Pharmacokinetics total human exposure

In the rat, testicularatrophy associated with 2,5-HD exposure can occur at cumulative exposure levels below those that produce clinical neurotoxicity. High-level exposure for relatively brief periods produced testicular injury without clinical evidence of distal polyneuropathy (28), whereas chronic low-level exposure produced clinical evidence of distal polyneuropathy without testicular injury (31). In fact, the testicular injury was dose-rate sensitive, whereas the extent of nervous system toxicity was related to the total dose over a range of dose-rates (22, 32). These tissue-selective pharmacokinetic effects may, in part, explain the predominance of neurotoxicity in human exposures to 2,5-HD precursors. In addition, the clinical manifestations of neurotoxicity are obvious, whereas those of testicular injury are subtle. 

Human populations are likely to be exposed to a pollutant through more than one exposure route at a time. Total exposure may combine intake through ingestion of different substances, dermal absorption from surface water and water supply, and inhalation at different locations in the study area (e.g., work, home, recreational areas, commuting routes). Calculation of total exposure requires that the pharmacokinetics (absorption, metabolism, storage, excretion) for different exposure routes are understood for the pollutant of concern. Otherwise, only exposures by route can be combined. 

Data adequacy The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study. ... 

Factors to account for various uncertainties are applied to the NOAEL, LOAEL, or BMD to derive a UEL. The total size of the uncertainty factor (UF) varies, accounting for assumed or known interspecies differences, variability within humans, quality and quantity of the data, consistency, slope of the dose-response curve, background incidence of the effects, and pharmacokinetic data. The relevance of the species, type of effect, dose, route, timing, and duration of exposure are additional factors that might influence its size. A discussion of UFs is provided in several papers (e.g., Lewis et al. 1990 Renwick 1991,1998 Dourson et al. 1996 Renwick and Lazarus 1998). 

In order to represent the total risk at low doses from several independent types of tumors, it is evidently necessary to separately determine the potency at each site and then use an appropriate procedure to add the individual potencies. A comparison of the results obtained by the approaches reviewed here is shown in Table 29.7. All the values shown are animal potency values (i.e., not corrected for human body weight or pharmacokinetics), using the rodent metabolized dose as the exposure metric, and were calculated as qf values (95% upper confidence limits) or qi (MLE)... 

The validity of the animal data addresses not only the accuracy of the findings but also the relevance of the experimental data for man. If comparative metabolic or pharmacokinetic studies reveal a quantitative difference between the test animal and human responses or routes of exposure, the findings may totally lack predictive value. Such studies are rarely performed because of the limitations imposed by time and funding thus there is usually no alternative but to err on the side of prudence and accept positive animal findings. Unless there is evidence to the contrary, a regulator has no choice but to assume that test animal data may be predictive of the response among at least some individuals in the heterogeneous human population. 

For dosimetry calculations, the concentrations of total radioactivity in rat tissues from a tissue distribution study are used as the basis for calculating the estimated radiation exposure in humans following a 100-p,Ci oral dose of [ C]-test article. Pharmacokinetic parameters generated by WinNonLin are transferred into Excel Version 8.0e (Microsoft Corporation) for calculation of human dosimetry parameters. 

Both of these approaches allow for assessment of systemic absorption by not conducting complete mass balance studies (e.g., expired air to catch absorbed compound metabolized to COj or HjO expired end products). In vivo dermal absorption studies not taking into account other routes of excretion must be interpreted with caution. One extension of this mass balance excretory analysis is to assess dermal absorption by only monitoring the primary excretory route for the compound studied. Dermal bioavailability has been assessed in exhaled breath using real-time ion trap mass spectrometry to track the uptake and ehmination of compounds (e.g., trichloroethylene) from dermal exposure in humans and rats (Poet et al., 2000). A physiologically based pharmacokinetic model can be used to estimate the total bioavailability of compoimds. The same approach was extended to determine the dermal uptake of volatile chemicals imder non-steady-state conditions using real-time breath analysis in rats, monkeys, and humans (Thrall et al., 2000). 

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