Toxicity reversible effects

Not all contaminants or chemicals are created equal in their capacity to cause adi ersc effects. Thus, cleanup standards or action levels are based in part on the compounds toxicological properties. Toxicity data are derived largely from animal experiments in which llie aninuils (primarily mice mid rats) are exposed to increasingly liighcr concentrations or doses. Responses or effects can vary widely from no obscn ablc effect to temporary and reversible effects, to permanent injury to organs, to chronic functional impairment to ultimately, death. 

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. 

Exposures resulting in nonlethal, irreversible effects of dimethylhydrazine were not well defined. For most studies, responses were described in terms of no visible signs of toxicity or lethality. However, Weeks et al. (1963) described nonlethal (but reversible) effects in dogs exposed to 1,1-dimethylhydrazine at varying concentrations. In this study, dogs were exposed to 1,1-dimethylhydrazine at 1,550 ppm or 4,230 ppm for 5 min or 360, 400, or 1,530 ppm for 15 min. The highest cumulative exposures at each of two exposure periods (Ct =352-383 ppm-h) were associated with marked tremors, convulsions and death, while the lower concentration exposures at each of two periods caused behav... 

Key study Toxicity endpoint Weeks et al. 1963 1-h LC50 of 981 ppm in dogs reduced by a factor of three to 327 ppm as an estimate of a lethality threshold. Weeks et al. (1963) provided data showing that 15-min exposure of dogs at 36 100 ppm produced only minor, reversible effects (behavioral changes and mild muscle fasciculations)... 

Pharmacologically, carbofuran inhibits cholinesterase, resulting in stimulation of the central, parasympathetic, and somatic motor systems. Sensitive biochemical tests have been developed to measure cholinesterase inhibition in avian and mammalian brain and plasma samples and are useful in the forensic assessment of carbamate exposure in human and wildlife pesticide incidents (Bal-lantyne and Marrs Hunt and Hooper 1993). Acute toxic clinical effects resulting from carbofuran exposure in animals and humans appear to be completely reversible and have been successfully treated with atropine sulfate. However, treatment should occur as soon as possible after exposure because acute carbofuran toxicosis can be fatal younger age groups of various species are more susceptible than adults (Finlayson et al. 1979). Carbofuran labels indicate that application is forbidden to streams, lakes, or ponds. In addition, manufacturers have stated that carbofuran is poisonous if swallowed, inhaled, or absorbed through the skin. Users are cautioned not to breathe carbofuran dust, fumes, or spray mist and treated areas should be avoided for at least 2 days (Anonymous 1971). Three points are emphasized at this juncture. First, some carbofuran degradation... 

The literature emphasizes that arsenic metabolism and toxicity vary greatly between species and that its effects are significantly altered by numerous physical, chemical, and biological modifiers. Adverse health effects, for example, may involve respiratory, gastrointestinal, cardiovascular, and hematopoietic systems, and may range from reversible effects to cancer and death, depending partly on the physical and chemical forms of arsenic tested, the route of administration, and the dose. 

Chase RM, Liss GM, Cole DC, et al Toxic health effects including reversible macrothrombocytosis in workers exposed to asphalt fumes. Am J Ind Med 25 279-289, 1994... 

While over 33 million people are living with HIV/AIDS, the impact of HIV therapies has been shown by a nationwide decline in AIDS-related deaths. The vast majority of anti-HIV therapeutic agents have been limited to reverse transcriptase and protease inhibitors.5,6 However, the development of resistance to these inhibitors7 and the toxic side effects associated with these compounds8 indicate a major need for further discovery and development of alternative strategies such as those targeting other stages... 

The most common and bothersome dose-related adverse effect of the oxazolidinediones is sedation. An unusual adverse effect is hemeralopia, a glare effect in which visual adaptation is impaired it is reversible upon withdrawal of the drug. Accumulation of dimethadione has been reported to cause a very mild metabolic acidosis. Trimethadione has been associated with many other toxic adverse effects, some of which are severe. These drugs should not be used during pregnancy. 

Define sublethal effects, reversible effects, and margin of safety. What is an irreversible toxic effect ... 

No inhalation MRLs were derived for DEHP due to inadequate data for this route of exposure. As summarized in Section 2.2, the inhalation database for DEHP is essentially limited to two studies in rats that found some reversible effects in the lungs and liver following exposure for 28 days and no evidence for reproductive or developmental toxicity (Klimisch et al. 1991 Merkle et al. 1988). 

Extent of Damage to Mucosal Cells. Permeation enhancement implies possible alteration of the protective permeability barrier either by 1) an increase in the fludity of intercellular lipids (relatively non-toxic) and/ or 2) extraction of intercellular lipids or denaturation of cellular proteins (much more damaging/toxic). Therefore, it is imperative that the permeation enhancer 1) exert a reversible effect 2) not be systemically absorbed and 3) not cause cumulative toxicity or permanent changes in the barrier properties. Application of up to 1% sodium lauryl sulfate or cetylpyridinium chloride to the ventral surface of the tongue of dogs resulted in desquamation, widening and separation of keratin.f The buccal mucosa of rabbits treated with... 

Morales JM, Andres A, Prieto C, Diaz Rolon JA, Rodicio JL. Reversible acute renal toxicity by toxic sinergic effect between gentamicin and cyclosporine. Clin Nephrol 1988 29 272. 

Most BEIs are defined as concentrations of determinants or biomarkers anticipated in biological specimens collected from healthy workers whose exposure to certain chemicals by all routes is equivalent to that of workers with inhalation only exposure at the OEL. Others measure reversible effects on the body, and still others are those that are below the concentrations associated with health effects. However, other definitions are common. For example, the German biological tolerance values (BAT) can be defined as rates of excretion of the chemical or its metabolites, or the maximum possible deviation from the norm of biological parameters induced by these substances in exposed humans. BEIs for some chemicals use other criteria, such as direct comparison with a measurable toxic effect, like carboxyhemoglobin in blood for carbon monoxide. 

Studies of carbamazepine on rat cerebellar granule cells have shown inhibition of NMDA-stimulated calcium entry in a rapid and reversible manner. These findings occurred in therapeutic concentrations of carbamazepine, which may help explain the antiseizure activity of carbamazepine. It is believed that the toxic cerebellar effects of carbamazepine may be due to this mechanism. 

Reversible versus irreversible toxicity Reversible toxic effects are those that can be repaired, usually by a specific tissue s ability to regenerate or mend itself after chemical exposure, while irreversible toxic effects are those that cannot be repaired. 

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