Lethal toxic potencies

Table I. Lethal Toxic Potencies of Hydrogen Chloride (LCM Values in ppm)...

ISO 13344 1996 Estimation of lethal toxic potency of fire effluents. 

ISO DIS 13344 [129] concerns the determination of the lethal toxic potency of fire effluents. This standard gives methods of calculating toxic potencies from analytically determined fire gas concentrations. 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

All fire smoke is toxic. In the past two decades, a sizable research effort has resulted in the development of over twenty methods to measure the toxic potency of those fire smokes (6). Some methods have been based on determinations of specific chemical species alone. Values for the effect (e.g., lethality) of these chemicals on humans are obtained from (a) extrapolation from preexisting, lower concentration human exposure data or from (b) interpretation of autopsy data from accident and suicide victims. The uncertainty in these methods is large since ... 

A second approach to the problem of toxic potency measurement has been to expose laboratory animals, usually rodents, to the smoke from the combustion of small samples of a burning material. Measurement of their response to the smoke leads to one of several biological endpoints, such as the LC50 (the concentration of smoke lethal to 50% of the test animals). In this approach, the animals respond to all the toxicants that are present in the smoke. It presumes that rodent mortality can be related to human mortality or, more simplistically, that the relative toxicity of the smokes will be similar in humans and rodents. However, since the relative contributions of the individual toxic chemicals in the smoke are not determined, a quantitative relationship between man and rodent is impossible using this approach. 

Table III presents the results of calculating the "time to lethal concentration" for each one of the PVC products investigated. The toxic potency values used for all the materials are based on 30 min exposures in the NBS cup furnace toxicity test, in the Non-Flaming mode, the one most relevant to this scenario.

Organonitriles are organic substances that contain the cyano (-C = N) group. Nitriles have wide commercial applications that include solvents, synthetic intermediates, pharmaceuticals, and monomers, to name just a few. As a class of substances, there are two types of toxicity associated with exposure to nitriles acute lethality and osteolathyrism. Some nitriles are known to cause both. The mechanisms by which nitriles cause these toxic effects, the corresponding relationships between nitrile structure and toxic potency for each effect, and the use of this information as a basis to design substances that may need to contain the functionality of the cyano group but will cause minimal toxicity have been discussed in detail [7]. Only the biochemical mechanism and SARs related to acute lethality of nitriles are discussed here. More detailed discussions are available [7, 8, 61]. 

Figure 4.5 Acute lethality values of some commonly used nitriles. Nitrile toxic potency is measured in mice, and expressed as oral median lethal dose (LD50) in millimoles of the nitrile per kilogram body weight [7].

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osleolathyrsm. Nitnles vary broadly in their ability to cause acute lethality and subtle differences in stmetnre can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metabolism in the body. 

The general approach in generating toxic potency data from chemical analysis is to assume additive behavior of individual toxicants, and to express the concentration of each toxicant as its fraction of the lethal concentration for 50% of the population for a 30 min exposure (LC50). Thus an fractional effective dose (FED) equal to one indicates that the sum of concentrations of individual species will be lethal to 50% of the population over a 30 min exposure. Two equations have been developed for the estimation of the FED for lethality from the chemical composition of the environment in the physical fire model. Each begins with the precept that the fractional lethal doses of most gases are additive, as developed by Tsuchiya and Sumi.32... 

Both equations have been taken from ISO 1334431 and use LC50 values for lethality to provide reference data for the individual gases to calculate toxic potency, based on rats exposed for 30 min. The N-Gas model in Equation 17.1 assumes that only the effect of the main toxicant CO is enhanced by the increase in respiration rate caused by high C02 concentrations (expressed as a step function with one value of m and b for C02 concentrations below and another for those above 5%). 

The minimum lethal dose to mice by oral administration that has been reported is 0.25 mg/kg however, lethality fluctuates depending on individuals and age (Ito et al. 2002). Interestingly, the intraperi-toneal and oral lethal doses in mice are fairly close for azaspiracid-1, which is not the case for other groups of marine toxins (Ito et al. 2002 Ito et al. 2000). The relative toxic potency for different analogues is only known for azaspirazids-1 to -5, and the comparison is based in monse lethal doses by intraperitoneal injection. Azaspiracids-1, -2, and -3 are the more toxic forms, with monse lethal doses of 0.2 mg/kg, 0.11 mg/kg, and 0.14 mg/kg, respectively (Ofuji et al. 1999a Satake et al. 1998a), followed by azaspiracid-4 (0.47 mg/kg) and the less toxic azaspiracid-5 (approximately 1.0 mg/kg) (Ofuji etal. 2001). 

At a temperature range of 427-548°C and a pressure range of 55-300 torr, MIC has been shown to decompose into HCN (Blake and Ijadi-Maghsoodi, 1982). However, the temperature inside the culprit MIC-containing tank was estimated to be only 250°C (Varadarajan et al, 1985) at which temperature MIC does not degrade into HCN. There is evidence that MIC can combine with HCN even at low temperatures (Slotta and Tschesche, 1927) however, this reaction can only reduce toxicities of both HCN and MIC and not make more lethal cyanogens as speculated by Sriramachari (2004) because the toxic potency of cyanides depends upon the dissociation of the -CN ion (Goldstein e/u/., 1968). 

In summary, acute-toxicity testing in small mammals such as rats provides a range of valuable information on chemical toxicity, including lethal doses by different routes of exposure, mechanism(s) of lethal toxicity, the extent to which the lethal effect may be reversible in some members of the exposed population while others die, and the relative potencies of toxic chemicals as lethal agents. 

Hermens, J., Canton, H., Janssen, P., and de Jong, R. Quantitative structure-activity relationships and toxicity studies of mixtures of chemicals with an anaesthetic potency acute lethal and sublethal toxicity to Daphnia magna, Aquat. Toxicol, 5(2) 143-154, 1984. 

In smdies in animals, the lethal potency of the substance based on the LD50, the LC50, the discriminating dose, and/or the acute toxic class... 

As mentioned above, a NOAEL is usually not derived in acute toxicity smdies. It is more usual that the only numerical value derived is the LD50 or LC50 value. The LD50 or LC50 values (or the discriminating dose if the Fixed Dose Procedure was used or the result of the Acute Toxic Class Method) give an indication of the relative lethal potency of a substance. The slope of the dose-response curve is a particularly useful parameter as it indicates the extent to which reduction of exposure will reduce the lethality the steeper the slope, the greater the reduction in response for a particular finite reduction in exposure. 

It should be noted that all three are lethal, however, and so the acute toxicity of these compounds is not entirely due to C-40 substituent effects. Potency does follow the oxidation series from alcohol to aldehyde to acid vivo, suggesting that perhaps these substituents influence the degree of accessibility of each lipid-solvent soluble toxin to its membrane site of action. Being that the toxins in their natural forms are so soluble in non-polar solvents, and tend to bind to or solubilize in the lipid components of membrane... 

Initial toxicity data on an uncharacterized agent usually are obtained by oral, intraperi-toneal, or dermal administration to laboratory animals. This provides an estimate of the lethal potency of the material. Observation of the animals after administration of the material often provides valuable information concerning the effects that may occur in humans. Autopsy of the animals will show the likely target organs in humans. 

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