Prologue

We believe no one has presented the predicament of human life more accurately than Rachel Carson in her book when she stated:

As crude a weapon as the cave man’s club, the chemical barrage has been hurled against the fabric of life – a fabric on the one hand delicate and destructible, on the other miraculously tough and resilient, and capable of striking back in unexpected ways. These extraordinary capacities of life have been ignored by the practitioners of chemical control who have brought to their task no high‐minded orientation, no humility before the vast forces with which they tamper.

Rachel Carson, 1962, Silent Spring

In 2014, according to the Centers for Disease Control and Prevention, USA, one in 68 children suffered from Autistic Spectrum Disorder (ASD); and, in 2015, one in 45 children were considered autistic. If a doomsday prediction is to become a reality, is one out of two children to be born autistic within a decade?

For the literally millions affected by ASD, our silent offspring, and even more desperate parents who find themselves bewildered at the alarming rise of autism, we need to identify and curb the chemical barrage and further onslaught that harm mankind’s future.

In this book, we have done our best to present scientific data supporting previous observations that were only anecdotal to attempt to understand the complex puzzle that is autism. We describe the rapid proliferation of synthetic chemicals in our modern world and the effects on the developing human brain, endocrine‐disturbing chemicals that alter DNA, epigenetics, and hormones. From chemical fragrances to herbicides, synthetic chemicals are abundant in everyday life and the chapters in this book examine the evidence surrounding these chemicals and their effects, including on the developing human brain, and how that might explain certain characteristics observed in autism.

Yet, this only begins to scratch the surface and we do not claim to have all the answers to the autism puzzle. Our goal in this book is to try to bring together as many pieces of the puzzle as possible in one place to begin to clarify the picture and spark discussion to ensure a safe environment for all of us, especially our silent offspring.

Orangeburg, SC, USA, August 2017

Omar Bagasra

Cherilyn Heggen

1

Introduction to Autism Spectrum Disorders

The question is whether any civilization can wage relentless war on life without destroying itself, and without losing the right to be called civilized.

Rachel Carson, 1962, Silent Spring

The belief that there is a single defining autism spectrum disorder brain dysfunction must be relinquished. The noise caused by the thorny brain‐symptom inference problem must be reduced. Researchers must explore individual variation in brain measures within autism.

Lynn Waterhouse and Christopher Gillberg, 2014, Why autism must be taken apart. J. Autism Dev. Disord., 44(7):1788–92

The transition from a paradigm in crisis to a new one from which a new tradition of normal science can emerge is far from a cumulative process, one achieved by an articulation or extension of the old paradigm. Rather it is a reconstruction of the field from new fundamentals, a reconstruction that changes some of the field’s most elementary theoretical generalizations as well as many of its paradigm methods and applications. During the transition period there will be a large but never complete overlap between the problems that can be solved by the old and by the new paradigm. But there will also be a decisive difference in the modes of solution. When the transition is complete, the profession will have changed its view of the field, its methods, and its goals.

Thomas Kuhn, 1969, The structure of scientific revolutions, in Foundations of the Unity of Science, Volume 2, pp.146–7. Originally published in 1939

In the process of scientific research, data occasionally emerge that cannot be easily correlated with present theories. Still, scientists, like others, are naturally reluctant to adopt new theories when established concepts still appear viable, although in need of major updates or revision. Typically, the effects of such scientific reluctance manifest themselves in enlivened discussions at professional conferences, in academic circles and journals, or in books written by journalists, scientists, and medical doctors. In the area of autism pathogenesis, however, the consequences of decades of inadequate progress in coming to grips with the basic underlying biology of autism spectrum disorder (ASD) may be calculated not in journal publications, but in the quality of human lives for literally millions of silent offspring, and even more desperate parents, who find themselves bewildered at the effects of the disorder on both their children and themselves. This alarming rise in autism is not a case of some sudden rise in avian flu from the 1950s, or the unexpected Ebola epidemic in West Africa a few years ago that could have rapidly killed millions but fortunately quickly burned itself out. Another case in point is the epidemic of Zika virus, which is harming unborn fetuses that are then born with small heads (microcephaly) but this is also bound to pass within a couple of years. These are the cases that we may hear about now but then not again for decades or even centuries until they rise again, like the proverbial phoenix.

The traditional paradigm regarding the underlying causes of autism asserts that it is a genetic disease that emerges when children inherit two bad genes from their parents that show up in the toddler (in genetic terms, recessive genes). Although thousands of genes or genetic mutations have been suggested as links to autism by a growing number of scientists, none provides the causative link that is clearly authentic and replicable. As appealing as the bad genes explanation appears at a superficial level, this fails to withstand scientific scrutiny. A fundamental reason why autism cannot be labeled as simply a genetic disease is that genes simply do not change that fast. And so many genes (now numbering in the thousands) cannot be responsible for causing ASD – a spectrum of heterogeneous symptoms.

Consider sickle cell anemia. It results from the replacement of a single nucleotide in the beta‐globin chain, which occurred among our ancestors, somewhere in Africa, in the far distant past. This genetic adaptation to the malaria‐infested environment produced a defective gene that has been inherited. A child, who inherits just one gene (i.e., sickle trait) from just one parent, is protected against deadly malaria, but a minority of the children will inherit the defective gene from both parents and succumb to sickle cell disease. If a corrective major mutation could take place in decades, sickle cell anemia would have disappeared eons ago when people of African descent migrated to the Americas between two hundred and four hundred years ago.

The emergence of sickle cell anemia gives additional evidence of natural selection and mutation that has affected countless individuals. The adaptation of sickled red blood cells is most common among people with origins in malaria‐infested regions, such as the Western parts of Africa and the Mediterranean. The people with sickle cell disease inherited a copy of the recessive gene from both parents. Like a genetic Trojan horse, they carry this seemingly harmless hemoglobin S (HbS) gene because one copy of it brings a great survival benefit by reducing susceptibility to the deadly form of malaria; two copies, however, threatens health and even life. Zero copies of the HbS gene commonly resulted in infant mortality from malaria, which increased the percentage of persons with at least one copy of the HbS gene. In this case more is not better: children of two parents with the HbS gene are much more prone to die of sickle cell anemia, which, again, leaves a greater living population of those who have just one parent with the HbS gene [1].

Similar adaptations to new environments took place when our ancestors moved from Africa and faced varying temperatures, altitudes, and a lower degree of sun UV radiation than that of their progenitors in Africa. Our ancestors adapted to the new mutagenic plants and chemicals that they came across during their journey out of Africa. For example, skin pigmentation accompanied geographic mobility as our ancestors migrated to Asia, Europe, Australia, and elsewhere.

Adaptation of lactose tolerance is another example of genetic inheritance, where 65% of the human population is lactose intolerant. This appears to be a relatively new mutation. The gene that allows human children to digest milk shuts off after three years of age when they are weaned. Certain human populations, however, evolved to be lactose tolerant. This rise of lifelong lactose tolerance in particular is pronounced in populations whose ancestors experienced the time in history when the domestication of cows and other herd animals occurred, a time in which the populations needed supplemental proteins throughout their lives.

Can autism be due to genetic mutations or deletions? Does this relate to survival mechanisms? In reality, human communication and patterns of behavior are governed by a large number of genes and by a complex orchestra‐like communication between these genes that are formed and organized during the early stages of human fetal development. It appears unlikely that a large number of genes involved in human communications and survival mechanisms would just begin to mutate in a precise manner so suddenly. Counterintuitively, and so suddenly, from the epidemiological point of view, has this improbable mutation transpired and done so rapidly?

Autism was relatively rare about four decades ago. In 1960, only one child in 10,000 was diagnosed with autism. By 2011, one in 100 children (1%) was diagnosed with ASD; in 2013, the ratio had worsened to one in 88; in 2014, according to the Centers for Disease Control and Prevention (CDC), USA, one in 68 children suffered from ASD; and, in 2015, one in 45 children were considered autistic [2]. This sudden rise in ASD, should it continue its rapid increase, could potentially lead to even more devastating results [3,4]. Where will it end: one child in five; one in two? The genes in humans, or any other large living organism, do not change that rapidly!

It is illogical to believe that literally thousands of genes suddenly arose in the human race to cause autism. In the cases of sickle cell anemia, lactose tolerance, and human skin pigmentation, these are each determined by a different single gene. But dozens or even hundreds of genes determine most of the traits that make us who we are. Human behavior and communication abilities – the majority of the traits that we perceive as causing differences among individuals and among populations – are complex traits. It is against the laws of nature that those genes involved in what makes us a human are developing mutations at the speed of light, in evolutionary terms, so we must look for another cause or causes of this disorder.

The obvious culprit is the environment. As is often quoted in computer programming circles: garbage in, garbage out. More elegantly, we are dealing with the law of the harvest. Consider three basic elements that have changed in the industrialized nations or so called developed world in the last 40–50 years. The first and foremost is the introduction of synthetic fragrances that initially were discovered by accident. For example, musk ketone was discovered by Albert Baur in 1888 when he was making TNT explosive by condensing toluene and isobutyl bromide in the presence of aluminum chloride [5]. Similarly, artificial vanilla was synthetized by two German chemists, Ferdinand Tiemann and Wilhelm Haarmann, in 1874 [6]. These were huge innovations for the flavor industry which would grow into the multibillion dollar industry it is today. Most of the synthetic chemicals are made from coal‐tar, petroleum by‐products and deadly phenolic ring compounds. The next infringement on our naturally adapted lives was the introduction of insecticides and herbicides that Rachel Carson wrote about in her groundbreaking book Silent Spring. Introduction of synthetic chemicals to kill insects and herbicides to kill unwanted weeds have permeated into our lives. Many of these chemicals produce endocrine disturbing effects. They either mimic our own natural hormones or bind the receptors found on our cells imitating the natural biochemical and physiological signaling processes. We will describe the effects of these chemicals in detail in Chapter 7 and in other appropriate sections. We are well aware that the use of these three elements has crept into our way of life, although this creeping has been so silent, so gradual, that we hardly noticed the invasion, and largely overlooked the damage inflicted. Few pay even the slightest attention to these three major shifts that have quietly invaded our lives in the Western World, and are now quickly sweeping the rest of the developing and underdeveloped populations as they imitate the economic and behavioral patterns that have brought so much wealth, and so much anguish, to the developed world. The last one is the introduction of vaccines that contain organic mercury, a known neurotoxin, a real fetal brain damaging agent. Its use is rapidly decreasing due to public outcry but it is still in use. We will discuss this topic and the potential solution in Chapter 9.

Smell of Autism

The first of these three major elements is the global rise in the use of synthetic fragrances. These innocent, seemingly essential elements that we feel it necessary to use every day, if not truly made from quality natural sources (and usually they are not), can cause genetic mutations in fetal brain cells at extremely miniscule concentrations. They selectively eliminate certain types of brain cells, a point we will discuss in Chapter 6. Could it be that the highly pleasant‐smelling environment in which our society lives is one of the culprits in this unpleasant outcome? Could it be that the outcome for mothers and their babies would be more pleasant if mothers‐to‐be breathed air that was free from such pleasant smells? Should prenatal precaution involve not only abstinence from alcohol and other drugs that can be mutagenic to the fetus but also the substances of fragrant smell? Is more actually less in the aromatic arena of life? We have shown in our research that many synthetic chemicals found in fragrances can induce a huge number of genetic mutations in human fetal brain neurons (Figure 1.1). To find a major root cause of autism, we may need to look no farther than our own noses. It should be noted that as a result of a giant loophole in the Federal Fair Packaging and Labeling Act of 1973 [7], fragrance and cosmetics producers were explicitly exempted from having to enumerate cosmetic ingredients on product labels. Fragrance concealment is not illegal and is often used by the industry to hide from the public the full list of ingredients, even substances that can cause grave health problems. It is common practice for businesses to list the chemicals as simply fragrance, which may mean that about half of the ingredients are never revealed to buyers. Even worse, people who use cologne, synthetic fragrances, body spray, and other scented cosmetics are blindly exposed to dangerous chemicals since the Food and Drug Administration lacks authority to control mandates to manufacturers that require testing of all synthetic chemicals in fragrances for safety before being released to the public

Figure 1.1 Mutagenic/carcinogenic effects of various perfumes as assessed by the Ames test. Only perfumes with high mutagenic/carcinogenic activities are shown. Briefly, 1 μl of each perfume was added into 150 ml of liquid agar containing Salmonella typhimurium, and 1 μl of histidine, mixed well and plated on a Petri dish for 48 h. The number of bacterial colonies was counted visually. Each experimental variable was performed in triplicate, and plotted as shown.

Source: Adapted from Ref. [9].

We have shown that chemicals found in fragrances can be extremely harmful for developing fetal brain cells (neuroblastoma cells: Figure 1.2).

Figure 1.2 Bar graph showing the cytotoxicity of various perfumes against a neuroblastoma cell line.

Source: Adapted from Ref. [10].

When applied on the skin or sprayed, many chemicals from fragrances are either absorbed or inhaled, and many of the chemicals damage fetal brain cells [8–11]. Also, during pregnancy the use of fragrances and other cosmetics may expose the growing fetus to diethyl phthalate (DEP), a common fragrance solvent that can cause abnormal development of reproductive organs in infant males [11–28].The most commonly used fragrances contain thousands of synthetic chemicals, many of them capable of changing the normal pattern of a fetus’s brain development. In Figure 1.3, some of the harmful chemicals are listed.

Figure 1.3 Most popular fragrances and their number of secret ingredients.

Source: Adapted from Ref. [64].

One may question why these synthetic chemicals have not affected adult human brains and caused adults to get autism. As discussed below, in an adult brain, there is very little neural division going on. There are only two small parts of an adult human brain where one can detect neurogenesis (or replication of neurons). These two places participate in odor detection and building long‐term memory. Therefore, in an adult human only dentate gyrus (a small part of the hippocampus) and olfactory bulb neurons are constantly replicating. And, these two small brain parts are damaged in individuals with Alzheimer’s disease and other degenerative neurological diseases. We explain in Chapter 7 how these illnesses of the elderly may be connected to environmental insults.

The Roundup™ Conundrum

The second most commonly used element that has crept into our lives, and that lingers for lengthy periods of time, is a chemical found in a widely used herbicide: glyphosate. This common ingredient in RoundupTM is also found in dozens of other related products. Recently, glyphosate has been shown to be an important factor in the development of ASD, as proposed by MIT scholar Dr Seneff. The use of Roundup™ has been increasing steadily and stealthily since the 1990s [29–32]. Figure 1.4 depicts the correlation between the use of glyphosate and the rise in ASD [29–32].

Figure 1.4 Bar graph showing the number of children diagnosed with ASD versus the amount of glyphosate used on corn and soy crops in the USA from 1995 to 2010. Of note, this correlation does not prove causation and the correlation may be simply an unusual event.

Source: Adapted from Ref. [9].

Glyphosate is one of the most widely used herbicides, derived from glycine, an amino acid. It was introduced to agriculture in the 1970s. Glyphosate targets and blocks a plant metabolic pathway known as the Shikimate pathway that is not found in animals but occurs in certain plants and bacteria. The Shikimate pathway is required for the synthesis of aromatic amino acids in plants [29–33]. After four decades of commercial use, and multiple regulatory approvals including toxicology evaluations, literature reviews, and numerous human health risk assessments, the clear and consistent conclusions are that glyphosate is of low toxicological concern, and no concerns exist with respect to glyphosate use and the risk of cancer in humans. Mainly because of these reports and its inexpensiveness, its use has skyrocketed 6,504% from 1991 to 2010, according to data from the United States Department of Agriculture’s (USDA’s) National Agricultural Statistics Service [30]. Glyphosate is the most widely used herbicide in the world, mainly because it is believed to be nontoxic to humans and it is inexpensive. Most importantly, glyphosate is perceived to be harmless because its mechanism of action is to disrupt, in plants only, the biochemical pathway known as the Shikimate pathway [(32]. Interestingly, the Shikimate pathway is absent from human cells. However, human gut bacteria do contain this pathway [34]. Inhibition of the Shikimate pathway by glyphosate can have an adverse effect on gut bacteria and the gut microbiome can change, and this has been associated with autism [35–37]. The Shikimate pathway is essential in the synthesis of aromatic amino acids in both plants and microbes. These amino acids are the precursors to all the monoamine neurotransmitters, including serotonin, dopamine, and melatonin. Seneff claims that this disruption of the Shikimate pathway in human gut microbes poses significant threats to health. Seneff further argues that glyphosate may be a key contributor to the autism epidemic in the USA [29–31].

She explains that glyphosate kills beneficial forms of bacteria in the gut and causes an overgrowth of pathogenic bacteria, including Bacteroides fragilis and Clostridium difficile [35]. This bacterium induces leaky gut syndrome and produces p‐cresol, which is a phenolic compound and a known biomarker for autism. A higher level of p‐cresol in urine is associated with autism [38]. Glyphosate exposure also disrupts sulfate synthesis, as well as sulfate transport from the gut to the liver and pancreas. Serum sulfate deficiency is another known biomarker for autism. Defects in serotonin supply have been associated with various mood disorders. Seneff argues that glyphosate’s disruption in the synthesis of serotonin can lead to a defective serotonin transporter gene, which would decrease the bioavailability of serotonin for neuronal signaling. This decreased supply of serotonin in the brain is a major feature of autism [38]. The absence of the Shikimate pathway in human cells and the presence of the pathway in beneficial forms of bacteria in the gut (Bacteroides fragilis) should not be taken lightly, since the total number of these bacteria in our gut is 10 times higher than the total number of cells in an adult human body. The vital questions are how does this mechanism cause autism and do various herbicides cause other adverse effects? The answers to these questions have been the center of numerous investigations and many respectable investigators are looking at these questions. In brief, we can state that glyphosate causes profound alteration of the gut microbial environment and studies have confirmed that this herbicide may be associated with ASD [36,37]. However, it should be noted that Seneff’s hypothesis does not explain the gender bias in ASD [29,39,40].

Testosterone and Male Gender Bias

The third element that could help explain male gender predominance in autism is still a hypothesis. There is a commonly recognized, but inexplicable, bias toward males in classical autism, with a ratio of ~5:1 in ASD [1–3,41], and in Asperger syndrome, the ratio is ~10:1 [1–3]. Aside from the familiar dogma that genetic components form the basis of ASD, not a single gene has been conclusively linked to ASD as the single leading causative factor. In fact, over 1,000 genes, or thousands of single nucleotide based mutations (single nucleotide polymorphisms, SNPs), have been suggested as possible causal factors of ASD. It should be noted that in the example we gave earlier of the sickle cell gene, it is an SNP, where a single nucleotide A is replaced with T. Therefore, looking for thousands of SNPs that might cause ASD is illogical. Moreover, several epigenetic influences have been identified as potential co‐factors in ASD’s complex etiology. Numerous environmental factors can potentially induce genetic mutations [41–56]. We will cover this topic in detail in Chapter 5.

It has been hypothesized that exposure to higher levels of male hormones during the fetal or perinatal periods of development could heighten the risk of autism [56–59]. The extreme male brain (EMB) theory of ASD argues that exposure to fetal testosterone could cause gender differences in various autistic traits. A causative link between the organizational impacts of fetal testosterone on cerebral development and on ASD development is often suggested using a 2D:4D digit [60] ratio (Figure 1.5), a presumed biomarker. The leading popular hypothesis to explain why more males experience ASD than females is the EMB theory, which proposes that children with ASD show a heightened type of the male cognitive profile, and postulates that gestational exposure to testosterone produces biological effects that are a cause of autism. Some animal studies evidence indicates that testosterone could mediate differences in cognitive ability between the sexes through its organizational impact on the brain. Recent evidence that upholds the EMB theory reported that the levels of sex steroid found in amniocentesis samples were correlated with ASD diagnosis [61,62]. The ratio of index finger (second digit) to ring finger (fourth digit) (2D:4D) has been extensively utilized in autism investigations as a proxy to determine levels of gestational testosterone exposure.

Figure 1.5 A loose association of abnormal 2D:4D ratio with autism.

Source: Adapted from https://i1.wp.com/www.handresearch.com/news/pictures/finger‐digit‐ratio‐stock‐traders‐income.jpg.

One observation states that 2D:4D is sexually dimorphic, and explains that ASD males tend to have a lower 2D:4D ratio than females. In other words, normal males have an index finger (2D) that is shorter when compared with the ring finger (4D) than do females. This finding is not universally accepted as valid [62]. EMB theory advocates usually argue that sexual dimorphism is evident beginning with the first trimester of pregnancy, that it seems later to be basically static following birth, and that it is not affected by the androgen that accompanies puberty. The 2D:4D based evidence of sexual dimorphism is also based on endocrine models with lower or higher levels of fetal testosterone exposure, associated with complete androgen insensitivity syndrome or congenital adrenal hyperplasia, respectively. There appears to be strong evidence to link elevated fetal levels of testosterone in amniotic fluid to autistic symptomatology, as well as an increase in rightward asymmetry of the corpus callosum [57–61]. We will discuss this in detail in Chapter 5. Figure 1.6 depicts a possible connection between fetal testosterone and 2D:4D ratio.

Figure 1.6 Possible connection between 2D:4D ratio and autism and differences between male and female 2D:4D ratio, associated with fetal testosterone (see Chapter 5 for more detail).

Source: Adapted from https://stynoski.wordpress.com/research/digit‐ratios/.

Some of the most interesting studies, based on the research of various teams led by Baron‐Cohen, focus on elevated fetal hormones in males and the resultant development of autism. Taking advantage of the rich data available in the Danish Historic Birth Cohort and Danish Psychiatric Central Register, these researchers have analyzed the amniotic fluid samples of 128 males who were born during the 1993–1999 period and who were given diagnoses, consistent with the recommendations of the International Classification of Diseases, 10th Revision (ICD‐10), of autism, of Asperger syndrome, or of other related conditions lumped together under the acronym PDD‐NOS (pervasive developmental disorder not otherwise specified). These diagnosed individuals were subsequently compared with a control group of typically developing individuals. These investigators examined the concentration of four different sex steroid hormones (testosterone, androstenedione, progesterone, and 17α‐hydroxyprogesterone) in amniotic fluids, and determined how the levels of these hormones correlated with later diagnosis of ASD. These findings have provided the first specifically demonstrated evidence that individuals with autism have higher fetal male hormonal activity than typically developing individuals. This research suggests a correlation that involves elevated levels of fetal testosterone [57]. However, it does not really explain the causation behind the surge of autism over the past few decades. More recent analyses of EMB hypothesis have not found persuasive digital ratio evidence. Therefore, Guyatt et al. [62] analyzed a large number (6,015) of children with ASD and a corresponding control group but were unable to find a 2D:4D association related to ASD for either males or females. Here, it must be emphasized that ASD is a spectrum and a clear‐cut answer to a spectrum that relates to fetal brain development may not be possible. We will further explain this conundrum in Chapter 5.

Connecting the Dots

As illustrated in Figure 1.7, over the past four decades, a startling rise in ASD prevalence has been reported, rising from ~1 per 10,000 in the 1960s, to about one in 45 children today. We maintain that the alarming 20‐fold increase in autism in recent years is due to exposure of the human population to an increasingly diverse set of synthetic chemicals including fragrances, many of which involve endocrine disrupting chemicals (EDCs) (male and female hormone‐like chemicals) [63]. Published laboratory and epidemiological scholarship have indicated that undisclosed chemicals labeled as fragrance, including those that produce many different scents, and increase product shelf life, control the time‐release mechanisms of various fragrances and that improve stability, possess endocrine‐disrupting properties [64–80]. These disruptors have a troubling track record, with links to augmented cancer risks [8,64], negative effects on fetal development [9,10], and metabolic diseases. For instance, chemicals with the capacity to increase the expression of human estrogen receptors include oxybenzone, octinoxate, benzyl salicylate, benzyl benzoate, benzophenone‐1, benzophenone‐2, butylphenyl methylpropional, and various synthetic musks (e.g., musk ketone, tonalide, and galaxolide). Of these, benzophenone‐1, tonalide oxybenzone, and galaxolide also have an effect on androgens. Moreover, octinoxate, benzophenone‐2, and butylated hydroxytoluene have links to hormonal disruption of the thyroid [8–10,64]. Even at very low concentration levels, fragrances with these chemicals as ingredients can be carcinogenic and mutagenic [10,64]. One ingredient used under the elusive label fragrance is acetyl ethyl tetramethyl tetraline (AETT) [76]. It was used for over two decades in soaps and cosmetics, and it has been found to cause behavioral changes and to promote white matter degeneration in the brain, including substantial demyelination and troubling axonal degeneration within the central peripheral nervous systems. In 1978, its use was voluntarily discontinued.

Figure 1.7 The alarming rise in synthetic chemical use and autism.

Source: Adapted from https://naturaltothecore.wordpress.com/2013/03/10/autism‐head‐lag‐and‐the‐core‐of‐wellbeing/.

Musk ambrette, a fragrance ingredient that was banned in the European Union although allowed in the USA, causes myelin sheath production in addition to distal axonal degeneration [18,70,72,73].

Even if one considers the high fetal testosterone levels present during the early stages of gestation, this still does not explain the rapid rise of ASD in recent decades; one must also consider the impact of synthetic chemicals that behave like hormones, particularly like fetal testosterone or that bind to androgen receptors in the fetal brain and can enter the blood circulation of the developing fetus [63,64]. We maintain that numerous synthetic fragrances contain testosterone‐like hormones [63,64]. Chlordane was widely used in termite prevention in buildings in the USA starting in the 1960s. In 1979 its use inside homes was banned, and then in 1983 it was also banned as a soil treatment for areas underneath homes [78]. Then, in 1988, citing concerns about environmental degradation and harm to human wellbeing, the United States Environmental Protection Agency (US EPA) proclaimed a complete ban on chlordane [78].

At this point it is pertinent to ask why the three factors mentioned in the preceding sections (synthetic fragrances, glyphosate, and fetal testosterone‐like chemicals or EDCs) may be contributing to ASD development in children while they do not seem to have any apparent adverse effects in adult brains. An adult body has a minuscule degree of cell differentiation taking place in the brain compared with the degree of differentiation in a rapidly developing fetal body, especially during weeks 4–24 of gestation. The majority of adult brain cells are already differentiated and only very few types of cells are still regenerating but no longer differentiating. These include olfactory neurons and a few cell types in the amygdala that are involved in solidifying our permanent memories (we will return to this later in Chapter 7 explaining why Alzheimer’s patients lose their olfaction ability and lose their memory); at birth our muscle cells are already differentiated. The major cell types that are still regenerating are neutrophils, immune cells, glandular and other epithelial cells. Our immune cells are already built, and B and T lymphocytes are regenerating and differentiating from pre‐terminal to terminal phases constantly. These differentiations are not the same as with the primordial and progenitor cells that differentiate in the early stages of human fetus development and especially in the fetal brain neurons. Therefore, any environmental agents that interfere with fetal brain development can cause major adverse effects even after birth. The most vulnerable period is during weeks 4–24 of gestation. There are many external agents that can inflict damage to the DNA of differentiating and rapidly replicating cells in an adult immune system but adult muscle cells have already completed their differentiation during the late fetal period. Thus, they are in no real danger, but glandular and epithelial cells are vulnerable. There is little surprise that the incidence of prostate and breast cancers, as well as leukemia and lymphoma, has increased dramatically since 1960, with no thanks to the endocrine disrupting synthetic chemicals [63].

A fetus, and especially a fetal brain, can be a major target for any synthetic chemical that can cause mutations and/or interrupt the well‐orchestrated pattern of fetal brain development. A human