Studies, dose-response

Hearne, F.T., Grose, F., Pifer, J.W., Friedlander, B.R. Raleigh, R.L. (1987) Methylene chloride mortality study dose-response characterization and animal model comparison. J. occup. Med., 29, 217-228... 

The committee recommends that results from the Boston Naming Test in the Faroe Islands study be used in the calculation of the RfD. For that study, dose- response data based on Hg concentrations in cord blood should be modeled using the K-power model (K > 1). On the basis of that study, that test, and that model, the committee s preferred estimate of the BMDL is 58 parts per billion (ppb) of Hg in cord blood (approximately corresponding to 12 ppm Hg in hair). To estimate this BMDL, the committee s calculations involved a series of steps, each involving one or more assumptions and related uncertainties. Alternative assumptions could have an impact on the estimated BMDL value. In selecting a single point of departure, the committee followed established public-health practice of using the lowest value for the most sensitive, relevant end point... 

Thus, there may be a case for saying that in early drug development the regression approach is appropriate whereas in phase 111 studies comparing (say) two doses with placebo the disconnected treatment approach may be relevant. Compromise positions are also possible for example, there is a long tradition of studying dose-response simply using order relationships. The paper by Bretz (2006) considers some alternatives to the classic approach of Williams (1972). Some of these intermediate approaches will be discussed in due course below. 

Fig. 11. Dose—response curves for (A,A) inhibition of cyclic AMP formation and stimulation of IP formation by carbachol (A,D) before and (A,H) after reduction of receptor number by irreversible alkylation (carbachol) is in M. Error bars ( ) are shown for some studies.

If possible, there should be measurement of the toxic effect in order quantitatively to relate the observations made to the degree of exposure (exposure dose). Ideally, there is a need to determine quantitatively the toxic response to several differing exposure doses, in order to determine the relationship, if any, between exposure dose and the nature and magnitude of any effect. Such dose—response relationship studies are of considerable value in determining whether an effect is causally related to the exposure material, in assessing the possible practical (in-use) relevance of the exposure conditions, and to allow the most reasonable estimates of hazard. 

Dose—response evaluation is used in describing the quantitative relationship between the amount of exposure to a substance and the extent of toxic injury or disease. Data may be derived from animal studies or from studies in exposed human populations. Dose—response toxicity relationship for a substance varies under different exposure conditions. The risk of a substance can not be ascertained with any degree of confidence unless... 

Acute Toxicity Studies. These studies should provide the following information the nature of any local or systemic adverse effects occurring as a consequence of a single exposure to the test material an indication of the exposure conditions producing the adverse effects, in particular, information on dose—response relationships, including minimum and no-effects exposure levels and data of use in the design of short-term repeated exposure studies. 

Reproductive Toxicity. No data are available that impHcate either hexavalent or trivalent chromium compounds as reproductive toxins, unless exposure is by way of injection. The observed teratogenic effects of sodium dichromate(VI), chromic acid, and chromium (HI) chloride, adininistered by injection, as measured by dose-response relationships are close to the amount that would be lethal to the embryo, a common trait of many compounds (111). Reported teratogenic studies on hamsters (117,118), the mouse (119—121), and rabbits (122) have shown increased incidence of cleft palate, no effect, and testicular degeneration, respectively. Although the exposures for these experiments were provided by injections, in the final study (122) oral, inhalation, and dermal routes were also tried, and no testicular degeneration was found by these paths. 

The main objective of air quality guidelines and standards is the protection of human health. Since fme particulates (PM,) are more likely to cause adverse health effects than coarse particulates, guidelines and standards referring to fine particulate concentrations are preferred to those referring to TSP, which includes coarse particulate concentrations. Scientific studies provide ample evidence of the relationship between exposure to short-term and long-term ambient particulate concentrations and human mortality and morbidity effects. However, the dose-response mechanism is not yet fully understood. Furthermore, according to the WHO, there is no safe threshold level below which health damage does not occur. 

Scientific information for the process of establishing OELs may come from human or animal data obtained using different methods, from studies of acute, subacute, and chronic toxicity through various routes of entry. Human data, which is usually the best source, is not easily available, and frequently it is incomplete or inadequate due to poor characterization of exposure and clear dose-response relationships. Human data falls into one of the following categories ... 

After the critical study and toxic effect have been selected, the USEPA identifies the experimental exposure level representing the highest level tested at which no adverse effects (including the critical toxic effect) were demonstrated. This highest "no-obserx cd-adversc-effcct-lever (NOAEL) is the key datum obtained from the study of the dose-response relationship. A NOAEL obserx ed in an animal study in which the exposure was intermittent (such as five days per week) is adjusted to reflect continuous exposure. 

Using dose-response information from short-term exposure studies to predict the effects of long-term e.xposures, and vice versa... 

Using dose-response information from animal studies to predict effects in humans... 

Uncertainty on tlie other hand, represents lack of knowledge about factors such as adverse effects or contaminant levels which may be reduced with additional study. Generally, risk assessments carry several categories of uncertainly, and each merits consideration. Measurement micertainty refers to tlie usual eiTor tliat accompanies scientific measurements—standard statistical teclmiques can often be used to express measurement micertainty. A substantial aniomit of uncertainty is often inlierent in enviromiiental sampling, and assessments should address tliese micertainties. There are likewise uncertainties associated with tlie use of scientific models, e.g., dose-response models, and models of environmental fate and transport. Evaluation of model uncertainty would consider tlie scientific basis for the model and available empirical validation. 

Pharmacodynamics is a discipline within the broader topic of pharmacology, which focuses on how a drug brings about a particular response, and the effective levels that are required in order to elicit such a response. Some of these basic data will have emerged from the research-based activities that initiate the development of most drugs today. However, considerable additional studies are required to establish detailed dose-response curves so that the optimum therapeutic level can be chosen. 

---