Full opinion text
FINDINGS OF FACT AND CONCLUSIONS OF LAW GILES, District Judge, Sitting by Designation. INTRODUCTION Plaintiff Jacqueline Wade-Greaux commenced this product liability action on her own behalf and on behalf of her daughter, TiaNicole Greaux, on January 21, 1988. Plaintiff alleges that her use during pregnancy of Primatene® Tablets and Primatene® Mist, over-the-counter asthma medications sold by the defendant, Whitehall Laboratories, Inc. (“Whitehall”), caused TiaNicole to be born with true malformation of her upper limbs and other skeletal defects. She has asserted, on behalf of herself and her daughter, claims of strict liability, breach of warranty, negligence and misrepresentation. On October 21, 1991, this court granted Whitehall’s motion for summary judgment against the claims asserted by the plaintiffs mother on her own behalf because they were barred by the applicable statute of limitations. On August 6, 1992, Whitehall moved for summary judgment as to the remainder of plaintiffs claims on the grounds that plaintiffs experts’ opinions were inadmissible at trial or insufficient as a matter of law on the issue of causation. Whitehall’s motion was predicated upon the curricula vitae, written reports and deposition testimony obtained from plaintiffs five causation witnesses: Alan K. Done, M.D.; Enid F. Gilbert-Barness, M.D.; John A. Tilelli, M.D.; Stuart A. Newman, Ph.D.; and John D. Palmer, M.D., Ph.D. The motion was vigorously opposed by plaintiff. After consideration of competing paper submissions of experts’ opinions, the court denied Whitehall’s motion "without prejudice and scheduled a “Downing hearing” to determine finally the admissibility and/or sufficiency of plaintiffs expert opinion evidence on causation. It was agreed that the plaintiff minor’s case was totally dependent upon expert opinion. Following the criteria set forth in Daubert v. Merrell Dow Pharmaceuticals, Inc., — U.S. -, 113 S.Ct. 2786, 125 L.Ed.2d 469 (1993), DeLuca by DeLuca v. Merrell Dow Pharmaceuticals, Inc., 911 F.2d 941 (3d Cir.1990), on remand to 791 F.Supp. 1042 (D.N.J.1992), aff'd, 6 F.3d 778 (3d Cir.1993), and Downing, this court conducted a hearing spanning seven separate days. Testimony was adduced from each of the plaintiffs expert witnesses listed above, with the exception of Dr. Palmer, whose deposition testimony was submitted by plaintiff because he was on a teaching sabbatical in New Zealand and could not attend. Plaintiffs witnesses were required to address both general causation and specific causation. “General causation” concerns whether the agent at issue is capable of causing birth defects in humans at therapeutic dose levels, while “specific causation” concerns whether that agent caused the particular malformations found in this particular plaintiff. Plaintiff also offered testimony from Warren E. Cohen, M.D., a geneticist who offered no opinion as to either general or specific causation, but provided opinion testimony purporting to exclude genetic origins of TiaNicole’s malformations, an opinion upon which plaintiffs causation witnesses relied. Plaintiff withdrew Alan K. Done, M.D. as an expert witness following defendants’ cross-examination of the witness. However, the court refused to exclude the testimony already received from him. Testimony was also received from four expert witnesses offered by Whitehall: Lewis B. Holmes, M.D.; Ellice S. Lieberman, M.D.; Mildred S. Christian, Ph.D.; and Paul A. Greenberger, M.D. The testimony addressed the subjects of teratology, epidemiology, mammalian experimentation, fetal development, genetics, and asthma and its treatment. FINDINGS OF FACT I. Incidence and Causes of Birth Defects 1. TiaNicole Greaux has malformed upper limbs. Each of plaintiffs expert witnesses has reviewed TiaNicole’s medical records, including X-rays, and some have performed physical examinations of her. Plaintiffs experts have attempted to exclude certain possible causes of the malformations. Having done so to their own satisfaction, they have assigned causation to defendant’s products because the drugs in question were allegedly ingested during a critical period of gestation. 2. Defendants, on the other hand, argue that not only have all other possible causes not been excluded but plaintiffs theory of general causation is speculative and inadmissible. Birth defects have existed throughout human history. Palmer Dep. (6/12/92) at 14. Limb deformities, in particular, are as old as recorded history. Cohen Test., Tr. 11/10/93 at 28-29. 3. Roughly 3% of all children born in the United States are born with malformations. Done Test., Tr. 11/16/93 (Mid-Morning) at 32. Data, collected by the Centers for Disease Control in Atlanta, Georgia, show that 1.5 of every 10,000 children born in the United States has a deformity of the upper limbs. Def.Ex. M; Cohen Test., Tr. 11/10/93 at 27-28. 4. Birth defects can be caused by a variety of factors, including genetic and chromosomal abnormalities and environmental agents. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 22; Done Test., Tr. 11/16/93 (Mid-Morning) at 32. Environmental agents may include bacterial or viral infections, chemicals, radiation and drugs, and may account for between 10% and 20% of human malformations. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 22, 27; see Palmer Dep. (6/12/92) at 15. The majority of birth defects, as many as 65%, are of unknown origin. Cohen Test., Tr. 11/10/93 at 25; Done Test., Tr. 11/16/93 (Mid-Morning) at 32; Palmer Dep. (6/12/92) at 14-15. 5. Family history is not dispositive in assessing whether a birth defect has a genetic etiology. There can, for example, be a spontaneous mutation of genes in a child. Cohen Test., Tr. 11/10/93 at 21, 32. Alternatively, a child may suffer from a recessive genetic disorder, in which case each parent passes on a defective gene although neither parent is affected. Holmes Test., Tr. 11/16/93 (Late Afternoon) at 10-12. II. Drugs at Issue 6. Primatene® Mist is an over-the-counter asthma medication that is distributed in a metered-dose inhaler that delivers 0.2 milligrams (“mg”) of epinephrine with each administration. Greenberger Test., Tr. 11/19/93 (Vol. I) at 22-23. Of that amount, only about 10%, or 20 micrograms, of epinephrine gets to the bronchial tubes, with the other 90% being metabolized and deactivated by enzymes in the stomach. Greenberger Test., Tr. 11/19/93 (Vol. I) at 22-23. The 20 micrograms that go to the bronchial tubes are metabolized there. Greenberger Test., Tr. 11/19/93 (Vol. I) at 23. Only about 1 microgram, or .001 mg, of epinephrine gets to the bloodstream per administration of Pri-matene® Mist. Greenberger Test., Tr. 11/19/93 (Vol. I) at 23. In the bloodstream, that 1 microgram gets diluted in the entire blood volume. Greenberger Test., Tr. 11/19/93 (Vol. I) at 23. 7. Epinephrine, also known as adrenaline, is a substance produced endogenously by the adrenal glands. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 18; Tilelli Test., Tr. 11/15/93 (Vol. II) at 67. There is no difference pharmacologically between endogenous and exogenous epinephrine, such that the same blood level of each should produce the same effects. Tilelli Test., Tr. 11/15/93 (Vol. II) at 68; Done Test., Tr. 11/16/93 (Mid-Morning) at 31. 8. Primatene® “P Formula” Tablets are an over-the-counter medication sold for the treatment of asthma; each tablet contains 130 mg of theophylline, 24 mg of ephedrine and 8 mg of phenobarbital. Jacobs Aff. at ¶ 4. 9. Epinephrine and ephedrine are classified as sympathomimetic drugs. The sympa-thomimetic class of drugs includes, among others, pseudoephedrine, phenylpropanola-mine, phenylephrine and isoproterenol. Theophylline is classified as a methylxan-thine drug. The xanthine class includes caffeine and aminophylline. III. Causation A. Teratology 10. The science dealing with the causes of birth defects and their prevention is called teratology. Holmes Test., Tr. 11/16/93 (Vol. II) at 9-15; Tilelli, Tr. 11/15/93 (Vol. II) at 22-23; Newman Test., Tr. 11/12/93 at 48-49. An agent that causes birth defects is known as a teratogen. See, e.g., Holmes Test., Tr. 11/16/93 (Vol. II) at 15. 11. Whitehall called Lewis B. Holmes, M.D., to testify about the science of teratolo-gy and the methodology employed by teratol-ogists. Dr. Holmes is a well-recognized tera-tologisVgeneticist. See Tilelli Test., Tr. 11/15/93 (Vol. II) at 23 (recognizing Dr. Holmes as an eminent teratologist); Newman Test., Tr. 11/12/93 at 14-15. He is a member and past-president of the Teratology Society, the professional organization of tera-tologists. Holmes Test., Tr. 11/16/93 (Vol. II) at 11-12. Dr. Holmes is on the faculty of Harvard Medical School and has been affiliated for 30 years with Massachusetts General Hospital, where he is Chief of the Embryology/Teratology Unit. Holmes Test., Tr. 11/16/93 (Vol. II) at 7-9. 12. Persons who study teratology may come from different medical or scientific disciplines, including pediatrics, obstetrics, embryology, epidemiology and genetics. Holmes Test., Tr. 11/16/93 (Vol. II) at 31-32. Nevertheless, physicians and scientists who study the causes of birth defects, regardless of their specific training and experience, comprise a single medical/seientific community and are known as teratologists. Holmes Test., Tr. 11/16/93 (Vol. II) at 14. The Tera-tology Society, founded in the early 1960’s, has over 600 members. Holmes Test., Tr. 11/16/93 (Vol. II) at 11. B. The Methodology for Determining Human Teratogenicity or General Causation 13. The community of teratologists has developed a methodology for determining whether an agent is a human teratogen. Holmes Test., Tr. 11/16/93 (Vol. II) at 14-26. While different teratologists may articulate their community’s methodology differently, the methodology can be summarized as follows: a. the exposure during pregnancy should be associated with an increased frequency of a distinctive pattern of birth defects, as shown through repeated, consistent epidemiological studies; b. there should be an animal model that duplicates the defects resulting in the human from the exposure; c. there should be a dose/response relationship between the exposure and the effect on the experimental fetus; and d. the mechanism of teratogenicity of the agent should be understood and make biologic sense. Def.Ex. ii; Holmes Test., Tr. 11/16/93 at 15-16, 25-26. See Def.Exs. A, B, D; see also Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 80 (noting that Robert L. Brent, M.D., the author of Def.Ex. ii, is “the king of teratology”); Done Test., Tr. 11/16/93 (Mid-Morning) at 17-18 (noting that James Wilson, whom Dr. Done cited as an authority in teratology, has espoused similar standards). See also Def.Ex. ff at 13 (“studies of terato-genesis in man will of necessity be of a clinical and epidemiological nature”). 14. This methodology is generally accepted within the community of teratologists as that required to determine whether a substance is a human teratogen. Holmes Test., Tr. 11/16/93 at 16-17, 24-26. This methodology has been (i) published in books deemed authoritative within the community of tera-tologists, such as Dr. Thomas H. Shepard’s Catalog of Teratogenic Agents, see Def.Ex. A; see also Tilelli Test., Tr. 11/15/93 (Vol. II) at 23 (recognizing Dr. Shepard’s Catalog as a standard book in the field of teratology), (n) published in authoritative peer-reviewed journals such as Teratology, see Def.Ex. ii, and (iii) taught in universities and medical schools around the country. See Holmes Test., Tr. 11/16/93 (Vol. II) at 26, 33-34; Def.Exs.B, D. Indeed, teratologists do not publish conclusions that a specific agent is a human teratogen unless they have data to satisfy each of the community’s required criteria. Holmes Test., Tr. 11/16/93 (Vol. II) at 24. 15. Regardless of the particular articulation of the teratology community’s methodology, positive human epidemiologic studies are always required to reach a conclusion as to whether a specific agent is teratogenic in humans. Holmes Test., Tr. 11/16/93 (Vol. II) at 17. 16. Each of plaintiffs causation experts, however, has asserted that, while positive human epidemiologic studies would certainly be helpful in reaching a conclusion, such studies were not necessary for them to reach such a conclusion. See, e.g., Gilbert Test., Tr. 11/9/93 (Morning) at 105; Tilelli Test., Tr. 11/15/93 (Vol. I) at 12-17; Palmer Dep. (6/12/92) at 16; Done Test., Tr. 11/16/93 (Mid-Morning) at 21. 17. Despite this testimony, to the extent any of those expert witnesses has engaged in out-of-court medical and scientific activities relating to teratology, they have subscribed to the teratology community’s criteria, specifically requiring positive human epidemiologic studies to reach an opinion as to the terato-genicity of the agent being considered. See Gilbert Test., Tr. 11/9/93 (Afternoon) at 11; Def.Ex. E; Done Test., Tr. 11/16/93 (Mid-Morning) at 13-15, 18-20; Def.Exs. cc, dd. 1. Epidemiology 18. To determine whether exposures to a specific agent during pregnancy are associated with an increased frequency of birth defects, teratologists employ human epidemiological studies. Holmes Test., Tr. 11/16/93 (Vol. II) at 17-18; see Def.Exs. A, B, D. Epidemiology is the study of the distribution of disease in populations and the risk factors associated with particular diseases. Lieberman Test., Tr. 11/18/93 (Vol. I) at 6. It is observational, as opposed to experimental, research, in that epidemiologists observe the differences between those who have had a particular exposure and those who have not. Lieberman Test., Tr. 11/18/93 (Vol. I) at 6-9, 21. A “case control” epidemiologic study tends to be retrospective, comparing persons that have experienced a particular outcome to other persons without that outcome and determining how many in each group were exposed to the risk factor being studied. Lieberman Test., Tr. 11/18/93 (Vol. I) at 6. In a “cohort” study, epidemiologists follow persons with a particular exposure in comparison to other persons not so exposed, and look prospectively to determine the outcome. Lieberman Test., Tr. 11/18/93 (Vol. I) at 8. 19. Epidemiologists use an analytic tool known as the “null hypothesis,” which postulates that there is no association between a specific exposure and a particular outcome. Lieberman Test., Tr. 11/18/93 (Vol. I) at 9. The goal of an epidemiological study is to determine whether one can reject the null hypothesis and conclude that, in fact, there is an association between the exposure and the outcome. Lieberman Test., Tr. 11/18/93 (Vol. I) at 9. 20. Epidemiologists use a measure called the relative risk, or rate ratio, to compare the incidence of disease occurrence in exposed individuals to the incidence of disease occurrence in unexposed individuals. Lieberman Test., Tr. 11/18/93 (Vol. I) at 10-11. A relative risk of “1.00,” therefore, indicates that the disease occurs among the exposed population with the same frequency as the disease occurs among the unexposed population. See Lieberman Test., Tr. 11/18/93 (Vol. I) at 10-11. A relative risk of “2.00” means that the disease occurs among the exposed population with twice the frequency as the disease occurs among the unexposed population. See Lieberman Test., Tr. 11/18/93 (Vol. I) at 10-11. It means that there is a 50% chance that a particular case of the disease was associated with the exposure and a 50% chance that the disease was not associated with the exposure. 21. Epidemiologists use a statistical tool called the “p-value” to measure the probability that a particular relative risk is due to chance. Lieberman Test., Tr. 11/18/93 (Vol. I) at 10. The most common value used to establish significance and to say that an observed association is probably real is “p< .05,” which means that the probability that the association observed is due to chance is less than 5%. Lieberman Test., Tr. 11/18/93 (Vol. I) at 10, 16. 22. A related method of evaluating significance is the confidence interval, which provides a range of values consistent with the data collected. Lieberman Test., Tr. 11/18/93 (Vol. I) at 11. Most common is the 95% confidence interval, which corresponds to the .05 p value. Lieberman Test., Tr. 11/18/93 (Vol. I) at 55. In a 95% confidence interval, there is a 95% probability that the true value of the relative risk lies within that interval. Lieberman Test., Tr. 11/18/93 (Vol. I) at 11. If the confidence interval contains the value of 1.00, then the results are not considered statistically significant. Lieberman Test., Tr. 11/18/93 (Vol. I) at 12-13, 17; Def.Ex. jj. If the lower bound of the confidence interval exceeds 1.00, then the results are considered statistically significant. Lieberman Test., Tr. 11/18/93 (Vol. I) at 13-14, 17; DefiEx. jj. 23. A “positive” epidemiologic study is one that presents a statistically significant association between a particular exposure and an increased risk of experiencing a particular outcome. Lieberman Test., Tr. 11/18/93 (Vol. I) at 38. 24. Regardless of statistical significance, one can never exclude the possibility that a particular association occurred by chance. Even using a 95% confidence interval, there is a 5% likelihood that any association found is not a true association, but is rather a chance occurrence. Lieberman Test., Tr. 11/18/93 (Vol. I) at 10-12. Because of this fact, absent a large single study with an overwhelmingly high rate ratio, epidemiologists generally require several individual positive studies linking a specific exposure with a particular outcome before they draw any conclusions as to an association. Lieberman Test., Tr. 11/18/93 (Vol. I) at 22, 54; see Def.Exs. A, B, D, ii (incorporating that criterion into the teratology methodology). 25. A “confounding factor” is an exposure to one agent that is temporally associated with exposures to other agents, such that they appear to be having the same effect. Lieberman Test., Tr. 11/18/93 (Vol. I) at 14. Thus, for example, because alcohol use is associated with smoking, both may appear to be associated with an increased risk of lung cancer. Lieberman Test., Tr. 11/18/93 (Vol. I) at 14. Epidemiologists use statistical techniques, such as subgroups, multivariate analysis or statistical regression, to eliminate the possible effects of confounding factors. Lieberman Test., Tr. 11/18/93 (Vol. I) at 15, 21. 26. Anecdotal reports of the claimed adverse experiences associated with drug use by individual humans (whether case reports published in medical or scientific journals, drug experience reports filed with manufacturers or regulatory authorities or claims for injuries asserted in a lawsuit) do not constitute epidemiologic data or studies and are not considered by teratologists in studying causation. Holmes Test., Tr. 11/16/93 (Late Afternoon) at 45; Lieberman Test., Tr. 11/18/93 (Vol. I) at 18, 48. Such reports record nothing more than a temporal association between an exposure and a particular occurrence. Lieberman Test., Tr. 11/18/93 (Vol. I) at 18. Because of individual confounding factors, one cannot draw causation conclusions from such anecdotal data. Holmes Test., Tr. 11/16/93 (Late Afternoon) at 45; Lieberman Test., Tr. 11/18/93 (Vol. I) at 18; Tilelli Test., Tr. 11/15/93 (Vol. II) at 50. Epidemiologists use their population studies to eliminate the chance associations and confounding factors, which inherently infect anecdotal reports, to determine whether a statistically significant positive association exists. Lieberman Test., Tr. 11/18/93 (Vol. I) at 15, 18; see Lieberman Test., Tr. 11/18/93 (Vol. I) at 29-30, 48; Tilelli Test., Tr. 11/15/93 (Vol. II) at 50-51. 27. Absent consistent, repeated human epidemiological studies showing a statistically significant increased risk of particular birth defects associated with exposure to a specific agent, the community of teratologists does not conclude that the agent is a human tera-togen. Holmes Test., Tr. 11/16/93 (Vol. II) at 34; Def.Exs. A, B, D, ii. 28. While consistent, repeated positive epidemiological studies are a necessary component for a teratological conclusion, positive epidemiologic findings are, standing alone, insufficient to permit a conclusion that a particular agent is teratogenic because the scientific community also requires confirmatory evidence from experimental animal studies. See Holmes Test., Tr. 11/16/93 (Vol. II) at 22; Def.Exs. B, D, ii. 2. In Vivo and In Vitro Animal Studies 29. In vivo animal studies are those conducted in a living animal. In vitro animal studies are those employing animals cells in a controlled environment, such as a test tube or Petri dish. 30. Although animal studies play a role in teratological investigations, it is scientifically invalid to extrapolate observations in animal experiments directly to human beings to determine human teratogenicity. Christian Test., Tr. 11/18/93 (Vol. II) at 17; see Def. Exs. A, B, D, ii. While there are approximately 2,000 agents that have been shown to be teratogenic in some animal species, there are only about 25-30 proven human terato-gens. Done Test., Tr. 11/16/93 (Mid-Morning) at 42; Tilelli Test., Tr. 11/15/93 (Vol. II) at 60. Sugar and table salt have been shown to be teratogenic in some animal species, although they are not human teratogens. Palmer Dep. (6/12/92) at 128-131. The agents that are considered to be proven tera-togens in humans were established as such by human data. Done Test., Tr. 11/16/93 (Mid-Morning) at 42-43. As Dr. Done testified, human data is the glue that holds together all other data. Id. 31. Expert witnesses for both the plaintiff and the defendant recognize the principle of “species specificity.” See Christian Test., Tr. 11/18/93 (Vol. II) at 18; Tilelli Test., Tr. 11/15/93 (Vol. II) at 59-60; Done Test., Tr. 11/16/93 (Mid-Morning) at 38; Palmer Dep. (6/12/92) at 126; Newman Test., Tr. 11/12/93 at 66; Gilbert Test., Tr. 11/9/93 (Morning) at 45, 47. Species specificity refers to the fact that different mammalian species present different physiological, biochemical and meta-bolie systems. Christian Test., Tr. 11/18/93 (Vol. II) at 18. Similarly, mammals differ from non-mammalian species in at least these same respects. Christian Test., Tr. 11/18/93 (Vol. II) at 16-18. Because of these differences, different species have varying sensitivities to drugs and chemical agents. Christian Test., Tr. 11/18/93 (Vol. II) at 18; Tilelli Test., Tr. 11/15/93 (Vol. II) at 59-60; Palmer Dep. (6/12/92) at 126; Newman Test., Tr. 11/12/93 at 68; see Gilbert Test., Tr. 11/9/93 (Morning) at 45, 47. Different strains within the same species have different sensitivities to a particular agent. Christian Test., Tr. 11/18/93 (Vol. II) at 18. Thus, some drugs are teratogenic in some species and not tera-togenic in others. Tilelli Test., Tr. 11/15/93 (Vol. II) at 59. Because of this recognized biological fact, if animal data shows that an agent is teratogenic in one species, one cannot conclude based on that data alone that the agent will be teratogenic in another species. Tilelli Test., Tr. 11/15/93 (Vol. II) at 59; see Gilbert Test., Tr. 11/9/93 (Morning) at 45, 47; Done Test., Tr. 11/16/93 (Mid-Morning) at 41; Palmer Dep. (6/12/92) at 126-128; Christian Test., Tr. 11/18/93 (Vol. II) at 18. 32. Because of the differences among species, there is recognized within the tera-tology community a hierarchy of in vivo animal studies. Newman Test., Tr. 11/12/93 at 126. Mammalian studies are accorded more weight than are non-mammalian studies, and within mammalian species, primate studies are given greater weight than any other. Newman Test., Tr. 11/12/93 at 126-127; Ti-lelli Test., Tr. 11/15/93 (Vol. I) at 16. In vitro studies, which are not conducted in living organisms, are given less weight than in vivo studies. See Christian Test., Tr. 11/18/93 (Vol. II) at 17; Done Test., Tr. 11/16/93 (Mid-Morning) at 37. 33. In addition to species specificity, the results of animal studies cannot be extrapolated to humans because such studies often employ quantities of the agent far in excess of the equivalent human therapeutic dose. Holmes Test., Tr. 11/16/93 (Vol. II) at 29; Done Test., Tr. 11/16/93 (Mid-Morning) at 38^10. A principle of teratology, known as Karnofsky’s law or “sledgehammer teratolo-gy,” recognizes that at some dosage level, virtually any substance, even sugar or salt, can cause malformations. Holmes Test., Tr. 11/16/93 (Vol. II) at 29-30; see Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 22; Palmer Dep. (6/12/92) at 128-131. High dosage animal studies cannot be relied upon to determine whether a substance is teratogenic in humans in therapeutic doses. Holmes Test., Tr. 11/16/93 (Vol. II) at 29; see Done Test., Tr. 11/16/93 (Mid-Morning) at 41. 34. The route of administration of an agent, which affects potential teratogenic result, is often different in experimental animal studies from the route employed by humans. Done Test., Tr. 11/16/93 (Mid-Morning) at 39; Tilelli Test., Tr. 11/15/93 (Vol. II) at 60-62; Holmes Test., Tr. 11/16/93 (Late Afternoon) at 21-22. While humans may ingest an agent, animal studies investigating use of that same agent may involve injections subcutaneously, intramuscularly, intravenously or sometimes directly into the uterine cavity. Done Test., Tr. 11/16/93 (Mid-Morning) at 39; Tilelli Test., Tr. 11/15/93 (Vol. II) at 60-61; see Holmes Test., Tr. 11/16/93 (Late Afternoon) at 21-22. Indeed, the stress caused by the means of administration in the experimental animal may itself cause the defects observed in the fetus. Done Test., Tr. 11/16/93 (Mid-Morning) at 39-40; Gilbert Barness Test., Tr. 11/9/93 (Afternoon) at 20. 35. One particular reason why the route of administration affects teratogenic potential relates to maternal metabolism. Metabolism is the process by which the body uses enzymes to alter the chemical composition of a foreign substance. The products of metabolism are called metabolites. Tilelli Test., Tr. 11/15/93 (Vol. II) at 61; Palmer Dep. (6/12/92) at 81. 36. Although maternal metabolism in the human may affect any teratogenic potential of an agent, animal studies that involve direct application of the agent to the embryo or fetus do not account for maternal metabolism. For example, some in vivo tests inject the agent directly into the uterine cavity and some in vitro tests involve dripping the agent directly onto the embryonic system or placing cells in a solution containing the agent. Done Test., Tr. 11/16/93 (Mid-Morning) at 39; Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 108-09; Newman Test., Tr. 11/12/93 at 113. In such tests, the agent is never subjected to the metabolism of the maternal animal system and is never eliminated from the biologic system. Tilelli Test., Tr. 11/15/93 (Vol. II) at 61-62; Palmer Dep. (6/12/92) at 85-86. Such tests provide little, if any, understanding of the human exposure. 37. Animal studies, appropriately conducted, can be helpful in determining human teratogenicity. Animal studies provide information regarding the pattern of response and possible biologic mechanisms that may help explain how malformations detected in human beings develop. Christian Test., Tr. 11/18/93 (Vol. II) at 17-18. Once a potential teratogenic effect in humans is identified by positive epidemiologic studies, a mechanistic study in an animal model can help determine whether that observed effect is biologically plausible. Christian Test., Tr. 11/18/93 (Vol. II) at 14. 38. A dose/response relationship refers to the fact that an increase in the dosage of a teratogenic agent should lead to an increase in both the number and severity of malformations. Holmes Test., Tr. 11/16/93 (Vol. II) at 21; Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 115-118, (Afternoon) at 126. Animal studies also are used to determine whether there is a dose/response relationship that will help to establish a teratogenic effect. IV. Methodologies and Data Used By Plaintiff’s Expert Witnesses to Opine on General Causation 39. Plaintiff offered five witnesses to express opinions regarding the teratogenicity of Primatene® Tablets and Mist in humans at therapeutic doses. As discussed separately below, each witness described his or her credentials and experience, the methodology followed, the data considered and the ultimate opinions he or she derived therefrom. 40. Plaintiffs expert witnesses each opined that sympathomimetics and methylx-anthines, active ingredients of Primatene® Tablets and Mist, are potentially teratogenic in humans. E.g., Gilbert-Barness Test, Tr. 11/9/93 (Morning at 64, 82). None of plaintiffs experts, however, offered a non-speculative basis for concluding that the Prima-tene® products are teratogenic in humans in therapeutic doses. A. Enid F. Gilbert-Barness, M.D. 41. Dr. Gilbert is a respected pediatric pathologist, developmental pathologist and genetic pathologist and she describes herself as a teratologist. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 13, 16. 1. Dr. Gilbert’s Methodology 42. Dr. Gilbert testified that she does not believe that repeated, consistent epidemio-logic studies showing a statistically significant increased risk of malformations associated with the use of a medication are required to reach a scientifically valid conclusion as to whether that medication can cause malformations in humans at therapeutic dosage. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 104-105. This is contrary to the methodology generally accepted in the teratology community and published in the authoritative teratological literature. 43. Dr. Gilbert subscribes to the view that no drug is 100 percent safe during pregnancy and would advise any pregnant woman to refrain from taking any drug that is not essential to her health. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 89. Dr. Gilbert’s prophylactic philosophy is that any compound that manifests a developmental defect in an animal species must have a potential for injury in humans. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 63; Tr. 11/9/93 (Morning) at 45-47. Dr. Gilbert believes if one gets a significant positive result in a chick embryo, that while you could not extrapolate directly to a human, that positive result should cause a reasonable person to become suspicious about what could happen in human bodies by the ingestion of that drug. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 47, 67). This approach is a prospective, predictive risk/benefit analysis that is irrelevant to an after-the-fact approach to determining causation-in-fact. 44. Although Dr. Gilbert disavows in the courtroom the methodology generally accepted by the scientific community, she has published articles to the scientific community regarding the potential teratogenic impact of agents in humans in which she has recognized and adopted that methodology. 2. Dr. Gilbert’s Lack of Epidemiological Support 45. Dr. Gilbert was unable to offer repeated, consistent epidemiologic studies in support of her opinion. Indeed, Dr. Gilbert pointed to only one epidemiologic study that she claimed supported her opinion: an article written by Martha Werler entitled First Trimester Maternal Medication Use in Relation to Gastroschisis, 45 Teratology 361 (1992) (“Werler”). Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 93; Def.Ex.C. 46. The Werler study found a statistically significant association between pseudoephed-rine and gastroschisis. See Def.Ex.C. Pseu-doephedrine is a sympathomimetic drug that is not found in Primatene® and gastroschisis is a defect of the abdominal wall that is not found in TiaNicole Greaux. See Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 96-97. The Werler study, however, also considered limb defects, which TiaNicole Greaux does have, and concluded that there was no statistically significant association between limb defects and the use of the sympathomimetic pseudoephedrine. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 98; Def.Ex.C. Even with respect to the positive finding for gas-troschisis, Werler cautioned that, because of significant confounding factors, additional questions needed to be “answered before drawing even tentative conclusions about the teratogenicity of vasoactive medications.” Gilberk-Barness Test., Tr. 11/9/93 (Morning) at 99; Def.Ex.C. Further, even as to gas-troschisis, the report stated, “[o]ur findings were not examined according to the dose, frequency, duration or timing. We were not able to rule out whether an underlying illness, perhaps an influenza virus, could have accounted for the finding, or for the elevated risks .for analgesic/antipyretic use. There may be confounding by other factors, such as cocaine use.” Def.Exh.C, p. 367. Given its stated limitations and cautions, no testifying expert’s opinion could reasonably rely upon the Werler study to draw a conclusion that any of the ingredients of Primatene® Tablets or Mist do cause limb defects in humans at therapeutic doses. Lieberman Test., Tr. 11/18/93 (Vol. I) at 45. To the extent Dr. Gilbert-Barness’ opinion is premised upon the Werler study, it is inadmissible on the question of general causation. 3. Dr. Gilbert’s Chick Embryo Studies 47. Dr. Gilbert has performed a number of chicken embryo studies during her career. Her particular interest in performing these studies has been to contribute to the understanding of cardiac development. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 106-07. Nevertheless, she relies upon certain of those studies for opinions expressed in this case because she associates heart malformations with skeletal differentiations. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 28-29, 93. While those studies may suggest to a scientist that a drug in humans may not be entirely safe under all circumstances, see Gilbert-Barness Test Tr., 11/9/93 (Morning), at 45, human risk precautionary interest does not translate into human causation evidence. 48. Dr. Gilbert conducts her chick embryo studies by taking a fertile egg weighing approximately two ounces, removing a small, rectangular section of the shell, while leaving the chorioallantoic membrane intact, and applying to the developing embryo the agent that is being studied. Gilber1>-Barness Test., Tr. 11/9/93 (Morning) at 108-09. Such chick embryo studies are an in vitro, not an in vivo, animal model, and do not replicate a mammalian, let alone a human, exposure. Christian Test., Tr. 11/18/93 (Vol. II) at 16; Done Test., Tr. 11/16/93 (Mid-Morning) at 37. 49. The chick model is disfavored in the teratology community because it does not replicate human exposure. See Def.Exs. B, D. While Dr. Gilbert disputes that the chick model is disfavored, she does not contend that it replicates human exposure. At least four things happen in the exposure of a human fetus that do not occur in the chick embryo model: (i) absorption of the agent by the mother, (ii) distribution of the agent throughout the maternal and fetal systems, (iii) metabolism of the agent by the maternal system and (iv) elimination of the agent by the mother and fetus, thereby limiting the duration of the exposure. Christian Test., Tr. 11/18/93 (Vol. II) at 16-17. In chick embryo studies, the agent is dropped directly onto the embryo and is not subjected to maternal metabolism, Christian Test., Tr. 11/18/93 (Vol. II) at 17; Tilelli Test., Tr. 11/15/93 (Vol. II) at 64; Palmer Dep. (6/12/92) at 85-86; Newman Test., Tr. •11/12/93 at 117, is not distributed throughout the maternal and embryonic systems, Christian Test., Tr. 11/18/93 (Vol. II) at 17; see Newman Test., Tr. 11/12/93 at 32, and is not eliminated from the embryonic system, resulting in constant exposure until birth. Christian Test., Tr. 11/18/93 (Vol. II) at 17; see Newman Test., Tr. 11/12/93 at 113, 118-119 (regarding prolonged exposure in Petri dish experiments). 50. The chick embryo model is also disfavored in the scientific community because it is so sensitive that virtually any exposure will cause a malformation. Christian Test., Tr. 11/18/93 (Vol. II) at 16; see Def.Exs. B, D. 51. Dr. Gilbert cited two chicken embryo studies in support of her opinion: one relating to the administration of Tedral® to chick embryos and another relating to the administration of certain sympathomimetics and methylxanthines to chick embryos. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 30-31. In the first study, theophylline levels of between 1.0 mg and 2.8 mg were administered to eggs weighing approximately 2 ounces, the equivalent of administering, at a minimum, between 7 and 18 tablets of Tedral® or Primatene® to a 110 pound woman. See Def.Ex. -F; Gilbert-Barness Test., Tr. .11/9/93 (Afternoon) at 34. In the second study, between 2.5 mg and 5.0 mg of theophylline were applied, the equivalent of administering, at a minimum, between 17 and 33 tables of Tedral® or Primatene® to a 110 pound woman. See Def.Ex. FI. The maximum recommended dose of Primatene® tablets is 2 tablets. 52. The two chick studies cited by Dr. Gilbert are not helpful in determining effects in humans because of the principles of species specificity and “sledgehammer” teratolo-gy, and because the chick embryo model is so vastly different from the human experience. Dr. Gilbert testified that she could not estimate the degree to which she could extrapolate from those studies to the human experience “because every animal species varies in susceptibility.” Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 45. 4. Dr. Gilbert’s Tedral® Case Report 53. The second article cited by Dr. Gilbert was a case report written by her and others published under the title An Aborted Human Fetus with Truncus Arteriosus Communis—Possible Teratogenic Effect of Tedral®, 1 Heart and Vessels 176 (1985). Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 31; Tr. 11/9/93 (Afternoon) at 4-12; see Def.Ex. E. 54. The Tedral® case report concerns a woman who aborted a malformed fetus after being treated with several medications during an emergency hospitalization for an overdose of Tedral®. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 31; Tr. 11/9/93 (Afternoon) at 7; see Def.Ex. E. In her case report, Dr. Gilbert notes that Tedral® had never previously been implicated as a human teratogen, and discloses that there were a number of environmental factors confounding any association. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 7-9; see Def.Ex. E. For example, during her pregnancy, the woman in the report (i) had smoked one to three packs of cigarettes per day, (ii) had suffered with an upper respiratory infection, (iii) had a familial history of alcoholism and, (iv) most significantly, when being treated for the Tedral® overdose, was given other medications, including Ativan, Valium, aspirin and Corgard. See Def.Ex. E. Another of plaintiffs expert witnesses, John A. Tilelli, M.D., testified that Corgard is vasoactive and that Ativan and Valium have had embryopathies reported in association with their use. Tilelli Test., Tr. 11/15/93 (Vol. II) at 57-58. 55. When asked whether she believed that Tedral® caused the malformations reported in her article, Dr. Gilbert responded that it seemed to her that Tedral® and the malformations “may be related.” Gilberts Barness Test., Tr. 11/9/93 (Morning) at 40. This is a speculative opinion that does not meet either a reasonable certainty or reasonable probability standard. As the published title of the case report reflects, Dr. Gilbert did not assert that Tedral® caused the observed malformations of the fetus, but concluded only that Tedral® was a possible cause. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 6; see Def.Ex. E. 56. Dr. Gilbert concluded that case report by stating that “[f]urther human epidemiological studies and mammalian experimentation will be needed to confirm a teratogenic effect of Tedral® during early pregnancy.” Gilberfi-Barness Test., Tr. 11/9/93 (Afternoon) at 11; see Def.Ex. E. This statement, published in a peer-reviewed scientific journal, is consistent with the methodology generally accepted by the community of teratolo-gists (ie., the need for human epidemiologic data disclosing a statistically significant elevated risk), which methodology Dr. Gilbert sought to disavow in court. 5. Dr. Gilbert’s Rabbit Study 57. As noted, non-mammalian studies, such as those involving chick embryos, are accorded less weight by teratologists than are mammalian studies. Newman Test., Tr. 11/12/93 at 126-127; Tilelli Test., Tr. 11/15/93 (Vol. I) at 16. Dr. Gilbert acknowledged that one necessary component for reaching a conclusion as to the human teratogenicity of an agent is a mammalian animal model that demonstrates both a dose/response relationship and malformations at exposures comparable to the therapeutic dose in humans. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 105, (Afternoon) at 69; see Def.Exs. B, D. 58. Dr. Gilbert cited in support of her opinion only one mammalian study: her own experimental study involving the administration of Primatene® Tablets and Mist to rabbits. Gilbert-Barness Test., Tr. 11/9/93' (Morning) at 29-30. The court finds that this study is analytically invalid, inadmissible and fatal to any expert opinion dependent thereon. a. Purpose Of The Study 59. The rabbit study is an essential predicate for Dr. Gilbert’s opinion. When she was first contacted by plaintiffs counsel, she had already performed numerous studies of the effects of sympathomimetics and methylxan-thines on chick embryos and had written the Tedral® case report. At that time, Dr. Gilbert, advised plaintiffs counsel that she could not give him an opinion that Primatene® Tablets and Mist were teratogenic in humans at therapeutic dosage until she had performed a mammalian study that would support such an opinion. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 66. Dr. Gilbert acknowledged at the hearing that she did not have an opinion as to causation in the absence of a positive study in mammals. Gil-berh-Barness Test., Tr. 11/9/93 (Afternoon) at 67. 60. Plaintiffs counsel paid for Dr. Gilbert’s out-of-pocket costs related to the pilot study involving the administration of Prima-tene® Tablets and Mist to rabbits. Gilberb-Barness Test., Tr. 11/9/93 (Morning) at 29; Tr. 11/9/93 (Afternoon) at 134. b.Rejection by Teratology 61. Although the study was conceived by Dr. Gilbert, it was designed in part and performed by Barbara Spennetta, an animal resources coordinator at Promega Laboratories. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 69-71. Once the study had been completed, Dr. Gilbert prepared a manuscript that she submitted to Teratology, the peer-reviewed journal of the Teratology Society. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 120; Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 106-07. Teratology rejected the manuscript and returned it with criticisms. GilberWBarness Test., Tr. 11/9/93 (Morning) at 120; Gilberh-Barness Test., Tr. 11/9/93 (Afternoon) at 106-07. 62. Thereafter, Dr. Gilbert enlisted John A. Tilelli, M.D., another of plaintiffs expert witnesses, to rewrite her report of the study. Tilelli Test., Tr. 11/15/93 (Vol. II) at 70. Dr. Tilelli had never collaborated with Dr. Gilbert before and did not know her prior to his involvement with this case. Tilelli Test., Tr. 11/15/93 (Vol. II) at 72. Dr. Gilbert sent Dr. Tilelli two drafts of the manuscript of her study, but did not send him, and he did not see, any of the data underlying the rabbit study. Tilelli Test., Tr. 11/15/93 (Vol. II) at 72-73; see Def.Exs. T. U. Dr. Tilelli simply revised Dr. Gilbert’s draft, added his own name as an author and, with Dr. Gilbert’s approval, submitted the revised draft to a veterinary publication, Veterinary and Human Toxicology. 63. Dr. Gilbert did not report either in her manuscript to Teratology or in the later manuscript to Veterinary and Human Toxicology that plaintiffs counsel contributed to the costs of the study. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 134. The authors intend to provide this information if they resubmit the manuscript. 64. Neither Dr. Gilbert nor Dr. Tilelli is an expert in the characteristics of rabbits, particularly the New Zealand white rabbit strain used in the study. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 117-120; Dr. Tilelli Test., Tr. 11/15/93 (Afternoon) at 23. c. Qualifications of Those Involved in the Study 65. While Dr. Gilbert had performed dozens of chick embryo studies, she had conducted only one previous rabbit study in her career. Gilbert-Barness Test., Tr. 11/9/93 (Morning) at 112; Tr. 11/9/93 (Afternoon) at 124. Ms. Spennetta, who actually conducted the test, was an animal husband technician who cared for animals at Promega Laboratories, a manufacturer of biological products. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 70. Her only previous experience with a mammalian teratological study was her involvement in Dr. Gilbert’s earlier rabbit study. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 125. Dr. Tilelli, who revised the manuscript, is neither a teratologist nor a research scientist. This was the only teratol-ogy study in which he had ever been involved. Tilelli Test., Tr. 11/15/93 (Vol. I) at 6, 11; Tr. 11/15/93 (Vol. II) at 22. d. Scientific Invalidity of Conclusions 66. The rabbit study, as rewritten by Dr. Tilelli and endorsed by Dr. Gilbert, concluded that administration of Primatene® (i) caused malformations in rabbits, (ii) had an adverse effect on fertility, (iii) increased the incidence of post-partum deaths and (iv) affected post-natal somatic growth. Def.Ex. X. 67. Plaintiffs experts demonstrated great confusion as to the number of rabbits used in the study. Since they are confused, a jury would be no less confused. Although the written report indicated that there were 21 rabbits, see Def.Ex. X, both Dr. Gilbert and Dr. Tilelli testified that they thought there were actually 13 rabbits. See Gilberb-Barness Test., Tr. 11/9/93 (Morning) at 55, 113; Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 99; Tilelli Test., Tr. 11/15/93 (Vol. II) at 75, 78. These variations could affect substantially the statistical conclusions given the small number of rabbits used in the study by any measure. Christian Test., Tr. 11/18/93 (Vol. II) at 24-25. Ms. Spennetta’s laboratory notebook for the test indicates that there were only 16 female rabbits used in the study. Christian Test., Tr. 11/18/93 (Vol. II) at 20; see Déf.Ex. L. Moreover, these rabbits were spread over multiple dosage groups, so that most dosage groups had only one rabbit in them. Christian Test., Tr. 11/18/93 (Vol. II) at 21-24. Because too few animals were used in too many dosage groups, there is no scientifically valid basis for identifying causal relationships in the test. Christian Test., Tr. 11/18/93 (Vol. II) at 24-25. Aggregated results from all “high dose” and “low dose” groups made it appear as if there were only two dosage groups. This was a scientifically inappropriate procedure. Christian Test., Tr. 11/18/93 (Vol. II) at 22-23. 68. Dr. Gilbert contended that her rabbit study was a mere pilot study to see if malformations could be induced using defendant’s products. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 51, 71, 72. Even if it qualified as a pilot study, however, Dr. Gilbert admitted that scientists would consider the pilot test only to determine whether it suggested reasonable hypotheses that should be further tested to determine if the products in fact had a teratological impact in that animal model. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 51, 72. Consequently, it would follow that it is inappropriate for Dr. Gilbert or any other scientist to rely upon this rabbit study to support an opinion offered in a court of law. Further, neither Dr. Gilbert nor Dr. Tilelli was familiar with the underlying data of the study which, when considered, undercuts conclusions in the written report regarding malformations. 69. While Dr. Tilelli’s report of the study indicates that there were four pups born with “ventral, midline, chest and abdominal wall defects,” see Def.Ex. X, the underlying data show only one fetus with that condition and only three with any kind of malformation. Christian Test., Tr. 11/18/93 (Vol. II) at 30-32. The abdominal wall defect described is known as thoracogastroschisis, a condition that occurs spontaneously in between 2-10% of the type of rabbits used in Dr. Gilbert’s test. Christian Test., Tr. 11/18/93 (Vol. II) at 30-31; Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 117, 119. Because all malformations were found in low-dose groups and none in a high-dose group, the required dose/response relationship does not exist. Christian Test., Tr. 11/18/93 (Vol. II) at 31; Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 126,127; This shows either that the test was invalidly constructed or that the drugs are not teratogenic in the rabbit. 70.The finding regarding the adverse effect on fertility is also invalid: First, Ms. Spennetta purchased “retired breeders” for the test. This indicates that the female rabbits used were past their prime period of fertility. Christian Test., Tr. 11/18/93 (Vol. II) at 33-34. Second, the fertility finding is compromised by the fact that the protocol’s directions regarding the mating of male rabbits was not followed. Christian Test., Tr. 11/18/93 (Vol. II) at 33. Specifically, Ms. Spennetta did not give all of the male rabbits the required rest period for sperm recovery. Christian Test., Tr. 11/18/93 (Vol. II) at 27-28. At least two of the females who experienced breeding problems had been mated to a male that had not been given sufficient rest. Christian Test., Tr. 11/18/93 (Vol. II) at 28. Although Dr. Gilbert attributed such breeding problems to the administration of Pri-matene®, it is at least as likely, if not more likely, that the breeding problems were due to Ms. Spennetta’s failure to give the males the required rest period. Dr. Gilbert testified that she had determined that Ms. Spennetta followed a written protocol. Gilberb-Barness Test., Tr. 11/9/93 (Morning) at 53-54. However, the protocol was not followed. Third, the fertility finding is compromised by the fact that breeding histories were unavailable for two of the rabbits that experienced breeding problems. Christian Test., Tr. 11/18/93 (Vol. II) at 35. The records for four of the 16 rabbits had been lost in the computer of the supplier providing the rabbits, and neither Dr. Gilbert nor Ms. Spennetta had ever seen those records. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at-64, 112. Dr. Gilbert first testified that she personally reviewed the histories of each of the rabbits before the test started. Gilberh-Barness Test., Tr. 11/9/93 (Morning) at 55-56. This was shown not to be true. As Dr. Gilbert herself acknowledged, the absence of the breeding histories by itself renders the study vulnerable within the scientific community. Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 115. Fourth, New Zealand White rabbits have a fertility likelihood of 85% (i.e., 85% of the matings will result in pregnancy); the treated animals were compared to the 6 control animals, which experienced 100% fertility in this test. Christian Test., Tr. 11/18/93 (Vol. II) at 33. Fifth, there were three rabbits in low dose groups that did not produce a litter, while there was only one rabbit in a high dose group that did not produce a litter, indicating once again the lack of a dose/response relationship. Christian Test., Tr. 11/18/93 (Vol. II) at 33. 71. In its fertility finding, the report also concluded that Primatene may have caused early embryonic death. Def.Ex. X. This could have been confirmed either by performing a cesarean section on the mother or by searching for the blood expelled when early embryonic death occurs. Christian Test., Tr. 11/18/93 (Vol. II) at 36. Because neither procedure was performed nor any blood observed, there is no basis for that conclusion. Christian Test., Tr. 11/18/93 (Vol. II) at 35-36). 72. The report’s finding regarding postpartum death is false. Christian Test., Tr. 11/18/93 (Vol. II) at 37. The underlying data disclose that there was a control rabbit that had a litter of nine pups, all of which died post-partum. Christian Test., Tr. 11/18/93 (Vol. II) at 37. This fitter and the nine pup deaths were then excluded from the study and replaced by a substituted “control” Utter. Christian Test., Tr. 11/18/93 (Vol. II) at 37-38. Had the dead fitter been included, it would have dramatically altered the relative incidence of post-partum death. 73. In addition, Ms. Spennetta cross-fostered some pups into other Utters. Christian Test., Tr. 11/18/93 (Vol. II) at 38. Because mothers sometimes reject pups that are fostered into their Utter, that may explain why the pups that were fostered died. Christian Test., Tr. 11/18/93 (Vol. II) at 38. 74. The report’s findings regarding postnatal somatic growth are not scientifically valid. Christian Test., Tr. 11/18/93 (Vol. II) at 39. It is impossible to attribute any claimed growth or fimb/torso ratio differences in the pups to the administration of Primatene ® because any differences in size and proportions are genetically affected, Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 133; see Christian Test., Tr. 11/18/93 (Vol. II) at 42, and neither Dr. Gilbert nor Ms. Spennetta measured the limbs or torsos of the parents of any of the pups. Gilbert Barness Test., Tr. 11/9/93 (Afternoon) at 130-31; Christian Test., Tr. 11/18/93 (Vol. II) at 42. Absent that measurement, no one can make a valid scientific finding with respect to fimb/torso ratios. Christian Test., Tr. 11/18/93 (Vol. II) at 42. Christian Test., Tr. 11/18/93 (Vol. II) at 42. The following features of the test also render the conclusion invalid: First, the pups were not measured or weighed until they were 18 days old, so pups that died before that date were not included in any growth or proportion findings. Christian Test., Tr. 11/18/93 (Vol. II) at 39, 44. Second, the size and weight of individual pups is dependent upon the number of pups in the fitter and yet this factor was nowhere considered in the analysis. Christian Test., Tr. 11/18/93 (Vol. II) at 40. Third, there was no dose/response relationship observed. Christian Test., Tr. 11/18/93 (Vol. II) at 41. 75. The design of Dr. Gilbert’s rabbit study was not the type that could have produced scientifically valid data upon which a scientist in the field of teratology could reasonably rely to draw conclusions as to the teratogenicity of Primatene® Tablets or Mist in rabbits, let alone in humans at therapeutic doses. Christian Test., Tr. 11/18/93 (Vol. II) at 44. Moreover, the procedures employed in the study were not the kind that could have produced results upon which the scientific community could reasonably rely. Christian Test., Tr. 11/18/93 (Vol. II) at 44. Finally, none of the reports of the study, especially the one rewritten by Dr. Tilelli, accurately reports the data underlying the study. Christian Test., Tr. 11/18/93 (Vol. II) at 49. 76. Because Dr. Gilbert’s general causation opinion rests upon that study, it is inadmissible. 6. Dr. Gilbert’s Letter to the Editor of Teratology 77. Dr. Gilbert’s opinion regarding the human teratogenic potential of the ingredients of Primatene®, at least as she disclosed it to the scientific community, was, and remains, that they may cause malformations, not that they do cause malformations. See Gilberb-Barness Test., Tr. 11/9/93 (Morning) at 40; Gilberb-Barness Test., Tr. 11/9/93 (Afternoon) at 6; see Def.Ex. E. What she means by reasonable degree of medical certainty as to causation is that some effect in humans is possible. Id. at 64. She opined only as to her suspicions that the drug ingredients in question are potentially hazardous in therapeutic dosages. Id. at 84. 78. Within the last 12 months, after having conducted numerous chick embryo studies involving sympathomimetic agents, having reported the Tedral® overdose in a woman and having conducted her study on the administration of Primatene® to rabbits, Dr. Gilbert wrote a letter to Dr. Robert L. Brent, the editor of Teratology. Gilberb-Barness Test., Tr. 11/9/93 (Afternoon) at 13. In that letter, she expressed her opinion “that sym-pathomimetic drugs may be teratogenic in humans.” Def.Exs. G, H (emphasis added); Gilbert-Barness Test., Tr. 11/9/93 (Afternoon) at 14. Thus, the opinion that she is prepared to share with the scientific community is that there is a mere possibility of human teratogenicity. She has not offered a qualitatively different opinion to this court. B. Stuart A. Newman, Ph.D. 79. Dr. Newman is a professor of cellular biology and anatomy at New York Medical College. Newman Test., Tr. 11/12/93 at 4. His areas of specialization are developmental biology, cell biology, molecular biology, biochemistry and molecular genetics. Newman Test., Tr. 11/12/93 at 15. He is a highly regarded bench scientist who works exclusively with in vitro research. Newman Test., Tr. 11/12/93 at 57. He is not a physician and does not work with humans or human data. Newman Test., Tr. 11/12/93 at 102, 110. 1. Dr. Newman’s Qualifications and Methodology 80. Dr. Newman’s focus as a scientist is in the area of biological mechanisms, i.e., how something might occur during embryonic development. Newman Test., Tr. 11/12/93 at 48, 50, 122, 130. His work pertains to controlled in vitro experiments using chick embryo cells, which studies permit him to examine proposed mechanisms of cellular development. Newman Test., Tr. 11/12/93 at 19, 36. 81. Dr. Newman’s work is directed towards satisfying one criterion of the teratolo-gy community’s methodology for determining human teratogenicity—plausible biologic mechanisms, Newman Test., Tr. 11/12/93 at 130, but satisfaction of that one criterion alone is an insufficient basis to establish human teratogenicity. See Exs. A, B, D, ii. Biologically reasonable hypotheses developed from in vivo or in vitro animal studies do not necessarily occur in actual human fetal development. See Tilelli Test., Tr. 11/15/93 (Vol. I) at 25. Dr. Newman diverges from the community’s methodology by making precisely that speculative leap. Dr. Newman testified that, in assessing human teratogenicity, he considers only whether the agent has caused similar defects in the. cells of another vertebrate system. Newman Test., Tr. 11/12/93 at 36-37. 82. Dr. Newman does not consider human data, and testified that he finds it confusing. Newman Test., Tr. 11/12/93 at 110. Dr. Newman’s approach for assessing general causation inappropriately amounts to a direct extrapolation from in vitro animal cell data to humans. Because it improperly fails to consider species specificity, metabolism, duration of exposure and other factors that affect teratogenicity in mammals, including humans, Newman Test., Tr. 11/12/93 at 66, it is not helpful and cannot be admitted. 2. Dr. Newman’s Opinions and Data Regarding Mechanisms 83. Dr. Newman postulated two possible biological mechanisms: (i) that sympathomi-metics and methylxanthines elevate cyclic AMP, thereby causing precocious and abnormal limb cell differentiation, Newman Test., Tr. 11/12/93 at 22-25, 42, and (ii) that sympa-thomimetics are vasoconstrictive, causing cellular disruption either through hemorrhage or insufficient blood supply, Newman Test., Tr. 11/12/93 at 43-44. 84. Regarding the first potential mechanism, Dr. Newman is of the opinion that sympathomimetics such as ephedrine raise cyclic AMP and that methylxanthines, like theophylline, inhibit the natural breakdown of cyclic AMP. Newman Test., Tr. 11/12/93 at 22-23, 39^43. He is also of the opinion that, when cyclic AMP is elevated, chick limbs, and therefore human limbs, develop in a precocious and abnormal fashion. Newman Test., Tr. 11