Toxicity reference dose derivation

The measure used to describe the potential for noncarcinogenic toxicity to occur in an individual is not expressed as tlie probability of an individual suffering an adverse effect. The EPA does not at tlie present time use a probabilistic approach to estimate tlie potential for noncarcinogenic healtli effects. Instead, tlie potential for non carcinogenic effects is evaluated by comparing an exposure level over a specified time period (e.g., lifetime) witli a reference dose derived for a similar exposure period. Tliis ratio of exposure to toxicity is called a liazard quotient and is described below. (The reader is referred to Chapter 11 for additional details on tlie material tliat follows). The noncancer liazard quotient assumes tliat tliere is a level of exposure (i.e., RfD) below which it is unlikely for even sensitive populations to experience adverse healtli effects. 

The potential for noncarcinogcnic health effects is evaluated by comparing iui exposure level over a specified lime period (c.g., lifetime) with a reference dose derived for a similar exposure period. The ratio of exposure to toxicity in called a liazard quotient and, when it is greater tlien unity tlierc is a higher level of concern for potential noncancer effects. 

The EPA has derived an oral reference dose (RfD) of 2.00x10 Vig/kg/day for mirex (IRIS 1994). The RfD is based on liver cytomegaly, fatty metamorphosis, angiectasis, and thyroid toxicity in rats (NTP 1990). No reference concentration is available for mirex. Neither a reference dose nor a reference concentration exist for chlordecone. 

SSLs are risk-based concentrations derived from standardized equations combining exposure information assumptions with US-EPA toxicity data. For the ingestion, dermal, and inhalation pathways, toxicity criteria are used to define an acceptable level of contamination in soil, based on a one-in-a-million (10 individual excess cancer risk for carcinogens and a Hazard Quotient (HQ) of 1 for noncarcinogens. The hazard quotient is defined as the ratio of an exposure estimate over the Reference Dose or Concentration (Section 5.1), i.e., HQ = Exposure/(RfD or RfC). 

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 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 use of increased mortality as the critical effect for derivation of a reference dose is not appropriate. Furthermore, the intragastric intubation technique used for rabbits in this study concentrates the test article on the gastric mucosa more effectively than simple gavage administration thereby making the apparent increased sensitivity of rabbits more an artifact of administration than acmal toxicodynamics. In the discussion of the study, Hackett et al. noted that the fetal toxicity observed in the rabbits appeared to be... 

The U.S. EPA has not adopted any Reference Doses for lewisite consequently, an RfD for lewisite will be derived using available data. No controlled studies are available that have evaluated the oral toxicity of lewisite in humans therefore, extrapolation from animal data is necessary. 

The existing methods available for scientifically defensible risk characterization are not yet ideal since each step has an associated uncertainty resulting from data limitation and incomplete knowledge on exact mechanism of action of the toxic chemical on the human body. For noncancer end points, safety factors or uncertainty factors are applied since these effects are assumed to have a threshold below which no adverse effect is expected to be observed. US EPA has used the concept of a reference concentration (RfC) to estimate acceptable daily human exposure from HAPs. The RfC was adapted for inhalation studies based on a reference dose (RfD) method previously used for oral exposure assessment. The derivation of the RfC differs from that for the RfD in the use of dosimetric adjustment to extrapolate the exposure concentration for animals to a human equivalent concentration. Both are estimates, with uncertainty spaiming perhaps an order of magnitude, of a daily exposure to the human population, including sensitive subgroups, which would be without appreciable risk of deleterious effects over a lifetime. 

The initial process in the application of toxicity (dose-response) data in risk assessment is the extrapolation of findings to establish acceptable levels (AL) of human exposure. These levels may be reference values (inhalation reference concentrations, RfC or oral reference doses, RfD), minimal risk levels (MRL) values, occupational exposure limits, and so on. When the toxicity data are derived from animals, the lowest dose representing the NOAEL (preferably) or the LOAEL defines the point of departure (POD). In setting human RfD, RfC, or MRL values, the POD requires several extrapolations (see [13] and revisions). Extrapolations are often made for interspecies differences, intraspecies variability, duration of exposure, and effect level. Each area is generally addressed by applying a respective uncertainty factor having a default value of 10 their multiplicative value is called the composite uncertainty factor (UF). The UF is mathematically combined with the dose at the POD to determine the reference value ... 

The purpose of this chapter is to present a summary of the findings of the committee concerning the health effects of methylmercury (MeHg), end points of toxicity, the critical studies, exposure and dose metrics, and sources of uncertainty that should be considered by EPA in deriving the reference dose (RfD). It includes a discussion of the relevant health end points and the scientific basis and public-health rationale for selecting neurotoxicity in children exposed in utero as the critical end point for the EPA RfD. 

An oral reference dose (RfD) of 0.1 mg/kg/day has been derived by EPA for carbon disulfide (IRIS 1995). The RfD is based on a NOAEL of 11 mg/kg/day carbon disulfide for fetal toxicity in rabbits following inhalation exposure (Hardin et al. 1981). An inhalation reference concentration (RfC) of 0.7 mg/m3 (0.2 ppm) was also derived for carbon disulfide (IRIS 1995). The RfC was based on a benchmark concentration (human-equivalent) of 19.7 mg/m3 (6.3 ppm) divided by an uncertainty factor of 30 (Johnson et al. 1983). 

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