Toxicity, mechanisms thresholds

Once the inputs euid orrtputs are determined, the second and third steps of LCA, impact analysis and improvement analysis, can be prrrsued (Fava et al. 1991). For impact analysis, the analyst Unks the inventory of a substance released to an envirorrmental load factor such as acid deposition, which is defined in Table 6 (Potting et al. 1998). Environmental load factors are a frmetion of characteristics such as location, merlirrm, time, rate of release, route of exposrrre, natural environmental process mechanisms, persistence, mobility, accrrmrrlation, toxicity, and threshold of effect. Owens argues that because inventory factors do not have the spatial, temporal, or threshold characteristics that are inherent to the environmental load, other risk-assessment tools shorrld be used to evaluate a local process (Owens 1997). 

There are three types of TAP emissions continuous, intermittent, and accidental. Both routine emissions associated with a batch process or a continuous process that is operated only occasionally can be intermittent sources. A dramatic example of an accidental emission was the release of methyl isocyanate [624-83-9] in Bhopal, India. As a result of this accident, the U.S. Congress created Tide III, a free-standing statute included in the Superfund Amendments and Reauthorization Act (SARA) of 1986. Title III provides a mechanism by which the pubHc can be informed of the existence, quantities, and releases of toxic substances, and requires the states to develop plans to respond to accidental releases of these substances. Eurther, it requires anyone releasing specific toxic chemicals above a certain threshold amount to aimuaHy submit a toxic chemical release form to EPA. At present, there are 308 specific chemicals subject to Title III regulation (37). 

The 1990 Clean Air Act Amendments Hst 189 hazardous air pollutants (HAPs) that the EPA must regulate to enforce maximum achievable control technology (MACT) to standards which are to be set by the year 2000. The 33/50 project calls for reduction of emissions of 17 specified solvents to predetermined levels by 1995. The SARA statute provides a mechanism by which the community can be informed of the existence, quantities, and releases of toxic chemicals, and requires that anyone releasing specific toxic chemicals above a threshold level to annually submit a toxic chemical release form to the EPA. The status of various ketones under these regulations is shown in Table 4. 

For some toxins it is possible to demonstrate an apparent improvement in functional response at levels of exposure which are below a threshold. This effect, which has been termed hormesis , is most effectively demonstrated in the consistently improved longevity of animals whose caloric intake is restricted rather than allowing them to feed ad lib (Tannenbaum, 1942). Clearly in this instance, the observed effects are the result of exposure to a complex mixture of chemicals whose metabolism determines the total amount of energy available to the organism. But it is also possible to show similar effects when single chemicals such as alcohol (Maclure, 1993), or caffeic acid (Lutz et al., 1997) are administered, as well as for more toxic chemicals such as arsenic (Pisciotto and Graziano, 1980) or even tetrachloro-p-dibenzodioxin (TCDD) ( Huff et al., 1994) when administered at very low doses. It is possible that there are toxins that effect a modest, reversible disruption in homeostasis which results in an over-compensation, and that this is the mechanism of the beneficial effect observed. These effects would not be observed in the animal bioassays since to show them it would be necessary to have at least three dose groups below the NOAEL. In addition, the strain of animal used would have to have a very low incidence of disease to show any effect. 

AEGL-1 (Non-disabling) NRa NR NR NR Not recommended due to steep dose-response relationship, mechanism of toxicity, and because toxicity occurs at or below the odor threshold... 

Reference The available human and animal data indicate that there is very little margin between seemingly inconsequential exposures and lethal exposures. The mechanism of arsine toxicity (hemolysis and subsequent renal failure) and the fact that toxicity has been demonstrated at or below the odor threshold justify the inappropriateness of AEGL-1 values for any exposure period. 

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. 

Critical research needs include definition of thresholds for adverse health effects and how these thresholds vary with exposure concentration and duration. Such data would be valuable for affirming AEGL values. Additionally, the mode of dimethylhydrazine toxicity is not fully understood and, therefore, research providing insight into the underlying mechanism(s) of dimethylhydrazine toxicity would reduce current uncertainties in quantitative health risk issues. 

The mechanism of sulfite-induced asthma is not well-understood. Reactions to sulfited foods probably depend on the sulfite residue level in the food, the sensitivity threshold of the individual, the type of food consumed, and whether sulfite exists in the free (more toxic) form or combined (less toxic) form. The toxicology of sulfites has been reviewed by Madhavi and Salunkhe (1995). Sulfite sensitivity is not a true allergic reaction (Taylor et al., 1988). The FDA initially estimated that more than 1 million Americans are sensitive to sulfites, but more recent estimates lowered the number of asthmatics who may be sulfite sensitive to 80,000-100,000 (Bush et al., 1986). 

We can now proceed to demonstrate how scientific information and the regulatory defaults of Table 8.2 can be applied. It is useful and important to separate the dose-response evaluations into those used for substances that produce their toxic effects through threshold mechanisms, as these terms were described or used in Chapters 3 and 6, and those that may involve no-threshold mechanisms. As a practical matter, only carcinogens have, to date, been treated as belonging in the latter category. 

There have been attempts to develop explicit risk estimates for agents presumed to act through threshold mechanisms. Some investigators have proposed the use of models which assume that toxic responses and the thresholds for them follow a certain distribution over the population. The use of such models may reveal how the distribution of response shifts as dose shifts. Unfortunately most toxicology data are not reported in a form that allows ready use of such distribution models. 

Simple similar action (simple joint action or concentration/dose addition) is a noninteractive process in which the chemicals in the mixture do not affect the toxicity of one another. All the chemicals of concern in the mixture act on the same biological site, by the same mechanism of action, and differ only in their potencies. The correlation of tolerances is completely positive (r=+l) and each chemical contributes to the toxicity of the mixture in proportion to its dose, expressed as the percentage of the dose of that chemical alone that would be required to obtain the given effect of the mixture. Thus, the individual components of the mixture act as if they were dilutions of the same toxic compound and their relative potencies are assumed to be constant throughout all dose levels. An important implication is that, in principle, no threshold exists for dose additivity. 

The number of receptor sites and the position of the equilibrium (Eq. 1) as reflected in KT, will clearly influence the nature of the dose response, although the curve will always be of the familiar sigmoid type (Fig. 2.4). If the equilibrium lies far to the right (Eq. 1), the initial part of the curve may be short and steep. Thus, the shape of the dose-response curve depends on the type of toxic effect measured and the mechanism underlying it. For example, as already mentioned, cyanide binds very strongly to cytochrome a3 and curtails the function of the electron transport chain in the mitochondria and hence stops cellular respiration. As this is a function vital to the life of the cell, the dose-response curve for lethality is very steep for cyanide. The intensity of the response may also depend on the number of receptors available. In some cases, a proportion of receptors may have to be occupied before a response occurs. Thus, there is a threshold for toxicity. With carbon monoxide, for example, there are no toxic effects below a carboxyhemoglobin concentration of about 20%, although there may be... 

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