The scientific world has been abuzz lately from eye-popping revelations by scientists world-wide of gene mapping, genomics and proteomics. Though many comments have rightly seized on the "historic" nature of the announcements made by the Human Genome Project, it is still uncertain what the new developments will mean long-term for the medical and scientific communities, and most importantly, for the multiple communities that must interact with them. One area fraught with ambiguity even before the announcements of genomics and proteomics is that of toxic testing, particularly as it confronts the issue of science in the courtroom. Since a large number of our readers are intimately involved with toxic tort, we thought it would be helpful, in light of these recent developments, to revisit the issue of testing, first examined in MTI Review in 1996.
As readers of that issue recall, traditionally, there have been three basic types of testing methodologies accepted by both mainstream scientists and courtroom judges in the assessment of toxicity: in vivo(in life), using live animal models; in vitro(in glass), using tissue or cell cultures from humans or animals; and epidemiology studies,charting the incidence and distribution of disease in the human population. Newer alternative methods, such as constructing computer models and futuristic in vitromethods which rely on established data to generate results, have also been developed. These, along with the revelations of the mapping of the genetic code, are now increasingly being discussed as legitimate additions to the mix on toxic testing, thereby clouding the already murky area of proving causation.
This desire to use the new technologies is particularly in the forefront with pharmaceutical issues. Spurred by the exorbitant cost of bringing a new chemical product through the increasingly complex and labyrinthian regulatory phase, pharmaceutical companies have been quick to use the fruits of genomics and proteomics in the toxic testing of new drugs. Genomicsis the study of all genes encoded by an organism's DNA while proteomicsis the study of all the expressed proteins in a cell and thus represents the functional expression of the genome. In seizing upon these technologies, companies hope that earlier recognition of potential toxicity in the product will eliminate many of the costly errors which have occurred in pharmaceuticals in the past, both in terms of dollars and human health; however, it is too early to know how judges are going toview these complex developments, or more importantly, whether they will "view" them at all.
This is particularly the case with genomics, as noted in a recent National Capital Area Symposium of the Society of Toxicology, in Washington, D.C., since the validation of the work is problematic. Still in its infancy, genomics requires elaborate, sophisticated technology on a scale almost unimaginable. Sequencing the human genome involves precise measurements of the ways in which the tiniest portions of the body's cells--the minute, practically invisible building blocks of life--are organized. Cells, chromosomes in cells, and the DNA and genes in chromosomes are analyzed by researchers using extraordinarily powerful microscopes and computers which record not the cells, DNA, or genes themselves but instead chemical reactions involving them. For instance, a DNA molecule is so thin researchers in the Human Genome Project cannot discern the molecule's details for mapping even when using an electron microscope that magnifies cells on the order of 200,000 times, an astronomic scale of magnification and a capability well beyond the average laboratory microscope. To give you an idea of the magnification that results from such a microscope, an ant magnified that amount would be half-a mile in length. Nor is the scientific requirement in viewing the only mind-boggling figures with which both science and the court has to deal. One small gene chip containing only 4,000 of the more than 50,000 genes of the human body mapped so far comes with a price tag of $40,000 and numerous chips are required for just one experimental procedure. It is easy to see how rapidly cost of these new technologies can reach astronomical proportions. The sheer complexity and expense of the process make it impossible to replicate what the Human Genome Project has done, a key component to the "gate-keeping" authority given to judges in the 1993 Supreme Court ruling Daubert v Merrell Dow Pharmaceuticals. When only a handful of scientists even have access to the technology, replicating the results to establish validity is all but impossible and without establishing validity there is little chance of the court accepting unproven methodology.
Of course, it is hoped that at least the monetary end of the problem may resolve itself. In science, as in most other fields of human endeavor, once advances are made with some regularity, the process gradually becomes more affordable. A good example of how this has occurred in the genetic field already is that of DNA testing. The tiniest amount of hair, sweat, semen, blood, skin, etc. can be taken from the crime scene and analyzed to match the DNA to a suspect and help prove either guilt or innocence. The process, once an exotic field of study that seemed to be more in league with science fiction than with science in the courtroom, has become almost routine in criminal cases and the science has been well validated and replicated by peer review many times over. Furthermore, not only has the science become mainstream but the cost has as well. Instead of just one laboratory where you could have the testing done, there are now many and one sample can be tested for under $1000. With alternative methods and the burgeoning technologies, then, the more significant challenge is that of the scientific methodology itself. As pointed out in MTI Reviewin our earlier discussion of toxic testing, one of the chief disadvantages to in vivo testing is that of how animal testing has increasingly come to be viewed. Beyond the eternal problem of extrapolation from one species to another, the issue of more humane treatment of animals has spurred the development of a plethora of alternative methods that mainly utilize computer technologies in creative and innovative ways.
For example, Dr. Theresa Hoffman-Till, at the Bresslar Research Laboratory, at the University of Maryland, reports that her current research involves the determination of whether uranium in military shrapnel caused adverse reproductive effects in the sperm of Gulf War veterans. At the same time, the study seeks to find if computer analysis can be more objective than the traditional manual determination of adverse changes in sperm structure. The sperm is placed on a conventional slide and stained; then, instead of making a qualitative visual assessment of the physical appearance, as has traditionally been done, the specimen is computer analyzed. The British software manufacturer that developed this technique contends that this makes a better quantitative analysis of the specimen and is therefore more accurate in the results which it reports.
In the event the published results of this study--due to be completed in 2002--were to be used in a legal case which argued that reproductive problems were traceable to the shrapnel, what would have to be considered, besides the already inherent variables, would be the validity of the methodology and the reliability of the computer software program which generated the experimental findings. According to Dr. Hoffman-Till, the validity of the methodology is being evaluated using "controls read" by another research lab and then "read" by the software and subsequently used to evaluate the experimental slides. Receiving court approval, however, would be no small challenge, since this program is only one of hundreds of unique softwares that are currently being developed worldwide.
The abundance of computer programs, however, actually may present alternative methodologies with their greatest asset in eventually achieving acceptance in the courtroom. In 1993 combined animal welfare and industrial concerns about alternative tests resulted in Public Law 103-43 that directed the National Institute of Environmental Health Sciences (NIEHS) to devise criteria and processes for the validation and regulatory acceptance of alternative testing. As a result, an ad hoc federal Interagency Coordinating Committee on the Validation of Alternative Methods(ICCVAM) was established. Fourteen federal regulatory and research agencies are now participating in a new standing ICCVAM established as an integral part of the process to review and consider new test methods for acceptance.
ICCVAM VALIDATION AND ACCEPTANCE PROCESS
1. Determine and clearly state the need for a new method.
2. Conduct research to better understand the biologic processes involved.
3. Development of the test method by establishing a model system.
4. Prevalidation by standardizing the test method to minimize variation.
5.Validation by testing a large number of chemicals in several laboratories.
6.Evaluation by an independent scientific peer review panel.
7.Information forwarded to the applicable agencies for acceptance.
8. Implementation of the new test method.
While the ICCVAM's mission is to validate alternative methods of testing, this does not bode the elimination of animal testing. The committee is highly cognizant of the regulators' primary mission to protect human health and recognize "concern for animals can and should be an important consideration, but is secondary tothe mission."
The "gold standard" of toxic testing for the regulatory world has long been the rodent bioassay. Dr. George Parker of BIOTECHNICS, located in Chapel Hill, NC, along with most knowledgeable scientists, believes that animal testing currently affords the greatest validity with tried and true methodology. Animal testing, he observes, involves the complex biochemical milieu of the intact mammal, as opposed to the selected parameters that can be incorporated in computer models. Actually, new technologies are in some sense dependent on in vivo testing, for once all of the biochemistry of the animal is known, then a complete computer model can be constructed. Federal law recognizes the primacy of animal testing inasmuch as it requires that any new chemical product put on the market must first be tested on animals. The Federal Register gives guidelines on how the test is to be conducted, including the minimum number of animals, dosage, length of time administered and follow-up. Although there is little argument in the scientific community over the validity of this methodology for establishing adverse effects in a given species of animal, problems can sometimes arise in extrapolating the findings to the human population. Dr. Parker notes that reasonable scientists continually question the applicability of animal data to the human species, but adds that objective reviews have repeatedly indicated that animals and humans respond similarly to most environmental insults.
Additionally, regulatory agencies have developed elaborate models to estimate risk and in many cases have taken products off the market based on animal studies alone. However, agencies and courts are different forums and have very different perspectives on the use of animal testing results. While agencies act on a mixture of scientific and political grounds, the burden of proof in the courtroom is on the plaintiff to prove--backed by a solid armature of scientific fact--that the exposure sustained caused the adverse effect in a particular person, irrespective of the adverse effects that may have been seen in laboratory animals or perceived by regulatory agencies.
| TOXIC TESTING
METHODOLOGY: MEETING THE DAUBERT GUIDELINES
ANIMAL TESTING GENOMIC TECHNOLOGY
| ||
| A. Technique has been tested | Yes | Yes |
| B. Technique has been subjected to peer review and publication | Yes | No |
| C. Known of potential rate of error of employing technique | Known | Unknown |
| D. Technique has achieved general acceptance in the scientific community | Yes | No |
| Main Advantage | Proven Methodology | Uses the human gene |
| Main Disadvantage | Must be extrapolated to humans | Ethical constraints will still limit in vivo testing in humans |
| Cost | Expensive | Exorbitant |
The new technologies may prove to be the link that can bridge the problem of extrapolating animal studies to humans. In time, as methodologies are validated utilizing genomics, proteomics, computer modeling and other innovative toxic testing methods, we may be able to solve the riddle of mice and men in proving causation.Complete Bibliography Available on Request
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Toxic
Notes
On June 8, 2000, The Environmental
Protection Agency announced Dursban, one of the most commonly used pesticides
in homes and gardens across the United States, would be phased out of pesticide
products and taken off the market within a year. This action was taken
against Dursban, also known by its chemical name chlorpyrifos,
in spite of numerous recent human studies (including the deliberation of an
eight member scientific panel convened by the EPA in concert with the chemical
manufacturer, Dow AgroSciences) which found the chemical caused little or no
harm to human health other than its known effects associated with acute poisoning.
J Toxicol Environ Health B Crit Rev Vol 2, Iss 3 &4, 1999.
The immediate result of this regulatory decision has been to create even more
uncertainty in the area of toxic testing, a field already filled with ambiguity.
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