Dose-response assessment epidemiological studies

UCL takes into account measurement uncertainty in the study used to estimate the dose-response relationship, such as the statistical uncertainty in the number of tumors at each administered dose, but it does not take into account other uncertainties, such as the relevance of animal data to humans. It is important to emphasize that UCL gives an indication of how well the model fits the data at the high doses where data are available, but it does not indicate how well the model reflects the true response at low doses. The reason for this is that the bounding procedure used is highly conservative. Use of UCL has become a routine practice in dose-response assessments for chemicals that cause stochastic effects even though a best estimate (MLE) also is available (Crump, 1996 Crump et al., 1976). Occasionally, EPA will use MLE of the dose-response relationship obtained from the model if human epidemiologic data, rather than animal data, are used to estimate risks at low doses. MLEs have been used nearly universally in estimating stochastic responses due to radiation exposure. 

Exposures in the population of interest will generally reveal that incurred dose is only a small fraction, and sometimes a very tiny fraction, of that at which toxic responses has been or can be directly measured, in either epidemiology or animal studies. Occupational populations (Table 8.1, Scenario C) may be exposed at doses close to those for which data are available, but general population exposures are usually much smaller. Thus, to estimate risk it will be necessary to incorporate some form of extrapolation from the available dose-response data to estimate toxic response (risk) in the range of doses expected to be incurred by the population that is the subject of the risk assessment. 

Pharmacokinetics has played a crucial and somewhat unusual role in the assessment of health risks from methylmercury. Some of the epidemiology studies of this fish contaminant involved the measurement of mercury levels in the hair of pregnant women, and subsequent measurements of health outcomes in their offspring (Chapter 4). Various sets of pharmacokinetic data allowed estimation of the level of methylmercury intake through fish consumption (its only source) that gave rise to the measured levels in hair. In this way it was possible to identify the dose-response relationship in terms of intake, not hair level. Once the dose-response relationship was established in this way, the EPA was able to follow its usual procedure for establishing an RfD (which is 0.1 ag/(kg b.w. day)). 

The lARC has concluded that epidemiological studies have established the relationship between benzene exposure and the development of acute myelogenous leukemia and that there is sufficient evidence that benzene is carcinogenic to humans. Although a benzene-leukemia association has been made, the exact shape of the dose-response curve and/or the existence of a threshold for the response is unknown and has been the source of speculation and controversy. Some risk assessments suggest exponential increases in relative risk (of leukemias) with increasing cumulative exposure to benzene. At low levels of exposure, however, a small increase in leukemia mortality cannot be distinguished from a no-risk situation. In addition to cumulative dose other factors such as multiple solvent exposure, familial connection, and individual sus-... 

The prime objective in epidemiologic studies is to associate particular exposures with potential health effects and thus to define cause-effect relationships. Since this process is an indirect assessment, it is highly dependent on the accuracy and specificity of observations recorded both for exposure and outcome. It is a more powerful study if dose-response relationships can be shown, that is, if increasing levels of exposure are associated with increasing frequency of the health effects in individuals. 

Exposure assessments may be conducted for one of four purposes hazard evaluation leading to appropriate control efforts, monitoring to ensure compliance with workplace standards, dose-response characterization within the context of epidemiological studies, and estimation of dose or uptake for risk assessments. Assessment strategies and measurement techniques will differ depending on the purpose at hand. 

The health assessment chapters of these documents contain the available dose-response data from animal experiments and human epidemiology studies for the chemical or class of chemicals of concern. By assessing the risks associated with various doses, acceptable daily intakes (ADIs - for systemic toxicants) or risk-specific doses (for carcinogens) were derived. These levels were divided by appropriate exposure assumptions (e.g., estimated average water consumption) to derive a criterion. 

Currently, human risk assessment utilising the target dose approach must be based on quantitative dose-response data generated in one or more presumed-sensitive biological models. The risk estimates developed using this approach must be carefully checked against the results of current and future human epidemiological studies. 

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