Dourson and Stara (1983) have argued that they are not.  Their argument was based on the distribution of empirical ratios for each factor (e.g. animal to human; long-term to short term) and nothing that a factor 10 generally was close a value that would be exceed less than 5% of the time.  But really, they just replaced one arbitrary number with another; the 5^th percentile is the 50^th percentile divided by 10.

A strategy that has been suggested (e.g. Barnes and Dourson, 1988; WHO, 2009) for adapting the Safety Assessment paradigm to non-premarket approval applications has been to dispense with the safety factors.  Known as the “Margin of Exposure” approach, the idea is to compare a NOAEL or BMD to an estimate of exposure, and to employ the resulting ratio as a measure of the hazard.  Although dispensing with the precaution may be a good idea, failing to adjust for known differences (e.g. between animals and humans) is not.

Adjustment Factors and the Human Equivalent Dose

Compared to a quantitative risk assessment, the main attraction of the safety assessment paradigm is that it both simple and transparent.  However, that doesn’t mean that safety factors can’t be subdivided into adjustment factors and precautionary factors.  An EPA methodology for replacing the animal-to-human uncertainty factor does exactly that.  Instead of applying a standard safety factor, a Human Equivalent Dose is estimated using a ¾ power body weight scaling factor that results in a species-specific adjustment to the traditional presumption that the dose is directly proportional to body weight (EPA, 2011).  As a result a larger factor is used to scale doses from smaller animals than larger animals.  For example, a typical scaling factor is 7.2 for a mouse study, 4.1 for a rat study, and 1.6 for a dog study will result.  As a precautionary measure, an additional factor of 3 is recommended as well.  This means that instead of a traditional safety factor of 10 for all species, an overall factor of about 22 for mice, 12 for rats, and 5 for dogs.

Turning Factors Into Distributions

Since replacing the NOAEL with a BMD is now widely accepted, a considerable amount of effort has been expended make the safety assessment process more like risk assessment by replacing safety factors with distributions.  This results in “harmonized paradigm” that lacks the simplicity of the safety assessment paradigm, but still presumes that the eventual goal of the analysis is to identify a safe or acceptable level of exposure.  There also has been an effort to turn safety factors into distributions instead of factors.  WHO (2014) gives a recent summary of this work.  In particular, uncertainty distributions for factors used to adjust for exposure duration, human equivalent doses, route of exposure, and human variability (a two dimensional distribution that includes both a population frequency dimension and an uncertainty dimension).  Most of these distributions could also be used for a true risk assessment, where the goal is to provide risk estimates, instead of just setting a level.

References

Barnes DG and Dourson ML (1988).  Reference Dose (RfD): Description and Use in Health Risk Assessments.  Regul Pharmacol Toxicol 8:471-486.  Also at http://www.epa.gov/IRIS/rfd.htm

Dourson, M.L. and J.F. Stara (1983). Regulatory Toxicology and Pharmacology 3: 224-238

Lehman AJ and Fitzhugh OG (1954).  100-Fold Margin of Safety.  Quarterly Bulletin of the Association of Food and Drug Officials 18:33-35.

US Environmental Protection Agency (2011).  Recommended Use of Body Weight 3/4 as the Default Method in Derivation of the Oral Reference Dose

World Health Organization (2010).  Principles and methods for the risk assessment of chemicals in food. Environmental Health Criteria 240.

World Health Organization (2014).   International Programme on Chemical Safety, Harmonization Project Document 11.  Guidance Document on Evaluating And Expressing Uncertainty in Hazard Characterization.  In particular, see Chapter 4.