Exposure-Response Relationships

Uncertainty Factors/Rationale Total uncertainty factor 30 Interspecies 10—The 10-min LC50 value for the monkey was about 60% of the rat value and one-third the rabbit value. The mouse data were used to calculate the AEGL levels, because the data exhibited a good exposure-response relationship and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity. In addition, arsine has an extremely steep dose-response relationship, allowing little margin in exposure between no effects and lethality. 

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. ... 

The AEGL values reflect the steep exposure-response relationship exhibited by the toxicity data. Additional information regarding the mechanism(s) of action and metabolism of monomethylhydrazine may provide further insight into understanding and defining the threshold between nonlethal and lethal exposures. 

The AEGL-3 values were derived based upon the 1-h LC50 value of 82 ppm reported for squirrel monkeys (Haun et al. 1970). As previously noted, there appears to be a critical and narrow threshold between an exposure that induces only minimal toxicity and one that causes death. For squirrel monkeys, 1-h exposure to a mean concentration of 82 ppm (range, 70-95 ppm) killed two of four animals. For derivation of the AEGL-3, the lethality threshold for squirrel monkeys was estimated by a 3-fold reduction of the LC50 (82 ppm) to obtain a value of 27.3 ppm. This estimate can be justified by the known steep exposure-response relationship for the toxic effects of monomethylhydrazine, and the fact that the resulting 27.3-ppm value represents an exposure concentration that does not produce overt toxicity in test animals. 

The most notable data deficiency is the absence of a well-defined exposure response relationship for monomethylhydrazine toxicity related to AEGL-2 effects. This deficiency precluded a definitive determination of the thresholds... 

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. ... 

Intraspecies Because the species used was the most sensitive to monomethylhydrazine toxicity and the most closely related to humans, an uncertainty factor of 3 is justified. A factor of 3 was used. Although the mechanism of toxicity is uncertain and sensitivity among individuals may vary, the exposure-response relationship is steep, suggesting limited variability in the toxic response to methylhydrazine. Furthermore, it is likely that acute toxic responses are, at least initially, a function of the extreme reactivity of methylhydrazine. The interaction of the highly reactive monomethylhydrazine with tissues (e.g., pulmonary epithelium) is not likely to greatly vary among individuals. 

Data Adequacy Adequate lethality data were available for several species including nonhuman primates. Although the variability in response to the lethal effects of monomethylhydrazine among all species tested appeared to be relatively small (2- to 3-fold difference), the squirrel monkey appeared to be somewhat more sensitive. The AEGL values for monomethylhydrazine reflect the steep exposure-response relationship suggested by available 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... 

Kovarik, J.M. et al. 2002. Exposure-response relationships for everolimus in de novo kidney transplantation Defining a therapeutic range. Transplantation. 73 920. 

The prevalence of airways obsfrucfion in this workforce was 3.3 times greater than expected when compared to national data. Nineteen of the 21 workers identified wifh airways obstruction had fixed airways obstruction. Cumulative worker exposures were calculated in parts per million diacetyl-years and workers were placed in equally sized worker categories of least, minimally, moderately, and most exposed. When successive categories of leasf fo greatest exposed workers were compared, it was found fhaf fhe proportion of workers with airways obstruction increased and average-percent-predicted FEVi decreased, demonstrating an exposure-response relationship with diacetyl. Five of... 

---