Current Perspectives on the Use of Alternative Species in Human Health and Ecological Hazard Assessments

Background: Traditional animal toxicity tests can be time and resource intensive, thereby limiting the number of chemicals that can be comprehensively tested for potential hazards to humans and/or to the environment. Objective: We compared several types of data to demonstrate how alternative models can be used to inform both human and ecological risk assessment. Methods: We reviewed and compared data derived from high throughput in vitro assays to fish reproductive tests for seven chemicals. We investigated whether human-focused assays can be predictive of chemical hazards in the environment. We examined how conserved pathways enable the use of nonmammalian models, such as fathead minnow, zebrafish, and Xenopus laevis, to understand modes of action and to screen for chemical risks to humans. Results: We examined how dose-dependent responses of zebrafish embryos exposed to flusilazole can be extrapolated, using pathway point of departure data and reverse toxicokinetics, to obtain human oral dose hazard values that are similar to published mammalian chronic toxicity values for the chemical. We also examined how development/safety data for human health can be used to help assess potential risks of pharmaceuticals to nontarget species in the environment. Discussion: Using several examples, we demonstrate that pathway-based analysis of chemical effects provides new opportunities to use alternative models (nonmammalian species, in vitro tests) to support decision making while reducing animal use and associated costs. Conclusions: These analyses and examples demonstrate how alternative models can be used to reduce cost and animal use while being protective of both human and ecological health. Citation: Perkins EJ, Ankley GT, Crofton KM, Garcia-Reyero N, LaLone CA, Johnson MS, Tietge JE, Villeneuve DL. 2013. Current perspectives on the use of alternative species in human health and ecological hazard assessments. Environ Health Perspect 121:1002–1010; http://dx.doi.org/10.1289/ehp.1306638


Ta b l e o f C ontents
. Results for bisphenol A tested in the ToxCast TM battery of assays p 3 Figure S2. Results for prochloraz tested in the ToxCast TM battery of assays p 4 Figure S3. Results for propiconazole A tested in the ToxCast TM battery of assays p 5 Figure S4. Results for fipronil tested in the ToxCast TM battery of assays p 6 Figure S5. Results for prometon tested in the ToxCast TM battery of assays p 7 Figure S6. Results for atrazine tested in the ToxCast TM battery of assays p 8 Figure S7. Results for methoxychlor tested in the ToxCast TM battery of assays p 9 Figure S8. Results for vinclozolin tested in the ToxCast TM battery of assays p 10 Figure S9. Results for fenarimol tested in the ToxCast TM battery of assays p 11 Reference. p 12 2 Supplemental Material, Figure S1. Molecular screening assay results for bisphenol A tested in the ToxCast TM battery of assays (Derived from Knudsen et al. 2011). An AC50 is the in vitro chemical concentration yielding 50% of the maximal activity produced by an assay-specific standard chemical. Assays were identified in which a significant response was detected. Assays were then ranked by AC50. Assays relevant to molecular initiating events associated with established reproductive adverse outcome pathways of fathead minnow (Pimephales promelas) are outlined in red.
3 Supplemental Material, Figure S2. Molecular screening assay results for prochloraz tested in the ToxCast TM battery of assays (Derived from Knudsen et al. 2011). An AC50 is the in vitro chemical concentration yielding 50% of the maximal activity produced by an assay-specific standard chemical. Assays were identified in which a significant response was detected. Assays were then ranked by AC50. Assays relevant to molecular initiating events associated with established reproductive adverse outcome pathways of fathead minnow (Pimephales promelas) are outlined in red.
4 Supplemental Material, Figure S3. Molecular screening assay results for propiconazole tested in the ToxCast TM battery of assays (Derived from Knudsen et al. 2011). An AC50 is the in vitro chemical concentration yielding 50% of the maximal activity produced by an assay-specific standard chemical. Assays were identified in which a significant response was detected. Assays were then ranked by AC50. Assays relevant to molecular initiating events associated with established reproductive adverse outcome pathways of fathead minnow (Pimephales promelas) are outlined in red.
5 Supplemental Material, Figure S4. Molecular screening assay results for fipronil tested in the ToxCast TM battery of assays (Derived from Knudsen et al. 2011). An AC50 is the in vitro chemical concentration yielding 50% of the maximal activity produced by an assay-specific standard chemical. Assays were identified in which a significant response was detected. Assays were then ranked by AC50. Assays relevant to molecular initiating events associated with established reproductive adverse outcome pathways of fathead minnow (Pimephales promelas) are outlined in red.
6 Supplemental Material, Figure S5. Molecular screening assay results for prometon tested in the ToxCast TM battery of assays (Derived from Knudsen et al. 2011). An AC50 is the in vitro chemical concentration yielding 50% of the maximal activity produced by an assay-specific standard chemical. Assays were identified in which a significant response was detected. Assays were then ranked by AC50. Assays relevant to molecular initiating events associated with established reproductive adverse outcome pathways of fathead minnow (Pimephales promelas) are outlined in red.
7 Supplemental Material, Figure S6. Molecular screening assay results for atrazine tested in the ToxCast TM battery of assays (Derived from Knudsen et al. 2011). An AC50 is the in vitro chemical concentration yielding 50% of the maximal activity produced by an assay-specific standard chemical. Assays were identified in which a significant response was detected. Assays were then ranked by AC50. Assays relevant to molecular initiating events associated with established reproductive adverse outcome pathways of fathead minnow (Pimephales promelas) are outlined in red.
8 Supplemental Material, Figure S7. Molecular screening assay results for methoxychlor tested in the ToxCast TM battery of assays (Derived from Knudsen et al. 2011). An AC50 is the in vitro chemical concentration yielding 50% of the maximal activity produced by an assay-specific standard chemical. Assays were identified in which a significant response was detected. Assays were then ranked by AC50. Assays relevant to molecular initiating events associated with established reproductive adverse outcome pathways of fathead minnow (Pimephales promelas) are outlined in red.
9 Supplemental Material, Figure S8. Molecular screening assay results for vinclozolin tested in the ToxCast TM battery of assays (Derived from Knudsen et al. 2011). An AC50 is the in vitro chemical concentration yielding 50% of the maximal activity produced by an assay-specific standard chemical. Assays were identified in which a significant response was detected. Assays were then ranked by AC50. Assays relevant to molecular initiating events associated with established reproductive adverse outcome pathways of fathead minnow (Pimephales promelas) are outlined in red.
Supplemental Material, Figure S9. Molecular screening assay results for fenarimol tested in the ToxCast TM battery of assays (Derived from Knudsen et al. 2011). An AC50 is the in vitro chemical concentration yielding 50% of the maximal activity produced by an assay-specific standard chemical. Assays were identified in which a significant response was detected. Assays were then ranked by AC50. Assays relevant to molecular initiating events associated with established reproductive adverse outcome pathways of fathead minnow (Pimephales promelas) are outlined in red.