A Framework to Guide Selection of Chemical Alternatives (2014) / Chapter Skim
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8 Human Health
8 Human Health
Pages 93-122
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analysis. Data from experimental animal studies are often 34 GHS health hazards are agreed upon internationally for used to draw inferences about the potential hazard characterizing chemical hazards (76 Fed.
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that must be addressed in the alternatives assessment Gather available data on health hazards associated with the chemical of interest and alternatives. Use authoritative lists to record previously identified health concerns.
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Human Health 95 FIGURE 8-1 Committee's framework highlighting the human health hazard assessment.
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For example, the GHS health hazards in chemical alternatives assessments defines acute mammalian toxicity as "adverse effects and to inform the development of the committee's occurring following oral or dermal administration of framework. Table 8-1 shows specific health end a single dose of a substance, or multiple doses given points; prioritized end points; the criteria and within 24 hours, or an inhalation exposure of 4 information sources the reviewed frameworks use hours" (UNECE 2013c)
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Acute Mammalian GHS criteria 1.2.4.5.6,8 MSDS7 OELs OELs OELs Toxicity1,2,4,5,6,7,8 Authoritative IDLH7; LD50/ LC507 GHS 1-5; lists/databases2,4 OELs (NIOSH, LD50/ Priority7 EU Risk phrases, Hazard OSHA, ACGIH) 7 LC50; statements2,4,8 HSDB7; RTECS7 IDLH NIOSH7 Carcinogenicity1,2,3,4,5,6, GHS criteria1,2,3,4,5.6.7,,8 EU Risk phrases, GHS 1A GHS 1B GHS 1B, 2 7,8 Authoritative lists Hazard Priority2,3,4,5,7 2,3,4,6,7,8 statements2,3,4,8 Mutagenicity/ GHS criteria 1,2,3,4,5,6, 7,,8 EU R-phrases, GHS 1A GHS 1B GHS 1B; Genotoxicity1,2,3,4,5,6,7,8 Authoritative lists Hazard 2 Priority 2,3,4,5, 2,3,4,6,7,,8 statements2,3,4,5,6,7,,8 Reproductive GHS criteria2,3,4,5,6,7,8 Authoritative GHS 1A GHS 1B GHS 1B; 2 Toxicity1,2,3,4,5,6,7,8 EPA OPPT criteria lists2,3,4,6,7,8 Priority 2,3,4,5, (HPV)
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End Points Human Animal Human & In Vitro Animal (WOE) Respiratory GHS criteria 1,2,4,5 EU Risk phrases, GHS 1A; Sensitization1,2,3,4,5, Authoritative lists Hazard-statements2,4 1B /databases2,4 EU Annex VI Priority3,5 Category 13 Skin Sensitization1,2,4,7,8 GHS criteria1,2,4, EU Risk phrases, GHS GHS 1A; Authoritative lists2,4 Hazard- 1A;1B 1B statements2,4,8 HSDB7; Sax7; MSDSs7 Skin & Eye Irritation GHS criteria2,4,5,8 EU Risk phrases, HSDB; GHS 1, REACH /Corrosivity 1,2,4,5,7,8 Authoritative lists 2,4,8 Hazard- MSDSs; 2A, 2B skin NIOSH7 statements2,4,8 NIOSH irritation Respiratory Irritation5,7 EPA Office of Pesticide HSDB7 & corro Programs 1 MSDSs7 sion tests Endocrine Activity1,2,4,7/ All available data2,4,7 Toxicity3,5,6,7,8 Authoritative lists2,3,4,6,8 Priority 2,3,4,5 Epigenetic Toxicity 6 No information provided NA NA NA NA 1DfE; 2 IC2; 3CASCP; 4 BizNGO; 5REACH; 6UCLA MCDA (Malloy et al.
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to what extent scientific rigor which uses authoritative lists and databases to determines the level of confidence in lists; and (d) how the classify chemical health hazards.
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, which in the future must be based on GHS criteria, as a source of information to To facilitate comparison of hazard levels across compare the toxicity of chemicals 38 Another data chemicals, some frameworks use hazard classification levels to describe information about the severity of 38 Under the revised Hazard Communication Standard (77 the effect. Hazard classification levels are used most Fed.
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Identifying and addressing the specific. For example, if a chemical meets Benchmark potential impacts of health hazard data gaps in 2 based on hazard analysis but fails to meet the alternatives assessments is an important issue minimum requirements for this benchmark because because it can help ensure that what are thought to of gaps in data, it is assigned an "unspecified" be safer chemical substitutes do not subsequently designation.
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The use of Reproductive toxicity health end points that are aligned with health Development toxicity hazards identified in GHS ensures that assessments address internationally recognized chemical hazards. Respiratory sensitization In addition, using GHS criteria enables alternatives assessments to use toxicity information on chemicals Skin sensitization submitted as Screening Information Data Sets (SIDS)
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health end point that the list is addressing. While supporting the use of GHS criteria, the Use authoritative lists only to identify hazards committee suggests the following refinements to the reliance on GHS criteria and hazard descriptors: Assessments following the committee's framework would consider existing health hazard Use available human data when GHS criteria assessment guidance to classify chemicals based on indicate that they should be used.41 their end point effects, when GHS criteria require the use of expert judgment to establish a health end Describe criteria used.
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Sufficient Experimental Animal Evidence/Limited Human Data The minimum 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 minimum 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)
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process. The question of how various types of reasoned that toxicity pathway-based models human health assessments of chemicals, including are unlikely to contribute quantitatively to chemical alternatives assessment, will be conducted decision making for several reasons, including once a proper suite of in vitro assays, in silico that the statistical variability inherent in such models, and other novel data streams become complex models will hinder their ultimate utility available has come to the forefront of the debate in for estimating small changes in response, and the environmental health community, largely because that such models will likely continue to involve the feasibility of obtaining complex data on empirical modeling of dose-response hundreds, if not thousands, of chemicals became a relationships.
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It offers an opportunity to not that have been associated with known toxicity only compare alternatives with regard to the outcomes and to identify the concentration at potential of human health hazard, but also take which these effects occur. Reverse toxicokinetic into account the quantitative and variability modeling and in vitro to in vivo extrapolations aspects of the underlying adverse effects.
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For example, a classification model that utilized in vitro screening data of 309 environmental chemicals in human constitutive androstane receptor (CAR/NR1I3) , pregnane X receptor (PXR/NR1I2)
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However, while appropriate in vitro solutions for the hazard identification step appear to be within reach, the field is now faced with the challenge of obtaining robust in vitro data on the potency of identified skin-sensitizing chemicals. The availability of such quantitative information may be crucial for an alternatives assessment, if the potential for human exposure varies widely among the chemicals being evaluated.
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; Health Hazards Using in vitro data to fill data gaps for an end In silico models exist for a variety of human point of concern (e.g., endocrine toxicity) ; health end points, but the accuracy of these predictions can vary dramatically.
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Human health risk assessments, including alternatives assessments, will likely be improved if these approaches also consider inter and intraspecies adjustments and biological considerations relating to the assessed in vitro end points (Chiu et al.
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Published models are available in commercial packages such as Case Ultra and Leadscope Model Applier. In addition, Derek Nexus also contains some structural alerts for DART effects that have been
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(2013) recently published "an empirically based decision tree for determining whether or not a chemical has receptor-binding properties and structural features that are consistent with chemical structures known to have toxicity for DART end points." As with the above models and structural alerts, the performance of this decision tree has not been independently assessed, so its performance for truly novel chemical series that have not been previously tested may well be limited.
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. Use of Novel In Vitro Data and In Silico and DNA (direct genotoxicity)
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. In addition to screening for unintended and Use of Novel In Vitro Data and In Silico unexpected consequences by looking at mode- of Models to Fill Data Gaps action information, it is also possible to use high High throughput in vitro data can also be used throughput in vitro screening to look for evidence of to fill certain primary data gaps for particular health nonselective chemical activity at low concentrations.
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Across Approaches Similarity in chemical structure is often used in Limitations of Using In Vitro Data in read-across and QSAR models to identify chemical Alternatives Assessments structures with known activities that could be used to infer the activity of a molecule with unknown High throughput in vitro screening to identify activity. In other words, the idea is to infer that the chemical hazards and prioritize chemicals for less understood chemical will produce an equivalent additional in vivo testing is an area of heightened test result as the more well-understood one (OECD scientific inquiry and regulatory scrutiny.
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. Strategies for predicting in vivo toxicity outcomes from in vitro data are detailed in Figure A and in Martin et al.
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explains this process in more detail. In this analysis, the chemicals with high ToxPi scores may be considered as representing a higher degree of reproductive health hazard.
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. Comparisons mutagenicity or the uncoupling of oxidative between structures are then performed using one of phosphorylation, which are dependent on the a variety of indices that have been developed; for presence or absence of structural alerts, the less example, Euclidean distance measures or maximum applicable the concept of similarity becomes.
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have reproductive effects. Because a large number of proposed general schemes to integrate available QSARs are categorical, and their use in cheminformatics and bioinformatics for improved alternatives assessment is likely even if the prediction understanding of chemical effects on biological outcome is of active/inactive type, the assessors systems.
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alternatives assessments. Specific advice for the completion of Step 6.1 includes: FUTURE RESEARCH NEEDS The assessment should focus on health hazards Implementation of the committee's framework as opposed to health risks.
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Specifically, EPA can help develop best novel in vitro and in silico approaches. This is practices by determining which information available especially true as the development and through the Tox21 and ToxCast programs are most application of tools to assess and integrate informative in assessing human health hazards and novel data streams into the alternatives how and when such data may be incorporated in assessment process evolves.
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