Limitations of toxicity characterization in life cycle assessment: Can adverse outcome pathways provide a new foundation?

Life cycle assessment (LCA) has considerable merit for holistic evaluation of product planning, development, production, and disposal, with the inherent benefit of providing a forecast of potential health and environmental impacts. However, a technical review of current life cycle impact assessment (LCIA) methods revealed limitations within the biological effects assessment protocols, including: simplistic assessment approaches and models; an inability to integrate emerging types of toxicity data; a reliance on linear impact assessment models; a lack of methods to mitigate uncertainty; and no explicit consideration of effects in species of concern. The purpose of the current study is to demonstrate that a new concept in toxicological and regulatory assessment, the adverse outcome pathway (AOP), has many useful attributes of potential use to ameliorate many of these problems, to expand data utility and model robustness, and to enable more accurate and defensible biological effects assessments within LCIA. Background, context, and examples have been provided to demonstrate these potential benefits. We additionally propose that these benefits can be most effectively realized through development of quantitative AOPs (qAOPs) crafted to meet the needs of the LCIA framework. As a means to stimulate qAOP research and development in support of LCIA, we propose 3 conceptual classes of qAOP, each with unique inherent attributes for supporting LCIA: 1) mechanistic, including computational toxicology models; 2) probabilistic, including Bayesian networks and supervised machine learning models; and 3) weight of evidence, including models built using decision-analytic methods. Overall, we have highlighted a number of potential applications of qAOPs that can refine and add value to LCIA. As the AOP concept and support framework matures, we see the potential for qAOPs to serve a foundational role for next-generation effects characterization within LCIA. Integr Environ Assess Manag 2016;12:580-590. Published 2015. This article is a US Government work and is in the public domain in the USA.

Systems toxicology identifies mechanistic impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite.

BACKGROUND: A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to develop holistic effects characterizations for the wildlife bird model, Northern bobwhite (Colinus virginianus) dosed with the explosives degradation product 2-amino-4,6-dinitrotoluene (2A-DNT). A subchronic 60 d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2A-DNT. Effects on global transcript expression were investigated in liver and kidney tissue using custom microarrays for C. virginianus in both sexes at all doses, while effects on proteome expression were investigated in liver for both sexes and kidney in males, at 30 mg/kg-d. RESULTS: As expected, transcript expression was not directly indicative of protein expression in response to 2A-DNT. However, a high degree of correspondence was observed among gene and protein expression when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Analysis of networks statistically enriched for both transcripts and proteins demonstrated common responses including inhibition of programmed cell death and arrest of cell cycle in liver tissues at 2A-DNT doses that caused liver necrosis and death in females. Additionally, both transcript and protein expression in liver tissue was indicative of induced phase I and II xenobiotic metabolism potentially as a mechanism to detoxify and excrete 2A-DNT. Nuclear signaling assays, transcript expression and protein expression each implicated peroxisome proliferator-activated receptor (PPAR) nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. CONCLUSION: Although the differential expression of transcripts and proteins was largely unique, the consensus of functional pathways and gene networks enriched among transcriptomic and proteomic datasets provided the identification of many critical metabolic functions underlying 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and trinitrotoluene exposures.