Many of the screening-level hazard data being collected and analyzed under ChAMP that pertain to human health are derived from traditional laboratory animal studies. The National Academy of Sciences (NAS) recently offered a "new paradigm for toxicity testing" in its 2008 report Toxicity Testing in the 21st Century: a Vision and a Strategy. Can ChAMP hazard data be used to facilitate the development of new testing strategies?
First, more about the new toxicity testing paradigm envisioned by NAS: Instead of exposing whole animals to chemicals to examine their effects, which takes a lot of time, costs a lot of money and may not always be a good model for how humans can be affected, might we use human cells or tissues (e.g., liver, kidney) to determine how chemicals act biologically? Where chemicals interact with the cells and alter (e.g., inhibit or over-stimulate) critical biochemical pathways, such perturbations may well represent early events or signals that can eventually lead to an adverse effect.
There is an EPA initiative called ToxCast that is exploring the use of high-throughput screening (HTS) test methods to predict hazard, characterize so-called "toxicity pathways," and prioritize among large numbers of chemicals. According to the ToxCast website: "In its first phase, ToxCastTM is profiling over 300 well-characterized chemicals (primarily pesticides) in over 400 HTS endpoints." The endpoints include tests that measure DNA and protein synthesis activities, multi-cell interactions and developmental assays in zebrafish. These methods are among those being developed to realize the vision described in NAS' report.
The results of the first set of ToxCast assays are still being validated – meaning that they are being analyzed to determine how similar the outcomes are to those of standard laboratory animal tests. This is one important step in determining whether the ToxCast testing array can actually substitute for some standard laboratory animal testing.
But we would suggest there are already two timely and useful applications of the data that ToxCast can generate in aiding EPA's effort to evaluate hazard information under ChAMP.
Supporting alternatives analysis
The first idea would be to compare the relative capacity for chemicals in the same functional use class (e.g., solvent, chelator, fragrance) or chemical category (e.g., fatty nitrogen derived cationics) to effect biological changes detectable by the ToxCast HTS methods. In doing so, we would be testing the hypothesis that chemicals that demonstrate less capacity for effecting changes in the HTS tests are more likely to have lower hazard profiles.
As we described in a previous post, alternatives analysis is a tool that compares hazard assessments of chemicals that are used to perform similar functions, in order to identify those that have a lower hazard profile. Using ChAMP hazard data and characterizations for this purpose would start by comparing the results of laboratory animal study data. By running some of the ChAMP chemicals through the ToxCast HTS system and comparing the results of the HTS tests with the ChAMP hazard data, EPA could both support the identification of safer chemicals and test how well the HTS methods predict in vivo effects – a true win-win.
Validating (or refuting) chemical categories
About 80% of the chemicals sponsored under EPA's HPV Challenge Program are members of proposed chemical categories. Within these categories, sponsors and EPA propose that hazard data for tested category members can be "read across" to untested members, as an alternative to direct testing of each chemical.
Grouping chemicals into a category starts with an hypothesis that distinct chemicals that show similarity or regularity in their physical-chemical properties and chemical structures actually possess similar or predictably regular patterns of biological activity. Establishing a valid category requires that the hypothesis actually be demonstrated to be true, once the available data on physical-chemical properties, environmental fate and toxicity/ecotoxicity for the proposed category members are assembled. Then, some degree of read-across among category members can be justified.
However, as our comments on the several ChAMP assessments we've analyzed in recent posts make clear (see here, here and here), both industry sponsors under the Challenge and EPA under ChAMP appear frequently to be over-relying on category approaches, lumping together chemicals that are insufficiently related or similar to warrant read-across.
HTS data could play a very useful role, therefore, in helping either to demonstrate – or to negate – an hypothesis that members of a proposed category of chemicals actually exhibit similar biological activity. If category members in fact exhibit similar or regular patterns of activity across an array of different cellular and subcellular assays, then the case for grouping them for purposes of read-across would be much stronger than a case based solely on similarity or regularity in their physical-chemical properties and chemical structures. Alternatively, if HTS data do not show such patterns, the category should not be utilized and either it should be broken up into smaller groupings or its putative members should be tested individually.
Both of these uses of ChAMP hazard data and characterizations side-by-side with HTS data developed under ToxCast – in supporting alternatives analysis and in category validation – would offer the added benefit of helping to advance the transition to the "new paradigm for toxicity testing."