Irritancy, prediction

Shopsis, C. (1989). Validation study ocular irritancy prediction with the total cell protein, uridine uptake, and neutral red assays applied to human epidermal keratinocytes and mouse 3t3 cells. In Alternative Methods in Toxicology, Vol. 7 (Goldberg, A.M., Ed.). Mary Arm Liebert, New York, pp. 273-287. 

This method is easy to perform and is reproducible. However, when only skin irritation prediction is of interest, the RBC test does not provide any significant advantage over the above-described methodologies and shows the same limitations as all other protein denaturation tests (e.g., not valid in the presence of magnesium, nonapplicable in the absence of anionic surfactants). 

The pretreatment of MH-susceptible patients with oral or intravenous dantrolene prior to surgery in order to avoid a crisis is controversial. Most physicians do not recommend prophylactic pretreatment except in patients who have had a previously documented episode. However, if pretreatment is desired, it is recommended that therapy be begun with intravenous dantrolene in a dose of 2 mg/Kg just prior to induction of anesthesia. This prevents the uncertainty of predictive blood values associated with the use of the oral route. The adverse effects of intravenous dantrolene prophylaxis include phlebitis and tissue necrosis. Patients who receive prophylactic treatment with oral dantrolene often complain of incapacitation, gastrointestinal irritation, prolonged drowsiness, and clinically significant respiratory muscle weakness. 

Hart 1976). These studies, however, do not conclusively predict the human risk of skin irritation or sensitivity, but it is not believed that levels found in water near the RMA would cause dermal effects. 

No studies were located regarding interactions with other substances in humans or animals after exposure to diisopropyl methylphosphonate. However, the potential for multiple chemical interactions does exist. Diisopropyl methylphosphonate has been identified in the RMA in the presence of many other chemicals (such as endrin, dieldrin, dicyclopentadiene, bicycloheptdiene, diethyl benzene, and diethyl disulfide). The nervous system is a target of many of these compounds found at the RMA, including diisopropyl methylphosphonate. Therefore, there is potential for interaction, and studies examining multiple exposures would be useful in predicting risk to humans. Workers at the RMA reported skin irritation after dermal exposure to diisopropyl methylphosphonate at concentrations around 11.3 ppm in water. However, several other chemicals were also in the area (NIOSH 1981). Therefore, it is not clear if diisopropyl methylphosphonate contributed to the effects. 

Intravenous medication is injected directly into a vein either to obtain an extremely rapid and predictable response or to avoid irritation of other tissues. This route of administration also provides maximum availability and assurance in delivering the drug to the site of action. However, a major danger of this route of administration is that the rapidity of absorption makes effective administration of an antidote very difficult, if not impossible, in most instances. Care must often be... 

ACD/Tox Suite is a collection of software modules that predict probabilities for basic toxicity endpoints. Predictions are made from chemical structure and based upon large validated databases and QSAR models, in combination with expert knowledge of organic chemistry and toxicology. ToxSuite modules for Acute Toxicity, Genotoxicity, Skin Irritation, and Aquatic Toxicity have been used. 

Table 10 includes the results for skin irritation. No clear results have been obtained. All models are in agreement only for the absence of irritative potential of BDE 100. Multiple results from ToxTree are due to the five different alerts used by the model (Schiff base formation, SNAr, Acyl transfer agent, skin sensitization, and Michael acceptor). A global evaluation of ToxTree data could suggest that all the analyzed compounds are not able to induce skin sensitization. These predictions are in clear contrast with that obtained by applying CAESAR and in partial agreement with the results of Toxsuite. 

AEGL-1 is the airborne concentration (expressed as ppm (parts per million) or mg/m3 (milligrams per cubic meter)) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 

BZ dependence is defined by the appearance of a predictable withdrawal syndrome (i.e., anxiety, insomnia, agitation, muscle tension, irritability, nausea, malaise, diaphoresis, nightmares, depression, hyperreflexia, tinnitus, delusions, hallucinations, and seizures) upon abrupt discontinuation. 

Chemical disasters are not very easy to predict and prevent. Depending on the extent of the accident, they may produce the following health manifestations asphyxiation, central nervous system depression, defeating dermatitis, aspiration pneumonitis, myocardial sensitization and irritability and hepatorenal toxicity. 

Alarie, Y. (1981b). Bioassay for evaluating the potency of airborne sensory irritants and predicting acceptable levels of exposure in man. Food Cosmet. Toxicol. 19 623-626. 

If it is predicted that the test substance does not have the potential to be severely irritating or corrosive to the eye, continue to Section 11.4.2, Rabbit Screening Procedure. 

Another proposed in vitro assay for muscle irritancy for injectable formulations is the red blood cell hemolysis assay (Brown et al., 1989). Water-soluble formulations in a 1 2 ratio with freshly collected human blood are gently mixed for 5 min. The percentage of red blood cell survival is then determined by measuring differential absorbance at 540 nm this value is then compared to values for known irritants and nonirritants. Against a very small group of compounds (four), this assay reportedly accurately predicts muscle irritation. 

Kane, L.E., Barrow, C.S., andAlarie, Y. (1979). A short-term test to predict acceptable levels of exposure to airborne sensory irritants. Am. Ind. Hyg. J. 40 207-229. 

In recent years, much attention and effort have been directed toward the search for non-whole-animal tests to predict ocular irritation by drugs and chemicals. A variety of in vitro assays, as well as nonexperimental approaches, have been proposed. These model systems run the gamut of responses observed in vivo using biological... 

The correlation (or lack of correlation) of other physiochemical characteristics has not yet been established. For instance, are all surfactants irritants Can one classify severity by the size of the molecule Can octanol water partition coefficients predict irritation potential does a propensity to partition out of the ocular fluid mean that a compound presents more of an irritation hazard than one which is more water soluble Theoretically, these data should reflect the ability of a compound to penetrate the eye and cause an irreversible lesion. However, until definitive data are available, physical and chemical parameters will probably have limited utility in an overall assessment of irritation. 

Data from Other Toxicological Testing. Another question under study has been whether dermal or systemic (acute) toxicity is predictive of ocular irritant potential. Little work has been reported in the literature regarding the correlation... 

To summarize the utility of nonexperimental methods, it is obvious that the more available information there is about a compound, the more likely one will be able to substantially reduce the amount of testing involved in prediction of ocular irritation potential. However, at this point in time, none of the individual methods, alone or in combination, are sufficiently predictive to provide a definitive assessment of in vivo ocular irritation. There is definitely a place, however, for consideration of the above factors in a battery of tests, as well as for prioritizing compounds to be tested further. 

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