Introduction
Congenital microcephaly, abnormally small head circumference, is caused by environmental or genetic factors.
Genetic causes of microcephaly do their damage through Mendelian patterns of inheritance of a defective or damaged gene or chromosome. Many cases of microcephaly are denominated “idiopathic” because the likely causal factor(s) are not known. Nonetheless the vast majority of the idiopathic cases of microcephaly are not genetic, but rather are environmental.
Environmental causes of microcephaly are the result of deleterious exposures which occur during pregnancy and which interfere with normal proliferation and migration of neural cellsthe fundamental building blocks of the central nervous system. Environmental factors commonly associated with microcephaly include: ethanol ingestion; inhalation of mixed solvent vapor [as in glue or paint sniffing]; certain pharmaceutical drugs; maternal infection, e.g. rubella; and radiation. Certain chemicals, such as methyl ethyl ketone [MEK], have the capacity to produce microcephaly because they target the developing fetal brain and interfere with proper, timely, and adequate proliferation and migration of the neural cells.
Properties of MEK
MEK is a colorless, volatile, organic solvent with a pleasant pungent odor akin to lacquer thinner. It is commonly used as a cleaning solvent in industry..
Chronic inhalation of MEK vapors at concentrations in the range of 100-300 PPM and higher is toxic to the adult central nervous system. Headache, dizziness, and mental confusion are common early signs of MEK’s neurotoxic potential. MEK also has the peculiar property of potentiating the neurotoxicity of other organic solvents.
MEK’s remarkable ability to enter the body through intact human skin has been known for years. For example,because the threshold limit value [TLV] for workplace exposure to concentrations in air of MEK does not take into account skin contact as a common route of exposure, one must question the reliability of the TLV concept as offering adequate protection even for adult workers.
Animal developmental toxicology studies on MEK in peerreviewed literature show it is fetotoxic; it has the capacity to interfere with normal fetal growth and development.
There are several ways that chemicals can cause harm to a fetus. This entire spectrum of harm is often referred to as developmental toxicity, and it comprises not only externally visible structural malformations but also fetotoxicity an endpoint often measured in terms of intra uterine growth retardation.
Thalidomide is the most famous example of how ingesting a toxin just once at a critical time in pregnancy can produce structural malformations [“dysmorphologic” effects] such as foreshortened limbs.
But chemicals which interfere with the normal growth and development of the fetus throughout gestation can actually cause much more devastating and irreparable harm, especially if the affected system is the developing central nervous system.
MEK’s fetotoxic ability is dosedependent, with the nature and extent of fetal harm increasing as the daily dose and the duration of exposure increases. The animal toxicology studies on MEK are all large, welldesigned studies and all demonstrate significant doserelated fetotoxicity, namely intrauterine growth retardation.
A 1974 study by Schwetz et al, Embryo and Fetotoxicity of Inhaled Carbon Tetrachloride, 1,1Dychlorethane and Methyl Ethyl Ketone in Rats, Toxicology and Applied Pharmacology 28:452 (1974) [for Dow Chemical] reports significant fetotoxicity in rats at several doses and a significant incidence of structural malformations [imperforate anus and “bird jaw”] in the most heavilyexposed rats.
A followup rat study jointly commissioned by MEK manufacturers in 1978 and delivered to one manufacturer in 1979 also had strong positive findings of intrauterine growth retardation and other signs of fetotoxicity. Deacon et al, EmbryoFetoxicity of Inhaled Methyl Ethyl Ketone in Rats, Toxicology and Applied Pharmacology, 59:620 (1981).
In 1991 a mouse study found significant fetotoxic effects in MEKexposed offspring examined immediately after birth. Schwetz et al, Developmental Toxicity of Inhaled Methyl Ethyl Ketone in Swiss Mice, 16:742 (1991).
After reviewing these three developmental toxicity studies and making appropriate inter and intraspecies extrapolations, the U.S. EPA set a “reference dose” of .3 PPM for human inhalation exposure to MEK. The dose of MEK absorbed into the bloodstream of a pregnant woman is approximately the dose delivered through the placenta to her fetus. As a result, if a pregnant woman is routinely breathing air containing significantly more than .3 PPM of MEK, her fetus will be receiving a fetotoxic dose of MEK.
Daily doses of MEK in common industrial settings, where MEK is used as a solvent without positive ventilation or protective equipment, result in air concentrations several hundred times greater than the socalled “safe harbor” reference dose.
MEK Targets the Fetal Brain
The rodent studies described above establish, beyond any doubt, that MEK induces intrauterine growth retardation and is thus a developmental toxicant.
These findings are confirmed by a 1990 European study reported in the peerreviewed literature in which rats were exposed to MEK during gestation and the postnatal period, when significant brain growth and development normally occurs in rodents. StoltenburgDidinger et al, Neurotoxicity of Organic Solvent Mixtures and Fetotoxicity, Neurotoxicology and Teratology, 12:585 (1990). Examination of the MEKexposed brains showed significant retardation of growth and development of the cerebellar cortex. The implications of this finding are profound and compelling. Damage to the cortex interferes with intellectual functioning, reasoning, and judgment.
Defenses Raised by Manufacturers
Although exposure to organic solvents during pregnancy poses a very severe risk to the developing human fetus and had been a fundamental fact known to toxicologists for decades, in litigated cases of congenital brain damage caused by MEK, manufacturers argue that because there are no human epidemiologic studies or case reports which explicitly identify MEK, acting alone, as the cause of human developmental harm, it is “junk science” to attribute a given child’s developmental harm to MEK. Such arguments weak for several reasons.
First, nobody has, or ever will, test MEK on pregnant women. The days of Mengele are over. It is immoral and unethical to knowingly expose pregnant women to a potential developmental toxicant to observe outcomes. In fact, a number of studies where volunteers were exposed to MEK for short periods explicitly excluded pregnant women from participation.
Second, and equally relevant, typically workplace exposures involve mixed solvents rather than a single agent. In contrast, medications are prescribed and taken during pregnancy on an individualistic and closely monitored basis. In the case of thalidomide, for example, there were realistic opportunities for alert clinicians to observe and report adverse developmental effects of drugs they prescribed to pregnant patients.
With workplace exposures to mixed solvents, on the other hand, because physicians and their patients are often unaware of the potential for harmful exposure, a reliable exposure history is not obtained and thus the potential role of a specific solvent exposure in any subsequent adverse outcome becomes virtually untraceable.
Given these significant threshold, frontend limitations to full documentation of workplace exposures, the numerous retrospective studies which do find associations between solvent exposure and adverse effects cannot possibly fill in the data gap in the way defendant insinuates it must be filled before there is “proof” that MEK has the ability to cause developmental toxicity in humans.
Reputable scientists concede that the scientific method involves considerations of the weight of evidence rather than some sort of “litmus test” for whether a given chemical can cause human developmental toxicity.
The evidence that MEK can cause human developmental toxicity, including microcephaly and mental retardation, does not stop with retrospective case control epidemiologic studies which link mixed industrial solvent exposure with central nervous system malformations and other fetal damage, either. A solid body of scientific literature confirms the biological foundation that MEK is a developmental toxin.
By the late 1970s two independent sources of human data were accumulating which pointed to organic solvents as a major factor in environmentallycaused microcephaly and mental retardation.
The first data concerned fetal alcohol syndrome [FAS]a devastating condition associated with maternal ingestion of ethanol during critical phases of fetal brain growth and development. FAS children are mentally retarded because their brain growth is slowed during gestation; ethyl alcohol and/or its metabolites disrupts orderly proliferation and migrational of neural cells, resulting in a small brain, a retarded intellect, and of course, microcephaly.
The second data focused on what has been dubbed “fetal solvent syndrome.” The first case report was published in 1979 and involved a woman who chronically inhaled solvents during pregnancy as a form of recreational stimulus. Her child was microcephalic and mentally retarded. Numerous case reports since have described mentally retarded, microcephalic children whose mothers sniffed the vapor from all manner of solventbased paints, glues, thinners, cements during pregnancy. While these unfortunate children are typically described as having “toluene embryopathy” it is more accurate to describe them as victims of “fetal solvent syndrome” for this reason: the chemical constituents in commercially available spray paints, glues, cements, adhesives and thinners are mixes of solvents and a significant constituent solvent in many of these mixtures is MEK.
Proving Chemically Induced Microcephaly
To determine the cause environmental or genetic of any case of microcephaly is an iterative process of systematically narrowing the possible explanations by ruling out as many potential causes as possible.
It is necessary to determine whether microcephaly is due to
- a recognized genetic condition, such as Fragile (X) syndrome
- chromosomal anomalies
- maternal infection, e.g. rubella
- maternal exposure to radiation
- maternal ingestion of medication
- recreational “sniffing” of solventbased paint, glue and/or paint thinner
- maternal ingestion of alcohol during pregnancy [“fetal alcohol syndrome”] or
- toxic chemical exposure.
The next question in the iterative process is: Of all the potential causes of microcephaly, genetic or environmental, how likely is any one of them in particular to have played a role?
In an actual litigated case of congential microcephaly there were several reasons for concluding that that the cause was unlikely to have been genetic, i.e., the result of a dominant or recessive trait passed on via the rules for Mendelian inheritance. First, the child not have any recognized genetic syndrome. Second, there was no family history and no consanguinity between his parents and thus no basis to suspect that a familial syndrome might be uncovered if one searched the family tree. Third, the patient had no physical features that suggest that his microcephaly was autosomal recessive in origin.
Idiopathic Often Means the Cause is Environmental
Although many cases of congenital microcephaly are labelled “idiopathic” because no apparent environmental or genetic cause can be convincingly identified, about four in five cases of isolated microcephaly fall into the idiopathic category.
It is commonly reported that of the universe of children with socalled “idiopathic” microcephaly, only 57% have younger siblings who are affected the sine qua non evidence that in these children the original microcephaly is of autosomal recessive origin rather than environmental.
Of the universe of children born with isolated microcephaly and mental retardation for whom no cause is apparent, a very small percentage are likely to turn out ultimately to be of true genetic origin. The inescapable inference is that the vast majority of socalled “idiopathic” cases are in fact the result of an environmental insult in the womb. Thus, any given case of “idiopathic” microcephaly is much more likely to be environmental than genetic.
The final question in the iterative process becomes: Can it be established to a reasonable degree of scientific probability that MEK was the specific environmental factor causing microcephaly?
MEK Can and Does Cause Microcephaly
Once all other potential causes have been ruled out, environmental exposures are often the cause and if there is a chronic, in utero exposure to MEK, it is most probably the cause of microcephaly or mental retardation.
MEK is a fetotoxic chemical that induces developmental delay, including retarded brain development in humans and in utero exposure to MEK can readily cause microcephaly and mental retardation. The current scientific evidence is compelling.
- Animal Models for MEK’s capacity to Induce Microcephaly: The evidence for MEK’s developmental neurotoxicity is consistent and positive in four animal toxicology studies in peerreviewed literature, culminating with the dramatic evidence that MEK actually targets the developing central nervous system, producing abnormally small brains in exposed test animals.
- IntraSpecies Differences: The weight of evidence is that the human species is at least as vulnerable as the rat or mouse to the effects of in utero MEK exposure. In fact, because humans are a higher life form, public health officials always assume that we are much more vulnerable to toxic exposures than rats, mice, guinea pigs or rabbits.
- Maximum Safe Daily Dose During Pregnancy: The EPA’s derivation from these animal data of a human Reference Dose of .3 PPM for MEK, i.e., the maximum daily dose of MEK a pregnant woman can absorb without risking fetal harm is far less than the amounts of airborne MEK to which industrial workers are commonly exposed.
- Critical Time(s) in Fetal Brain Growth: In normal fetal development in humans, the most significant brain growth occurs in the second half of pregnancy. A child born with microcephaly and mental retardation has to have sustained a significant interference with brain growth over an extended period during pregnancywith the second half of pregnancy being most significant.
- Human Evidence on Solvents and Fetal Brain Damage: The human epidemiologic data on mixed organic solvent exposure shows associations with adverse developmental outcomes, including microcephaly and mental retardation
- Lessons from Alcohol Ingestion, “Glue Sniffing” etc.: The large body of peerreviewed literature on Fetal Alcohol Syndrome, Fetal Solvent Syndrome, and on experimental chemical induction of microcephaly, elucidate the mechanisms by which microcephaly is actually produced.
- Biologic Plausibility of the Association: The biological foundation for the existence of an association between in utero MEK exposure and damage to the developing fetal brain, is MEK’s neurotoxic properties, its affinity for lipid rich tissue including the brain, its ready skin penetration, and its ability to cross the placenta, and the fetal liver’s inability to detoxify it.
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