Birth defects: a consequence of animal testing

Birth defects: a consequence of animal testing

About one in a thousand live human births results in a birth defect caused by a teratogen, or chemical that damages the unborn child.   In a paper in Biogenic Amines (Vol. 19, No. 2, pp. 97–145 (2005)) Jarrod Bailey and his team publish a complete evaluation of the animal practice, which leaves the reader wondering how such a method could be defended by even the most cynical vivisector.  It’s also available online - www.vsppub.com.  For a shorter summary of the statistics involved, see the secion on birth defects on this page.

The team outline their research thus: “We show here, via a comprehensive systematic review and analysis of this data, that these methods constitute questionable science and pose a hazard to humans. Mean positive and negative predictivities barely exceed 50%; discordance among the species used is substantial; reliable extrapolation from animal data to humans is impossible, and virtually all known human teratogens have so far been identified in spite of, rather than because of, animal-based methods. Despite strict validation criteria that animal-based teratology studies would fail to meet, three in vitro alternatives have done so. The embryonic stem-cell test (EST) is the best of these. We argue that the poor performance of animal based teratology alone warrants its cessation; it ought to be replaced by the easier, cheaper and more repeatable EST, and resources made available to improve this and other tests even further.”

The team found evidence of variation in levels of susceptibility to teratogens between species and within species, in all studies they examined. They agreed with previous research that this was due to genetic constitution (eg differences between individuals) environmental differences, differences in the way chemicals are metabolized, and the activities of the placenta.[1]

Birth defects only result when a given dose has been exceeded[2], and after this, the likely effects increase in line with the dose.  A profile like this defines a true teratogen.[3]  However, a problem arises in the fact that virtually all animals used have much shorter gestation periods, so doses given need to be acute (short and large) while humans often have longer–term exposure. Short-term dosing schedules are more dangerous than regular dosing for some chemicals[4] while the reverse is true with others. These aspects of exposure are especially important when considering teratogenicity in many cases[5].


The animal model – how does it work?

When selecting a species to use as a test, we have nothing suitable, the team concludes.“…none comes close to fulfilling the criteria. No one  species absorbs, metabolises and eliminates test substances just like a human nor possesses the same placental transfer properties; no one species has the same pre-term developmental and metabolic patterns as do humans…” On top of this, experimenters also want animals with a short pregnancy for sheer convenience, yet they also want the to act like humans.

Dogs (mainly beagles) have been used but have been found to withstand many drugs which are dangerous in humans.  Cats are (like dogs) known to metabolise a significant number of drugs differently, some uniquely.  Pigs were found to be as insensitive as dogs, and ferrets did not live up to some early expectations.

 Non-human primates have been particularly disappointing as a predictive model.[6] Over 100 chemicals classified as ‘possible’ or ‘probable’ have been tested in nonhuman primates.  Of the known human teratogens tested, only about half were found also to be teratogenic in one or more primate species, and indicated as undamaging in the other species used.

The main reasons for this, according to the paper are:

1. Anatomical differences.  For example, there is one placenta in humans, but two in rodents and rabbits.

2. Metabolic differences in both adults and foetuses of different species.  The way chemicals are absorbed, distributed, metabolised and excreted varies massively.   The birth defects are caused by processes such as cell death and breakdowns of the normal process, eg by veins restricting the flow of blood.  These subtle differences easily vary between species.

3. Variations in response to potential teratogens.

4. Sensitivity of animals to environmental factors. The metabolism of test animals can be affected by matters as forgettable as pesticide residues in bedding.[7]  They can also be induced in some species by alterations in temperature, barometric pressure, noise and the visual environment, and diet. Results can also be significantly affected by poor treatment, excess or shortage of companions, maternal age and the season of the year.

5. Route of administration and dose of the test substance and the vehicle used. The route of administration (eg nose, mouth, adding to food, skin, inhalation etc.) can produce markedly different results between animals.  Some methods make certain chemicals more dangerous, others make them less so.[8] [9] [10]

 

Lab practice continues to involve large doses to overcome:

a) humans exposure of longer periods, and

b) humans being more sensitive than lab animals to the chemicals.[11]

The paper suggests we should accept that humans are more sensitive, than trying to overcome this difference by creating unrealistic dose regimes which don’t translate to humans.

This dosing system has resulted from animal experimenters trying to force their practice to be right, by recreating birth defects in animals following the discovery that the drug is dangerous to humans.  This has resulted in Karnofsky’s Law, which states ‘Anything can be teratogenic if given in the right dose, to the right species, at the right time’.  There are NO EXCEPTIONS to this bold statement – just find the right species at the right time and administer a large dose. 

If every single drug, chemical and indeed substance can be teratogenic in some particular animal at some specific dose, then to produce a positive result one need only find a suitably sensitive species and administer a suitably high dose.[12] This process could be taken to a ridiculous conclusion where any, obviously safe, material is feared to be dangerous.  Even materials essential to life could test positive as a teratogen.

In ‘Dangerous Properties of Industrial Materials’[13] a list of teratogens is included which includes many such essential and natural matter.  Drinking water is an animal lab teratogen[14] as is table salt.[15]  Also suspect are oxygen, sugars in the form of sucrose and lactose, palm oil, corn oil and nutmeg oil, other naturally occurring food constituents such as cholesterol and papain  which is common in pineapples.  Vitamins including A, D2, K, B7 and B12 are all suspect thanks to the animal lab, despite human evidence showing the value of taking B vitamin supplements in pregnancy.  Naturally occurring and essential hormones such as estradiol, progesterone and various prostaglandins; the amino acid methionine, and the DNA constituent adenine are all implicated. Aspirin is feared dangerous (it isn’t) and causes cardiac malformations in several species of animals (such as the rat and the rhesus monkey).[16] [17] [18] [19] [20]

6. Other factors. Other confounding variables include the standardization of litter size, postnatal effects, and the manner in which animals are housed and handled. 

How reliable is the animal model?

Animal studies are used because they’re cheap, and one chemical can be done at a time.[21] The report authors studied extensive medical textbooks, databases and other resources to evaluate the accuracy of the method.  They looked at the incidence of animal studies correctly giving positive results – ‘positive’ means showing that a substance IS a teratogen.

Existing data shows that the rabbit, a common species for teratology experiments, predicts positively just 40% of the time, and also shows false positives (eg indicates that safe chemicals are dangerous) at a rate of 40%.  The average (mean) rate at which dangerous materials were identified as teratogens was under 55% for the mouse, rat, rabbit, hamster, primate and dog.[22] It’s worth considering that as there were only two possible outcomes, pure guesswork could be expected to give a result of about 50%.

More existing research[23] [24]examined similar data for 35 individual substances, all of which were linked with danger to the unborn human by human experience.  Of the 139 individual conclusions drawn across the species tested, 78 (56%) were positive (indicating danger) the remaining 44% of results were almost entirely negative. The best results were given by hamsters, but an American Food and Drug Administration study[25] into the results from rodent and monkey use in such tests found the hamster to be only 45% accurate.  The average (mean) percentage of correct positives was only 60%.

Claims that drugs known to be dangerous to humans can be shown to be in the lab are seen in perspective thanks to the group’s examination of false positives.  Many chemicals and drugs highlighted as dangerous in animal tests have no reason to be suspected of being so in humans.  Consideration of data from several sources[26] [27] concludes: “This means that of 1223 definite, probable and possible animal teratogens, fewer than 2.3% were linked to human birth defects.”

What else instead?

However, Bailey and his team cannot be accused of offering only problems, and no solutions.  They refer to evidence that  “virtually every substance or dietary deficiency currently recognized as being teratogenic in humans was initially identified as a result of case reports and clinical series”.[28]

The delay caused to developing scientific methods through relying on animal methods is criticized, although the new methods are evolving.  They are now cheaper, faster and more reliable.[29]  Computer modeling of the way a drug will be metabolized, it’s molecular structure and properties give valuable information.  In cell culture several methods are currently used and are being developed further.  The Embryonic Cell Test (EST) gives accuracy rates overall of 78%, higher than animal methods and hopefully to be improved as this cell culture method is continually worked on.  The Micromass (MM) test is proven particularly effective for chemicals causing specific forms of damage to the growing embryo.

The main argument in support of animal testing for teratogens is this: all human teratogens test positive in at least one species of animal.  What this statement fails to account for is that these same materials simultaneously test negative in a greater number of species.  Furthermore, all (without exception) materials test positive as a teratogen – and that includes insulin, water, oxygen, and vitamins A, B12, etc….and less that one in forty teratogens identified by animals affects humans.

The article is referenced to over 130 articles and textbooks and lists comprehensive statistics on testing of separate classes of drugs.  Yet again, evidence the practitioners have no answers for, other than to ignore it.

 

References

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