Measuring toxicity endpoints

Several papers have also reported toxicity data for a variety of metals and organic substances simultaneously. Reasons for conducting such investigations include 1) establishing the concentrations at which chemicals exert their adverse effects (e.g., at the ng/L, pg/L or mg/L levels), 2) estimating environmental risk based on measured toxicity endpoints and predicted environmental concentrations for specific chemicals and 3) defining toxicant concentrations harmful for specific biotic levels and/or assemblages of species within each level. 

Toxic endpoint Assessment metric Measurement metric... 

Many of the studies done in safety assessment are multiple endpoint screens. Such study types as a 90-day toxicity study or immunotox or neurotox screens are designed to measure multiple endpoints with the desire of increasing both sensitivity and reliability (by correspondence-correlation checks between multiple data sets). 

Toxicity endpoints measured on Mysifdopsis bahia shrimp, fathead minnow and Daphnia magna. Adapted from [25]. 

QSAR models for legislative purposes have to show that the predicted value has a certain quality. However, its assessment is not easy. In the last year, the debate on the real validity of the QSAR models has seen both supporters and critics. Thousands of models have been produced, and this complicates the evaluation. Indeed, the prediction of some easy physico-chemical properties is surely simpler, while some complex toxicity endpoints, such as carcinogenicity, is much more problematic. But, how to measure the performances and reliability of the QSAR models ... 

To be useful, an assessment endpoint must be measurable. Therefore, one selects a measurement endpoint that provides a quantitative expression related to the assessment endpoint. For the example above, the measurement endpoint may qualify the frequency of mortality within the trout population, using either toxicity tests or field monitoring as to changes in the abundance of species relative to the discharge location and dilution. The toxicity endpoints of chemicals to birds include clutch size, shell thickness, hatchability of eggs, embryiotoxicology, and viability of chicks. In the case of plants, most of the work has been done to assess the effects of metals that can be accumulated by plants known as metallophytes. Some metallophytes are able to grow naturally on metal-contaminated soils. A number of... 

For risk assessments addressing significant acute toxicity endpoints, the arithmetic mean or other reasonably high-end measure of exposure should be... 

Collins JMaEMJ. Measurements of Endpoints in Phase I Drug Design, Toxicity Versus Alternatives. In Budman DR, Calvert AH, Rowinsky EK, Hill BT, ed. 

Toxicologists must rely on results obtained from an alternative method if it is to serve as a replacement for an in vivo toxicity test. Two measures of alternative method performance must be known in order to define reliability from a test user s point of view. First, a toxicologist must know it is possible to consistently reproduce the data obtained from the alternative method over long periods of time. A test that does not provide the same results on the same test substance repeatedly would not be useful in the safety assessment process. Second, it must be possible to consistently predict in vivo toxicity endpoints at a known level of accuracy and precision. These measures of reliability are objective endpoints that can be measured experimentally. The part of the validation process that provides the data needed to confirm the reliability of an alternative method as proposed by its developers is the validation study. 

Figure 2 Plot showing a hypothetical relationship between a specific toxic endpoint measured in vivo and corresponding results from an alternative method. In order for an alternative method to be useful, there must be a consistent and definable relationship between toxicity measured in vAroand corresponding results in the alternative method. In this case, the relationship may be described in terms of a mathematical algorithm, y= mx+ b. If this algorithm is true for all test materials, then any result, x, from this alternative method could be input into the algorithm y=mx+b, to obtain an output, y, which represents the prediction of toxicity in vivo. Such algorithms can be incorporated into prediction models that translate the results from an alternative method into a prediction of toxicity in vivo. Reproduced from Toxicology In Vitro 10 479-501, 1996, Bruner, L. Proctor Gamble.

It is difficult to obtain a set of test substances that has consistent, high-quality toxicity data. The difficulty arises because many different schemes are used for measuring and classifying toxicity endpoints. The situation is made worse by the fact that there is no consistent source for the information that currently exists. This has meant that toxicity data used in validation studies have often come from many laboratories that have used different protocols and produced different kinds of data. 

Ideally, alternative method results should provide nearly perfect predictions of the toxic endpoints measured in the in vivo method. However, there are important technical factors that prevent this ideal from being reached. One of the most important is the variability in the in vivo and alternative method data. If perfect prediction is unrealistic, then what is the best performance that can be expected from an alternative method One approach that can be taken to answer this question is to use computer simulations based on the known performance characteristics of the in vivo test and the alternative method to create a picture that describes how the results from the... 

In order to measure toxicity, it is important to know what to look for. We must have an endpoint for the test. An endpoint can be very precise and easy... 

FIGURE 9.2 Toxicity endpoints and risk measures used in ecological models that have been used to assess the risk of pesticides for nontarget organisms in papers published between 2000 and May 2007. (a) Toxicity endpoints, (b) Measure used to quantify risk. Note that some publications made use of more than 1 toxicity endpoint and more than 1 measure of risk. 

In studies conducted on diseases mainly affecting pediatric patients, the development will be entirely in pediatric patients. However, in addition to the appropriate usual toxicology and neonate animal toxicology, the first-in-humans studies for toxicity and safety are usually done in healthy adult volunteers. Clearly, however, drugs such as the surfactants would yield no useful data from adult testing. For these unique pediatric situations, new measurements and endpoints may need to be developed and validated. Frequently the FDA will involve an advisory panel to help determine what these might be. 

Also the renal 3D models, which have been described recently, have been tested with <10 compounds and their predictivity is unclear. One of these renal 3D models is based on hydrogel-embedded PT isolated from murine kidneys (Astashkina et al., 2012a). Thus, two of the main potential advantages of in vitro models do not apply here, which are (1) use of human cells and (2) avoidance of animal experiments. The four compounds tested with this model included doxorubicin, which gave in addition to cisplatin the most consistent positive resnlts (cytokine release was measured as endpoint). However, in humans doxorubicin toxicity usually does not affect the PT. Doxorubicin has substantial hepato- and cardiotoxicity, but only ntinor toxic effects on the kidney, which are mainly limited to the glomerulus (Tacar et al., 2013). 

Tables 13.4 and 13.5 tabulate cross-sectional epidemiological data for nonoccupational populations sustaining cardiovascular effects from lead exposures using either PbB (Table 13.4) or bone Pb measurements (Table 13.5) as the exposure indicator and BP and/or hypertension as the toxic endpoints. The largest cohorts among these stodies used the exposure marker PbB the U.S. NHANES 11, NHANES 111, and more recent NHANES nationwide surveys (Den Hond et al., 2002 Muntner et al., 2005 Nash et al., 2003 Schwartz 1988 Scinicariello et al., 2010 Vupputuri et al., 2003) and the international surveys. Health Survey for England (HSE Bost et al., 1999), the British Regional Heart Study (BRHS Pocock et al., 1988), and the Belgian Cadmibel Study (BCS Staessen et al., 1993).

Lead nephropathy as a toxicological topic has presented various interpretive clinical and empirical dilemmas. Some appear to have resolved to some extent. Some are mainly confined to nephropathic responses per se. Some are shared with other lead-associated toxic endpoints. A classical endpoint in Pb-induced nephropathy is a reduced estimated or measured glomerular filtration rate (GFR), typically employing creatinine clearance rates, in tandem with measurements of blood urea nitrogen (BUN) and serum creatinine levels. Such declines in GFR are proportional to the level of PbB in chronic injury, subsequent to any transitory hyperfiltration. 

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