Comparison of Studies for Use in Risk Assessment

Cicmanec JL. 1996. Comparison of four human studies of perinatal exposure to methylmercury for use in risk assessment. Toxicol 111(1-3) 157-162. 

In estimating the cumulative risk of a chemical in LCA, dose-response extrapolations can be based on toxicological benchmarks. Such a benchmark approach is considered more appropriate for use in comparative assessment contexts, such as in an LCA study. Benchmarks are an exposure measure associated with a consistent change in response, such as the 10% or even the 50% effect level. Regulatory-based measures do not necessarily provide a consistent risk basis for comparison, as they were often never developed for use in such a comparative context or to facilitate low dose-response extrapolation. Other data differences include the use of median, rather than extreme, data in the fate and exposure modeling, as well as the consideration of safety factors only as part of the uncertainty assessment and not as an integral part of the toxicological effects data. 

Validation of the Model. Outputs from the various models were compared to observations of blood concentrations reported from studies of oral gavage or intravenous exposures of rats to di- -butyl phthalate (NIEHS 1994, 1995). Based on the comparisons of model outputs to observed time courses for blood mono- -butyl phthalate concentrations from NIEHS (1994, 1995), Keys et al. (2000) concluded that the diffusion-limited, pH-trapping model more closely represents the empirical data. However, it is difficult to interpret this finding if the same data were used in the model optimization (see Table 4 of Keys et al. 2000). The diffusion-limited, pH-trapping model simulated reasonably well the time courses for blood concentrations of mono- -butyl phthalate reported by NIEHS (1994, 1995). A log-likelihood ratio test was used to compare the fit of the various augmented models to that of the flow-limited model. The diffusion-limited, pH-trapping model gave a better statistical fit to the empirical data than the other four models, with the next best fit achieved with enterohepatic circulation model. However, the latter model appeared to underestimate peak mono- -butyl phthalate plasma concentrations, which would be an important limitation for its use in risk assessment. 

The 1996 Food Quality Protection Act (FQPA) now requires that an additional safety factor of 10 be used in the risk assessment of pesticides to ensure the safety of infants and children, unless the EPA can show that an adequate margin of safety is assured with out it (Scheuplein, 2000). The rational behind this additional safety factor is that infants and children have different dietary consumption patterns than adults and infants, and children are more susceptible to toxicants than adults. We do know from pharmacokinetics studies with various human pharmaceuticals that drug elimination is slower in infants up to 6 months of age than in adults, and therefore the potential exists for greater tissue concentrations and vulnerability for neonatal and postnatal effects. Based on these observations, the US EPA supports a default safety factor greater or less than 10, which may be used on the basis of reliable data. However, there are few scientific data from humans or animals that permit comparisons of sensitivities of children and adults, but there are some examples, such as lead, where children are the more sensitive population. It some cases qualitative differences in age-related susceptibility are small beyond 6 months of age, and quantitative differences in toxicity between children and adults can sometimes be less than a factor of 2 or 3. 

For the interpretation of monitoring results in general two approaches might be used (i) the comparison with a reference values obtained from representative studies and (ii) a risk assessment methodology related to the hazard of the compound. The latter results in guideline values. 

The primary motivation of PSAs is to assess the risk of the plant to the public. The immediate purpose of the RSS was to support the Price-Anderson hearings on liability insurance (i.e., assess the financial exposure of a nuclear power reactor operator) a purpose which, even today, is beyond PSA technology. However, PSA is sufficiently precise to provide relative risk comparisons of reactor designs and sites. These uses of PSA were presented at the Indian Point hearings, and in defense of Shoreham. The PSAs for the high-population-zone plants (Limerick, Zion, and Indian Point) were prepared to show that specific features of these plants compensate for the higher population density relative to plants studied in the RSS. 

Limited excretion data are available in humans receiving 2-hexanone via inhalation, oral, and dermal exposure, in dogs via inhalation exposure, and in rats via oral exposure (DiVincenzo et al. 1977, 1978). However, human data on excretion of 2-hexanone via feces are not available, and the available information in dogs concerns excretion via exhaled breath only. In these and any other studies, information on all routes of excretion would help to evaluate the potential for 2-hexanone clearance in the exposed species. Excretion data in rats receiving 2-hexanone via inhalation and dermal application and in other species receiving 2-hexanone via all three routes would be useful for comparison with the human data and to assess the comparative risks of exposure by each route. In addition, information on excretion rates in each species via each route would be helpful in understanding how long 2-hexanone and its metabolites may persist in the body. 

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