Acceptable daily intake safety factor approach

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. ... 

In 1961, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint Meeting of Experts on Pesticides Residues (JMPR) adopted this approach in a slightly modified form The safe level was called the Acceptable Daily Intake (ADI) and expressed in mg/kg body weight per day (Vermeire et al. 1999, ECETOC 2003). Usually, a safety factor of 100 is used by JECFA and JMPR for establishing ADIs by this ADI approach however, the procedures adopted by JECFA and JMPR do not generate a clear justification for deviation from the factor of 100, but in some individual cases, an expert explanation is given for the use of factors other than 100 (Vermeire et al. 1999). 

There are of course many mathematically complex ways to perform a risk assessment, but first key questions about the biological data must be resolved. The most sensitive endpoint must be defined along with relevant toxicity and dose-response data. A standard risk assessment approach that is often used is the so-called divide by 10 rule . Dividing the dose by 10 applies a safety factor to ensure that even the most sensitive individuals are protected. Animal studies are typically used to establish a dose-response curve and the most sensitive endpoint. From the dose-response curve a NOAEL dose or no observed adverse effect level is derived. This is the dose at which there appears to be no adverse effects in the animal studies at a particular endpoint, which could be cancer, liver damage, or a neuro-behavioral effect. This dose is then divided by 10 if the animal data are in any way thought to be inadequate. For example, there may be a great deal of variability, or there were adverse effects at the lowest dose, or there were only tests of short-term exposure to the chemical. An additional factor of 10 is used when extrapolating from animals to humans. Last, a factor of 10 is used to account for variability in the human population or to account for sensitive individuals such as children or the elderly. The final number is the reference dose (RfD) or acceptable daily intake (ADI). This process is summarized below. 

The use of the terms upper bound and worst-case refer to the expectations that this approach is likely to be highly conservative and will not underestimate potential risk. These terms are not meant to connote that statistical analysis to estimate error bounds would be performed, or that additional safety factors (traditional for extrapolation to acceptable daily intake values for non-carcinogens) would be incorporated into the extrapolation. 

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. 

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. 

---