Toxicological benchmarks

Feng, J., Lurati, L., Ouyang, H., Robinson, T., Wang, Y., Yuan, S., and Young, S.S. Predictive toxicology benchmarking molecular descriptors and statistical methods./. Chem. Inf. Comput. Sci. 2003, 43, 1463-1470. 

In addition to the need for scientific improvements to allow probabilistic risk assessments to be properly performed and interpreted, there also exists a need to educate stakeholders about what the US system for tolerance establishment and monitoring does and does not do. In simplest terms, the US system can be described as a food quality system but not necessarily a food safety system. This results from the fact that the pesticide tolerances are not safety standards but rather exist as enforcement tools that allow an assessment of how well pesticide application regulations are adhered to. Violative residues demonstrate the likelihood of pesticide misuse but should not be considered, in the vast majority of cases, to represent unsafe residues. Safety considerations govern whether or not the use of pesticides on specified commodities will be permitted tolerances, when granted, serve as indicators of good agricultural practices rather than as toxicological benchmarks. 

USDoE, 1996. Toxicological Benchmarks for Wildlife 1996 Revision. ES/ER/TM-86/R3, United States Department of Energy. 

An approach to estimating thresholds of effect for multiple endpoints within a species has been proposed in which distributions of effect measures from different assay endpoints in a species can be used to extrapolate to a no-effect measure for all possible endpoints (Hanson and Solomon 2002). In practice, a distribution of effect measures is constructed and extrapolated to a low probability (Figure 1.5). This value is used as an estimate of the toxicological benchmark concentration (TBC), below which no effect... 

FIGURE 1.5 Illustration of the method for determining a toxicological benchmark concentration (TBC). Note A distribution of endpoints for a species is used to extrapolate to a TBC, below which the likelihood of unmeasured responses being observed is very small. 

In estimating the cumulative risk of a chemical in LCA, dose-response extrapolations can be based on toxicological benchmarks. Such a benchmark approach is considered more appropriate for use in comparative assessment contexts, such as in an LCA study. Benchmarks are an exposure measure associated with a consistent change in response, such as the 10% or even the 50% effect level. Regulatory-based measures do not necessarily provide a consistent risk basis for comparison, as they were often never developed for use in such a comparative context or to facilitate low dose-response extrapolation. Other data differences include the use of median, rather than extreme, data in the fate and exposure modeling, as well as the consideration of safety factors only as part of the uncertainty assessment and not as an integral part of the toxicological effects data. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological or epidemiological data to calculate a BMD. 

Ermer, for example, utilized LCQ to monitor impurity profiles of various batches of ramorelix used in toxicological studies, clinical stndies and scale-up. Ramorelix is a synthetic glycosylated decapeptide with monoisotopic of 1530.7. The toxicological batch served as the benchmark against which all other batches were compared. Molecnlar weights of impurities were determined by ESI mass spectrometry, and nsed in conjunction with UV peak area % to gauge impurities in batches nsed in clinical trials. These impurity profiles were compared to those of batches used in the toxicologically qualified batch. Eour impurities were detected with the same value. They were believed to be diastereoisomers of ramorelix, i.e., a peptide sequence with one of the amino acids in the opposite enantiomeric form. 

Barlow, S. 2005. Threshold of Toxicological Concern (TTC). A tool for assessing substances of unknown toxicity present at low levels in the diet. ILSI Europe Concise Monograph Series. Europe, Bmssels, Belgium ILSI. http //europe.ilsi.org/publications/Monographs/ThreshoIdToxicoIogicaIConcem.htm Barnes, D., G. Daston, J. Evans, et al. 1995. Benchmark dose workshop Criteria for use of a benchmark dose to estimate a reference dose. Regul. Toxicol. Pharmacol. 21 296-306. 

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 initial formulation for most drugs is to allow basic in vivo toxicology, pharmacology and biopharmaceutical assessments to be conducted. Aqueous solutions for injection are optimum for this application since the entire dose is administered at a single time point and the problem of bioavailability does not arise. It is important that these formulations are considered carefully, particularly for drugs that are poorly water soluble, because potentially useful compounds may be rejected inadvertently. These early formulations are also crucial because they set an in vivo benchmark for the drug s future performance. 

Occupational and toxicological studies have demonstrated adverse health effects from exposure to toxic contaminants. Emissions data from stationary and mobile sources are used in an atmospheric dispersion model to estimate outdoor concentrations of 148 toxic contaminants for each of the 60,803 census tracts in the contiguous United States for 1990. Approximately 10% of all census tracts had estimated concentrations of one or more carcinogenic HAPs at a greater than l-in-10,000 risk level. Twenty-two pollutants with chronic toxicity benchmark concentrations had modeled concentrations in excess of these benchmarks, and approximately 200 census tracts had a modeled concentration 100 times the benchmark for at least one of these pollutants. This comprehensive assessment of air toxics concentrations across the United States indicates hazardous air pollutants may pose a potential public health problem (Woodruff et al., 1998). 

In traditional toxicological methods of determining virtually safe doses of hazardous chemicals, nominal thresholds for deterministic responses in humans are estimated based on a NOAEL obtained in human or animal studies. In most high-quality studies, NOAEL is approximately the same as the lower confidence limit of the benchmark dose that corresponds to a 10 percent increase in the number of responses. Thus, as an alternative to the benchmark dose method, the nominal threshold in humans could be set at a factor of 10 or 100 lower than NOAEL obtained in a high-quality human or animal study. However, the benchmark dose method preferred by NCRP... 

The ATSDR use of QSAR and models to predict toxicity is well described by El-Masri et al. (2002). In 1998, the ATSDR established a computational toxicology laboratory and initiated efforts to use Physiologically Based PharmacoKinetic (PBPK) models, BenchMark Dose (BMD) models, and QSARs. PBPK models are used by the ATSDR to ... 

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