Lethal response

Data on acute exposures of humans to both isomers of dimethylhydrazine are limited to case reports of accidental exposures. Signs and symptoms of exposure include respiratory irritation, pulmonary edema, nausea, vomiting, and neurologic effects. However, definitive exposure data (concentration and duration) were unavailable for these accidents. The limited data in humans suggest that the nonlethal toxic response to acute inhalation of dimethylhydrazine is qualitatively similar to that observed in animals. No information was available regarding lethal responses in humans. In the absence of quantitative data in humans, the use of animal data is considered a credible approach for developing AEGL values. 

Figure 5.9. Dose-response profile in a population. (A) Relationship between responding patients, expressed as percentage of individuals, and plasma drug concentrations. With increasing drug concentration, the proportion of patients who derive therapeutic benefit, without concentration-limited side effect peaks, and then declines. (B) A schematic representation of dose-response curves. Typical therapeutic and lethal responses at indicated doses are evaluated in animal models to estimate therapeutic index, TI. ED50, effective dose needed to produce a therapeutic response in 50% of animals, exhibiting therapeutic response LD50, effective dose needed to produce lethal effects in 50% of animals.

Golding LA, Timperley MH, Evans CW. 1997. Non-lethal responses of the freshwater snail Potamopyrgus antipodarum to dissolved arsenic. Environ Monit Assess 47 239-254. 

Acute lethality data in animals are summarized in Table 8.7. Based upon the animal data, interspecies variability in the lethal response to sulfur mustard vapor is less than an order of magnitude. For nonlethal effects, the animal data suggest that test species exhibit signs of toxicity that are qualitatively similar to humans when acutely exposed to sulfur mustard vapor. Ocular and respiratory tract irritations are clearly evident in studies using dogs, rats, mice, rabbits, and guinea pigs. 

Uncertainty factors An uncertainty factor of 3 for interspecies variability was applied because the toxic response to dimethylhydrazine was similar across the species tested. This was especially true for lethality responses (LC50 values for varying time periods ranging from 5 min to 4 h) among rats, mice, dogs, and hamsters. A comparison of LC50 values for the same exposure durations in these species did not vary more than 3-fold. 

McCahon, C.P., S.F. Barton, and D. Pascoe. 1990. The toxicity of phenol to the freshwater crustacean Aselus aquaticus (L.) during periodic exposure—relationship between sub-lethal responses and body phenol concentrations. Arch. Environ. Contam. Toxicol. 19 926-929. 

Acute toxicity and short-term bioaccumulation. Studies of acute toxicity measure the lethal response after 24 or 96 h of exposure in various bodies of water. Test species should be chosen from amongst most commonly used organisms and standardized procedures should be applied. The test should include at least three different trophic levels, namely primary producers, primary consumers and secondary consumers. Normally, organisms such as green algae, daphnids and fish are utilized. 

Derivatives of [14]N4(10) (cyclam) even in low doses have a good efficiency in reducing the lethal response to nickel. These macrocycles significantly enhance the urinary and biliary excretion of Nr and restore the altered levels of other trace metal ions such as Cu-+, Zn-, and Fe They are more efficient in this application than linear chelating agents such as EDTA or triethylenetetraamine (Athar et al., 1987 Misra et al., 1988). 

Equation 1 (TABLE 2) is the toxicity QSAR for this data set a slope of essentially negative one and r of 0.99 is achieved. Equation 2 is generated using equation 1 and the bioconcentration/Kow relationship of Halfon (1985). It indicates that a whole-body toxicant concentration of approximately 6,500 yumol L or 0.0065 mol L (or mol Kg when the density is about 1.0) is associated with an acutely toxic lethal response in half the exposed population of fathead minnows at essentially infinite time, i.e., threshold. 

A wide range of effects has been reported, from lethal responses, usually expressed as LC50 values, to effects on photosynthesis, growth, enz)mie activity, and behaviour. Information is available about the responses of 70 marine and over 30 freshwater organisms at various stages in their life cycles from eggs to adults. 

Thirdly, it is apparent that some of the sub-lethal responses may simply be early symptoms of an eventual lethal response. Hara et al, (1976) showed that 30 ftg/L of mercuric chloride caused a significant inhibition in the olfactory response of Salmo gairdneri in four hr however, it had already been shown by Macleod and Ressah (1973) that the 96-hr LC50 for this species was only 28 ftg/L. Sub-lethal responses must always be interpreted with care, particularly in the absence of LC50 data. 

These four findings by no means constitute unequivocal evidence of genetic hazards. Obviously, the most reliable evidence of mutagenic hazards from any agent in mice is the production of heritable mutations, which directly represent hazards. Thus it would certainly be highly desirable to determine the relationship of the presumed dominant lethal responses and the observed cytogenetic damage in females to heritable... 

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