Exposure response curves

Consistent with the human responses to arsine exposure, observations in several animal species (rats, mice, and hamsters) indicated hematologic involvement. Cumulative exposures of 540-1,800 ppm-min produced decreases in hematocrit levels, RBC counts, packed cell volumes, and increases in absolute and relative spleen weights (consistent with erythrocyte damage). For acute exposures, the exposure-response curve is steep generally less than a 10-fold difference between no-effect and lethality exposures. 

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. 

Jacobson et al. (1955) assessed the lethality of monomethylhydrazine in hamsters exposed for 4 h. Based on the estimated LC50 (143 ppm, or 270 mg/m3), hamsters were somewhat less sensitive to inhaled monomethylhydrazine. Similar to mice and rats, the slope of the exposure-response curve was steep (2.46), suggesting little variability in the response. 

Endpoint/Concentration/Rationale The 60-min LC50 of 82 ppm was reduced to 27.3 ppm by using a 3-fold adjustment as an estimate of the lethality threshold the available data indicated the squirrel monkey to be the most sensitive species tested. That is a reasonable estimate of the lethality threshold, because monomethylhydrazine has a steep exposure-response curve, and data on other chemicals with similar dose response curves indicate that this approach represents a likely estimate of the threshold for lethality. For the 1-h exposure, 2/2 monkeys died at 90 ppm, 2/4 at 85 ppm, and 0/2 at 75 ppm. A similar spectrum of response is seen with the rhesus monkey and dog. 

Jacobson et al. (1955) assessed the lethality of 1,2-dimethylhydrazine and 1,1-dimethylhydrazine in rats following a 4-h exposure. Lethality was assessed over a 14-d post-exposure variability in the response. For 1,1-dimethylhydrazine, an LC50 of 252 ppm was calculated, and an LC2o of 210 ppm (515 mg/m3) was estimated from the exposure-response graphs in the report. The exposure-response curve was steep (slope = 8.65 SE = 2.8), suggesting very little variability among the test groups. 

The most notable database deficiencies were the absence of quantitative exposure data regarding the human experience, the absence of a well-defined exposure-response curve relationship in animals, and understanding of individual variability in response to inhaled dimethylhydrazines. 

Figure 3. Exposure response curve of GMC at high gel fractions and varying...

The exposed samples were dip-developed in appropriate mixtures of methylethylketone and ethanol, rinsed in pure ethanol and finally postbaked above their respective Tg s for 1 hr. Film thicknesses were measured optically using a Nanometrics Nanospec/AFT microarea thickness gauge. Characteristic exposure response curves were plotted as normalized film thickness remaining vs. log dose (expressed in jtC/cm2). 

Figure 15. Exposure response curves of a series of PCMS with different...

Figure 18. Exposure response curves of the chlorinated P-p-MSl series.

In the most straightforward risk-based approach, epidemiologic studies have developed exposure-response relationships based on biomarker measurements in hair, blood, urine, or other matrices (e.g., mercury, lead) (see Figure 5-2a). The relationships can be applied directly to new biomonitoring data to determine where on the exposure-response curve any person is. That may facilitate an understanding of risk, but it does not analyze sources of exposure, so other techniques (such as environmental sampling and behavioral surveys) may be needed to assess where the exposure came from. 

Lithographic Characteristics. The exposure response curves for P(SI-CMS) and Sl-novolac containing PMPS (SI-NPR) are shown in Figure 4, and their lithographic characteristics are summarized in... 

The BMC method has a number of advantages over the traditional NOAEL approach. The BMC is derived from a statistical analysis of the exposure-response relationship and is not subject to investigator selection of exposure levels. It is a reflection of the exposure-response curve. Although the number of animals used in a study will affect the NOAEL and BMC estimates, the BMC, when compared with the maximum likelihood estimate (MLE), will explicitly reflect the variability in the study and the uncertainty around the number of subjects. The greater the variability and uncertainty, the greater the difference between the BMC and the MLE. The BMC calculation allows for the statistical estimation of a BMC in the absence of an empirical NOAEL. 

If an exposure that does not produce death is estimated by dividing an LC50 value by 3 (or some other divisor), then give the slope of the exposure response curve or enough data points to support the division by 3 (or some other divisor). 

When experimental lethality data have been insufficient to determine statistically an LCqi value, but an LC50 value was determined and all exposure levels caused lethality, a fraction of the LC50 value is used to estimate the threshold for lethality. In aU cases, the exposure-response curve was steep, and the LC50 value was divided by 3. Eowles et al. (1999) analyzed 120 published inhalation animal lethality data sets using the BMC method. Their analyses of inhalation toxicity experiments revealed that for many chemicals the ratio between the LC50 and the experimentally observed nonlethal level... 

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