Cancer safety factor approach

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. 

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. ... 

Gaylor, D.W., R.L. Kodell, J.J. Chen, and D. Krewski. 1999. A unified approach to risk assessment for cancer and noncancer endpoints based on benchmark doses and uncertainty/safety factors. Regul. Toxicol. Pharmacol. 29 151-157. 

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. 

Application of this 1/100 safety factor to the NOAEL (1 ng/kg/day or 1000 pg/kg/day) defined in the lifetime rat study (30) that is considered most definitive by essentially all of the regulatory agencies was the basis for the Ontario MOE expert panel to recommend a Maximum Daily Intake for 2,3,7,8-TCDD (or its toxic equivalent of other chlorinated dioxins and furans) of 10 pg/kg B.W./day for humans (38). This more recent approach used by these four non-U.S. groups demonstrate the manner in which carcinogenicits based lifetime exposure control limit recommendations for humans can be realistically derived from the data available from the animal cancer bioassays when interpreted in concert with the data available regarding the likely mechanism of action by which the carcinogenic response occurred in the animal bioassays. 

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