Virtually safe dose determination

In the dose-response assessment to determine a dosage that is risk-free for human health, the JFCFA has never used mathematical models to extrapolate risks at low dose and determine a virtually safe dose, on the grounds that the lack of validation would produce very different results. However, the IFCFA could usefully address this matter in its deliberations. When progress in this area permits selection from various validated models, this exercise should no longer be solely associated with risk assessment but will also incorporate an element of risk management. 

Carcinogenic, non-threshold chemicals will be considered differently from noncarcino-genic chemicals, which is considered to have no threshold. In the case of carcinogens, a virtually safe dose (VSD) may be determined. 

In traditional toxicological methods of determining virtually safe doses of hazardous chemicals, nominal thresholds for deterministic responses in humans are estimated based on a NOAEL obtained in human or animal studies. In most high-quality studies, NOAEL is approximately the same as the lower confidence limit of the benchmark dose that corresponds to a 10 percent increase in the number of responses. Thus, as an alternative to the benchmark dose method, the nominal threshold in humans could be set at a factor of 10 or 100 lower than NOAEL obtained in a high-quality human or animal study. However, the benchmark dose method preferred by NCRP... 

Virtually safe dose (VSD) The dose of chemical corresponding to the level of risk determined and accepted by regulatory agencies the dose-to-risk relationship is based on a chemical dose-response curve. 

The European Union (Commission Directive 93/67/EEC, Article 3, paragraph 1 repealed) and WHO (1994) have used the NOAEL/uncertainty factor approach for nongenotoxic carcinogens that are believed to have an effect threshold (WHO 1994). Eor genotoxic carcinogens, however, the regulatory default is applied that is based on the assumption that if one hit could cause a mutation and eventually result in cancer, then any exposure level could be associated with a finite cancer probability. Under such circumstances, a mathematical model (that quantitatively describes the relation between dose [exposure] and cancer [probability]) would be required to determine a virtually safe dose (VSD), a dose associated with an insignificantly small cancer risk. The choice of the model has an impact on risk predictions, because it usually involves extrapolation to low doses for which no data may be available, and has remained controversial. 

If a compound gives a carcinogenic response in the bioassay, the multistage model is used to determine the level of insignificant risk which is considered to be 1 in 1 million (4). The mathematically derived value is called the Sq or virtually safe dose. The Sq value is multiplied by consumption factors as described above after it is multiplied by 3 to convert the value to the meat portion of man s diet... 

---