The use of safety factors

Uncertainty is introduced at many stages in the sizing of pressure relief systems for runaway chemical reactions, and the application of a safety factor to offset this uncertainty may be appropriate. This Annex gives some guidance on the selection of an appropriate value for any safety factor. 

The chosen safety factor may be applied to increase the calculated relief area. Alternatively, the value of the required mass relief rate from the reactor may be multiplied by the safety factor before calculation of the relief area required to pass this flowrate. 

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Gaylor, D.W. 1983. The use of safety factors for controlling risk. J. Toxicol. Environ. Health 11 (3) 329-336. 

In 1954, the Food and Drug Administration published a paper that defined the basis for the acceptable daily intake (ADI). The ADI was a threshold for intake of a chemical for a large population, below which there should be no significant toxic risks. The paper not only defined a procedure for the ADI, but also described the use of safety factors and how animal data could be used to estimate risk to humans. A no effect level was determined from animal studies and a safety factor of 100 was used to establish a safe level. Tolerances for chemical additives and pesticides were calculated, comparing the safe level to the residue concentration of these chemicals in crops (e.g., wheat) and that crop s contribution to the individual s daily diet. 

No. The fit factors of 100 and 500 only define what fit factor is necessary to pass the fit test. The preamble states that the standard incorporates a safety factor of ten because protection factors in the workplace tend to be much lower than the fit factors achieved during fit testing. The use of a safety factor is a standard practice supported by most experts to offset this limitation. The use of safety factors of ten is recommended by a number of experts and is included in the ANSI standard for respiratory protection. 

The 1997 consultation addressed the topic of safety factors, which is vitally important for die protection of public health. Setting MRLs is in fact based on a series of assumptions. One assumption is that humans are at least as sensitive as the most sensitive laboratory animal to a potentially toxic residue. Another assumption is diat all the residues covered by the MRLs are as toxic as the parent substance. A third assumption is that residues free from the human gastrointestinal tract are all totally bioavailable. A fourth assumption is the safety factor used to infer an ADI from a NOEL, including the additional safety factor, generally with a value of 2, to establish a provisional ADI until further information is available to convert this into a definite ADI. Other assumptions are the overestimation of consumer exposure to drug residues and the reduction of MRL values to take account of normal conditions under which the veterinary drugs are administered. 

Differences in MRL/tolerances more often reflect differences in the use of that compound in a particular country, or in the choice of safety factors, food consumption values, or the analyte used in monitoring programs. The United States will, but does not always, assign tolerances when preslaughter drug withdrawal period is zero. Generally, the European Union assigns an MRL even when withdrawal periods are not required. 

The original use of the safety factor approach in regulation was by Lehman and Fitzhugh (13), who considered that animals may be more resistant to the toxic effects of some chemicals than humans are. They proposed the use of a factor of 10 when extrapolating from animals to humans and the use of another factor of 10 to account for differential sensitivities within the human population (13). These are not, however, rigid rules, and they should be applied with a strong infusion of scientific judgment. 

While simpler methods are useful for understanding the key effects involved, rigorous methods are recommended for final designs. This subsection also discusses the range of safety factors that are required if simpler methods are used. 

There are two possible approaches to estimating the human safe dose for chemicals that cause deterministic effects the use of safety and uncertainty factors and mathematical modeling. The former constitutes the traditional approach to dose-response assessment for chemicals that induce deterministic effects. Biologically-based mathematical modeling approaches that more realistically predict the responses to such chemicals, while newer and not used as widely, hold promise to provide better extrapolations of the dose-response relationship below the lowest dose tested. 

A third important assumption relates to selecting the critical response. EPA assumes that if the dose is below that required to cause the most sensitive response, then other deterministic responses will not occur. However, if other responses have shallower slopes in the dose-response curves near their thresholds, estimating RfD on the basis of the critical response may not be sufficiently protective to preclude a noncritical response from occurring. For this reason, EPA may use information on the slopes of dose-response curves to determine the critical response and the number of safety factors to be applied, although EPA rarely does so. 

Although dose-response assessments for deterministic and stochastic effects are discussed separately in this Report, it should be appreciated that many of the concepts discussed in Section 3.2.1.2 for substances that cause deterministic effects apply to substances that cause stochastic effects as well. The processes of hazard identification, including identification of the critical response, and development of data on dose-response based on studies in humans or animals are common to both types of substances. Based on the dose-response data, a NOAEL or a LOAEL can be established based on the limited ability of any study to detect statistically significant increases in responses in exposed populations compared with controls, even though the dose-response relationship is assumed not to have a threshold. Because of the assumed form of the dose-response relationship, however, NOAEL or LOAEL is not normally used as a point of departure to establish safe levels of exposure to substances causing stochastic effects. This is in contrast to the common practice for substances causing deterministic effects of establishing safe levels of exposure, such as RfDs, based on NOAEL or LOAEL (or the benchmark dose) and the use of safety and uncertainty factors. 

In general design work, the magnitudes of safety factors are dictated by economic or market considerations, the accuracy of the design data and calculations, potential changes in the operating performance, background information -available on the overall process, and the amount of conservatism used in... 

The European-Commission definition of the precautionary principle should be distinguished from the use of uncertainty factors during risk assessment or margins of safety during risk management46 [255]. Assessment factors account for assumptions made during the risk assessment process, such as when deriving no-effect levels. 

When levels of safety for risk management measures do not adequately cover variations in the use of assessment factors or differences in anticipated exposure levels in risk assessment data (see also [477])... 

In estimating the cumulative risk of a chemical in LCA, dose-response extrapolations can be based on toxicological benchmarks. Such a benchmark approach is considered more appropriate for use in comparative assessment contexts, such as in an LCA study. Benchmarks are an exposure measure associated with a consistent change in response, such as the 10% or even the 50% effect level. Regulatory-based measures do not necessarily provide a consistent risk basis for comparison, as they were often never developed for use in such a comparative context or to facilitate low dose-response extrapolation. Other data differences include the use of median, rather than extreme, data in the fate and exposure modeling, as well as the consideration of safety factors only as part of the uncertainty assessment and not as an integral part of the toxicological effects data. 

As with MAK values, BAT values are established on the assumption that persons are exposed at work for at most 8 h daily and 40 h weekly. BAT values established on this basis may also be applied without the use of correction factors to other patterns of working hours. BAT values can be defined as concentrations or rates of formation or excretion (quantity per unit time). BAT values are conceived as ceiling values for healthy individuals. They are generally established for blood and/or urine and take into account the effects of the substances and an appropriate safety margin, being based on occupational medical and toxicological criteria for the prevention of adverse effects on health. 

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