100-Fold safety factor

Historically, the so-called safety factor approach was introduced in the United States in the mid-1950s in response to the legislative needs in the area of the safety of chemical food additives (Lehman and Fitzhugh 1954). This approach proposed that a safe level of chemical food additives could be derived from a chronic NOAEL from animal studies divided by a 100-fold safety factor. The 100-fold safety factor as proposed by Lehman and Fitzhugh was based on a limited analysis of subchronic/chronic data on fluorine and arsenic in rats, dogs, and humans, and also on the assumption that the human population as a whole is heterogeneous. Initially, Lehman and Fitzhugh reasoned that the safety factor of 100 accounted for several areas of uncertainty ... 

The 100-fold safety factor has traditionally been interpreted as the product of two factors with default values of 10. For example, according to WHO/IPCS (1987), the safety factor is intended to provide an adequate Margin of Safety (MOS) by assuming that the human being is 10 times more sensitive than the test animal and that the difference of sensitivity within the human population is in a 10-fold range. 

The safety factor Itself may vary, depending upon the nature of the test data available and on other Judgmental factors. When long-term animal studies are available, the 100-fold safety factor generally Is applied. The food additive procedural regulations (21-CFR 170.22) refer to a safety factor of 100 to 1 in applying animal test data to humans. Exceptions to the 100-fold safety factor may be allowed for certain substances and under certain circumstances of use for example, in the case of micronutrients or macronutrients, or when information on dose-response effects in humans Is available. 

Use of an extra tenfold safety factor in addition to the traditional 100-fold safety factor, unless, on the basis of reliable data, a different factor is determined to be safe for children. 

The recent data on the oral toxicity of PTX-2, -11, and -2 seco acid allow comment on the acute reference doses of these compounds and hence tolerable levels for their presence in shellfish. No effects were recorded with any of these compounds after admiiustration to mice by gavage at 5000 Tg/kg. The lethal dose of these compounds is therefore greater than 5000 [tg/kg. Application of the standard 100-fold safety factor [63] gives a dose of >50 [ig/kg as a predicted non toxic acute dose for a human. This equates to >3000 Tg for a 60 kg adult, and if a shellfish intake of 380 g in a single meal is assumed, the predicted safe level in shellfish is >7.9 mg/kg. 

The CVMP and the FEEDAP calculated an ADI of 0.003 mg/kg bw for monensin, based on the NOEL of 0.345 mg/kg bw/day for inotropy in dogs and the NOEL of 0.3 mg/kg bw/day for maternal toxicity in a rabbit developmental toxicity study. JECFA noted the cardiovascular effects in dogs, but did not consider them to be adverse. " Instead, JECFA calculated an ADI of 0.01 mg/kg bw by applying a 100-fold safety factor to the NOEL of 1.14mg/kgbw/day for decreased bodyweight gain in a two-year rat dietary study. 

Acute in vitro MIC (minimum inhibitory concentration) data were submitted for effects of narasin on a range of bacteria, but FEEDAP did not use these data in their calculation of the ADI. The JECFA " noted that there was no need to calculate a microbiological ADI as a faecal-binding study showed that most of the narasin in the gut is bound and inactive. In addition there is no risk of selection of resistance to antibiotics that are important for human medicine. Both FEEDAP and JECFA " calculated an ADI of 0.5mg/kgbw/day by applying a 100-fold safety factor to the NOEL of 0.5mg/kgbw/day from the one-year dog study. 

An added ten-fold safety factor shall be added in setting pesticide reference doses (RfDs) (i.e. acceptable daily intakes) to account for the unique risks faced by infants and children, unless the EPA administrator has solid data supporting a determination that existing RfDs are fully health protective, even for infants and that exposures are fully and accurately characterized and... 

Humans are more sensitive chan the test animals, so caution is required in extrapolating animal data to humans. The authors estimated a 6,650-fold safety factor between the EC50 for these threshold values and the CS concentration likely to cause the least detectable corneal damage in the human eye. 

Health and Welfare Canada calculated a value of 0.02 mg/kg/day or 700 /zg/L by using 90 mg/kg/day as the minimum effect dose from the National Cancer Institute bioassay in the rat and applying a 5000-fold safety factor (40). 

The most recent USEPA dietary assessment for atrazine used 1.8mg/kg (chronic NOAEL from a 6-month rat study) with a 1000-fold safety factor (cRfD = 0.0018mg/kg/day). This analysis also confirmed that potential dietary exposure for all exposed population subgroups was less than 1% of the cRfD (USEPA, 2003). 

This protein has a billion-fold safety factor for humans and is acceptable for engineering into plants for insect control. The Farm Chemicals Handbook contains this statement about the B.t. toxin "Harmless to humans, animals and useful insects. Safe for the environment. Exempt from requirements for a tolerance on all raw agricultural commodities when applied to growing crops, for both preharvest and postharvest uses" (8). 

A 1000-fold safety factor for infants and children As children grow rapidly, their brains and organs are forming, and they eat more for their size than do adults. Therefore, the addition of a 10-fold safety factor is needed to ensure the health of infants and children. 

The Food Quality Protection Act of 1996 mandated USA EPA to "upgrade its risk assessment process as part of the tolerance setting procedures" (3), The changes to risk assessment were based in part on recommendations from the National Academy of Sciences report (22), The act required an explicit determination that tolerances were safe to children. US EPA was required to use an extra 10-fold safety factor to take into account both pre-/post natal developmental toxicity and the completeness of the database, unless US EPA determined, based on reliable data, that a different margin would be safe. In addition, US EPA must consider available information on 1/ aggregate exposure from all non-occupational sources 2/ effects of cumulative exposure to the pesticide plus others with a common mechanism of toxicity 3/ effects of in utero exposure 4/ the potential for endocrine disrupting effects. 

The CVMP had concerns over the paucity of data on metabolism in rats and chickens, so it applied a 200-fold safety factor to the NOEL of... 

Commercially available clear sihcas typically have tensile strengths of 50—70 MPa (7,250—10,150 psi) and compressive strengths of 500—1900 MPa (72,500—275,500 psi). The opaque sihcas have tensile strengths of 5—50 MPa (725—7250 psi) and compressive strengths of 190—300 MPa (27,550—43,500 psi) (162). Safety factors of 10—20-fold are usually employed when developing stmctural elements made of vitreous sihca. 

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