The susceptibility of the fetus and child to chemical pollutants. Behavioral implications of prenatal and early postnatal exposure to chemical pollutants.
Weiss B, Spyker JM, Pediatrics 1974 May;53(5):851-9

Extracted from full report
Although this Conference focuses on the fetus and child, it should not deflect us from the larger issue - effects over the total lifespan. Early developmental stages are important less in themselves than in what they portend.

So that you do not conclude, to our immense embarrassment, that we are about to envelop you in a Freudian mist, let us immediately brace these statements with some quantitative perspectives.

Assume that exposure to an environmental contaminant takes place over a lifetime - a contaminant that, like methylmercury, can destroy brain tissue (although we don't know whether a threshold for damage exists for methylmercury). What are the implications for central nervous system function and performance? Figure 1 represents . . . aging of the brain. It shows a decline in neuronal cell density (paralleled by declines in oxygen consumption and blood circulation) of about 20% to 25% between age 25 and 75. There is substantial evidence that the central nervous system undergoes a continuous loss of cells throughout postnatal life, that a large proportion of cells die during morphogenesis, and that numerous structural and chemical changes take place both in the developing and the aging brain. An important, in fact a key, concurrent process is the decline with advancing age in a wide range of behavioral performance measures.

Weiss and Simon calculated the additional decrease that would be imposed by enhancing the rate of loss calculated by Kety. Even as minute an increment as 0.1% represents a significant acceleration in terms of equivalent brain age. It is easier to see this process in Figure 2, which gives these brain ages directly. A change of 0.1% per year makes the brain of a 65-year-old individual equivalent in neuronal cell density to the brain of an 82-year-old individual. It is extremely difficult to evaluate whether such a difference is a significant biological change and whether it represents a potential for significant functional differences. The brain possesses an enormous reserve capacity. Still a process that reduces this reserve capacity may, at some time late in life, because of additional losses imposed (say by a degenerative process) make the brain incapable of coping with any additional loads.

There is yet another dimension to this problem. Suppose the structural or chemical lesion remains dormant over a major part of the lifespan and is manifested later, much as Parkinsonism resulting from encephalitis. We can conceive, even under the difficult circumstances posed by trying to detect such a process, the possibility of doing so because the final criteria are so striking. However, suppose the deficit is not easily observable but, instead, is a subtle functional one. Consider some possibilities: a slowing of motor reactions, impaired regulation of appetite, and reduced visual discrimination capacity under low levels of illumination. These are not deficits that induce people to seek out physicians, but they represent significant losses just the same. Is there any evidence for processes of this kind?

One affirmative answer comes from investigations by Spyker and her co-workers, who have carried out a series of long-term developmental and behavioral studies of mice from mothers exposed to methylmercury at different stages of gestation.

In the absence of any overt signs, offspring from treated mothers behaved differently from controls when tested for subtle deviations at various stages of postnatal development. Not only did a larger number of prenatally exposed offspring overtly normal at birth, die by 1 month of age and grow less rapidly than controls, but even offspring apparently unaffected were significantly different from controls when tested by behavioral measures. On the open field test, which measures the response of an organism to an unfamiliar environment, the treated animals waited longer to move from the center portion of the field, and 50% (10/20) displayed the odd behavior of "backing," that is, taking three or more backward steps. Only 1 out of 19 control animals exhibited this behavior. When placed in water, they swam differently than controls. Unlike the characteristic posture assumed by the controls (Fig 3a), 12 of the 20 methylmercury offspring showed one or more peculiarities. There were frequent episodes during which the mice floated motionless, with al four legs extended and askew. On occasion a mouse would float vertically. Subsequent analysis of brain weight, brain protein, cholinesterase, and choline acetyltransferase showed no significant differences between controls and treated animals.

For many offspring, deviations from normal were not detectable until much later (3 months to 2 years). Gait disturbances, disappearance of righting reflexes and other neurological signs appeared in some progeny after 2.5 months. Various neuromuscular tests administered between 1 and 2 years of age detected deficiencies in a significant number of treated offspring that appeared unaffected with more gross evaluations.

As the animals approached old age (2.5 to 3 years), the relative incidence of postural defects, muscular atrophy, weight loss, and general debilitation rose in the group exposed to methylmercury. Even more striking, the exposed group exhibited a remarkable incidence of hyperphagia (abnormally increased appetite) and aphagia (inability to swallow) of the type typically associated with hypothalamic (brain) damage.

Other chemical treatments can induce similar postnatal functional deficits. Experiments by Werboff and his co-workers suggest long-term postnatal effects on open field behavior and seizure susceptibility of reserpine, chlorpromazine, and meprobamate. Even more compelling are the data from Sechzer, Fao, and Windle, who discovered that monkeys (M. mulatta) subjected to asphyxia (lack of oxygen) at birth may display deficits in delayed response performance 8 to 10 years later.

. . .

Discussion of lead poisoning, Minamata (mercury toxicity) disease, minimal brain dysfunction (old term for ADHD), and testing of new chemicals.

. . .

Prenatal exposure testing has been a requirement of the Food and Drug Administration since the thalidomide incident. It should be a part of every chemical introduced into the environment. Even more important (in many respects) than the structural deformities produced by thalidomide, are the behavioral teratologies (birth defects) described in earlier sections of the paper. A chemical whose effects are likely to be expressed only over the long term and as subtle functional impairments - because its effects are not obvious and because huge segments of the population might be exposed before its dangers are unmasked - represents a threat to health of wider dimensions than an easily visible defect that causes an abrupt end to discharges into the environment.

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