The following are excerpts from a report by the Greater Boston Physicians for Social Responsibility, May 2000, "IN HARM’S WAY --- TOXIC THREATS TO CHILD DEVELOPMENT" Principle Authors: Ted Schettler MD, MPH; Jill Stein MD, Fay Reich PsyD, and Maria Valenti. Contributing Author: David Wallinga MD.  The full 140 page report is available for free online at: http://www.igc.org/psr/ihw.htm
 

Introduction Learning, behavioral and developmental disabilities prevent our children from reaching their full human potential. This report examines the contribution of toxic chemicals to such disabilities, while acknowledging that disabilities are clearly the result of complex interactions among genetic, environmental and social factors Toxic exposures deserve special scrutiny because they are preventable causes of harm.

An Epidemic of Disabilities

It is estimated that nearly 12 million children (17%) in the United States under age 18 suffer from one or more learning, developmental, or behavioral disabilities, according to the U.S. Centers for Disease Control and Prevention.

Attention deficit hyperactivity disorder (ADHD), according to conservative estimates, affects 3 to 6% of all school children, though recent evidence suggests the prevalence may be as high as 17%. The number of children taking the drug Ritalin for this disorder has roughly doubled every 4 to 7 years since 1971 to reach its current estimate of about 1.5 million.

• Learning disabilities alone may affect approximately 5 to 10% of children in public schools.

The number of children in special education programs classified with learning disabilities increased 191% from 1977 to 1994. Approximately 1% of all children are mentally retarded. The incidence of autism may be as high as 2 per 1000 children. One study of autism prevalence between 1966 and 1997 showed a doubling of rates over that time frame. Within the state of California, the number of children entered into the autism registry increased by 210% between 1987 and 1998. Studies suggest there are both genetic and environmental components to autism.

These trends may reflect true increases, improved detection, reporting or record-keeping, or some combination of these factors. Whether new or newly recognized, these statistics suggest a problem of epidemic proportions.

Health Study Results Animal and human studies demonstrate that a variety of chemicals commonly encountered in industry and the home can contribute to developmental, learning and behavioral disabilities in children. Developmental neurotoxicants are chemicals that are toxic to the developing brain. They include lead, mercury, cadmium, manganese, nicotine, pesticides and solvents that are used in paints, glues and cleaning solutions. These chemicals may be directly toxic to cells or interfere with hormones(endocrine disruptors), neurotransmitters, or other growth factors.  Monkeys exposed to dioxin [and PCBs] as fetuses show evidence of learning disabilities. Humans and animals exposed to low levels of PCBs as fetuses have learning disabilities.

• Children exposed to PCBs during fetal life show IQ deficits, hyperactivity, and attention deficits when tested years later.

Although genetic factors are important, they should not be viewed in isolation. Certain human genes may be susceptible to or cause individuals to be more susceptible to environmental "triggers." Particular vulnerability to a chemical exposure may be the result of a single or multiple interacting genes.

Background Levels May Already Be Toxic

Neurotoxicants are not merely a potential threat to children. In some instances, adverse impacts are seen at current exposure levels.

• Prenatal exposure to PCBs at ambient [background] environmental levels adversely affects brain development, causing attention and IQ deficits which remain detectable years later and may be permanent.

• Breast-fed infants are exposed to levels of dioxin [plus PCBs] that exceed adult exposures by as much as a factor of 50. Dioxin exposures of this magnitude have been shown to cause abnormal social behavior in monkeys exposed before birth through the maternal diet. (While breast milk contaminants may compromise some of the cognitive [mental] benefits of breast feeding, breast milk remains strongly preferred over infant formula due to numerous important benefits to infant health.)

The Social and Economic Impacts Could Be Serious

Neurotoxicants that appear to have trivial effects on an individual have profound impacts when applied across populations. For example, a loss of 5 points in IQ is of minimal significance in a person with an average IQ. However a shift of 5 IQ points in the average IQ of a population of 260 million increases the number of functionally disabled by over 50% (from 6 to 9.4 million), and decreases the number of gifted by over 50% (from 6 to 2.6 million).

Government Protection Programs Have Failed

The historical record clearly reveals that our scientific understanding of the effects of toxic exposures is not sufficiently developed to accurately predict impacts. Our regulatory regime has failed to protect children.

• "Safe thresholds" for known neurotoxicants have been continuously revised downward as scientific knowledge advances. For example, the initial "safe" blood lead level was set at 60 micrograms per deciliter (ug/dl) in 1960. This was revised down to 10 ug/dl in 1990. Now current studies suggest that lead may have no identifiable exposure level that is "safe." The estimated "toxic threshold" for mercury has also relentlessly fallen, and like lead, any level of exposure may be harmful.

• Even when regulated, the risks from chemical exposure are estimated for one chemical at a time, while children are exposed to many toxicants in complex mixtures throughout development. Multiple chemical exposures often interact to magnify damaging effects or cause new types of harm. For example, new studies in humans and in the laboratory show that PCBs and mercury interact to cause harm at lower thresholds than either substance acting alone. [Both PCBs and mercury are found together in Fox River, Green Bay and Lake Michigan fish and ducks.]

• Animal studies generally underestimate human vulnerability to neurotoxicants. Animal studies of lead, mercury and PCBs each underestimated the levels of exposures that cause effects in humans by 100-10,000-fold. Regulatory decisions that rely largely on toxicity testing in genetically similar animals under controlled laboratory conditions will continue to fail to reflect threats to the capacities and complexity of the human brain as well as important gene-environment interactions.

Key Animal Studies

• Monkeys exposed in the womb to dioxin through a maternal diet containing 5-25 parts per trillion (ppt), within the range of background human breast milk contamination, show deficits in discrimination-reversal learning (retarded learning of shape reversals).(1) In this test, animals initially learn to respond correctly to a particular shape, form, color, or position. Then the correct answer is reversed so that the previous incorrect response now becomes correct. This requires changing a response strategy, a task more difficult than simply learning to discriminate initially. [Note: the fish and ducks in the Fox River and Green Bay area are also contaminated with dioxins, along with the PCBs and mercury.]

• Monkeys fed from birth to age twenty weeks with a PCB mixture and concentration representative of PCBs typically found in human breast milk showed significantly impaired learning and performance skills when tested between 2.5 and 5 years of age.(2) In addition to retarded learning, exposed monkeys showed perseverative behavior (constant repitition) and an inability to inhibit inappropriate responses.(3) The affected monkeys had blood PCB levels of 2-3 parts per billion (ppb), similar to levels in the general human population. Other investigators report similar effects on learning and behavior in monkeys exposed to PCBs shortly after birth, including hyperactivity. (4,5)

• Rats exposed to PCBs prenatally show reduced visual discrimination, increases and decreases in activity level and impaired learning. (6,7) Depending on the particular PCB(s) used in the study, effects are seen at maternal doses as low as 2 micrograms per kilogram per day, every second day from day 10 to 20 of gestation, with no no-effect level identified. [In other words, even the smallest PCB dose caused effects.]

[Please visit our webpage sections on Human Health Effects of PCBs, including The Baby Studies.]

Mechanisms of Neurotoxicity

The mechanisms of action of dioxins and PCBs on early neurological development are incompletely understood. Dioxins and some PCBs share one mechanism of action but differ in others. However, because their chemical characteristics are similar, they tend to co-exist in biological tissues, making it difficult to distinguish between their toxic effects in human epidemiological studies.

Dioxins and dioxin-like PCBs (so-called coplanar or non-ortho PCBs) share a common mechanism of action by binding to the Ah receptor, an important neurotransmitter. This complex is then further processed and passes into the cell nucleus where it binds to DNA, influencing the production and metabolism of a variety of growth factors, hormones and hormone receptors. However, many non-coplanar or ortho-PCBs that do not readily attach to the Ah receptor also have biological activity, which substantially contributes to their neurodevelopmental toxicity. At least some of this toxicity may result from interference with thyroid hormone function.

PCBs may interfere with thyroid hormone in a variety of ways. In animal tests, some PCBs displace thyroxine from its carrier protein, transthyretin, in the circulation. In many animals, thyroxine, attached to transthyretin, is the form by which thyroid hormone gains access to the fetal brain. Any chemical that interferes with this binding has the potential to alter normal brain development. However, in humans, another protein, thyroid binding globulin, is the main carrier protein for thyroxine, and their binding is less affected by PCBs.

Dioxin and PCBs may also interfere with thyroid hormone function by increasing the turnover of thyroxine through induction of an enzyme, which facilitates the metabolism and excretion of the hormone.(8) PCBs may also interfere with thyroid-hormone-mediated gene transcription.(9) A recent report, however, shows that, although prenatal PCB exposure does reduce thyroxine levels, thyroid-dependent protein synthesis in the brain is not affected by the dose used.(10) This finding implies that the neurodevelopmental effects of prenatal PCB exposures are not exclusively due to decreased thyroid hormone levels.

Some PCBs also alter normal brain neurotransmitter levels, although the nature of change depends on PCB structure.(11) For example, ortho-PCBs decrease dopamine synthesis while non-ortho PCBs increase dopamine levels after in utero and lactational exposure in rats.(12) This effect may also be related to the neurodevelopmental delays described in children exposed to PCBs in the womb.

Conclusion

PCBs and dioxin adversely affect brain development and function at background levels of exposure. The effects of prenatal exposure to PCBs appear to be permanent. Psychomotor developmental delays, attention deficits, changes in play behavior, and cognitive impairment, including IQ deficits, have been described in large human study populations. The mechanism(s) by which these chemicals exert their neurotoxic effects are not fully understood but probably include alterations in neurotransmitter levels and thyroid hormone function.

References

1.  Schantz SL, Bowman RE, Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotoxicol Teratol 11(1):13-19, 1989.

2. Rice DC, Hayward S. Effects of postnatal exposure to a PCB mixture in monkeys on nonspatial discrimination reversal and delayed alternation performance. Neurotoxicol 18(2):479-494, 1997.

3. Rice DC. Behavioral impairment produced by low-level postnatal PCB exposure in monkeys. Environ Res Sect A 80:S113-121, 1999.

4. Bowman RE, Heironimus MP, Barsotti DA. Locomotor hyperactivity in PCB-exposed rhesus monkeys. Neurotoxicol 2:251-268, 1981.

5. Levin ED, Schantz SL, Bowman RE. Delayed spatial alteration deficits resulting from perinatal PCB exposure of monkeys. Arch Toxicol 62:267-273, 1988.

6. Holene E, Nafstad I, Skaare JU, et al. Behavioral effects of pre-and postnatal exposure to individual polychlorinated biphenyl congeners in rats. Environ Toxicol Chem 14(6):967-976, 1995.

7. Lilienthal H. Winneke G. Sensitive periods for behavioral toxicity of polychlorinated biphenyls: Determination by cross-fostering in rats. Fundament Appl Toxicol 17:368-375, 1991.

8. Sewall CH, Flagler N, Vanden Heuvel JP, et al. Alterations in thyroid function in female Sprague-Dwaley rats following chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 132(2):237-244, 1995.

9. Zoeller RT. Effects of developmental exposure to PCBs on thyroid hormone action in the developing brain are not consistent with effects on circulating thyroid hormone. Abstract: Children’s Health and the Environment: Mechanisms and Consequences of Developmental Neurotoxicology. Little Rock AR, Oct. 1999.

10. Zoeller RT, Dowling A, Vas A. Developmental exposure to polychlorinated biphenyls exerts thyroid hormone-like effects ont he expression of RC3/neurogranin and myelin basic protein messenger ribonucleic acids in the developing rat brain. Endocrinology 141:181-189, 2000.

11. Tilson HA. Neurochemical effects of PCBs - an overview. Neurotoxicology 18(3):727-744,1997.

12. Seegal RF, Brosch KO, Okoniewski RJ. Effects of in utero and lactational exposure of the laboratory rat to 2,4,2,4, -3,4,3,4,-tetrachlorobiphenyl on dopamine function. Toxicol Appl Pharmacol 146(1):95-103, 1997.