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Introduction
The Human Toxicology Project Consortium (HTPC) was formed in 2009 as an international collaboration between the Humane Society of the United States (HSUS), consumer product manufacturers, and nonprofit public interest organizations, uniting to advance a new toxicity testing paradigm proposed by the National Research Council (NRC) in its 2007 report, "Toxicity Testing in the 21st Century: A Vision and a Strategy."

The HTPC currently consists of the following corporations and organizations:

Dow Chemical

DuPont

Exxon Mobil

Hamner Institutes for Health Sciences

HSUS family

- Humane Society of the United States (Consortium Coordinator)

- Humane Society International

- Humane Society Legislative Fund

ILSI Health and Environmental Sciences Institute

The Johns Hopkins Center for Alternatives to Animal Testing (CAAT)

L'Oreal

Procter & Gamble

Toxicology Excellence for Risk Assessment (TERA)

Unilever

Background
"Toxicity Testing in the 21st Century: A Vision and a Strategy" provides the scientific foundation for the HTPC's global initiative. The NRC report committee identified shortcomings that undermine the traditional approach to toxicity testing, and outlined an entirely new testing paradigm to replace it. Among the kinds of limitations highlighted by the committee:
 * The traditional toxicity testing approach exposes test animals to high doses of chemicals, and then extrapolates the predicted effects at lower doses (the doses at which humans are more likely to be exposed). This assumes linear dose-response relationships that often do not exist. The high dose procedure also masks early signs of toxicity that may occur at lower doses. Further, because test protocols are costly in time, money, and animal lives, it is not feasible to test multiple, lower doses.
 * The strategy of extrapolating from animals to humans is also problematic, as such extrapolations have repeatedly proven to be misleading and unreliable:  indeed, 92% or more of drugs tested on animals ultimately fail in human trials – either because of toxicity or lack of efficacy.
 * Outside of the carefully controlled laboratory setting, chemicals are most likely to be encountered in mixtures with other substances, and exposures take place at numerous developmental stages;  testing a nearly infinite variety of mixtures (and in animals at many different life stages) is prohibited by finite resources.

Given these limitations, the capacities of traditional toxicity screening protocols would be quickly outstripped by the increased testing demands imposed by recent and anticipated chemical regulation in Europe (REACH), the United States (the EPA's Endocrine Disruptor Screening Program EDSP, and proposed revisions to Toxic Substances Control Act TSCA) and elsewhere around the world. In addition, despite significant costs in time, money, and animal lives, resulting risk assessments would still have questionable relevance for human biology.

Twenty-first century toxicity testing
The NRC report outlines a "paradigm shift" – a new approach to toxicity testing, and a strategy for implementing the approach on a broad scale. The approach argues for moving the traditional toxicity testing focus on apical endpoints to toxicity pathways and the sequence of events leading to adverse health effects in the exposed organism (see Figure 1). A toxicity pathway is a regular cell-signaling pathway that has been perturbed (e.g., by chemical exposure) so severely it cannot resume normal activity. Toxicity pathways can be probed with a series of in vitro biochemical assays. To investigate points in the pathways for which assays have not yet been developed, targeted (and limited) in vivo animal testing can be conducted.

Importantly, the use of suites of in vitro assays and cultured human cells allows a shift to an automated high-throughput approach to testing. This format allows for more rapid screening and categorizing of chemicals, expands the possibilities for testing mixtures and doses efficiently and economically, and assures human relevance. Since there are tens of thousands of chemicals already in the environment for which regulators need data, traditional animal tests would require many years and potentially hundreds of thousands of animals to completely profile each chemical.

Representatives of the HTPC have advocated in particular for the development and application of Adverse Outcome Pathways (AOPs) as a means to coordinate and implement components of the NRC paradigm. An AOP is a conceptual framework that facilitates the mapping and linking of information and relationships that are "causal, mechanistic, inferential, or correlation based, and the information on which they are based may derive from in vitro, in vivo, or computational systems" (see Figure 2). The AOP framework can be used to consolidate existing information from these multiple sources to create more complete descriptions of each toxicity pathway, reduce redundancy in testing, expose knowledge- and data gaps, and ultimately facilitate more precise risk assessment.

HTPC Activities
The twenty-first century toxicity testing paradigm outlined by the NRC committee combines insights from systems-, computational-, and molecular biology, with technological advances in cell- and tissue-culturing. The approach stands to generate more accurate, cost-efficient and human-relevant toxicity data, leading to more informed and precise risk assessments. To accelerate implementation of the NRC's paradigm, the HTPC works to facilitate proof-of-concept studies, increase financial support and incentives for continued development of necessary technologies, and increase public and regulatory acceptance of pathway-based, non-animal approaches to toxicity testing. It does so by:
 * 1) implementing and advancing the science behind the NRC's approach, through collaboration, informational workshops and strategic investments;
 * 2) communicating the benefits of this paradigm shift to diverse stakeholders through numerous workshop presentations and educational outreach; and
 * 3) Lobbying for increased institutional support and regulatory acceptance of new toxicity-testing methods.

The Human Toxicology Project Consortium documents its activities and outreach at its informational web site, http://humantoxicologyproject.org.