Epidemiology dose—response relations

Wu, M.-M., Kuo, T.-L., Hwang, Y.-H. and Chen, C.-J. (1989) Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular diseases. American Journal of Epidemiology, 130(6), 1123-32. 

The second step, termed dose-response evaluation, involves Identifying the observed quantitative relationship between exposure and risk, and extrapolating from the conditions of exposure for which data exist to other conditions of Interest( ). This step almost always Involves high-to-low dose extrapolation and frequently Involves extrapolation from experimental animals to humans. This step requires the assumption that dose-response relations do not simply disappear at the detection limit of our experimental or epidemiologic systems. It also requires that a biologically plausible... 

Studies in Phase IV are all studies (other than routine surveillance) performed after drug approval and related to the approved indication. They are studies that were not considered necessary for approval but are often important for optimizing the drug s use. They may be of any type but should have valid scientific objectives. Commonly conducted studies include additional drug-drug interaction, dose-response or safety studies, and studies designed to support use under the approved indication, for instance, mortality/morbidity studies, epidemiological studies. 

The approaches described previously can be used to relate biomonitoring results to a reference population or to workplace exposures, but they do not evaluate the risk associated with the amount of a chemical found in the body. To do that, one needs to develop a relationship between biomarker concentration and toxic response, a relationship that is not commonly derived in standard toxicologic practice. The following sections outline methods for deriving such a relationship. The approaches include the ideal case of existing risk assessments based on biomarker-response relationships established in epidemiologic research. Lead and mercury are used as examples of cases in which exposure was quantified according to hair or blood biomarkers and dose-response associations were developed on this basis. 

This section integrates safety information from all sources, including perti nent animal data, clinical pharmacology trials, controlled and uncontrolled trials, foreign marketing experience (if any), and epidemiologic trials related to any use of the drug. Dose-response and blood level-response relationships for adverse effects should be identified,... 

Comparative Dose Response Data There are only a limited number of cases in which it has been possible, even on a crude level, to compare animal and human dose responses to the same carcinogens. The paucity of data in this area is related to the fact that in most epidemiological studies the actual doses of the toxic substance is not known with certainty and that while complete dose response curves can be obtained in animal studies, such studies are very expensive. A systematic attempt to estimate human exposures and compare human and animal dose response relationships for several known carcinogens has been made and is contained in a report by the National Academy of Sciences and National Research Council on Environmental Studies Board on Pest Control.The carcinogens for which responses were compared in the study were benzidine chlornaphazine diethylstilbestrol aflatoxin Bl vinyl chloride, and cigarette smoke. 

Many researchers claim that there are several argummts for the assumption that responses from high-level and high-LET radiation may not be directly extrrqmlated to low-dose low-LET radiation. Many are of the opinion that the natural radiation background is harmless, and some even claim that it is beneficial (radiation hormesis). Thus, looking for effects at low doses can be a vain study. Walinder has pointed out that it is impossible to arrive to a reliable dose-effect relation at doses <50 mSv by epidemiological studies. 

In addition to obtaining information to perform a hazard and dose-response evaluation, an exposure assessment will need to be conducted to estimate and characterize any potential risks associated with nanomaterials. If the hazard identification process reveals that a nanomaterial is iimocuous and does not pose a potential for eliciting any adverse human health or environmental effects, it may not be necessary to conduct additional toxicological studies or an extensive exposure assessment. In cases where the hazard evaluation determines a potential for adverse effects for the nano-material, in vitro and/or in vivo studies may be conducted to evaluate the potential for systemic exposure from inhalation, oral, or dermal penetration. Such information may help to refine the exposure assessment by providing estimates of internal doses. Much of the published human toxicological and epidemiology data relate to airborne exposme to nanoparticles or ultrafine particles. However, there are additional routes by which humans can be exposed to nanomaterials that may need to be considered, including ... 

Dose—response relationships for lead, in terms of PbB as the dose/ exposure biomarker or administered doses in experimental systems versus some adverse effect, are probably better known for lead than for virtually any other environmental contaminant and certainly for any other metal or metal-related pollutant. Furthermore, these relationships are buttressed by a vast scientific and pubhc health literature derived from clinical and epidemiological studies, experimental animal testings, and a large variety of sophisticated mechanistic toxicological studies in vivo and in vitro. 

In the context of medical causation. Sir Austin Bradford Hill, suggested in 1965 that to imply causation from the observation of association we should consider its (1) strength, (2) consistency, (3) specificity - the restriction to specific conditions, (4) temporality - the order of events, (5) dose-response relationship, (6) theoretical plausibility, and (7) coherence - the consistency with other related phenomena. Although these guidelines were presented in the context of medicine and epidemiology, it would be very usefiil to keep these necessary conditions for causality in mind when evaluating crash causation on the basis of statistical associations. 

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