Behavioral and Somatic Disorders in Children Exposed in Utero to Synthetic Hormones

A Testimony-Case Study in a French Family Troop

Using a familial case control study, Marie-Odile Soyer-Gobillard – former director emeritus at the CNRS (French National Center for Scientific Research) – and Charles Sultan show that there are serious effects on the psychological and physical health of the descendants of women treated with synthetic hormones during their pregnancy: psychiatric illnesses are often found associated with somatic disorders which are well known to be the DES and EE signature.

Behavioral and Somatic Disorders in Children Exposed in Utero to Synthetic Hormones: A Testimony-Case Study in a French Family Troop, Endocrinology and Metabolism, intechopen, DOI: 10.5772/48637, October 3, 2012.

Synthetic hormones, acting as endocrine disturbers, are toxic for humans, especially for pregnant women and their children, probably partly in relation with their toxic degradation status.

In all cases girls suffered more than boys either of somatic and/or psychiatric disorders due to the estrogen receptor alpha or beta concentration higher in female fetus than in male. It is also clear that in all the families most of the exposed children are ill while quite the unexposed are not.

2012 Study Overview

  • Materials and methods: Gathering questionnaires and the evidence
  • Results / Data Analysis / Discussion
  • A multi-generational effect? By what mechanism?
  • Conclusion

A multi-generational effect? By what mechanism?

Multi-generational carcinogenesis studies were realized on mice after diethylstilbestrol impregnation with impressive and undisputable results. Our observations presented in this present work from the French HHORAGES troop raises the question of the mechanism through with synthetic hormones as DES cause either psychiatric disorders in exposed children and/or adverse effects in subsequent generations. Since Abdomaleky et al  concluded that modulation of gene-environment interactions may be trough DNA methylation, authors put forward hypothesis that DES-induced changes in epigenetic background and alteration of DNA methylations could be significant factors. The pregnant mother’s exposure to DES at very early neurodevelopment time and/or at time of sex determination would appear to be sufficient to alter the remethylation of neuron precursors and/or of the fetus germ line. Only a few third-generation children suffering psychiatric illness are mentioned in testimonies. This is understandable because third generation exposed children are still too young (excepted in some cases) to present psychiatric disorders as schizophrenia which is not the case for hypospads that are detectable from birth in male children and grand-children. Work is already under way concerning the gene X environment DES impact hypothesis by comparing DES and EE exposed children, various genetic and epigenetic factors to those of mother and unexposed children of the same family as studied by the INSERM team U796 in collaboration with the HHORAGES families.


In the present familial case control study, we have shown that there are serious effects on the psychological and physical health of the descendants of women treated with synthetic hormones during their pregnancy: psychiatric illnesses are often found associated with somatic disorders which are well known to be the DES and EE signature. Synthetic hormones, acting as endocrine disturbers, are toxic for humans, especially for pregnant women and their children, probably partly in relation with their toxic degradation status. In all cases girls suffered more than boys either of somatic and/or psychiatric disorders due to the estrogen receptor alpha or beta concentration higher in female fetus than in male. It is also clear that in all the families most of the exposed children are ill while quite the unexposed are not.

So what now? As the precautionary principle was not applied in the past, and still is not in force today, and since the lessons of recent history were never taken into account , it is our common duty to repair the damage by supporting the devastated families, and by pursuing research work on the observation of trans-generational effects. Such effects are already highlighted by the demonstration that cancers are observed even in the fourth generation in mice . According to the Skinner’s mini review “the ability of an environmental compound (as DES or EE) to promote the reprogramming of the germ-line appears to be the causal factor in the epigenetic transgenerational phenotype,” we observed an increase of the genital malformations in the third generation in male infants whose mothers were treated with xenoestrogens. In the HHORAGES troop, DES and EEexposed infants are already pointed out as bodily and/or psychologically impaired after their mothers were treated with clomifene citrate (an ovulation stimulator previously used for IVF-type medically assisted procreation). Another concern is the putative future effect of ethinylestradiol containing oral estrogenic contraception on future generations due to its lipophily after its metabolization and its future release in fetus through the placenta. As for the demonstration of the causality link within the HHORAGES troop, will we have to wait for a large-scale epidemiological study, or are we allowed to think that the impressive figures that we are publishing in this work are not merely random? The only way now is to respect absolutely the precautionary principle and to delete completely or to give the less possible toxic (synthetic) hormone medication: for example Clavel Chapelon and her Endogenous Hormones and Breast Cancer Collaborative Group in Villejuif informed that natural hormone as micronized (natural) progestin associated with estrogens (synthetic alas!) is more often ordered for SHT (Substitutive Hormonal Treatment) in order to avoid breast cancer. Unfortunately, she said also that in the contrary the same SHT is not recommended to avoid the endometrium cancer …

As Newbold et al said after they reviewed the damages caused by DES ,

“only new advances in the knowledge of genetic and epigenetic mechanisms of the disruptions of fetal development will enable us to be aware of the risks entailed by the other estrogenic disruptors which are present around us and in ourselves, even at very low doses”

, whilst Theo Colborn insists on the fact that the foetus cannot be protected against endocrine disruptors, whatever they may be, except at zero level.

Click to download the complete PDF.

More DES DiEthylStilbestrol Resources

Against Genetic Exceptionalism

Courts have generally grappled with the issue of prenatal torts for the last fifty years. Prenatal torts are commonly defined as “actions involving injuries that result from tortious acts that occurred before a plaintiffs birth.” The most well-known instance of these torts being litigated is cases involving diethylstilbestrol (DES) exposure. DES was a drug administered to pregnant women from 1947 to 1971 to prevent miscarriages. The drug caused damage in utero to the fetuses, who later in life developed abnormalities such as cervical cancers or malformations of the uterus. DES is an example of a teratogen, which is “a chemical or physical agent that produces or raises the incidence of congenital malformations” in utero.

Against Genetic Exceptionalism: An Argument in Favor of the Viability of Preconception Genetic Torts, Journal of Health Care Law and Policy, Volume 10 | Issue 2 Article 4, 2007.

Because the effects of DES did not manifest until the plaintiffs were adult women, these women had possibly already reproduced, producing putative additional plaintiffs. Many plaintiffs have successfully litigated DES claims, and generally, courts have not voiced concern with the prospect of multiple generations of plaintiffs litigating in DES cases. For example, in McMahon v. Eli Lilly, the court reversed a directed verdict granted to the defendant drug manufacturer. The plaintiffs, a woman and her husband representing themselves and their deceased son, were second- and third-generation plaintiffs in the DES-based action. The court ruled that the plaintiff-mother was not barred from recovery either for herself or for her child simply because she was a second-generation victim of injuries caused by the teratogenic effects of prior exposure to DES.

There is a plethora of literature addressing prenatal torts caused by teratogens such as DES. However, a distinct, but related, issue has yet to be appropriately handled either by the courts or by state legislatures: preconception genetic torts. The DES claims are all based on prenatal, postconception genetic torts, where the chromosomal breakage, if any, occurred in utero. Chromosomal breakage occurs as a result of the addition or deletion of chromosomes or specific parts of chromosomes. In each human cell there are forty-six chromosomes; these chromosomes contain the nearly three billion base pair sequences that comprise each individual’s genetic code.  A mutation in these chromosomes is “any permanent heritable change in the sequence of genomic DNA.” What makes chromosomal breakage due to mutagenic effect unique is that it can occur to preexisting DNA. This bears special significance for females, who are born with all of the gametes they will ever need in their lifetime, unlike males who continuously produce gametes for most of their lives. Where a particular mutagen alters or breaks the chromosomes of the reproductive cells, including the eggs or oocytes, a later-fertilized egg may possess the chromosomal alteration. This mutative process is the phenomenon of chromosomal breakage.

In the past thirty years, courts have seen a slow rise in the number of actions brought based entirely on preconception genetic torts-where the chromosomal damage occurs to the mother before the child is conceived. Unlike in the DES cases, courts have generally been unwilling to grant as much freedom to preconception torts plaintiffs.

This article addresses the status of preconception genetic torts. Preconception torts may be defined as “actions involving injuries that result from tortious acts that occurred before a plaintiff’s conception.
A “preconception genetic tort” is the shorthand I will use to refer to those injuries that alter the chromosomal structure of the mother rather than cause damage to somatic cells.

There are a host of complicated questions that arise in the preconception genetic tort paradigm, including:

  1. Is chromosomal breakage a legally compensable injury in and of itself, or must an attendant syndrome or condition manifest to constitute a legally compensable injury?
  2. Should the extent of the relief be limited to injuries resulting from developments prior to conception?
  3. What relief should be granted where chromosomal breakage occurs during preconception, but where the genetic syndrome is multifactorial and only develops in utero?
  4. Is increased risk of cancer due to a preconception mutagen a legally compensable injury?
  5. Who may sue? The mother? The child? The grandchildren of the mother? The great-grandchildren?
  6. Will it be impossible to prove that but for a defendant’s negligence, a child would not have been born with chromosomal alteration or subsequent genetic disorders?
  7. Should fears of multigenerational liability justify courts in denying preconception tort actions based on an analysis of proximate cause?
  8. Should fears of the growing relevance of an individual’s private genetic information to a personal injury action justify courts in denying the viability of preconception genetic torts?

I will examine each of these questions in turn.

  1. Part I considers the problems relating to the injury: when does it occur, and is it (such as increased risk of cancer due to chromosomal breakage) cognizable.
  2. Part II surveys the intricate problems of causation that attend preconception genetic torts, including the policy considerations that animate proximate cause analyses, as well as difficulties in adducing adequate proof of causation.
  3. Finally, Part III considers the problems of preconception genetic torts from a broad-based, policy-oriented view, and concludes that there is little justification for denying the viability of preconception genetic torts, or for treating them altogether differently from preconception torts in general. The judicial system is well-equipped to handle any of the difficulties and problems presented by claims for preconception genetic torts. There is little policy justification for rejecting such claims as non-cognizable.


A. When Does the Injury Occur?

The first notable case involving preconception genetic torts was Jorgensen v. Meade Johnson Laboratories, Inc. In this case, a father brought an action based on theories of negligence, strict liability, and breach of express and implied warranties on behalf of his daughters afflicted with Down syndrome. The plaintiffs wife took birth control pills manufactured by the defendant for a period of approximately six months. Nine months after she ceased taking the birth control pills, she gave birth to twin daughters. The plaintiff contended that the birth control pills altered the chromosomal structure of his wife, which directly and proximately caused his twin daughters to develop the trisomy 21 mutation responsible for Down syndrome in utero. The district court dismissed the action for failing to state a claim because it concluded that no cause of action existed in Oklahoma for preconception injury to the chromosomal structure of the mother.

The United States Court of Appeals for the Tenth Circuit reversed and held that the plaintiff had stated an actionable claim for two reasons. First, broadly reading the complaint, the court reasoned that because the plaintiff pled that the genetic disorder developed in utero due to the mother’s altered chromosome structure, “the pleading should not be construed as being limited to effects or developments prior to conception.” Second, because the twin daughters, rather than the mother, were the plaintiffs, the only relevant injuries were those suffered by the twin daughters. The court then drew an analogy to several cases where defendant manufacturers were held liable for manufacturing a defective food product prior to conception that ultimately caused injury to the infant child upon consumption. The court reasoned that ample precedent supports the notion that tortious conduct occurring prior to conception is actionable if it ultimately causes injury to the infant.

The court’s analysis is noteworthy for several reasons. First, the court avoids the difficult question of whether the mother’s altered chromosome structure is in and of itself an injury by referring to the fact that the plaintiffs pleading contained references to injuries from teratogenic phenomena rather than injuries that occurred prior to conception (in which case the causes would be mutagenic in nature). Jorgensen says nothing about whether there are two distinct injuries in this fact pattern (those of the twin daughters and those of the mother). Second, the analogy to the defective food product line of cases is inapposite, largely because in all of these cases, it was only the tortious conduct in manufacturing the defective product that occurred prior to conception. By the court’s analogy, the injury occurred only when the infant child consumed the defective food product. The court thus begs the question by assuming or at least implying that the only relevant injury to the twin daughters occurred postconception, as did all of the injuries from the defective food products. If this were not the assumption and the possibility that the daughter’s injury occurred preconception was left open, then the defective food product cases where the injuries unquestionably occurred postconception would not be analogous.

The contention that by altering the chromosomal structure of the mother, the injury to the twin daughters themselves occurred preconception is not implausible. Naturally, this claim could only be brought by children who were subsequently born,  but the science supporting this chain of reasoning is sound. Once the chromosomal structure of the putative mother is altered, any subsequent fetus may have its chromosome structure altered as well.

The core of the problem lies in the nature of genetics. Because any alteration in the germline chromosome structure of a mother’s eggs may be passed on to descendants, it is difficult to pinpoint exactly when the injury occurs. Perhaps the injury to later-born children occurs when the mother’s chromosome structure is altered. Perhaps it occurs at the moment of conception, in which case it is even more unclear whether the injury is preconception, postconception, or neither. Or perhaps the injury in the form of a genetic disorder only occurs in utero, in which case the injury is postconception. Yet another possibility is that the genetic disorder is multifactorial, requiring both inheritance of the mother’s altered chromosomal structure as well as environmental influences in utero. The boundaries between these options are hard to discern. Perhaps the best solution is to act as the Jorgensen court did by implying that the boundaries between preconception and postconception injury are unclear, and that where a plaintiff pleads both, he ought not be barred from recovery.

B. Is Increased Risk of Cancer Due to Chromosomal Breakage a Viable Cause of Action?

At least one court has held that a plaintiff who presents evidence of increased risk of cancer due to chromosomal breakage ought to be able to submit the evidence to the trier of fact. In Bryson v. Pillsbury Co., the plaintiff was exposed to the chemical Captan. The plaintiff presented evidence of extensive chromosomal breakage and claimed that she had an increased risk of cancer as a result of the exposure to Captan. The defendant moved for summary judgment, claiming that the plaintiff assumed the risk of harm and that, in any case, the plaintiffs claimed damages were too speculative as a matter of law. Agreeing with the defendant, the trial court granted the motion.

The Court of Appeals of Minnesota reversed the entry of summary judgment for not proving a present injury, reasoning that there was precedent supporting the idea that whether chromosomal breakage constitutes a present injury is a question of fact.  So long as the plaintiff proffers expert testimony alleging that chromosomal breakage is a present injury, the court ruled that whether the chromosomal alteration rises to the level of a legally compensable injury is an issue for the trier of fact. The court also reversed the grant of summary judgment as to the plaintiffs claims for present damages, which amounted to claims of damages for emotional distress and medical monitoring expenses. The court found that since there were genuine issues of material fact as to the existence of a present injury, there were similar issues of fact as to the damages caused by those injuries.

However, the court of appeals affirmed the grant of summary judgment as to the plaintiffs claim for future damages, finding that the plaintiffs expert witness “admitted that the plaintiffs increased risk of cancer could not be measured or quantified.” Thus, the court held that the claim of future damages was too speculative and not capable of being established with reasonable certainty. Though increased risk of cancer has generally been perceived as a viable cause of action in the sense that plaintiffs usually survive motions to dismiss and or summary judgment motions, many jurisdictions accept increased risk of cancer cases only reluctantly, or dismiss the damages as too speculative.

Furthermore, the scope of the injury affects who has standing to bring an action. If chromosomal alteration is not an actionable injury in and of itself, then, for example, the mother of the plaintiffs in Jorgensen could not recover. Her only injury was the alteration in her chromosome structure; it was her twin daughters who developed Down syndrome. In addition, by denying chromosomal breakage status as a sui generis injury, the problem of multi-generational liability may diminish. This is because subsequent generations may have chromosomal alterations. However, unlike first-generation children, who have both chromosomal breakage and a concomitant genetic disorder, the subsequent generations may have no attendant disorder. Thus, the later-generation children will have no actionable injury if no genetic disorder manifests. In these scenarios, the question of whether increased risk of cancer is an actionable injury is particularly salient, because this may be the only avenue for the later-generation children to obtain relief. As knowledge of the link between specific mutations and disease increases, it is not difficult to see that if increased risk of cancer is an actionable injury, so too might increased risk of Alzheimer’s disease, increased risk of osteoporosis, and so on and so forth. The dangers of the “geneticization of lawsuits” are all too real, where plaintiffs may simply run down the line of genetic disorders until they find one that may have some link to the particular mutation they possess. This factor may bear on courts’ general unwillingness to recognize preconception genetic tort claims as viable.


A. Proximate Causation & Policy Concerns

The majority of courts, however, have disagreed with the Tenth Circuit’s analysis in Jorgensen on the grounds of proximate causation rather than on the nature of the injury. The requirement that a plaintiff prove proximate cause is longstanding in the law of negligence. Generally, to show proximate cause, a plaintiff must prove that he or she was in the foreseeable zone of risk of a defendant’s negligence.  The idea is that actionable negligence requires a significant relation in time and place between the parties. As acknowledged by Chief Judge Cardozo, “proof of negligence in the air …will not do.”, The notion of foreseeability embodies the requirement that the causal connection be proximate, or related in time and space. Moreover, proximate cause enmeshes the concepts of duty and foreseeability. Palsgraf v. Long Island Railroad Co. stands for the proposition that one does not owe a duty to anyone not in the foreseeable zone of risk. In addition, where a court finds a lack of proximate cause, the plaintiff is cut off from recovery largely for policy reasons.

A prime example of a court denying recovery in a preconception tort case based on a proximate cause analysis is Albala v. City of New York. In this case, New York’s highest court denied relief to a child born with severe brain damage. Four years prior to the plaintiffs conception, the mother’s uterus had been perforated due to medical malpractice. In Albala, the injury was to the uterus, an organ, rather than to a chromosome. Because the mother’s genetic code was not altered, there was no question that the child’s injury occurred postconception and in utero. The court, thus, did not focus on the injury, but rather denied recovery based on a lack of proximate cause. Moreover, the court was alarmed at the prospect of endless liability where a physician’s negligence caused foreseeable harm to a later-conceived child. It seems difficult to comprehend how, based on the facts of Albala, the defendant in this case could possibly be exposed to multigenerational liability. Where the structural harm was not genetic, the structural defect is extremely unlikely to be passed on from parent to offspring past the first generation.

The New York court’s analysis seems more apposite to the facts in Enright v. Eli Lilly & Co. There, the New York court refused to impose liability in a strict products liability claim brought by a third-generation plaintiff against a manufacturer of DES. In coming to its decision, “the Enright court was concerned that imposing a duty in one case could lead to an expansion of liability beyond manageable boundaries., The source of the court’s fear of boundless liability was the prospect of multiple-generation liability.  The specter of multiplegeneration liability was enough to persuade the court to limit liability to those who ingested the drug or were directly exposed to its teratogenic effects in utero.

In 1986, the Supreme Court of New York in Erie County extended the ruling of Albala to preconception genetic torts in Catherwood v. American Sterilizer Co. In this case, an action was brought on behalf of a child decedent who was conceived subsequent to the mother’s exposure to the mutagen ethylene oxide. The plaintiff claimed that this mutagen caused the child’s chromosomal damage.  The court acknowledged that the issue of whether a preconception genetic tort gave rise to a cause of action was one of first impression in New York.  The court characterized the court of appeals’ decision in Albala as based purely on policy considerations,  and framed the issue of liability in Catherwood solely in terms of proximate cause and policy analyses.

The court granted the defendants’ motion to dismiss for policy reasons. First, the court distinguished Jorgensen by noting that the plaintiff in Catherwood brought a negligence action, as opposed to the strict liability action at issue in Jorgensen. Furthermore, the court reasoned that limitations on liability are less necessary in strict liability actions than they are in negligence actions brought on the basis of exposure to a toxin or mutagen.  In addition, the court stated that imposing liability in a preconception tort case is untenable because the plaintiff would garner a cause of action before he or she actually came into existence.

This last point, of course, is a policy consideration based not on an analysis of causation, but on the difficulty of determining the specific point at which the injury occurs. The Supreme Court of Erie County inverts the assumption made by the Jorgensen court in identifying the point in time when the injury occurred. Where the court in Jorgensen implied that the only actionable injury occurred postconception, the court in Catherwood, in denying the viability of the preconception genetic tort, assumes that the injury claimed by the plaintiff occurred entirely preconception. If it did not, the perilous policy the court is afraid of endorsing vanishes. The court very easily could have narrowed its decision so as to hold that claims brought where the injury is entirely preconception will be disallowed. It is entirely plausible to reason that though the exposure in Catherwood occurred preconception, the injury to the later-conceived child occurred only after conception.

Under the latter analysis, preconception genetic torts are conflated with the more well-settled postconception torts, with the caveat that the exposure itself occurs prior to conception. The consequence of this perspective, however, is that chromosomal damage with no attendant genetic disorder or syndrome may no longer be viewed as an injury sui generis, because, by definition, the only compensable injury would occur after conception. If the injury is perceived as occurring preconception, then the Catherwood court’s concern of a cause of action accruing to a person not yet in existence is relevant. This is because the chromosomal breakage that affected the later-conceived child occurred prior to conception.

Whether or not chromosomal damage is seen as an actionable injury has many implications for the viability of claims such as increased risk of cancer. Perhaps much of this may turn upon the pleadings themselves. If the plaintiff in Catherwood had pled that the exposure occurred before conception and the injuries occurred subsequent to conception, as did the plaintiffs in Jorgensen, perhaps the New York court would have decided differently.  At the very least, its predilection against animating a cause of action where the plaintiff is not conceived at the point of injury might not be implicated if a postconception injury is pled.

The court in Catherwood also clothed its decision in terms of duty, stating that “in order to allow a cause of action for pre-conception tort there requires the finding of a duty to the unconceived. Such a duty can only be couched in terms of a duty to protect the potentiality of life …. New York has not recognized any such duty.”, Of course, the court’s reliance on the concept of duty converges perfectly with its analysis of proximate cause because the two concepts are intertwined. As Dean Prosser explicitly noted, cases involving prenatal torts are a common locus for issues of limited duty due to the plaintiff not being in the foreseeable zone of risk. However, as Dean Prosser also noted,

There is a duty if the court says there is a duty; the law, like the Constitution, is what we make it. Duty is only a word with which we state our conclusion that there is or is not to be liability; it necessarily begs the essential question. When we find a duty, breach and damage, everything has been said.

Dean Prosser’s analysis explains that the divergence between courts in extending or restraining the boundaries of a particular duty rests on conflicting policy analyses, rather than any disagreements about whether a legal mandate compels a particular boundary. Whereas the court in Catherwood was concerned with extending a duty from defendants to unconceived plaintiffs, other courts have not felt similarly constrained. For example, the Supreme Court of Indiana expressed no such qualms in Walker v. Rinck. In that case, the plaintiffs were children who brought an action against a physician for misdiagnosing their mother’s Rh-compatibility during a previous pregnancy. The resultant Rh-sensitivity in the mother’s blood allegedly caused injuries to later-conceived children. The court reversed a lower court’s grant of summary judgment to the defendant physician, reasoning that where the plaintiffs were foreseeable, the physician had a duty to use reasonable care in administering care to the mother. The facts of the case, according to the court, sufficiently illustrated that it was foreseeable when the defendant physician initially treated the mother knowing that she might conceive again. Accordingly, the court held that the defendant physician did owe a duty to the later-conceived children of the mother because they were foreseeable plaintiffs.

However, in reiterating his point that a court’s refusal to extend duty or proximate cause follows rather than precedes the court’s conclusion that liability ought not attach to a defendant based on the given fact pattern, Dean Prosser cautions that duty and foreseeability are not interchangeable concepts. That is, courts do not always impose liability where a plaintiff was foreseeable.  The Albala court’s decision evinces this notion. The court granted that it was foreseeable that when the mother underwent an abortion, she might at some point wish to conceive again, and thus any later-conceived children were in the foreseeable zone of risk of the defendant’s negligence in performing the prior abortion. Nevertheless, the court found that the presence of foreseeability alone was not enough to establish a duty from the defendant to the plaintiff in this case. Whereas foreseeability was enough to establish a duty from the defendant to the plaintiff in Walker, it was not sufficient to establish a duty in Albala. If issues of proximate cause and duty turn on policy considerations, the logical question becomes what policy considerations have prompted the majority of courts to deny proximate cause and duty to plaintiffs in preconception genetic torts?

The major reason courts deny recovery for preconception genetic torts is fear of multiple-generation liability. Courts are afraid that no practical limit on liability may exist. A commentator described the rationale of courts in this position:

If courts were to allow the first generation of plaintiffs to recover, they would also be required to allow later generations to recover. Subjecting a tortfeasor to these claims by multiple generations would impose a burden disproportionate to the risk created. To avoid such a result, and to keep from drawing unprincipled distinctions between first generation and later generation plaintiffs, it is better to deny recovery to all preconception injury plaintiffs.

Thus, multiple-generation liability is disfavored not only because it is inherently unfair to the defendant. Courts also fear that if they allowed first generation plaintiffs to recover, in order to avoid imposing limitless liability on a defendant, they might have to cut off second and third generation plaintiffs for no reason other than that they are second and third generation plaintiffs. This, according to Professor Greenberg, is too arbitrary for the courts, and so they deny recovery to any plaintiff for preconception genetic torts.

The Supreme Court of Illinois may have been the first to address the issue of multiple-generation liability for preconception torts in Renslow v. Mennonite Hospital. In this case, a physician negligently transfused the plaintiffs mother with 500 cubic centimeters of Rh-positive blood. The transfusion caused sensitization of the mother’s Rh-negative blood. Nine years later, she gave birth to the plaintiff, who suffered from severe brain and organ damage, allegedly caused by the Rh-sensitivity. Though the majority found that the plaintiff had stated a viable cause of action, Justice Ryan dissented.  Among the reasons for his dissent were fears of multiple-generation liability. Furthermore, Justice Ryan introduced the issue of insurance into the equation. He opined that “under these circumstances, it is difficult to perceive how an individual or institution could adequately provide insurance coverage, or how an insurer could establish reserves to cover a potential loss.”

According to this line of reasoning, the difficulty in obtaining insurance would increase the unfairness of exposing a defendant to multiple-generation liability, not to mention the burden that the insurer of the putative defendant would have to carry. Should the burden become unmanageable, it may lead manufacturers and service providers to stop providing potentially useful commodities and services. a In addition, second and third generation plaintiffs might be unable to recover anything from a defendant that has either gone bankrupt due to litigation or that has been unable to obtain insurance. In this case, the fear of the arbitrary cut-off between first and later generation plaintiffs that motivated the court in Enright and Justice Ryan in Renslow may be drawn by the market, rather than the judicial system.

B. Difficulties of Proof and Consequences of Proving Causation

Another policy consideration that has motivated courts to deny the viability of preconception genetic torts are the extremely difficult issues of proof, which revolve around “the difficulty of establishing the causal link between a child’s health problem and the defendant’s preconceptual conduct. For example, the mother in the Jorgensen case was apparently told that the pills she took were completely safe to use, and was given no warning of any possible harm. Nonetheless, “whether she could have proved this warranty and lack of warning, and then proven that the pills caused an alteration in her chromosomes, is not at all clear.”

The case of Wintz v. Northrop Corp. demonstrates the significant burden the plaintiff has in mustering enough evidence of causation. In this case, a husband and wife brought an action both individually and on behalf of their daughter, Jessica, against Eastman Kodak Company and Northrop Corporation, the latter of which was the mother’s employer. The mother worked as an industrial engineer both prior to and during her pregnancy. Her line of work involved mixing various chemicals, one of which was bromide, to develop photographic film. She alleged that she had inhaled bromide dust both prior to and during her pregnancy with her daughter. After Jessica was born, she exhibited several abnormalities, including poor muscle tone, a weak sucking reflex, infrequent cry, and anomalous facial features.

The treating physician suspected elevated bromide levels were the cause of the baby’s behavioral abnormalities, and ordered bromide tests for both the child and the mother. Four years later, Jessica was examined by a different physician, Dr. Barbara Burton, an expert in genetic disorders. After examining Jessica’s symptoms, which then included myopia, problems with the enamel in her teeth, frequent respiratory infections, and abnormal mental development, Dr. Burton diagnosed Jessica with a genetic disorder known as Prader-Willi syndrome. Subsequent tests confirmed this diagnosis. According to the court’s findings of fact, Prader-Willi syndrome “is caused by a deletion of genetic material from the father’s chromosomes. It is a purely genetic disorder which occurs prior to conception, and it cannot be caused by environmental exposure.”‘

The plaintiffs retained a toxicologist as an expert witness.  The toxicologist was going to testify that exposure to bromide, rather than Prader-Willi syndrome, caused Jessica’s developmental anomalies.  The defendants filed a motion for summary judgment. They claimed that a toxicologist was not properly qualified under Federal Rule of Evidence 702 to testify as to the comparative effects of bromide and Prader-Willi syndrome on a child because the toxicologist was not a licensed physician. The federal district judge granted the motion, and the Court of Appeals for the Seventh Circuit affirmed.’

The Seventh Circuit agreed with the defendants that the toxicologist simply did not have the requisite knowledge and experience to enable him to offer expert testimony on the principles of toxicology as applied to a human. As the court noted, he had no knowledge of the frequency or quantity of the bromide to which the mother was exposed, nor the extent to which her work environment was ventilated, nor whether she wore a mask at work. The court reasoned that at best the toxicologist professed expertise as to a “general understanding of bromide, with only unsupported speculation having been used to relate the general knowledge to the facts surrounding the mother’s exposure.” Moreover, the original treating physician testified that Jessica’s physical and mental abnormalities were very likely to have been caused by Prader-Willi syndrome. The court found that under these circumstances, the plaintiffs had not met their burden of showing proximate cause under Illinois law, which required a showing to a reasonable medical certainty that the defendant’s acts caused the injury.

It is not clear what the plaintiffs could have done to survive summary judgment. Arguably, the defendants could have attacked the qualifications of any physician proffered as an expert witness by the plaintiffs on the grounds that he or she did not possess the requisite knowledge on the toxic effects of bromide. Perhaps both a toxicologist and a physician would have to be called, although the defendant might object on the grounds that an expert in genetics would be needed. It is simply not clear what expert testimony would have been required to sustain the plaintiffs claim. The question of how to present expert testimony on genetics moves this inquiry into a different constellation of issues-the role that genetic information may play in personal injury litigation.

C. The “Geneticization ” of Personal Injury Litigation

A related policy concern is the fear of the so-called “geneticization” of civil litigation. Consider Severson v. Markem Corp., an unreported 1990 California case. In that case, a plaintiff claimed that her son’s severe birth defects were caused by in utero exposure to methyl ethyl ketone. The defendant claimed that the plaintiffs injuries were caused by a genetic disorder called fragile X syndrome. The defendant filed a motion asking the court to require the plaintiff to undergo genetic testing to ascertain whether the plaintiff was afflicted with fragile X syndrome. The court granted the motion, “rejecting the argument that this was an invasive procedure which would cause severe distress.

The facts in Severson are analogous to those in Wintz, but there are two significant differences. However, these differences only render the analogy imperfect. First, the plaintiff in Severson unquestionably suffered a postconception injury in that the exposure occurred in utero, whereas there was a question as to when the daughter’s injuries occurred in Wintz. Second, the plaintiff daughter in Wintz unquestionably was afflicted with a genetic disorder, while this was a crucial question in Severson. It does not tax the imagination, however, to envision an amalgam of these two cases: where a plaintiff brings a claim for a preconception genetic tort and where there is substantial dispute as to whether the plaintiff suffers from a genetic disorder unrelated to the defendant’s negligence. In this scenario, a defendant would in all likelihood make a motion to compel the plaintiff to undergo genetic testing to confirm or disconfirm whether the plaintiff is afflicted with the relevant genetic disorder.

Gary Marchant argues that because “there are major data gaps and uncertainties about the health risks of most potentially toxic substances,” new “genetic developments” have the potential to fill some of these conceptual gaps take on increased importance in toxic tort litigation. On the other hand, he notes that use of genetic data may render toxic tort litigation “even more complex, contentious, and ethically problematic.” He notes two kinds of genetic data most likely to be used in toxic tort litigation: “data on genetic susceptibility of individual plaintiffs” and “genetic biomarkers of exposure and effect.” As to the former, he acknowledges the likelihood that toxic tort claims that turn on issues of genetic susceptibility will require “genetic test data from the individual plaintiff showing the presence or absence of the genetic trait at issue” to survive summary judgment on the issue of causation.  He even cites an expert who has argued that it should be common practice “for defendants to seek genetic testing of plaintiffs in order to identify potential alternative causes.”

In a 1996 article, Professor Mark Rothstein canvassed the public policy reasons militating against permitting coerced genetic testing of the kind in Severson. He argues that forcing a plaintiff to undergo genetic testing is a serious infringement on the plaintiffs right to privacy.  Rothstein identifies three different forms of privacy threatened by the sort of compelled genetic ordered in Severson: (1) physical privacy, (2) informational privacy, and (3) decisional privacy. By forcing the plaintiff to have blood drawn or even a cotton swab deployed in his or her mouth, the plaintiffs physical privacy is violated. The results of the genetic test constitute a compelled disclosure of information and thereby are a violation of the right not to disseminate information about oneself, constituting a violation of informational privacy.  Finally, forcing the plaintiff to submit to the genetic test without his or her consent constitutes a transgression on decisional privacy.

Rothstein argues that the decision of whether or not to undergo genetic testing can be extremely difficult, and that forcing a plaintiff to undergo this procedure violates the plaintiffs autonomy by taking the decision out of his or her hands.

Second, compelled genetic testing raises concerns regarding confidentiality. In contrast to privacy, which relates to the right to prevent anyone from acquiring personal information, “confidentiality refers to an individual’s reasonable expectation that certain sensitive information revealed within a confidential relationship will not be redisclosed to a third party without the individual’s consent. Although the view prevails that in personal injury litigation the patient impliedly consents to the disclosure of medical information by making his or her medical status an issue in the case, the unique nature of genetic information makes the consequences of compelled disclosure all the more stark.

Disclosure of genetic information subjects an individual to risks of public stigma and humiliation.  Such information has been referred to as a future diary, inasmuch as it reveals information about an individual’s past, present, and future relatives. Furthermore, genetic testing may reveal information about paternity, which is somewhat prone to error. Fears of later disclosure of such information may have a chilling effect on genetic research, in that individuals may refuse to participate in genetic research because of concerns that genetic test results could conceivably be discovered by employers, insurers, or other third parties.

These scenarios by their nature are particularly likely to arise in preconception genetic tort cases. This is because the injury in a preconception genetic tort case will either simply be a chromosomal alteration or a concomitant (and perhaps resultant) genetic disorder. Where a particular genetic disorder could not be caused by exposure to any kind of mutagen or toxin, a defendant will in all likelihood desire to show that the plaintiffs injury was a consequence of the genetic disorder rather than the defendant’s negligence. The fact that this problem has not yet arisen-or, at least, that no court has mentioned it-in a preconception genetic tort case can be explained first by the paucity of such cases in general, and second by courts’ general unwillingness to recognize preconception genetic torts as a viable cause of action. Nonetheless, the inherent problems raised by compelled genetic testing may well factor into a future court’s analysis regarding whether to recognize a preconception genetic tort claim as viable or to dismiss the claim for policy reasons.

In short, Rothstein concludes that concerns of privacy and confidentiality merit attempts to prohibit defendants from seeking to compel plaintiffs in personal injury litigation to undergo genetic testing. While I agree with Rothstein that the privacy and confidentiality concerns are serious and merit careful attention, the significance of his recommendations is to urge that genetic information be treated exceptionally. I think genetic exceptionalism in the realm of preconception genetic torts is exceedingly unwise for a variety of reasons, a topic to which I turn now.


A. The Pitfalls of Genetic Exceptionalism

Preconception torts are more widely accepted as viable causes of action than are preconception genetic torts, evidenced by the DES cases. The fact that preconception genetic torts are not generally recognized necessitates some distinguishing factor between preconception torts where chromosomal breakage to the mother is not involved, and where it is. This article has attempted to suggest some possible reasons for the divergent treatment by the courts, including multiplegeneration liability, difficult proof issues, and concerns about the geneticization of personal injury litigation.

The question is, are these reasons enough to justify the distinction between preconception torts and preconception genetic torts? More broadly, several scholars are alarmed at the culture of “genetic exceptionalism” that permeates the legislative and judicial landscape. For example, Gostin and Hodge have expressed concern at the number of laws protecting genetic privacy, compared to the dearth of statutes comprehensively addressing privacy in general.

Suter argues that “genetic information is not unique and that concerns about abuses of information should not be limited to genetic information, but should extend to other medical information.” She reasons that “the presumption that genetic information is unique is severely tested by the fact that no sharp line divides genetic from nongenetic information. Instead, there is a great deal of overlap between these categories, making line-drawing exceedingly difficult.”

Even assuming that unique concerns are raised in a genetic paradigm, it does not necessarily follow that preconception genetic torts ought to be treated in drastically different ways from preconception torts not involving chromosomal breakage. Professors Gostin and Hodge frame the inquiry in terms of the adverse consequences that arise out of legislatures creating law that treats genetic policy issues differently from other kinds of policy issues.

The point is that the common law ought to grapple with these issues on a case-by-case basis. Simply banning preconception genetic torts by declaring that they are not viable claims is ill-advised. As nearly all courts specifically addressing the problem have noted explicitly or implicitly, preconception genetic torts pose novel and challenging issues. However, setting precedent denying the cause of action in and of itself is a knee-jerk response to a problem that is unlikely to vanish altogether. Moreover, upon examination of court’s cited fears regarding injury and causation in a preconception genetic tort paradigm, the knee-jerk response is not justified.

B. Difficulties in Pinpointing the Injury

Do Not Justify Denial of Relief In many cases, a genetic disorder will manifest itself in conjunction with a chromosomal alteration. In Jorgensen, the plaintiffs were born with Down syndrome. In Wintz, the daughter Jessica was diagnosed with Prader-Willi syndrome. The fact that a plaintiff has undoubtedly suffered some harm does not relieve the plaintiff from any difficulties in proving causation, but where a genetic disorder or condition is present, it is clear that some kind of harm has befallen the later-conceived person.

Moreover, new research on biomarkers, or biologic markers, has dramatically increased geneticists’ ability to “delineate more precisely how a given ambient toxic exposure causes disease by tracing the ‘molecular footprints’ as the toxin passes through the body, interacts with critical target molecules in the body, and produces the molecular and cellular effects that eventually manifest as pathology. This new research has particular importance for occupational or environmental exposure cases. In other words, biomarkers may help in determining the specific steps in the causal pathway that a toxin takes in producing a given injury. In effect, biomarkers may help to pinpoint the point at which a particular genetic disorder manifests by identifying the sequence of causal effect on the genetic level. As such, “biomarkers may be important in … establishing the subclinical or preclinical harms upon which damages for future harms may be based.” The establishment of these types of harms is absolutely crucial in preconception genetic tort claims, and the biomarker research may indicate whether the injury occurs preconception, at the moment of conception, or postconception based on the particular step in the causal pathway that the disorder manifests.

However, even assuming the difficulties in pinpointing when the precise injury occurs are not overcome, these difficulties do not justify barring relief for every preconception genetic tort. The distinction between permitting recovery for postconception torts and preconception torts seems somewhat arbitrary, especially in light of the fact that increased risk of cancer due to chromosomal alteration is generally an actionable, albeit controversial tort. Where a plaintiff cannot adequately prove that an injury occurred, or cannot prove the causal link between the negligence and the injury, that plaintiff ought to be barred from recovery. However, the difficulty in pinpointing when the injury has occurred is a weak justification for barring any recovery whatsoever for plaintiffs who have undoubtedly suffered harm in most cases. Furthermore, the most controversial aspect of the injury issue in preconception genetic tort cases is often the mother’s individual claim for increased risk of cancer due to chromosomal alteration. Where many courts now, at a minimum, refuse to dismiss such claims or refuse to grant summary judgment, the reasons for denying the viability of preconception genetic tort claims because of the questions surrounding the claimed injuries are even less persuasive.

C. Proximate Cause Policy Considerations Do Not Justify Barring Recovery

In spite of many courts’ doubts about the existence of a duty owed to persons not yet in existence, “courts throughout the country have abandoned the no-duty rule, and virtually all jurisdictions presently recognize a child’s cause of action for the consequences of prenatal injuries.” Part of the reason for this is that the concept of foreseeability can be used by courts to limit preconception genetic tort liability. Where a potential injury to a later-conceived person is foreseeable, it is much easier for courts to impose a duty. Again, the link between foreseeability and duty reflects the intertwining of the concepts of proximate cause and duty. As Chief Judge Cardozo noted in Palsgraf, a duty is owed to someone in the foreseeable zone of risk. If the injury to the later-conceived person is deemed foreseeable, then a proper Palsgraf analysis dictates that the court ought to impose a duty on the defendant charged with negligence who caused the injury. If the injury is not foreseeable, then the plaintiff is not within the zone of risk, and no duty should be imposed. As Professor Greenberg explained, “any action that would foreseeably harm a woman’s reproductive system and her ability to carry a child to term would presumably also foreseeably harm a child she conceives in the future.”

The court in Albala, for example, recognized that where a doctor’s negligence resulted in a woman’s perforated uterus, it was foreseeable that this negligence could deleteriously affect the health of later-conceived children. However, this did not stop the Albala court from denying the viability of a preconception tort. Nonetheless, the fact that a proper Palsgraf analysis of foreseeability may be used to set boundaries of reasonable recovery for preconception genetic torts is reason for affirming the viability of preconception genetic torts. In addition, the applicability of a Palsgraf foreseeability analysis underscores the notion that genetic torts need not be treated differently from other kinds of torts. This follows inasmuch as modem courts frequently apply analyses of foreseeability to determine whether to deny proximate cause; there is no reason that such an analysis cannot be applied to preconception genetic torts.

Moreover, the problem of multi-generational liability is the proverbial storm in a teacup. First, few claims involving multi-generational liability in preconception tort cases have been reported or even cited in any case where a court raises the issue. Second, where a later-generation plaintiff brings such a claim.

The injury suffered by the first generation must be significant enough to constitute a compensable injury, but not so significant that it alters the first generation’s ability to conceive. Although toxic agents may exist that are capable of causing such harm, no such claims have been brought to date.

DES is one such agent, as demonstrated by the third generation plaintiff in Enright. Judge Hancock explained in his dissent in Enright the somewhat grotesque irony of denying relief to later-generation victims because of fears of boundless liability:

When defendants’ arguments are applied here to urge that although claims of DES daughters should be allowed the claims of granddaughters should not be, their forebodings strike a particularly ironic note: i.e., the very fact of the “insidious nature” of DES which may make the defendants liable for injuries to a future generation is advanced as the reason why they should not be liable for injuries to that generation.

The irony of this argument ought not mask its injustice. There seems something intuitively unfair about denying recovery to later-generation plaintiffs solely because the particular agent responsible for their injuries has multigenerational effects. This unfairness is compounded by the dearth of such latergeneration preconception tort claims. Perhaps if such claims were inundating the courts, concerns of boundless liability might be relevant, but such cases are rare.

Moreover, there are dangerous policy implications arising from signaling to drug and chemical manufacturers that any liability they may accrue from marketing a defective product will automatically cut off after one generation of plaintiffs.

Third, if and when multiple-generation liability claims begin to frequent, or occur at all, in the judicial system, “the courts or legislatures will need to establish reasonable boundaries for recovery.” Furthermore, to deny recovery by dismissing cases where obvious harm has been done to a plaintiff before it reaches the trier of fact, and where a defendant has been negligent, is irrational when justified on the basis of a fear that has yet to materialize.

Finally, the fears of the possible geneticization of civil litigation are reasonable and worrisome. However, these concerns extend beyond the parameters of preconception genetic tort claims into all types of personal injury claims. In any personal injury action, a defendant may seek to compel a plaintiff to submit to genetic testing, on the theory that if the plaintiff has a reduced life expectancy due to a genetic disorder, the plaintiff will be entitled to a lower damage amount. Thus, these concerns are relevant in the entire arena of personal injury litigation. Using these fears as a justification for rejecting the viability of preconception genetic tort claims will do little to solve the systemic problem that may grow into the geneticization of personal injury litigation. The problem will still exist, regardless of whether preconception genetic torts are viable causes of action.

Moreover, there seems little justification for “exceptionalizing” the geneticization of litigation by prohibiting compelled genetic testing. Marchant seems to agree, arguing that a “blanket prohibition on any use of genomic data in order to protect plaintiffs’ confidentiality would be unwise, because both plaintiffs and defendants can benefit from such data in appropriate cases. He also contends that “plaintiffs who put their health status at issue by bringing the litigation cannot expect such a blanket prohibition., This point is directly analogous to the generally required disclosure of health records of plaintiffs bringing medical malpractice suits. The argument in the latter scenario, which is not widely disputed, is simply that if the plaintiff is uncomfortable sharing details of their health information, then they should not bring a suit that places the contents of that health information directly at issue. Why litigation implicating genetic information should be treated so differently is unclear.

Of course, the argument here is simply that exceptionalizing genomic data by prohibiting its usage or even prohibiting compelled genetic testing if a court finds that genetic information is vital to the litigation is unwise. It does not follow that courts ought to admit such evidence with no hesitation or freely order plaintiffs to undergo genetic testing. The argument that genetic information does not seem to merit exceptional treatment does not imply that there are no material differences between genetic information and other kinds of individually identifiable health information. Requests for the disclosure of genetic information or requests to compel the plaintiff to undergo genetic testing should, like many other evidentiary matters in toxic tort litigation, be handled on an individual basis.

Marchant points out that “focused and scientifically-justified genetic inquiries and tests can help to resolve some lawsuits., However, he acknowledges, that “broader and more intrusive ‘fishing expeditions’ into the plaintiffs genome that lack any probable cause in terms of having a reasonable basis for investigating a specific gene or trait are likely to create more mischief than insight needed to resolve a case.” Rather than prohibiting the use of such information, or even the compelled genetic testing, courts have a variety of tools in their judicial armamentarium for assessing the merits of such requests in the course of discovery. Indeed, determining whether to compel disclosure or deny it on the basis that it is a “fishing expedition” is one of a trial judge’s more common activities in the discovery process. Similarly common is the use of protective orders that circumscribe and narrow the disclosure of sensitive and personal information.

Thus, there seems little basis for arguing that genetic information is so different that the judge’s diverse set of instruments in this regard should be ignored by simply stating that no plaintiff ever may be compelled to undergo genetic testing even where the basis of their case turns on the plaintiffs genome. Garrison argues that “the court system already deals with highly personal and protected information on a daily basis, and there is no reason why such safeguards cannot be successfully applied to genetic information.” A fortiori, there is even less merit in using the concerns of the geneticization of litigation as a reason for denying altogether the viability of preconception genetic torts.


There is little reason, neither for “pure” legal considerations, nor for policy concerns, to prevent any preconception genetic tort claim from being brought before a trier of fact. To be sure, difficult issues of proof, especially of causation, may prove daunting to the success of these claims in obtaining compensation. However, this is hardly a reason to deny all such claims before a plaintiff has an opportunity to bring forth such proof. Moreover, the Albala court’s concern over the proliferation of frivolous lawsuits that could occur if preconception genetic torts are ruled to be viable causes of action seems to be much ado about nothing, particularly where so few preconception genetic tort claims have been brought in the last twenty years. In any case, even if such cases do begin to proliferate, courts have a ready armamentarium of implements at their collective disposal that may be used to fashion reasonable boundaries on liability and recovery.

Daniel S. Goldberg, 2007.

More DES DiEthylStilbestrol Resources

1991 DES Case: Enright v. Eli Lilly & Co.


The question in this case is whether the liability of manufacturers of the drug diethylstilbestrol (DES) should extend to a so-called “third generation” plaintiff, the granddaughter of a woman who ingested the drug. According to the allegations of the complaint, the infant plaintiff’s injuries were caused by her premature birth, which in turn resulted from damage to her mother’s reproductive system caused by the mother’s in utero exposure to DES.” …

ENRIGHT v. ELI LILLY & CO., Leagle, 1990219155AD2d64_1211, March 22, 1990.

… ‘The Legislature and this Court have both expressed concern for the victims of this tragedy by removing legal barriers to their tort recovery — barriers which may have had their place in other contexts, but which in DES litigation worked a peculiar injustice because of the ways in which DES was developed, marketed and sold and because of the insidious nature of its harm.

For example, prior to 1986, the long-standing rule in this State was that a cause of action for personal injuries caused by a toxic substance accrued and the limitations period began to run upon exposure to the substance (see Fleishman v Lilly & Co.). The Legislature, recognizing that under this rule claims for injuries caused by exposure to DES and other toxic substances were often time barred before the harmful effects of the exposure could be discovered, changed the law to provide that the limitations period in exposure cases begins to run upon discovery of the injury At the same time, the Legislature revived for one year previously time-barred causes of action based on exposure to DES and four other toxic substances.

More recently, this Court responded to the fact that — for a variety of reasons unique to the DES litigation context — a DES plaintiff generally finds it impossible to identify the manufacturer of the drug that caused her injuries. We held that liability could be imposed upon DES manufacturers in accordance with their share of the national DES market, notwithstanding the plaintiff’s inability to identify the manufacturer particularly at fault for her injuries (see Hymowitz v Lilly & Co.).

In the present case, we are asked to do something significantly different. We are asked, not to remove some barrier to recovery that presents unique problems in DES cases, but to recognize a cause of action not available in other contexts simply (or at least largely) because this is a DES case.”…

” … the mother’s injuries in this case were caused by exposure to DES instead of by medical malpractice. A different rule is justified, therefore, only if that distinction alters the policy balance we struck in Albala.

The primary thrust of plaintiffs’ argument and the Appellate Division’s decision is that DES itself alters that balance. From the Legislature’s actions in modifying the applicable Statute of Limitations and reviving time-barred DES cases and from our adoption of a market-share liability theory in Hymowitz, plaintiffs perceive a public policy favoring a remedy for DES-caused injuries sufficient to overcome the countervailing policy considerations we identified in Albala. The implication, of course, is that the public interest in providing a remedy for those injured by DES is stronger than the public interest in providing a remedy for those injured by other means — medical malpractice, for example. We do not believe that such a preference has been established.

To be sure, recent developments demonstrate legislative and judicial solicitude for the victims of DES, but they do not establish DES plaintiffs as a favored class for whose benefit all traditional limitations on tort liability must give way. To the extent that special rules have been fashioned, they are a response to unique procedural barriers and problems of proof peculiar to DES litigation.

For example, the Legislature’s enactment of a “discovery” Statute of Limitations was directed at opening up traditional avenues of recovery by removing a procedural barrier that was unreasonable given the nature of DES injuries. Nothing in the legislation suggests that the Legislature intended to expand the basis for liability. Indeed, the language of the statute suggests the opposite conclusion. The discovery rule applies in cases of injury caused by “the latent effects of exposure to any substance * * * upon or within the body”. Exposure is defined as “direct or indirect exposure by absorption, contact, ingestion, inhalation or injection”. Implicit in this language is the notion that “some contact with the substance is essential to a cause of action”, an element lacking here. …

… “I am convinced that existing legal doctrine and established policy point unequivocally to a decision upholding Karen Enright’s cause of action. Let us assume for the sake of argument, however, that this is not so and that the appeal presents a “hard case” where there are no clearly discernible legal or policy guidelines. On this assumption, is there any underlying principled reason in fairness, justice or moral doctrine why Karen Enright’s claim should be turned away?

There are two fundamental principles of justice, however, which dictate that Karen Enright should be permitted to prove her case.

First, Karen Enright is a victim of what — if the allegations of her complaint are proven — amounts to a wrong of enormous proportions which inflicted grievous injuries on her and countless other innocent persons. Unless her case is barred on some legal or policy ground, she should be justly compensated for her injuries to the extent that our judicial system can accomplish this.

Second, she is damaged no less than other victims of DES who make up the class. If they are permitted to recover, so should she be. To say that Karen Enright cannot recover is to abrogate one of the most basic of all principles — that “like cases should be treated alike.”…

… Read the full paper ENRIGHT v. ELI LILLY & CO., on Leagle.

More DES DiEthylStilbestrol Resources

1990 DES Case: Sorrells v. Eli Lilly & Company


Plaintiff, Susan Sorrells, claims that she and her infant daughter Shanna were injured due to her mother’s ingestion of the drug diethylstilbestrol (“DES”) in 1951-1952 when she was pregnant with Susan..

Susan’s daughter, Shanna, was not exposed to DES in any way, but claims that her grandmother’s use of DES affected her mother’s ability to carry her to term, thus causing Shanna’s profound hearing loss and other injuries.

SORRELLS v. ELI LILLY AND COMPANY, Leagle, 19901415737FSupp678_11285, United States District Court, District of Columbia, May 24, 1990.

At bar is defendant’s motion to dismiss all of Shanna’s individual claims of negligence and strict liability on the grounds that Lilly owed no foreseeable duty to Shanna and plaintiff’s motion for certification of the issue to the Maryland Court of Appeals.. ” …

… continue reading SORRELLS v. ELI LILLY AND COMPANY on Leagle.

More DES DiEthylStilbestrol Resources


Medicine and the Law : First DES third-generation injury claim, 1991

On Feb 19, 1991, the New York Court of Appeals rejected the right to claim for a third-generation injury resulting from ingestion of diethylstilboestrol (DES) during pregnancy. The plaintiff was a 9-year-old girl with cerebral palsy. Her grandmother had taken DES during pregnancy in 1959, and her mother (born in 1960) had deformities in her reproductive system which, it was claimed, led to premature birth and neurological injuries in the third generation.

Medicine and the Law Diethylstilboestrol: third-generation injury claims, sciencedirect, Feb 19,1991.

DES was marketed for about 30 years in the belief that it reduced the risk of miscarriage. Over two hundred firms manufactured it, and it was widely prescribed in the Netherlands and USA. In 1971 it was “banned” by the US Food and Drug Administration (FDA) because of evidence of an abnormal incidence of vaginal and cervical cancer in the daughters of women who had taken DES during pregnancy. There were also adverse effects in male children.

… the daughters reached puberty at the earliest. Another problem has been to identify which manufacturer produced the brand of DES that each woman took. Furthermore, records have been destroyed or lost, manufacturers have closed down, prescribers have retired or died, and memories have faded. Early claims named the FDA as co-defendants but all claims against the Administration were dismissed.

One approach was the “concerted action petition”, which aimed to identify all distributors who participated in the “common purpose” of supplying DES to a particular area in which the plaintiffs mother had lived at the time of ingestion. This ploy was seldom successful, but in Michigan and New York courts ruled that the manufacturer’s marketing strategy showed evidence of conscious parallel strategies, and two cases did succeed. An attempt to shift the burden of proof on to a defendant, so that a manufacturer would have to establish his innocence, failed. The courts ruled that it would be unjust to find a firm guilty of dispensing an unsafe product when that individual manufacturer was merely one of a group whose identity was doubted. In California in 1980 plaintiffs were allowed to sue, on the basis of market share, all DES manufacturers who had supplied the drug to a particular area. This approach, though much criticised, has been the model for the later cases in which the plaintiff has been able to prove the manufacturer’s failure to test the safety of the drug or to warn the users of potential harm.

The claims for third-generation injuries by about 100 “DES granddaughters” marks a new stage in the battle for compensation. They allege that maternal uterine hypoplasia, cervical stenosis, and/or endometriosis caused by their mothers’ exposure to DES ingestion while in utero are responsible for their own congenital deformities. They also claim for large sums to compensate for anxiety over the increased risk of clear-cell adenocarcinomas. In most cases, thirty years or more have elapsed since the original DES ingestion, and such cases would normally be well outside time limits for bringing a suit. Even under the Consumer Protection Act 1987, which is not retrospective and which came into force in Britain on March 1, 1988, there is a maximum time limit of ten years in which claims may be brought. Beyond that, the plaintiff must pursue a claim in negligence in the normal way, if not time barred.

By a majority of 6 to 1, the New York Court of Appeals rejected in principle the right to pursue a third-generation DES injury claim.

Giving the judgment of the majority, Chief Judge Sol Wachtler said:

“For all we know, the rippling effects of DES exposure may extend for generations. It is our duty to confine liability within manageable limits. Limiting liability to those who ingested the drug or who were exposed to it in utero serves this purpose.”

Judge Stewart F. Hancock Jr, dissenting, argued that the girl

“should have the same right to sue the drug makers for her injuries as her mother… she is one of a class of thousands of persons who have allegedly suffered devastating abnormalities and injuries resulting from defendants’ marketing of DES … Is there any basis in the law or social policy or any principled reason in justice and fairness for holding that she-unlike other members of the class–should not be permitted to prove her case?”

The New York decision is likely to be persuasive in other states, though it is not binding outside New York, and with so much at stake the large numbers of would-be plaintiffs are unlikely to give up the struggle just yet.

Diana Brahams, 1991.

Click to download the full paper.

More DES DiEthylStilbestrol Resources

Preconception tort liability: recognizing a strict liability cause of action for DES grandchildren

” DES cases are breaking new ground in tort litigation. In March 1990, J. David Roberts filed a $ 2,000,000 lawsuit in the United States District Court for the District of Columbia against drug manufacturer Eli Lilly and Company, alleging that his in utero exposure to DES caused his daughter’s cancer. Roberts sued under theories of strict liability, emotional distress, breach of warranty, negligence and misrepresentation. He also alleged that DES manufacturers conspired to produce the drug after they knew of its dangers. “


Over the past decade more than 1,000 “DES daughters” have filed lawsuits against the manufacturers of DES, alleging that their in utero exposure to the drug caused various reproductive tract abnormalities, including cancer.

Plaintiffs now allege that their grandmothers’ use of DES during pregnancy caused genetic damage leading to cancer in third generations. This Note addresses the validity of preconception tort liability in the context of third-generation DES cases.

Plaintiffs in preconception tort liability cases have sought recovery under both negligence and strict liability causes of action. Courts should recognize the validity of preconception tort liability and allow a strict liability cause of action in third-generation cases.

Sources and More Information
  • Preconception tort liability: recognizing a strict liability cause of action for DES grandchildren, American journal of law & medicine, NCBI PubMed PMID: 1812769, 1991.
  • Preconception Tort Liability: Recognizing a Strict Liability Cause of Action for DES Grandchildren, Boston University School of Law, LexisNexis, 17 Am. J. L. and Med. 435, 1991.
More DES DiEthylStilbestrol Resources

Medical/legal implications of DES long-term sequelae, including 3rd generation


The spectrum of teratogenic and carcinogenic effects which can be exerted when the unborn child is exposed to diethylstilbestrol (DES) has been shown to be broad.

Animal work indicates the need for vigilance as regards genetic susceptibility to DES sequelae. The emergence of third generation sequelae has been demonstrated in mice, and has been postulated to occur in humans.

Diethylstilbestrol, teratogenesis, and carcinogenesis: medical/legal implications of its long-term sequelae, including third generation effects, International Journal of Risk and Safety in Medicine, vol. 1, no. 3, pp. 171-193, 1990.

Given the emergent data establishing problems of infertility in men and women and of relatively late onset cancer, and the possibility that in utero exposure to DES may prime a variety of tissues to noxious environmental influences there is an urgent need for measures to provide just coverage for those harmed by the drug.

The DES disaster also raises important ethical and research questions which demand attention.

More DES DiEthylStilbestrol Resources

EDCs: The Endocrine Society’s Second Scientific Statement

Endocrine-Society banner
Five years after the Endocrine Society’s first Scientific Statement in 2009, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life.


Executive Summary to EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, The Endocrine Society,, September 28, 2015.
Full study: EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, The Endocrine Society,, November 06, 2015.

The Endocrine Society’s first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease.

Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans—especially during development—may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans.

In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest:

  1. obesity and diabetes;
  2. female reproduction;
  3. male reproduction;
  4. hormone-sensitive cancers in females;
  5. prostate;
  6. thyroid;
  7. and neurodevelopment and neuroendocrine systems.

Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health.

Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

Discussion (DES and Fertility-specific)

Diethylstilbestrol and beyond: perhaps the best-studied endocrine-based example is in utero exposure to diethylstilbestrol (DES), a potent synthetic nonsteroidal estrogen taken by pregnant women from the 1940s to 1975 to prevent miscarriage and other complications. DES was prescribed at doses from less than 100 mg (in most cases) upward to 47 000 mg, with a median dose of 3650 to 4000 mg in the United States (IARC 2012). Most women received low doses (ie, 5 mg) and increased their intake (up to 125 mg) as symptoms or pregnancy progressed, translating to doses of about 100 μg/kg to 2 mg/kg DES per day. In 1953, a study proved DES was ineffective. Its use was discontinued when a subset of exposed daughters presented with early-onset vaginal clear-cell adenocarcinoma, with a 40-fold increase in risk compared to unexposed individuals. A highly significant incidence ratio for clear-cell adenocarcinoma was also found in the Dutch DES cohort, a population that may have had lower exposures than US women. It was subsequently determined that exposed offspring of both sexes had increased risk for multiple reproductive disorders, certain cancers, cryptorchidism (boys), and other diseases, although the risk for sons is more controversial. New data are emerging to implicate increased disease risk in grandchildren. Not surprisingly, a plethora of examples is emerging for increased disease susceptibility later in life as a function of developmental exposures to EDCs that include BPA, phthalates, PCBs, pesticides, dioxins, and tributyltin (TBT), among others.

Epigenetics and transgenerational effects of EDCs: EDC-induced epigenetic changes are also influenced by dose of exposure, and they are tissue specific. Thus, it is important to consider both dose of EDC and the tissue before making firm conclusions about the epigenetic effects of EDCs. DNA methylation changes are the best-studied mechanism in this regard. For example, prenatal exposure to DES caused hypermethylation of the Hoxa10 gene in the uterus of mice and was linked to uterine hyperplasia and neoplasia later in life. Beyond the effects of prenatal exposure to DES on the daughters exposed in utero are suggestions that this leads to transgenerational effects of the chemical on the reproductive system, although whether this is linked to DNA methylation changes in humans is unknown.

Little is known about the ability of EDCs to cause histone modifications and whether this leads to transgenerational effects in animals or humans. The herbicides paraquat and dieldrin caused histone modifications in immortalized rat mesencephalic dopaminergic cells, and the insecticide propoxur causes histone modifications in gastric cells in vitro. DES caused histone deacetylation in the promoter region of the cytochrome P450 side chain cleavage (P450scc) gene. Further studies, however, need to be conducted to identify other EDCs causing histone modifications in animals and humans and to determine whether such modifications lead to transgenerational effects.

Female Reproductive Health: in the past 5 years, no new information became available on the effects of DES on the postnatal human ovary. Recent animal studies indicate that DES adversely affected the postnatal ovary. Neonatal exposure to DES inhibited germ cell nest breakdown (408) and caused the formation of polyovular follicles in mice, likely by interfering with the ERβ pathway and inhibiting programmed oocyte death and germ cell loss. It also reduced the primordial follicle pool and increased atresia in prepubertal lambs, and it caused polyovular ovaries in hamsters. Although these previous studies provide solid evidence that DES adversely affects ovarian structure in a variety of species, studies are needed to determine whether other synthetic estrogens adversely affect the ovary.

Effects of EDCs on uterine structure and function: synthetic estrogens are well known disruptors of uterine structure and function in humans and animals. Consistent with previous studies, recent data indicate that neonatal DES exposure caused endometrial hyperplasia/dysplasia in hamsters and increased uterine adenocarcinoma and uterine abnormalities in Donryu rats. Neonatal DES exposure also caused the differential expression of 900 genes in one or both layers of the uterus. Specifically, DES altered multiple factors in the PPARγ pathway that regulate adipogenesis and lipid metabolism, and it perturbed glucose homeostasis, suggesting that DES affects energy metabolism in the uterus. In the mouse uterus, DES altered the expression of chromatin-modifying proteins and Wnt signaling pathway members, caused epigenetic changes in the sine oculis homeobox 1 gene, and decreased the expression of angiogenic factors. DES also altered the expression of genes commonly involved in metabolism or endometrial cancer in mice, and it activated nongenomic signaling in uterine myometrial cells and increased the incidence of cystic glands in rats.

Effects of EDCs on the vagina: only a limited number of studies assessed the effects of EDCs on the vagina, and of these, all but one on phthalates focused on DES. A recent study of women showed an association between in utero exposure to DES and clear cell carcinoma of the vagina, confirming previous findings. Furthermore, DES disrupted the expression of transformation-related protein 63, which makes cell fate decisions of Müllerian duct epithelium and induces adenosis lesions in the cervix and vagina in women.

Studies in mice showed that DES induced vaginal adenosis by down-regulating RUNX1, which inhibits the BMP4/activin A-regulated vaginal cell fate decision; induced epithelial cell proliferation and inhibited stromal cell proliferation (520); and caused persistent down-regulation of basic-helix-loop-helix transcription factor expression (Hes1, Hey1, Heyl) in the vagina, leading to estrogen-independent epithelial cell proliferation. Neonatal exposure to DES caused persistent changes in expression of IGF-1 and its downstream signaling factors in mouse vaginas. It also up-regulated Wnt4, a factor correlated with the stratification of epithelial cells, in mouse vaginas. Interestingly, the simultaneous administration of vitamin D attenuated the ability of DES to cause hyperplasia of the vagina in neonatal mice.

In the one study in the previous 5 years that did not focus on DES, polypropylene and polyethylene terephthalate did not increase vaginal weight in Sprague-Dawley rats. Although a few studies have been conducted during the previous 5 years on the effects of EDCs on the vagina, such studies are very few in number, small in scope, and focused on DES. Thus, future studies are needed in this largely understudied area before we fully appreciate whether other EDCs impair the vagina.

Premature ovarian failure/early menopause: combined data from three studies on DES indicated that in utero exposure was associated with an increased lifetime risk of early menopause in women (602). However, animal studies have not determined whether DES exposure causes premature ovarian failure. Thus, future studies should focus on this issue.

Fibroids: a few recent studies confirmed the known association between DES exposure and fibroids. In the Sister Study, in utero exposure to DES was positively associated with early-onset fibroids. Similarly, in the Nurses’ Health Study II, prenatal DES exposure was associated with uterine fibroids, with the strongest risk being for women exposed to DES in the first trimester. Given the consistency in findings, future studies should be focused on determining the mechanism by which DES exposure increases the risk of fibroids.

Click to download the summary.
Click to download the full study.

More DES DiEthylStilbestrol Resources

DES-treated tall girls fertility, a dose-response relationship

Fertility of tall girls treated with high-dose estrogen.


Fertility of tall girls treated with high-dose estrogen, a dose-response relationship, National Institutes of Health, NCBI PubMed PMID 22723330, 2012 Sep.

Full text: The Endocrine Society,, June 20, 2012.

High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life.

The aim was to study the effect of estrogen dose on fertility outcome of these women.

We conducted a retrospective cohort study of university hospital patients.

We studied 125 tall women aged 20-42 yr, of whom 52 women had been treated with 100 ?g and 43 with 200 ?g of ethinyl estradiol (EE) in adolescence.

Time to first pregnancy, treatment for infertility, and live birth rate were measured.

The time to first pregnancy was increased in treated women. Of untreated women, 80% conceived within 1 yr vs. 69% of women treated with 100 ?g EE and 59% of women treated with 200 ?g EE. This trend of increased time to pregnancy with increasing estrogen dose was significant (log rank trend test, P = 0.01). Compared with untreated women, fecundability was reduced in women treated with both 100 ?g EE [hazard ratio = 0.42; 95% confidence interval (CI), 0.19-0.95] and 200 ?g EE (hazard ratio = 0.30; 95% CI, 0.13-0.72). We also observed a significant trend in the incidence of treatment for infertility with increased estrogen dose (P = 0.04). Fecundity was affected in women treated with 200 ?g EE who had reduced odds of achieving at least one live birth (odds ratio = 0.13; 95% CI, 0.02-0.81), but not in women treated with 100 ?g EE.

We report a dose-response relationship between fertility in later life and estrogen dose used for the treatment of tall stature in adolescent girls; a higher estrogen dose is associated with increased infertility.


It has been shown that high-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life (3, 4). Here, we studied the effect of estrogen dose on fertility outcome of these women. We compared women who received no treatment to women who received either 100 ?g EE or 200 ?g EE. Our study confirms that tall women treated with high-dose estrogen have an increased time to pregnancy and experience more fertility problems compared with untreated women. We demonstrate for the first time that the association between estrogen treatment and the observed infertility is dose-dependent.

Although human studies on the effects of treatment with estrogens have mostly focused on OCP users, animal studies have focused on environmental exposure to EE as an endocrine-disruptor and on the effects of diethylstilbestrol (DES). In rodents, both in utero and postnatal exposure to EE or DES produces permanent adverse effects on the developing female reproductive system. Animal studies on in utero exposure to DES have shown disruption at the follicle level. In DES-exposed mice, reduced numbers of primordial follicles and of oocytes after ovulation induction have been found. Neonatal exposure to DES in lambs reduces the primordial follicle pool by stimulating their initial recruitment, resulting in increased numbers of atretic follicles. Finally, DES induces transient changes in gene expression during gestation; these changes could be involved in follicle development, rate of atresia, or patterns of secretion or metabolism of steroid hormones. These animal studies suggest that pharmacological doses of estrogens may influence fertility in many ways and at various time points. This knowledge, although difficult to extrapolate, may help in better understanding the mechanism behind the observed infertility in tall women treated with high-dose estrogen.

Previously, it has been shown that a considerable number of tall women treated with high-dose estrogen in adolescence suffer from primary ovarian insufficiency with concomitant early follicle pool depletion diagnosed by increased serum FSH levels, decreased serum anti-Müllerian hormone levels, and low antral follicle counts. Although the mechanism behind this accelerated follicle loss observed in these women remains unknown, based on our results we conclude that estrogen may play a key dose-dependent role. This is supported by a study on in utero exposure of women to DES, who reported an earlier age at menopause with cumulating doses of DES.

Click to download the full study.

More DES DiEthylStilbestrol Resources

EDCs: an Endocrine Society Scientific Statement

EDC-statement banner
The group of molecules identified as endocrine disruptors include synthetic estrogens used as pharmaceutical agents such as Diethylstilbestrol DES.


Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement, The Endocrine Society,, April 17, 2009.

There is growing interest in the possible health threat posed by endocrine-disrupting chemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction.

In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology.

Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor ?, retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use.

We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness.

Discussion (DES and Fertility-specific)

General Introduction: the group of molecules identified as endocrine disruptors is highly heterogeneous and includes synthetic chemicals used as industrial solvents/lubricants and their byproducts [polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), dioxins], plastics [bisphenol A (BPA)], plasticizers (phthalates), pesticides [methoxychlor, chlorpyrifos, dichlorodiphenyltrichloroethane (DDT)], fungicides (vinclozolin), and pharmaceutical agents [diethylstilbestrol (DES)].

Reproduction: in the adult female, the first evidence of endocrine disruption was provided almost 40 yr ago through observations of uncommon vaginal adenocarcinoma in daughters born 15–22 yr earlier to women treated with the potent synthetic estrogen DES during pregnancy. Subsequently, DES effects and mechanisms have been substantiated in animal models. Thus, robust clinical observations together with experimental data support the causal role of DES in female reproductive disorders. However, the link between disorders such as premature pubarche and EDCs is so far indirect and weak, based on epidemiological association with both IUGR and ovulatory disorders. The implications of EDCs have been proposed in other disorders of the female reproductive system, including disorders of ovulation and lactation, benign breast disease, breast cancer, endometriosis, and uterine fibroids.

In the case of DES, there are both human and experimental observations indicating heritability.

Premature ovarian failure, decreased ovarian reserve, aneuploidy, granulosa steroidogenesis: interestingly, mice exposed in utero to DES, between d 9–16 gestation, have a dose-dependent decrease in reproductive capacity, including decreased numbers of litters and litter size and decreased numbers of oocytes (30%) ovulated in response to gonadotropin stimulation with all oocytes degenerating in the DES-exposed group, as well as numerous reproductive tract anatomic abnormalities. In women with in utero exposure to DES, Hatch et al reported an earlier age of menopause between the 43–55 yr olds, and the average age of menopause was 52.2 yr in unexposed women and 51.5 yr in exposed women. The effect of DES increased with cumulative doses and was highest in a cohort of highest in utero exposure during the 1950s. These observations are consistent with a smaller follicle pool and fewer oocytes ovulated, as in DES-exposed mice after ovulation induction.

Reproductive tract anomalies: disruption of female reproductive tract development by the EDC DES is well documented. A characteristic T-shaped uterus, abnormal oviductal anatomy and function, and abnormal cervical anatomy are characteristic of thisin utero exposure, observed in adulthood, as well as in female fetuses and neonates exposed in utero to DES. Some of these effects are believed to occur through ER? and abnormal regulation of Hox genes. Clinically, an increased risk of ectopic pregnancy, preterm delivery, miscarriage, and infertility all point to the devastating effect an endocrine disruptor may have on female fertility and reproductive health. It is certainly plausible that other EDCs with similar actions as DES could result in some cases of unexplained infertility, ectopic pregnancies, miscarriages, and premature deliveries. Although another major health consequence of DES exposurein utero was development of rare vaginal cancer in DES daughters, this may be an extreme response to the dosage of DES or specific to pathways activated by DES itself. Other EDCs may not result in these effects, although they may contribute to the fertility and pregnancy compromises cited above. Of utmost importance clinically is the awareness of DES exposure (and perhaps other EDC exposures) and appropriate physical exam, possible colposcopy of the vagina/cervix, cervical and vaginal cytology annually, and careful monitoring for fertility potential and during pregnancy for ectopic gestation and preterm delivery.

Endometriosis is an estrogen-dependent gynecological disorder associated with pelvic pain and infertility. There are suggestive animal data of adult exposure to EDCs and development of or exacerbation of existing disease, and there is evidence that in utero exposure in humans to DES results in an increased relative risk = 1.9 (95% confidence interval, 1.2–2.8).

Environmental estrogens effects on the prostate: DES exposure is an important model of endocrine disruption and provides proof-of-principle for exogenous estrogenic agents altering the function and pathology of various end-organs. Maternal usage of DES during pregnancy resulted in more extensive prostatic squamous metaplasia in human male offspring than observed with maternal estradiol alone. Although this prostatic metaplasia eventually resolved during postnatal life, ectasia and persistent distortion of ductal architecture remained. These findings have led to the postulation that men exposed in utero to DES may be at increased risk for prostatic disease later in life, although the limited population studies conducted to date have not identified an association. Nonetheless, several studies with DES in mouse and rat models have demonstrated significant abnormalities in the adult prostate, including increased susceptibility to adult-onset carcinogenesis after early DES exposures. It is important to note that developmental exposure to DES, as with other environmental estrogens, has been shown to exhibit a biphasic dose- response curve with regard to several end-organ responses, and this has been shown to be true for prostatic responses as well. Low-dose fetal exposure to DES or BPA (see full study) resulted in larger prostate size in adulthood compared with controls, an effect associated with increased levels of prostatic ARs. This contrasts with smaller prostate sizes, dysplasia, and aging- associated increases in carcinogenesis found after perinatal high-dose DES exposures as noted above. This differential prostatic response to low vs. high doses of DES and other EDCs must be kept in mind when evaluating human exposures to EDCs because the lack of a response at high doses may not translate into a lack of negative effects at low, environmentally relevant doses of EDCs.

Linking basic research to clinical practice: it should be clear from this Scientific Statement that there is considerable work to be done. A reconciliation of the basic experimental data with observations in humans needs to be achieved through translation in both directions, from bench to bedside and from bedside (and populations) to bench. An example of how human observation and basic research have successfully converged was provided by DES exposure in humans, which revealed that the human syndrome is faithfully replicated in rodent models. Furthermore, we now know that DES exposure in key developmental life stages can have a spectrum of effects spanning female reproduction, male reproduction, obesity, and breast cancer. It is interesting that in the case of breast cancer, an increased incidence is being reported now that the DES human cohort is reaching the age of breast cancer prevalence. The mouse model predicted this outcome 25 yr before the human data became available. In the case of reproductive cancers, the human and mouse data have since been confirmed in rats, hamsters, and monkeys. This is a compelling story from the perspective of both animal models and human exposures on the developmental basis of adult endocrine disease.

Prevention and the “precautionary principle”: although more experiments are being performed to find the hows and whys, what should be done to protect humans? The key to minimizing morbidity is preventing the disorders in the first place. However, recommendations for prevention are difficult to make because exposure to one chemical at a given time rarely reflects the current exposure history or ongoing risks of humans during development or at other life stages, and we usually do not know what exposures an individual has had in utero or in other life stages.

In the absence of direct information regarding cause and effect, the precautionary principle is critical to enhancing reproductive and endocrine health. As endocrinologists, we suggest that The Endocrine Society actively engages in lobbying for regulation seeking to decrease human exposure to the many endocrine-disrupting agents. Scientific societies should also partner to pool their intellectual resources and to increase the ranks of experts with knowledge about EDCs who can communicate to other researchers, clinicians, community advocates, and politicians.

Click to download the full study.

More DES DiEthylStilbestrol Resources