Reference-Dose Calculation

Benchmark dose (BMD). The BMD is used as an alternative to the NOAEL for reference dose calculations. The dose response is modeled and the lower confidence bound for a dose at a specified response level is calculated. For a further description, see the section on BMD calculation. 

Models for transport distinguish between the unsaturated zone and the saturated zone, that below the water table. There the underground water moves slowly through the sod or rock according to porosity and gradient, or the extent of fractures. A retardation effect slows the motion of contaminant by large factors in the case of heavy metals. For low level waste, a variety of dose calculations are made for direct and indirect human body uptake of water. Performance assessment methodology is described in Reference 22. 

For each clironic exposure padiway (i.e., seven years to lifetime exposure), calculate a sepmate clironic hazard index from die rados of the clironic daily intake (GDI) to die clironic reference dose (RfD) for individual chemicals as described below ... 

The purpose of this chapter is not to discuss the merits, or lack thereof, of using plasma cholinesterase inhibition as an adverse effect in quantitative risk assessments for chlorpyrifos or other organophosphate pesticides. A number of regulatory agencies consider the inhibition of plasma cholinesterase to be an indicator of exposure, not of toxicity. The U.S. Environmental Protection Agency, at this point, continues to use this effect as the basis for calculating the reference doses for chlorpyrifos, and it is thus used here for assessing risks. 

In the case of noncarcinogenic substances, there exists a threshold this is an exposure with a dose below which there would not be adverse effect on the population that is exposed. This is the reference dose (RfD), and it is defined as the daily exposure of a human population without appreciable effects during a lifetime. The RfD value is calculated by dividing the no observed effect level (NOEL) by uncertainty factors. When NOEL is unknown, the lowest observed effect level (LOEL) is used. NOEL and LOEL are usually obtained in animal studies. The main uncertainty factor, usually tenfold, used to calculate the RfD are the following the variations in interspecies (from animal test to human), presence of sensitive individuals (child and old people), extrapolation from subchronic to chronic, and the use of LOEL instead of NOEL. Noncancer risk is assessed through the comparison of the dose exposed calculated in the exposure assessment and the RfD. The quotient between both, called in some studies as hazard quotient, is commonly calculated (Eq. 2). According to this equation, population with quotient >1 will be at risk to develop some specific effect related to the contaminant of concern. 

The range of doses calculated when only basal cells are assumed at risk is also shown in Figure 5. For unattached daughters, doses are approximately one half and for attached daughters three quarters of values derived by averaging over all cells. These doses are to be compared with the range derived by the NEA (NEA, 1983). The reference values recommended by the NEA and adopted by UNSCEAR (UNSCEAR, 1982) lie at the bottom of the range of doses to basal cells derived here. 

First, the procedure now used by the EPA for inhalation data differs from what we have described above, in that the ten-fold factor for interspecies extrapolation (animal-to-human) is dropped in favor of a specific model that describes the well-known physiological differences between animals and humans that affect the relative rates of movement of a given administered dose of a chemical in the respiratory tracts of animals and humans. These physiological models provide fairly accurate predictions of the relative doses of chemicals delivered into the respiratory regions of animals and humans who have received identical administered (inhaled) doses. The estimate of delivered dose offers a well-accepted scientific approach to at least part of the problem of interspecies differences. Details of the delivered dose calculations are beyond the scope of this book (see references in Sources and recommended reading). 

The more classical approach to assess the presence of marine biotoxins in seafood is the in vivo mouse bioassay. It is based on the administration of suspicious extracted shellfish samples to mice, the evaluation of the lethal dose and the toxicity calculation according to reference dose response curves, established with reference material. It provides an indication about the overall toxicity of the sample, as it is not able to differentiate among individual toxins. This is a laborious and time-consuming procedure the accuracy is poor, it is nonspecific and generally not acceptably robust. Moreover, the mouse bioassay suffers from ethical implications and it is in conflict with the EU Directive 86/609 on the Protection of Laboratory Animals. Despite the drawbacks, this bioassay is still the method of reference for almost all types of marine toxins, and is the official method for PSP toxins. 

Table 4 Estimated daily intakes (EDI) of phthalates based on the geometric mean values for urinary metabolites estimated by David [137] for CDC data measured in 289 US individuals [138] and the tolerable daily intake (TDI) values calculated by EFSA [62], CSTEE [134], and MHLW [68], as well as the reference dose of phthalates (RfD) calculated by EPA [136] (in pg/kg b.w./day)...

The POD is used as the starting point for subsequent extrapolations and analyses. For linear extrapolation, the POD is used to calculate a slope factor, and for nonlinear extrapolation the POD is used in the calculation of a Reference Dose (RfD) or Reference Concentration (RfC). In a risk characterization, the POD is part of the determination of an MOE, defined as the ratio of the POD over an exposure estimate (MOE = POD/Exposure). 

The ERA has calculated a subchronic oral reference dose (RfD) of 7x10 mg/kg/day for carblon tetrachloride based on a NOAEL of 1 mg/kg/day (converted to 0.71 mg/kg/day based on intermittent exposure) for rats in a 12-week study (Bruckner et al. 1986 ERA 1989b IRIS 1993). The critical effect was liver toxicity. A chronic oral RfD of 7x10 mg/kg/day was also calculated based on the same NOAEL used for the subchronic RfD. The ATSDR has calculated an acute inhalation MRL of 0.2 ppm based on a LOAEL of 50 ppm for liver effects in an acute 4-day rat inhalation study (David et al. 1981), and an intermediate inhalation MRL of 0.05 ppm based on a NOAEL of 5 ppm for liver effects in an intermediate-duration (187-192 days) inhalation study in rats (Adams et al. 1952). The ATSDR has also calculated an acute oral MRL of 0.02 mg/kg/day based on a LOAEL of 5 mg/kg/day over 10 days for liver effects in the rat (Smialowicz et al. 1991), and an intermediate oral MRL of 0.007 mg/kg/day based on a NOAEL of 1 mg/kg/day over 12 weeks (converted to 0.71 mg/kg/day based on intermittent exposure) for liver effects in the rat (Bruckner et al. 1986). 

The oral reference dose (RfD) for nickel is 0.02 mg/kg/day (IRIS 1996). The RfD is based on the 5-mg-nickel/kg/day NOAEL identified in the Ambrose et al. (1976) 2-year study in rats. The effect level in this study was 50 mg/kg/day, a dose associated with changes in body and organ weights. The RfD was calculated using an uncertainty factor of 300 (10 for interspecies extrapolation, 10 to protect sensitive individuals, and 3 to account for inadequacies in reproductive studies) (Ambrose et al. 1976 RTT 1988a, 1988b). EPA (IRIS 1996) states that the RfD is at a level that will not sensitize individuals to nickel, but that it may not protect individuals who are already sensitized to nickel. 

The NOAEL, LOAEL or BMD approach can be used to calculate a guidance or reference level of exposure below which no adverse effects above background would be expected. These guidance levels include reference dose (RfD), acceptable daily intake (ADI) and tolerable daily intake (TDI). 

NOAEL (or LOAEL if NOAEL is not available) is used as a point of departure to calculate a reference dose (RfD), which is the highest dose of the chemical at which no statistically significant adverse effects are expected in the most sensitive humans. RfD of a particular substance is calculated from NOAEL (or LOAEL) by applying one or more safety and uncertainty factors. RfD usually is 100 to 1,000 times lower than NOAEL or 1,000 to 10,000 times lower than... 

Due to the high doses necessary for acute effects as observed in short-term toxicity tests and to the lack of effects seen at earlier time-points in long-term studies, only chronic reference doses are used in conjunction with exposure for the calculation of triazine dietary risk. Therefore, the remainder of this discussion is limited to chronic exposure and risk. 

For the final assessment of risk, we can then assess the exposure against a maximum permissible risk (i.e., the reference dose) to calculate a critical soil concentration associated with the exposure scenario (Figure 5.7). This information can then... 

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

The U.S. Environmental Protection Agency (EPA) has slightly modified the ADI approach and it calculates a reference dose (RfD) as the acceptable safety level for chronic non-carcinogenic and developmental effects. Similarly the ATSDR (Agency for Toxic Substances and Disease Registry) calculates minimal risk levels (MRLs) for non-cancer endpoints. 

Non-carcinogenic risk is normally characterized in terms of a hazard index defined by the ratio of the estimated intake dose from exposure to the reference dose (RfD). Reference doses depend on the exposure route and may be used with its exposure data. The hazard index is calculated as... 

Most chemicals do not cause toxic or adverse effects until a certain dose has been given. These are called threshold chemicals. The lowest dose level at which there are no adverse effects observed in the test animals is called the No Observed Adverse Effect Level (NOAEL) and is the starting point for the calculation of the reference dose. While the terminology used may differ among regulatory agencies, the concepts are similar. In North America, the term margin of safety or exposure is used, whereas in Europe an Acceptable Operator Exposure Level (AOEL) is used. Care is taken to choose the NOAEL for an effect which is relevant to humans and that the duration, frequency and route of exposure in the test animals are relevant to the human exposure. 

The next step is to calculate a reference dose (RfD) by dividing the NOAEL by the safety or uncertainty factors appropriate for the pesticide under review. Additional safety factors can be used for severity of the toxicological effect, if sensitive sub-populations such as children are likely to be exposed to the pesticide and if there are scientific uncertainties in the data. This approach is used for establishing the risk from exposure to threshold chemicals. 

When in situ dosing onto two different samples of Pt/silica (45, 48) and onto Cu/MgO was used (49), no evidence for spillover was found from NMR. Only one detailed study based on fully relaxed spectra led to observation of a non zero spillover (4T). In a Ru/Si02 catalyst, the silanol protons w ere exchanged for deuterons, the sam.ple was evacuated at 623 K, and a reference NMR spectrum w as taken at room, temperature. The sample was then exposed to 20 Torr of H2, an NMR spectrum was taken, and the difference with respect to the reference was calculated (line in Fig. 14). This represents the sum of reversible and irreversible hydrogen on the metal (resonating at -65 ppm) and spilled over on the support (at about 3 ppm). Then the sample was pumped out at room temperature for 10 min, and again a difference spectrum with the reference state was obtained (dashed line in Fig. 14) this represents irreversible hydrogen both on the support and on the metal. Similar in situ NMR techniques were used... 

The Environmental Protection Agency (Cincinnati, OH, USA) reported investigations regarding the health effects of antimony and its compounds. The conclusion of the report is as follows Oral reference dose values (RfDo) were derived for antimony and selected compounds based on the LOAEL (lowest-observed-adverse-effect-level) for antimony of 350/zgkg" day" associated with potassium antimony tartrate (15) in the drinking water of rats for lifetime exposure. Reduced lifespan was observed in both sexes and altered blood biochemical characters in males. The only concentration tested was of 5 ppm antimony. RfDo values for antimony of 24.5/ig dayfor antimony potassium tartrate of 65.5 fig day and for antimony tri-, tetra- and pentoxides of 29.3, 30.9 and 32.5 /igday" respectively, were calculated. It should be noted that orally administered antimony has been inadequately tested for carcinogenicity. 

---