Toxicological endpoints

If tlie pollutant causes iui acute non carcinogenic risk, tlie inaximuin one hour concentration is used for C, and tlie acute reference exposure limit is used for tlie REL. Likewise, if tlie pollutant causes a clironic non carcinogenic risk, tlie one year average concentration is used, as is tlie clironic reference exposure limit. In tliis procedure, a Iiazard index is calculated for each pollutant separately, and tlien tlie indices are summed for each toxicological endpoint (i.e., tlie respiratory system, tlie central nervous system, etc.). Finally, tlie total hazard index is tlien compared to a value wliich is considered significant. 

Enslein, Kurt. Estimation of toxicological endpoints by structure-activity relationships. Pharmacol Rev 1984 36 (2, Suppl.) 131-5. 

Cronin, M.T.D., Deardon, J.C., Duffy, J.C. et al. (2002) The Importance of Hydrophobicity and Electrophilicity Descriptors in Mechanistically-Based QSARs for Toxicological Endpoints. SAR and QSAR in Environmental Research, 13(1), 167-176. 

The most commonly used approach, and most conservative, for assessing risks to humans is to compare tire exposure results directly to the appropriate toxicological endpoint by calculating the margin of exposure (MOE margin of safety in many countries), which is given by ... 

The second method involves determination of the probability of an exposure exceeding a known toxicological endpoint. If it is assumed that the absorbed... 

Carcinogenicity is one of the toxicological endpoints that pose the highest concern for human health. Nowadays, protection against cancer resulting from exposure to chemicals in the environment is a critical goal in public health management. 

Different toxicological endpoints which can be useful for a risk-oriented profiling have been evaluated ... 

The US EPA T.E.S.T. is a downloadable program to estimate different toxicological endpoints and physicochemical properties from molecular structure using a variety of QSAR methodologies [58],... 

There are no occupational exposure limits for many hazardous substances which may require control of inhalation exposures. The necessary data and other resources required for setting such limits is restricted and unlikely to match the potential demand. A hazard categorisation scheme was, therefore, developed for application within the chemical industry. The scheme used readily-available information on toxicological endpoints to place hazardous substances into a limited range of hazard categories, expressed as Occupational Exposure Bands. These Bands could be used as a basis for risk assessment and the selection of appropriate control regimes. 10 refs. EUROPEAN COMMUNITY EUROPEAN UNION UK WESTERN EUROPE... 

For some substances, information on some toxicological endpoints is available from clinical and physiological investigations such as provocation tests for detecting allergy, lung function tests, and analyses of biochemical parameters and biomarkers for exposure or effects. 

When data do not exist for a given toxicological endpoint, or when data are limited, the use of SARs may be considered in the hazard assessment. The potential toxicity of a substance, for which no or limited data are available on a specific toxicological endpoint can, in some cases, be evaluated by read-across from structurally or mechanistically related substances for which experimental data exist. The read-across approach is based on the principle that structurally and/or mechanistically related substances may have similar toxicological properties. 

Quantitative Stmcture-Activity Relationships (QSARs) are estimation methods developed and used in order to predict certain effects or properties of chemical substances, which are primarily based on the structure of the substance. They have been developed on the basis of experimental data on model substances. Quantitative predictions are usually in the form of a regression equation and would thus predict dose-response data as part of a QSAR assessment. QSAR models are available in the open literature for a wide range of endpoints, which are required for a hazard assessment, including several toxicological endpoints. 

In recent years, concern that chemicals might inadvertently be disrupting the endocrine system of humans and wildlife has increased. The concerns regarding exposure to these endocrine disrupters are based on adverse effects observed in certain wildlife, fish, and ecosystems increased incidences of certain endocrine-related human diseases and adverse effects observed in laboratory animals exposed to certain chemicals. The main effects reported in both wildlife and humans concern reproductive and sexual development and function altered immune system, nervous system, and thyroid function and hormone-related cancers. Endocrine dismption is not considered a toxicological endpoint in its own right, but a functional change or toxicological mode(s) of action that may lead to adverse effects. Endocrine dismpters are addressed further in Section 4.11. 

For each toxicological endpoint as well as for toxicokinetics, relevant guidance documents, criteria documents, and evaluations from international bodies are mentioned. 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

Munro et al. (1996) explored the relationship between chemical structure and toxicities through the compilation of a large reference database consisting of 613 chemical substances tested for a variety of noncarcinogenic toxicological endpoints in rodents and rabbits in oral toxicity tests, including subchronic, chronic, reproductive, and developmental toxicity. For many of the substances, more... 

They suggested the effect parameter the Critical Effect Dose (CED, a benchmark dose. Section 4.2.5) derived from the dose-response data by regression analysis. This CED was defined as the dose at which the average animal shows the Critical Effect Size (CES) for a particular toxicological endpoint, below which there is no reason for concern. The distribution of the CED can probabilistically be combined with probabilistic distributions of assessment factors for deriving standards... 

The risk characterization is carried out by quantitatively comparing the outcome of the hazard (effects assessment) to the outcome of the exposure assessment, i.e., a comparison of the NOAEL, or LOAEL, and the exposure estimate. The ratio resulting from this comparison is called the Margin of Safety (MOS) (MOS = N(L)OAEL/Exposure). This is done separately for each potentially exposed population, i.e., workers, consumers, and man exposed via the environment, and for each toxicological endpoint, i.e., acute toxicity, irritation and corrosion, sensitization, repeated dose toxicity, mutagenicity, carcinogenicity, and toxicity to reproduction. 

Where a N/LOAEL has been identified for any of the toxicological endpoints mentioned above, it will be compared with the exposure estimate for the exposed human population. Where more than one N/LOAEL has been identified for a specific endpoint, then the most relevant N/LOAEL will be used. 

Since the formulation of precise and well defined substructure queries is not trivial, other approaches to identify unwanted substructures are used as well. If the decisions made by medicinal chemists whether to accept or reject individual screening hits based on purely structural criteria has been captured, this can be used to train a statistical model predicting medicinal chemists judgment on chemical structures. The consensus among medicinal chemists has been demonstrated to be limited [48]. Therefore, this exercise must be based on the decision of a larger group of chemists in order not to bias the model towards the preferences of any individual chemist. In a similar way such models can be trained on experimental toxicity data for an individual experimentally determined toxicological endpoint. 

Roberts, D. W., Aptula, A. O., Patlewicz, G. (2006) Mechanistic applicability domains for non-animal based prediction of toxicological endpoints. QSAR analysis of the Schiff base applicability domain for skin sensitization. Chem Res Toxicol 19, 1228-1233. 

The nature of the toxicological endpoint to be measured. Some endpoints are more readily measured in certain cell types or cell lines. For example, the human hepatoma cell line HepG2 forms colonies with very low efficiency. Therefore some genetic toxicology assays, such as the induction of gene locus mutations, cannot be easily measured in this cell line. 

In addition, we can look forward to refinements in the means to extrapolate from cDNA-expressed enzymes to the balance of enzyme present in human liver in vivo. The examples developed in this chapter were all based on toxicological endpoints using data sets which had previously been published. While this approach shows considerable promise, clearly more extensive validation of the approach, using drugs and drug candidates, is in order. Cyclophosphamide and ifosphamide are two good candidate drugs because of the multiplicity of enzymes which metabolize these compounds. 

All of the previously mentioned exposure methods can be used to estimate either chronic exposure (over a period of years) or acute exposure (single day) for the United States population and population subgroups. Both chronic and acute assessments are usually based on a no observed adverse effect level (NOAEL) in an animal species. Acute exposure is defined relative to an acute (single dose) toxicological endpoint (usually a NOAEL) and may be expressed as a margin of exposure (MOE) or as a percentage of an acute reference dose that is based on a NOAEL and an uncertainty factor (see below). 

Table 27.1 Triazine structures, toxicological endpoints and safety factors...

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