Uncertainty and safety factors

OCCUPATIONAL AND RESIDENTIAL RISK ASSESSMENT 371 AOELs Versus MOEs 371 Route Considerations 372 Uncertainty and Safety Factor Selection 372 Aggregation and Cumulative Risk Assessment 372 CO-OPERATIVE REGULATORY ACTIVITIES 373 SUMMARY AND CONCLUSIONS 374 Terminology 374 Framework 374 Data Requirements 374 Methodological Guidance 375 Development and Utility of Databases 375 Modeling Initiatives 375 Data Analysis 375 Metric Selection 376 Research Needs 376 Exposure Mitigation 376 Risk Assessment 376 REFERENCES 376... 

Differences in approaches to application of uncertainty and safety factors can lead to divergent regulatory decisions. 

There are differences as to how safety factors greater than 100 are applied to risk assessment for workers. Some regulatory authorities (e.g. Canada) apply additional uncertainty and safety factors when conducting occupational risk assessments. Other jurisdictions (e.g. the USA) do not. Such divergent approaches can lead to different risk assessment outcomes. Consistent approaches to application of uncertainty and safety factors would greatly facilitate harmonization. 

Consistent approaches to application of uncertainty and safety factors. 

Federal agencies such as the FDA and EPA require a battery of toxicity tests in laboratory animals to determine an additive s or a pesticide s potential for causing adverse health effects, such as cancer, birth defects, and adverse effects on the nervous system or other organs. Tests are conducted for both short-term (acute) and long-term (chronic) toxicity. For chronic effects other than cancer, laboratory animals are exposed to different doses to determine the level at which no adverse effects occur. This level is divided by an uncertainty or safety factor (usually 100) to account for the uncertainty of extrapolating from laboratory animals to humans and for individual human differences in... 

In 1988, the US-EPA adopted the ADI approach in its regulatory measures against environmental pollution with a number of modifications (US-EPA 1988, 1993). Instead of the terms ADI and safety factor, the terms Reference Dose (RfD) and uncertainty factor (UF), respectively, were selected. The RfD is derived from the NOAEL by dividing by the overall UF. The overall UF originally suggested and reconfirmed in 2002 (US-EPA 2002) generally consists of a 10-fold factor for each of the following ... 

Screening assessments incorporate variability and uncertainty implicitly, by using worst-case assumptions and safety factors. As mentioned earlier, these have rarely been based on a quantitative analysis and may not take account of the full range of uncertainties, so in principle they should be reviewed to determine whether they provide adequate margins of safety. 

Because of the first of these uncertainties (the extrapolation across species), assessments of risks to human health apply an uncertainty or safety factor of 100 to the experimentally derived no observed adverse effect concentration (NOAEC), in other words the NOAEC is divided by 100 to derive a no-effect level for human toxicity. This factor has been used since 1961, when it was chosen on an essentially arbitrary basis (RCEP, 2003, p22). In the assessment of risks to the environment, application factors of 10, 50, 100 or 1000 are applied to the results of tests carried out on specific species,2 depending on the species used and whether the tests were long term or short term. Evidence to the Royal Commission on Environmental Pollution (RCEP) for their report Chemicals in products indicated that these are merely extrapolation factors — they express the statistical variability of test results but do not effectively take into account inter-species variability, the vulnerability of threatened species, lifetime exposures or the complexity of biological systems... 

Another interesting aspect of differences in the documentation is the use of uncertainty or safety factors. These are commonly used in food safety and environmental risk assessment, but customarily not used when deriving occupational exposure limits. A study of the margins of safety used in OELs comprising 14 substances and 45 OELs and the documentation for these only found four instances where explicit safety or uncertainty factors had been used (Schenk, 2010). Two of these instances concerned p-dichlorobenzene making this substance rather unique. The documentations in question are from the EU and France. The magnitude of the uncertainty factors differs between them the EU applied a factor of 10 and France a factor of hundred. But this is again explainable by the different severity of the concluded critical effects (Table 9.6). 

Health organizations throughout the world utilize a safe dose concept in the dose-response assessment of noncancer toxicity. This safe dose has often been referred to by different names, such as acceptable daily intake (ADI), tolerable daily intake (TDI) or tolerable concentration (TC), minimal risk level (MRL), reference dose (RfD), and reference concentration (RfC). The approaches used by various health organizations share many of the same underlying assumptions, judgments on critical effect, and choices of uncertainty (or safety) factors. 

Scientists then determine the appropriate uncertainty (or safety) factors to apply to the no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) for the critical effect, based on considerations of the available toxicity, toxicodynamic, and toxicokinetic data. Uncertainty factors (UFs) used in the estimation of safe doses are necessary reductions to account for the lack of data and inherent uncertainty in these extrapolations. Other areas of uncertainty include extrapolations of subchronic-to-chronic exposure, LOAEL to NOAEL, and use of an incomplete database. The major assumptions underlying each of these UFs are described in Table 1. 

Chemical analyses should be provided for all anodes used in the offshore and harbor area, together with results for current content in A h kg and current output in amperes [2,3]. The geometric shape and the number of anodes required is determined by these parameters. Expensive calculations for design based on grounding resistances are made only in exceptional cases because in practice there are too many uncertainties and the number and mass of the anodes have to be quoted with a corresponding safety factor. 

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

Toxicologists tend to focus their attention primarily on c.xtrapolations from cancer bioassays. However, tlicrc is also a need to evaluate the risks of lower doses to see how they affect the various organs and systems in the body. Many scientific papers focused on tlic use of a safety factor or uncertainty factor approach, since all adverse effects other than cancer and mutation-based dcvclopmcnUil effects are believed to have a tlu cshold i.e., a dose below which no adverse effect should occur. Several researchers have discussed various approaches to setting acceptable daily intakes or exposure limits for developmental and reproductive toxicants. It is Uiought Uiat an acceptable limit of exposure could be determined using cancer models, but today tliey arc considered inappropriate because of tlircsholds. ... 

As with any engineering design, the ET cover should be designed with safety factors because both design and construction introduce uncertainty regarding performance. Some safety factor concerns are similar between ET covers and conventional covers. However, control of water flow into the waste requires new safety factor considerations for the ET cover, including the following ... 

Uncertainty is a factor in all of the impacts associated with TSCA. It was seen that it is a source of unnecessary resource diversion and toxicological testing. How much of a factor it becomes is a matter for debate. It can be said that for an industry such as coatings polymers, it is related to the company s commitment to safe and healthful products in the absence of TSCA. The more of a safety and health commitment that existed pre-TSCA, in that innovation was strongly linked to such concerns, the less uncertainty is going to be a significant impact. 

A governing principle of pharmaceutical safety assessment is the determination of safety factors the ratio between the therapeutic dose (that which achieves the desired therapeutic effect) and the highest dose which evokes no toxicity. This grows yet more complex (but has less uncertainty) if one bases these ratios on plasma levels rather than administered doses. Traditionally based on beliefs as to differences of species sensitivity, it has been held that a minimum of a five-fold (5X) safety factor should be observed based on toxicity findings in nonrodents and a ten-fold (10X) based on rodents. 

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