Dose-conductance relationship

Figure 4. Dose-conductance relationship for a) acetylcholine ( ) and levamisole ( ), and b) morantel (O) and pyrantel ( ). Each point is the mean of results from at least two cells Vertical lines indicate the standard error of the mean. The number of cells contributing to each point is shown in parenthesis above or below the error bar. (Reproduced with permission from Ref. 2 Copyright 1985, Society of Chemical Industry).

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. 

Single exposures to 12,000 mg/kg kerosene and 12,150 mg/kg Deobase by oral gavage induced unsteady gait and drowsiness in rats however, no neurological effects occurred from exposure to 8,000 mg/kg kerosene (Muralidhara et al. 1982). These data are limited since statistical analysis was not conducted and effects in the controls were not described. Also, a dose-response relationship cannot be identified from the Deobase data, since only one dose was tested. 

Immunotoxicity. There are currently no data on the effects of 2-hexanone on the human immune system via any route of exposure. Animal data included an inhalation study in which there was a 40% decrease in peripheral white blood cells in rats exposed to 2-hexanone (Katz et al. 1980). In addition, 2,5-hexanedione, a metabolite of 2-hexanone, was shown to adversely affect lymphoid organs of the immune system in rats and to cause impairment of immunity in mice (Upreti and Shanker 1987). Immunological assessments, including analysis of peripheral blood components and effects on lymphoid tissue, conducted as part of intermediate-or chronic-duration studies and skin sensitization tests would be useful in developing a dose-response relationship and assessing the potential risk to chronically exposed persons in the vicinity of hazardous waste sites or to exposed workers. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

Uncertainties and Deficiencies in Dose-Response Assessment. Any approach to determining the dose-response relationship for hazardous chemicals involves many attendant uncertainties that limit its accuracy. In addition, many dose-response assessments suffer from deficiencies in the way they are conducted, which further decreases accuracy. These two aspects of dose-response assessment, which in some ways have led to adoption of such conservative approaches as large safety factors and UCLs in applying the results to health protection of the public, are discussed in the following two sections. 

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... 

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