Exposure response studies

Exposure-response data, using short-term biomarkers or surrogate endpoints, can sometimes make further exposure-response studies from clinical endpoints xmnecessary. For example, if it can be shown that the short-term effect does not increase beyond a particular dose or concentration, there may be no reason to explore higher doses or concentrations in the clinical trials. Similarly, short-term exposure-response studies with biomarkers might be used to evaluate early (i.e., first dose) responses seen in clinical trials. 

The regulatory authorities place great emphasis on exposure-response studies. Poorly designed studies are likely to confoxmd essential properties of drug molecules as a result, the protocols must be written with preciseness and clarity to prevent misinterpretations. 

Finkelstein MM, Vingilis JJ. 1984. Radiographic abnormalities among asbestos-cement workers An exposure-response study. Am Rev Respir Dis 129 17-22. 

To summarize, conducting effective dose-finding or exposure-response studies early in clinical development (e.g., preclinical. Phase 1, and Phase 2) is an essential component of an effective clinical development strategy. The creation of an informative drug label is an ethical imperative. 

Measurements of workplace air are frequently made to demonstrate compliance with legal or other standards, bur may also be made for other purposes, including identifying unknown potential hazards, obtaining data for epidemiological (exposure-response) studies, and demonstrating the efficiency of control measures. 

Model equations can be augmented with expressions accounting for covariates such as subject age, sex, weight, disease state, therapy history, and lifestyle (smoker or nonsmoker, IV drug user or not, therapy compliance, and others). If sufficient data exist, the parameters of these augmented models (or a distribution of the parameters consistent with the data) may be determined. Multiple simulations for prospective experiments or trials, with different parameter values generated from the distributions, can then be used to predict a range of outcomes and the related likelihood of each outcome. Such dose-exposure, exposure-response, or dose-response models can be classified as steady state, stochastic, of low to moderate complexity, predictive, and quantitative. A case study is described in Section 22.6. 

Immunotoxicity. The data in humans are limited to a few studies of immune function in lead workers and a study of firearm instructors. In both type of studies, inhalation is assumed to be the primary route of exposure. One study reported significant suppression of IgA levels (Ewers et al. 1982). Another study indicated that serum immunoglobulin levels were not significantly altered (Alomran and Shleamoon 1988). Another large study examined several parameters of immune function (serum immunoglobulins, PHA response, and natural killer cell activity) and found no differences in exposed workers and controls (Kimber et al. 1986b). The study of firearm instructors found functional impairment of cell-mediated immunity in subjects with PbB levels >25 pg/dL (Fischbein et al. 1993). A recent study that evaluated a... 

Impact the exposure response relations are based on epidemiological studies. 

Exposure-response data from animal studies were used to derive acute exposure guideline level (AEGL) values for arsine. AEGL values derived with animal data which had complete exposure data were more scientifically valid than AEGLs estimated from limited anecdotal human data. The greater conser... 

Data Adequacy The study was considered adequate for AEGL-3 derivation. It was carefully designed and performed, used adequate numbers of animals, used an appropriate exposure regimen, and identified an endpoint consistent with AEGL-3 definition and with the known effects of arsine. The available data indicate that the exposure-response relationship for arsine is very steep, thereby justifying the approach taken to derive the AEGL-3 values. ... 

Haun et al. (1970) also assessed the acute lethal toxicity of rats. Groups of 10 Sprague-Dawley rats were exposed to monomethylhydrazine (30, 60, 120, or 240 ppm) for 30, 60, 120, or 240 min. Similar to the results of Jacobson et al. (1955) the exposure-response curve was steep. The study authors calculated 30-, 60-, 120-, and 240-min LC50 values of427,244, 127, and 78 ppm, respectively. 

Acute lethality data for inhalation exposure to monomethylhydrazine are available for monkey, dog, rat, mouse, and hamster. Based upon the available data, hamsters appear to be the most resistant species, and the squirrel monkey and beagle dog are the most sensitive. The lethality of monomethylhydrazine appeared to follow a linear relationship for exposures up to 1 h. Most animal data focus on lethality as the toxicity endpoint with very limited exposure-response information available regarding nonlethal effects. The most significant effect reported in the acute exposure studies was the notable hemolytic response that was reversible upon cessation of exposure. However, the preponderance of the data suggest that there is little margin between exposures associated with nonlethal, reversible effects and those that result in death. 

Key study An AEGL-1 was considered to be inappropriate because significant irritation and possible toxic effects may occur at concentrations at or below the odor threshold and because of the exposure-response relationship exhibited by available toxicity data. ... 

Inhalation lethality data are available for several laboratory species, including dogs, rats, mice, and hamsters. Most of the available data, however, were collected using 1,1-dimethylhydrazine as the test material. Independent studies and reports confirm a steep exposure-response relationship for the dimethyl... 

Vorderstrasse, B., Cundiff, J., and Lawrence, B.P, A dose-response study of the effects of prenatal and lactational exposure to TCDD on the immune response to influenza A virus, J. Toxicol. Environ. Health,69, 445. 

Sanders Do non-cumulative dos response studies have any effect on your Ca2+ force curves In other words, do you bias your data by doing cumulative doso-response curves towards Ca2+ sensitization When there is a short exposure to the compound do you get a shift ... 

However, no studies on fetal exposure are available for setting TEFs. Thus there is a need for dose-response studies of the critical effects, based on synthetic mixtures reflecting the human exposure situation. The WHO TEFs for dioxins, dibenzofurans and PCBs for humans and mammals are given in Table 3. 

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