Chemical’s toxicity

The mechanisms of each hazardous chemical s toxic effects differ and depend on many factors. The majority of substances take effects... 

A necessary, indeed critical, element in understanding whether a chemical s toxic properties will be expressed is the size of the dose incurred by individuals who are exposed. How exposure leads to dose is the subject of the next chapter. Here we set the stage for the next chapter by describing the many ways in which people can become exposed to all the categories of chemicals we have described. 

The conditions of exposure (dose and duration) under which the chemical s toxicity can be produced. 

In the absence of information to demonstrate that such a selection is incorrect, data from the animal species, strain, and sex showing the greatest sensitivity to a chemical s toxic properties will be selected as the basis for human risk assessment. 

The toxic effect occurring at the lowest dose (the most sensitive indicator of a chemical s toxicity) is selected as the critical health concern for risk assessment. 

Children, as well as the unborn child, have in some cases appeared to be uniquely vulnerable to chemical s toxic effects because periods of rapid growth and development render them more susceptible to some specific toxic endpoints when compared to adults. Furthermore, there may be windows of vulnerability or periods of development when chemical exposures may substantially alter organ stmcmre and function. In addition to such toxicodynamic factors, differences in toxicokinetics may contribute to an increased susceptibility during these periods. The greatest differences in comparison with adults occur in neonates and infants (<1 year). However,... 

The majority of compounds that enter the organism require metabolism in order to be excreted. If the parent compound is responsible for the toxicity and its metabolites are less toxic, an increased biotransformation rate will reduce the toxicity, and conversely. However, if the chemical s toxicity is mainly due to its metabolite, stimulating the biotransformation will enhance the toxicity. 

In the evaluation of a chemical s toxic characteristics, determination of the irritant/corrosive effects on the eyes of mammals is an important parameter. Data obtained from this test indicate hazards likely to arise from exposure of the eyes and associated mucous membranes to the toxic chemical under test. 

In the subchronic toxicity study, if interim sacrifices are planned, the number of animals should be increased so that there is no shortage of animals at the termination of the study this ensures meaningful conclusions about the test chemical s toxicity. In addition, a satellite group of 20 animals (10 of each gender) may be treated with the high dose of the test chemical for 90 days. These animals should be observed for signs of adverse effects, (e.g., reversibility, persistence, delayed occurrence of toxic effects). The observation period should last for a posttreatment period of appropriate length not less than 28 days. 

Subchronic dermal toxicity is the study of adverse effects occurring as a result of the repeated daily dermal application of a test chemical to animals for a part (not exceeding 10%) of the life span. In the evaluation of a chemical s toxic characteristics, the determination of subchronic dermal toxicity may be performed after initial information on toxicity has been obtained by acute testing. This study provides information on health hazards likely to arise from repeated exposure via the dermal route over a limited period of time. 

Detoxification Reduction of a chemical s toxic properties by means of biotransformation processes, to form a more readily excreted or a less toxic chemical than the parent compound. 

A chemical s toxicity may be predicted based on its similarity in structure to that of a chemical whose toxicity is known. This is called the structure-activity relationship (SAR). The value of SAR in risk assessment is limited because of exceptions to the predicted toxicity. 

Dose additivity It is assnmed that each chemical behaves as a concentration or dilntion of every other chemical in the Cumnlative Assessment Group (or chemical mixture). The response of the combination is the response expected from the eqnivalent dose of an index chemical. The equivalent dose is the sum of the component doses, scaled by each chemical s toxic potency relative to the index chemical (USEPA, 2002). 

Adaptive effect An adaptive effect enhances an organism s performance as a whole and/or its ability to withstand a challenge. An example of an adaptive effect is an increase in hepatic smooth endoplasmic reticulum, but only if hepatic metabolism reduces the chemical s toxicity. 

Yet another classification system refers to the nature of the host s response to the causative agent. Some agents, referred to as intrinsic hepatotoxicants, will cause hepatotoxicity in most individuals of most species. In the case of idiosyncratic hepatotoxicants, where a chemical s toxic effects are a function of unusual susceptibility of the exposed individual, it may not be clear whether the lesion is a manifestation of the hepatotoxic properties of the substance in question or a manifestation of the individual s untoward response to the agent. This response may mean hypersensitivity (allergic) reactions or exaggerated responses to minor alterations in liver function. For example, anabolic or contraceptive steroids cause diminished biliary excretion (cholestasis) in most... 

This formula adjusts each chemical s toxicity by the information on pairwise toxicological interactions involving that chemical. ATSDR has posted several interaction profiles with WOE determinations. If no interactions existed, then the second sum is always 1 and the formula reduces to the HI formula based on dose addition given in eqn (2) Hertz-berg provides additional details about this equation. 

Acceptance. New ideas are slowly accepted in science. However, the tendency of scientists to accept new ideas too readily may result in long-term problems. For example, the in vitro studies, such as microbial mutation to give preliminary evaluations of a chemical s toxicity, are readily accepted by some. The assessment and critical evaluation of theories is a time-consuming process and requires flexibility to modify one s own ideas. 

Neutralization. Neutralization involves the elimination of a chemical s toxicity by applying another chemical that reacts with it, such as neutralizing an acid with an alkali. These reactions can produce heat, which is potentially as damaging as the original chemical. This method is almost never used on contaminated victims. This is more applicable to decontaminating environmental surfeces than victims. 

The range and diversity of toxic materials used in process industries are large, but common toxic and volatile chemicals include, e.g., chlorine, bromine and phosgene. Large release of any of these could present lethal risk many kilometers downwind. The hazard arising from toxic releases is a function of the chemical s toxicity (obviously), the discharge rate (which will affect airborne concentration), the chemical volatility, whether Are or other heat source are present (since this may induce buoyancy and reduce ground-level concentrations), local population density, and local weather at the time of the release. 

Chemical risk and chemical hazard are synonymous. Like chanical hazard, chemical risk is a composite function of the harmfulness of a chemical and the conditions of its use. Strictly speaking, a chemical risk may arise from any harmful property a chemical possesses (e.g., flammability, corrosiveness, toxicity, etc.). In this book, the term chemical risk refers to the risk associated with a chemical s toxicity. 

In addition to the failures of biotransformation reactions to promote the elimination of some xenobiotics. Phase I reactions occasionally have the effect of increasing rather than reducing a chemical s toxicity. For example, several enzymes in the cytochrome P-450 family are known to convert foreign chemicals into electrophiles. Electrophiles are molecules that are deficient in electrons as such, they tend to react with molecules that are relatively electron-rich such as proteins, lipids, and DNA, which are essential to the health of cells. When a cellular molecule is attacked by an electrophile, its structure is altered, and its function is undermined (Chapter 7). 

Chemical Toxicity. In chemistry courses students learn a lot about what a chemical can do for them, but they know woefully little about what a chemical can do to them This deficiency in their chemical education is a result of standard and currently recommended academic practices. (For example, almost all new laboratory manuals in general and organic chemistry have eliminated the use of benzene and dichromate because of their carcinogenic status.) For reasons of safety and economy teaching laboratories tend to make use of small amounts of reagents with minimum toxicity, and use low-risk procedures, such as microscale. Students have only a single or at most a few exposures to any one chemical, and learning about a chemical s toxicity is minimal. These procedures often continue into advanced courses, and even research projects. Spills and waste disposal are handled by the instructors. 

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