The next step in a toxicity test is recording the changes in the organisms over time. A standard observation period is daily, every 24 hours for at least 4 days 96 hours. For each interval of time, observations must be recorded for:. Then apply a statistical procedure to estimate the median concentration of the toxin that maimed or killed half the organisms and write up the results. The key is to write it up with enough information so that someone else can exactly duplicate the test.
Added to all this, the design of a toxicity test must include a number of features to insure there is no bias in the results. Finally, the researcher must write a report that not only describes the experiment and results, but also puts them in context with similar data from other studies reported in the scientific literature.
These are the steps scientists go through to determine if a substance is toxic and at what concentration levels. In reality, today, toxicity testing is even more complicated and detailed. The final use of toxicity data is comparison with concentrations measured or expected in the field.
If concentrations in the field are higher, then there is cause for concern. By Alan Mearns, Ph. Mearns is an ecologist and senior staff scientist with the Emergency Response Division. Go to full glossary Add 0 items to collection. Download 0 items. Twitter Pinterest Facebook Instagram. Email Us. See our newsletters here.
Would you like to take a short survey? This survey will open in a new tab and you can fill it out after your visit to the site. Some epidemiologists disagree with IARC's cancer classification judgments in particular cases, and there seems to be even greater potential for scientific controversy regarding the strength of the epidemiologic evidence of non-cancer e.
There has been much less epidemiologic study of other toxic effects, in part because of lack of adequate medical documentation. When epidemiologic studies are not available or not suitable, risk assessment may be based on studies of laboratory animals. One advantage of animal studies is that they can be controlled, so establishing causation assuming that the experiments are well conducted is not in general difficult. Another advantage is that animals can be used to collect toxicity information on chemicals before their marketing, whereas epidemiologic data can be collected only after human exposure.
Indeed, laws in many countries require that some classes of chemicals e. Other advantages of animal tests include the facts that. The quantitative relationship between exposure or dose and extent of toxic response can be established. The animals and animal tissues can be thoroughly examined by toxicologists and pathologists, so the full range of toxic effects produced by a chemical can be identified.
The exposure duration and routes can be designed to match those experienced by the human population of concern. But laboratory animals are not human beings, and this obvious fact is one clear disadvantage of animal studies. Another is the relatively high cost of animal studies containing enough animals to detect an effect of interest. There are reasons based on both biologic principles and empirical observations to support the hypothesis that many forms of biologic responses, including toxic responses, can be extrapolated across mammalian species, including Homo sapiens , but the scientific basis of such extrapolation is not established with sufficient rigor to allow broad and definitive generalizations to be made NRC, b.
One of the most important reasons for species differences in response to chemical exposures is that toxicity is very often a function of chemical metabolism.
Differences among animal species, or even among strains of the same species, in metabolic handling of a chemical, are not uncommon and can account for toxicity differences NRC, Because in most cases information on a chemical's metabolic profile in humans is lacking and often unobtainable , identifying the animal species and toxic response most likely to predict the human response accurately is generally not possible. It has become customary to assume, under these circumstances, that in the absence of clear evidence that a particular toxic response is not relevant to human beings, any observation of toxicity in an animal species is potentially predictive of response in at least some humans EPA, a.
This is not unreasonable, given the great variation among humans in genetic composition, prior sensitizing events, and concurrent exposures to other agents. As in the case of epidemiologic data, IARC expert panels rank evidence of carcinogenicity from animal studies.
It is generally recognized by experts that evidence of carcinogenicity is most convincing when a chemical produces excess malignancies in several species and strains of laboratory animals and in both sexes. The observation that a much higher proportion of treated animals than untreated control animals develops malignancies adds weight to the evidence of carcinogenicity as a result of the exposure. At the other extreme, the observation that a chemical produces only a relatively small increase in incidence of mostly benign tumors, at a single site of the body, in a single species and sex of test animal does not make a very convincing case for carcinogenicity, although any excess of tumors raises some concern.
EPA combines human and animal evidence, as shown in Table , to categorize evidence of carcinogenicity; the agency's evaluations of data on individual carcinogens generally match those of IARC. For noncancer health effects, EPA uses categories like those outlined in Table Animal data on other forms of toxicity are generally evaluated in the same way as carcinogenicity data, although this classification looks at hazard identification qualitative and dose-response relationships quantitative together.
No risk or hazard ranking schemes similar to those used for carcinogens have been adopted. The hazard-identification step of a risk assessment generally concludes with a qualitative narrative of the types of toxic responses, if any, that can be caused.
Limited evidence from epidemiologic studies and sufficient evidence from animal studies B1 ; or inadequate evidence from epidemiologic studies or no data and sufficient evidence from animal studies B2. In addition to the epidemiologic and animal data, information on metabolism and on the behavior of the chemical in tissues and cells i. Identifying the potential of a chemical to cause particular forms of toxicity in humans does not reveal whether the substance poses a risk in specific exposed populations.
The latter determination requires three further analytic steps: emission characterization and exposure assessment discussed in Chapter 3 , dose-response assessment discussed next , and risk characterization discussed in Chapter 5.
In the United States and many other countries, two forms of dose-response assessment involving extrapolation to low doses are used, depending on the nature of the toxic effect under consideration. One form is used for cancer, the other for toxic effects other than cancer. For all types of toxic effects other than cancer, the standard procedure used by regulatory agencies for evaluating the dose-response aspects of toxicity involves identifying the highest exposure among all the available experimental.
The sufficient-evidence category includes data that collectively provide enough information to judge whether a human developmental hazard could exist within the context of dose, duration, timing, and route of exposure.
This category includes both human and experimental-animal evidence. Sufficient Human Evidence : This category includes data from epidemiologic studies e.
A case series in conjunction with strong supporting evidence may also be used. Supporting animal data might or might not be available. Sufficient Experimental Animal Evidence or Limited Human Data : This category includes data from experimental-animal studies or limited human data that provide convincing evidence for the scientific community to judge whether the potential for developmental toxicity exists.
The minimal evidence necessary to judge that a potential hazard exists generally would be data demonstrating an adverse developmental effect in a single appropriate, well-conducted study in a single experimental-animal species. The minimal evidence needed to judge that a potential hazard does not exist would include data from appropriate, well-conducted laboratory-animal studies in several species at least two that evaluated a variety of the potential manifestations of developmental toxicity and showed no developmental effects at doses that were minimally toxic to adults.
This category includes situations for which there is less than the minimal sufficient evidence necessary for assessing the potential for developmental toxicity, such as when no data are available on developmental toxicity, when the available data are from studies in animals or humans that have a limited design e.
The difference between the two values is related to the definition of adverse effect. The NOAEL is the highest exposure at which there is no statistically or biologically significant increase in the frequency of an adverse effect when compared with a control group. A similar value used is the lowest-observed-adverse-effect level LOAEL , which is the lowest exposure at which there is a significant increase in an observable effect.
All are used in a similar fashion relative to the regulatory need. For human risk assessment, the ratio of the NOAEL to the estimated human dose gives an indication of the margin of safety for the potential risk. In general, the smaller the ratio, the greater the likelihood that some people will be adversely affected by the exposure.
The uncertainty-factor approach is used to set exposure limits for a chemical when there is reason to believe that a safe exposure exists; that is, that its toxic effects are likely to be expressed in a person only if that person's exposure is above some minimum, or threshold.
At exposures below the threshold, toxic effects are unlikely. To establish limits for human exposure, the experimental NOAEL is divided by one or more uncertainty factors, which are intended to account for the uncertainty associated with interspecies and intraspecies extrapolation and other factors.
Depending on how close the experimental threshold is thought to be to the exposure of a human population, perhaps modified by the particular conditions of exposure, a larger or smaller uncertainty factor might be required to ensure adequate protection.
For example, if the NOAEL is derived from high-quality data in necessarily limited groups of humans, even a small safety factor 10 or less might ensure safety, provided that the NOAEL was derived under conditions of exposure similar to those in the exposed population of interest and the study is otherwise sound.
If, however, the NOAEL was derived from a less similar or less reliable laboratory-animal study, a larger uncertainty factor would be required NRC, There is no strong scientific basis for using the same constant uncertainty factor for all situations, but there are strong precedents for the use of some values NRC, The regulatory agencies usually require values of 10,, or 1, in different situations.
For example, a factor of is usually applied when the NOAEL is derived from chronic toxicity studies typically 2-year studies that are considered to be of high quality and when the purpose is to protect members of the general population who could be exposed daily for a full lifetime 10 to account for interspecies differences and 10 to account for intraspecies differences.
The requirement for uncertainty factors stems in part from the belief that humans could be more sensitive to the toxic effects of a chemical than laboratory animals and the belief that variations in sensitivity are likely to exist within the human population NRC, a. Those beliefs are plausible, but the magnitudes of interspecies and intraspecies differences for every chemical and toxic end point are not often known.
Uncertainty factors are intended to accommodate scientific uncertainty, as well as uncertainties about dose delivered, human variations in sensitivity, and other matters Dourson and Stara, EPA's approaches to risk assessment for chemically induced reproductive and developmental end points rely on the threshold assumption. The RfD is obtained as described above. The total adjustment or uncertainty factor referred to in the proposed guidelines for use in obtaining an RfD from toxicity data "usually ranges" from 10 to 1, The adjustment incorporates as needed uncertainty factors "often" 10 for " 1 situations in which the LOAEL must be used because a NOAEL was not established, 2 interspecies extrapolation, and 3 intraspecies adjustment for variable sensitivity among individuals.
EPA's revision of its guidelines for developmental-toxicity risk assessment state that "human data are preferred for risk assessment" and that the "most relevant information" is provided by good epidemiologic studies. When these data are not available, however, reproductive risk assessment and developmental-agent risk assessment, according to EPA, are based on four key assumptions:.
An agent that causes adverse developmental effects in animals will do so in humans, with sufficient exposure during development, although the types of effects might not be the same in humans as in animals.
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