Safety factor approach

This step utilizes either a safety factor approach or various extrapolation models. 

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 ... 

Ito et al. (1995) examined the combined dietary administration to rats of 19 organophosphate pesticides and 1 organochlorine pesticide, aU permitted for use in Japan, each at its ADI level. The dietary exposure at this level did not enhance the development of diethyl nitrosamine initiated pre-neoplastic lesions whereas at 100 times the ADI, the number and area of lesions were increased. The authors concluded that the study provided direct support for the present use of the safety factor approach in the quantitative hazard evaluation of pesticides. 

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. 

Safety factor approach for chemicals that cause deterministic effects. Traditional toxicologic procedures for chemicals that can induce deterministic effects, which are assumed to have a threshold dose, define RfD for humans or animals as some fraction of NOAEL. This fraction is determined by establishing safety factors to account for weaknesses and uncertainties in the data and in the extrapolation from animals to humans. In the safety factor approach, doses below RfD are assumed not to result in a response because they are below the threshold of toxicity (Dourson and Stara, 1983 Renwick and Lazarus, 1998 Weil, 1972). 

Clausen, J., Hansson, S.O. and Nilsson, F. (2006) Generalizing the safety factor approach. 

It appears, then, that some modification in the "NOEL-safety factor approach is in order. There are difficulties that must be overcome before we can arrive at suitable alternative methods but it is time to begin to move away from the concept that toxicologists can decide what is "safe by simply selecting arbitrary "safety factors". We need to find ways to use the dose-response information in establishing ADIs, and also to distinguish explicitly the scientific aspects of these types of analyses from the policy aspects. 

All in all, it would seem that the safety factor approach has served us well and is amply conservative. Why should anybody consider changing it ... 

The next question to be addressed was that of the mathematical model to be used for the extrapolation. Most particularly, would one model do for all effects or was more than one required This is obviously particularly a problem with cancer. Various models have been proposed for cancer, but there has been little consideration of the use of dose/response extrapolation for effects other than cancer the safety factor approach is assumed adequate. For reasons given above, the Committee did not agree. 

The traditional method, used widely in nutrition, pharmacology, and toxicology, is to assume the equivalence between species of doses expressed as milligrams of test substance per kilogram of body weight. This method was adhered to by the Scientific Committee of the Food Safety Council and is implicit also in the traditional safety factor approach. 

As early as 1981, Rodricks (72) suggested that in light of TCDD s lack of genotoxicity, the safety factor approach would be appropriate for setting an acceptable daily intake (ADI) using this approach, he calculated a 10 pg/kg/day figure. More recently, the Province of Ontario and several Western European countries, as well as European scientists, have estimated TCDD risk to humans that Is significantly less than EPA s estimate. 

In these courses, the stability analyses are carried out using both global safety factors and the partial safety factors approach from Eurocode 7 (EN 1997-1 2004). 

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