Case study dose-response relationship

In particular, high-dose data usually cannot identify a threshold. A threshold is a dose or exposure below which there is no effect. It is often assumed that there is no threshold for an end point, like a gene mutation, that may involve one molecule of the toxicant and one target molecule in such a case, the dose-response relationship would be linear at low doses. If the observed relationship is linear over the dose range studied and if the fitted line is extrapolated to no effect (or the background frequency of effects) at zero dose, linear kinetics with no threshold are likely. But data are usually not clear. Even such a large carcinogenesis study as the EDqi study conducted by... 

Results from this extensive effects testing demonstrates that PDMS has a relatively low toxicity to freshwater, marine and terrestrial organisms. As a result, in most cases no dose/response relationships or toxicity differences between species exist. The toxicity test methods that most realistically simulate PDMS exposure in the environment produce the most reliable measure of potential PDMS environmental effects. For example, sediment-bound PDMS will be the primary route of exposure in the aquatic environment, because PDMS has not been measured in overlying water (due to its negligible water solubility and potential for sorption onto sediments). Therefore, studies in which PDMS was dosed as a component of sediment are the most realistic exposure... 

A retrospective case-control study conducted in humans compared spontaneous abortion rates among women who had been exposed occupationally or nonoccupationally to trichloroethylene and other solvents to rates among women without solvent exposure (Windham et al. 1991). The authors observed approximately three times the risk of spontaneous abortion with exposure to trichloroethylene. This risk increased further when women with less than a half hour of exposure to trichloroethylene each week were excluded from the analysis. However, a consistent dose-response relationship was not observed, and most of the women were exposed to a variety of solvents, not just trichloroethylene. 

In 1981, Lawson et al.,87 for example, compared a group of 210 women hospitalized for fibrocystic disease with 241 women who had breast cancer and were drawn from two ongoing studies in different countries. They matched each case to three female control patients on age, current smoking habits, country, and study. Recent coffee and tea consumption in cases and controls were compared and were shown to have a modest positive association with hot beverage consumption for both fibrocystic disease and breast cancer, but there was no dose-response relationship. The risk of fibrocystic disease associated with heavy consumption of hot beverages (7+ cups per day) vs. none was elevated but not statistically significant. 

Effect of Dose and Duration of Exposure on Toxicity. No studies were located where -hexane concentration was measured in workplace air before workers became ill, so no dose-response relationship can be defined for human neurotoxicity as the result of -hexane exposure. Information on duration of exposure leading to toxicity is available from some case series reports. An occupational exposure caused sensory disturbances in the lower extremities after approximately 2 months (Herskowitz et al. 1971). A case of peripheral neuropathy after 7 months of exposure was reported among press-proofing workers in Taipei (Wang et al. 1986) a serious case resulting in quadriplegia after 8 months of exposure was reported among sandal workers in Japan (Yamamura 1969). Based on case reports, it can be estimated... 

The critical effect of intermediate-duration exposure to -hexane in humans is neurotoxicity, specifically peripheral neuropathy. No inhalation MRL was derived for this duration because the reports of neurological effects in humans were predominantly case reports with inadequate documentation of exposure levels or comparison with unexposed groups. A large database on neurological effects in rats exists for this duration however, the design of these experiments precluded documentation of clear dose-response relationships within a single study. Because of the limited database for oral exposure to -hexane and the lack of toxicokinetic data for this route, no MRL was derived for oral exposure to -hexane. 

A few definitive experiments are needed to complete our knowledge of acute dose-response relationships for ozone. Research is necessary in the case of PAN and other oxidants. More important is the need for studies of crop and native species over growing seasons with chronic oxidant exposures. At the same time, additional work with field chambers, filtered or nonfiltered, is needed. 

No biomarkers of effect have been identified for cresols. Studies designed to investigate subtle effects might discern these biomarkers, which would enable finer delineation of the dose-response relationship for an effect and allow better estimation of the levels of cresols to which people could be exposed without risk. Case reports in humans have reported methemoglobinemia and Heinz body formation that may be predictive of hemolytic anemia (Chan et al. 1971 Cote et al. 1984). 

Adaptation of the original micronucleus test to circulating lymphocytes has made it feasible to consider this test for screening of human populations.73 155 The test showed a positive dose-response relationship with x rays and mitomycin C, although in the former case the response was small below 100 R. The micronucleus test needs more study before it can be used to monitor populations. It should be useful for small numbers of persons and hence be especially valuable. 

Standards that are derived using SSDs for the soil ecosystem can in some cases be validated in the held. The overview by Posthuma et al. (2002) reported on some validation studies in which it was shown that the HC5 was lower than the no-effect concentration of studied ecosystems (i.e., in mesocosm or held conditions). An array of further studies has been published since that time. However, held studies are often difhcult to interpret in terms of dose-response relationships. This difficulty in interpreting held data is sometimes due to soil heterogeneity and a highly variable soil ecosystem. Nevertheless, held soils are relevant test systems and represent a more realistic environment. Although causality may be difhcult to assess, the use of pragmatic methods, derived from an expert judgment process, can improve the overall accuracy of standards. 

Whole mixture approach for unique mixtures. This is an option if dealing with a mixture of completely unknown or unique origin and composition. In this case, results of previous effect studies cannot be used to assess the effects of the mixture of concern. Determination of a safe concentration level or a dose-response relationship for these mixtures is inefficient, as the effect data cannot be reused to assess the risks of other mixtures. The mixture of concern has to be tested directly in the field or the laboratory, like in the whole effluent toxicity (WET) test, resulting in a direct indication of the potential effects. 

As for the relationship between dose and concentration, the same controlled studies, where drug is administered under close supervision, provide results which are strongly suggestive that such a dose-response relationship exists between drug levels in beard hairs and the administered dose. This is not the case in chronic abusers or treated patients, where daily doses vary significantly from day to day so that the establishment of a dose-response relationship would require a large amount of data to attenuate the effects of any bias due to individual differences. 

CHARACTERIZING DOSE AND RISK IN A CUMULATIVE ASSESSMENT 277 CASE STUDY 280 Case Study Defining Risk 280 Case Study The Dose-Response Relationship 280 Case Study Using the Margin of Exposure to Characterize the Risk 281 Case Study Benchmark Doses 282 Case Study Margins of Exposure 284... 

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