Fifty years ago the drug thalidomide was found to cause serious damage to the unborn child.
The Challenge of Thalidomide: A pilot study of the educational needs of children in Scotland affected by the drug (Author) M.L. Kellmer Pringle and D.O. Fiddes
Publisher The National bureau for co-operation in child care, Longman 1970
by McCredie (Author) Publisher: Harper Collins Canadaltd
Thalidomide - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References.
(Author) Health Publications Publisher: Icon Health Publications (June 2004)
Suffer the Children: The Story of Thalidomide (Author), Elaine Potter
Publisher: Viking Press (February 1979)
Thalidomide: Index of New Information for Research, Reference & Therapy
(Author) Max C. Dobber Publisher: Abbe Pub Assn of Washington Dc (March 1998)
The Thalidomide Children and the Law: a report by Sunday Times
Publisher: André Deutsch Limited (1973)
Thalidomide and the Power of the Drug Companies
(Author) Henning Sjöström and Robert Nilsson Publisher: Penguin Books (1972)
Contergan/Thalidomid : Ein Unglück kommt selten allein (Author) Catia Monser
Publisher: Eggcup-Verlag (1993)
Thalidomide Embryopathy in Japan
Edited by Mitsushiro Kida and Published by Kodansha LTD (1987)
For bibliographies see amazon
The thalidomide controversy involves numerous issues. Our claims are as follows and will be examined in order:
Scientists did know that chemicals crossed the placenta
A myth dating back to the Middle Ages said that the placenta did not allow harmful chemicals to cross over to the fetus. Some have claimed that animal studies, specifically studies using pigs in the 1920s and 1930s were responsible for finally disproving this myth. In fact, scientists had good evidence that the placenta was permeable in the late 1800s based on human observations. By the 1930s, a combination of human and animal data had definitively disproven the myth. Moreover, drugs like thalidomide, that crossed the blood brain barrier thereby decreasing nausea, would also be expected to cross the placenta.
In 1874, Zweifel performed research that revealed that chloroform crossed the human placenta. . This was again demonstrated in dogs in 1912. Other anesthetic agents such as opioids, barbiturates, and tranquilizers (e.g., chlorpromazine), were also known before the 1950s to cross the placenta. In 1878, a case was published that reported sodium salicylate was found in the urine of the baby after having been given to the mother 30 minutes prior to delivery. This appears to be the first time the scientific literature suggested that chemicals were able to cross the placenta. In 1909, alcohol was measured in the umbilical cord blood and revealed to be in the same concentration as in the mother. The alcohol had been administered one hour prior to delivery. Between 1909 and 1933, Nicloux and others had conducted research that led them to think that drugs such as quinine passed through the placenta. Taylor wrote in 1935: “that the placenta is permeable to drugs is well established.”Dille in 1934 had shown that Amytal passed the placenta in cats, rabbits, and guinea pigs and pointed out that the effects of morphine had been demonstrated numerous times on the human fetus. Pettey , in 1912 had pointed out a case where a newborn infant from a mother addicted to morphine was also addicted and went so far as to suggest that any infant born to an opiate addicted mother should receive an opiate for three days following birth. He based this on the fact that opiates crossed the placenta and, since the placenta had been severed, no more opiates were available for the infant. Burnet, in 1920 suggested the same. Taylor, in 1932 also reported that cyanosis of the newborn had all but been eliminated by abandoning twilight sleep, a practice involving giving opiates to women in labor. Taylor summarized by stating: “The obstetrician has long since recognized the permeability of the placenta to drugs.” Clearly, human and animal data was available in the 1930s that proved drugs did cross the placental barrier.
(Statements such as Taylor’s must be interpreted in the context of the day. The fact that any drugs crossed the placenta would have been viewed as proof of the concept that at least some drugs were capable of crossing, not that all drugs could or did cross the placenta. As we now know, placental transfer is highly dependent upon a number of factors including the lipophilicity of the drug. All drugs do not, in fact, cross the placenta. For example, polar molecules such as muscle relaxants (like curare) do not cross.)
Thiersch in the 1950s, had shown repeatedly that some drugs could cross the placenta and cause the mother to abort the fetus. Sjöström and Nilsson  referred to Thiersch when they stated in court testimony at Södertälje that by 1959 at least 25 chemicals had been shown to affect the fetus, either killing the fetus or inducing malformations, that these studies had been performed in the US, Japan, and Europe, : “The findings by the various investigators were published in scientific journals and distributed internationally.” Other studies supporting the placental transfer of a number of drugs were also available to the manufacturer of thalidomide. It had been shown that any chemical with a molecular weight less than 1000 was at least a candidate for crossing the placenta. it was written in 1957 that chemicals with a molecular weight below 350 or 450 Da were known to be capable of crossing the placenta. The molecular weight of thalidomide is 258 Da and entering the fetal circulation should have been considered a strong possibility based on the knowledge of the time.
Conclusion the scientific community was clearly aware of the fact that chemicals could cross the placenta before thalidomide was developed and marketed. With the passage of time, more has been learned about the mechanisms of placental transfer. Chemicals can pass via simple diffusion, pumps, plasma membrane carriers, and biotransforming enzymes but the general principle was appreciated well before the 1950s.
Scientists did test thalidomide on pregnant animals
Testing for teratogenicity was common practice in the pre-thalidomide era. Review articles had been published in the 1950s and early 1960s tracing the history of teratology testing. The first use of animals for this purpose dates back to 1891, when Dareste experimented with chick embryos and induced congenital defects. Scientists had studied the effects of radiation, nutrients, hormones, and eventually chemicals including specific drugs.. Many others continued this research using various mammals. some went so far as to suggest that publications regarding teratogens and teratology in general did not even increase because of thalidomide.
Nobel laureate chemist Roald Hoffmann observed:
Indeed animal testing for teratogenicity of new drugs was routine in the major pharmaceutical companies. Hoffmann-LaRoche’s Roche Laboratories published a major reproductive-system study of its Librium in 1959. Wallace Laboratories did so for Miltown in 1954. Both incidents antedate the thalidomide story.
The Sunday Times of London, on June 27, 1976 published the results of their very extensive investigation into the thalidomide disaster and stated that, by 1958, teratogenicity testing was routine. Moreover, according to a German medical journal of the era, toxicity tests on animals were conducted prior to thalidomide’s release.
Because all the records from Grünenthal were destroyed , we will never know exactly what testing was performed with thalidomide. However, we do know that teratogenicity testing on animals was common at that time. This leads us to the critical question: Would more animal testing have prevented the thalidomide disaster?
Thalidomide causes numerous birth defects in humans including microphthalmia (small eyes), coloboma (a hole in a part of the eye), other abnormalities of the eyes, and abnormalities of the ears, internal organs, and genitals. However, the congenital anomaly for which it is most infamous is phocomelia. Phocomelia comes from the Greek meaning seal and limb— seal limbs. It was coined by Étienne Geoffroy Saint-Hilaire in 1836. Today, it is synonymous for the thalidomide-induced complete absence of limbs or the presence of very abbreviated limbs. In order for the human fetus to suffer from phocomelia, thalidomide must be administered between days 39-45 post-menstruation. Other birth defects can be seen if thalidomide is administered from day 34-50 post-menstruation.
In the mid-1960s, Karnofsky stated what has subsequently been referred to as Karnofsky’s law:
Any drug administered at the proper dosage, and at the proper stage of development to embryos of the proper species-and these include both vertebrates and invertebrates-will be effective in causing disturbances in embryonic development.
In other words, all medications are teratogenic in at least one species, if given in a large enough dose and at the proper time in development. To illustrate the sensitivity level for some species to some chemicals, even sodium chloride (common table salt) and water are teratogens in some species when they are administered in the required dose at the right time. An immense amount of animal testing has proven Karnofsky correct. Therefore, some form of congenital abnormality can be found in one or more animal species for essentially every drug.
The significance of this observation is further complicated by the fact that even drugs that are routinely given to women in pregnancy may occasionally be associated with a birth defect in an individual woman—an idiosyncratic response. The only way to assure that women will not give birth to a baby with birth defects secondary to taking drugs during pregnancy is to avoid administering or prescribing drugs to women who may be pregnant. There is no foolproof testing scheme, even today, for determining whether a specific woman will react to a specific drug by giving birth to an infant with congenital malformations. The drugs that are prescribed to pregnant women are given based on a long history of safety, epidemiological data relating the same, or based on chemistry that precludes placental transfer, not because of animal testing.
Many species have been studied in an attempt to discover the mechanism for thalidomide–induced phocomelia. These studies have been frustrating for many reasons. First, thalidomide does not cause phocomelia in all species or even most. Second, thalidomide is metabolized to possibly greater than 100 metabolites.Third, an abundance of factors that can lead to phocomelia. Over thirty hypotheses have been offered to explain thalidomide’s developmental effects. Therapontos et al. recently provided evidence that, at least in some animals, angiogenesis inhibition is responsible for the limb defects seen from thalidomide. Thalidomide acts as an anti-inflammatory agent and as an angiogenesis inhibitor, either of which can account for the changes in limb formation associated with its use. Changes in the signaling system have also been proposed.
Taussig, writing in 1962, provides an interesting note regarding Grünenthal’s after-the-fact testing:
Grunenthal has tried to reproduce phocomelia in rats, mice, and rabbits and has failed. In Keil the drug was fed to hens and the chicks were normal. Grunenthal has shown that the drug passes through the placenta of rabbits but in their experience the offspring were normal.
Recent work has revealed the chick embryo to be sensitive to thalidomide despite early reports that they were not , proving yet again that even the same species under different testing conditions will yield different results. Stephens perhaps unintentionally summarized the mindset of some that use animals in teratology research today when he stated:
The historic irony is that even though it has been clearly demonstrated that thalidomide does not cause limb defects in mice and rats, these animals are still being used to examine mechanisms of thalidomide’s teratogenic action.
the United States government did not approve thalidomide because animal tests had raised suspicions about the drug. Reality tells a different story. Frances Kelsey, a medical officer at the FDA, stated the decision not to allow thalidomide was based on resulting peripheral neuritis—numb and tingling fingers in adult humans. Animal tests had nothing to do with the decision. Kelsey noticed a case report in the British Medical Journal that linked thalidomide to peripheral neuropathy. She wrote to Richardson-Merrell, who was trying to obtain license to market the drug, expressing concern that they had known about these cases but had failed to include them in their report (this turned out to be true) and stated they would now have to prove that the link between thalidomide and peripheral neuropathy was false if they wanted to gain a license for thalidomide in the US. Interestingly, Kelsey had also aided in repudiating the notion that the placenta was impermeable to all drugs. In the 1930s, she and her future fiancée conducted research on quinine using rabbits. They found that adults easily metabolized the drug, but that fetuses did not metabolize any of the drug. They showed that quinine crossed the placenta and that the mother and fetus did not necessarily metabolize all chemicals the same.
The deleterious effects of thalidomide appeared very early, after the disaster was noted, to vary among species and strains.[162-164] Testing numerous species would have produced a hodgepodge of results and been uninterpretable to the scientists of the 1950s, just like the results from animal testing for teratogenicity are un-interpretable to scientists today. Red flags are not raised because a drug-to-be is teratogenic in an animal species. This is the norm and is part of the reason why most new drugs are labelled Class C. Animal tests did not and could not have prevented the thalidomide disaster and, in fact, delayed the acknowledgment of its severe side effects. When an Australian physician observed the link between thalidomide and birth defects, he sounded an alarm that was largely ignored because of messages from Chemie Grünenthal asserting that if thalidomide crossed the placenta, it would be unlikely to cause harm. .
Currently, the only way to determine for certain whether a drug is a teratogen is through epidemiology. Better monitoring of medication intake could facilitate establishing a safety profile.
Based on the above, we conclude the following: