Slope Factor Using Animal Data

Use of the 95 percent UCL vcdue means that the actual potency of a chemiccd is likely to be lower than or equcd to the vcdue 95 percent of the time. In only five of one hundred cases would the potency of the chemical be underestimated. In this way, use of the slope factor will usually lead to cm overestimation of the true cancer potency of a chemical, cissuming the LMS model accurately captures the shape of the dose-response curve at low doses. The 95UCL in this example is shown as the dotted line on figure 7.3. 

The slope of the 95UCL curve is then used by the U.S. ERA as the slope factor to set safe concentrations for hnman exposure. 

So far, we have discussed various aspects of toxicology. This discipline identifies the manner in which chemicals exert toxicity, and the potency of chemicals of various species. The majority of toxicology studies are conducted under controlled conditions in the laboratory. This is necessary to establish cause and effect relationships and to develop dose-response information on specific chemicals. However, as discussed in the last chapter, humans are not typically exposed to concentrations tested in these laboratory studies. We learned about the uncertainty in trying to extrapolate toxicity information to humans or other species. In spite of this uncertainty, we are ultimately concerned with the potential impact of chemicals released into the environment. This issue concerns all of us because of the myriad ways we might interact with these chemicals. They can be present in our water, air, soil, or food. Estimating the likelihood of toxicity from exposure to chemicals in the environment is the focus of the discipline of risk assessment. 

The same is true for chemicals. There is a risk of toxicity from exposure to any amount of a chemical. This risk might be so large that we can be fairly certain toxicity would result (e.g., carbon monoxide poisoning from running your car in an enclosed space for a long period of time), or so small that it is essentially unmeasurable (e.g., one molecule of toluene in a reservoir). Part of the risk assessment discipline is to identify what risk is small enough that we can ignore it. We will discuss this in more detail in chapter 9. 

There are occasional accidental releases of chemicals into air from industrial plants (e.g., oil refineries). Under what circumstances should we be concerned for our health when releases occur What about industrial accidents (e.g., oil spills, train accidents, and spillage) How much chemical needs to be released in such an accident to impact health  

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Figure 7.3. Development of a Slope Factor Using Animal Data...

Table 8.5 Selected potencies, or cancer slope factors, used by the US EPAd For those based on animal data, the potencies include a factor for interspecies scaling (see text)...

Because the slope factor is often an upper 95 percentile confidence limit of the probability of response based on experimental animal data used in tlie multistage model, tlie carcinogenic risk estimate will generally be an upper-bound estimate. Tliis means tliat tlie EPA is reasonably confident tliat tlie true risk will not exceed the risk estimate derived tlirough use of tliis model and is likely to be less than tliat predicted. 

No studies were located regarding cancer incidence in animals after inhalation exposure to hexachloroethane. EPA has derived an inhalation unit risk (cancer slope factor) of 1.4x102 (mg/kg/day) 1 for hexachloroethane (IRIS 1995). This inhalation unit risk was calculated using data from oral studies (see Section 2.2.2.8) and Figure 2-2. 

Some aspects of degree of concern currently can be considered in a quantitative evaluation. For example, EPA considers human and animal data in the process of calculating the RfD, and these data are used as the critical effect when they indicate that developmental effects are the most sensitive endpoints. When a complete database is not available, a database UF is recommended to account for inadequate or missing data. The dose-response nature of the data is considered to an extent in the RfD process, especially when the BMD approach is used to model data and to estimate a low level of response however, there is no approach for including concerns about the slope of the dose-response curve. Because concerns about the slope of the dose-response curve are related to some extent to human exposure estimates, this issue must be considered in risk characterization. (If the MOE is small and the slope of the dose-response curve is very steep, there could be residual uncertainties that must be dealt with to account for the concern that even a small increase in exposure could result in a marked increase in response.) On the other hand, a very shallow slope could be a concern even with a large MOE, because definition of the true biological threshold will be more difficult and an additional factor might be needed to ensure that the RfD is below that threshold. 

The estimated comparative carcinogenic potency can be used to derive a slope factor (SF) or qi for sulfur mustard. The slope factor converts the estimated daily intake averaged over a lifetime exposure to incremental risk of an individual developing cancer. Because the slope factor is an upper 95th percentile confidence limit on the probability of response based on experimental animal data, the carcinogenic risk will generally be an upper-bound estimate. 

In the past, due to lack of knowledge regarding cancer potency at low concentrations, a conservative model has been used to identify slope factors from high dose data in animals. 

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