Virtually Safe Dose

To convert to a dose or concentration of aniline that would cause an excess cancer risk of 10-4 (a virtually safe dose), the risk is divided by the slope factor dose=risk/slope... 

To convert a 70-y exposure to a 24-h exposure, the virtually safe dose is multiplied by the number of days in 70 yr ... 

Risk oflxlO-4=(lxlO-4/l)xl mg/m3=lxl0-4 mg/m3 (virtually safe dose). 

The estimates of the parameters, qj and qi, are used to provide estimates either of the risks associated with specific doses, or conversely the dose associated with a specific increase in risk. The risk associated with a one in a million, 10 , extra lifetime incidence of cancer in the experimental species can be related to the dose this dose is often referred to as the Virtually Safe Dose (VSD). 

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... 

FIGURE 1.4 Illustration of range extrapolation from laboratory animal data (left) to potential responses in humans (right) and the influence of the extrapolation model on the choice of the virtual safe dose. 

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 EPA has established63 a virtually safe dose of 0.006 pg TEQ kg 1 d1, which represents one excess cancer in a million in exposure population. Many European countries use the World Health Organization value of 10 pg kg 1 d 1 Tolerable Daily Intake (TDI). US daily intake of PCDD/Fs by the general population (1.8 pg TEQ kg 1 d1) greatly exceeds the EPA s virtually safe dose, but falls within the World Health Organization TDI. 

Gaylor, D.W., and L.S. Gold. 1995. Quick estimate of the regulatory virtually safe dose based on the maximum tolerated dose for rodent bioassays. Regul. Toxicol. Pharmacol. 22 57-63. 

The various ways that the dose-response relationship may be portrayed includes the simple, intuitive concept of a virtually safe dose . This has its roots in the portrayal of what is termed the margin of exposure , a concept itself derived from the pharmaceutical industry when portraying to the physician the ratio between the amount of a drug that produces a harmful effect and that which produces the desired beneficial one. 

States Environmental Protection Agency, realizing that small amounts of dioxins are found ubiquitously (especially in food), has established a virtually safe dose for these chemicals. This dose is the dioxin level that is assumed to cause cancer in only one out of one million exposed persons. The caveat to the latter is that dose results from an upper bound estimate of cancer potency and the probability of cancer for the exposed population may be far less, or, in fact, zero. 

Virtually Safe Dose (VSD), Pages 445-446, Stephen M. DiZio SummaryPlus Full Text + Links PDF (53 K)... 

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. 

Once the BMD is identified, the one-sided lower 95th confidence interval on the BMD called the BMDL (benchmark dose lower bound) is used as the POD. Similar to noncancer risk assessment, the POD is then divided by uncertainty factors to account for potential interspecies differences, intraindividual variability, and so on. The current risk assessment paradigm has accepted that, by accounting for uncertainty through use of the BMDL and other uncertainty factors, the resulting dose is either below a toxic threshold or so low as to constitute a virtually safe dose (Bogdanffy et al. 2001). 

The high to low dose extrapolation problem is conceptually straight-forward. The probability of a toxic response is modeled by a dose-response function P(D) which represents the probability of a toxic response when exposed to D units of the toxic agent. A general mathematical model is chosen to describe this functional relationship, its unknown parameters are estimated from the available data, and this estimated dose-response function P(D) is then used to either (1) estimate the response measure at a particular low dose level of interest or (2) estimate that dose level corresponding to a desired low level of response (this dose estimate is commonly known as the virtually safe dose, VSD). 

Table IV. Cougarison of Virtually Safe Doses (VSD) Leading to an Excess Risk of 10 for Various Dose-Response Extrapolation Models (models applied to data from (41)...

Table VI. Virtually Safe Doses (VSD) for 2-AAF Based Multistage and Log Normal Models Applied To Different Dose Level Combinations...

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... 

This question of whether it is scientifically valid to derive the lifetime control limit by using threshold or non-threshold models defines what cleanup levels are proposed for a site. The action level proposed by CDC for residential soil in Missouri is 1 ppb, based on a series of exposure assumptions and on virtually safe doses for 10"° cancer risk of 0.0276 pg/kg/day (U). If one assumes a different threshold - based model, as did Dutch, Swiss, German, and Canadian workers (9), one obtains maximum allowable daily intake of 1-10 pg/kg/day. If one uses the same exposure calculations as CDC, one could then accept 4-40 ppb in residential soil according to these allowable daily intakes. CDC and ERA have allowed 7 ppb as acceptable residual concentrations at an industrial site in New Jersey (IJ). At Seveso, cleanup levels were set at 45 ppt for nonagricultural soil and 7 ppt for agricultural soil... 

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