The Mother of All FDA Fails
The FDA has never required drug safety assessment for fetal germline impact, even though FDA staff understand that gestational exposures can adversely affect developing germ cells. We must end this catastrophic omission, while also granting all Americans access to their own prenatal medical records.
Now for some good news: the NIEHS seeks input on multigenerational consequences of exposures
Kudos to the NIEHS (National Institute for Environmental Health Sciences)! They seem to be sensing that something is going on with multigenerational consequences of chemical, pharmaceutical and other exposures, and ... they want to hear from us about it. Responding to their Request for Information (RFI): Input on a Literature Review Approach “Evaluation of the State of the Science for Transgenerational Inheritance of Health Effects”, I penned the following letter.
Let's hope this nascent effort on their part opens new doors to understanding autism etiology and the hidden sources of other raging public health disasters.
Escher Fund for Autism
Vickie R. Walker
Office of Health Assessment and Translation
Division of the National Toxicology Program
National Institute of Environmental Health Sciences
111 TW Alexander Dr., PO Box 12233 MD: K2-04
Durham, NC 27709
May 10, 2013
Re: Input on “Evaluation of the State of the Science for Transgenerational Inheritance of Health Effects”
Dear Dr. Walker and OHAT,
I appreciate this opportunity to respond to the RFI on multigenerational impacts of ancestral exposures. Based on personal experience, as well as interviews with more than 70 autism families and the extant scientific literature, I share the concern that certain chemical and pharmaceutical exposures, given in certain timeframes of susceptibility, can, via molecular epigenetic impact on germline, adversely affect the health and developmental integrity of subsequent generations, sometimes dramatically.
I am grateful that the NIEHS is exploring this urgent question, and would like to provide the following comments. As background to my involvement in this field (as it’s not common for a non-scientist to take such a keen interest), please see a short video regarding my personal story at http://www.ucdmc.ucdavis.edu/mindinstitute/videos/video_es.html. Simply scroll down to the top video, called, “An autism mom asks: Who says you can’t have a genetic epidemic?”
A. Comments on the proposed approach for exploratory screening: (1) importance of direct germline impacts, (2) targeting highly impactful exposures, and (3) adding additional relevant search terms
1. Direct germline (in F1 or F2) exposure effects are of utmost importance, and should be central to OHAT’s inquiry.
As the NIEHS evaluates the state of the science in this area, it should involve a strong focus on the health and developmental effects of direct germline exposures, in other words, exposures that directly affect the molecular genetic integrity of the sperm, egg, or their precursors. These direct germline exposures can occur in at least three ways:
(1) Exposure of fetal germ cells, affecting F2 health. In a gestating female (F0), the fetus would be F1, and the fetal germ cells F2. If the F0 female takes a pharmaceutical or drug, smokes cigarettes, or is otherwise exposed to a stressor, that stressor may impact the F1 fetus as well as the fetal germline (F2), which is highly epigenetically vulnerable to exogenous exposures during the first half of gestation. F2/fetal germline exposures were rampant in the mid-20th century, with almost unrestrained prenatal pharmaceutical use, widespread maternal smoking, the use of potent endocrine disruptors such as dioxin, flame retardants, PCBs and DDT, and even air pollution.
(2) Exposure of the very early embryo, affecting F1 health. At around the time of fertilization, abnormal exposures can affect the germline epigenome. As the embryonic stem cell epigenome is altered due to this germ line transmission, all the resulting organismʼs cell populations and tissues will have an altered epigenome and corresponding transcriptome. Although not all cell types or tissues will develop a disease state, those tissues that have a sufficiently altered transcriptome will have a greater susceptibility to abnormal development. Two examples of abnormal exposures that could affect the F1 early embryo are:
--IVF and assisted fertility: Assisted reproductive technology (ART) may play a role in the etiology of some cases of ASD through epigenetic perturbations, particularly loss of DNA methylation in the early embryo. Various ART factors contributing to epigenetic disturbance include artificial ovulation induction, culturing of cells in certain media, and the physical manipulation of germ cells and early embryos.
--Oral contraceptive pills: Although birth control pills are generally effective at preventing pregnancy, many women continue, unaware, to take the pills post-conception. These pills are made from synthetic hormones, which are likely to have epigenetic impacts on the egg and early embryo.
(3) Exposure of the post-natal gametes, affecting F1 health. In the male, for example, it takes two months for a spermatozoa to mature from the spermatogonial stem cells. During this time, the developing sperm are vulnerable to exogenous exposures, and paternal drug or pharmaceutical use or smoking, for example, may impair the proper synthesis of the germline epigenome. Unlike other cells, sperm are lacking in internal mechanisms that repair DNA.
The idea that exposures to the germ cells can impact health and development of the later-resulting organism is largely noncontroversial. Unfortunately, however, these impacts are ignored almost entirely in the FDA and EPA safety review processes, and have not been evaluated in NIH studies apart from some study of the DES third generation. Moreover, these exposures are likely extremely relevant to many of today’s public health challenges, including skyrocketing rates of neurodevelopmental disability (autism spectrum disorders included), asthma, diabetes, autoimmune disease, and obesity.
In sum, while “transgenerational” effects that do not stem from direct exposures are also extremely important, OHAT’s present inquiry should begin with the more fundamental and relevant (yet under-explored) question of direct germline effects of xenobiotic exposure, since that is where ancestral exposures are likely to have greatest effect, and where all multigenerational consequences on gene expression begin.
2. Stressors to be studied. I would like to suggest four particular categories for ancestral stressors for study.
a. Gestational exposures: Historic prenatal pharmaceutical use of the 1950s-70s, plus current prenatal pharmaceutical use
The Prenatal Pharmaceutical Craze of the 1950s, 60s and 70s – though largely forgotten by the public, historians, and researchers – ranks among the most toxic events in human history, as it placed acute doses of potent synthetic chemicals and endocrine disruptors directly into the bodies of pregnant women, and therefore, their fetuses and germline. Countless millions of us were exposed.
In the decades after the war, chemical and drug companies produced an explosion of novel synthetic pharmaceutical products, and the medical profession, intoxicated by the same boundless faith in the progress of science that gripped the rest of the country, was eager to administer the new concoctions to its patients, including pregnant women. An excerpt from the book, “Origins,” by Annie Murphy Paul (2010) summarizes the history, beginning with the medical profession's early views regarding the risks of alcohol:
Doctors' confidence in the harmlessness of alcohol was based on their beliefs about the placenta. This organ, which implants itself in the uterus soon after conception to form a way station between woman and fetus, was thought to provide seamless protection from harmful substances. Medical historian Ann Dally traces this sanguine notion back to the attitudes of the late nineteenth century. "The Victorian tendency to put woman on a pedestal led to the idealization of the woman as well as of the woman," she writes, and to 'a belief in the placenta as a perfect barrier against damaging influences." This conviction was still current in the 1950s, when Dally attended medical school; there she was taught that a toxin would affect the fetus only if it actually killed the mother. Pregnant women were not counseled about the dangers of medications or alcohol, Dally notes, and new drugs were not thoroughly tested for their safety during pregnancy.
And new drugs there were in abundance. The middle of the twentieth century was a golden age of pharmaceutical innovation, a time when serene sleep and steady nerves and a slim figure could be found inside the medicine cabinet. Pregnant women, too, were promised relief from all the complaints, small and large, of their condition: sleeplessness, morning sickness, miscarriage. The remedies were touted by advertisers in women's magazines, and by the publications' writers and editors themselves; an article about miscarriage in the November 1950 issue of Women's Home Companion celebrated "the miracle drugs that have tumbled from the laboratories in such heartening profusion recently." The sales job worked: those who gave birth in the postwar years, writes one chronicler of the period, "were among the most medicated women in history." Between 1958 and 1965, according to one study, half of all new mothers took two to four pharmaceutical products while pregnant.
Origins, pp 79-80.
What have been the germline effects of this unprecedented mass use of gestational synthetic pharmaceuticals? We don’t know. No one has yet asked the question. The pharmaceutical exposures of concern include synthetic hormones (progestins, estrogens, corticosteroids, thyroid hormones), barbiturates and other sedatives, psychoactive drugs, amphetamines, anti-nausea medications, and anti-hypertensives, among others.
As for the synthetic hormones, this information from a 1969 medical text, “The Use of Progestins in Obstetrics and Gynecology,” by RW Kistner explains the old standard of care for “habitual aborters,” defined as women who had two or more miscarriages, and the acute nature of the timing and dosage:
Provera: ... 10 mg daily, orally, during the first trimester of pregnancy; then 20 mg daily, orally, during the second trimester and 30 mg, daily, orally, during the third trimester.
Delalutin: (hydroxyprogesterone caproate) 375-500 mg (3-4 cc., intramuscularly) every week, starting as soon as pregnancy is confirmed and continuing to fetal viability.
Deluteval (hydroxyprogesterone caproate plus estradiol valerate): 500 mg. Delalutin plus 10 mg Delestrogen, intramuscularly, every week from the time of confirmation of pregnancy until fetal viability.”
“If progesterone is administered, it is best started before conception and continued during pregnancy.... Progesterone, hydroxyprogesterone caproate and oral medroxyprogesterone acetate may be used in the prophylatic management of the habitual aborter.”
Also advised, for example by Edward Tyler in his influential 1960 book, “Sterility: Office Management of the Infertile Couple,” was the use of prednisolone very early in the at-risk pregnancy.
It is worth noting that no evidence shows these old enhanced hormonal methods (which continue to various degrees in some assisted fertility practice) were effective at sustaining pregnancy or reducing miscarriage rates. The old practices were based purely on hypothesis and conjecture and not empirical data.
b. Gestational and non-gestational exposure case study: Flame retardant disaster of Jackson County, Michigan
In 1973, it was discovered that Michigan Chemical had accidentally used the flame retardant chemical PBB instead of a vitamin additive for cattle feed.
That contaminated feed was then fed to cattle, pigs, and chickens throughout Michigan. It's estimated that nine out of 10 Michiganders consumed contaminated meat, dairy, or poultry during the two years it took to discover the human error.
For the past 40 years, the Michigan Department of Community Health and now Emory University have been involved in studying the effects that consumption of PBB-contaminated food has had on human health. Research found an increase in breast cancer, thyroid disease, and early puberty in girls, as well as infertility in women born to mothers who consumed the PBB-contaminated food. Phase II of the research is now looking at additional cancers, Alzheimer's, Parkinson's, and fertility problems in males born to mothers who consumed the PBB-contaminated food.
As this is among largest studies of human chemical contamination in the world, I suggest OHAT’s evaluation look closely at the data for germline and multigenerational effects.
c. Non-gestational exposures: Dioxin and DDT
Both dioxin and DDT are potent endocrine disruptors to which people, particularly in certain localities, suffered acute exposures in the mid 20th century. Both chemicals accumulate in fatty tissue and persist in the body for many years. Therefore, a fetus and its germline can be considered “exposed” to these chemicals many years after the parental contact with the chemicals, owing the parental body burden.
These compounds should be of particular concerns, for reasons expressed so well in the landmark book, “Our Stolen Future.”
“Hormonally active synthetic chemicals are thugs on the biological information highway that sabotage vital communication. They mug the messengers or impersonate them. They jam signals. The scramble messages. They sow disinformation. They wreak all manner of havoc. Because hormone messages orchestrate many critical aspects of development, from sexual differentiation to brain organization, hormone-disrupting chemicals pose a particular hazard before birth and early in life.” (Pp 263-64.)
I would suggest reviewing the literature on multigenerational effects of Agent Orange, PCBs, and DDT. With respect to Agent Orange I would suggest partnering with the military to access their studies and files. Agent Orange was tested domestically before it was used in Vietnam, but finding data from those exposed in Vietnam, whether US soldiers or native Vietnamese, is exceedingly important. It is worth noting that autism rates among both the US military and the Vietnamese (families of immigrants to the US, and in Vietnam itself) have skyrocketed.
d. Non-gestational exposures: paternal pre-conception smoking, drug or pharmaceutical use, ionizing radiation
In the male, for example, it takes two months for a spermatozoa to mature from the spermatogonial stem cells. During this time, the developing sperm are vulnerable to exogenous exposures, and paternal drug or pharmaceutical use or smoking, for example, may impair the proper synthesis of the germline epigenome. Unlike other cells, sperm are without internal mechanisms that repair DNA.
Men are not warned about the risks to their sperm integrity caused by pre-conception exposures. Yet, there is literature to suggest this is occurring.
3. Additional search terms.
The approach to conduct the exploratory screening of the literature should include these additional search terms, in various combinations as may be appropriate: “germline,” “germ cell,” “primordial germ cell,” “spermatogonial stem cell,” “epigenetic,” “methylation,” “histone,” “in utero,” “intrauterine,” “prenatal,” and “gestational.”
B. identification of scientists with knowledge or expertise relevant to this topic.
The following is a list of scientists of whom I am aware, who are involved in this or closely related areas of research.
[omitted from blog]
C. Unpublished, ongoing, or planned studies related to transgenerational inheritance
In many ways, experiments in multigenerational experiments on human subjects have already been done, as acute gestational exposures to synthetic chemicals, given in the form of pharmaceutical drugs, were widespread after World War II, particularly in the 1950s, 60s, and into the 70s. In an effort to look at F2 outcomes of these historic exposures, I have been working with epidemiologists to locate cohorts for which there are both F0 reliable gestational exposure records and a good likelihood of obtaining F2 health and developmental outcomes. As you can imagine, this is not an easy task.
That said, one such epidemiological study is in the works, funded by our fund and Autism Speaks. It is a first-of-its-kind three-generation study based on Denmark’s Prenatal Development Project Cohort, a cohort of women who gave birth in about 1960 at a Copenhagen hospital. Thanks to Denmark’s system of health registries, the researchers, Reinisch and Mortensen, hope to be able to cross reference the F0 exposures to the F2 grandchildren. The F0 exposures are primarily synthetic hormone drugs, barbiturates, other drugs common in that era, and cigarette smoking. You can learn details about this new study in a video posted here: http://www.ucdmc.ucdavis.edu/mindinstitute/videos/video_es.html (scroll down to video featuring Reinisch and Mortensen).
Other cohorts being investigated for possible grandchild-effect studies include the CHDS, the CPP, and a cohort in Israel. Of personal interest are smaller cohorts, for which there are outstandingly detailed prenatal drug exposure records, from Los Angeles in New Jersey. The F1 offspring of these pregnancies were studied by Reinisch in the 1970s (as a child, I was a subject in her 1977 Los Angeles study). However, these studies are not yet underway.
In closing, the process of germline development depends on the appropriate delivery of precise chemical messages, including hormonal molecules. Impostor hormones and other synthetic chemicals can hijack a fragile and unfathomably complex system that evolved over billions of years, upsetting the normal molecularly-controlled developmental processes necessary for normal sperm and egg development. And these perturbations may have multigenerational consequences.
Thank you for your interest in multigenerational impacts of exposures and for your consideration of these comments.